Anemia Management and the Delay of Chronic Renal Failure Progression
Jerome Rossert,
Bruno Fouqueray and
Jean Jacques Boffa
University of Paris VI, Tenon Hospital (AP-HP) and INSERM U489, Paris, France.
Correspondence to Dr. Jerome Rossert, Department of Nephrology and INSERM U489, Tenon Hospital, 4 rue de la Chine, 75020 Paris, France. Phone: 33-1-56-01-60-29; Fax: 33-1-56-01-69-99;
ABSTRACT. Interstitial fibrosis plays a key role in the progressionof chronic kidney diseases. Analysis of the biologic effectsof erythropoietin and of the pathophysiology of interstitialfibrosis suggest that treatment with epoetin may slow the progressionof chronic kidney disease, both by decreasing interstitial fibrosisand by protecting against its consequences. The results of twosmall prospective studies and of a retrospective one also suggestthat treatment with epoetin may have such protective effects.E-mail: jerome.rossert@tnn.ap-hop-paris.fr
End-stage renal disease is a major health problem resultingin considerable increase of morbidity and mortality, in decreaseof quality of life, and in heavy costs from renal replacementtherapies. Furthermore, for the past decade, the incidence ofESRD has been relentlessly increasing at an annual rate of about6 to 8% in most European countries, and even more rapidly inthe United States. Slowing the progression of renal failurethus appears to be a major therapeutic challenge. Besides treatmentof the underlying disease whenever possible, the main therapeutictools that are available to slow the progression of renal failureare optimal control of BP, use of angiotensin converting enzyme(ACE) inhibitors or of angiotensin II receptor blockers (ARB),and protein restriction (reviewed in 1, 2). The efficacy ofthese therapies is however limited, and there is a need foradditional treatments. Among the therapeutic interventions thatcould possibly slow the progression of CKD is correction ofanemia through administration of epoetin.
Mechanisms of Progression of Chronic Renal Failure
Regardless of the underlying renal disease, progression of CKDleads to a common histologic endpoint, the "end-stage kidney,"that is characterized by nonfunctional sclerotic glomeruli,atrophied tubules, and a fibrotic interstitium. Nephron destructionis not only a direct consequence of the underlying renal disease,but it is also due to progressive glomerulosclerosis secondaryto nephron reduction, and to tubular damage associated withinterstitial fibrosis (Figure 1).
Figure 1. Schematic representation of the mechanisms of progression of glomerular diseases. An initial glomerular insult is responsible for glomerulosclerosis, leading to reduction in nephron number. Reduced nephron number induces an increase in glomerular capillary pressure and/or in glomerular volume, leading to further glomerular damage (left-hand side). Reduced nephron number is also associated with tubular dysfunction responsible for interstitial fibrosis, that is associated with destruction of peritubular capillaries and leads to tubular destruction (right-hand side). Destruction of interstitial capillaries may also increase glomerular capillary pressure, and thus enhance glomerular damage (dotted line). Proteinuria enhances tubular dysfunction and, thus, interstitial fibrosis (dotted line).
Glomerulosclerosis
Various experimental studies in rats have demonstrated thatreduction in nephron number favors the occurrence of glomerulosclerosis(reviewed in 3). Histological and physiologic studies of ratsundergoing subtotal nephrectomy have shown that nephron lossincreases capillary pressure and flow in the remaining glomeruliand induces hypertrophy of these glomeruli, which in turn leadsto podocyte injury and to overproduction of extracellular matrixby mesangial cells (reviewed in 4–6). Experimental datasuggest that PDGF and TGF- play an important role in this process(7,8). Furthermore, they show that the occurrence of glomerulosclerosiscan be prevented by the use of ACE inhibitors or by a low proteindiet (reviewed in 9). In humans, sequential studies of few patientswith an important reduction of their renal mass have also shownthat a decrease in nephron number can also be responsible forthe development of glomerulosclerosis (10,11).
Interstitial Fibrosis
The notion that interstitial fibrosis plays an important rolein the progression of CKD is mostly supported by two kinds ofobservations. First, for many renal diseases, there is a strikingcorrelation between renal function at the time of biopsy andseverity of interstitial fibrosis on renal biopsy (reviewedin 12). Second, the extent of interstitial fibrosis is the besthistologic prognostic marker of most renal diseases (reviewedin 13). Studies of human renal biopsies and of experimentalmodels of CKD have shown that one of the most striking featuresassociated with interstitial fibrosis is the presence of so-called"atubular glomeruli," which consist of nonsclerotic glomerulithat are not linked to a tubule (14,15). This suggests thatinterstitial fibrosis decreases nephron number by inducing tubularlesions that lead to tubular destruction, with formation ofnonfunctional atubular glomeruli. Analyses of renal biopsiesobtained from patients with renal failure and from animals withvarious experimental renal diseases have also shown that, besidestubular destruction, interstitial fibrosis is associated witha decrease in the number of peritubular capillaries (reviewedin 16), and that there is a good inverse correlation betweenthe severity of interstitial fibrosis and the number of peritubularcapillaries as well as between renal function and the numberof interstitial capillaries (12,17,18). Thus, it is likely thatthe destruction of peritubular capillaries links interstitialfibrosis and tubular destruction (Figure 1). The combinationof an overproduction of thrombospondin-1 by tubular and interstitialcells, and of a loss of VEGF synthesis by tubular cells couldplay a key role in this process (reviewed in 16). However, theischemic lesions of tubular cells are probably due not onlyto a destruction of peritubular capillaries, but also to aninterposition of extracellular matrix between capillaries andtubules, which decreases oxygen delivery to tubular cells. Furthermore,they are worsened by an increased consumption of oxygen by theremaining tubular cells, and this is likely to be one of themechanisms by which proteinuria or high protein diet acceleratethe progression of CKD (19). Finally, obstruction of peritubularcapillaries may also increase the hydrostatic pressure in glomerularcapillaries, and thus favor the occurrence of glomerulosclerosis(6,20).
Tubular cells appear to play a key role in the pathogenesisof interstitial fibrosis, because they can both transdifferentiateinto fibroblastic cells through a process called epithelial-mesenchymaltransition (21) and release various proinflammatory and profibroticmolecules (22,23). Hypoxia and overproduction of reactive oxygenspecies are two of the factors that promote the release of theseproinflammatory and profibrotic molecules, as shown by in vitrostudies (24–26). Furthermore, hypoxia and reactive oxygenspecies directly enhance the synthesis of extracellular matrixby fibroblastic cells (27–31).
It is well known that correcting anemia with epoetin increasesoxygen delivery to tissues and thus reduces hypoxia. Nevertheless,this treatment may have other beneficial effects, includingprotection against oxidative stress and apoptosis (Figure 2).
Figure 2. Schematic representation of the potential beneficial effects of epoetin treatment. Epoetin may protect against tubulointerstitial injury by increasing oxygen delivery to tubular and interstitial cells, by decreasing oxidative stress, and by protecting cells that express the erythropoietin receptor against apoptosis (see text for details).
The links between oxidative stress and anemia come mostly fromthe fact that erythrocytes represent a major antioxidant componentof the blood (reviewed in 32). Their antioxidant effects aremediated through the glutathione system, enzymes such as superoxidedismutase or catalase, and cellular proteins that are devoidof 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 regenerateconsumed redox equivalents through the pentose phosphate pathway,and through reduction of oxidized glutathione by glutathionereductase. In addition to increasing the number of red bloodcells, epoetin may also reduce oxidative stress by increasingthe antioxidant potential of erythrocytes. Experimental datahave shown that the binding of epoetin to its receptor activatesNF-B, which in turn enhances the expression of genes encodingproteins, such as superoxide dismutase or glutathione, thathave antioxidant properties (33).
The ability of erythropoietin to promote survival of red bloodcells via the binding to its receptor has been clearly establishedfor a long time. It appears to be mostly mediated by an overexpressionof anti-apoptotic proteins such as Bcl-xL and Bcl-2, but alsoX-IAP or c-IAP, and by the activation of PKB/Atk that phosphorylateproapoptotic molecules such as Bad and caspase 9 (34,35). Recentin vivo data have shown that the anti-apoptotic effects of epoetincan also be observed with other cell types expressing the erythropoietinreceptor, such as neuronal cells, and that systemic administrationof epoetin can dramatically decrease the neurologic consequencesof various experimental injuries (36–39). In vitro, epoetinhas also been shown to protect endothelial cells or vascularsmooth muscle cells against apoptosis (40,41). One can thusspeculate that this effect also exists for other cells thatexpress the erythropoietin receptor, such as proximal tubularcells and renal endothelial cells (42). Furthermore, in vitroand in vivo experiments suggest that erythropoietin may alsohave proangiogenic properties (43,44).
Potential Effects of Epoetin Treatment on the Progression of Chronic Kidney Disease
As previously outlined, hypoxia of tubular cells appears tobe the main link between interstitial fibrosis and tubular destruction(reviewed in 45). Thus, correcting anemia with epoetin shouldincrease oxygen delivery to tubular cells, decrease tubulardamage, and ultimately protect against nephron loss inducedby tubular injury. Furthermore, because hypoxia stimulates theproduction of extracellular matrix by tubular cells and by renalinterstitial fibroblasts, as well as the release of profibroticcytokines such as TGF-, decreasing hypoxia should slow the rateof extracellular matrix accumulation (24,31). Part of the beneficialeffects of epoetin on hypoxia may also be mediated through itsproangiogenic properties (43,44), that will oppose the decreasein the number of interstitial capillaries.
Besides its effects on hypoxia, treatment with epoetin couldalso have beneficial effects on the progression of CKD througha reduction of oxidative stress. In case of chronic reductionin nephron number, oxygen consumption by the remaining nephronsincreases, which leads to increased production of reactive oxygenspecies (reviewed in 19). This oxidative stress probably enhancesnot only tubular damage but also interstitial inflammation andfibrosis. Experimental data have shown that oxidative stressstimulates the production of extracellular matrix by fibroblasts.For example, in vitro, noncytolytic doses of hydrogen peroxidestimulate collagen synthesis by renal fibroblastic cells, aswell as TGF- production (29). Similarly, lipid peroxidationproducts, which are produced in increased amounts in responseto oxidative stress, upregulate collagen production by fibroblasts(27,28). Furthermore, in vitro, reactive oxygen species canactivate NF-B in proximal tubular cells, and thus the releaseof proinflammatory molecules such as MCP-1 (26) The physiologicrelevance of these in vitro effects is suggested by experimentsshowing that, in vivo, treatment of rats with antioxidants canprotect against the development of interstitial fibrosis, whereasdeprivation of antioxidants has opposite effects (29,30).
The anti-apoptotic effects of epoetin could also be beneficialfor the progression of CKD, because apoptosis has been implicatedin the progressive loss of tubular cells observed during CKD(46). For example, apoptosis appears to play an important rolein the progression of tubular lesions observed in rats submittedto subtotal nephrectomy or to experimental anti-glomerular basementmembrane nephritis (47,48). The mechanisms underlying the increasedapoptosis of tubular cells are still poorly understood, butreactive oxygen species could play a role in this process (47,48).Thus, treatment with epoetin may have beneficial effects notonly by protecting tubular cells against apoptosis, but alsoby decreasing the production of reactive oxygen species.
Clinical Studies Suggest That Epoetin May Slow the Progression of Renal Failure
The fact that correcting anemia does not accelerate the progressionof CKD has been shown by different clinical studies performedin the early 1990s, and it is no longer questioned. Nevertheless,the question of whether it slows the progression of renal failureremains unanswered. So far, two prospective clinical studiesincluding a relatively large number of patients and a retrospectivestudy support this hypothesis (49–51).
The first study included 83 patients with severely impairedrenal function (mean GFR 10 ml/min), and severe anemia (meanhematocrit 26.8%) (49). After a 2-mo stabilization period, 40patients were randomly assigned not to receive epoetin and 43to receive epoetin for their hematocrit levels to reach 35%.The patients were followed for 48 wk. No beneficial effect ofepoetin could be demonstrated by simply comparing renal survivalor GFR (GFR) decrease between the two groups of patients. Nevertheless,when the data were analyzed after the hematocrit levels of thepatients in the epoetin group had reached target values (i.e.,after week 16), the rate of GFR decline was three times slowerin the treated group than in the control group (-0.13 ±0.35 ml/min/mo versus -0.39 ± 0.65 ml/min/mo, P = 0.05).
The second study included 73 patients with anemia (mean hematocrit27.4%) and severe renal failure (mean creatinine clearance 18.2ml/min) (50). After an 8-wk stabilization period, the patientswere randomly assigned to receive or not to receive epoetin.Thirty one patients were left untreated; 42 patients receivedepoetin to increase their hematocrit levels to 33 to 35%. Duringthe 36-wk follow-up period, creatinine doubled in about 52%of patients in the treated group, and in more than 90% of patientsin the control group (P < 0.0005). Furthermore, although64% of patients in the control group required dialysis, only33% of those in the epoetin group needed to start dialysis (P< 0.005).
More recently, a retrospective and noncontrolled study alsosuggested that epoetin treatment may slow the progression ofrenal failure (51). In this study, the authors compared 20 patientswith chronic renal failure who were treated with epoetin with43 patients who had a similar degree of renal failure but whowere less anemic and thus did not receive epoetin. The rateof decline of creatinine clearance did not change over timein the control group, whereas, in the treated group, it wassignificantly slower after epoetin treatment had been started(-0.36 ± 0.16 ml/min per 1.73 m2 per month versus -0.26± 0.15 ml/min per 1.73 m2 per month; P < 0.05).
Different experimental data support the hypothesis that correctionof anemia with epoetin may slow the rate of progression of renalfailure, and few small clinical studies also suggest the importanceof testing this hypothesis. The definite answer should comefrom a large clinical trial that is much awaited.
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Top
Abstract
Introduction
play an important role in this process (7,8). Furthermore, they show that the occurrence of glomerulosclerosis can be prevented by the use of ACE inhibitors or by a low protein diet (reviewed in 9). In humans, sequential studies of few patients with an important reduction of their renal mass have also shown that a decrease in nephron number can also be responsible for the development of glomerulosclerosis (10,11). 
B, which in turn enhances the expression of genes encoding proteins, such as superoxide dismutase or glutathione, that have antioxidant properties (33). 
