Treatment Options in Dialysis: World Congress of Nephrology, Berlin, June 2003 (Special Issue: Kidney & Blood Pressure Research 2003, 2)

Kidney & Blood Pressure Research Treatment Options in Dialysis Editor Walter H. Hörl, Vienna 13 figures and 17 tabl...

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Kidney & Blood Pressure Research

Treatment Options in Dialysis

Editor

Walter H. Hörl, Vienna

13 figures and 17 tables, 2003

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Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

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Vol. 26, No. 2, 2003


Contents

64 Editorial Hörl, W.H. (Vienna) 65 Inflammation in Uremic Patients: What Is the Link? Galle, J.; Seibold, S.; Wanner, C. (Würzburg) 76 Hypertension and Dialysis Hörl, M.P. (Düsseldorf); Hörl, W.H. (Vienna) 82 Rationale for the Use of Blood Volume and Temperature Control Devices

during Hemodialysis Donauer, J. (Freiburg); Böhler, J. (Wiesbaden) 90 Treatment Options to Intensify Hemodialysis Haag-Weber, M. (Straubing) 96 Experience with the GENIUS® Hemodialysis System Fassbinder, W. (Fulda) 100 Vitamin C in Chronic Kidney Disease and Hemodialysis Patients Deicher, R.; Hörl, W.H. (Vienna) 107 Angiogenin: A Novel Inhibitor of Neutrophil Lactoferrin Release during

Extracorporeal Circulation Schmaldienst, S. (Vienna); Oberpichler, A.; Tschesche, H. (Bielefeld); Hörl, W.H. (Vienna) 113 Glucose Degradation Products in Peritoneal Dialysis: From Bench to

Bedside Jörres, A. (Berlin) 118 Effluent CA 125 Concentration in Chronic Peritoneal Dialysis Patients:

Influence of PD Duration, Peritoneal Transport and PD Regimen Fusshöller, A.; Grabensee, B.; Plum, J. (Düsseldorf) 123 Continuous Renal Replacement Therapy in Acute Renal Failure Riegel, W. (Darmstadt) 128 Cytokine Removal in Septic Patients with Continuous Venovenous

Hemofiltration Heering, P. (Solingen); Grabensee, B.; Brause, M. (Düsseldorf) 135 How to Calculate Clearance of Highly Protein-Bound Drugs during

Continuous Venovenous Hemofiltration Demonstrated with Flucloxacillin Meyer, B.; Ahmed el Gendy, S.; Delle Karth, G.; Locker, G.J.; Heinz, G.; Jaeger, W.; Thalhammer, F. (Vienna)

141 Author Index Vol. 26, No. 2, 2003 142 Subject Index Vol. 26, No. 2, 2003

© 2003 S. Karger AG, Basel Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

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Kidney Blood Press Res 2003;26:64 DOI: 10.1159/000071237

Editorial

End-stage renal disease (ESRD) patients suffer from cardiovascular complications. Various endogenous and exogenous risk factors contribute to oxidative stress and inflammation. These factors play a major role in the pathogenesis of atherosclerosis and cardiovascular disease. The majority of ESRD patients are hypertensive. High systolic and normal or low diastolic blood pressure as well as wide pulse pressure resemble isolated systolic hypertension of elderly subjects but occurs decades earlier in chronic renal failure patients. Long-standing high (but also low) blood pressure is also a major cardiovascular risk factor for the dialysis population, and needs to be corrected. Symptomatic hypotension during hemodialysis is a risk factor, particularly for the elderly and diabetic patient population requiring renal replacement therapy. Devices for blood volume and blood temperature control allow the reduction in the incidence of intradialytic hypotension. Modification of the dialysis regimen (e.g. short daily or slow daily nocturnal hemodialysis) improves nutritional status, quality of life, control of blood pressure, phosphorus and anemia as well as survival. Unique bacteriological qualities, simple but effective volume control and extreme flexibility in adapting the composition of the dialysate to the patient’s needs are combined in the GENIUS® hemodialysis system. Loss of vitamin C during hemodialysis or hemodiafiltration may reduce plasma ascorbate levels, particularly if vitamin C supplementation is inadequate. Ascorbate is a potent antioxidant both in plasma and intracellularly. Therefore, adequate vitamin C supplementation (up to

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Accessible online at: www.karger.com/kbr

200 mg/day) is recommended for ESRD patients on renal replacement therapy. Biocompatibility of dialyzers is still a clinical issue. White blood cell activation during extracorporeal circulation, however, does not only depend on the membrane material used but also on the presence or absence of endogenous inhibitors of leukocyte activation. Biocompatibility is also an issue in peritoneal dialysis. Glucose degradation products (GDPs) generated during heat sterilization of the peritoneal dialysis fluid affect peritoneal cell function. On the other hand, GDP reduction improves clinical outcomes. Cancer antigen 125 serves as an in vivo marker of biocompatibility in peritoneal dialysis. It may be used to monitor mesothelial cell mass with regard to biocompatibility. Continuous renal replacement therapy is the treatment of choice for management of acute renal failure in critically ill patients. This treatment modality improves cardiovascular stability in patients with multiple organ failure. The amount of dialysis also has a significant influence on mortality. Nevertheless, the role of extracorporeal therapy on the removal of inflammatory mediators and/or toxins remains unclear. Of particular importance are pharmacological considerations for clearance calculations and dosages of antibiotic therapy in critically ill patients. The issue ‘Treatment Options in Dialysis’ summarizes new insights for the optimal care of patients with chronic and acute renal failure. Walter H. Hörl, MD, PhD, FRCP Professor of Medicine


Kidney Blood Press Res 2003;26:65–75 DOI: 10.1159/000070986

Inflammation in Uremic Patients: What Is the Link? Jan Galle Stefan Seibold Christoph Wanner Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany

Key Words Oxygen radicals W Atherosclerosis W Uremia W Inflammation W C-reactive protein W Antioxidants W Vitamin E W Oxidative stress W Superoxide

Abstract Uremic patients suffer to an extremely high degree from cardiovascular disease. Cardiovascular disease results mainly from atherosclerotic remodeling of the arterial system. Inflammation is considered to contribute significantly to development of atherosclerosis, and albeit many different factors may lead to inflammation, generation of enhanced oxidative stress is believed to be an important common feature of pro-inflammatory causes. Studies in the general population without renal disease could clearly show that markers of inflammation, in particular C-reactive protein, predict the cardiovascular risk. In this review article, we discuss the presence and the predictive value of inflammation in patients with endstage renal disease, and analyze whether uremic patients are exposed to specific pro-inflammatory and prooxidative conditions. Particular emphasis is set on oxidative stress induced by oxidatively modified lipoproteins and angiotensin II. Based on pathophysiological considerations valid for uremic patients, we discuss therapeutical options that might help to reduce cardiovascular disease in uremic patients.

Introduction

Renal insufficiency has been associated with incident cardiovascular disease events and mortality in prospective studies [1, 2], and cardiovascular disease, resulting from atherosclerotic remodeling of the vessel system, reflects the main cause of death in patients with end-stage renal disease (ESRD) [3]. The aim of this article is to emphasize the role of inflammatory processes for the development of atherosclerosis and cardiovascular disease. The relevance of inflammatory processes will be discussed for the general population first, followed by analysis of specific issues valid for patients with renal insufficiency and/or undergoing dialysis treatment. Finally, therapeutical options based on specific pro-inflammatory pathomechanisms in uremic patients are presented.

Atherosclerosis – A State of Chronic Inflammation

Atherosclerosis defines a disease in which the arterial wall becomes thickened and loses elasticity. This is clearly not a static condition. Instead, atherogenesis reflects a continuous development over time, ranging from macroscopically intact arteries to ruptured sclerotic plaques. Different stages at different sites can be present simultaneously within one individual. The pathophysiology of

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Prof. Dr. med. J. Galle Department of Medicine, Division Nephrology University of Würzburg, Josef-Schneider-Strasse 2 D–97080 Würzburg (Germany) Tel. +49 931 201 36194, Fax +49 931 201 36502, E-Mail [email protected]

atherogenesis comprises various important steps, including enhanced endothelial permeability, expression of adhesion molecules, monocyte adhesion and immigration, foam cell formation, fatty streaks, smooth muscle cell migration and plaque formation, and finally plaque rupture and thrombus formation. Some decades ago, it was assumed that an initial injury, leading to intimal lesions, was the first step in the development of atherosclerosis, followed by subsequent repair mechanisms (‘response to injury’ hypothesis [4]). While this concept still may hold true for certain situations, it was complemented by the discovery that even in macroscopically intact arteries processes take place that can be best defined as chronically inflammatory [5]. The hypothesis of a chronic inflammation in atherosclerosis is supported by the following findings: Atherosclerosis is associated with enhanced serum levels of inflammation parameters (see below); the arteriosclerotic artery produces different hydrolytic enzymes, adhesion molecules, cytokines and growth factors as seen in chronic inflammation; cells found in early atherosclerotic lesions are typically inflammatory cells (monocytes/ macrophages and T lymphocytes); early in atherosclerosis, enhanced vascular oxygen radical formation can be detected, as well as enhanced activity of lipoxygenases.

Atherosclerosis in Uremia

The question is: Can our knowledge about the pathophysiology of atherosclerosis in the general population without renal disease be extrapolated to uremic patients? Autopsies of patients with ESRD indicate the existence of a more severe and different type of atherosclerosis, in particular a significantly higher number of STARY type VII lesion which defines the calcified plaque [6]. X-ray diffraction analysis demonstrates the deposition of calcium hydroxyapatite in calcified plaques, an observation with potential implications for calcium and phosphate levels as the underlying cause. In addition to increased calcification of plaques, marked calcification of the arterial media, in particular in the aorta, is found in uremic patients. The formation of these microcalcifications can be favored by the above-described alterations in elastic fiber content and architecture, as well as by derangement in calcium, phosphate and PTH metabolism. Post-mortem and coronaroangiography studies demonstrate that ischemic heart disease, due to stenosis of coronary arteries, is common in patients with renal failure. The prevalence of coronary artery stenosis varies from 24% in young non-diabetic hemodialysis patients to

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Kidney Blood Press Res 2003;26:65–75

Table 1. Biological characteristics of CRP

Acute-phase protein Formation in the liver Under control of various cytokines Interleukin-6 Tumor necrosis factor-· Rapid reactivity (within 6 h) Up to 1,000-fold increase Plasma half-life of approx. 19 h

85% in elderly uremic patients (145 years) with type I diabetes. It is of interest that in uremic patients atherosclerotic lesions are far more advanced, i.e. more calcified, than in non-renal control patients. Patients also have a higher risk of plaque rupture but this may be due to the high density of activated macrophages in the plaques [6].

Can Inflammation Markers Predict Cardiovascular Disease and Provide Information Exceeding That of Classical Risk Factors?

Data of the Framingham Study and of many other clinical trials led to the identification of so-called traditional risk factors for cardiovascular disease such as hypercholesterolemia, arterial hypertension, diabetes mellitus, or smoking. However, the prevalence of cardiovascular disease cannot always be explained on the basis of these risk factors. For instance, coronary heart disease occurs in approximately 35% of patients with a total cholesterol of !200 mg/dl, and there is a wide overlap of cholesterol values in populations with and without coronary heart disease [7]. One interpretation of this observation is that other, as yet undefined risk factors (nowadays called ‘new emerging risk factors’) play an important role. Thus, it was noted with great interest when Ridker et al. [8] reported in 1997 in the Physicians Health Study that a single measurement of serum C-reactive protein (CRP) could predict the risk for a future myocardial infarction in apparently healthy men. In that study, 543 men were separated into four quartiles according to their CRP levels, and those within the highest quartile (CRP 1 2.11 mg/l) had a 3-fold increased risk, compared to the patients in the lowest quartile (CRP ! 0.55 mg/l). Follow-up in that study was more than 8 years, and it was most astonishing that a single CRP measurement at the start of this study had such a high predictive power. However, this observa-

Galle/Seibold/Wanner

tion was confirmed in later trials, and CRP was identified as a risk factor not only for coronary heart disease, but also for peripheral artery occlusive disease or for stroke in both men and women [9, 10]. Table 1 summarizes some of the characteristics of CRP.

CRP as Risk Factors for Dialysis Patients

The next question that arises is: Can we transfer our knowledge about CRP as risk factor for cardiovascular disease in the general population to patients with renal insufficiency and/or ESRD? Chronically uremic patients show a 20- to 40-fold increased mortality for cardiovascular disease in comparison to patients without renal disease, and interestingly, CRP levels are approximately 10fold increased in dialysis patients [11] (fig. 1). The question whether increased CRP levels in dialysis patients also predict increased mortality, in analogy to the general population, was analyzed in a prospective study in 280 patients. Zimmermann et al. [12] found an increased cardiovascular risk, depending on a singular measurement of serum CRP in dialysis patients. Similar to the Physician’s Health Study [8], patients were separated according to their CRP levels into four quartiles, and the risk for a cardiovascular event as well as for total mortality increased with the magnitude of CRP during the follow-up of 24 months. CRP possesses its predictive power not only for ESRD patients undergoing hemodialysis, but also for those treated with peritoneal dialysis [13]. A recent publication [14] demonstrated that markers of inflammation continue to rise in the early stages of relatively mild renal insufficiency. Shlipak et al. [14] analyzed a subgroup of the Cardiovascular Health Study, a population-based cohort study of 5,888 subjects 665 years, with a serum creatinine level of 61.3 mg/dl in women and 61.5 mg/dl in men. The authors found that renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers such as CRP, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer. Of course, the question arises whether increased levels of CRP and other biomarkers of inflammation are an epiphenomenon of an inflammatory vascular disease, or whether e.g. CRP eventually plays a causal role for atherosclerosis and cardiovascular disease.

Inflammation and Uremia

Fig. 1. CRP in hemodialysis patients. Serum CRP levels (mg/l) in 312 hemodialysis patients and 300 controls [from 11, with permission].

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Table 2. Mediators of inflammation in atherosclerosis

Cytokines (interleukin-6, tumor necrosis factor-·) Advanced glycation end product Homocysteine Lipoprotein(a) Gut toxins Infection Oxidized low-density lipoprotein Advanced oxidation protein products Activated renin-angiotensin system

Oxidative stress

Does CRP Play a Role in the Pathogenesis of Atherosclerosis?

As depicted in table 1, CRP is synthesized mainly in the liver, where it is under control of various cytokines. However, CRP can also be found in early stages of atherosclerosis within the vascular wall in co-localization with atherogenic lipoproteins [15]. CRP has many features that might contribute to an inflammatory process: it binds to damaged cells and activates the complement system after myocardial infarction [16]; CRP binds to atherogenic lipoproteins and induces aggregation of LDL and VLDL in vitro [17]; CRP stimulates production of tissue factor in monocytes [18] and stimulates thrombus formation. Thus, it is conceivable that CRP has a causal, proinflammatory role. Certainly, CRP is not the only factor that could contribute to inflammation in the context of atherosclerosis. Based on experimental evidence, a number of substances are suspected to act pro-inflammatory. For patients with ESRD, it


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Fig. 2. Reaction pathways of superoxide anion. SOD: superoxide

dismutase; O –2: superoxide anion; NO: nitric oxide; OH W : hydroxyl radical; H2O2: hydrogen peroxide; ONOO – : peroxynitrite; NO2W: nitrite [modified according to 93].

makes sense to distinguish between endogenous and exogenous factors, because the dialysis treatment per se, in addition to uremia, may be a cause for continuous exposure to pro-inflammatory stimuli. What these different factors have in common is that they all – albeit by different mechanisms – enhance oxidative stress. Table 2 lists potential mediators of inflammation relevant for the pathogenesis of atherosclerosis, and principal considerations regarding oxidative stress will be discussed in the following.

Oxidative Stress

The unspecific defense system of an organism relies in part on formation of reactive oxygen species (ROS). Thus, detection of ROS does not necessarily indicate the presence of oxidative stress. Instead, ROS such as hydrogen peroxide (H2O2) or hypochloride (HOCl), and free radicals such as superoxide (O –2), hydroxyl radical (OH W ) and nitric oxide (NO W ) are continuously formed in vivo [19]. However, ROS may also affect cells of the host organism, in particular at sites of inflammation. Recent studies indicate that this plays a role in a variety of renal diseases and contributes for example to acute or chronic renal failure, to tubulointerstitial nephritis, or to proteinuria associated with glomerulonephritis [20, 21]. Enhanced formation of oxygen radicals has repeatedly been shown to be causally involved in the pathogenesis of ischemia reperfusion injury [22]. In addition, oxygen radicals are potent mitogens, contributing to tubular hypertrophy [23] and influencing cell cycle decisions [24].

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As mentioned above, detection of ROS per se does not yet define oxidative stress; instead, it is defined by an imbalance between formation of ROS and defense mechanisms. The balance between antioxidative defense mechanisms and formation of ROS depends on the activity of enzymes such as superoxide dismutases (SODs), catalase, NO synthase, and glutathione peroxidase. This balance is rather fragile and difficult to predict. The direction of various possible reactions strongly depends on environmental conditions [19]. Figure 2 illustrates possible reaction pathways on the basis of superoxide anion: once O –2 is formed, the activity of SOD will transform it to H2O2. H2O2, in case of sufficient catalase activity, will react to harmless H2O and O2. However, too much SOD, in relation to H2O2-removing catalase, can be deleterious, giving rise to the formation of the highly reactive hydroxyl radical in the presence of metal ions such as Fe2+ or Cu2+ (Fenton reaction) [19]. On the other hand, when there is little SOD activity, OH W can be produced from O –2 via the Haber-Weiss reaction, too. Another pathway of O –2 is its reaction with NO W , resulting in peroxynitrite (ONOO – ). This is presumably the most important reaction leading to inactivation of NO W , thus resulting in endothelial dysfunction in the arteriosclerotic vessel [25]. Peroxynitrite itself can be substrate for NO W formation [26], or can result in protein nitrosylation, that can be detected via nitrotyrosine [27]. Sources of ROS formation can be a variety of enzymes: myeloperoxidase, mitochondrial oxidases, lipoxygenase, cyclooxygenase, NADPH oxidase, xanthine oxidase, and, in case of L-arginine or tetrahydrobiopterin depletion, NO synthase itself [28–32].

Examples for Induction of Oxidative Stress Relevant for Atherosclerosis

If all the influences listed in table 2 contributing to inflammation and oxidative stress were discussed here in detail, the scope of this article would be disrupted. Instead, we will focus on two factors, angiotensin II (AngII) and oxidized low density lipoprotein (OxLDL), for three reasons: (1) we possess pharmacological tools to interfere with their activity; (2) AngII and OxLDL are well characterized as agents that potently induce oxidative stress, and (3) AngII and OxLDL co-localize in the atherosclerotic plaque. While accumulation of OxLDL in atherosclerotic arteries is a well-known event in the development of atherosclerosis [33], it has become apparent only recently that atherosclerotic arteries (human atherectomy preparations and arteries of hypercholesterolemic


monkeys) also show enrichment with AngII, co-localizing with resident macrophages in the same region where OxLDL accumulates [34]. In addition, there is strong experimental evidence that these agents interact with each other, with relevance for vascular biology and atherosclerosis.

Another result of AngII-induce oxidative stress relevant for cellular turnover in atherogenesis is its impact on cell cycle decisions. In vascular and non-vascular tissue, AngII causes cell hypertrophy and/or cell proliferation [44, 45].

Oxidative Stress Induced by OxLDL Interaction between AngII and Oxidized LDL

Experimental studies showed that the expression of the OxLDL receptor LOX-1 and of the AT1 receptor is stimulated by the respective other receptor agonist [35, 36]. In cultured smooth muscle cells, LDL induced expression of the AT1 receptor [35]. Thus, LDL may sensitize the vascular tissue to AngII. On the other hand, expression of the OxLDL receptor LOX-1 and uptake of OxLDL in HUVEC is increased by AngII [36]. These studies imply that AngII and OxLDL amplify the effect of the respective other agonist, and they provide a basis why in clinical studies ACE inhibitors were of particular benefit for e.g. endothelial function in patients with high LDL levels [37, 38]. Therefore, the pathophysiological action of AngII and OxLDL with relevance for atherosclerosis and inflammation will be discussed here in more detail.

Pro-Oxidative Effects of AngII

AngII has been identified as a potent stimulator of oxidative stress in the vascular system, thus contributing to endothelial dysfunction and inflammation [39, 40]. While first experimental evidence for stimulation of O –2 formation by AngII derived from cell culture studies with smooth muscle cells [39], it has been shown in the meantime that AngII also induces O –2 formation in endothelial cells and non-vascular tissue via stimulation of NAD(P)H oxidase, after binding to the AT1-receptor [23, 41]. One important effect of AngII-induced oxidative stress is the impairment of endothelium-dependent dilations [42]. Evidence that AngII-induced O –2 formation, leading to endothelial dysfunction, takes place also in humans was provided by a study using the forearm plethysmography method, allowing direct measurement of vasomotor actions. Constrictor actions of AngII in the human forearm were enhanced during NO inhibition and were attenuated during vitamin C infusion, suggesting AngII-associated stimulation of endothelial NO and of oxygen radicals, respectively [43].


First indirect evidence for stimulation of O –2 by LDL was obtained from animal studies with cholesterol fed rabbits. Vessels from hypercholesterolemic rabbits produced significantly more superoxide than control aortas [46]. The impact of atherogenic lipoproteins on O –2 formation could be shown directly by our group: incubation of vascular cells with oxidized LDL or Lp(a) induced O –2 formation [47]. Oxidative stress induced by OxLDL has quite similar effects as oxidative stress induced by AngII: it impairs endothelium-dependent dilations [47] and influences cell cycle decisions, giving a clue to the role of OxLDL in the development of atherosclerosis. On the one hand, OxLDL can induce cell proliferation, mediated by superoxide anion [48], and on the other, it has been shown repeatedly that OxLDL induces apoptosis in vascular cells [49–51], and that antioxidants such as SOD, vitamin C/E, or butylated hydroxytoluene prevented the induction of apoptosis, supporting the concept that oxidative stress was again the underlying cause. Thus, OxLDL has a dual effect on cell growth and on cell death, and both effects involve oxygen radicals. Of note, enhanced cellular turnover with both increased cell proliferation and cell death is a feature of atherosclerotic plaques [52].

What Contributes to the Pro-Inflammatory Situation in Hemodialysis Patients?

To what extent can our knowledge about oxidative stress and inflammation associated with atherosclerosis in general be transferred to the specific situation of patients with ESRD? There is good evidence that oxidative stress is generally enhanced in uremia [20, 53]. For patients with ESRD, various factors were identified that – in addition to risk factors relevant for the general population – might contribute to inflammation and oxidative stress (table 3). The underlying renal disease, in principle all forms of glomerulonephritis, can be defined as an inflammatory process. But also e.g. diabetes mellitus is associated with enhanced oxidative stress [54]. In uremia, the endogenous inhibitor of NO synthase, asymmetric dimethyl-L-argi-


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Table 3. Additional causes of inflammation in hemodialysis patients

Renal disease Uremia Asymmetric dimethyl-L-arginine Dialysate Vascular access, shunt Dialysis membrane-induced cell activation Dental status Malnutrition

nine (ADMA), accumulates [55]. Recently it has been shown that this process starts early in the development of renal insufficiency [56]. NO, as outlined above, is an important counterpart of O –2 in the concert of radical chemistry, and accumulation of ADMA is associated with endothelial dysfunction and increased cardiovascular risk [56, 57]. But also treatment of uremia with hemodialysis or peritoneal dialysis can contribute to inflammation via different mechanisms: important factors are removal of water-soluble antioxidants like vitamin C during hemofiltration [58], dialysis membrane-associated activation of macrophages [59], uptake of endotoxins into the circulation via backfiltration [60], or chronic exposition to bacteria via the vascular access. In this context, the dental status also deserves special attention. Another factor contributing to oxidative stress and inflammation is the status of hydration: it could be shown that patients that are chronically volume overloaded due to chronic heart failure develop an increased intestinal permeability, facilitating the entry of bacteria and endotoxins from the bowels to the circulation [61]. A similar mechanism may take place in volume overloaded hemodialysis patients. Malnutrition that is frequently present in hemodialysis patients also contributes to inflammation, or is a consequence of inflammation and a catabolic metabolism [62]. This complex was termed MIA syndrome (malnutrition, inflammation, atherosclerosis).

How Can the Chronic Inflammatory Process Be Linked to the Specific Form of Uremia-Associated Atherosclerosis?

The current hypothesis for patients without impairment of renal function links formation of oxygen free radicals induced by e.g. oxidatively modified lipoproteins

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and subsequent cytokine-stimulated CRP formation to active processes in the plaque and to atherosclerosis. Can this view be transferred to the different type VII lesion atherosclerosis that is the heavy calcified vessel wall? Recently, Ketteler et al. [63] showed the existence of a protein called fetuin, or ·2-glycoprotein, which is abundant in man and which functions as a calcium phosphate precipitation inhibitor. As long as fetuin is present in sufficient concentrations in serum, calcification – and in particular calciphylaxis – should not occur. However, the serum level of fetuin appears to be affected by inflammatory stimuli, decreasing its serum concentration. Thus, it acts as a negative acute phase protein. Indeed Ketteler et al. [64] could also demonstrate that fetuin, in close correlation with inflammation, predicts all-cause and cardiovascular mortality in a cohort of 312 hemodialysis patients followed over a period of 33 months. These findings provide an explanation why inflammation and CRP are linked to the specific calcifying atherosclerosis in uremia.

What Are Therapeutical Approaches in Hemodialysis Patients?

Based on established and potential risk factors for atherosclerosis and inflammation, various preliminary treatment recommendations can be derived. Large controlled endpoint studies for cardiovascular disease in ESRD patients are not yet available. At present, nephrologists have to extrapolate from non-renal population based studies, and have to take into consideration the generally increased risk of ESRD patients.

Therapy with Acetyl Salicylic Acid, Statins, and RAAS Inhibitors

The best database for treatment of cardiovascular disease is available for therapy with acetyl salicylic acid (ASS), statins, and inhibitors of the renin-angiotensinaldosterone system (RAAS). The Physicians Health Study did not only report on the predictive power of CRP measurement (see above), but also proved that 100 mg/day ASS significantly reduced cardiovascular event rate [8]. This therapeutical effect of ASS was confirmed repeatedly in various different study designs [65, 66]. Accordingly, the National Kidney Foundation Task Force on Cardiovascular Disease recommended already some years ago to treat hemodialysis patients with 75–325 mg/day ASS [67]. However, safety data for dosing of ASS in hemodialysis


patients are available only up to 100 mg/day [UK-HARP Pilot Study, Wheeler et al., pers. commun.]. Treatment of atherosclerosis and cardiovascular disease with statins in the non-renal population is well documented in a series of large, controlled, prospective endpoint studies. Both primary as well as secondary prevention of cardiovascular endpoints and associated mortality can effectively be achieved with statins [68–74]. However, for ESRD patients there are as yet no endpoint trials available. The 4D Study (Die Deutsche Diabetes Dialyse Studie) will provide first information about potential reduction of cardiovascular risk with atorvastatin in type 2 diabetes mellitus patients undergoing hemodialysis treatment in 2004 [75]. There is strong evidence meanwhile that statins lower cardiovascular risk not only via cholesterol lowering. Statin therapy lowers CRP levels already 6 weeks after initiation of treatment, and in hemodialysis patients, simvastatin lowers CRP levels by approximately 50% after a period of 8 weeks’ treatment [76]. Indeed, it has been suggested that the level of serum CRP should be taken into consideration when estimating the individual risk profile of a patient, thus influencing treatment options [77]. Interestingly another lipid-lowering agent, sevelamer, which is used as a potent phosphate binder in dialysis patients, also decreases CRP by half when given orally over prolonged periods of time. Like for statin therapy, there exist no studies specific for ESRD patients evaluating the effect of RAAS inhibitors on cardiovascular disease. Thus, nephrologists again have to rely on extrapolation of nonrenal population based studies. The HOPE Study (Heart Outcome Prevention Evaluation) is one of most convincing trials showing a significant reduction of cardiovascular endpoints in 9,297 high-risk patients treated with the ACE inhibitor ramipril [78]. In a subgroup analysis of the HOPE trial on 732 patients, it could be shown in addition that ramipril slowed the progression of atherosclerosis, measured via carotid intima media thickness [79].

Therapy of Dental Status

An underestimated source of creeping bacterial infection could be the frequently poor dental status of hemodialysis patients. Chronic gingivitis or paradontitis can contribute to acute phase activation [80]. Restoration of the dental status and a regular dentist control could help to reduce the state of inflammation in hemodialysis patients.


Biocompatible Membranes

The selection of biocompatible membranes could play an important role in the context of inflammation. In a crossover study in 18 hemodialysis patients it could be shown that the change from cuprophane to polyamide membranes reduced serum CRP as well as an endogenous interleukin-1 receptor antagonist, supporting the view that biocompatible membranes should be used preferably [81].

Improved Water Quality

Bacterial contamination of the dialysate within a dialysis unit with endotoxins (e.g., lipopolysaccharide) can lead to a stimulation of cytokine-producing cells and thus to acute phase activation. Use of ultra-pure, sterile, lipopolysaccharide-free dialysate reduces cytokine production of monocytes [82, 83]. Thus, acceptance of aggravated quality guidelines regarding water quality could mean a significant advantage for hemodialysis patients.

Antioxidative Treatment in the General Population

Treatment with antioxidants can improve surrogate parameters of cardiovascular disease such as endothelial dysfunction, which has predictive power for cardiovascular disease mortality [84, 85]. Furthermore, observational studies in the 1990s suggested a beneficial impact of nutritional vitamin E consumption on cardiovascular event rates [86]. However, in the general, non-renal population the vast majority of several large, prospective, placebocontrolled trials looking at hard endpoints such as mortality and cardiovascular events failed to demonstrate a positive effect of antioxidants on cardiovascular event rates, as shown by the GISSI Study [87], the HOPE Study (Heart Outcomes Prevention Evaluation Study) [88], the SECURE Study (Study to Evaluate Carotid Ultrasound changes in patients treated with ramipril and vitamin E) [79] as well as the HPS Study (Heart Protection Study). In the HPS Study, a combination of 600 mg vitamin E, 250 mg vitamin C and 20 mg ß-carotene administered daily in 20,536 patients was used, but failed to show a benefit for patients’ outcome [89]. An exception was the CHAOS Study (Cambridge Heart Antioxidant Study) [90], in which a beneficial effect of ·-tocopherol on cardiovascular event rates was found.


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Fig. 3. Endogenous and exogenous causes of inflammation in hemodialysis patients. AngII: angiotensin II; LPS: lipopolysaccharide; OxLDL: oxidized low density lipoproteins; AGE: advanced glycation end products; VCAM-1: vascular cell adhesion molecule-1; ICAM-1: interstitial cell adhesion molecule-1; IL-6: interleukin-6; IL-1: interleukin-1; MCP-1: monocyte chemoattractant protein-1; M-CSF: monocyte colony-stimulating factor; CVC, central venous catheter [modified according to 100].

Not only that most of the antioxidant studies failed to show beneficial effects, in a recent trial it was even suggested that antioxidant treatment with vitamins E and C may be potentially harmful because these vitamins blunt the protective HDL2 cholesterol response to HDL cholesterol-targeted therapy [91]. Thus, the safety aspect of antioxidative treatment must be further analyzed. Potential danger can be derived also from e.g. vitamin C overdosing, that may lead to excessive serum levels of vitamin C, resulting in hyperoxalemia that may contribute to vascular disease in uremic patients [92].

Antioxidative Treatment in Dialysis Patients

ed dialysis-induced endothelial dysfunction and increases in OxLDL [96], or resulted in a significant reduction of the percentage increase of the aortic calcification index after 24 months compared to the controls [97]. The SPACE Study (Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease) was the first trial with hard endpoints using oral antioxidative treatment. Vitamin E was given daily at a dose of 800 IU in 196 hemodialysis patients [98], and primary endpoint of this placebo-controlled study was a combination of myocardial infarction, angina pectoris, cerebral ischemia and peripheral vascular sclerosis. Albeit there was no significant difference on overall mortality, vitamin E treatment resulted in a significant decrease of the primary endpoint. Further support for the concept that ESRD patients suffer from particularly enhanced oxidative stress was provided in a recent publication by Tepel et al. [99]. The authors evaluated the effects of acetylcysteine, a thiolcontaining antioxidant, on cardiovascular events in patients undergoing hemodialysis, and found a reduction of the composite cardiovascular endpoints including fatal and non-fatal myocardial infarction, cardiovascular disease death, need for coronary angioplasty or coronary bypass surgery, ischemic stroke, peripheral vascular disease with amputation, or need for angioplasty. Future studies will have to confirm these results in a larger group of uremic patients.

Conclusion

ESRD patients are exposed to various endogenous and exogenous factors, which in their sum contribute to a chronic inflammatory situation and increase the cardiovascular risk (fig. 3). A common feature of these endogenous and exogenous factors is that they induce oxidative stress. Increasing evidence indicates that these factors play a central role in the pathogenesis of atherosclerosis and cardiovascular disease.

In view of the mostly negative results of antioxidant treatment in the general population, the question arises whether the situation might be different for patients with renal disease. ESRD patients are particularly exposed to enhanced oxidative stress [93–95], and might therefore have a greater benefit from antioxidative treatment as compared to the general population. Indeed, several studies looking at surrogate parameters as well as at hard endpoints suggest that this might be the case. For example, hemodialysis using vitamin E-coated membrane prevent-

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Hypertension and Dialysis Matthias P. Hörl a Walter H. Hörl b a Diabetes Research Institute, University of Düsseldorf, Germany and b Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Austria

Key Words Dialysis W Hypertension W Left ventricular hypertrophy

Abstract The high mortality rate seen in dialysis patients is related to long-standing high blood pressure and the presence of other traditional as well as non-traditional risk factors for cardiovascular disease. Hypertension is associated with increased risk for left ventricular hypertrophy, coronary artery disease, congestive heart failure and cerebrovascular complications. High blood pressure is frequent and difficult to control in the dialysis population. Available therapeutic options to normalize blood pressure in these patients include dietary salt and fluid restriction in combination with reduction of dialysate sodium concentration. A possible treatment option for these patients may be long, slow hemodialysis (3 ! 8 h per week); short daily hemodialysis (2–3 h 7 times per week); nocturnal hemodialysis (6–7 times overnight per week). Reduction of residual renal function is a major cause of blood pressure increase in the peritoneal dialysis patient population. Therefore, hyperhydration should be avoided. If antihypertensive medication is needed, ACE inhibitors, ß-blockers and/or calcium channel blockers are recommended. Optimal blood pressure in dialysis patients is not different from recommendations for the general population. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 1420–4096/03/0262–0076$19.50/0



Prevalence of Hypertension

The majority of end-stage renal disease (ESRD) patients are hypertensive [1]. The majority of hypertension in patients with chronic renal failure and in maintenance dialysis patients is systolic, frequently diastolic blood pressure is normal or low [2]. Pulse pressure is significantly increased in these patients. This situation closely resembles isolated systolic hypertension of elderly subjects, but occurs decades earlier in chronic renal disease patients [3]. Hypertension is an established risk factor for cardiovascular events in dialysis patients. Studies with a mean followup longer than 5 years found a positive relationship between hypertension and mortality [4–7], while hypertension did not have an adverse effect on patient survival in studies with a mean follow-up of 1–2 years [8–11]. Uncontrolled hypertension in renal failure patients before starting dialysis treatment is a major risk factor for cardiovascular mortality during hemodialysis [7]. These data indicate that adequate control of blood pressure and treatment of hypertension are of particular importance in this patient population. Cardiovascular disease is also a major cause of death in patients with pediatric ESRD. Gruppen et al. [12] found left ventricular hypertrophy in 47% of all male patients and in 39% of all female patients. A high left ventricular mass index was associated with a current high blood pressure, male gender, diastolic dysfunction, glomerular filtration rate !25 ml/min/1.73 m², and aortic value calcification with prolonged peritoneal dialysis.

Prof. Walter H. Hörl, MD, PhD, FRCP Head, Division of Nephrology and Dialysis Department of Medicine III, University of Vienna Währinger Gürtel 18–20, A–1090 Vienna (Austria) Tel. +43 1 40400 4390, Fax +43 1 40400 4392, E-Mail [email protected]

Initially, peritoneal dialysis allows better blood pressure control and regression of left ventricular hypertrophy. Blood pressure increases with reduction of residual renal function, probably due to continuous hyperhydration of the patients [13]. Wang et al. [14] found an increase in left ventricular mass index with the decrease in glomerular filtration rate and weekly Kt/V. On the other hand, CAPD patients with better preserved residual renal function had higher Kt/V, they were less anemic and less hypoalbuminemic. These patients also had lower systolic blood pressure and lower pulse pressure. These data demonstrate the importance of residual renal function with respect to the development of hypertension and left ventricular hypertrophy. In patients on CAPD for 26 months, the prevalence of hypertension was 84% when using office blood pressure measurements and 82% when using daytime ambulatory blood pressure monitoring (ABPM). CAPD patients with uncontrolled hypertension (1135/85 mm Hg) were taking more antihypertensive medications as compared to normotensive patients. Inferior vena cava diameter and left ventricular mass index were also higher in the hypertensive CAPD patient group [15].

office diastolic blood pressure, an elevated 24-hour pulse pressure and an elevated nocturnal systolic blood pressure were found to be independent predictors of cardiovascular mortality in treated hypertensive hemodialysis patients [21]. ABPM is a superior method for assessing the important issue of diurnal blood pressure variation and predicting adverse cardiovascular outcome. It is probably a marker for poor autonomic function and possibly adverse structural arterial changes [22].

Interdialytic Weight Gain – Intradialytic Weight Reduction

Pulse pressure is a stronger predictor of future cardiovascular mortality than systolic or diastolic blood pressure in patients with coronary heart disease [16] and in maintenance hemodialysis patients [17]. Pulse pressure may be an attractive surrogate measure of aortic stiffness but has its origins in both cardiac and aortic performance. Aortic pulse wave velocity is a direct measurement of arterial stiffness, and is greatly increased in hypertensive as well as uremic patients as compared to the general population. It has a much stronger correlation with end-organ damage than does any measurements of peripheral blood pressure [18]. ACE inhibitors (and most likely angiotensin receptor blockers), nitrates and the prevention of vascular calcification are the best remedies to ameliorate vascular stiffening [3]. Reduction in the fall in diurnal blood pressure with sleep in uremic patients is related to autonomic dysfunction and obstructive sleep apnea [19]. Volume expansion of ESRD patients is not responsible for this abnormality. Short-hours daily hemodialysis reduced blood pressure, left ventricular hypertrophy and blood volume expansion in these patients as compared to those on three times weekly conventional hemodialysis. The diurnal blood pressure rhythm, however, was not improved [20]. Low

Volume status of ESRD patients influences both preand postdialysis blood pressure. Interdialytic weight gain is not always correlated with predialysis mean arterial pressure [23]. On the other hand, blood pressure usually falls during hemodialysis with fluid removal. In the HEMO study [24], systolic blood pressure decreased during hemodialysis from 153.1 B 24.7 to 136.6 B 22.7 mm Hg, while diastolic blood pressure decreased from 81.7 B 14.8 to 73.9 B 13.6 mm Hg. The mean intradialytic decrease in body weight (3.1 B 1.3 kg) was slightly larger than those reported in most other studies. The mean intradialytic decrease of plasma volume was 10.1 B 9.5%. Intradialytic changes in systolic blood pressure were significantly associated with intradialytic decreases in both body weight and plasma volume. However, such a relationship did not exist between mean arterial blood pressure or diastolic blood pressure and intradialytic decreases in body weight and plasma volume. These data indicate that the effects of intradialytic decreases in body weight and plasma volume are greater on systolic than on diastolic blood pressure. Several studies reported a significant association of predialysis blood pressure with intradialytic reduction in body weight or the ultrafiltration rate [25–27]. In the HEMO study, each kilogram reduction in body weight during hemodialysis was associated with a 2.95 and 1.65 mm Hg higher preand postdialysis systolic blood pressure, respectively [24]. Cardiac status alters the relationship between blood pressure and fluid removal during hemodialysis [28, 29]. Blood pressure decreases more substantially in patients with cardiac failure than in those without cardiac failure for equivalent intradialytic decreases in plasma volume [30]. Volume status of ESRD patients influences both preand postdialysis blood pressure. Low dialysate sodium concentration may lead to large sodium removal but also to an impaired preservation of blood volume, while high dialysate sodium concentration may improve hemodynamic

Hypertension and Dialysis


Importance of Pulse Pressure and ABPM

77

Table 1. Reasons for hypertension in hemodialysis patients

Extracellular volume excess/volume overload Derangements of renin-angiotensin system Sympathetic overactivity Impaired endothelium-dependent vasodilation Uremic toxins (ADMA, homocysteine, parathyroid hormone) Genetic factors Geographic factors/influence of climate Correction of renal anemia by rhuEPO/darbepoetin-· Secondary hyperparathyroidism Sodium intake/dialysate sodium concentration Hemodialysis regimen Noncompliance

instability during hemodialysis but increases interdialytic weight gain and blood pressure. Diffuse sodium flux into the patients occurs when the difference between dialysate sodium and predialytic serum sodium is 15 mmol/l [31]. Individualized dialysate sodium (predialytic plasma conductivity ! 10) allows an enhanced ionic removal as compared to dialysate sodium of 140 mmol/l without large differences in blood volume changes [31]. Intradialytic reduction in body weight is a good approximation to the interdialytic weight gain in maintenance hemodialysis patients who are at steady state and whose postdialysis body weight is relatively constant [24]. Usually postdialysis blood pressures are measured soon after the completion of treatment, but blood pressure may rebound thereafter [32]. Determination of the volume of extracellular fluid is probably more important than the evaluation of the volume of total body water [33, 34].

Pathophysiology of Hypertension

The pathophysiology of hypertension in hemodialysis patients (table 1) has recently been summarized [1]. A low production of the endogenous inhibitor nitric oxide (NO) in patients with chronic kidney disease [35] and in dialysis patients [36, 37] may contribute to hypertension. NO deficiency is associated with endothelial dysfunction and atherosclerosis. NO deficiency is caused by (1) substrate (arginine) deficiency; (2) impaired transcellular arginine transport (e.g. by urea); (3) impaired endothelial NO synthase activity; (4) increased levels of the NOS inhibitor asymmetric dimethylarginine (ADMA), and (5) oxidative stress-related NO inactivation. Plasma obtained from ESRD patients significantly inhibits NOS activity by about 30% [38]. ADMA concentra-

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tions found in ESRD patients also significantly inhibit NOS activity [39], while urea inhibits L-arginine transport and promotes intracellular substrate deficiency. Plasma ADMA levels are particularly enhanced in hemodialysis patients with atherosclerotic complications [40]. A high plasma ADMA concentration may be responsible for impaired endothelium-dependent vasodilatation observed in uremia. No significant correlation, however, was observed between ADMA concentration and blood pressure in dialysis patients [41]. Uremia is associated with a 10- to 20-fold increase in cardiovascular death [42]. Even mild renal insufficiency is an independent cardiovascular risk factor [43]. Inflammation is a key factor in the pathogenesis of atherosclerosis [44]. Uremia is associated with inflammation [45]. Circulating interleukin-6 (IL-6), tumor necrosis factor-· (TNF-·), and C-reactive protein (CRP) levels are elevated in ESRD patients [46, 47]. Left ventricular hypertrophy is an independent risk factor for mortality in ESRD patients. Principal hemodynamic factors responsible for the progression of left ventricular hypertrophy in ESRD patients are increased systolic blood pressure, anemia, the arteriovenous fistula and overhydration. Among the antihypertensive agents, ACE inhibitors appear to have the greatest ability to reduce left ventricular mass in renal failure patients with left ventricular hypertrophy, independently from hypotensive effects [48]. London et al. [49] determined the effect of parallel lowering of blood pressure and attenuation of anemia on left ventricular size and function and determined the effect of left ventricular changes on survival. During the study, blood pressure decreased significantly from 169.4 B 29.7 mm Hg systolic and 90.2 B 15.6 mm Hg diastolic to 146.7 B 29 mm Hg systolic and 78 B 14.1 mm Hg diastolic. Hemoglobin increased also significantly from very low levels (8.65 B 1.65 g/dl) to 10.5 B 1.45 g/dl. Left ventricular mass decreased significantly. Left ventricular mass regression positively affected survival. During follow-up, 48/83 nonresponders died versus 10/70 responders indicating that partial regression of left ventricular hypertrophy in ESRD patients has a favorable and independent effect on patients’ all-cause and cardiovascular survival [49]. Angiotensin II is an important pro-inflammatory, prothrombotic and pro-fibrotic mediator in the pathogenesis of atherosclerosis. It acts synergistically with oxidized LDL to promote reactive oxygen species formation [50], and activates the transcription factor NF-ÎB [51] which coordinates inflammatory genes involved in the development of atherosclerosis. Serum ACE (angiotensin-converting enzyme) activity is an independent predictor for

Hörl/Hörl

cardiovascular events and all-cause mortality in diabetic peritoneal dialysis patients [52, 53]. Inhibition of the renin-angiotensin system reduces CRP [54], TNF-· [55], IL-6 [56], NF-ÎB [57] and AGE (advanced glycation endproduct) [58] levels. Further, ACE inhibition preserves residual renal function in peritoneal dialysis patients without significant risk of hyperkalemia [59], while hyperkalemic episodes have been reported in hemodialysis patients treated with ACE inhibitors [60].

untreated group, mortality was decreased significantly in the treated group, with a risk reduction of 52%, while blood pressure was not different between both groups. The absolute risk reduction of mortality was 79% in ACE inhibitor-treated patients 65 years or younger. However, Kestenbaum et al. [69] did not find an association between the use of ACE inhibitors, ß-blockers, or aspirin and the risk of mortality among ESRD patients. In this study the use of a calcium channel blocker was associated with a 21% lower risk of total mortality and a 26% lower risk of cardiovascular specific mortality.

Antihypertensive Medication

In the HEMO study, 72% of the patients received antihypertensive medication, 48% were prescribed calcium channel blockers, 24% were prescribed ACE inhibitors and 21% were prescribed ß-blockers [24]. Also in the study of Mittal et al. [61], most patients were treated with calcium channel blockers (39%), whereas 27% received ß-blockers and 14% received ACE inhibitors. Calcium antagonists were also the most frequently administered antihypertensive drugs (71%) by Zazgornik et al. [62] followed by ACE inhibitors (57%), ·-blockers (31%), ßblockers (26%), or centrally acting drugs (16%). The use of adrenergic blockers increased 2-fold over the duration of the study reported by Agarwal [63]. Atenolol was administered three times weekly after dialysis, and effectively controlled hypertension. ß-Blocker treatment is known to improve left ventricular function in patients with dilated cardiomyopathy. Left ventricular dimension both at end-systole and at end-diastole was decreased, and fractional shortening increased significantly in hemodialysis patients after 4 months of treatment with metoprolol. Metoprolol also decreased plasma levels of natriuretic peptides in these hemodialysis patients [64]. ß-Blocker use showed a robust association with survival in hemodialysis patients [65]. Treatment with ACE inhibitors enhances antioxidative activity in animal experiments [66] but also in hemodialysis patients [67]. ACE inhibitor therapy increases intracellular levels of glutathione, glutathione peroxidase activity and ß-carotene concentration as compared to hemodialysis patients without ACE inhibitors. The ACE inhibitor induced accumulation of bradykinin results in NO release with further increase in antioxidative capacity [67]. ACE inhibitors may dramatically reduce mortality among chronic hemodialysis patients. Efrati et al. [68] reviewed clinical data for patients on hemodialysis therapy with (treated group) and without (not treated group) ACE inhibitors. Comparing the treated patients with the


Effect of the Dialysis Regimen

Antihypertensive medications alone do not adequately control blood pressure in hemodialysis patients. There are, however, several therapeutic options available to normalize blood pressure in these patients, often without the need for additional drug therapy (e.g., long, slow hemodialysis; short daily hemodialysis; nocturnal hemodialysis, or, most effectively, dietary sodium concentration) [1]. Most dialysis patients would be normotensive or their blood pressure would be easily controlled with low doses of antihypertensive drugs, if they were able to comply with their prescribed salt and water restriction. Increasing dialysis dose leads to a decrease in morbidity and mortality. Impressive results of patient survival have been reported using long duration [70] as well as high-frequency hemodialysis [71]. Nocturnal hemodialysis combines high frequency and long duration [72]. Successful blood pressure control has been reported with long hemodialysis [73] and short daily hemodialysis [74]. Such a dialysis regimen may also reverse left ventricular hypertrophy in uremic patients. Blood pressure is also well controlled during nocturnal hemodialysis. The average number of antihypertensives decreased from 2.67 B 1.12 while on conventional hemodialysis to 1.78 B 1.20 at 6 months and 1.67 B 1.17 at 12 months on nocturnal hemodialysis [72]. Treatment options to intensity hemodialysis have recently been summarized [75].

Conclusion

Hypertension has been independently correlated with cardiovascular morbidity and mortality in the dialysis population [76]. Pre- and postdialysis blood pressure values have independent associations with mortality, in a way that implicates wide pulse pressure [65]. At present,


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target blood pressure recommendations in ESRD patients from those for the general population [1]. In the study of Rahman et al. [77], young age, black race, male sex, diabetes as cause of ESRD, erythropoietin therapy, and smoking were associated with higher blood pressure in hemodialysis patients. Patients skipping or shortening

one or more dialysis treatments also had a higher blood pressure [77]. Large interdialytic wide gains were associated with short survival when co-morbidity is taken into account [65]. Management of hypertension therefore also includes therapeutic regimens emphasizing improved compliance with the dialysis regimen [77].

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50 Harrison DG: Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997;100:2153–2157. 51 Valen G, Yan ZQ, Hansson GK: Nuclear factor kappa-B and the heart. J Am Coll Cardiol 2001;38:307–314. 52 Wong TY, Szeto CC, Chow KM, Chan JC, Li PK: Prognostic role of serum ACE activity on outcome of type 2 diabetic patients on chronic ambulatory peritoneal dialysis. Am J Kidney Dis 2002;39:1054–1060. 53 Wong TY, Szeto CC, Chow KM, Chan JC, Li PK: Contribution of gene polymorphisms in the renin-angiotensin system to macroangiopathy in patients with diabetic nephropathy. Am J Kidney Dis 2001;38:9–17. 54 Stenvinkel P, Andersson P, Wang T, Lindholm B, Bergström J, Palmblad J, Heimburger O, Cederholm T: Do ACE-inhibitors suppress tumor necrosis factor-alpha production in advanced chronic renal failure? J Intern Med 1999;246:503–507. 55 Fukuzawa M, Satoh J, Sagara M, Muto G, Muto Y, Nishimura S, Miyaguchi S, Qiang XL, Sakata Y, Nakazawa T, Ikehata F, Ohta S, Toyota T: Angiotensin converting enzyme inhibitors suppress production of tumor necrosis factor-· in vitro and in vivo. Immunopharmacology 1997;36:49–55. 56 Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries SE, Montgomery HE: Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release. Heart 2002;87:252–255. 57 Hernandez-Presa MA, Bustos C, Ortega M, Tunon J, Ortega L, Egido J: ACE inhibitor quinapril reduces the arterial expression of NF-kappa-B-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis. Am J Pathol 1998;153:1825–1837. 58 Miyata T, van Ypersele de Strihou C, Ueda Y, Ichimori K, Inagi R, Onogi H, Ishikawa N, Nangaku M, Kurokawa K: Angiotensin ii receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: Biochemical mechanisms. J Am Soc Nephrol 2002;13: 2478–2487. 59 Li PK, Chow KM, Wong TY, et al: Preservation of residual renal function in peritoneal dialysis patients by angiotensin-converting enzyme inhibitor. A prospective randomized study. J Am Soc Nephrol 2002;13:F-FC004. 60 Knoll GA, Sahgal A, Nair RC, Graham J, van Walraven C, Burns KD: Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients. Am J Med 2002;112:110–114. 61 Mittal SK, Kowalski E, Trenkle J, MacDonough B, Halinski D, Devlin K, Boylan E, Flaster E, Maesaka JK: Prevalence of hypertension in a hemodialysis population. Clin Nephrol 1999;51:77–82. 62 Zazgornik J, Biesenbach G, Forstenlehner M, Stummvoll K: Profile of antihypertensive drugs in hypertensive patients on renal replacement therapy (RRT). Clin Nephrol 1997;48: 337–440.

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Rationale for the Use of Blood Volume and Temperature Control Devices during Hemodialysis Johannes Donauer a Joachim Böhler b a Department

of Nephrology, University Hospital Freiburg and b Deutsche Klinik für Diagnostik, Division of Nephrology, Wiesbaden, Germany

Key Words Dialysis-induced hypotension W Blood volume W Blood temperature W Hemodialysis W Dialysate temperature

Abstract Despite substantial progress in blood purification techniques over the last three decades, treatment-related hypotensive episodes remain one of the major problems in hemodialysis therapy. There are two main reasons for hypotension occurring during dialysis treatments. First, hypovolemia is frequently induced by rapid fluid removal from the blood compartment which is in excess of refilling of fluids from the interstitial space. Second, many patients fail to support blood pressure by adequate vasoconstriction or increased heart rate as a response to hypovolemia. The capacity to respond adequately to volume contraction may be reduced due to patient- or treatment-related factors, among which heat accumulation within the body plays a major role. Recently, two newer technical developments became commercially available for use in hemodialysis therapy: devices for blood volume and blood temperature control were designed to reduce the incidence of intradialytic hypotension. Although blood volume and temperature mea-

ABC

© 2003 S. Karger AG, Basel 1420–4096/03/0262–0082$19.50/0



surements are easy to perform today, there is some uncertainty in the dialysis community how and when their use may be helpful and in which patients it is indicated. This review critically discusses the application of blood volume- and temperature-measuring devices with regard to their usefulness in the clinical setting. Copyright © 2003 S. Karger AG, Basel

Introduction

Symptomatic hypotension during hemodialysis (HD) remains one of the most frequent side effects. It is a major cause of morbidity in patients with end-stage renal disease [1] and its effect on mortality is unknown. Although knowledge about pathophysiologic mechanisms leading to hypotension during dialysis has improved over the last decades (fig. 1), the frequency of hypotensive episodes has not decreased significantly. The percentage of patients at risk for hypotension during HD is growing, as increasing numbers of older patients with cardiovascular and diabetic disease require renal replacement therapy [1–5]. The reported prevalence of hypotension occurring in conventional HD treatments varies between 10 [6] and 20% [7] in recent publications.

Dr. Johannes Donauer Medizin IV, Universitätsklinikum Freiburg Hugstetter Strasse 55 D–79106 Freiburg (Germany) Tel. +49 761 2703251, Fax +49 761 2703286, E-Mail [email protected]

Fig. 1. Mechanisms leading to dialysis-in-

duced hypotension.

Hypovolemia due to ultrafiltration is an obvious cause of HD-associated hypotension. However, fluid withdrawal alone does not explain why some patients do and others do not experience symptomatic hypotension during HD. The first prerequisite of a hemodynamically stable dialysis treatment is the correct definition of dry weight. If a large amount of fluid is withdrawn after the patient has reached his true dry weight, no compensatory physiologic mechanism and no technical device will succeed to keep the blood pressure stable. The assessment of dry weight is one of the most difficult tasks in the care of dialysis patients, and moreover the result needs frequent re-evaluation during the year. The assessment of dry weight is not subject of this review and for the purpose of the following discussion it will be assumed that hypotension occurs in affected patients despite correct definition of dry weight. Beside a too rapid ultrafiltration and ultrafiltration far below the patient’s dry weight, several additional factors have been suggested to increase the susceptibility to hypotension: autonomic dysfunction [2, 8–12], decreased plasma osmolality [13, 14] decrease in plasma volume [15], impaired venous compliance [15, 16], decreased cardiac reserve [15–17], serum electrolyte changes [18], accumulation of nitric oxide (NO) [20, 22–24], or heat accumulation during the treatment [19–21]. Over the last decade, blood temperature and relative blood volume (BV) measurement matured from a research tool to a routine clinical option. Blood volume monitors (BVM) and blood temperature monitors (BTM) are now available and promise to prevent intradialytic hypotension in many cases. Some of the modules are integrated in dialysis machines and permit not only measurement but also control of BV and temperature during dialysis sessions. However, criteria how to employ these

devices are largely unknown among clinicians, as data from the literature do not give consistent advice.

Use of Blood Volume and Temperature Control Devices during HD


Blood Volume and Hypotension

At the beginning of a HD session, the volume load accumulated since the last treatment is mainly located in the interstitial space and has to be removed over 3–5 h. Plasma water removal by ultrafiltration increases oncotic pressure in the blood and decreases hydrostatic pressure in the venous system. Both changes will enhance the refilling of plasma volume from the interstitial space. However, refilling usually proceeds slower than ultrafiltration and only partially compensates for the BV loss. As a consequence, intravascular water content progressively decreases and this can be detected by measuring hemoconcentration during dialysis [25]. Increasing hemoconcentration reflects the reduction of relative BV. Several methods were developed for continuous and non-invasive measurement of BV changes. They all measure specific blood properties, such as electrical conductivitiy [32, 33], optical density [34–37] or velocity of sound waves in blood [38, 39]. All methods were proven to be reliable and to give an indication of hemoconcentration, which correlates with relative BV. Using these techniques it has been shown repeatedly that changes in relative BV during dialysis correlate with the incidence of hypotensive episodes [1, 4, 6, 25, 30, 31]. Interpretation of BV Data Many dialysis patients react appropriately to hypovolemia with an increase in cardiac rate and contractility, venoconstriction of splanchnic and dermal blood vessels

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as well as an increase in arteriolar tone in order to shift blood to the central blood compartment and to preserve cardiac filling [26, 27]. These patients show hypotension only during excessive hypovolemia. Other patients have a reduced capacity to adapt to hypovolemia [1, 4, 28, 29] and react with hypotension already at lower levels of hypovolemia. Initial data using BV measurements in context with hypotension originate from the early 1970s [30]. Several years later, BV measurement using an online-absolute hematocrit measurement system became available (Critline, In-Line Diagnostics, Riverdale, Utah, USA). The first studies using this device lead to the assumption that symptomatic hypotensive episodes take place at a patientspecific absolute hematocrit [4]. More sophisticated analysis suggested that the change of BV over time or the BV slope may be valuable as a predictors of maximally tolerated BV change or dry weight to be reached [40–42]. BV changes can possibly detect fluid overload and help to define dry weight [43]. Flat BV or hematocrit curves during HD may indicate clinically undetected edema [44]. Steuer et al. [45, 46] described that cramping and lightheadedness occurring during treatments were preceded by a pronounced reduction in BV. However, a general and simple principle on how to efficiently use and interpret BVM measurements is still lacking. Simple calculation of BV losses during HD do not reliably predict hypotension. In our own study a subgroup of hypotension-prone patients showed a correlation between BV changes and blood pressure during HD [6]. From these data, we concluded that only a part of patients suffering from ‘hypovolemia-induced hypotension’ may benefit from BV measurement and control, whereas in one third of symptomatic patient’s hypotension occurred independently of BV reduction. In addition, we observed that during hemodiafiltration (HDF) and lower temperature dialysis, a BV that was significantly lower compared to standard HD nevertheless allowed for stable hemodynamics [47]. Thus, the effect of a given BV reduction on hemodynamic stability may not only be influenced by the patient’s physiologic response to ultrafiltration but may also depend on the treatment modality employed. Manual and Automatic Feedback Control of BV Changes There are several devices available which allow a realtime surveillance of relative BV. Manual systems require that the obtained data be interpreted by the staff and the operating parameters of the dialysis machines be modified manually. Automatic devices are integrated in the

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dialysis machine and induce an automatic response, if the measured BV deviates from an expected level. Automatic feedback systems modify the ultrafiltration rate and/or dialysate conductivity in order to reduce hypovolemia. Three examples for this technique are given below: The Crit-line monitor is a fluid management device based on non-invasive measurement of absolute hematocrit values. In addition, it calculates the percentage of BV change, continuous oxygen saturation and access recirculation. The data displayed are used by the staff and intervention is initiated depending on the individual patient. The Hemocontrol system (HBS; Hospal, Bologna, Italy) is based on BV measurements using an optical absorbance system and an adaptive controller. In case of low BV it decreases the ultrafiltration rate and increases the dialysate conductivity in order to enhance refilling and assure that the BV curve follows patient specific predefined BV trajectories. Those trajectories are individual time courses of BV defined during a ‘learning’ phase of previous dialysis treatments sessions. One critical point of this concept may be the temporary administration of higher sodium concentrations via the dialysate which supposedly is removed again later in the treatment. Sodium administration is an established method to stabilize blood pressure, but may aggravate thirst and in consequence lead to increased weight gain and hypertension [44, 48]. Basile et al. [34] showed in a recent prospective study on hypotension-prone dialysis patients, that HBS treatment lowered the incidence of symptomatic hypotension and muscle cramps significantly. The mean observation period for HBS treatment was 24 B 1.6 months, and during that time, no significant changes in blood pressure or dry weight were observed compared to the control group. However, the possibility of net sodium administration could not be ruled out completely, as in both the HBS and the control group, an unexplained substantial increase of serum sodium concentrations during treatments was observed. In a randomized controlled study, Santoro et al. [76] achieved a 30% reduction of hypotensive episodes in a selected group of high-risk patients using the BV tracking system (BVT Hemocontrol, Hospal). Increases in hypertension or sodium concentration were not observed. In our own experience, the stabilizing effect in hypotension-prone patients is impressive but the possibility that this may in part be due to sodium administration remains a point of concern. The option to switch off sodium modeling and use ultrafiltration control alone would be helpful.

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Another available automatic feedback system is based on measurement of ultrasonic sound pulses, which are sent through the blood line of the extracorporeal system [49] This measurement allows for the continuous calculation of the relative protein concentration of the whole blood from which relative BV is extrapolated (BVM; Fresenius Medical Care, Bad Homburg, Germany). The BVM automatically reduces the ultrafiltration rate of the HD machine, if the relative BV shows a critical decline. Based on a preset algorithm, the BVM incrementally reduces the ultrafiltration rate, if BV decreases and tends to reach the critical value. Since there are no data from the literature to support a strict threshold valid for all patients, this threshold value has to be chosen by the operator, based on his experience with the patient’s individual needs. This concept is simple but may overlook that not only the minimal BV, but also the change of the BV slope over time may play a role for induction of hypotension [50]. Therefore, the concept of ideal BV curves over time may appear more sophisticated and could prove to be superior to that of a fixed minimal value for BV during dialysis. In summary, there is convincing data indicating that at least one third of patients with hypotensive episodes during HD may benefit from systems that modify ultrafiltration rates in response to BV changes. This technology can be recommended for patients with frequent hypovolemiainduced hypotension. To define ideal relative BV profiles and fine tune the methods, more experience is needed. However, such ideal trajectories always need to be adopted to the individual patient, since there is no general threshold of BV reduction at which side effects occur. If sodium modeling is applied in addition to ultrafiltration rate control, careful attention should be paid to the longterm effects on thirst, dry weight and hypertension.

Blood Temperature

More than 20 years ago, Maggiore et al. [19] showed that a stabilization of blood pressure during dialysis can be achieved using cool dialysate. Later studies confirmed that high dialysate temperatures, e.g. 37.5 ° C, cause hemodynamic instability, compared to cool dialysate, e.g. 35.5 ° C [19, 20, 51–60]. Although independently demonstrated by many investigators, these findings were mostly ignored by the dialysis community for many years. One reason to avoid cooling of patients was that many patients complained about feeling cold with use of cool dialysate or substitution fluid. This occurred if the patient’s core


temperature before the dialysis treatment was not known and cool dialysate was thus used under uncontrolled conditions. A decade later, the temperature balance hypothesis was revived when devices for continuous measurement of blood temperature during dialysis became available. They allowed to study the influence of blood temperature on incidence of hypotension during HD treatments in more detail [44, 61–64] and provided new insights to thermal balance during dialysis. Standard HD leads to an increase in body temperature. The average temperature increase during conventional HD published in two recent articles were between 0.39 ° C [47] and 0.67 ° C [65], respectively. A number of possible causes for this rise in body temperature during dialysis have been discussed. The temperature of the patient can increase either because external heat is added to the body, or the body could produce more heat from metabolism or the body reduces heat losses via the skin. Heat Transfer to the Patient Core Temperature Prior to Dialysis A subgroup of HD patients [53, 66] has a subnormal core temperature. The mechanisms leading to hypothermia in HD patients are unknown. In a study of Fine and Penner [53], repetitive measurements of patients’ predialysis core temperature revealed that 23% of dialysis patients had a core temperature of !36 ° C, and only 38% were euthermic (136.5 ° C). Patients with a core temperature !36 ° C were at highest risk for developing hypotension during HD if dialysate temperature was set at 37 ° C. This study also showed that hypothermic patients had a significantly reduced incidence of side effects with use of lower temperature dialysate whereas normothermic patients had no benefit. Standard Dialysate Temperature Until recently, a dialysate temperature of 37 ° C was thought to be adequate for routine HD. Although this is somewhat higher than the physiologic core temperature, the amount of thermal energy delivered to the extracorporeal system via the dialysate was thought to compensate for heat losses from the blood lines into the environment. Thus, it was assumed that overall no energy was transferred to the patient. However, during standard HD many patients experience a net energy influx, especially if they start with a low core temperature prior to treatment. This warming increases their risk for hypotensive side effects [53].


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use of sterile dialysate and biocompatible membranes, thus making the contribution of endotoxins or interleukins less likely.

Ultrafiltration

Blood volume reduction

Decreased heat loss via the skin

Hypovolemia Increased core temperature Vasoconstriction Vasodilatation Peripheral resistance

Peripheral resistance

Stable blood pressure Hypotension

Fig. 2. Effect of ultrafiltration on vascular tone and blood tempera-

ture.

Endogenous Heat Production or Accumulation The dialysis circuit is not the only source of heat to explain the rise in core temperature during dialysis. Maggiore [65] performed ‘thermoneutral’ dialysis that avoids heat transfer to the patient from the extracorporeal system because temperature of the blood returning to the patient is exactly the same as the temperature in the arterial line. Nevertheless, a mean increase of body core temperature of 0.47 ° C still occurred, indicating that during dialysis treatments endogenous heat sources may be responsible for the temperature increase and need to be considered. It has long been suggested that patients may increase their basal metabolic rate during HD [67]. This could be due to shifts of solutes and water between body compartments inducing energy-requiring adaptive processes or increased sympathetic activity with higher activity of vasoconstrictor muscles, which may require a higher energy spending. Other possible mechanisms to explain the temperature increase during dialysis were discussed in the literature: The interleukin hypothesis states that endotoxins from contaminated dialysate may lead to an activation of blood cells, mainly monocytes and macrophages, which secrete mediators such as IL-1 and other ‘pyrogens’ [68]. These are potent mediators for the induction of fever reactions and could easily induce a mild rise in body temperature by changing the hypothalamic set-point for body temperature. However, body temperature also rises with

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Decreased Heat Loss via the Skin From normal physiology it is known [69] that body temperature increases slightly if a person arises from the supine to the upright position. As the blood shifts to the lower half of the body, particularly the legs, vasoconstriction predominantly of skin vessels prevents a decrease in blood pressure. Heat loss via the skin, however, declines due to vasoconstriction of the blood vessels and thus the core temperature increases. This appears to be the main mechanism for the temperature increase in dialysis patients, and was first described by Gotch et al. [70] who coined the term ‘volume hypothesis’. Ultrafiltration induces an acute reduction of BV, which is physiologically followed by a sympathetic response inducing vasoconstriction of peripheral blood vessels. As a consequence, the capacity for heat loss via the skin is impaired and heat accumulates in the body. The same phenomenon was observed by Rosales et al. [63]. They demonstrated that the amount of heat accumulation in dialysis patients correlates directly with the ultrafiltration volume removed during a HD session. The more volume is removed, the more heat accumulates. Data of this study suggest that the likelihood of a hypotensive episode increases with high ultrafiltration rates because at some point the impulse to vasodilate blood vessels in order to reduce heat accumulation is stronger than the impulse to maintain vasoconstriction for the stabilization of blood pressure. Patients at risk are those with impaired compensatory capacity due to subnormal core temperature [53], chronic inflammatory processes identified by an elevation of CRP [71], patients with high ultrafiltration rates [63], autonomic dysfunction [72] or arteriosclerosis [73; for review, see 74]. Blood Temperature Measurement and Control To maintain vasoconstriction and prevent hypotensive episodes (fig. 2), HD should be carried out under isothermic conditions. This implies: (1) the dialysate should not warm the patient, instead (2) the dialysate should remove the amount of energy that cannot leave the body via the skin because of ultrafiltration-induced vasoconstriction. As a result of the energy removal, the patient’s core temperature will remain at predialysis levels. The purpose of using cooler dialysate is not to cool the patient below his own temperature set point but to prevent heat accumulation and a rise in core temperature. The relevance of

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this concept was shown recently by Maggiore [65] in a study enrolling 95 hypotension-prone dialysis patients: ‘Isothermic dialysis’, keeping body temperature unchanged during treatments, was compared to ‘thermoneutral’ treatments, which merely avoided extracorporeal heat transfer to the patient, but did not prevent endogenous heat accumulation. An impressive decrease of hypotensive episodes from 50 to 25% took place in the isothermic group. A device for non-invasive blood temperature measurement and control is commercially available and its effect on blood pressure and incidence of hypotensive episodes has been the subject of several studies [49, 65, 75]. The Blood Temperature Monitor (BTM, Fresenius Medical Care, Bad Homburg, Germany) measures the temperatures of the blood in the arterial and the venous blood line. It extrapolates patient’s core temperature and calculates the arteriovenous temperature gradient. This gradient can be multiplied by blood flow and blood heat capacity, resulting in thermal energy flow within the extracorporeal circuit. Via a feedback system the patient’s core temperature can be kept stable by modifying dialysate temperature [49]. Thus, this device allows for automated isothermic dialysis. In summary, blood temperature measurement and control can be recommended for hypotension-prone patients to avoid temperature-related drops of blood pres-

sure. Above all, patients with subnormal core temperature and high ultrafiltration volumes may benefit from blood temperature control. Isothermic dialysis prevents a change in patients core temperature in order to keep the temperature at the patient’s own hypothalamic set point.

Conclusion

To assure the safety of the HD procedure, measuring patient parameters, e.g. blood pressure, has been the standard of care for many years. Recently, monitoring during dialysis has made a significant transition from manual measurement of a parameter (e.g. blood pressure) to closing the feedback loop between the patient and the dialysis machine: (1) a parameter is measured to give information about the patient’s condition; (2) the measurement is carried out automatically by the dialysis machine, and (3) the result of the measurement directly modifies the operational settings of the machine The purpose of the feedback loop is that the patient’s condition directly controls the operating conditions of the dialysis machine. Automatic control of BV (BVT-Hospal, BVM-Fresenius) and of thermal balance (BTM-Fresenius) are important achievements. This type of direct feedback loops will help to more safely dialyze the everincreasing number of unstable HD patients.

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59 Sherman RA, Rubin MP, Cody RP, Eisinger RP: Amelioration of hemodialysis-associated hypotension by the use of cool dialysate. Am J Kidney Dis 1985;5:124–127. 60 Bazzato G, Coli U, Landini S, Lucatello S, Fracasso A, Morachiello P, Righetto F, Scanferla F: Temperature monitoring in dialysis-induced hypotension. Kidney Int Suppl 1985;17:161– 165. 61 Dheenan S, Henrich WL: Preventing dialysis hypotension: A comparison of usual protective maneuvers. Kidney Int 2001;59:1175–1181. 62 Maggiore Q, Pizzarelli F, Santoro A, Panzetta G, Bonforte G, Hannedouche T, Alvarez de Lara MA, Tsouras I, Loureiro A, Ponce P, Sulkova S, Van Roost G, Brink H, Kwan JT: The effects of control of thermal balance on vascular stability in hemodialysis patients: Results of the European randomized clinical trial. Am J Kidney Dis 2002;40:280–290. 63 Rosales LM, Schneditz D, Morris AT, Rahmati S, Levin NW: Isothermic hemodialysis and ultrafiltration. Am J Kidney Dis 2000;36:353– 361. 64 Schneditz D, Martin K, Kramer M, Kenner T, Skrabal F: Effect of controlled extracorporeal blood cooling on ultrafiltration-induced blood volume changes during hemodialysis. J Am Soc Nephrol 1997;8:956–964.


65 Maggiore Q: Isothermic dialysis for hypotension-prone patients. Semin Dial 2002;15:187– 190. 66 Jones PG, Kauffman CA, Port FK, Kluger MJ: Fever in uremia: production of leukocytic pyrogen by chronic dialysis patients. Am J Kidney Dis 1985;6:241–244. 67 Ikizler TA, Wingard RL, Sun M, Harvell J, Parker RA, Hakim RM: Increased energy expenditure in hemodialysis patients. J Am Soc Nephrol 1996;7:2646–2653. 68 Shaldon S, Deschold G, Branger B, Granoleras C, Baldamus CA, Koch KM, Lysaght MJ, Dinarello CA: Hemodialysis hypotension: The interleukin hypothesis restated. Proc EDTAERA 1985;22:229–243. 69 Tikuisis P, Ducharme MB: The effect of postural changes on body temperatures and heat balance. Eur J Appl Physiol Occup Physiol 1996; 72:451–459. 70 Gotch FA, Keen ML, Yarian SR: An analysis of thermal regulation in hemodialysis with oneand three-compartment models. ASAIO Trans 1989;35:622–624.

71 Tomita M, Malhotra D, Dheenan S, Shapiro JI, Henrich WL, Santoro TJ: A potential role for immune activation in hemodialysis hypotension. Ren Fail 2001;23:637–649. 72 Sato M, Horigome I, Chiba S, Furuta T, Miyazaki M, Hotta O, Suzuki K, Noshiro H, Taguma Y: Autonomic insufficiency as a factor contributing to dialysis-induced hypotension. Nephrol Dial Transplant 2001;16:1657–1662. 73 Matsumae T, Matsumae M, Hasegawa Y, Tanaka T, Yoshitake K, Noda R, Ogahara S, Murata T, Kaneoka H: Relationship between fluctuation pattern of blood pressure during hemodialysis treatment and cardiovascular morphology: An autopsy study of 53 cases. Nephron 2001;88:113–119. 74 Sherman RA: Intradialytic hypotension: An overview of recent, unresolved and overlooked issues. Semin Dial 2002;15:141–143. 75 Krämer M, Polaschegg HD: Control of blood temperature and thermal energy balance during hemodialysis. Proc Annu Int Conf IEEEEMBS 1992;14:2299–2300. 76 Santoro A, Mancini E, Basile C, Amoroso L, Di Giulio S, Usberti M, Colasanti G, Verzetti G et al: Blood volume-controlled hemodialysis in hypotension-prone patients: A randomized, multicenter controlled trial. Kidney Int 2002; 62:1034–1045.


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Treatment Options to Intensify Hemodialysis M. Haag-Weber Department of Nephrology, St. Elisabeth Hospital, Straubing, Germany

Key Words Short daily hemodialysis W Nocturnal hemodialysis W Hemodialysis, 8 h 3 times/week W Mortality W Phosphate W Middle molecule

Abstract At present, three methods are practiced to intensify hemodialysis (HD): 3 times weekly, 8-hour HD, short daily HD and slow daily nocturnal HD. Three times weekly 8-hour dialysis increase both the dialysis dose and time. The longest experiences are in Tassin. Five-year survival in Tassin was better in all age groups compared with the major registries – Japan, EDTA and US Medicare and more obvious for older age groups. The data of Tassin show that increasing the dialysis time provides better blood pressure control, need for no or less antihypertensive drugs, less intradialytic complications, better middle molecule and phosphate clearance, better nutritional status, less requirement for erythropoietin and increased survival. These data of Tassin could be mainly confirmed in our dialysis center. The main difference to Tassin was that in our center most of the patients still need few antihypertensive drugs. The reasons for the difference are that in Tassin the patients are on very low sodium diet (! 5 g/day) and in Tassin extracellular volume (ECV) is

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reduced as far as possible independent of residual renal function. The concept of our center was to preserve residual renal function and accept slightly higher ECV and few antihypertensive drugs. Another concept to intensify HD is short daily HD (6 times/week for 90– 180 min). This form of dialysis is offered as in-center and home HD with and without dialysis partner. All studies demonstrated significant improvement of nutritional status, quality of life, control of blood pressure, phosphate and anemia. Survival of AV fistula even with daily double punctures was excellent. The most extensive form of dialysis is slow daily nocturnal dialysis (6 times/week for 8–10 h). This form of dialysis provides excellent urea, phosphate clearance and fourfold increase of ß2-microglobulin clearance. Patients discontinue phosphate binders and several patients need phosphate addition to dialysis. Blood pressure control is excellent, all patients are off antihypertensive drugs. Improvement of nutrition, anemia, blood pressure and quality of life is even more pronounced compared to short daily HD or 3 times weekly 8-hour HD. Nocturnal dialysis was able to improve sleep apnea. Nocturnal dialysis is offered only as home HD with and without dialysis partner. Any patient who could be trained for home HD was eligible. Presence of co-morbidities was not a contraindication. Copyright © 2003 S. Karger AG, Basel

Prof. Dr. Marianne Haag-Weber Klinikum St. Elisabeth Straubing Elisabethstrasse 23 D–94315 Straubing (Germany) Tel. +49 9421 782633, Fax +49 9421 782646, E-Mail [email protected]

With this form of dialysis both dialysis time and dose are significantly increased. The longest and greatest experiences are in Tassin. For many years, patients have been

dialyzed at this center for 8 h 3 times/week during the day and night. Charra et al. [4] compared the 5-year survival of their patients with three major registries – Japan, EDTA and US Medicare. The results of their cohorts were better in all age groups but more obvious for older age groups. The following reasons for these excellent results in Tassin are discussed: high Kt/V, adequate ultrafiltration, low incidence of hypertension, non-drug treatment of hypertension and physician attendance. Laurent and Charra [5] found that among treatment-related factors the pre-dialysis MAP is the most powerful predictor of mortality. For each 1 mm Hg increment of pre-dialysis MAP, the risk of death increases by 3.9% (39% for 10 mm Hg). To investigate the effect of long dialysis treatment, Charra et al. [6] switched 124 unselected dialysis patients being treated for at least 6 months on a 5-hour (or less) schedule to 8-hour dialysis schedule. After 3 months of long dialysis the mean post-dialysis weight was slightly reduced, pre-dialysis MAP was lowered from 118 to 92 mm Hg and antihypertensive treatment was discontinued in all but 1 patient. 52% of the patients were on antihypertensive drugs before. Thereafter, blood pressure continued to decrease but body weight increased because of anabolism. Conversely, 49 long-HD Tassin patients were switched to a 5-hour schedule. All patients had been dialyzed for 8 h for 6 months and longer and were without antihypertensive drugs. After 1 year, MAP increased significantly (10 mm Hg) despite a 2.5-kg average weight reduction and antihypertensive medications were introduced in 4 cases. These authors argued that long dialysis reduces the chances of intradialytic events, especially hypotension, is less unphysiological, reduces the hazards of operational underdelivery of dialysis and makes it easier to achieve optimal dry weight. Katzarski et al. [7] investigated the fluid state and blood pressure in normotensive patients on long HD (8 h) in Tassin using bioimpedance and compared them with normoand hypertensive patients on short HD (3–5 h) at centers in Sweden. Hypertensive Swedish patients had higher extracellular volume (ECV) than the normotensive Swedish patients and normotensive Tassin patients. However, a subgroup of normotensive Tassin patients had even higher ECV than the hypertensive Swedish patients. The authors concluded that normotension may also be achieved in patients with fluid overload provided that the dialysis time is long enough to ensure more efficient removal of one or more vasoactive factors that cause or contribute to hypertension. Similar results were found by Luik et al. [8]. These authors increased dialysis time by 2 h without changing the dry weight and observed a significant reduction of blood pressure.

Intensified Hemodialysis


Introduction

Over 1 million patients are currently maintained on dialysis, a therapy that has been in clinical practice for 30–40 years. Still we cannot say with confidence which treatment-related factors affect the outcome of dialysis. Over the last decade there has been a steady decrease of mortality rate although the end-stage renal disease (ESRD) patient population is now older with a greater incidence of diabetes [1]. In the intervening last decade the delivered dose of dialysis was increased and patients were accepted earlier to dialysis [2]. Nevertheless, despite all the interventions, the 1-year mortality rate of 20% is still very high. The possible influence of different treatment-related factors on the outcome of dialysis was the topic of the Dialysis Opinion Survey in 1998 [3]. A questionnaire was distributed asking for their opinion on how the outcome of dialysis is affected by dose, time, membrane, frequency and self-care. The opinion poll collected 4,567 responses in total. Over 90% of the nephrologists expressed the opinion that a marked increase of the delivered dose of dialysis above the DOQI minimum level (SpKt/V = 1.2) would have a positive effect on patient survival. Increasing the treatment time by 50% would lead to an increased survival to the opinion of nearly 90% of the responders. Increasing the dose of dialysis without manipulating the time has only little effect on mortality. In total, 75% of the responders said that the use of high-flux, biocompatible membranes would have a positive impact on survival, but the majority felt that it would be only a trend. Distributing the weekly treatment time of hemodialysis (HD) over 6 days rather than 3 days is believed to influence survival positively. One third of the responders said that such an effect would be significant, while another one-third felt it would be a trend. Over half of the responders expressed the opinion that extended use of home/selfcare dialysis would improve the survival of dialysis patients, although this would be seen mainly as a trend. At present, three methods are practiced to intensify HD: 3 times/week 8-hour dialysis, short daily and slow daily nocturnal HD. The aim of this review is to discuss these different possibilities.

Three Times 8-Hour Dialysis

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Table 1. Clinical parameters before

switching from 3 ! 5 h HD and 6 months after switching to 3 ! 8 h HD (9 patients)

Phosphate, mg/dl MAP, mm Hg Antihypertensive drugs Dry weight, kg EPO dose, U/kg/week SpKt/V Interdialytic weight gain, kg

3!5 h HD

3!8 h HD

6.9B0.65 (4.0–10) 108.3B3.0 (95–124) 2.5B0.47 (1–5) 79.2B5.3 61.2B21.2 1.2B0.1 2.9B0.44 (0.5–3)

4.8B0.34* (4.0–6.3) 98B2.8 (80–106) 1.6B0.34* (0–3) 80.3B5.4 42.0B17.6* 1.9B0.15* 3.0B0.45 (0.5–5)

* p ! 0.05.

Table 2. Calcium/phosphate metabolism of 1 patient 1 month after

switching from 3 ! 5 to 3 ! 8 h HD

Calcium, mmol/l Phosphate, mg/dl Ca ! P, (mg/dl)2 PTH, pmol/l Phosphate binder

3!5 h

3!8 h

2.1 10.4 88.9 22.9 Sevelamer

2.4 4.7 45.3 14.3 Calcium carbonate

In summary, the data of Tassin show that increasing the dialysis time provides better blood pressure control, need for no or less antihypertensive medications, less intradialytic complications, better middle molecule and phosphate clearance, better nutritional status, less requirement for erythropoietin and increased survival. The main criticism of the concept of Tassin is that the patient loses a lot of time, since the 8-hour dialysis sessions are mainly performed during the day. This was the reason that this kind of dialysis is now offered in more and more centers during the night with the advantage of gaining free time by better dialysis.

Single-Center Experience with Dialysis Overnight

Since 1999, 18 patients have been dialyzed 3 times/ week for 8 h overnight in Straubing. Nine patients switched from 3 ! 5 h dialysis to 3 ! 8 h dialysis, 9 patients started directly with this form of dialysis. The dialysis regimen was the same as during standard dialysis using also high-flux membranes, blood flow between 200 and 350 ml/min and dialysate flow between 500 and

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800 ml/min. Blood pressure controls took place until the patients fell asleep. Table 1 summarizes the clinical and laboratory results of 9 patients 6 months after changing from standard dialysis to long dialysis therapy. Although only phosphate-binding agents on the basis of calcium were used, plasma phosphate was normalized in all patients after changing to long dialysis. Table 2 shows in the example of one single patient the improvement of calcium/phosphate metabolism 1 month after switching from standard dialysis to long dialysis. Erythropoietin could be reduced significantly from 61.2 B 21.2 to 42.0 B 17.6 U/kg/week. After 6 months the post-dialytic weight had slightly increased, the pre-dialytic MAP was significantly lowered and the antihypertensive medications were markedly reduced. In contrast to the data of Tassin, our patients were not free of antihypertensive drugs. An explanation for the different result could be that in Tassin the patients were far more compliant in terms of lower interdialytic weight gain and acceptance of lower sodium diet (!5 g sodium intake per day). Furthermore, it is the concept in Tassin to remove all antihypertensive drugs and reduce the ECV as far as possible independent of residual renal function. The policy of our center was to preserve residual renal function and accept few antihypertensive drugs by slightly higher ECV. Quality of life improved markedly after changing to the long dialysis overnight. The patients had better wellbeing, more free time by improved dialysis and less confrontation with the illness. After 1–3 weeks the patients were able to sleep well during the night dialysis session. Instead of a sleeping drug the patients received a glass of beer. Indications for this form of dialysis are patients with severe hypertension, hyperphosphatemia, cardiac insufficiency, elderly patients, patients with high body weight, anuric patients and employed patients.

Haag-Weber

Daily Hemodialysis

Daily HD is not new but the clinical results from studies of patients undergoing daily dialysis have rekindled the interest of these different dialysis schedules. The rationale for daily dialysis is that increased frequency of treatment more closely approximates normal kidney function than does weekly treatment by ‘smoothing the peaks and valleys’ of fluid and toxin accumulation. There are two main forms of delivery of daily HD: short daily HD and nocturnal HD performed overnight, both delivered 6 or 7 days/week [9]. Short Daily Hemodialysis Short daily HD involves dialysis for 90–180 min daily 6–7 days/week. Weekly dialysis treatment time with this method is comparable to standard dialysis. By using computer simulation, Gotch [10] and Clark et al. [11] calculated that short daily dialysis for 100 min 7 times weekly (700 min/week) provides 5% better equivalent renal urea clearance and 12% greater vitamin B12 clearance than a conventional regimen of 4 h 3 times weekly (720 min/ week). Both non-protein-bound uremic compounds such as uric acid, creatinine and urea and some protein-bound solutes such as indole-3-acetic acid, indoxyl sulfate and p-cresol were lower during short daily HD [11]. Furthermore, switching from standard dialysis to short daily dialysis was effective in lowering the concentration of all the measured glycation parameters [12]. The systematic use of short daily dialysis was instituted by Buoncristiani [14] and was used in several Italian centers. Recent attempts to use daily HD were also reported from the USA [15], the Netherlands [16] and elsewhere. Short daily dialysis was offered as in-center and home HD with and without dialysis partner. If no partner is available, patients are connected online with the dialysis center transferring main dialysis data like blood pressure, fluid removal, body weight and dialysis alarms. A blood flow of 250–400 ml/ min and dialysate flow of 500–800 ml/min were used. As dialysis access, central venous catheters and AV fistulas were used. The survival of the AV fistula even with daily double punctures was excellent and comparable to weekly standard dialysis [17, 18]. Nutrition Malnutrition is deemed one of the most important factors that may influence morbidity and mortality in ESRD patients. Therefore, it is quite impressive to see the universal normalization of serum albumin, increased protein intake by increased appetite and the maintenance or


increase in ideal body weight in these patients after switching from standard dialysis to short daily dialysis treatment [14–17, 19–21]. Galland et al. [20] demonstrated with a 3-day dietary record a spontaneous 24% increase in protein intake and 13% increase in calorie intake. There was also an increase of other nutritional parameters like pre-albumin, total cholesterol and transferrin. These changes were accompanied by an increase in dry body weight of 2.4 B 1.6 kg at 6 months and 4.2 B 2.8 kg at 1 year [19]. In our own center, 2 patients were switched from 3 ! 8 h to 6 ! 3 h dialysis. These patients had a body weight increase of 5 kg at 6 months. The cause for the improvement of nutritional status is due to improved appetite reported in all patients and documented in dietary interviews. This may be due to general wellbeing, minor post-dialysis fatigue, fewer dietetic rules, diminution in unpalatable medications, reduction of urea retention, less fluid overload with interdialytic weight gain decrease from 3.2 B 1.1 kg at baseline to 1.6 B 0.5 kg with daily dialysis. Other factors should be discussed, but are not yet proven: the diminution of protein metabolism disturbance due to more physiological treatment and a potential decrease in resistance to anabolic factors such as growth hormone, insulin, etc. Blood Pressure Control All the studies of patients undergoing short daily HD consistently reported improved blood pressure control [9, 14–17, 21]. There was a significant decrease of pre-dialytic MAP. In the majority of patients, antihypertensive drug therapy could be markedly reduced. Both Kooistra et al. [16] and Ting et al. [15] described an approximately 50% reduction of antihypertensive drugs. Fagugli et al. [22] found that 90% of the patients were free of antihypertensive drugs under short daily HD. This good blood pressure control was accompanied by left ventricular mass reduction and reversal of left ventricular hypertrophy [22]. Phosphate/Bone Disease Phosphate control improves on short daily HD. Although there is no good documentation in the literature [9], a lower dose of phosphate binders has been reported by Kooistra et al. [16]. Short daily dialysis did not lead to discontinuation of phosphate binders. In our center we could demonstrate in 2 patients a marked improvement of phosphate control even after switching from 3 ! 8 h to 6 ! 3 h dialysis regimen.


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Anemia Nearly all studies on short daily HD found a decrease in the erythropoietin dose of 30–50% [9, 14, 17]. Controversially, Kooistra et al. [16] did not find a reduction of erythropoietin dose. This could be due to a decrease of serum ferritin, possibly as a result of increased iron losses. Quality of Life All studies reported significant improvements of quality of life measured by different life quality questionnaires. A significant improvement was found in several parameters, including uremic and dialysis-related symptoms, mental and physical function, sexual function, social function and rehabilitation [9, 21]. Morbidity and Mortality Short daily HD improves many factors like blood pressure, anemia, nutrition, phosphate and quality of life which are associated with mortality. There are no controlled studies on morbidity and mortality comparing standard dialysis and short daily dialysis. The 2-year survival rate of the patients studied by Woods et al. [17], however, was excellent with 93%. A reduction in hospitalization of 30–80% was described in several studies with small patient numbers [21]. Daily Nocturnal Home Hemodialysis Nocturnal dialysis was started and further developed in Toronto [9]. It includes dialysis for 8–10 h nightly, 6–7 nights/week during sleep. Compared to standard dialysis, this form of dialysis provides beside the increased frequency marked elevation of weekly dialysis time and dose. In view of the hemodynamic stability, no partner was required. The patients are also connected online with the dialysis center, where the alarms are transferred. Blood flow has been maintained between 200 and 400 ml/min. Originally, dialysis flow was kept low at 100 ml/min to minimize the probability for overdialysis and deficiency syndromes. Since no deficiency syndrome has been identified, the flow has been increased up to 800 ml/min to provide excellent dialysis in patients of large body size. Initially only central venous catheters were used as dialysis access. It was assumed to be less prone to accidental disconnection. Meanwhile, 30% of the patients use AV fistula. Daily nocturnal dialysis provides excellent urea clearance, phosphate clearance and a fourfold increase of ß2microglobulin clearance [24]. Phosphate control was excellent. Patients discontinue phosphate binders usually

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within 1 week of initiation of nocturnal dialysis. Despite the increase in phosphate intake, several patients need phosphate addition into the dialysate. Phosphate removal is twice as a high as on conventional dialysis [25]. There was a decrease of calcium/phosphate product and PTH levels. Since the patients do not take any phosphate binders and therefore no calcium supplements, the dialysate calcium was increased to 1.75–2.25 mmol/l. Nutrition The improvement of the nutritional status in daily nocturnal dialysis is even more pronounced compared to short daily dialysis. Diet is completely free and patients are encouraged to maintain high phosphate and protein diet. Potassium, salt and water intake were also unrestricted. Despite the substantial loss of amino acids on nocturnal dialysis in the range of 10–15 g/day, there was an increase of plasma levels of essential and non-essential amino acids. Most patients were followed with total body nitrogen measurements and were found to be anabolic [23]. Blood Pressure Blood pressure control was excellent without the use of antihypertensive drugs. Only a few patients were on lowdose ß-blockers. Similar to the results of daily short HD, regression of left ventricular hypertrophy was also observed with daily nocturnal HD [26, 27]. Anemia At the beginning no reduction of erythropoietin was observed, which might be due to iron deficiency. Since patients now self-administer iron at home there has been a 40% decrease of erythropoietin [23]. Quality of Life All patients reported significant improvement in wellbeing and level of energy. These changes were apparent sometimes within days. Within months the patients reported softer skin, improved appetite and in many there was a disappearance of the uremic look. Quality-of-life questionnaires showed significant improvement of life in several of the measured parameters [23]. Sleep Tolerance of the dialysis during the night was very good. Within 1–2 weeks almost all patients and their spouses adjusted well and the presence of the dialysis machine did not seem to disturb their sleep. Nocturnal dialysis was able to significantly improve sleep apnea.

Haag-Weber

Sleep apnea is common in patients with chronic renal failure [28]. Patient Selection Patient selection criteria were not rigid. Any patient who could be trained for home HD was eligible. The presence of co-morbidities was not a contraindication [23]. Survival and Morbidity Although there are not enough data on hospitalization rate and patient survival, one would anticipate significant benefits in both areas. Pierratos [23] has data for 30 patients having 3.5 hospital days per patient-year.

Future Directions

Today, a variety of dialysis methods and regimens are offered to patients. There is convincing evidence that there are several benefits from long dialysis thrice weekly and daily short and nocturnal dialysis. This includes improvement in uremic and dialysis-related symptoms, hemodynamic stability, quality of life, nutritional status and blood pressure control. There is a need for lower dose of erythropoietin and less antihypertensive drugs. Possible advantages to be documented in the future are lower morbidity, hospitalization rates, mortality, as well as financial benefits. To attract more patients for home HD, a simplification of the dialysis process, with shorter time necessary for preparation of the equipment, should be developed.

References 1 Wolfe RA, Held PJ, Hulbert-Shearon TE, Agodoa LYC, Port FK: A critical examination of trends in outcomes over the last decade. Am J Kidney Dis 1998;32(suppl 4):9–15. 2 Hull AR: The 1989 morbidity and mortality meeting: How far have we come? Am J Kidney Dis 1998;32(suppl 4):6–8. 3 Lebedo I, Lameire N, Charra B, Locatelli F, Kooistra M, Kessler M, Jacobs J: Improving the outcome of dialysis – Opinion vs. scientific evidence. Nephrol Dial Transplant 2000;15: 1310–1316. 4 Charra B, Calemard E, Ruffet M, Chazot C, Terrat JC, Vanel T, Laurent G: Survival as an index of adequacy of dialysis. Kidney Int 1992; 41:1286–1291. 5 Laurent G, Charra B: The results of an 8 h thrice weekly hemodialysis schedule. Nephrol Dial Transplant 1998;13(suppl 6):125–131. 6 Charra B, Laurent G, Chazot C, Jean G, Terrat JC, Vanel T: Hemodialysis trends in time, 1989–1998, independent of dose and outcome. Am J Kidney Dis 1998;32(suppl 4):63–70. 7 Katzarski KS, Charra B, Luik AJ, Nisell J, Divino Filho JC, Leypoldt JK, Leunissen KM, Laurent G, Bergström J: Fluid state and blood pressure control in patients treated with long and short haemodialysis. Nephrol Dial Transplant 1999;14:369–375. 8 Luik AJ, van der Sande FM, Weideman P, Cheriex E, Kooman JP, Leunissen KML: The influence of increasing dialysis treatment time and reducing weight on blood pressure control in hemodialysis patients: A prospective study. Am J Nephrol 2001;21:471–478. 9 Pierratos A: Daily hemodialysis: Why the renewed interest? Am J Kidney Dis 1998;32 (suppl 4):76–82.


10 Gotch FA: The current place of urea kinetic modelling with respect to different dialysis modalities. Nephrol Dial Transplant 1998;13:10– 14. 11 Clark WR, Leypoldt JK, Henderson LW, Sowinsik KM, Scott MK, Mueller BA, Vonesh EF: Effect of changes in dialytic frequency, duration and flow rates on solute kinetics and effective clearances (abstract). J Am Soc Nephrol 1997;8:280. 12 Fagugli RM, De Smet R, Buoncristiani U, Lameire N, Vanholder V: Behavior of non-protein-bound and protein-bound uremic solutes during daily hemodialysis. Am J Kidney Dis 2002;40:339–347. 13 Floridi A, Antolini F, Galli F, Fagugli RM, Floridi E, Buoncristiani U: Daily hemodialysis improves indices of protein glycation. Nephrol Dial Transplant 2002;17:871–878. 14 Buoncristiani U, Quintaliani G, Cozzari M, Giobini LRM: Daily dialysis: long-term clinical metabolic results. Kidney Int 1988;24 (suppl 24):137–140. 15 Ting G, Freitas T, Saum N, Carrie B, Kjellstrand C: Early metabolic, hematological, clinical and life quality changes with daily hemodialysis (abstract). Perit Dial Int 1998;18(suppl 1):78. 16 Kooistra MP, Vos J, Koomans HA, Vos PF: Daily home haemodialysis in the Netherlands: Effects on metabolic control, haemodynamics, and quality of life. Nephrol Dial Transplant 1998;13:2853–2860. 17 Woods JD, Port FK, Orzol S, Buoncristiani U, Young E, Wolfe RA, Held PJ: Clinical and biochemical correlates of starting ‘daily’ hemodialysis. Kidney Int 1999;55:2467–2476. 18 Quintaliani G, Buoncristiani U, Fagugli R, Kuluiranu H, Ciao G, Rondini L, Lowenthal DT, Reboldi G: Survival of vascular access during daily and three times a week hemodialysis. Clin Nephrol 2000;53:372–377.

19 Galland R, Traeger J, Arkouche W, Cleaud C, Deawari D, Fouque D: Short daily hemodialysis rapidly improves nutritional status in hemodialysis patients. Kidney Int 2001;60:1555– 1560. 20 Galland R, Traeger J, Arkouche W, Delewari E, Fouque D: Short daily hemodialysis and nutritional status. Am J Kidney Dis 2001; 37(suppl 2):95–98. 21 Lacson E, Diaz-Buxo JA: Daily and nocturnal hemodialysis: How do they stack up? Am J Kidney Dis 2001;38:225–239. 22 Fagugli RM, Reboldi G, Quintaliani G, Pasini P, Ciao G, Cicconi B, Pasticci F, Kaufman JM, Buoncristiani U: Short daily hemodialysis: Blood pressure control and left ventricular mass reduction in hypertensive hemodialysis patients. Am J Kidney Dis 2001;38:371–376. 23 Pierratos A: Nocturnal home hemodialysis: An update on a 5-year experience. Nephrol Dial Transplant 1999;14:2835–2840. 24 Raj DSC, Ouwendyk M, Francoeur R, Pierratos A: ß2-Microglobulin kinetics in nocturnal hemodialysis. Nephrol Dial Transplant 2000; 15:58–64. 25 Musci I, Hercz G, Uldall R, Ouwendyk M, Frnacoeur R, Pierratos A: Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis. Kidney Int 1998;53:1399–1404. 26 Chan CT, Floras JS, Miller JA, Richardson RMA, Pierratos A: Regression of left ventricular hypertrophy after conversion to nocturnal dialysis. Kidney Int 2002;61:2235–2239. 27 Hörl MP, Hörl WH: Hypertension and dialysis. Kidney Blood Press Res 2003;26:76–81. 28 Hanly PJ, Pierratos A: Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 2001;344:102–107.


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Experience with the GENIUS® Hemodialysis System Winfried Fassbinder Klinikum Fulda, Medizinische Klinik III, Fulda, Germany

Key Words Hemodialysis W GENIUS® W GENIUS® hemodialysis system W Ultrapure dialysate W Individualized dialysis fluid

Abstract The late B. Tersteegen devised a clever way to combine the advantages of a closed tank hemodialysis system with the efficacy and bacteriological safety of a singlepass system. The Teerstegen equipment is now marketed as the GENIUS® hemodialysis system. For each treatment, fresh dialysis fluid is prepared according to the physician’s prescription by mixing sterile ingredients (electrolytes and glucose) with preheated ultrapure water. The total amount of dialysis fluid is put into a thermally insulated glass tank (volume 75 l) of the hemodialysis machine. The filling and emptying process is completely automated. An UV radiator is used for desinfection. Due to a consequent hygienic concept, the system operates with an almost sterile and usually pyrogen-free dialysis fluid. During treatment, fresh dialysis fluid is taken from the top of the system, and the used dialysate is returned to the bottom. There is a sharp interface between the fresh and used dialysis fluids because of a small difference in temperature (1 ° C). True volumetric ultrafiltration control is simply achieved; ultrafiltration

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© 2003 S. Karger AG, Basel 1420–4096/03/0262–0096$19.50/0



rates between 100 and 1,000 ml/h can be selected as considered appropriate by the physician. Microbiological examination: We cultured more than 2,000 dialysate specimens to examine bacterial contamination, and found either no bacterial growth at all (in the vast majority of the cases) or less than 1 CFU/ml dialysate. Clinical experience: We have utilized the GENIUS® system since 1994. Meanwhile, more than 40,000 treatments have been performed in our center. Biochemical results of the first 19 stable hemodialysis patients (mean age 66 years, range 45–82), who had been treated with conventional hemodialysis systems for at least 6 months (range 6– 157) before changing to GENIUS®, were evaluated. We observed an increase of mean serum albumin concentration from 4.1 (B0.4 SD) g/dl to 4.8 (B0.3) g/dl (p ! 0.01) within 6 months. Most patients reported improved wellbeing. Of these 19 patients, 18 preferred further treatment with the GENIUS® system in comparison to conventional hemodialysis machines. Conclusion: The GENIUS® hemodialysis system permits an individualized therapy of high quality; most patients prefer this system to conventional hemodialysis machines. Serum albumin levels increased significantly from normal to high normal values after change from conventional hemodialysis machines to GENIUS®, probably due to less catabolic stress during the hemodialysis sessions. Copyright © 2003 S. Karger AG, Basel

Prof. Dr. W. Fassbinder Klinikum Fulda, Medizinische Klinik III Pacelliallee 4, D–36043 Fulda (Germany) Tel. +49 661 845450, Fax +49 661 845452 E-Mail [email protected]

Introduction

It is not too frequent that radically new technical developments are established in the field of dialysis. It is therefore of great interest to observe that an innovative type of hemodialysis equipment, originally developed by the late B. Tersteegen (1939–1995), has been introduced in almost 100 dialysis centers in the last few years. Our center in Fulda has been the first user outside Düsseldorf, where the system was created. This article reports about the concept, background and our experiences since 1994.

The Batch versus the Single-Pass System

In the early years of hemodialysis, the batch systems and the single-pass systems competed with each other, and for a while it looked as if single-pass had succeeded in winning. Re-enter the batch system, resetting matters back to square one. History: It is of interest that the first hemodialysis systems were all batch systems. Before the dialysis session, dialysate was prepared by mixing warm water and electrolytes in a tank. Using an electric heater, the temperature of the dialysis fluid was kept constant during the treatment. A pump recirculated the isotonic fluid from the tank through the dialyzer and returned it to the tank thereafter, thus continuously mixing fresh and spent dialysate. As a consequence, the concentration of urea (and that of other uremic toxins, hypothetical or otherwise) increased steadily during the treatment period. Accordingly, the diffusion gradient, and thus the efficiency of dialysis, decreased progressively with time. Not only was the batch system less efficient, it also posed serious bacteriological problems. Bacterial overgrowth was common and shivering attacks of the patients during dialysis were not unheard of. To overcome these disadvantages of the batch or tank model, the concept of single-pass systems was developed, according to which freshly prepared dialysate went to waste after passing the dialyzer. By 1975, batch systems had been almost completely replaced by single-pass systems throughout Europe.

Fig. 1. The GENIUS® hemodialysis system.

The late B. Tersteegen devised a clever way to overcome the above-mentioned disadvantages of the tank system, while preserving its advantages. The undoubted

advantages of this system are the simplicity of design and the high flexibility with respect to dialysate composition. This system is today marketed under the trade name of GENIUS®. All the dialysate destined to be used during one treatment session is stored in an air-free 75-liter glass container which is completely filled with the dialysate as shown in figure 1. The walls of the container are transparent and provide thermal insulation so that a separate dialysate heater becomes unnecessary. Special two-lumen quartz glass tubes in the axis of the tank allow to access the top and bottom fluid compartments of the tank separately. To prevent bacterial growth, an UV radiator is located within this tube. How is dialysis carried out? Fresh dialysate is taken out of the top compartment of the tank via the axial tube using a roller pump. After the dialysate has passed through the dialyzer, the used dialysate is returned to the bottom compartment of the tank. With this ingeniously simple device, spent dialysate can be stored underneath the fresh dialysate. Because of a small difference in temperature (the spent dialysate is about 1 ° C cooler than the fresh dialysate), used and fresh dialysate do not mix, so

Hemodialysis System


The Tersteegen System, Now Marketed as GENIUS® Hemodialysis System

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that the system combines the simplicity of a batch system with the efficacy and bacteriological safety of a single-pass system. Recently the complete separation of fresh and spent dialysate has been confirmed in a detailed study [1].

Volume Control

Safety of dialysis requires strict monitoring of ultrafiltration. Volumetric fluid balancing of dialyzer inflow and outflow has gained wide acceptance. It is completely independent of dialyzer properties such as ultrafiltration coefficient or transmembrane pressure. Here again, the simple system devised by Tersteegen, consisting of a completely filled rigid tank, provides a simple, reliable and exact method of volumetrically balancing fluid: only fluid that has been generated by ultrafiltration of the patient can leave the system under the control of the ultrafiltration monitor. Ultrafiltration rates between 100 and 1,000 ml/h can be selected as considered appropriate by the physician.

Dry concentrates: Because the solutes used for the preparation of dialysate are mostly dry or filled up in sterile plastic bottles (500–1,000 ml), the risk of bacterial contamination (a known hazard of liquid concentrates), is largely eliminated. Connectors: The system does not use the standard coupling elements (like Hansen couplings), which introduce hygienic safety hazards in standard dialysis systems. UV irradiation: An integrated UV radiator suppresses bacterial growth. It is automatically in operation during the filling, emptying and cleaning steps. Materials and surfaces: Materials (mostly glass) and geometry (no sharp corners or dead spaces in the fluid paths) are designed to prevent accumulation of microorganisms and facilitate effective cleaning and disinfection. Closed system: The system is not opened during normal operation, so that contamination from the environment is impossible. Microbiological examinations: We cultured more than 2,000 dialysate specimens to examine bacterial contamination, and we found either no bacterial growth at all (in the vast majority of the cases) or less than 1 CFU/ml dialysate. The excellent hygienic properties of the system have also been documented by Lonnemann et al. [3].

Bacteriological Safety

One of the most impressive aspects of the system is its bacteriological safety. Contamination of the dialysate by bacteria and endotoxin has plagued dialysis from the very beginning. Alarmed by the high frequency of pyrogenic reactions during hemodialysis, the Association for the Advancement of Medical Instrumentation (AAMI) issued guidelines in 1991 to limit acceptable values of bacterial contamination to 200 colony-forming units (CFU) per milliliter in incoming water, and 2,000 CFU/ml in dialysate, respectively. With respect to endotoxin concentration, a maximum limit of 5 IU was proposed for water. So far, no consensus has emerged concerning acceptable endotoxin burden in the dialysate. Why is a sterile and endotoxin-free dialysate so important? Bacterial products are thought to be responsible for some long-term complications of dialysis. Accordingly, Shaldon and Koch [2] stated that ultrapure dialysate was every bit at least as important as the biocompatibility of the membrane. The system of Tersteegen provides ideal hygienic properties because several factors could be combined in its design: Ultrapure water: This is essential to produce sterile and pyrogen-free dialysate.

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The Clinical Experience

If one believes in the importance of ultrapure dialysate, of individualized dialysate electrolyte composition and of ultrafiltration control, one will not be surprised to see that in the uncontrolled series of Kleophas et al. [4] a rate of long-term patient survival was observed which was about 10–20% higher than in other published series, e.g. the EDTA Registry data. Adequate nutrition and perhaps absence of a microinflammatory state is suggested by the observation that serum albumin levels are about 1 g/dl higher than those described by Lowrie and Lew [5]. The finding of an extremely low cumulative incidence of the carpal tunnel syndrome, i.e. less than 10% of patients treated for more than 10 years using the GENIUS® system, is reminiscent of the report of Baz et al. [6]. They also observed an impressively low rate of, and delayed onset of, carpal tunnel syndrome in hemodialysis patients who had been dialyzed using ultrapure dialysate throughout. We have utilized the GENIUS® system since 1994 in 19 stable hemodialysis patients who had been treated with conventional hemodialysis systems for at least 6 months (range 6–157). Their mean age was 66 years (range 45– 82). We observed an increase of mean serum albumin

Fassbinder

concentration from 4.1 (B 0.4 SD) g/dl to 4.8 (B 0.3) g/dl (p ! 0.01) within 6 months. The patients reported improved well-being, although this is difficult to verify in the absence of a blinded control. However, 18 of these 19 patients preferred further treatment with the GENIUS® system in comparison to conventional hemodialysis machines.

The Main Advantages of the System

Apart from the unique bacteriological qualities and the provision of simple but effective volume control, another important advantage has to be pointed out, namely that it provides extreme flexibility in adapting the composition of the dialysate to the patients’ needs by permitting individualized dialysate composition. Such flexibility can never be reached using standardized concentrates. The addition of ultrapure and bacteriologically safe components further provides therapeutic quality that is beyond the possibilities of standard dialysis machines. Beside its classical field of application, GENIUS® is used more and more in intensive care units for the treatment of acute renal failure [7, 8]. Here the inherent mobility of the system allows its application without requiring a technical infrastructure in the ward. The good hygienic properties

are advantageous here as well. Additionally, there are important economic advantages in comparison to the use of hemofiltration solutions.

Outlook

Recently the machine has been technically redesigned without violation of the classical concept. An increased tank volume of 90 l supports the delivery of an adequate dose of dialysis also for very heavy patients. The introduction of a blood leak detector is welcome, e.g. for long overnight treatments. At this point in time, it is difficult to make predictions about the perspectives of this dialysis modality in the future. Currently there are two opposing trends, one to ever more sophisticated systems with elaborate monitoring and closed-loop systems; on the other hand, there is the trend to adopt simple technologies, to go back to the roots so to speak. Such simplified systems might not only reduce cost, simplify logistics and render it more easy to adopt dialysis sessions of longer duration, but may also permit more widespread use of innovative procedures such as daily home hemodialysis. It is in the latter context that the batch system devised by Tersteegen may have an important role to play.

References 1 Dhondt A, Vanholder R, De Smet R, et al: Studies on dialysate mixing in the GENIUS® single-pass batch system for hemodialysis therapy. Kidney Int 2003;63:1540–1547. 2 Shaldon S, Koch K: Biocompatibility in hemodialysis: Clinical relevance in 1995. Artif Organs 1995;19:395–397. 3 Lonnemann G, Dumann H, Schmidt-Gürtler H: Improved dialysate quality is associated with decreased whole blood cytokine production in ESRD patients on the Genius® hemodialysis system. Blood Purif 1997;15:6.

Hemodialysis System

4 Kleophas W, Haastert B, Backus G, et al: Longterm experience with an ultrapure individual dialysis fluid with a batch-type machine. Nephrol Dial Transplant 1998;13:3118–3125. 5 Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate difference between facilities. Am J Kidney Dis 1990;5:458–482. 6 Baz M, Durand C, Ragon A, et al: Using ultrapure water in hemodialysis delays carpal tunnel syndrome. Int J Artif Organs 1991:14:681– 685.

7 Lonnemann G, Bechstein M, Linnenweber S, et al: Tumor necrosis factor-· during continuous high-flux hemodialysis in sepsis with acute renal failure. Kidney Int 1999;56(suppl 72):84–87. 8 Lonnemann G, Floege J, Kliem V, et al: Extended daily veno-venous high-flux haemodialysis in patients with acute renal failure and multiple organ dysfunction syndrome using a single-pass batch dialysis system Nephrol Dial Transplant 2000;15:1189–1193.


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Vitamin C in Chronic Kidney Disease and Hemodialysis Patients Robert Deicher Walter H. Hörl Universitätsklinik für Innere Medizin III, Klinische Abteilung für Nephrologie und Dialyse, Wien, Österreich

Key Words Vitamin C W Oxidative stress W Chronic kidney disease

Abstract Increments of oxidative stress have been addressed as one potential cause for the accelerated atherosclerosis of chronic kidney disease patients. Ascorbate represents one of the most prominent antioxidants both in plasma as well as intracellulary, exerting beneficial effects by an inhibition of lipid peroxidation and by reducing endothelial dysfunction. However, in the presence of transition metals like iron, ascorbate may give rise to an increased generation of oxidants, and ascorbylation may impose additional carbonyl stress to uremic patients. Unsupplemented dialysis patients have reportedly lower plasma levels of ascorbate in comparison to healthy controls, mostly due to a loss into the dialysate or, in case of not dialyzed patients, increased urinary losses. Currently, 60 mg of ascorbate are recommended for chronic kidney disease patients, and 1–1.5 g of oral ascorbate/week in case of suspected subclinical ascorbate deficiency or 300 mg parenteral ascorbate/dialysis session, respectively. Ascorbate’s role in modifying arterial blood pressure remains unclear, but anemic patients with functional iron deficiency might benefit from short-term, moderately dosed ascorbate supplements.

Introduction

Mortality due to cardiovascular disease is 10–20 times higher in dialysis patients than in the general population [1]. The annual mortality rate of young dialysis patients (25–34 years of age) equals that of general population cohorts in their 9th decade of life [1]. This excessive mortality has in part been attributed to a higher prevalence of classic risk factors including older age, hypertension, hyperlipidemia, diabetes and physical inactivity. Specific risk factors like hemodynamic and metabolic factors add to the ‘highest risk’ status of patients with chronic kidney disease, among others increments of oxidative stress have been implicated in the accelerated progression of atherosclerosis in uremic patients [2, 3]. Oxidants affect the early formation of fatty streaks in the arterial intima, the subsequent thickening of the intimal and medial wall and, probably, the terminal endpoint plaque destabilization and rupture [4]. Ascorbate is one of the most important water-soluble antioxidants in plasma [5]. A recent prospective large-scaled study in the UK on the relation between plasma ascorbate concentrations and mortality found only half the risk of mortality due to all causes for those with plasma ascorbate levels in the upper quintile in contrast to those with plasma levels in the lowest quintile [6]. Similar results have been reported in the 12-year follow-up of the second National Health and Nutrition

Copyright © 2003 S. Karger AG, Basel

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Robert Deicher, Universitätsklinik für Innere Medizin III Klinische Abteilung für Nephrologie und Dialyse Währinger Gürtel 18–20, A–1090 Wien (Austria) Tel. +43 1 40400 4391, Fax +43 1 40400 4392 E-Mail [email protected]

Examination Survey [7]. Several studies documented an inverse relation between plasma ascorbate concentrations and the increased risk for atherosclerosis [8–10]. Low plasma ascorbate concentrations render maintenance hemodialysis patients who smoke more susceptible to oxidative tissue damage than their non-smoking counterparts or healthy subjects [11]. In contrast, randomized clinical trials data regarding the role of the antioxidant vitamins in the prevention of cardiovascular diseases remained inconclusive [12]. However, results may have been biased by wrong selection of patient population [4, 13], use of secondary prevention endpoints as for instance ‘major vascular events’ in high-risk individuals [14], choice of antioxidants or lack of inclusion of biochemical markers of oxidative stress and of vascular response. Ascorbic acid bears two ionizable hydroxyl groups, at physiological pH formation of the mono-anion termed ascorbate is favored. Ascorbate is readily oxidized [15] to form dehydroascorbic acid (DHA). DHA is unstable at physiological conditions, it may either be recycled to ascorbate by glutathione-dependent regeneration systems, or hydrolyses to an open-chained derivative which undergoes further fragmentation to oxalate and others. Ascorbate exerts antioxidant, pro-oxidant and further effects as a cofactor for several enzymes such as prolyl and lysl hydroxylases which participate in collagen synthesis.

Direct Antioxidant Effects of Ascorbate

Ascorbate acts by reducing other molecules, mostly transition-metal ions like ferric iron (Fe3+) and copper, either at the active site of enzymes or as free ions. Ascorbate scavenges diverse radicals (superoxide, hydroxyl, peroxyl, thiyl, oxysulfur, nitroxide, nitrogen dioxide, drug-derived and uric acid-derived radicals) as well as non-radical reactive species (singlet oxygen, hypochlorus acid, peroxynitrous acid, ozone), and it effectively inhibits lipid peroxidation in plasma and cellular membranes, partly in cooperation with vitamin E [16]. Intracellulary, ascorbate serves as the primary antioxidant together with glutathione [17] and recent evidence points to a regulatory role of ascorbate on cytokine-dependent redox-signal transduction [18].

Vitamin C and Renal Failure

Pro-Oxidant Effects of Ascorbate via Reduction of Cellular, Free Iron

Free-radical oxidation of lipids, nucleic acids and proteins can effectively be stimulated by mixtures of iron salts and ascorbate in vitro. Oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+) in the presence of hydrogen peroxide gives rise to the highly reactive hydroxyl radical. Ascorbate readily recycles iron to its reduced form, iron may thus continuously generate reactive oxygen species that attack and oxidatively damage cellular targets. Free, i.e. chelatable, cytoplasmic iron constitutes up to 3% of total cellular iron, the major part of which is in the reduced, ferrous state [19]. The availability of intracellular reducing equivalents such as ascorbate and glutathione appears to have an important impact on cellular injuries mediated by reactive oxygen species and/or redox active iron [20, 21]. Nephrotoxicity of cyclosporine has been attributed to the enhanced formation of free radicals. Ascorbate-induced lipid peroxidation was reported to increase in cyclosporine A-administered rats [22]. In kidney cortex mitochondria and microsomes, ascorbate was observed to increase cyclosporine A-induced lipid peroxidation and viability loss similar to the effect of ferrous iron [23]. However, pro-oxidant effects of ascorbate are not necessarily deleterious: accelerated DNA repair activity has been suggested to be induced by short-term co-supplementation of ascorbate plus a Fe(II)-salt to healthy volunteers [24].

Carbonyl Stress by ‘Ascorbylation’

Non-enzymatic oxidation and glycation reactions of carbohydrates, proteins and lipids have been reported in chronic kidney disease patients and advanced oxidation and glycation end-products have been made responsible for the acceleration of atherosclerotic lesions. Following autoxidation of ascorbate the accumulation of aldeyhdes capable of modifying proteins via the Maillard reactions have been observed. In particular, ‘ascorbylation’ of proteins has been described in diabetes [25], cataract formation [26] and end-stage renal disease [27]. Dehydroascorbate (DHA) is a potent glycation agent [28], and plasma levels of DHA correlate with protein linked pentosidine in hemodialysis patients [27]. However, serum concentrations of advanced glycation end-products do not constitute an independent risk factors for the development of cardiovascular events or left ventricular hypertrophy in chronic kidney disease patients [29].


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Ascorbate Ameliorates Endothelial Dysfunction

Endothelial dysfunction supports the progression of atherosclerosis by promoting vasoconstriction, enhancing platelet aggregability, leukocyte adhesion and smooth muscle cell proliferation. Endothelial dysfunction largely results from a loss of nitric oxide biological activity and/or biosynthesis, and is related to increased oxidant stress [30]. Prospective controlled trials on the effect of chronic antioxidant use on endothelial dysfunction produced both positive and negative results, most likely due to nitric oxide dependency of conduit vessel but not resistance vessel function [31]. In renal allograft recipients high-dose ascorbate acutely improved flow-mediated, endotheliumdependent dilatation of the brachial artery, probably in response to a decrease of oxidant stress as indicated by an increased resistance of serum lipoproteins to oxidation [32]. Endothelial dysfunction of the renal vasculature has been described in experimental hypercholesterolemia, both in vitro and in vivo [33, 34]. Chronic antioxidant supplementation to hypercholesterolemic pigs (vitamin E plus ascorbate) reduced lipoprotein oxidizability, normalized endothelium-dependent relaxation of the renal artery, improved renal vascular smooth muscle response to exogenous nitric oxide, and restored stimulation-dependent increments of renal blood flow [35]. To date, convincing evidence for a beneficial effect of long-term antioxidant use on the progression of atherosclerosis in renal or cardiac vasculature is lacking. Although long-term supplementation of ascorbate alone or co-supplementation of ascorbate plus vitamin E reduced oxidative stress parameters in chronic heart failure or coronary artery disease patients, alterations of endothelial function did not correlate with such reductions [36, 37]. 500 mg of ascorbate together with 400 IU retarded the early progression of cardiac arteriosclerosis in cardiac transplant recipients after 1 year follow-up [38]. However, the observed benefit occurred through a decrease of plaque growth rather than less progressive endothelial dysfunction. Plaque growth and rupture depend on the oxidant state [4], but lipid peroxidation was not analyzed in this study [38]. Ascorbate might improve endothelial cell function by stabilizing intracellular tetrahydrobiopterin, an essential cofactor of nitric oxide synthases. In mice, ascorbate treatment increased vascular levels of tetrahydrobiopterin, restored endothelial nitric oxide synthase activity, improved endothelial dysfunction and reduced atherosclerotic lesions [39].

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Ascorbate in Chronic Kidney Disease Patients

Chronic kidney disease patients are at high risk for ascorbate deficiency. Most studies relying on specific and sensitive HPLC methods documented lower than normal plasma ascorbate concentrations in non-supplemented, hemodialyzed patients [40–43], that further decline with age [42] as has been observed in the general population [44]. The dietary intake was found below the recommended daily dose in Brazilian children on dialysis [45], or below that of matched controls in Indian end-stage renal disease patients [46]. In healthy subjects, 100 mg of ascorbate/day produce average plasma levels of about 60 Ìmol/l [47], higher levels might pose at risk for increased oxidative DNA damage [24]. 200 mg/day almost maximize plasma and lymphocyte levels [47]. In developed countries mean daily ascorbate intake ranged from 62 mg/day in chronic renal failure patients, to 80–84 mg/ day in dialysis patients, to 161–189 mg/day in renal transplant recipients [48–50], indicating appropriate ascorbate intake yielding plasma levels of 62–80 Ìmol/l [48]. Mean reference values of healthy, non-smoking, middle-aged European residents of five countries not on vitamin supplements were estimated as 54 Ìmol/l for males (95% confidence interval 52–57) and 64 Ìmol/l for females (95% confidence interval 61–67) [51]. Predialysis plasma ascorbate levels increased 160 Ìmol/l in 4 out of 7 dialysis patients after 2 weeks of 200 mg oral ascorbate/day [41]. Furthermore, plasma concentrations of malondialdehyde were higher in vitamin-supplemented dialysis patients (mean plasma ascorbate concentration 34 Ìmol/l) when compared to matched controls or nonsupplemented dialysis patients [40]. In a cross-sectional analysis of our hemodialysis population (University Hospital of Vienna, Austria) plasma malondialdehyde levels did not correlate with plasma ascorbate concentrations (fig. 1). Currently, 60 mg of oral ascorbate are recommended for chronic kidney disease patients [53]. In the case of suspected subclinical ascorbate deficiency (as might be in patients that are hyporesponsive to exogenous erythropoietin, see below) 1–1.5 g of oral ascorbate/week for chronic kidney disease patients or 300 mg of parenteral ascorbate/ dialysis session are recommended [54]. These doses are considered safe for up to 8 weeks with respect to the danger of secondary oxalosis [55]. Chronic kidney disease patients lose ascorbate excessively due to its water solubility. Furosemide increases urinary excretion of ascorbate [56], ascorbate clearance is increased in diabetic nephropathy in comparison to only

Deicher/Hörl

Fig. 1. Spearman rank order correlation be-

tween plasma malondialdehyde and ascorbate (n = 134, R = 0.14, p = 0.1). Both parameters were assayed by HPLC (malondialdehyde according to Fukunaga et al. [52], ascorbate using a commercial kit from Immundiagnostik, Germany). Analysis included all hemodialysis patients during a 4-month observational period in 2001 at the University Hospital of Vienna, Austria, with a median age of 61 years (interquartile range 48–71), 87 males (65%), median time on dialysis of 21 months (interquartile range 11–36), median hemoglobin level of 12.2 g/ dl (interquartile range 11.2–12.8 g/dl), including 29 diabetes mellitus patients (22%).

microalbuminuric diabetes patients [57], and ascorbate is freely filtered and lost into the dialysate. Plasma levels are reduced by 33–50% during hemodialysis [40, 41, 49] or hemodiafiltration, mounting to an estimated loss of 200 mg/week [43]. Theses losses are accompanied by increments of oxidant stress parameters. Malondialdehyde, indicative of lipid peroxidation, advanced oxidation protein products [43] and DHA [58, 59], the oxidation product of ascorbate, were observed to increase during one dialysis session, plasma gluthatione peroxidase activity decreased [43]. It is of note that DHA concentration peaked during cuprophane dialysis in parallel to the leukocyte nadir [40] suggesting increased oxidation of ascorbate by neutrophil-derived oxidants.

Plasma concentrations of DHA in hemodialyis patients were reported to be lower [42, 58] or in the same range [60] when compared to controls, were shown to correlate with concentrations of lipid peroxide in hemodialysis patients [42], and the ratio of DHA/ascorbate was reported elevated [61] or low [42] in comparison to controls. DHA competes with glucose for cellular uptake by facilitative glucose transporters, ascorbate is taken up via sodium-dependent transport proteins. The cytosolic concentration of DHA is kept low by immediate reduction to ascorbate by NADPH, glutathione and other thiols. DHA

thus oxidizes NADPH and glutathione intracellularly, but subsequently stimulates the pentose phosphate pathway to produce NADPH and glutathione above basal levels [62]. Continuous reduction of DHA increases cellular ascorbate stores to levels 10–100 times higher than plasma concentration depending on the cell type. Insulin was observed to increase DHA uptake [63], high levels of blood glucose as in poorly controlled diabetes theoretically decrease DHA uptake by 30–80% [64]. Slowing of DHA uptake may render cells that primarily rely on DHA uptake such as some cells of the kidney and intestine [65] with an impaired antioxidant capacity. Consequently, the development of diabetic nephropathy has in part been attributed to the exclusion of DHA from cellular uptake resulting in a disturbed intracellular redox homeostasis [64]. Deficient regeneration of ascorbate from DHA may contribute to the development of osteopenia since ascorbate is a cofactor for collagen synthesis by osteoblasts [63]. Plasma ascorbate levels of diabetic subjects are reduced by at least 30% in comparison to healthy controls [66] and mononuclear cell levels were significantly lower in type 1 diabetes [67]. However, the latter did not differ between subjects with long-term complications and subjects without [67]. In streptozocin diabetic rat treatment with ascorbate resulted in markedly increased plasma and renal cortical ascorbate concentrations, prevented increments in glomerular volume and in albumin clearance when compared to untreated controls [68]. Accordingly, 1.25 g of



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oral ascorbate plus 680 IU of vitamin E given daily for 4 weeks lowered urinary albumin excretion rate by 19% in microalbuminuric type 2 diabetes patients in a doubleblind, randomized cross-over trial [69]. Mean plasma ascorbate concentration raised from 42 to 79 Ìmol/l at the end of the intervention period, a value at risk of oxidative DNA damage [24].

Ascorbate and Blood Pressure

Numerous trials have been conducted to evaluate the relation between ascorbate intake or plasma ascorbate concentrations and blood pressure. Recent reviews concluded that, to date, observational data do suggest an inverse association between ascorbate intake or plasma ascorbate concentration and blood pressure [70]. However, there is no convincing evidence from the few randomized controlled trials that one single nutrient like ascorbate can affect blood pressure regulation [71]. The DASH study [72] reported significant reductions of blood pressure with a combination of foods that contained 266 mg ascorbate/day in contrast to 133 mg/day. Ascorbate thus appears as only one important nutrient among and/or in concert with others.

Ascorbate in Functional Iron Deficiency

mentation [55]. Nevertheless, moderately dosed ascorbate supplements are recommended in the setting of functional iron deficiency [53, 78].

Conclusions

Oxidative stress may in part explain the excessive cardiovascular mortality among chronic kidney disease patients. Ascorbate is a potent antioxidant both in plasma and intracellularly. In the presence of transition metals like iron, pro-oxidant effects might result in an extra oxidative damage, and ascorbylation might contribute to the carbonyl stress of uremia. Ascorbate is readily oxidized to DHA. Although the exact role of DHA in cellular metabolism remains to be determined, a reduced cellular uptake of DHA in the presence of high blood glucose levels may leave the intracellular redox balance of susceptible cells shifted towards a more oxidizing setting. Ascorbate plasma concentrations are low in unsupplemented dialysis population. Estimated intakes range between 62 and 189 mg/day, close to the recommended daily intake of about 60 mg. Increased water diuresis, osmotic diuresis and loop diuretics all increase urinary ascorbate losses. About 200 mg of ascorbate are lost via the dialysate/week. Ascorbate deficiency might impede iron utilization by the erythron. Excessive supplementations should be avoided in light of the resulting risk of secondary oxalosis.

Ascorbate may increase iron absorption and mobilization from inert tissue stores, and may improve iron utilization in the erythron [73]. Ascorbate supplements might therefore improve effectiveness of exogenous erythropoietin, in particular in patients with high serum ferritin concentrations but low saturation of transferrin, so-called functional iron deficiency. Studies on mostly iron-overloaded [55, 74–76] or functionally iron-deficient [77] dialysis patients reported intravenous ascorbate to improve erythropoiesis in some patients: those with a transferrin saturation !25% in the presence of replete iron stores, those with erythrocyte zinc protoporphyrin 1105 Ìmol/ mol heme, or those with hypochromic red cells 110% responded partially by a raise in hemoglobin concentration. However, efficacy of ascorbate supplementation was only observed for the short treatment period [55] and anemia worsened immediately after discontinuation of ascorbate [55, 74]. Plasma ascorbate levels were considered normal at the beginning of the trial [74], did not differ between responders and non-responders at baseline and rose in a similar manner in both groups during supple-

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Deicher/Hörl

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68 Craven PA, DeRubertis FR, Kagan VE, Melhem M, Studer RK: Effects of supplementation with vitamin C or E on albuminuria, glomerular TGF-ß and glomerular size in diabetes. J Am Soc Nephrol 1997;8:1405–1414. 69 Gaede P, Poulsen HE, Parving HH, Pedersen O: Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in type 2 diabetic patients. Diab Med 2001;18:756–760. 70 Ness AR, Chee D, Elliott P: Vitamin C and blood pressure: an overview. J Hum Hypertens 1997;11:343–350. 71 Svetkey LP, Loria CM: Blood pressure effects of vitamin C: what’s the key question? Hypertension 2002;40:789–791. 72 Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GH, Vogt TM, Cutler JA, Windhauser MM, Lin PH, Karanja N, for the DASH-Collaborative Research Group: A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997; 336:1117–1124. 73 Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure: European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 1999;14(suppl 5):1– 50. 74 Gastaldello K, Vereerstraeten A, Nzame-Nze T, Vanherweghem JL, Tielemans C: Resistance to erythropoietin in iron-overloaded haemodialysis patients can be overcome by ascorbic acid administration. Nephrol Dial Transplant 1995;10(suppl 6):44–47. 75 Tarng DC, Huang TP: A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload. Nephrol Dial Transplant 1998; 13:2867–2872. 76 Sezer S, Ozdemir FN, Yakupoglu U, Arat Z, Turan M, Haberal M: Intravenous ascorbic acid administration for erythropoietin-hyporesponsive anemia in iron loaded hemodialysis patients. Artif Organs 2002;26:366–370. 77 Giancaspro V, Nuzziello M, Pallotta G, Sacchetti A, Petrarulo F: Intravenous ascorbic acid in hemodialysis patients with functional iron deficiency: a clinical trial. J Nephrol 2000;13: 444–449. 78 Ziai F, Habicht A, Bieglmayer C, Deicher R, Hörl WH: Erythropoetin-Bedarf in Abhängigkeit vom Vitamin-C-Status bei Hämodialysepatienten (abstract). Nieren- und Hochdruckkrankheiten 2002;31:437.

Deicher/Hörl



Angiogenin: A Novel Inhibitor of Neutrophil Lactoferrin Release during Extracorporeal Circulation Sabine Schmaldienst a André Oberpichler b Harald Tschesche b Walter H. Hörl a a Division

of Nephrology, Department of Medicine, University of Vienna, Austria; b Department of Biochemistry, Faculty of Chemistry, University of Bielefeld, Germany

Key Words Hemodialysis W Hemodiafiltration W Polymorphonuclear leukocytes W Elastase

Abstract Degranulation of polymorphonuclear leukocytes (PMNL) occurs during extracorporeal circulation. A degranulation-inhibiting protein identical to angiogenin was recently isolated from high-flux dialyzer ultrafiltrate. This protein inhibits the release of lactoferrin and metalloproteinases from PMNL in vitro. In the present study, we investigated end-stage renal disease patients undergoing regular hemodialysis treatment with either high-flux dialyzers (n = 51) or low-flux dialyzers (n = 44), and chronically uremic patients undergoing hemodiafiltration (n = 30). Hemodialysis therapy with low-flux polysulfone or cellulose triacetate membranes caused no or only minimal reduction (^8%) of plasma angiogenin levels within 2 h of dialysis treatment associated with a 1.6-fold lactoferrin release from PMNL. Hemodialysis therapy with high-flux membranes (e.g. cellulose triacetate, polymethylmethacrylate) or hemodiafiltration resulted in a reduction of plasma angiogenin levels by 20–40% after

ABC

© 2003 S. Karger AG, Basel 1420–4096/03/0262–0107$19.50/0



2 h associated with a nearly 4-fold PMNL lactoferrin release. The release of PMNL elastase was not affected by the different treatment modalities used. We conclude that high angiogenin plasma levels protect against lactoferrin release from PMNL during extracorporeal circulation in chronically uremic patients. A decrease of plasma angiogenin between 20 and 40% during extracorporeal circulation, however, results in marked PMNL lactoferrin release. This novel mechanism may explain, at least in part, PMNL degranulation also in non complement activating high-flux membranes. Copyright © 2003 S. Karger AG, Basel

Introduction

Complement activation occurs during extracorporeal circulation [1]. In addition, there is activation of polymorphonuclear leukocytes (PMNL) during hemodialysis treatment [2]. Both complement activation and granulocyte activation depend on the dialyzer membrane material. Therefore, complement fragments and different PMNL parameters have been widely used as markers for dialyzer bioincompatibility [3–7]. There are complement-

Walter H. Hörl, MD, PhD, FRCP, Professor of Medicine Medizinische Universitätsklinik III Währinger Gürtel 18–20 A–1090 Wien (Austria) Tel. +43 1 40400 4390, Fax +43 1 40400 4392, E-Mail [email protected]

dependent and complement-independent PMNL activation pathways that occur during extracorporeal circulation. Reactive oxygen species production depends on complement activation. Degranulation of neutrophils is a typical complement-independent reaction. The release of granulocyte constituents such as elastase or lactoferrin has been observed during hemodialysis therapy independent of complement activation [7–9]. The mechanisms involved in PMNL degranulation are not fully understood. Intracellular calcium ions, however, play a major role. It has been shown that treatment with calcium channel blockers reduces the release of elastase or lactoferrin [10]. Hemodialysis treatment using citrate as an anticoagulant removes calcium in the extracorporeal circuit therapy blocking the release of lactoferrin [11] or myeloperoxidase [12] from PMNL. PMNL obtained from uremic individuals fail to elicit an increase in lactoferrin release after stimulation with the chemotactic peptide f-Met-Leu-Phe as compared to PMNL obtained from healthy volunteers [13]. Recently, a PMNL degranulation inhibitory protein (DIP) identical to angiogenin (molecular weight 14,400 daltons) has been isolated and characterized from ultrafiltrate of end-stage renal disease patients undergoing regular hemodialysis treatment with high-flux dialyzers. In vitro, this protein inhibits the release of lactoferrin or of the metalloproteinases collagenase and gelatinase from isolated PMNL [14]. The biological function of this protein under in vivo conditions has not been investigated thus far. Therefore, the aim of the present study was (1) to investigate whether high-flux dialyzers reduce DIP plasma levels as compared to low-flux dialyzers during regular hemodialysis treatment, (2) to determine whether changes in DIP plasma levels affect degranulation of PMNL during regular hemodialysis treatment, and (3) to compare the effects of high-flux hemodialysis therapy and hemodiafiltration on DIP plasma levels and PMNL degranulation.

Material and Methods Patients All clinical investigations described were conducted in accordance with the guidelines proposed in the Declaration of Helsinki. Informed consent was obtained from all patients studied. 125 endstage renal disease patients undergoing regular hemodialysis or hemodiafiltration treatment were investigated. None of the patients had clinical signs or symptoms of infection. The patients were subdivided into several groups.

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Group I consisted of 51 end-stage renal disease patients (22 female, 29 male), aged 52.3 B 2.3 years (mean values B SEM), with a range between 20 and 82 years, undergoing regular bicarbonate hemodialysis for 30.1 B 5.5 months (range 1–216 months). This group of patients was dialyzed with high-flux dialyzers made of polysulfone (F60, Fresenius, Bad Homburg, Germany), cellulose triacetate (N210, Nissho Corp., Osaka, Japan) or polymethylmethacrylate (BK2.1, Toray, Tokyo, Japan). Mean Kt/V was 1.30 B 0.03. Group II consisted of 44 end-stage renal disease patients (25 female, 19 male), aged 57.6 B 2.5 years (mean values B SEM), with a range between 21 and 87 years, undergoing regular bicarbonate hemodialysis for 27.2 B 5.2 months (range 2–194 months). This group of patients was dialyzed with low-flux dialyzers made of polysulfone (F6, Fresenius) or cellulose triacetate (Sure-flux N150E GA, Nissho Corp.). Mean Kt/V was 1.38 B 0.04. Group III consisted of 30 end-stage renal disease patients (10 female, 21 male), aged 54.0 B 2.6 years (mean values B SEM), with a range between 31 and 85 years, undergoing regular hemodiafiltration for 42.8 B 4.8 months (range 2–105 months). This group of patients was treated with high-flux dialyzers made of polysulfone (Fresenius), cellulose triacetate (Nissho Corp.) or polymethylmethacrylate (Toray). Mean Kt/V was 1.34 B 0.04. Fourteen healthy subjects, aged 28.4 B 0.5 years, served as the control group. The mean angiogenin plasma level of this population was 234.1 B 10.9 ng/ml. Assays Measurements were taken after each patient had been dialyzed for a minimum of 1 month with the designated procedure. Blood samples were taken immediately before and 2 h after the start of hemodialysis or hemodiafiltration treatment. Plasma angiogenin values were determined using a highly sensitive immunoenzymometric assay described by Bläser et al. [15]. Lactoferrin was quantified by a sandwich-type enzyme-linked immunosorbent assay according to Bergmann et al. [16]. Elastase in complex with ·1-proteinase inhibitor was assayed by a commercially available ELISA (Merck, Darmstadt, Germany). Statistics Statistical analysis was performed using Student’s t test.

Results

In the present study, 125 patients undergoing regular hemodialysis treatment or hemodiafiltration were investigated. Plasma angiogenin levels of all end-stage renal disease patients decreased significantly from 713.7 B 35.2 ng/ml at the beginning of treatment to 597.4 B 23.9 ng/ml (p ! 2 ! 10 –8) after 2 h of hemodialysis or hemofiltration. Plasma lactoferrin levels increased from 177.4 B 13.1 to 448.2 B 58.8 ng/ml (p ! 0.000004) and plasma elastase in complex with ·1-proteinase inhibitor increased from 41.3 B 3.76 to 80.7 B 7.7 ng/ml (p ! 0.0000008). These patients were subdivided as described above.

Schmaldienst/Oberpichler/Tschesche/Hörl

Fig. 1. Plasma levels of angiogenin, lactoferrin and elastase in com-

Fig. 2. Plasma levels of angiogenin, lactoferrin and elastase in com-

plex with ·1-proteinase inhibitor before (0 h) and after 2 h of hemodialysis therapy using different high-flux dialyzers (n = 51).

plex with ·1-proteinase inhibitor before (0 h) and after 2 h of hemodialysis therapy using different low-flux dialyzers (n = 44).

In hemodialysis patients dialyzed with high-flux dialysis membranes (group I) plasma angiogenin levels were reduced by 23.2% from 791.4 B 70.4 at the beginning to 607.9 B 40.2 ng/ml (p ! 3 ! 10 –5) after 2 h, whereas plasma lactoferrin and elastase levels increased from 179.4 B 24.0 to 513.0 B 117.9 ng/ml (p ! 0.003), and from 35.5 B 3.8 to 94.4 B 14.4 ng/ml (p ! 5 ! 10 –5), respectively (fig. 1). In hemodialysis patients dialyzed with low-flux dialysis membranes (group II), plasma angiogenin levels were reduced by only 5.7% and remained unchanged (671.0 B 43.0 ng/ml) at the beginning of dialysis therapy versus after 2 h of treatment (633.1 B 39.7 ng/ml; p ! 0.02). Plasma lactoferrin levels increased from 175.8 B 15.9 to 282.7 B 18.9 ng/ml (p ! 0.000002) within 2 h of extracorporeal therapy and plasma elastase levels increased from 48.4 B 8.0 to 73.0 B 11.7 ng/ml (p ! 0.02). These data are depicted in figure 2. Patients treated with polysulfone dialyzers were further subdivided according to the treatment modalities (table 1). During low-flux hemodialysis therapy, plasma angiogenin levels were unchanged (576.7 B 41.7 vs. 567.5 B 45.8 ng/ml, n.s.) and plasma lactoferrin increased from 189.2 B 31.1 to 287.2 B 26.8 ng/ml (p ! 0.0007). Plasma angiogenin decreased by 16% from 626.7 B 56.1 to 526.6 B 44.2 ng/ml (p ! 0.02) during hemodialysis therapy using the high-flux version of polysulfone. Plasma lactoferrin levels (163.8 B 46.0 vs. 337.5 B 58.6 ng/ml, p ! 0.004) were comparable to the low-flux polysulfone version.

Table 1. Effect of low- and high-flux dialyzers made of polysulfone

Angiogenin Inhibits Lactoferrin Release


during hemodialysis therapy on plasma angiogenin and lactoferrin values Polysulfone

Angiogenin, ng/ml

Lactoferrin, ng/ml

Low flux (n = 19)

0h 2h

576.7B41.7 567.8B45.8 (n.s.)

189.2B31.1 287.2B26.8 (p ! 0.0007)

High flux (n = 23)

0h 2h

621.7B56.1 526.6B40.2 (p ! 0.002)

165.6B38.8 301.0B43.7 (p ! 4 ! 10 –6)

Mean values B SEM, significance determined between the beginning (0 h) and after 2 h of treatment.

Table 2. Effect of low- and high-flux dialyzers made of cellulose tri-

acetate hemodialysis therapy on plasma angiogenin and lactoferrin values Cellulose triacetate

Angiogenin, ng/ml

Lactoferrin, ng/ml

Low flux (n = 25)

0h 2h

742.7B69.9 682.9B59.5 (p ! 0.02)

165.7B15.4 279.3B26.8 (p ! 0.0004)

High flux (n = 23)

0h 2h

837.1B90.6 657.8B70.8 (p ! 7 ! 10 –6)

184.3B34.6 712.8B252.4 (p ! 0.02)


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Table 3. Effect of high-flux dialyzers made

of polymethylmethacrylate on plasma angiogenin, lactoferrin and elastase values of patients undergoing either regular hemodialysis therapy (n = 5) or hemodiafiltration (n = 7)

Polymethylmethacrylate (n = 12)

0h 2h

Angiogenin ng/ml

Lactoferrin ng/ml

Elastase ng/ml

862.9B227.4 527.3B84.1 (p ! 0.03)

176.3B35.2 685.2B193.5 (p ! 0.01)

30.7B8.7 91.1B22.6 (p ! 0.006)


Table 4. Plasma angiogenin, lactoferrin and elastase in complex with

·1-proteinase inhibitor before (0 h) and after 2 h of hemodiafiltration (n = 30) Time

Angiogenin, ng/ml

Lactoferrin, ng/ml

Elastase, ng/ml

0h 2h

644.1B51.5 527.1B41.7 (p ! 1 ! 10 –5)

176.3B28.9 580.5B134.9 (p ! 0.002)

40.6B8.3 69.5B13.5 (p ! 0.03)


Patients treated with cellulose triacetate dialyzers were also subdivided according to the treatment modalities (table 2). Again, we compared low- and high-flux versions of this membrane material during hemodialysis therapy. Plasma angiogenin levels were unchanged (729.5 B 65.5 vs. 702.8 B 61.9 ng/ml, n.s.) during low-flux hemodialysis therapy. There was a small increase of plasma lactoferrin levels from 167.9 B 15.4 to 288.4 B 28.5 ng/ml (p ! 0.0002). In contrast to high-flux hemodialysis therapy with the polysulfone membrane, the high-flux dialyzer made of cellulose triacetate caused a significant decrease of plasma angiogenin levels (838.7 B 90.2 vs. 708.6 B 77.5 ng/ml, p ! 0.006). This decrease was associated with a markedly higher lactoferrin release (184.2 B 34.6 vs. 711.6 B 252.0 ng/ml, p ! 0.02). Ten patients (table 3) were treated with high-flux dialyzers made of polymethylmethacrylate (4 patients on hemodialysis therapy, 6 patients on hemodiafiltration). In this group of patients, plasma angiogenin levels decreased from 837.5 B 268.8 to 536.5 B 100.7 ng/ml (p ! 0.07), while plasma lactoferrin levels increased from 185.5 B 35.2 to 705.8 B 229.8 ng/ml (p ! 0.03) and elastase increased from 31.4 B 10.5 to 67.9 B 16.5 ng/ml (p ! 0.003). We had no low-flux version of this dialyzer in which to compare the patients on low- versus high-flux hemodialysis therapy.

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Table 4 shows plasma angiogenin, lactoferrin and elastase in complex with ·1-proteinase inhibitor before and after 2 h of extracorporeal circulation in all 32 patients undergoing regular hemodiafiltration. The significant decrease of angiogenin was associated with a marked lactoferrin release.

Discussion

Angiogenin is a potent angiogenesis-stimulating protein that was initially isolated from medium conditioned by a human adenocarcinoma cell line [17]. Shapiro et al. [18] reported the purification of this protein from normal human plasma. It was concluded that angiogenin is not a tumor-specific product and requires further investigation. Tschesche et al. [14] purified the protein from plasma ultrafiltrates of end-stage renal disease patients undergoing regular hemodialysis treatment with high-flux dialyzers. It was shown that angiogenin at concentrations in the nanomolar range inhibits spontaneous degranulation of PMNL to 40%. After stimulation with a chemotactic peptide, PMNL degranulation was inhibited by 70%, while other cellular functions such as chemotaxis, phagocytosis and the oxidative burst were not affected by angiogenin. A similar but reduced effect was induced by the disulfide C39–C92 containing tryptic fragment of angiogenin [14]. Plasma levels of angiogenin are elevated in patients with chronic renal failure as compared to healthy subjects. These levels are further increased in end-stage renal disease patients undergoing regular hemodialysis therapy or continuous ambulatory peritoneal dialysis. The biological function of angiogenin in end-stage renal disease patients is thus far unknown. High plasma levels of this PMNL degranulation-inhibiting protein in end-stage renal disease patients may contribute to their well-known PMNL dysfunctions. Based on the in vitro data of inhibition of PMNL degranulation [14], we hypothesized that angioge-


nin could also affect PMNL degranulation under in vivo conditions. We therefore selected a large group of chronic hemodialysis patients undergoing regular hemodialysis treatment with high- or low-flux dialyzers of different membrane materials. It is well known that extracorporeal therapy may induce degranulation of PMNL comparable to chemotactic peptides in vitro [7–12]. Figure 1 demonstrates that a decrease of plasma angiogenin levels during hemodialysis with high-flux dialyzers is associated with a marked increase of plasma lactoferrin levels. This phenomenon was observed with all high-flux dialyzers tested (tables 1–3). In contrast, low-flux dialyzers of identical membrane material did not change plasma angiogenin levels and resulted in only a mild increase of plasma lactoferrin levels (fig. 2, tables 1, 2). Both highand low-flux dialyzers induced a comparable release of elastase from PMNL (fig. 1, 2). These data are in agreement with the in vitro data [14] showing that angiogenin inhibits the release of lactoferrin and of metalloproteinases but not the release of elastase from PMNL. Patients on hemodiafiltration showed a decrease in angiogenin and an increase in lactoferrin comparable to patients on high-flux hemodialysis (table 4). There are however differences between patients undergoing high-flux hemodialysis therapy with polysulfone and cellulose triacetate membranes (table 1). It is possible that different adsorptive capacities of these membranes are responsible for the difference in angiogenin plasma levels. Differences between polysulfone and polyacrylonitrile have been shown with respect to angiogenin and complement factor D reduction. AN69 reduced plasma angiogenin level to 34.4% of the pre-dialysis values and factor D level to 72.5% during hemodialysis, whereas polysulfone reduced plasma angiogenin to 64.1% and did not change complement factor D level. These data demonstrate that endogenous PMNL inhibitors such as angiogenin and complement factor D must be considered if neutrophil activation parameters were measured to investigate bioincompatibility of dialyzer membrane materials. However, there must be more to this process than just removal of DIPs; otherwise, there would not be degranulation with low-flux cellulose membranes [19]. Human neutrophil elastase cleaves angiogenin. In the present study, plasma elastase levels were not different between patients with higher or lower plasma angiogenin levels. Plasma elastase levels in complex with ·1-proteinase inhibitor were comparable in patients treated with the polysulfone or the cellulose triacetate dialyzers. Furthermore, it has been shown that heparin partially protects angiogenin from cleavage by proteolytic enzymes [20].

Age, sex or duration of dialysis therapy had no effect on angiogenin plasma levels. We demonstrate in this study that a plasma factor inhibits neutrophil activation in chronically uremic patients during extracorporeal treatment. A decrease in angiogenin of only 15–30% results in a pronounced degranulation of PMNL during extracorporeal circulation even if biocompatible membrane materials are used. These data may also explain neutrophil degranulation during extracorporeal therapy in the absence of major anaphylatoxin formation [7–12]. PMNL degranulation in the absence of anaphylatoxin formation was observed more than one decade ago in patients undergoing regular hemodialysis treatment using a polymethylmethacrylate dialyzer [7, 8]. Data obtained in the present study suggest that, at least in part, the decrease of plasma angiogenin levels may be responsible for the lactoferrin release in patients on polymethylmethacrylate dialyzers (table 1). There are further pathways responsible for PMNL degranulation during extracorporeal circulation that have been identified such as ionized calcium. It has been shown that reduction of ionized calcium by citrate anticoagulation also reduces degranulation [11, 12]. Incubation studies and recirculation experiments revealed that neither prostaglandins nor leukotrienes are involved in PMNL degranulation [21]. In conclusion, the high plasma angiogenin levels present in uremic patients protect against lactoferrin release from PMNL during extracorporeal circulation. On the other hand, hemodialysis therapy with high-flux dialyzers causes a decrease in plasma angiogenin levels which induce a marked lactoferrin release. This novel mechanism of PMNL activation during extracorporeal circulation may explain PMNL degranulation with biocompatible non-complement activating high-flux dialyzers.

Angiogenin Inhibits Lactoferrin Release


Acknowledgement This work was supported by the Deutsche Forschungsgemeinschaft, DFG Ts 8/30-2.

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9 Cheung AK, Faezi-Jenkin B, Leypoldt JK: Effect of thrombosis on complement activation and neutrophil degranulation during in vitro hemodialysis. J Am Soc Nephrol 1994;5:110– 115. 10 Haag-Weber M, Schollmeyer P, Hörl WH: Granulocyte activation during haemodialysis in the absence of complement activation: Inhibition by calcium channel blockers. Eur J Clin Invest 1988;18:380–385. 11 Böhler J, Schollmeyer P, Dressel B, Dobos G, Hörl WH: Reduction of granulocyte activation during hemodialysis with regional citrate anticoagulation: dissociation of complement activation and neutropenia from neutrophil degranulation. J Am Soc Nephrol 1996;7:234– 241. 12 Bos JC, Grooteman MPC, van Houte AJ, Schoorl M, van Limbeek J, Nubé MJ: Low polymorphonuclear cell degranulation during citrate anticoagulation: A comparison between citrate and heparin dialysis. Nephrol Dial Transplant 1997;12:1387–1393. 13 Deicher R, Exner M, Cohen G, Haag-Weber M, Hörl WH: Neutrophil ß2-microglobulin and lactoferrin content in renal failure patients. Am J Kidney Dis 2000;35:1117–1126. 14 Tschesche H, Kopp C, Hörl WH, Hempelmann U: Inhibition of degranulation of polymorphonuclear leukocytes by angiogenin and its tryptic fragment. J Biol Chem 1994;269: 30274–30280.


15 Bläser J, Triebel S, Kopp C, Tschesche H: A highly sensitive immunoenzymometric assay for the determination of angiogenin. Eur Clin Chem Clin Biochem 1993;31:513–516. 16 Bergmann U, Michealis J, Oberhoff R, Knäuper V, Beckmann R, Tschesche H: Enzyme linked immunosorbent assays for the quantitative determination of human leukocyte collagenase and gelatinase. J Clin Chem Clin Biochem 1989;27:351–359. 17 Fett JW, Strydom DJ, Lobb RR, Alderman EM, Bethune JL, Riordan JF, Vallee BL: Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 1985;24:5480–5488. 18 Shapiro R, Strydom DJ, Olson KA, Vallee BL: Isolation of angiogenin from normal human plasma. Biochemistry 1987;26:5141–5146. 19 Hörl WH: Hemodialysis membranes: Interleukins, biocompatibility and middle molecules. J Am Soc Nephrol 2002;13:S62–S71. 20 Soncin F, Strydom DJ, Shapiro R: Interaction of heparin with human angiogenin. J Biol Chem 1997;272:9818–9824. 21 Böhler J, Donauer J, Birmelin M, Schollmeyer PJ, Hörl WH: Mediators of complement-independent granulocyte activation during haemodialysis: Role of calcium, prostaglandins and leukotrienes. Nephrol Dial Transplant 1993;8: 1359–1365.




Glucose Degradation Products in Peritoneal Dialysis: From Bench to Bedside Achim Jörres Department of Nephrology and Medical Intensive Care, Universitätsklinikum Charité, Campus Virchow-Klinikum, Humboldt-Universität zu Berlin, Germany

Key Words Glucose degradation products W Peritoneal dialysis fluids W Biocompatibility

Abstract In continuous ambulatory peritoneal dialysis patients, treatment success is inextricably linked to the functional and morphological integrity of the peritoneal membrane. This membrane, however, is repeatedly exposed to peritoneal dialysis fluids (PDFs) with unphysiological composition (e.g., acidic pH, high glucose content, hyperosmolarity). More recently, attention of researchers and clinicians has been focused on the presence of glucose degradation products (GDPs) that are generated during heat sterilization of PDF. These GDPs were found to adversely affect peritoneal cell function both acutely and chronically. Recently, a new family of multi-chambered PDFs has been introduced into clinical practice. By keeping the glucose in a separate compartment at very low pH, the generation of GDPs during heat sterilization is markedly reduced. Initial clinical studies indicate that treatment with these novel PDFs may lead to improved clinical outcomes. The current article reviews recent experimental and clinical experience with both conventional and multi-chambered PDFs. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 1420–4096/03/0262–0113$19.50/0



Introduction

Conserving the functional integrity of the peritoneal membrane is of critical importance for the long-term success of peritoneal dialysis (PD). An injury of this membrane may result in loss of ultrafiltration and solute transport capacity and, ultimately, therapy failure. PD in itself appears to carry a risk for peritoneal membrane damage since continuous ambulatory peritoneal dialysis (CAPD) patients show significant abnormalities in peritoneal membrane morphology. This encompasses ultrastructural alterations of the mesothelium such as a decrease of surface microvilli [3, 4], but also of the submesothelial layers which show a rarefaction of the connective tissue and sclerosis [2]. A comprehensive review of peritoneal membrane changes in long-term PD patients was recently published in the Atlas of Peritoneal Histology [Perit Dial Int 2000;20(suppl 3)]. The mechanisms responsible for these structural changes remain unknown at present, however, it has been suggested that these alterations might be related to the number of peritonitis episodes [35] and/or the time on PD treatment [47]. Loss of dialytic peritoneal membrane function may, however, also occur without a relevant histopathological correlate, suggesting that even mild structural abnormalities of the peritoneal membrane and/or subtle changes of peritoneal membrane cell function can be clinically relevant.

Dr. Achim Jörres Department of Nephrology and Medical Intensive Care Universitätsklinikum Charité, Campus Virchow-Klinikum Augustenburger Platz 1, D–13353 Berlin (Germany) Tel. +49 30 4505 53423, Fax +49 30 4505 59918, E-Mail [email protected]

Table 1. GPDs identified in PD solutions

GDP

Concentration, ÌM

Ref.

Acetaldehyde Formaldehyde 2-Furaldehyde Glyoxal 5-Hydroxymethylfuraldehyde Methylglyoxal Valeraldehyde 3-Deoxyglucosone 3,4-Dideoxyglucosone-3-ene

120–420 6–15 0.05–2 3–14 6–30 2–23 n.d. 118–154 9–22

31 31 31 31 31 31 31 22 21

During PD the peritoneal membrane is repeatedly exposed to an unphysiological environment composed of uremic solutes, infectious agents, dialysis solutions and plasticizers, all of which are potentially involved in membrane damage. In particular, the dialysis solutions constitute the primary interface between patient and treatment procedure and are clearly unphysiological in various respects. Their pH is acidic (pH 5.2–5.5), and glucose is present in high concentrations as the osmotic agent, resulting in a strong hyperosmolality of the peritoneal dialysis fluid (PDF) (up to 511 mosm/kg). Both conditions have been identified as being primary factors in the acute toxicity of PD solutions towards cell function [10, 16, 17]. Only recently, however, the less obvious problem of glucose degradation products (GDPs) has received increasing attention.

Glucose Degradation Products in Peritoneal Dialysis Fluids

Glucose in concentrated solutions undergoes spontaneous decomposition with time. This process is substantially accelerated by heating [33]. Accordingly it has been shown that the degradation of glucose in PD solutions occurs primarily during autoclaving and to lesser extent during storage [18, 26, 27]. If, however, PDFs are sterilized by filtration, GDP formation is substantially reduced [44]. A main product of glucose degradation is 5-hydroxymethylfuraldehyde which can be detected by a characteristic peak in UV absorbance at 284 nm [42]. In addition, a number of other compounds that are generated during heat sterilization were meanwhile identified in current PD solutions (table 1). It was a clinical observation that initially attracted the attention to the problem of GDPs. Henderson et al. [8]

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found that the intensity of inflow pain experienced by some CAPD patients correlated with the storage time of the solutions prior to use. These authors also observed a reduced ultrafiltration capacity in patients dialyzed with old PDF [9]. Their findings correlated with the presence of GDPs in aged PD solutions. Since then, several studies comparing heat- and filter-sterilized PD solutions found that heat-sterilized solutions compromised cell functions to a significantly greater extent than fluids sterilized by filtration [1, 14, 37, 43–46]. Recently, these observations were extended by studies in peritoneal cells indicating a significant impairment of human peritoneal mesothelial cell proliferation, viability and IL-6 release following a short-term (up to 24 h) treatment with six different GDPs [48]. The inhibitory effects observed during these acute exposure experiments were, however, evident only with GDP doses that by far exceeded those present in commercial PDFs. Therefore, we recently established an in vitro model in which human peritoneal mesothelial cells can be maintained in culture for up to 6 weeks. In this model of ‘chronic’ exposure mesothelial viability and function is significantly impaired in the presence of low, i.e. clinically relevant, GDP concentrations [49]. The hypothesis that GDPs are a critical factor related to functional abnormalities of the peritoneal membrane is supported by data derived from ex vivo experiments and animal studies. Peritoneal macrophages isolated from rats injected with heat-sterilized fluids show a reduced respiratory burst capacity compared to cells isolated from animals treated with filter-sterilized PDF [14]. Moreover, following the treatment with heat-sterilized PDF the number of rolling leukocytes in rat mesenteric venules was significantly reduced compared to those observed in tissues exposed to filter-sterilized solutions [13]. In addition, the combination of GDP and low pH was shown to increase peritoneal transport of small solutes during short-term dialysis in rats [29]. In addition to the direct acute and chronic toxicity related to glucose and GDPs, chronic PD therapy is associated with the progressive accumulation of advanced glycation end-products (AGE) in the peritoneal membrane [30]. Whilst these glycation processes were commonly viewed as being mediated by glucose present in the dialysate, recent evidence indicates that certain GDPs (in particular methylglyoxal and 3-deoxyglucosone) are even more powerful inducers of AGE formation than glucose per se [20, 32, 36, 41]. It is important to note that in CAPD patients, peritoneal AGE formation correlates with the development of interstitial fibrosis and microvascular sclerosis, which is associated clinically with im-

Jörres

paired peritoneal ultrafiltration [11]. In addition, a specific GDP, methylglyoxal, was recently found to stimulate the production of vascular endothelial growth factor (VEGF), a growth factor known to enhance vascular permeability and angiogenesis [12]. As VEGF and carboxymethyl lysine (formed from GDPs) co-localized immunohistochemically in mesothelial layer and vascular walls of the peritoneal membrane of chronic PD patients, it was suggested that GDP might be directly involved in peritoneal neoangiogenesis [12]. Overall, the evidence available at present suggests that GDPs are involved in the pathogenesis of peritoneal membrane dysfunction during chronic PD, either directly or indirectly via the enhanced formation of AGE. Consequently, the development of novel dialysis solutions with diminished GDPs content and AGE formation potential has been substantially advanced.

Strategies to Reduce the Presence of GDPs Content in Peritoneal Dialysis Fluids

An ideal osmotic agent with the potential to replace glucose as the osmotic agent in PD solutions is, at present, not available. The manufacturing process of glucosebased PD fluids may, however, be modified in a way that substantially reduces glucose degradation. A key point in this process is the separation of highly concentrated glucose at a very low pH from catalyzing electrolytes and buffers in dual-chambered containers [19, 42]. These dual-chambered containers also allow the use of sodium bicarbonate as the buffer system, thus enabling to finally reach a neutral pH after mixing of the two solution compartments and at the same time removing the problem of acidic pH. Consequently, the manufacturers of dialysis fluids have meanwhile introduced dual- or multi-chambered PDFs with neutral or near-neutral pH and markedly reduced GDP content (table 2). Clinical trials have meanwhile established the safety and efficacy of these novel solutions [5–7]. In addition, a large spectrum of laboratory studies indicate that the in vitro biocompatibility profile of these solutions is significantly improved compared to that of conventional PDF [15, 37–39]. Animal experiments showed that in contrast to conventional fluids, PD solutions with a reduced GDP content induce no major hemodynamic effects and may thus have the potential to better preserve peritoneal vascular integrity [28]. Finally, clinical trials and ex vivo studies have further corroborated the potential benefits of these novel solutions. Patients receiving bicarbonate- and

Glucose Degradation Products in Peritoneal Dialysis

Table 2. Multi-chambered dialysis solutions with reduced GDP con-

tent Fluid

Manufacturer

Gambrosol Trio Stay Safe Balance Stay Safe Bicavera Physioneal

Gambro Fresenius Medical Care Fresenius Medical Care Baxter Healthcare

bicarbonate/lactate-buffered PDFs displayed improved peritoneal macrophage function and host defense status [23, 24]. In a 2-year randomized clinical trial of a new PDF that is produced in a two-compartment bag, improved membrane transport characteristics, ultrafiltration capacity and effluent markers of peritoneal membrane integrity with the novel fluid as compared to standard PDF were reported [34]. In a randomized, prospective, controlled, 12-month study comparing a new 25-mM bicarbonate plus 15 mM lactate with a standard 40 mM lactate-buffered PD solution in 106 patients, the new solution was shown to be safe and effective in correcting uremic acidosis, to provide relief of inflow pain and discomfort, and to improve ultrafiltration [40]. A randomized, double-blind, cross-over study of novel bicarbonate (38 mM) or bicarbonate (25 mM)/lactate (15 mM) containing PD solutions reported a significant reduction of inflow pain with the novel solution [25]. Finally, a recent randomized prospective cross-over trial with Balance, a novel lactate-buffered, dual-chambered solution, indicated a significant increase of CA-125 (a surrogate marker for mesothelial cell mass) in patients treated with the novel solution [Williams JD et al: EuroPD 5, May 2002, Brussels, Belgium].

Conclusions

GDPs have been identified as being a major factor in the bioincompatibility of current PD solutions. Presently, a new generation of modern, dual-chambered PD solutions combining the advantages of neutral pH and reduced GDPs is being introduced into clinical practice. The available data derived from in vitro, animal and clinical studies suggest that these novel solutions not only improve acute peritoneal cell functions but may also help to better preserve the functional integrity of the peritoneal membrane during long-term PD.


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Effluent CA 125 Concentration in Chronic Peritoneal Dialysis Patients: Influence of PD Duration, Peritoneal Transport and PD Regimen Andreas Fusshöller Bernd Grabensee Jörg Plum Department of Nephrology and Rheumatology, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany

Key Words CA 125 W Peritoneal transport W Automated peritoneal dialysis W Biocompatibility

Abstract In terms of the integrity of the peritoneal membrane in peritoneal dialysis (PD), the peritoneal mesothelial cells play a pivotal role since its monolayer constitutes the first line of the peritoneal membrane. Cancer antigen 125 (CA 125) is released by peritoneal mesothelial cells and correlates with the mesothelial cell mass in PD. Since its effluent concentration is easy to determine in chronic PD patients, CA 125 serves as an in vivo marker of biocompatibility. We performed a cross-sectional study to investigate the relation between PD duration, peritoneal transport and the PD regimen (CAPD/CCPD) on effluent CA 125 concentration in 22 chronic PD patients. We compared long-term (1 6 months) with short-term PD treatment, patients with high small solute transport properties (MTAC 1 11 ml/min, d/p ratio of creatinine 10.72) to patients with low small solute transport and CAPD with APD patients. A peritoneal equilibration test was performed with 1.36% glucose. Dialysate/plasma (D/P) ratio and mass transfer area coefficient (MTAC) of creatinine were calculated and the 4-hour effluent concentration of CA 125 was determined. CA 125 tended to be lower in the

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long-term PD patients and also in APD patients, but statistical significance was missing. Effluent CA 125 was significantly increased in patients with an MTAC of creatinine 111 ml/min (40.2 B 11.2 vs. 20.7 B 1.2 U/ml) and in patients with a d/p ratio of creatinine 1 0.72 (48.2 B 11.0 vs. 21.6 B 1.6 U/ml). CA 125 and the d/p ratio of creatinine were positively correlated (r = 0.68). The positive correlation of CA 125 with peritoneal small solute transport especially in the early phase of PD treatment indicates an initial correlation of the mesothelial cell mass with the peritoneal surface area. A direct relation between the CA 125 concentration and peritoneal transport is unlikely. In our study the CA 125 effluent concentration tended to be lower in long-term PD patients and also in APD patients, possibly indicating a cell depletory influence of the conventional PD fluid. Copyright © 2003 S. Karger AG, Basel

Introduction

After the first in vitro biocompatibility study in 1981 [1], numerous studies investigated the impact of conventional peritoneal dialysis (PD) solutions on the vitality and function of intraperitoneal cell lines [2–9] identifying lactate, low pH and glucose as the determinants of in vitro bioincompatibility. Apart from in vitro studies on the

Andreas Fusshöller, Department of Nephrology and Rheumatology Heinrich Heine University of Düsseldorf Moorenstrasse 5, D–40225 Düsseldorf (Germany) Tel. +49 0211 8117726, Fax +49 0211 8117723 E-Mail [email protected]

peritoneal host defense, more recently research focused on how to preserve the structural and functional integrity of the peritoneal membrane as the dialyzing organ, which is the determinant of system survival in PD. In long-term PD, histological changes of the peritoneal membrane [10, 11] have been described and are possibly associated to alterations in peritoneal transport and ultrafiltration [12, 13]. Peritoneal fibrosis and ultrafiltration failure determine both system survival of PD and patient’s mortality [14–16]. In terms of peritoneal integrity in PD, peritoneal mesothelial cells play a pivotal role since its monolayer constitutes the first line of the peritoneal membrane in contact with the PD solution [17]. The discovery of CA 125, which is released by peritoneal mesothelial cells [18], opened the possibility to study the actual state of the mesothelial integrity in vivo [19]. Since effluent concentrations of CA 125 were found to correlate with the mesothelial cell mass and are unaffected of stimulation with TNF-· or IL-1ß [20], the CA 125 effluent concentration is considered as a useful marker of biocompatibility. Whereas a negative correlation has been described between time on PD and the CA 125 concentration [21, 22], the question of a potential relationship between mesothelial cell mass and peritoneal transport, which has intensively been discussed by Krediet et al. [21], is somewhat conflicting. Whereas a direct influence of the mesothelial cell layer on peritoneal transport properties is unlikely, a protecting effect of an intact mesothelial cell layer on peritoneal angiogenesis, fibrosis or AGE (advanced glycation endproduct) accumulation in the interstitial tissue during long-term PD treatment may be possible. Exciting new data also indicate the important capability of peritoneal mesothelial cells to differentiate into various peritoneal cell lines and may by this way represent an intrinsic repair system [23]. The question in how far the use of the continuous cyclic PD (CCPD) as a form of the automated PD (APD) compared to the CAPD mode has an impact on the mesothelial cell mass indicating reduced peritoneal integrity has not been systematically studied. APD with the larger volumes of solution and more frequent contact times with fresh and unphysiological dialysate may enhance the described adverse effects of the solutions. Since the usage of APD is still increasing, due to higher dialysis efficiency, lower rates of infections and higher quality of life [24–26], this hypothesis is of clinical relevance. We therefore performed a cross-sectional study to investigate the influence of PD duration, peritoneal transport and the PD regimen (CAPD/CCPD) on effluent CA 125 concentration in chronic PD patients.

CA-125 Effluent Concentration in Chronic PD Patients

Table 1. Clinical data of 22 chronic PD patients

All patients Number Age, years Sex, f/m Treatment time, months D/P ratio creatinine, % Weekly Ccr, l/min/1.73 m2 Weekly Kt/V (renal + peritoneal) CAPD/APD History of peritonitis/no peritonitis

22 49.2B4.2 8/14 16.5B6.5 0.75B0.03 157.9B33.6 2.55B0.22 11/11 7/15

D/P ratio: dialysate/plasma ratio; Weekly Ccr: weekly creatinine clearance; Kt/V: urea removal index.

Materials and Methods Patients The design of the study was non-randomized and cross sectional. Excluding any special selection criteria, the CA 125 effluent measurement after a 4-hour dwell in the effluent was performed within 6 months in 22 patients, who had their routine peritoneal equilibration test (PET). The patients were stable on PD, had not changed from CAPD to APD or vice versa during the last year and were free of peritonitis for at least 3 months prior to the transport analysis. Baseline sociodemographic data and clinical characteristics are shown in table 1. The patients had a mean age of 49.2 B 4.2 years, average treatment time was 16.3 B 6.5 months and did not differ between APD and CAPD. All patients were treated with lactate-based (Dianeal, Baxter) PD solutions of different glucose concentrations (1.36%, 3.86%). 11 CAPD and 11 APD patients were included. With regard to treatment time the patient group was divided into two groups of almost equal sample size (cut-off point at 6 months’ PD treatment). In terms of peritonitis, we compared those patients with one or more peritonitis episodes in their history to those with no history of peritonitis. For peritoneal transport data the patient group was divided into two groups of equal number by using the statistical median for the d/p ratio of creatinine (0.72%) and for the MTAC of creatinine (11 ml/min). Methods CA 125 was measured in the 4-hour effluent during a PET using a 1.36% glucose solution as previously described [13]. The 4-hour dialysate/plasma (d/p) ratio and the mass transfer area coefficient (MTAC) for creatinine were calculated: MTAC (ml/min):

VD + VE (C – CD1) ! ln P 2 ! t240min (CP – CD2)

(VD = dialysate volume, VE = effluent volume, CP = plasma concentration, CD1 and CD2 = dialysate concentrations at 0 and 240 min). Dialysis adequacy was determined via Kt/V and weekly creatinine clearance as described elsewhere [25]. The CA 125 concentration was measured in the 4-hour effluent using a commercial immunoassay (CA 125 II Immunoassay, Roche).


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Table 2. CA 125 effluent concentration in 22 PD patients in relation

to PD treatment time, transport properties (d/p ratio crea and MTAC crea), PD mode (CAPD/CCPD), history of peritonitis and dialysis adequacy (Kt/V)

Mean of all patients PD treatment 1 6 months PD treatment ! 6 months MTAC crea 1 11 ml/min MTAC crea ! 11 ml/min D/P ratio crea 1 0.72 D/P ratio crea ! 0.72 CAPD CCPD Peritonitis 61 Peritonitis = 0 Weekly Kt/V 1 2.5 Weekly Kt/V ! 2.5

1

n

CA 125, U/ml

22 9 13 11 11 12 10 11 11 7 7 11 11

35.0B9.1 27.57B3.56 40.18B11.16 46.1B4.6 20.7B1.2 45.97B11 21.8B1.6 41.88B6.14 28.17B4.31 31.38B3.38 35.05B9.8 31.78B4.86 38.27B11.8

p ! 0.05 p ! 0.05

MTAC crea: Mass transfer area coefficient of creatinine; D/P ratio crea: dialysate/plasma ratio creatinine; Kt/V: urea removal index.

Statistical Analyses Results are expressed as mean B SEM. Distribution was tested to be normal. Paired and unpaired t test was used for statistical analysis. An · error of p ! 0.05 was judged to be significant. Correlations were calculated by the method of least squares.

2

Results

3 Fig. 1. Effluent CA 125 concentration in relation to peritoneal small solute transport: d/p ratio and MTAC (mass transfer area coefficient) of creatinine. Fig. 2. Correlation of effluent CA 125 concentration and d/p ratio of creatinine in long-term PD patients (1 6 months); r = 0.49. Fig. 3. Correlation of effluent CA 125 concentration and d/p ratio of creatinine in short-term PD patients (! 6 months); r = 0.76.

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Mean d/p ratio of creatinine was 0.75 B 0.03 and the MTAC of creatinine 11.94 B 1.65 ml/min (table 1). Kt/V was adequate with 2.55 B 0.22. Mean CA 125 effluent concentration was 35 B 9.1 U/ml. Effluent CA 125 was significantly increased in patients with an MTAC of creatinine 111 ml/min (46.1 B 4.6 U/ ml) compared to an MTAC !11 ml/min (20.7 B 1.2 U/ ml) and in patients with a d/p ratio of creatinine 10.72 (45.97 B 11.0 U/ml) compared to a d/p ratio !0.72 (21.8 B 1.6 U/ml; table 2, fig. 1). A positive correlation was found for effluent CA 125 and the d/p ratio of creatinine (r = 0.68; p ! 0.05). The correlation was stronger in the patient group with a shorter time (!6 months) of PD treatment (r = 0.76) compared to the group with a longer time on PD (r = 0.49; fig. 2, 3). CA 125 levels were not related to the history of peritonitis episodes or the adequacy of the PD treatment (table 2). Also age or gender did not determine CA 125 effluent concentration. Effluent CA 125 in patients treated for more than 6 months tended to be lower but

Fusshöller/Grabensee/Plum

did not reach significance (27.56 B 3.56 vs. 40.18 B 11.16 U/ml). CA 125 also tended to be lower in patients on APD but again statistical significance was not reached (28.17 B 4.31 vs. 41.88 B 6.14 U/ml; table 2).

Discussion

Cross-sectional and longitudinal studies found a negative correlation of CA 125 with the time on PD treatment [21, 22] indicating a gradual loss of mesothelial cells. The correlation of low CA 125 effluent concentration indicating mesothelial cell mass and the time on PD is in accordance with biopsy studies. Mesothelial cells have been shown to be sensitive to the influence of conventional PD fluids as tested in vitro with regard to cytotoxicity or cell growth. Acute peritonitis often leads to an immediate, but temporary loss of mesothelial cells [27, 28], whereas longterm exposure to the fluids may result in a persistent loss of the mesothelium [11, 27, 28]. Additionally, interstitial and especially vascular changes have been described and may significantly influence peritoneal solute transport [10, 11]. The reason for the missing significance between CA 125 concentration and the time on PD in our study is probably the relatively short mean duration of PD treatment in our patient group. A PD treatment time of 16.5 months is moderate and shorter than in the equivalent studies [21, 22]. This is in accordance to the data by Pannekeet et al. [21], where the strongest relation of CA 125 concentration and time on PD has been found in patients treated for more than 5 years. Apparently, the loss of the mesothelial cell integrity under the long-term influence of the PD is a phenomenon which does not occur within months. This is in accordance to the missing acute effect of higher or lower glucose concentration on the CA 125 effluent concentration [22]. It was interesting to observe a trend to lower CA 125 concentrations in APD patients compared to those under CAPD treatment, even though statistical significance was missing. Treatment time did not differ between APD and CAPD patients. As the gradual loss of mesothelial cell mass over time on PD is interpreted as a long-term result of the more or less ‘cytotoxic’ conventional PD fluids, one might speculate that the same process occurs in APD due to the larger cumulative dialysate volume. In a preceding biopsy study we found that vascular alterations like peritoneal neoangiogenesis during PD treatment also tended to be more pronounced in APD patients [11]. With regard to fluid kinetics (transcapillary ultrafiltration and lymphatic absorption), we recently did not find a major dif-

CA-125 Effluent Concentration in Chronic PD Patients

ference between CAPD and APD patients [13]. Whether the more frequent contact of the peritoneum with fresh PD fluid and the higher cumulative glucose load in APD patients really implicates a more pronounced alteration of the peritoneal membrane needs to be investigated in longterm studies. The fact that mesothelial cells release a large amount of the mediators within the cytokine network of the peritoneal cavity [5, 6, 17, 29] may explain a negative correlation of its number within the peritoneal cavity and the incidence of peritonitis [30]. Data on the relation between CA 125 concentration and peritoneal transport are still somewhat conflicting. Krediet et al. [21] did not find a correlation of CA 125 concentration and peritoneal transport in chronic PD patients. According to animal and cell culture models it was suggested that the mesothelium influences peritoneal transport at least for high molecular substances [31, 32]. Whereas a direct influence of the mesothelial cell layer on peritoneal transport properties is unlikely, a protecting effect of an intact mesothelium from peritoneal neoangiogenesis, fibrosis or AGE accumulation in the interstitial tissue during long-term PD treatment may be possible. In contrast to Krediet et al., we found a correlation of CA 125 effluent concentration and peritoneal small solute transport. This correlation was stronger in the patients who had been treated with PD for a shorter period of time. The mean treatment time of our patient group was relatively low compared to other studies and it seems that a correlation of mesothelial cell mass and small solute transport is present in short-term PD patient and is vanishing over the time on PD. As the MTAC of creatinine is an indicator of the effective peritoneal surface area, it is reasonable to assure a correlation of mesothelial cell mass and the peritoneal surface area. Theoretically the production rate of CA 125 could represent the ‘anatomical’ peritoneal surface area. However, under the influence of chronic PD, a variable loss of mesothelial cell mass [22] occurs and an increase of the effective peritoneal surface area is observed [12, 13]. These counteracting influences probably reduce the correlation between peritoneal mass transport and CA 125 on a longer time scale. A recent biopsy study described a better preservation of the peritoneal mesothelium in rats after long-term exposure to a more biocompatible, bicarbonate-based fluid [33]. CA 125 effluent concentrations have also been shown to be higher in PD patients using a neutral buffered PD fluid [34]. Therefore, CA 25 effluent concentrations initially appear as a suitable intraindividual parameter to monitor the mesothelial cell mass with regard to questions of biocompatibility. However, peritoneal transport can probably not be predicted on the long term.


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References 1 Duwe AK, Vas SI, Weatherhead JW: Effects of the composition of peritoneal dialysis fluids on chemoluminescence, phagocytosis and bactericidal activity in vitro. Infect Immun 1981;33: 130–135. 2 Topley N, Alobaidi HM, Davies M, Coles GA, Williams JD, Lloyd D: The effect of dialysate on peritoneal phagocyte oxidative metabolism. Kidney Int 1988;34:404–411. 3 Doudevani A, Rapoport J, Konforti A, Zlotnik M, Chaimovitz C: The effect of peritoneal dialysis fluid on the release of IL-1ßa and TNF-· by macrophages/monoctytes. Perit Dial Int 1993;13:112–117. 4 Plum J, Schönicke G, Grabensee B: Osmotic agents and buffers in peritoneal dialysis solutions: Monocyte cytokine release and in vitro cytotoxicity. Am J Kidney Dis 1997;30:413– 422. 5 Plum J, Razeghhi P, Lordnejad RM, Perniok A, Fleisch M, Fussholler A, Schneider M, Grabensee B: Peritoneal dialysis fluids with a physiologic pH based on either lactate or bicarbonate buffer – Effects on human mesothelial cells. Am J Kidney Dis 2001;38:867–875. 6 Jörres A, Bender T, Finn A, Witowski J, Fröhlich S, Gahl G, Frei U, Keck H, Passlick-Deetjen J: Biocompatibility and buffers: Effect of bicarbonate-buffered peritoneal dialysis fluids on peritoneal cell function. Kidney Int 1998; 54:2184–2193. 7 Witowski J, Wisniewska J, Korybalska K, Bender T, Breborowicz A, Gahl GM, Frei U, Passlick-Deetjen J, Jörres A: Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal cells. J Am Soc Nephrol 2001;12:2434–2441. 8 Rippe B, Simonsen O, Heimburger O, Christensson A, Haraldson B, Stelin G, Weiss L, Nielsen FD, Bro S, Friedberg M, Wieslander A: Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products. Kidney Int 2001;59:348–357. 9 Lee JH, Reddy DK, Saran R, Moore HL, Twardowski ZJ, Nolph KD, Khanna R: Advanced glycosylation end-products in diabetic rats suing various solutions. Perit Dial Int 2000;20: 643–651. 10 Mateijsen M, van der Wal A, Hendriks P, Zweers M, Mulder J, Struijk D, Krediet R: Vascular and interstitial changes in the peritoneum of CAPD patients with peritoneal sclerosis. Perit Dial Int 1999;19:517–525. 11 Plum J, Hermann S, Fusshöller A, Schönicke G, Donner A, Rohrborn A, Grabensee B: Peritoneal sclerosis in peritoneal dialysis patients related to dialysis settings and peritoneal transport properties. Kidney Int 2001;59:42–47.

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12 Davies SJ, Bryan J, Phillips L, Russell GI: Longitudinal changes in peritoneal kinetics: The effect of peritoneal dialysis and peritonitis. Nephrol Dial Transplant 1996;11:498–506. 13 Fusshöller A, zur Nieden S, Grabensee B, Plum J: Peritoneal fluid and solute transport: Influence of treatment time, peritoneal dialysis modality, and peritonitis incidence. J Am Soc Nephrol 2002;13:1055–1060. 14 Davies SJ, Phillips L, Russell GI: Peritoneal solute transport predicts survival on CAPD independently of residual renal function. Nephrol Dial Transplant 1998;13:962–968. 15 Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR Oreopoulos DG, Page D: Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. J Am Soc Nephrol 1998;9:1285–1292. 16 Wang T, Heimbürger O, Waniewski J, Bergström J, Lindholm BL: Increased peritoneal permeability is associated with decreased fluid and small solute removal and higher mortality in CAPD patients. Nephrol Dial Transplant 1998;13:1242–1249. 17 Topley N, Williams JD: Role of the peritoneal membrane in the control of inflammation in the peritoneal cavity. Kidney Int 1994;46:71– 78. 18 Koomen GCM, Betjes MGH, Zemel D, Krediet RT, Hoek FJ: Cancer 125 is locally produced in the peritoneal cavity during continuous ambulatory peritoneal dialysis. Perit Dial Int 1994;14:132–136. 19 Krediet RT: Dialysate cancer antigen concentration as marker of peritoneal membrane status in patients treated with chronic peritoneal dialysis. Perit Dial Int 2001;21:560–567. 20 Visser CE, Brouwer-Steenbergen JJE, Betjes MGH, Koomen GCM, Beelen RHJ, Krediet RT: Cancer antigen 125:A bulk marker for the mesothelial mass in stable peritoneal dialysis patients. Nephrol Dial Transplant 1995;10:64– 69. 21 Pannekeet MM, Koomen GCM, Struijk DG, Krediet RT: Dialysate CA 125 in stable CAPD patients: No relation with transport parameters. Clin Nephrol 1995;44:248–254. 22 Pannekeet MM, Hiralall JK, Struijk DG, Krediet RT: Longitudinal follow-up of CA 125 in peritoneal effluent. Kidney Int 1997;51:888– 893. 23 Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, Dominguez-Jimenez C, Jiminez-Heffernan JA, Aguilera A, Sanchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, Del Peso G, Cirujeda A, Gamallo C, SanchezMadrid F, Lopez-Cabrera M: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003;348:403– 413.


24 Diaz-Buxo JA: The present and the future of APD. Clin Nephrol 2000;53:411–416. 25 Fusshöller A, Röwemeier H, Plum J, Grabensee B: Automatische Peritonealdialyse bei Patienten ohne renale Restfunktion und/ oder grosser Körperoberfläche. Nieren Hochdruckkr 2001;30:335–345. 26 Bro S, Bjorner JB, Tofte-Jensen P, Klem S, Almtoft B, Danielsen H, Meincke M, Friedberg M, Feldt-Rasmussen B: A prospective, randomised multicenter study comparing APD and CAPD treatment. Perit Dial Int 1999;19: 526–533. 27 Dobbie JW, Zaki MA, Wilson MS: Ultrastructural studies on the peritoneum with special reference to chronic ambulatory peritoneal dialysis. Scott Med J 1981;26:213–223. 28 Gotloib L, Shostak A, Bar-Sella P, Cohen R: Continuous mesothelial injury and regeneration during long-term peritoneal dialysis. Perit Bull 1987;7:148–155. 29 Breborowicz A, Martis L, Oreopoulos DG: Changes of biocompatibility of dialysis fluid during its dwell in the peritoneal cavity. Perit Dial Int 1995;15:152–170. 30 Betjes MG, Bos HJ, Krediet RT, Arisz L: The mesothelial cells in the CAPD effluent and their relation to peritonitis incidence. Perit Dial Int 1991;11:22–26. 31 Davenport A, Topley N, Williams JD: Control of polymorphonuclear leucocytes migration across human peritoneal mesothelial cell monolayer. Nephrol Dial Transplant 1994;9:1018– 1022. 32 Davenport A, Topley N, Williams JD: Neutrophil (PMN) transmigration across human peritoneal mesothelial cell monolayer is both ICAM-1 and IL-8 dependent. J Am Soc Nephrol 1994;5:713–717. 33 Hekking LH, Zareie M, Driesprong BA, Faict D, Welten AG, de Greeuw I, Schade K, Eestermans IL, Havenith CE, van den Born J, ter Wee, PE, Beelen RH: Better preservation of peritoneal morphologic features and defence in rats after long-term exposure to a bicarbonate/ lactate-buffered solution. J Am Soc Nephrol 2001;12:2775–2786. 34 Jones S, Holmes CJ, Krediet RT, Mackenzie R, Fauct D, Tranaeus A, Williams JD, Coles GA, Topley N; Bicarbonate/Lactate Study Group: Bicarbonate/lactate-based peritoneal dialysis solutions increase cancer antigen 125 and decrease hyaluronic acid levels. Kidney Int 2001; 59:1529–1538.

Fusshöller/Grabensee/Plum



Continuous Renal Replacement Therapy in Acute Renal Failure Werner Riegel Medizinische Klinik III, Klinikum Darmstadt, Germany

Key Words Hemodialysis W Continuous venovenous hemofiltration W Acute renal failure

Abstract The management of acute renal failure in the critically ill patient is extremely variable and there are no published standards for the provision of renal replacement therapy in this population. Continuous renal replacement therapy seems to be the treatment of choice because of its superior metabolic and hemodynamic control. There is better organ protection by continuous treatment but no evidence for better survival or renal recovery due to continuous treatment. The debate about optimal membrane as well as about optimal dialysis dose is ongoing. An effluent flow rate of at least 35 ml/kg/h as well as lower BUN level at treatment initiation seem to be necessary to provide better survival rate. Peritoneal dialysis is a less suitable option in continuous renal replacement of the adult intensive care patient but hybrid methods such as extended daily dialysis and sustained low efficient daily dialysis need consideration with respect to continuous hemofiltration/dialysis. Copyright © 2003 S. Karger AG, Basel

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© 2003 S. Karger AG, Basel 1420–4096/03/0262–0123$19.50/0



Introduction

Intermittent hemodialysis (IHD) treatment three times per week is still the classical treatment option for patients with end-stage renal disease (ESRD). In acute renal failure (ARF) it is also the mostly used modality in numerous countries [1, 2]. The management of ARF in the critically ill patient is extremely variable and there are no published standards for the provision of renal replacement therapy in this population. The choice of treatment in the intensive care unit (ICU) depends in spite of strong medical reasons on numerous factors, e.g. traditional behavior, availability of treatment methods, organization of the unit, knowledge and experience of nurses, existence of a nephrological unit in the hospital, costs, etc. The individual doctor must therefore know the advantages and disadvantages of different treatment options for ARF in the ICU.

Methods Available for Renal Replacement of the Critically Ill Patient

There is an ongoing discussion concerning the choice of extracorporeal treatment strategy and whether it influences both the clinical course and mortality. One controversy belongs to the treatment modality, i.e. continuous versus intermittent.

Prof. Dr. Werner Riegel Medizinische Klinik III Klinikum Darmstadt Grafenstrasse 7–9, D–64283 Darmstadt (Germany) Tel. +49 6151 1076600, Fax +49 6151 1076649, E-Mail [email protected]

IHD is performed daily or once every second day for 4 h with a blood flow of about 200 ml/min and a dialysate flow of 500 ml/min. In contrast, continuous treatment is prescribed for 24 h each day. In the case of continuous venovenous hemodialysis (CVVHD) the blood flow is 100 ml and the dialysate flow 15–40 ml/min. The continuous treatment which is mostly used is continuous venovenous hemofiltration (CVVH). The volume which is filtered in CVVH should be 35 ml/kg b.w./h, i.e. 2 liters/h or 35–40 ml/min [3]. The combination of both treatment options, i.e. hemofiltration (convective removal) and hemodialysis (diffusive removal), is hemodiafiltration (CVVHD). High-volume filtration is described in cases of septic shock [4]. Up to 6 liters/h are necessary to provide this treatment option for about 8 h which is not generally used in ICU patients. Arteriovenous treatment options were first described by Kramer et al. [5] in 1977. This method should be reserved for emergencies because of the limited efficacy to maintain adequate metabolic control. Disadvantages also include the need of an arterial catheter and the low fluid control due to the lack of pump-driven devices. The predominant potential advantages of continuous renal replacement therapy (CCRT) are hemodynamic stability, correction of hypervolemia and better solute removal. These advantages are also offered by recently described hybrid therapies, i.e. extended daily dialysis (EDD) and sustained low-efficient daily dialysis (SLEDD), bridging standard IHD and continuous therapy [6–8]. Peritoneal dialysis is an important treatment option in small children suffering from ARF. In a recent study, 80 ICU patients with ARF were treated either with CVVH or peritoneal dialysis. In the peritoneal group, 47% died in contrast to 15% in the hemofiltration group. Additionally, treatment costs were much higher in the peritoneal dialysis group [9].

Continuous Therapies Are Not Always Continuous

A recent analysis demonstrated that continuous therapy is not truly continuous. The treatments of 266 filters were observed [10]. The median period when CVVH was not applied to a patient (down-time) was 3 h/day. There was a significant inverse correlation between down-time and creatinine or urea reduction over a 24-hour time cycle. The authors measured that on average at least 16 h/day of CVVH was required to maintain creatinine

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and urea concentration for each 24-hour cycle [10]. Therefore, down-time seems to be more frequent than expected and adversely affects azotemic control.

Dialysis Dose for the Critically Ill Patient

Intermittent Hemodialysis The impact of how hemodialysis is prescribed and delivered is thought to have a significant impact on clinical outcomes in ARF [11]. Although it seems reasonable to also apply urea kinetic modeling in ARF, as is done in chronic renal failure, many of the fundamental assumptions used in developing these models in ESRD are violated in ARF [12, 13]. Urea should be a surrogate marker for the toxic metabolites of renal failure which is not established in ARF, especially in the setting of multisystem organ dysfunction. A second assumption includes that the patient is in a neutral nitrogen balance and that the pre-dialysis state remains relatively stable over a repetitive cycle of dialysis treatments. These assumptions are not valid in ARF patients because the majority are hypercatabolic and are in negative nitrogen balance. The third assumption that would allow the use of a single pool model is that all body fluid compartments are in equilibrium. In multiorgan failure, ARF is characterized by instability of the patient’s hemodynamic parameters and by the use of vasoactive substances which may produce disequilibrium in urea distribution. The double pool model would need a homogeneous distribution of urea which varies widely in ARF as compared to the ESRD patients. The same is true for the solute removal index quantifying the removed amount of urea which cannot be exactly correlated to the body mass due to metabolic and fluid imbalances. Despite these limitations, a recent investigation at a single tertiary care hospital studied 844 critically ill patients with ARF requiring renal replacement therapy. The severity of illness in this cohort of patients was assessed using the Cleveland Clinic Foundation ARF Severity Score [14]. Patients in the very low or very high group showed outcome independent of dialysis dose. In contrast, survival of patients with intermediate scores improved when delivered dialysis dose exceeded Kt/V 11 three times per week as compared to lower doses of dialysis treatment. The frequency of IHD should be daily [15] but the data is scarce and under criticism [16]. Continuous Renal Replacement In clinical routine, CVVH is typically chosen for treating patients with hemodynamic instability and volume

Riegel

overload. The clearance of non-protein bound low-molecular-weight substances is equal to the ultrafiltration rate if replacement fluids are administered post-hemofilter. One study has evaluated the effect of the dose of CRRT on clinical outcomes of ARF. In this randomized, controlled trial of three doses of CVVH in critically ill patients with ARF, an effluent flow rate of at least 35 ml/kg b.w./h was associated with a significantly higher survival than a flow rate of 20 ml/kg/h [3]. Survival at the lower effluent flow rate was 41% as compared with survival rates of 57% at a flow rate of 35 ml/kg/h and 58% at 45 ml/kg/h [3].

Different CRRT Treatment Options and Azotemic Control

Different techniques of CRRT might have different effects on azotemic control. Morimatsu et al. [17] tested whether CVVHDF or CVVH would achieve better control of serum creatinine and plasma urea levels. In a retrospective study they found that initial differences which existed in both groups were not changed after treatment with continuous treatment modalities with either CVVH or CVVHD [17]. In contrast, Swartz et al. [18] measured mean BUN levels of 66 mg/dl in CVVH patients versus 99 mg/dl in the IHD group (p ! 0.001). Clark et al. [19] calculated a similar difference for serum urea nitrogen (p ! 0.05). Therefore, CRRT-treated patients seem to have a better control of azotemia than IHD patients.

Which Membrane Should Be Chosen?

Considerable controversy exists to date whether the choice of the dialyzer membrane might be of significant relevance for the outcome of patients with ARF. Earlier studies indicated that the use of biocompatible membranes (i.e. synthetic vs. cellulose-based membranes) in these patients may result in improved patient survival and renal recovery. More recently, however, these results could not be confirmed by larger randomized, prospective clinical studies [20]. Subramanian et al. [21] recently published a metaanalysis about this topic. They analyzed all published trials comparing the use of synthetic membranes with cellulose-based membranes for hemodialysis in patients with ARF. The cumulative odds ratio for survival in favour of synthetic membranes was 1.37, p = 0.03, and that for renal recovery was 1.2, p = 0.18. The survival advantage of synthetic membranes was mainly limited to compari-

Continuous Renal Replacement Therapy in ARF

son with the unsubstituted cellulose group (i.e. cuprophane-unsubstituted vs. cellulose acetate-substituted). They concluded that the survival disadvantage for cellulose-based membranes may be limited to unsubstituted cellulose (cuprophane) membranes. Recently some methodological criticism was published [22] suggesting that the author’s conclusion – that synthetic membranes reduce mortality – should be viewed with skepticism.

Mortality as an Endpoint – Is Any Treatment Option Better?

ARF is a common complication in critical illness and mortality remains over 50% [23, 24]. A multicenter prospective randomized trial comparing CRRT to IHD reported a 28-day all-cause mortality of 59.9% (CRRT) vs. 41.5% (IHD) in 166 patients. The reasons for the observed results are unbalanced randomization, significantly higher APACHE II scores and a greater percentage of liver failure in patients included in the CRRT group. The analysis of the survival data of 349 patients with ARF who received either CRRT or IHD at a single center with an initial univariate analysis showed the odds of death for patients receiving CRRT to be more than twice that of patients receiving IHD [18]. However, when multivariate risk adjustment was performed to adjust for severity of illness, the calculated risk of death was 1.09 (p = 0.72) for CRRT as compared to IHD. Therefore, the main factors for mortality are: first, the serious impact of liver disease; second, septic or traumatic illness, and third, the unadjusted crude indication for CRRT versus HD [18]. A meta-analysis of 13 studies comparing continuous to intermittent renal replacement therapy encompassing a total of 1,400 patients with ARF has recently been reported [25]. Overall mortality was not different. Only 3 of the 13 studies were prospective and randomized trials. Adjusting for study quality and severity of illness, the authors calculated a relative risk of death in patients treated with CRRT of 0.72 (p ! 0.01). They concluded that, given the weakness in study quality, the current evidence was insufficient to draw strong conclusions regarding the mode of renal support in critically ill patients with ARF. This in accordance with Tonelli et al. [26] who also published a meta-analysis of these studies. Nevertheless, the data would suggest a potential benefit of continuous as compared to intermittent renal replacement therapy [25].


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Effects of Treatment on Organ Function

Dialysis disequilibrium syndrome may occur after the first dialysis treatments due to marked cerebral edema caused by a fall in plasma osmolality which is not accompanied by a parallel change in osmolality in the brain tissue. Ronco et al. [27] demonstrated in 12 patients with ARF that IHD led to a significant change in brain density measured by CT scan. No changes were observed after CVVH treatment. The physiological stability provided by continuous therapies, such as CVVH, avoids the unwanted effect of increased water content in the brain after each session of IHD therapy [27]. These effects could be either due to better endothelial function or due to systemic hemodynamic stability. John et al. [28] measured splanchnic regional perfusion in septic shock patients in a prospective, randomized clinical trial. Despite different changes of systemic hemodynamics between CVVH and IHD, CVVH did not improve parameters of splanchnic regional perfusion like pHi, pCO2i or pCO2 gap. This is in accordance with a study in 12 critically ill patients having a compromised endothelial integrity [29]. The factors which characterize the endothelial function like soluble tissue factor, thrombomodulin, E-selectin and endothelin-1 were not changed by CVVH. Renal recovery was investigated by Bouman et al. [30], who investigated early high volume (48 liters/day), early low volume (20 liters/day) and late low volume (19 liters/ day). All hospital survivors had recovery of renal failure at hospital discharge with one exception. They concluded that 28-day survival and recovery of renal function were not improved using high ultrafiltrate volumes or early initiation of hemofiltration. In a meta-analysis published by Tonelli et al. [26], the dialytic modality effect on renal recovery was investigated. Four studies were identified as eligible for renal outcome. IHD was associated with a relative risk for renal death of 1.02 and for dialysis dependency of 1.66. Both relative risk factors were not at a statistically significant level.

Timing of Renal Support

The generally accepted indications for the initiation of renal replacement therapy in ARF include persistent hyperkalemia, severe metabolic acidosis, volume overload unresponsive to diuretic therapy, and overt uremic symptoms, including pericarditis and severe encephalopathy. In addition, dialysis is often initiated ‘prophylactically’, before the development of overt uremic symptoms in

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response to severe, progressive azotemia. The appropriate timing for this criterion remains unresolved. Prophylactic hemofiltration was performed in a prospective study including 24 trauma patients [31]. Despite positive effects on hemodynamic parameters, hemofiltration did not show any benefit in respect to the severity, duration of the illness or outcome of the patients. The concept of removing some mediators is not supported by these results. The issue of potential removing mediators like interleukins and others by CRRT is discussed by Heering et al. [32]. Urea level seems to be a prognostic predictor in ARF. A recent study has addressed retrospectively early (BUN !60 mg/dl) versus late (BUN 160 mg/dl) initiation of CRRT in 100 adults suffering from posttraumatic ARF [33]. Early initiation (BUN 42.6 B 12.9 mg/dl) was associated with a 39% survival, as compared with 20.3% survival of patients with late (BUN 94.5 B 28.3 mg/dl) initiation of therapy (p = 0.041). In a study comparing different doses of CRRT by CVVH in ARF, it was observed that the mean starting BUN in patients who survived was lower than in non-survivors in all three groups [3]. No prospective studies of timing of the initiation of renal replacement therapy in ARF have been reported.

Conclusion

The studies actually published do not give clear evidence for a superiority of CRRT over IHD. Patients receiving CRRT are mostly more ill characterized by lower blood pressure, lower urine output or higher score values. Continuous treatment options have a better metabolic and hemodynamic control of the ARF patients. There is consensus that in hemodynamically unstable patients, CRRT can be more safely performed due to a lesser tendency to exacerbate hypotension. SLED and EDD are increasingly used to treat hypotensive ARF patients if CRRT is not available [34]. Nevertheless, it would be desirable that treatment options in ARF are not selected mainly on the basis of available experience with specific procedures and the cost of implementing RRT at the individual centers [18]. Characteristics of the patients who definitely need continuous treatment [17] as well as the practical matter of providing care of patients should be further addressed [35]. Therefore, well-designed studies in critically ill patients should enable a physician to provide a clear evidence-based decision for treatment options in renal replacement therapy.

Riegel

References 1 Mehta RL, Letteri JM: Current status of renal replacement therapy for acute renal failure. A survey of US nephrologists. Am J Nephrol 1999;19:377–382. 2 Hymann A, Mendelssohn DC: Current Canadian approaches to dialysis for acute renal failure in the ICU. Am J Nephrol 2002;22:29–34. 3 Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccini P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomized trial. Lancet 2000; 356:26–30. 4 Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P: High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978–986. 5 Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F: Arteriovenous haemofiltration: A new and simple method for treatment of overhydrated patients resistant to diuretics. Klin Wochenschr 1977;55:1121–1122. 6 Kumar VA, Craig M, Depner TA, Yeun JY: Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis 2000;36: 294–300. 7 Lonnemann G, Floege J, Kliem V, Brunkhorst R, Koch KM: Extended daily veno-venous high-flux haemodialysis in patients with acute renal failure and multiple organ dysfunction syndrome using a single patch dialysis system. Nephrol Dial Transplant 2000;15:1189–1193. 8 Marshall MR, Golper TA, Shaver MJ, Alam MG, Chatoth DK: Sustained low-efficiency dialysis for critically ill patients requiring renal replacement therapy. Kidney Int 2001;60:777– 785. 9 Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP, Winearls C, Farrar J, White N, Day N: Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 2002;347:895–902. 10 Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R: Continuous is not continuous: The incidence and impact of circuit ‘down-time’ on uraemic control during continuous veno-venous hemofiltration. Intensive Care Med 2003; 29:425–428. 11 Karsou SA, Jaber BL, Pereira BJG: Impact of intermittent hemodialysis variables on clinical outcomes in acute renal failure. Am J Kidney Dis 2000;35:980–991. 12 Clark WR, Mueller BA, Kraus MA, Macias WL: Dialysis prescription and kinetics in acute renal failure. Adv Ren Replace Ther 1997;4: 64–71.

Continuous Renal Replacement Therapy in ARF

13 Clark WR, Mueller BA, Kraus MA, Macias WL: Renal replacement therapy quantification in acute renal failure. Nephrol Dial Transplant 1998;13(suppl 6):86–90. 14 Paganini EP, Tapolyai M, Goormastic M, Halstenberg W, Kowlowski L et al.: Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis 1996; 28(suppl 3):81–89. 15 Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305–310. 16 Bonventre JV: Daily hemodialysis – Will treatment each day improve the outcome in patients with acute renal failure? N Engl J Med 2002;346:632–634. 17 Morimatsu H, Uchino S, Bellomo R, Ronco C: Continuous renal replacement therapy: Does technique influence azotemic control? Ren Fail 2002;24:645–653. 18 Swartz RD, Messana JM, Orzol SO, Port FK: Comparing continuous hemofiltration with hemodialysis in patients with severe acute renal failure. Am J Kidney Dis 1999;34:424–432. 19 Clark WR, Mueller BA, Alaka KJ, Macias WL: A comparison of metabolic control by continuous and intermittent therapies in acute renal failure. J Am Soc Nephrol 1994;4:1413–1420. 20 Jorres A, Gahl GM, Dobis C, Polenakovic MH, Cakalaroski K, Rutkowski B, Kisielnicka E, Krieter DH, Rumpf KW, Guenther C, Gaus W, Hoegel J: Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure: A prospective randomised multicentre trial. International Multicenter Trial Group. Lancet 1999; 254:1337–1341. 21 Subramanian S, Venkataraman R, Kellum JA: Influence of dialysis membranes on outcomes in acute renal failure: A meta-analysis. Kidney Int 2002;62:1819–1823. 22 Tonelli M, Pannu N, Manns B: Influence of dialysis membranes on outcomes in acute renal failure. Kidney Int 2003;63:1957. 23 Brivet FG, Kleinknecht DJ, Loirat P, Landais P: Acute renal failure in intensive care units – causes, outcome and prognostic factors of hospital mortality: A prospective, mulitcenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996;24:192–198. 24 Liano F, Junco E, Pascual J, Madero R, Verde E: The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group: Kidney Int 1998;53(suppl 66): 16–24.

25 Kellum JA, Angus DC, Johnson JP, Leblanc M, Grinnin M, Ramakrishnan N, Linde-Zwirble WT: Continuous versus intermittent renal replacement therapy: A meta-analysis. Intensive Care Med 2002;28:29–37. 26 Tonelli M, Manns B, Feller-Kopman D: Acute renal failure in the intensive care unit: A systematic review of the impact of dialytic mortality and renal recovery. Am J Kidney Dis 2002; 40:875–885. 27 Ronco C, Bellomo R, Brendolan A, Pinna V, La Greca G: Brain density changes during renal replacement in critically ill patients with acute renal failure. J Nephrol 1999;12:173–178. 28 John S, Griesbach D, Baumgartel M, Weihprecht H, Schmieder RE, Geiger H: Effects of continuous haemofiltration vs. intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: A prospective, randomized clinical trial. Nephrol Dial Transplant 2001;16: 320–327. 29 Cardigan R, McGloin H, Mackie I, Machin S, Singer M: Endothelial dysfunction in critically ill patients: The effect of haemofiltration. Intensive Care Med 1998;24:1264–1271. 30 Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J: Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med 2002;30:2205–2211. 31 Bauer M, Marzi I, Ziegenfuss T, Riegel W: Prophylactic hemofiltration in severely traumatized patients: Effects on post-traumatic organ dysfunction syndrome. Intensive Care Med 2001;27:376–383. 32 Heering P, Grabensee B, Brause M: Cytokine removal in septic patients with continuous venovenous hemofiltration. Kidney Blood Press Res 2003;26:128–134. 33 Gettings LG, Reynolds HN, Scalea T: Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med 1999;25:805–813. 34 Vanholder R, Van Biesen W, Lameire N: What is the renal replacement method of first choice for intensive care patients? J Am Soc Nephrol 2001;12:S40–S43. 35 Kellum JA, Mehta RL, Angus DC, Palevsky P, Ronco C for the ADQI Workgroup: The first international consensus conference on continuous renal replacement therapy. Kidney Int 2002;62:1855–1863.


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Cytokine Removal in Septic Patients with Continuous Venovenous Hemofiltration P. Heering a B. Grabensee b M. Brause b a Department b Department

of Medicine III, Solingen General Hospital, University of Cologne, Solingen and of Nephrology and Rheumatology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Key Words Cytokine removal W Sepsis W Continuous venovenous hemofiltration

Abstract Despite the progress that has been made in intensive care medicine, multiple organ failure is still associated with high mortality. Apart from the prevention of infectious complications, numerous efforts are being made to improve the treatment of sepsis through adequate antibiotic therapy, the development of new respirator therapies, better control of the hemodynamic situation, and adequate renal replacement therapy. Some authors advocate continuous renal replacement therapy not only for acute renal failure but also for the elimination of inflammatory molecules such as cytokines. Continuous renal replacement therapy improves the cardiovascular hemodynamics in patients with multiple organ failure. Therapeutic options such as volume control, clearance of uremic toxins, correction of acid base disturbances and temperature control are improved. Suitable renal replacement therapy improves not only cardiovascular hemodynamics but also patient survival. In current practice, continuous renal replacement therapy is not used to

ABC

© 2003 S. Karger AG, Basel 1420–4096/03/0262–0128$19.50/0



eliminate mediators such as cytokines. In patients with multiple organ failure and compromised cardiovascular hemodynamics, renal replacement therapy should be carried out as early as possible. In the following review, experimental and clinical findings concerning mediator elimination by continuous and intermittent renal replacement therapy are summarized. Copyright © 2003 S. Karger AG, Basel

Introduction

Sepsis is a major clinical problem in intensive care. Many critically ill patients with sepsis develop acute renal failure (ARF) as part of multiple organ failure. Mortality is still above 60% despite advances in the treatment of infections and in the technical support available. Cytokines are regarded as important mediators in the pathophysiology of sepsis and septic shock. Several studies have demonstrated increased serum levels of inflammatory cytokines in critically ill patients different stages of sepsis [1]. Continuous renal replacement therapy has been shown to improve cardiovascular hemodynamics in these patients and it has been postulated that removable myocardial depressing factors are present in the blood [2, 3]. A

Prof. Dr. med. P. Heering Department of Medicine III, Solingen General Hospital University of Cologne, Gotenstrasse 1 D–42653 Solingen (Germany) Tel. +49 212 5472418, Fax +49 212 5472254, E-Mail [email protected]

number of studies have investigated the role of dialyzers raising evidence for the use of synthetic membranes. Recent studies suggest that continuous renal replacement therapy removes cytokines from the serum of septic, critically ill patients [4–7]. Solute removal by hemofiltration is based on convection driven by a pressure gradient. Convective clearance is proportional to the ultrafiltration rate but independent of the molecular weight up to the membrane cut-off. Sepsis and septic shock are characterized by a stimulation of the immune system with complement activation, an increase in pro-inflammatory cytokines and chemokines and increased expression of adhesion molecules on endothelial cells and neutrophils. The increased immune response causes excessive cytokine stimulation. The coagulation system is activated, causing disseminated intravascular coagulation with hyperfibrinolysis. As a result, the hemodynamic situation is completely changed with peripheral vasodilatation, shock and tissue hypoxia, resulting in multiple organ failure. In the past, a number of studies have been carried out on the neutralization of special endotoxins or cytokines by means of monoclonal antibodies. All these efforts have failed and mortality has not been reduced. It was recently shown that the infusion of activated protein C, an agent with antithrombotic, antiinflammatory and profibrinolytic properties, led to a significant reduction of mortality of patients with severe sepsis [8]. Patients with ARF due to multiple organ failure have shown an improvement in cardiovascular hemodynamics after the start of renal replacement therapy [5, 9, 10, 12, 13]. A number of authors have been able to identify cytokines in the ultrafiltrate. Based on this, it had been speculated that hemofiltration could eliminate cytokines and other mediators and that cytokines or other mediators could be eliminated by renal replacement therapy and the clinical course of sepsis improved in this way [4, 11, 14]. This paper discusses the main mechanism of cytokine elimination by renal replacement therapy.

Results of Laboratory Studies

of cytokines. In vitro experiments with active charcoal, ion exchanger and specific antibody columns showed that a variable amount of different cytokines was eliminated. The amounts of the adsorbed cytokines were up to 100% for IL-8 and 90% for IL1-ß [18].

Results of Animal Studies

In animal sepsis models, isovolemic hemofiltration improved circulatory failure, pulmonary and heart failure achieving improved survival rates [2, 19, 20]. A remarkable improvement in cardiovascular function in hemodynamics was shown in a study by Grootendorst et al. [2, 21], who were able to demonstrate that the infusion of ultrafiltrate of septic animals had a considerable negative influence on cardiovascular hemodynamics and that continuous renal replacement therapy improved not only hemodynamics but also the survival of the animals in question. Lee et al. [20] and Kline et al. [30] showed that both cardiovascular data and survival improved. Gomez et al. [19] described an improvement in left ventricular function in dogs with septicemia and continuous venovenous hemofiltration (CVVH). Further improvement was achieved by high-volume hemofiltration. In this model, hemofiltration was performed at a rate of 6 l/h. It is unclear what kind of mediator acts as a cardiodepressant and a number of candidates have been discussed. Very few animal experiments have been performed in which different mediators were eliminated. Kellum and Dishart [22] showed that removal of IL-6 by adsorption is possible. It has been shown that NO and cGMP could be eliminated by CVVH. A number of authors have described decreased prostaglandin levels during CVVH. The TNF-· levels were not influenced. In summary, CVVH in the animal model stabilizes hemodynamics and reduces mortality in the animals in question, possibly through elimination of a mediator, although the mediator has not yet been identified.

Theoretic Background to Cytokine Elimination in Humans

It has been shown through in vitro models that cytokines can be eliminated by convective transport. Uchino et al. [15–17] were able to show that a dialysis with the use of a large pore polyamide membrane could achieve a high clearance of vancomycin, IL-1ß, IL-6 and IL-8. No adsorption could be seen in these studies. Other studies have shown that specific absorbers can increase the elimination

In CVVH, ultrafiltrate containing molecules up to 40 kDa is removed. The elimination of these molecules is directly proportional to the sieving coefficient. In hemofiltration the ultrafiltrate is substituted by a buffer combination, in addition dialysis can be achieved by hemodiafiltration. In humans, elimination can be achieved by con-

Cytokine Removal with CVVH


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Table 1. Experimental results on the

elimination of cytokines

Study (first author)

Model

Mediator

Therapy

Effect

Grootendorst [2] Gomez [19] Heidemann [35]

Pigs Dogs Rats

HV-CVVH HF CAVH

Survival Cardiac function Survival

+ + +

Stein [33] Lee [20] Bottoms [28]

Pigs Pigs Pigs

CAVH CAVH CVVH

Hemodynamics Survival No elimination

+ +

Kellum [22]

Rats

Not studied Not studied TXB2, ↓ PG1· ↓, TNF-· = Not studied Not studied Prostacyclin = PGE2 =, TNF = IL-6

HF

Elimination

+: Improved, ↓: reduced plasma levels, =: no change of plasma levels. HV-HF: Highvolume hemofiltration, HF: hemofiltration, CAVH: continuous arteriovenous hemofiltration, CVVH: continuous venovenous hemofiltration.

vective and diffusive transport. TNF has a size of 17 kDa, but typically it consists of a multimere with a molecular weight of 54 kDa. Adsorption of TNF and of IL-1 has been shown. The adsorption is influenced by the lifespan of the filter. At the beginning of sepsis there is bacteremia with release of toxins and activation of the immune system. TNF-· and IL-6 play a key role in this early activation. The interleukin cascade is also activated by inflammation. This cascade includes the platelet-activating factor (PAF), the expression of adhesion molecules and the stimulation of NO synthase. The biological half-life of these mediators is very short and some of them show a very high affinity to plasma proteins. There are pro-inflammatory cytokines but also inhibitory cytokines and cytokine receptors. Elimination is influenced by the amount of endocrine release, the biological half-life, protein binding, the molecular size and the multimere-binding capability. Because of their size, only a very small fraction of these molecules can be eliminated by hemofiltration. Significant cytokine elimination cannot be achieved even by plasma separation.

Results of Patient Studies

Most studies have investigated whether the elimination of mediators in sepsis is possible. Kellum et al. [23] studied 13 patients with systemic inflammatory response syndrome (SIRS) showing no effect on IL-6, IL-10, selectin and endotoxin. De Vriese et al. [24] investigated cytokine elimination over a period of time and found a

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decrease in cytokines 1 h after the start of therapy and 1 h after the start of filtration. There was no effect on the ratio of pro- and anti-inflammatory cytokines. These data confirm the hypothesis that the elimination of cytokines is induced mainly by absorption at the membrane. Sanchez et al. [25] found no difference after trauma in patients receiving continuous renal replacement therapy as compared with patients without treatment. We found that cytokines were eliminated by continuous hemofiltration without a decrease in plasma levels. We also found an improvement in the cardiovascular situation, which might have been due to high-volume ultrafiltration. In a prospective randomized study, Ronco et al. [26] found that the filtration volume had a significant influence on mortality. This was due to the improved dialysis quality and to the fact that higher hemofiltration increased cytokine and mediator elimination. Whether this is the explanation for success of the treatment and better clinical outcome has not yet been established. At the moment we can draw the following conclusions. Continuous renal replacement therapy leads to the elimination of only a small amount of cytokines. It is possible that cytokine elimination can be improved by intensified continuous renal replacement therapy, high-volume hemofiltration and frequent filter change. This has not yet been conclusively proved, however. Continuous renal replacement therapy could also improve cardiovascular hemodynamics as a result of the elimination of cardiodepressant factors, but experiments to eliminate different kinds of mediators by means of absorbers or renal plasma separation have been unable to prove this hypothesis.

Heering/Grabensee/Brause

Table 2. Clinical studies on the elimination of cytokines by renal replacement therapy

Study (first author)

Patients n/disease

Therapy

Mediator

Elimination in the ultrafiltrate

Effect on plasma levels

Clinical data

Heering [10]

33 sepsis/ cardiac failure

CVVH

TNF-·, IL-1ß, IL-6, IL-8, IL-2, IL-10, TNF-RII, IL-11ra, IL-2R, IL-6R

Detection of cytokines in the ultrafiltrate

No reduction

Improvement of cardiovascular hemodynamics

Hoffmann [11]

16 MOF

CVVH

TNF-·, IL-6, IL-1ß, IL-8, C5a, C3, C3a

Detection of IL-8

Complement ↓


Kellum [23]

13 ARF, SIRS

CVVH/D

TNF-·, IL-6, Selectin, Etox

Minimal

No reduction: IL-6, IL-10; reduction of TNF-·

n.s.

Van Bommel [34]

9 SIRS

CVVH

TNF-·, sTNFr I/II, IL-1ra

IL-1ra

No reduction

No effect

De Vriese [24]

15 sepsis

CVVH

TNF-·, IL-1ß, IL-6, IL-1ra, sTNFr-I/II, IL-10

TNF-·, IL-1ß, IL-6, IL-1ra, sTNFr-I/II

Reduction


Sanchez [25]

30 trauma ARF

15 CVVH 15 controls

TNF-·, IL-6

Elimination TNF-·, IL-6

No reduction

n.s.

Sander [31]

28 SIRS

CVVH, controls

TNF-·, IL-6

IL-6

No reduction

No improvement of hemodynamics

Schumacher [32]

Sepsis

CVVH

NO2/NO3

n.s.

Reduction

n.s.

Cole [4]

11 sepsis/ MOF

CVVH/ HV-HF

Anaphylatoxins C3a, C5a

Minimal

Reduction

Greater reduction of vasopressors by HV-HF

Cole [1]

24 early sepsis

CVVH vs. no CVVH

IL-6, IL-8, IL-10 and C3a, C5b

n.s.

No difference

No clinical improvement

ARF: Acute renal failure; MOF: multiorgan failure; SIRS: systemic inflammatory response syndrome; HV-HF: high-volume hemofiltration; HF: hemofiltration; CAVH: continuous arteriovenous hemofiltration; CVVH: continuous venovenous hemofiltration; CVVHD: continuous venovenous hemodiafiltration; ns: not studied.

Severe sepsis and resultant septic shock continue to pose a clinically important risk to critically ill patients. Cytokines are thought to play an essential role in this regard as they have been held responsible for the induction and regulation of inflammatory reactions triggered by infections. The primary cytokines involved in initiating the inflammatory cascade appear to be TNF-· and IL-1. Both are released from macrophages and other inflammatory cells as a result of contact with microbial endotoxin or other microbial components or products. TNF-· and IL-1 share a number of pro-inflammatory properties and cause not only the production of other inflammatory cytokines such as IL-8 or IL-6, but also

lethal shock in experimental animals. The inflammatory cascade also leads to the activation of regulatory mechanisms designed to model host defense, including antiinflammatory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-ß and specific anti-cytokine substances such as IL-1 receptor antagonist (IL-1ra), TNF receptors, and IL-1 receptors. Data of the Norasept study showed that the soluble TNF receptors I and II have an influence on the occurrence of an ARF [11]. A number of therapeutic approaches have been made to ameliorate or antagonize the cytokine-induced inflammatory response using specific anti-cytokine antibodies. Although single trials have demonstrated beneficial effects with regard to



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survival rate, available data have yielded conflicting results. The sequence of events that leads to septic shock seems to be more complex and follows too indirect a pathway for it to be influenced by single anti-inflammatory antibodies. Recent studies have demonstrated significant removal rates of inflammatory cytokines from the circulation of septic patients by continuous renal replacement therapy. In a prospective randomized trial, the effect of hemofiltration on plasma levels of TNF-·, IL-8 and IL-6 in 18 children following cardiopulmonary bypass was studied [27]. Elevated plasma levels were detected in a number of subjects in both groups, but a reduction in the plasma level of TNF-·, IL-6, IL-8 was achieved in the hemofiltration group only. In the relevant literature, the incidence of TNF-· detection ranges from 16 to 94%. The inability to detect TNF-· in many septic patients is connected with the phasic nature of TNF release and its short plasma halflife. Furthermore, the elimination by CVVH is limited by the high molecular weight of the biologically active trimer and its high endogenous clearance. IL-1 has two biochemically distinct forms: IL-1ß is secreted into the extracellular fluids whereas IL-1· remains cell-associated. Measurements of IL-1ß have yielded conflicting results, and high levels have not been described previously in septic patients. Although the molecular weight of IL-1 would allow passage through the hemofiltration membrane, the low incidence of IL-1ß detection in the plasma of septic patients, the presence of naturally occurring binding substances and the high endogenous clearance preclude a clinically important elimination of IL-1 in the filtrate. Cytokines are thought to be involved in the induction of hemodynamic abnormalities observed in sepsis and septic shock and left ventricular dysfunction. Grootendorst et al. [21] studied the influence of continuous highvolume hemofiltration on right ventricular function in 18 anesthetized pigs with endotoxin-induced shock. All animals that received endotoxin and underwent high-volume hemofiltration had an improved right ventricular ejection fraction and cardiac performance, while those given only endotoxin showed no improvement. It was concluded that high-volume hemofiltration removes vasoactive mediators, responsible for myocardial depression, from circulating blood. Gomez et al. [19] examined left ventricular function before and after hemofiltration in anesthetized dogs during continuous intravenous infusion of live Escherichia coli. Hemofiltration led to a reversal of left ventricular dysfunction (left ventricle contractility) and it was postulated that a filterable cardiodepressant factor

132


was responsible. Because hypotension remained unaffected, it was suggested that different factors might influence hypotension and cardiac dysfunction in patients with sepsis. Our study was designed to determine whether CVVH leads to a substantial fall in the plasma level of cytokines in septic patients with ARF. No correlation was found between cytokine levels and clinical prognosis. Although detectable levels of various cytokines (TNF-·, TNF·-RII, IL-6, IL-6R, IL-1ß, IL-1ra, IL-8) were measured in the ultrafiltrate, no significant reduction in plasma levels was achieved. There are a few plausible explanations. First, the presence of cytokines in ultrafiltrate alone does not mean that it is clinically important. Much of the cytokine production occurs at the tissue level, where it has important paracrine effects. The presence of cytokines in the circulation is often considered to be the ‘tip of the iceberg’, comparable with drugs with a large distribution volume (digoxin), and for this reason extracorporeal elimination influences only the small fraction of drug present in plasma water and is therefore not considered clinically relevant [2, 21]. Second, many cytokines have a high endogenous clearance rate and a short plasma half-life. Once produced they are rapidly consumed through interaction with ubiquitous cell-surface receptors or circulating natural inhibitors, resulting in a plasma half-life of only a few minutes. Third, extracorporeal clearance is dependent on the molecular weight and the hemofiltration membrane cut-off point. Cytokines like IL-6 (23– 30 kD) or IL-10 with a high molecular weight are difficult to filter effectively. There is evidence that cytokine production might be triggered by bioincompatible artificial surfaces. Membrane absorption of cytokines has been described, although it seems to be of minor importance in synthetic membranes. Future clinical studies will have to focus on modulation of cytokines instead of removal by extracorporeal procedures. There seems to be no argument in favor of establishing hemofiltration for elimination of cytokines in multiple organ failure. A number of case reports have reported their experiences concerning the application of plasmapheresis in sepsis. The biggest deficiency in these data is the lack of control patients and the chance of a reporter bias. It is more likely that clinicians will report successes than failures.


Conclusion

Continuous renal replacement therapy has a stabilizing effect on hemodynamics in patients with sepsis. The underlying reason has not yet been clarified. The effect of continuous renal replacement therapy is due to volume regulation, continuous elimination of uremic toxins, regulation of the acid base metabolism, and improvement in thermoregulation. This controls hyperdynamic circulation and makes adequate infusion therapy possible. With this reduction in renal function, adequate renal replacement therapy needs to be started at an early date. Hemo-

dynamics can be improved by increasing the amount of filtrate volume [26] and the kind of substitution fluid [29]. The amount of dialysis has a significant influence on mortality. At the moment there is no conclusive evidence as to whether the type of membrane has an influence on mortality. It has not yet been determined whether intermittent or continuous renal replacement therapy is preferable [36]. These forms of therapy should be applied only to patients with renal function impairment. If the renal function is impaired, dialysis should be started early with a regular change of filters.

References 1 Cole L, Bellomo R, Hart G, Journois D, Davenport P, Tipping P, Ronco C: A phase II randomized, controlled trial of continuous hemofiltration in sepsis. Crit Care Med 2002;30: 100–106. 2 Grootendorst AF, van Bommel EF, van der Hoven B, van Leengoed LA, van Osta AL: High volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig. Intensive Care Med 1992;18: 235–240. 3 Hörl WH, Riegel W: Cardiac depressant factors in renal disease. Circulation 1993;87(suppl 5):77–82. 4 Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P: High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978–986. 5 Hoffmann JN, Hartl WH, Deppisch R, Faist E, Jochum M, Inthorn D: Effect of hemofiltration on hemodynamic and systemic concentrations of anaphylatoxins and cytokines in human sepsis. Intensive Care Med 1996;22:1360–1367. 6 Bellomo R, Baldwin I, Cole L, Ronco C: Preliminary experience with high-volume hemofiltration in human septic shock. Kidney Int 1998;53(suppl 66):182–185. 7 Ronco C, Tetta C, Lupi A, Galloni E, Bettini MC, Sereni L, Mariano F, De Martino A, Montrucchio G, Camussi G, La Greca G: Removal of platelet-activating factor in experimental continuous arteriovenous hemofiltration. Crit Care Med 1995;23:99–107. 8 Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709. 9 Heering P, Ivens K, Thümer O, Heintzen M, Willer R, Leschke M, Passlick-Deetjen, Grabensee B: Cardiovascular hemodynamics and acid base disturbances in patients with CVVH – Comparison of different substitution fluids. Intensive Care 1999;25:1244–1251.


10 Heering P, Morgera S, Schmitz FJ, Schmitz G, Willers R, Schultheis HP, Strauer BE, Grabensee B: Cytokine removal and cardiovascular hemodynamics in septic patients with continuous hemofiltration. Intensive Care Med 1997; 23:288–296. 11 Iglesias J, Marik PE, Levine JS; Norasept II Study Investigators. Elevated serum levels of the type I and type II receptors for tumor necrosis factor-· as predictive factors for ARF in patients with septic shock. Am J Kidney Dis 2003;41:62–75. 12 Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D: Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock 1999;12:174–180. 13 Wakabayashi Y, Kamijou Y, Soma K, Ohwada T: Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome or multiple organ dysfunction syndrome. Br J Surg 1996; 83:393–394. 14 Schetz MRC: Classical and alternative indications for continuous renal replacement therapy. Kidney Int 1998;53(suppl 66):129–132. 15 Uchino S, Bellomo R, Morimatsu H, Goldsmith D, Davenport P, Cole L, Baldwin I, Panagiotopoulos S, Tipping P, Morgera S, Neumayer HH, Goehl H: Cytokine removal with a large pore cellulose triacetate filter: An ex vivo study. Int J Artif Organs 2002;25:27–32. 16 Uchino S, Cole L, Morimatsu H, Goldsmith D, Bellomo R: Clearance of vancomycin during high volume hemofiltration: Impact of predilution. Intensive Care Med 2002;28:1664–1667. 17 Uchino S, Bellomo R, Morimatsu H, Goldsmith D, Davenport P, Cole L, Baldwin I, Panagiotopoulos S, Tipping P, Morgera S, Neumayer HH, Goehl H: Cytokine dialysis: An ex vivo study. ASAIO J 2002;48:650–653. 18 Cole L, Bellomo R, Davenport P, Tipping P, Uchino S, Tetta C, Ronco C: The effect of coupled haemofiltration and adsorption on inflammatory cytokines in an ex vivo model. Nephrol Dial Transplant 2002;17:1950–1956.

19 Gomez A, Wang R, Unruh H, Light RB, Bose D, Chau T, Correa E, Mink S: Hemofiltration reverses left ventricular dysfunction during sepsis in dogs. Anesthesiology 1990;73:671– 685. 20 Lee PA, Weger GW, Pryor RW, Matson JR: Effect of filter pore size on efficacy of continuous arteriovenous hemofiltration therapy for Staphylococcus aureus induced septicemia in immature swine. Crit Care Med 1998;26:730– 737. 21 Grootendorst AF, van Bommel EF, van der Hoven B, van Leengoed LA, van Zanten RH, Huipen HJC, Goeneveld ABJ: Infusion of ultrafiltrate from endotoxemic pigs depresses myocardial performance in normal pigs. J Crit Care 1993;8:161–169. 22 Kellum JA, Dishart MK: Effect of hemofiltration filter adsorption on circulating IL-6 levels in septic rats. Crit Care 2002;6:429–433. 23 Kellum JA, Johnson JP, Kramer D, Palevsky P, Brady JJ, Pinsky MR: Diffusive versus convective therapy: Effects on mediators of inflammation in patients with severe systemic inflammatory response syndrome. Crit Care Med 1998;26:1995–2000. 24 De Vriese AS, Colardyn FA, Phillipe JJ, Vanholder RC, De Sutter JH, Lameire NH: Cytokine removal during continuous hemofiltration in septic patients. J Am Soc Nephrol 1999;10: 846–853. 25 Sanchez-Izquierdo JA, Perez Vela JL, Lozano Quintana MJ, Alted Lopez E, Ortuno de Solo B, Ambros Checa A.: Cytokines clearance during venovenous hemofiltration in the trauma patient. Am J Kidney Dis 1997;30:483–488. 26 Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000; 355:26–30.


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27 Millar AB, Armstrong L, van der Linden, Moat N, Ekroth R, Westwick J, Scallan M, Lincoln C: Cytokine production and hemofiltration in children undergoing cardiopulmonary bypass. Ann Thorac Surg 1993;56:1499–1502. 28 Bottoms G, Fessler J, Murphey E, Johnson M, Latshaw H, Mueller B, Clark W, Macias W: Efficacy of convective removal of plasma mediators of endotoxic shock by CVVH. Shock 1996;5:49–154. 29 Barenbrock M, Hausberg M, Matzkies F, Motte S, Schaefer RM: Effects of bicarbonateand lactate-buffered replacement fluids on cardiovascular outcome in CVVH patients. Kidney Int 2000;58:1751–1757.

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30 Kline JA, Gordon BE, Williams C, Blumenthal S, Watts JA, Diaz-Buxo J: Large pore hemodialysis in acute endotoxin shock. Crit Care Med 1999;27:588–596. 31 Sander AA, Armbruster W, Sander B, Daul AE, Lange R, Peters J: Hemofiltration increases IL6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNF-· plasma concentrations. Intensive Care Med 1997;23:878–884. 32 Schumacher T, Kelm M, Schäfer S, Buhn C, Heintzen MP, Heering P, Grabensee B, Strauer BE: Determinanten zirkulierender Nitratplasmaspiegel: Parenterale Ernährung, Nierenfunktion und kontinuierliche venovenöse Hämofiltration. Intensiv Notfallmed 2001;38: 561–569.


33 Stein B, Pfenniger E, Grunert A, Schmitz JE, Hudde M: Influence of continuous hemofiltration on hemodynamics and central blood volume in experimental endotoxin shock. Intensive Care Med 1990;16:494–499. 34 Van Bommel EF, Hesse CJ, Jutte NH, Zitse R, Bruining HA, Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome. Ren Fail 1997;19:443–454. 35 Heidemann SM, Ofenstein JP, Sarnaik AP: Efficacy of continuous hemofiltration in endotoxic shock. Circ Shock 1994;44:183–187. 36 Riegel W: Continuous renal replacement therapy in acute renal failure. Kidney Blood Press Res 2003;26:123–127.




How to Calculate Clearance of Highly Protein-Bound Drugs during Continuous Venovenous Hemofiltration Demonstrated with Flucloxacillin Brigitte Meyer a Salwa Ahmed el Gendy d Georg Delle Karth c Gottfried J. Locker b Gottfried Heinz c Walter Jaeger d Florian Thalhammer a a Department

of Internal Medicine I, Division of Infectious Diseases, b Department of Internal Medicine I, Intensive Care Unit, c Department of Internal Medicine II, Division of Cardiology, and d Institute of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria

Key Words Flucloxacillin W Hemofiltration W Continuous venovenous hemofiltration W Pharmacokinetics W Intensive care unit W Protein binding W Staphylococcal infections

Abstract Background: Flucloxacillin is an important antimicrobial drug in the treatment of infections with Staphylococcus aureus and therefore is often used in staphylococcal infections. Furthermore, flucloxacillin has a high protein binding rate as for example ceftriaxone or teicoplanin – drugs which have formerly been characterized as not being dialyzable. Methods: The pharmacokinetic parameters of 4.0 g flucloxacillin every 8 h were examined in 10 intensive care patients during continuous venovenous hemofiltration (CVVH) using a polyamide capillary hemofilter. In addition, the difficulty of calculating the hemofiltration clearance of a highly protein-bound drug is described. Results: Flucloxacillin serum levels were significantly lowered (56.9 B 24.0%) even though only 15% of the drug was detected in the ultrafiltrate. Elimination half-life, total body clearance and sieving coefficient were 4.9 B 0.7 h, 117.2 B 79.1 ml/min and 0.21 B 0.09, respectively. These discrepancies can be explained by

ABC

© 2003 S. Karger AG, Basel 1420–4096/03/0262–0135$19.50/0


Accessible online at: www.karger.com/kbl

the high protein binding of flucloxacillin, the adsorbing property of polyamide and the equation in order to calculate hemofiltration clearance. The unbound fraction of a 4.0 g flucloxacillin dosage facilitates time above the minimum inhibitory concentration (T 1 MIC) of 60% only for strains up to a minimum inhibitory concentration (MIC) of 0.5 mg/l. Conclusion: Based on the data of this study, we conclude that intensive care patients with staphylococcal infections on CVVH should be treated with 4.0 g flucloxacillin every 8 h which was safe and well tolerated. Moreover, further studies with highly protein-bound drugs are recommended to check the classical ‘hemodialysis’ equation as the standard equation in calculating the CVVH clearance of highly protein-bound drugs. Copyright © 2003 S. Karger AG, Basel

Introduction

Staphylococcal infections have increased in the last two decades and Staphylococcus aureus is one of the most common causes of hospital-acquired infections such as pneumonia, nosocomial bloodstream infections and surgical wound infections. In addition, intravascular catheters or prosthetic devices are increasingly being used [1].

Florian Thalhammer, MD Department of Internal Medicine I, Division of Infectious Diseases University of Vienna, Währinger Gürtel 18–20, A–1090 Vienna (Austria) Tel. +43 1 40400 4440, Fax +49 89 24431 8696 E-Mail [email protected]

One of the major options for penicillin-resistant and methicillin-sensitive staphylococci is flucloxacillin. Flucloxacillin is an isoxazolyl penicillin with a high activity against most Gram-positive cocci, including S. aureus, coagulase-negative staphylococci and streptococci such as S. pyogenes or viridans streptococci. Against S. aureus and coagulase-negative staphylococci, flucloxacillin is at least as active as the glycopeptide antibiotics teicoplanin or vancomycin as well as linezolid [2, 3]. Flucloxacillin is primarily excreted by the kidney (47– 72%) in patients with normal glomerular function [4, 5] and its protein binding rate is extremely high with about 95% comparable to ceftriaxone or teicoplanin [6]. The elimination half-life (t1/2) ranges between 0.75 and 1.1 h in individuals with normal renal function (package insert) and is prolonged up to 2.8 h in patients with renal impairment [7]. Dependent on the characteristics of the renal replacement technique and the membrane used, half-lives of flucloxacillin during intermittent hemodialysis and continuous renal replacement therapy (CRRT) are between 2.5 and 9.9 h, respectively [5, 8]. Although flucloxacillin is an ‘old’ but still important antimicrobial drug, no multiple-dose studies with new synthetic, highly efficient dialysis membranes are available. Thus, the aim of this study was to analyze the pharmacokinetics of the highly protein-bound drug flucloxacillin during continuous venovenous hemofiltration (CVVH) and to discuss the difficulty in calculating the real flucloxacillin clearance under these conditions.

Materials and Methods Patients The study was performed in accordance with the guidelines of the local ethics committee. Ten intensive care patients (table 1) with acute renal failure and suspected or proven Gram-positive infection were included. The mean age and body weight were 61.1 B 10.1 years and 88.6 B 13.9 kg, respectively. All patients were anuric. Concomitant drug therapy comprised intravenous catecholamines, anticoagulation with heparin and morphine derivatives. None of the patients received albumin substitution. All patients received parenteral nutrition and required mechanical ventilation. None of the patients had a known hypersensitivity to flucloxacillin or other ßlactam antibiotics. Continuous Venovenous Hemofiltration CVVH was performed as described previously using a polyamide capillary hemofilter with a membrane surface of 0.7 m2 (FH 66D, Gambro, Stockholm, Sweden) [9]. CVVH was accomplished with a roller pump (Brady BM 11, Brady, Vienna, Austria) in connection with an automatic balancing system (Equaline, Amicon, Ireland). Mean blood flow rate was 169 B 24 ml/min, and ultrafiltration rate as well as post-dilution rate 57 B 9 ml/min, respectively. Bicarbon-

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ate-based crystalloid solution was infused as substitution fluid aiming at a balanced fluid therapy. Drug Administration and Sampling All patients received 4.0 g flucloxacillin (GlaxoSmithKline (GSK), Vienna, Austria) every 8 h after initiation of CVVH. Flucloxacillin was dissolved in 100 ml of physiological saline solution and infused over a period of 30 min into a central venous catheter different from the venous catheter used for CVVH. Blood samples were collected from the arterial (input) and venous (output) line of the extracorporeal circuit immediately prior to (baseline) and 30, 60, 90, 180, 360 and 480 min after starting the first infusion as well as immediately prior to and 30 min after the start of the infusion of consecutive doses. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the hemofilter at corresponding times. All samples were separated immediately and stored at –70 ° C until analysis. Drug Assay The concentration of flucloxacillin in serum and ultrafiltrate was performed by a high-performance liquid chromatography (HPLC). Briefly, after the addition of 750 Ìl of acetonitrile to 250 Ìl of serum or ultrafiltrate, the samples were centrifuged (5,000 g for 5 min at 4 ° C), and 200 Ìl of the supernatant was injected onto the HPLC column. The chromatographic assay included a Merck ‘La Chrom’ system (Merck, Darmstadt, Germany), equipped with an L-7250 injector, an L-7100 pump, an L-7300 column oven (set at 35 ° C to keep the retention times constant), a D-7000 interface and an L-7400 UV detector (220 nm). Separation of flucloxacillin was carried out using a Hypersil BDS-C18 column (5 Ìm, 250 ! 4.6 mm i.d.; Astmoor, UK) preceded by a Hypersil BDS-C18 pre-column (5 Ìm, 10 ! 4.6 mm i.d.) at a flow rate of 1 ml/min. Mobile phase A consisted of ammonium acetate (10 mM, pH 5.0 with acetic acid) and mobile phase B consisted of methanol. The gradient ranged from 40% methanol (0 min) to 60% B at 11 min and decreased linearly to 40% again at 11.2 min. The columns were allowed to re-equilibrate for 8.8 min between runs. Linear calibration curves were performed from the peak areas of flucloxacillin to the external standard by spiking drug-free rat serum and ultrafiltrate with standard solutions of flucloxacillin (final concentration ranging from 0.5 to 400 Ìg/ml). Detection limits, defined as a signal-to-noise ratio of 3, ranged from 206 ng/ml for serum and 203 ng/ml for ultrafiltrate. Intra-day values ranged from 1.3 to 3.0%, inter-day values from 1.5 to 3.2% using flucloxacillin concentrations of 5, 50 and 200 Ìg/ml serum. Pharmacokinetic Analysis The methods of pharmacokinetic analysis used have been described recently [10]. In brief, an open one-compartment model was applied. The elimination half-life was calculated by t1/2 = ln2/kel. The area under the serum concentration time curve (AUC) was determined by the trapezoidal rule and by extrapolation of the terminal slope to infinity. The total clearance (Cltot) was estimated as Cltot = i.v. dose/AUC, the volume of distribution (Vd) as Vd = Cl/kel. The clearance of hemofiltration (ClHF) was determined twice, first according to the ‘hemofiltration’ formula ClHF1 = [UFR W CUF]/CA, where UFR refers to the ultrafiltration rate and CUF and CA to ultrafiltrate and arterial (dialyzer inlet) serum flucloxacillin concentrations, respectively. Secondly, ClHF was computed according the ‘hemodialysis’ equation ClHF2 = QB W (CA – CB)/CA, where QB refers to the dialyzer blood flow and CB is the venous dialyzer (dialyzer outlet)

Meyer/Ahmed el Gendy/Delle Karth/ Locker/Heinz/Jaeger/Thalhammer

Fig. 1. Mean serum flucloxacillin concentra-

tions after a dosage of 4.0 g flucloxacillin (z x) and the estimated amount of unbound flucloxacillin (P) levels every 8 h in critically ill patients during CVVH (n = 10). The dashed lines are the limits of the breakpoint MICs of S. aureus.

Table 1. Patient characteristics

Patient

Age years

Weight kg

Sex

1 2 3 4 5 6 7 8 9 10

60 47 46 77 62 78 54 61 62 64

90 114 70 88 108 90 80 96 70 80

M M M M M M M M F M

WBC g/l 3.9 8.8 8.5 24.7 10.4 12.3 16.8 25.4 38.2 3.8

CRP mg/dl 1.2 7.9 5.4 18.4 2.3 7.2 11.1 17.4 8.4 3.8

Diagnosis

cardiomyopathy cardiogenic shock pericarditis peritonitis cardiomyopathy cardiogenic shock cardiomyopathy cardiomyopathy ARDS Lyell syndrome

WBC = White blood cell count; CRP = C-reactive protein; ARDS = adult respiratory distress syndrome.

serum drug concentration, respectively. The sieving coefficient (Sc) was calculated as Sc = CUF/CA. Total removal (Re) of the drug during hemofiltration was calculated as Re = (Cmax – Cmin)/Cmax W 100, where Cmax and Cmin are arterial serum drug concentrations at the peak (47 min after the start of the drug infusion) and at the trough of the first dosing interval, respectively. Times above the MIC (T 1 MIC) were calculated according to the equation %T 1 MIC = ln[Dose/(Vd W MIC)] W [t1/2/ln(2)] W (100/DI), where ln is the natural logarithm and DI the dosing interval (h) [11]. Based on T 1 MIC, the total daily dose of flucloxacillin was calculated to achieve an average steady-state concentration of four times the breakpoint MIC of S. aureus and coagulase-negative staphylococci. Data are presented as mean B SD.

Flucloxacillin and Continuous Venovenous Hemofiltration

Results

In the 10 critically ill patients, the peak flucloxacillin concentrations 47 min after starting the infusion were 143.8 B 65.0 mg/l at the arterial port and 85.8 B 28.3 mg/l at the venous one. The mean trough levels of flucloxacillin 8 h after starting the infusion were 59.5 B 36.8 and 25.5 B 14.1 mg/l, respectively. Peak flucloxacillin concentrations of the next five infusions ranged between 139.1 B 57.4 and 179.7 B 76.0 mg/l at the arterial port. The corresponding arterial trough levels were 54.3 B 32.0 and 74.0 B 46.8 mg/l (fig. 1). The amount of flu-


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Table 2. Individual pharmacokinetic data

of 10 study patients

Patient

1 2 3 4 5 6 7 8 9 10

Pharmacokinetic parameters Cmax, mg/l

Cmin, mg/l

CUF, mg/l

Cltot, ml/min Vd, l

t½, h

142.2 153.4 139.8 56.4 153.5 43.7 102.1 284.4 172.6 189.6

38.1 71.7 131.8 14.4 26.9 15.1 71.9 50.6 107.8 66.7

4.8 12.4 13.2 8.2 4.3 8.9 15.3 14.3 19.5 22.0

100.4 87.9 87.7 307.8 116.3 224.7 71.3 57.9 69.3 48.6

4.2 5.3 4.2 5.1 5.7 4.7 6.2 5.1 3.6 4.8

21.6 39.7 32.2 136.7 57.3 92.3 38.4 25.5 21.6 16.0

Cmax = Peak serum concentration; Cmin = trough serum concentration; CUF = concentration in the ultrafiltrate; Cltot = total clearance; Vd = volume of distribution; t1/2 = half-life.

cloxacillin removed in ultrafiltrate was 350.9 B 285.2 mg, accounting for 15% of the total drug. The individual pharmacokinetic parameters are listed in table 2. Elimination half-life was 4.9 B 0.7 h. The mean AUC was 568.0 B 285.9 mg W h/ml and volume of distribution and sieving coefficient were 48.1 B 36.4 and 0.21 B 0.09 l, respectively. The average total removal during hemofiltration was 56.9 B 24.0% and the mean difference in flucloxacillin concentration between the arterial and venous port was 26.4 B 3.5%. The total body clearance was 117.2 B 79.1 ml/min. The results of the calculated flucloxacillin hemofiltration clearance were significantly different (p ! 0.001): ClHF1 (hemofiltration formula) was 10.3 B 4.5 ml/min and ClHF2 (hemodialysis formula) 41.7 B 23.5 ml/min, respectively. Maximal killing of ß-lactam antibiotics, especially for multiresistant bacteria, was reported to be highest at about the fourfold MIC of the target pathogen. Based on this aspect, the flucloxacillin clearance data obtained from our study were used to calculate the minimum daily dosage requirements. Based on the unbound flucloxacillin fraction, the calculated percentage of T 1 MIC was 20% related to a MIC of 1 mg/l and 60% to a MIC of 0.5 mg/l, respectively.

Discussion

Staphylococcal infections are among the most common causes of hospital-acquired infections in intensive care patients [12]. Oxacillin and flucloxacillin are the

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major option for penicillin-resistant and methicillin-susceptible staphylococci in the treatment of these infections [13]. Many intensive care patients are in need of renal replacement therapy [14, 15]. CVVH is an important option and usually performed for its good hemodynamic tolerance. Knowledge of the impact of CVVH on the elimination of drugs is essential, but studies with modern polysulfone membranes and the influence of highly proteinbound drugs are scarce. In addition, drug pharmacokinetics in critically ill patients can be altered by an increased volume of distribution and extended elimination half-life. The present study is focused on the pharmacokinetic and pharmacodynamic aspects of flucloxacillin treatment during CVVH with modern polysulfone membranes in critically ill patients and the complex discussion how to calculate hemofiltration clearance of highly proteinbound drugs. Pharmacokinetic Aspects All patients tolerated the intravenous infusion of 4.0 g flucloxacillin (46.2 B 7.1 mg/kg b.w.) every 8 h without apparent side effects. Peak levels of 144–180 mg/l after a 4.0 g flucloxacillin infusion in our study were significantly lower than the peak of 244 mg/l found in healthy volunteers after a 2.0 g infusion (specialized information, GSK). In contrast to the decreased peak levels, elimination half-life is increased to 4.9 B 0.7 h as compared to 0.75–1.1 h in healthy volunteers. In patients with impaired kidney function, half-life is reported in a wide range between 2.6 h in patients with renal impairment, 2.9 h during intermittent hemodialysis and 9.9 h during CVVH [5, 7, 8].


There is a great difference between the low sieving coefficient (Sc 0.2 B 0.9), the small hemofiltration clearance (ClHF 10.3 B 4.5 ml/min) as well as the small drug concentration in the ultrafiltrate (CUF 12.3 B 5.5 mg/l) and on the opposite side the high total clearance (Cltot 117.2 B 79.1 ml/min), the significant drug removal (Re 56.9 B 24.0%) and the high difference in flucloxacillin concentration between the arterial and venous port (AV difference 26.4 B 3.5%). Similar major differences are described with ceftriaxone and teicoplanin in patients during renal replacement therapy [16–18]. Both antimicrobial drugs are highly protein bound as flucloxacillin and both drugs are not (ceftriaxone), or only to a small degree (teicoplanin), detected in the dialysate/ultrafiltrate. Thus, a possible explanation for this discrepancy is the high protein binding of flucloxacillin, the adsorbing property of modern dialyzers and the equation in order to calculate hemofiltration clearance. Whereas the ClHF calculation is based on the equation ClHF = [UFR W CUF]/CA, where UFR refers to the ultrafiltration rate and CUF and CA to ultrafiltrate and arterial (dialyzer inlet) serum concentration, the clearance calculation for hemodialysis (ClHD) takes the venous (dialyzer outlet) serum concentration instead of the dialysate (ultrafiltrate) concentration into account according to the formula ClHD = QB W (CA – CB)/CA, where QB refers to the dialyzer blood flow. A decrease of serum drug concentration due to drug adsorption to the dialyzer or secondary membrane formation is ignored in the ClHF clearance calculations. As a consequence of these considerations it has to be discussed whether the hemodialysis equation has to be used to calculate clearance during continuous hemofiltration to avoid underdosing of important highly protein-bound antimicrobial drugs, because neither ceftriaxone nor teicoplanin are today known as non-dialyzable drugs, although these antimicrobial drugs are not detected in the dialysate/ultrafiltrate.

Pharmacodynamic Aspects The goal of dosing ß-lactam antibiotics is to maintain concentrations above the MIC at the site of infection throughout the dosing interval. Additionally, an average steady-state concentration of the fourfold MIC of the target organism is necessary to achieve maximum killing of ß-lactam antibiotics [11]. In our study a flucloxacillin dosage of 4.0 g every 8 h during CVVH ensures a sufficient T 1 MIC to cover methicillin-susceptible staphylococcal bacteria with a breakpoint MIC of 4 mg/l. In neutropenic patients, drug levels should exceed the MIC for the entire dosing interval (T 1 MIC = 100%) [11, 19]. We even believe that critically ill patients should receive maximal treatment (T 1 MIC close to 100%) to avoid treatment failures with often fatal consequences. A 4.0 g flucloxacillin every 8 h guideline theoretically facilitates T 1 MIC of 146% for all strains up to a MIC of 4 mg/l. However, based on the estimated unbound amount of flucloxacillin, the calculated percentage of T 1 MIC was 20% related to a MIC of 1 mg/l and 60% to a MIC of 0.5 mg/l, respectively. In summary, flucloxacillin is significantly reduced by CVVH, however our results suggest a regimen of 4.0 g flucloxacillin every 8 h to be appropriate for the treatment of most of the methicillin-susceptible Gram-positive infections of intensive care patients during CVVH. Secondly, further CRRT studies with highly protein-bound drugs are necessary to demonstrate a required modification in calculating drug clearance during CRRT.

Acknowledgements The study was supported by a grant of the Hochschuljubiläumsstiftung der Stadt Wien and by the European Commission within the IST Craft-2001-52107 project PharmDIS.

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Flucloxacillin and Continuous Venovenous Hemofiltration

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16 Gabutti L, Taminelli-Beltraminelli L, Marone C: Clearance of ceftriaxone during haemodialysis using cuprophane, haemophane and polysulfone dialysers. Eur J Clin Pharmacol 1997; 53:123–126. 17 Pea F, Brollo L, Lugano M, Dal Pos L, Furlanut M: Therapeutic drug monitoring-guided high teicoplanin dosage regimen required to treat a hypoalbuminemic renal transplant patient undergoing continuous venovenous hemofiltration. Ther Drug Monit 2001;23:587–588. 18 Hillaire-Buys D, Peyriere H, Lobjoie E, Bres J, Ossart M, Despaux E: Influence of arteriovenous haemofiltration on teicoplanin elimination. Br J Clin Pharmacol 1995;40:95–97. 19 Drusano GL: Role of pharmacokinetics in the outcome of infections. Antimicrob Agents Chemother 1988;32:289–297.


Author Index Vol. 26, No. 2, 2003


Ahmed el Gendy, S. 135 Böhler, J. 82 Brause, M. 128 Deicher, R. 100 Delle Karth, G. 135 Donauer, J. 82 Fassbinder, W. 96 Fusshöller, A. 118 Galle, J. 65 Grabensee, B. 118, 128 Haag-Weber, M. 90 Heering, P. 128 Heinz, G. 135 Hörl, M.P. 76

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2003 S. Karger AG, Basel


Hörl, W.H. 64, 76, 100, 107 Jaeger, W. 135 Jörres, A. 113 Locker, G.J. 135 Meyer, B. 135 Oberpichler, A. 107 Plum, J. 118 Riegel, W. 123 Schmaldienst, S. 107 Seibold, S. 65 Thalhammer, F. 135 Tschesche, H. 107 Wanner, C. 65

141

Subject Index Vol. 26, No. 2, 2003


Acute renal failure 123 Antioxidants 65 Atherosclerosis 65 Automated peritoneal dialysis 118 Biocompatibility 113, 118 Blood volume 82 – temperature 82 CA 125 118 Chronic kidney disease 100 Continuous venovenous hemofiltration 123, 128, 135 C-reactive protein 65 Cytokine removal 128 Dialysate temperature 82 Dialysis 76 – -induced hypotension 82 Elastase 107 Flucloxacillin 135 GENIUS® 96 – hemodialysis system 96 Glucose degradation products 113

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2003 S. Karger AG, Basel


Hemodiafiltration 107 Hemodialysis 82, 96, 107, 123 Hemofiltration 135 Individualized dialysis fluid 96 Inflammation 65 Intensive care unit 135 Oxidative stress 65, 100 Oxygen radicals 65 Peritoneal dialysis fluids 113 – transport 118 Pharmacokinetics 135 Polymorphonuclear leukocytes 107 Protein binding 135 Sepsis 128 Staphylococcal infections 135 Superoxide 65 Ultrapure dialysate 96 Uremia 65 Vitamin C 100 – E 65

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