Anaemia correction—does the mode of dialysis matter?

Editor's note See also Original Article by F. Locatelli et al. this issue, pp. 1399–1409

Kai-Uwe Eckardt

Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany

Introduction

The enormous success of treating renal anaemia with recombinant human erythropoietin (rhEpo) during the last 15 years easily lets one forget that the discussion about the pathogenesis of renal anaemia was dominated for decades by the question whether it is primarily due to relative Epo deficiency or uraemic inhibition of erythropoiesis. Although it has so far not been possible to identify or isolate a substance retained in uraemia with a suppressive action directed specifically against red cell production, dialysis therapy can improve the effect of both residual endogenous and exogenous rhEpo. To which extent mode and/or dose of dialysis influence Epo efficacy is yet poorly understood. In this issue Locatelli et al. report the results of a prospective multicentre trial that provides some new evidence related to this question and the potential role of uraemic inhibitors of red cell production [1].

Uraemic toxins as inhibitors of erythropoiesis?

Plasma Epo levels in patients with chronic renal failure do not rise appropriately for the degree of their anaemia. Instead they remain within or only slightly above the normal range of non-anaemic individuals. This relative deficiency in Epo is considered as the main cause of renal anaemia [2]. In addition, however, the rates of red cell production in haemodialysis patients were estimated to be only about one half of the rate in normal individuals despite the same or even higher Epo titres [3]. Conversely, serum Epo levels achieved with s.c. administration of 100 IU rhEpo/kg b.w.—a dose which many patients require to maintain a subnormal haemoglobin level—are higher than serum concentrations that have been measured during the correction phase of anaemia after kidney transplantation [4,5]. Thus factors other than Epo deficiency seem to blunt the effect of the hormone on red cell production in uraemic patients. Although such factors can usually be overcome by rhEpo, Epo resistance is a clinically and economically relevant problem.

Among the factors affecting red cell production in renal failure, iron deficiency, inflammatory mediators and several others have received considerable attention during recent years, but the role of specific uraemia-associated inhibitors of erythropoiesis has remained unclear. When canine or murine erythroid progenitor cells were cultured in vitro with Epo, the addition of uraemic human serum was found to inhibit the growth of erythroid colonies [6]. However, the clinical relevance of this inhibition is questionable, since it is not specific for red cell production and also affects granulo- and megakaryopoiesis [7], which are both not suppressed in chronic renal failure. Moreover, inhibition of erythropoiesis was not observed in cultures of marrow cells from uraemic patients incubated with autologous sera [8]. Among the polyamines, spermine was considered as an inhibitor of erythropoiesis that accumulates in patients with renal failure [9], but its effect also appears to be non-specific [10]. Parathyroid hormone was found to impair erythroid colony growth [11], but these results could not be reproduced in other experiments [12]. Probably the adverse effect of hyperparathyroidism on red cell production is at least partially due to marrow fibrosis [13]. Albumin bound metabolites such as furancarboxylic acid were reported to have some inhibitory effect on marrow cultures [14], but their role has also not been clarified. Moreover, in ferrokinetic studies the acute response to rhEpo was not found to be significantly different in normal and uraemic subjects [15], which argues against the general importance of uraemic inhibitors of red cell production.

Although direct proof for the existence of substances specifically inhibiting red cell formation in uraemia is lacking, this does not exclude that a variety of different molecules accumulating in the uraemic state may contribute to an impairment of erythropoiesis. In support of this it has been observed since several decades that haemoglobin levels can increase following the onset or a change of dialysis therapy.

Effects of dialysis in patients not treated with rhEpo

Once haemodialysis has been started, some patients experience a significant improvement in haematocrit, which occurs in the absence of a concomitant increase in the levels of endogenous Epo [16]. Moreover, Koch et al. demonstrated in 1974 that in patients already on haemodialysis an increase in treatment time from 2x10 to 3x10 h per week was associated with a marked rise in haematocrit levels [17]. A significant inverse relationship between haemoglobin levels and weekly duration of haemodialysis was also found in a large European survey of factors that influenced the degree anaemia before rhEpo became widely available [18]. In this study 11 or more hours of dialysis per week (up to >15 h) were associated with a steadily increasing haemoglobin concentration. Patients treated with long, slow dialysis sessions in Tassin (8 h) also have much lower rhEpo requirements for similar haematocrit levels than patients on short, more rapid dialysis schedules (3–5 h) [19].

Significant improvements of anaemia have also been noted in patients started on or shifted to continuous ambulatory peritoneal dialysis (CAPD) [20,21]. In general anaemia in CAPD patients appears to be somewhat less severe than in haemodialysis patients and a greater proportion of patients on CAPD achieve normal haematocrits than do patients on haemodialysis. The underlying mechanisms are complex and may include such diverse factors as lower plasma volume, reduced blood (and iron) loss and improved Epo production. Since the clearance of ‘middle-molecules’ is higher with CAPD than with standard HD, it is also tempting to speculate that higher-molecular weight uraemic erythropoietic inhibitors are being removed by CAPD.

Effects of dialysis on the responsiveness to rhEpo

In view of the above findings it is not surprising that dialysis treatment is also one of the factors that contributes to the efficacy of exogenous, recombinant Epo. Ifudu et al., in a study published in 1996, observed a direct correlation between the haematocrit and the intensity of dialysis, as determined by the urea-reduction value, in a group of haemodialysis patients in the US [22]. The rhEpo dose was not controlled, but it correlated inversely with the haematocrit and thus could not explain the variation in the degree of anaemia. Moreover, Ifudu et al. showed that in 20 ‘inadequately’ dialysed patients given a fixed dose of rhEpo an increase in ‘dialysis level’ from a mean baseline urea-reduction value of 60.7% to 72.0% was accompanied by an increase in mean haematocrit from 28.4 to 32.3% within 6 weeks. Although the authors concluded that increasing the ‘intensity’ of dialysis improved the response to rhEpo, the interpretation of this study was hampered by the fact that not only the duration of each dialysis treatment was prolonged, but patients were also switched from a cellulose acetate to a high-flux polysulphone dialyser. The question therefore arose from this trial whether improved Epo responsiveness was due to increased removal of substances cleared by conventional dialysers or the removal of additional, larger molecules through the high-flux dialyser and/or better biocompatibility of this type of membrane. In fact additional data from uncontrolled studies suggested that high-flux dialysis could improve anaemia (discussed in [1]).

Against this background Locatelli et al. have now performed a randomized controlled multicentre trial, in which they tested the question whether the use of a large-pore biocompatible membrane might improve anaemia in comparison to a conventional cellulose membrane, with the dialysis dose being kept constant [1]. Eighty-four stable patients without evidence of severe iron, folate or vitamin B12 deficiency, aluminium intoxication or severe hyperparathyroidism, who had relatively low haematocrit values (<30%) and thus should be sensitive to any factors improving erythropoiesis, were selected for study. They all received haemodialysis with a cellulose dialyser for at least 6 months before being randomized to either continue therapy with the cellulosic membrane or to switch to a high-flux membrane with the same surface area as the cellulose dialyser used before study entry. The study period was 12 weeks. Seventy-eight per cent of patients concluding the trial received rhEpo. The main result is that rhEpo dose and haemoglobin levels were not significantly different between the two groups [1].

Conclusions

What can be stated at present about the impact of the dialysis procedure on Epo therapy?

First, although the exact relationship between Epo efficacy and the amount of dialysis has not been determined, a level of dialysis that is considered ‘inadequately low’ with respect to mortality risk is associated with Epo resistance. The Italian trial supports this by indicating that the improvement of Epo efficacy observed within a few weeks in the setting studied by Ifudu et al. [22] was mainly due to increase in dialysis intensity rather than change of dialysis membrane.

Second, although the effects of dialysis on Epo efficacy support the concept that inhibitors accumulating in uraemia can play a significant role, the attempt to obtain evidence for the existence of higher-molecular weight inhibitors by use of a high flux membrane has failed. However, as in many previous studies related to this issue absence of evidence is not necessarily evidence for absence. Locatelli et al. are careful enough to point out that sample size and trial duration may have been too short to detect an effect, in particular since patients in the experimental group showed a (non-significant) trend towards increased haemoglobin levels.

Third, similar considerations hold true for the biocompatibility aspect. Although Locatelli et al. could not show that using a synthetic membrane improves anaemia, it is important to remember that factors other than the dialyser, in particular the quality of the dialysate, may influence the latent inflammatory state in uraemics. This, however, was not the focus of the trial and effects on cytokine levels or acute phase reactants were not reported.

Fourth, when considering the role of Epo resistance in general, it is noteworthy that in only very few patients the resistance is absolute. In the majority of patients moderate iron deficiency, inflammation, and also effects of the uraemic milieu can obviously be overcome to some extent by increasing the rhEpo dose. Most excitingly in this respect very high doses of rhEpo have recently even been shown to be effective in intensive care patients [23]. From an economic perspective, the question of Epo resistance will therefore probably become less significant once the costs of Epo therapy will fall. On the other hand it is possible that the ability to overcome Epo resistance declines with increasing target haemoglobin levels. In view of the current discussion about normalisation of haemoglobin in patients with renal failure the issue of optimising Epo efficacy may thus even gain importance.

In any case an increasing or comparatively high dose requirement for rhEpo in ESRD patients is and will remain a reason to check and ensure that the patient receives a sufficient amount of dialysis.

Notes

Correspondence and offprint requests to: Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, Humboldt University, D-13353 Berlin, Germany. Back

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