Anemia management and chronic renal failure progression
JEROME ROSSERT, MARC FROISSART, and CHRISTIAN JACQUOT
ˆ Paris-Descartes University School of Medicine, INSERM U652, AP-HP (Hopital Europ´ en Georges Pompidou), Paris, France e
Anemia management and chronic renal failure progression. Analysis of the biologic effects oferythropoietin and pathophysiology of chronic kidney diseases (CKD) suggests that treatment with erythropoiesis-stimulating agents (ESA) could slow the progression of CKD. By decreasing hypoxia and oxidative stress, it could prevent the development of interstitial ﬁbrosis and the destruction of tubular cells. It could have direct protective effects on tubular cells through its antiapoptoticproperties. It could help maintain the integrity of the interstitial capillary network through its effects on endothelial cells. Thus, suggesting that correcting anemia with ESA could slow the progression of CKD is biologically plausible. In patients with CKD, three small prospective studies and a retrospective study have suggested that treatment with ESA may have protective effects. Post-hoc analysis ofthe Reduction in Endpoints in Noninsulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan study has also shown that anemia was an independent risk factor for progression of nephropathy in patients with type 2 diabetes. In addition, a large clinical trial, which had to be stopped prematurely because of labeling change for subcutaneous administration of epoetin alfa, suggeststhat complete normalization of hemoglobin levels is safe in CKD patients not on dialysis and without severe cardiovascular disease. Thus, it seems reasonable to advocate starting a large randomized, prospective study to determine if normalization of hemoglobin concentration can effectively slow the progression of CKD.
need for additional treatments. Among the therapeutic interventions thatcould slow the progression of chronic kidney disease (CKD) is correction of anemia through administration of erythropoiesis-stimulating agents (ESA).
BIOLOGIC EFFECTS OF TREATMENT WITH ESA The most obvious beneﬁt of treatment with ESA is an increase in red blood cell concentration, which is responsible for increased oxygen delivery to tissues and reduction of hypoxia. However, administration ofESA has other effects, including protection against oxidative stress and apoptosis, and possibly stimulation of angiogenesis. Erythrocytes represent a major antioxidant component of blood . Their antioxidant effects are mediated through enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, and through cellular proteins that are devoided of enzymatic activity but can reactwith reactive oxygen species, such as low-molecular weight proteins of the erythrocyte membrane, vitamin E, vitamin C, or coenzyme Q. Furthermore, glutathione reductase can regenerate reduced glutathione from its oxidized form, using reduced nicotinamide adenine dinucleotide phosphate produced through the pentose phosphate pathway. The ability of erythropoietin to promote survival of erythroidprogenitors via the binding to its receptor has been established for a long time. However, recent studies have shown that erythropoietin receptors are also expressed in a variety of non-hematopoietic cells, such as neuronal cells, cardiomyocytes, vascular cells, and renal tubular cells, and that the binding of erythropoietin to these receptors can have antiapoptotic effects . Protection againstapoptosis appears to be mediated by different pathways, including (1) activation of the transcription of genes encoding antiapoptotic molecules such as Bclx L , XIAP, or c-IAP2; (2) inhibition of the transcription of genes encoding proapoptotic molecules such as Fas ligand or Bim; (3) activation of protein kinase B/Akt through the phosphatidylinositol 3-kinase pathway; and (4) induction of heat...