Epoetin treatment: what are the arguments to expect a beneficial effect on renal disease progression?

Jerome Rossert,1, William M. McClellan2, Simon D. Roger3 and Dierik L. Verbeelen4

1 AP-HP, The University of Paris VI and INSERM U489, Paris, France, 2 Department of Medicine, Emory University, Atlanta, GA, USA, 3 Department of Renal Medicine, Gosford Hospital, Gosford, Australia and 4 Renal Unit, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium

Keywords: anaemia; chronic kidney disease; epoetin; fibrosis; hypoxia; oxidative stress

Introduction

Progression of chronic kidney disease is usually a relentless process. It is initially induced by the underlying kidney disease and its consequences. But, when nephron numbers decrease beyond a certain threshold, it is also caused by deleterious effects of this reduction in nephron number, which creates a vicious circle. Besides treatment of the underlying renal disease whenever possible, the main therapeutic tools that are available to slow the progression of renal failure are optimal control of blood pressure, use of angiotensin-converting enzyme inhibitors, and to a lesser extent dietary protein restriction (reviewed in [1]). The efficacy of these therapies is, however, limited, and the need for other treatments is highlighted by the observation that, for the past decade, the incidence of end-stage renal disease has been increasing at an annual rate of about 6–8% in most European countries. Among the other therapeutic interventions that could slow the progression of renal failure is correction of anaemia through administration of epoetin. Its potential usefulness is suggested by analysis of the pathophysiological mechanisms underlying progression of renal failure and by a few clinical studies.

The roles of epoetin go beyond correction of hypoxia

It is unanimously recognized that correcting anaemia with epoetin increases oxygen delivery to tissues and thus reduces hypoxia, even if epoetin may have some vasoconstrictor properties [2]. Nevertheless, this treatment may have other beneficial effects, including protection against oxidative stress and apoptosis (Figure 1Go).



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Fig. 1.  Schematic representation of the mechanisms by which treatment with epoetin may modulate the progression of chronic kidney diseases. See text for details.

 
The links between oxidative stress and anaemia come from the fact that erythrocytes represent a major antioxidant component of the blood (reviewed in [3]). Their antioxidant effects are mediated through the glutathione system, enzymes such as superoxide dismutase or catalase, and cellular proteins that are devoid of enzymatic activity but can react with reactive oxygen species, such as low-molecular weight proteins of the erythrocyte membrane, vitamin E or coenzyme Q. Furthermore, erythrocytes can regenerate consumed redox equivalents through the pentose phosphate pathway, and through reduction of oxidized glutathione by glutathione reductase.

The ability of erythropoietin to promote survival of red blood cells via binding to its receptor has been clearly established, and it appears to be mediated by an inhibition of caspase activation, and by an induction of the expression of antiapoptotic proteins such as Bcl-xL and Bcl-2 [4,5]. Recent in vivo data have shown that anti-apoptotic effects can also be observed with other cell types expressing the erythropoietin receptor, such as neuronal cells [6,7]. In vitro, epoetin has also been shown to protect endothelial cells or vascular smooth muscle cells against apoptosis [8,9]. One can speculate that this effect also exists for other cells that express the erythropoietin receptor, such as proximal tubular cells and medullary collecting duct cells [10].

Interstitial fibrosis and tubular damage play a key role in the progression of renal failure

While for a long time nephrologists focused on glomeruli to try to decipher the mechanisms of progression of renal failure, a few years ago attention switched toward the tubulo-interstitial compartment of the kidney, and interstitial fibrosis is now recognized as one of the key factors of progression (Figure 2Go). The main reason for such a shift of paradigm was probably the observation that, in many cases, there is a striking correlation between renal function and severity of interstitial fibrosis, and that interstitial fibrosis is the best prognostic marker of progression (reviewed in [11]). The major mechanism by which interstitial fibrosis affects renal function seems to be the induction of tubular lesions that ultimately lead to tubular destruction, with formation of atubular glomeruli [12]. This has been nicely exemplified by study of a remnant kidney model. Histological examination 25 weeks after surgery showed that almost half of the remaining glomeruli were atubular and one fourth were connected to atrophic tubules while only 14% were globally sclerotic, suggesting that progression toward end-stage renal failure was mostly secondary to tubular destruction [13].



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Fig. 2.  Schematic representation of the mechanisms of progression of glomerular diseases. An initial glomerular insult is responsible for glomerulosclerosis, leading to reduction in nephron number (black colour). Reduced nephron number induces an increase in glomerular capillary pressure and/or in glomerular volume, leading to further glomerular damage (blue colour). Reduced nephron number is also associated with tubular dysfunction responsible for interstitial fibrosis, that, in turn, leads to destruction of peritubular capillaries and to tubular destruction (red colour). Destruction of interstitial capillaries may also increase glomerular capillary pressure, and thus enhance glomerular damage (dotted red line). Proteinuria enhances tubular dysfunction and, thus, interstitial fibrosis (dotted black line).

 

Hypoxia appears to link interstitial fibrosis and tubular damage

As suggested by Fine et al. [14], hypoxia of tubular cells may be the main link between interstitial fibrosis and tubular damage. Tubular hypoxia appears to be secondary not only to increased oxygen consumption by the remaining nephrons or to interposition of extracellular matrix between capillaries and tubules, but also to destruction of peritubular capillaries, since histological analyses have shown a strong inverse correlation between the number of peritubular capillaries and either the extent of interstitial fibrosis or the severity of renal failure. For example, in a rat model of glomerulonephritis, interstitial volume was tightly correlated with the number of interstitial capillaries, and in patients with diabetic glomerulosclerosis renal function was very strongly correlated with the relative area of postglomerular capillaries [15,16]. The concept that interstitial fibrosis is associated with hypoxia of tubular cells is also supported by a recent study of renal biopsies with various tubulo-interstitial diseases [17]. It showed not only a loss of peritubular capillaries but also an overexpression of vascular endothelial growth factor by tubular cells, suggesting that these cells are deprived of oxygen.

Hypoxia could play a role not only in inducing tubular damage, but also in favoring the development of interstitial fibrosis. In vitro, hypoxia has been shown to increase collagen production by different fibroblastic cells, including human renal fibroblasts [18,19]. Furthermore, the production of TGF-ß, which is a potent profibrotic cytokine, is stimulated by oxygen deprivation [18]. Finally, in some in vitro experiments, hypoxia also decreased the production of metalloproteases and increased the expression of one of their inhibitors, TIMP-1, suggesting that it may slow the degradation of extracellular matrix [19].

Oxidative stress and apoptosis may enhance the effects of hypoxia

Associated with chronic reduction in nephron number, is an increased oxygen consumption by the remaining nephrons, which leads to an increased production of reactive oxygen species (reviewed in [20]). This oxidative stress may enhance both tubular damage and interstitial fibrosis. Experimental data have shown that oxidative stress stimulates interstitial production of extracellular matrix, and for example, in vitro, non-cytolytic doses of hydrogen peroxide stimulate collagen synthesis by renal fibroblastic cells, as well as TGF-ß production [21]. Similarly, lipid peroxidation products, which are produced in increased amounts in response to oxidative stress, up-regulate collagen production by fibroblasts [22,23]. In vivo, treatment of rats with antioxidants can protect against the development of interstitial fibrosis, while deprivation of antioxidants seems to have opposite effects [21,24].

Recently, apoptosis has also been implicated in the progressive loss of tubular cells observed during chronic kidney diseases. For example, apoptosis appears to play an important role in the progression of tubular atrophy in kidneys of rats submitted to subtotal nephrectomy or to experimental anti-glomerular basement membrane nephritis [25,26]. The mechanisms underlying this increased apoptosis of tubular cells are still poorly understood, but reactive oxygen species have also been shown to have proapoptotic effects [27].

Clinical studies suggest that epoetin may slow the progression of renal failure

Since progressive destruction of tubules appears to play a key role in the progression of chronic kidney diseases, and to depend on hypoxia, oxidative stress, and apoptosis, it is easy to envisage a beneficial effect of correcting anaemia with epoetin. The possibility of such a protective effect is actually supported by a few clinical studies. The effects of correcting anaemia with epoetin on the progression of renal failure have been tested in two prospective studies including a relatively large number of patients [28,29]. The first study included 83 patients with severely impaired renal function [28]. No beneficial effect of epoetin could be demonstrated by simply comparing the two groups of patients. Nevertheless, when the patients were analysed only after their haemoglobin levels had reached the target values, the rate of glomerular filtration rate decline was three times slower in the treated group than in the control group. In the second study, which included patients with less severe renal failure, partial correction of anaemia with epoetin significantly slowed the rate of progression of renal failure [29]. During the follow-up period, creatinine doubled in about 50% of the patients in the treated group, and in more than 90% of the patients in the control group.

In conclusion, different experimental data support the hypothesis that correction of anaemia with epoetin may slow the rate of progression of renal failure, and a few small clinical studies also suggest that this hypothesis is worthy of testing. The definitive answer should come from the ECAP study (Effect of early Correction of Anaemia on the Progression of chronic kidney disease). In this trial, 630 patients from Europe, North America and Australia will be randomly assigned to partial or complete correction of anaemia and followed-up using iohexol-based measurements of glomerular filtration rate to assess disease progression.

Notes

Correspondence and offprint requests to: Jerome Rossert, Department of Nephrology, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France. Email: jerome.rossert{at}tnn.ap\|[hyphen]\|hop\|[hyphen]\|paris.fr Back

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