Slowing the progression of renal failure
2002; Elsevier BV; Volume: 61; Linguagem: Inglês
10.1046/j.1523-1755.61.s80.5.x
ISSN1523-1755
Autores Tópico(s)Erythropoietin and Anemia Treatment
ResumoSlowing the progression of renal failure. In recent years several multicentric prospective studies have demonstrated the efficacy of some therapeutic measures to slow the progression of renal diseases. Inhibition of renin-angiotensin system (RAS) both by ACE inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) is probably the strongest therapeutic alternative: The antiproteinuric effect of these drugs is an excellent surrogate marker and a predictor of the beneficial influences on the progression of renal failure. The type of renal disease, an inadequate control of blood pressure, and the presence of obesity may counteract the beneficial influences of RAS inhibition, whereas early treatment of all patients with significant proteinuria before the appearance of renal insufficiency and combined therapy with an ACEI and an ARA may augment it. Dietary protein restriction is a classic treatment of chronic renal insufficiency whose effectiveness has been validated by multicentric studies. However, a poor compliance of the patient and the risk of malnutrition with very strict protein restriction could limit the benefits of this treatment. Treatment of hyperlipidemia, prevention of obesity, avoidance of smoking, and regular physical exercise are interventions whose therapeutic potential is progressively recognized, particularly in type 2 diabetic nephropathy. Early correction of anemia may contribute to the slowing of renal disease progression. Although further studies are required, the accumulated evidence and the likelihood of additive beneficial effect of these therapeutic measures advise their combined implementation in patients with chronic renal diseases. Slowing the progression of renal failure. In recent years several multicentric prospective studies have demonstrated the efficacy of some therapeutic measures to slow the progression of renal diseases. Inhibition of renin-angiotensin system (RAS) both by ACE inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) is probably the strongest therapeutic alternative: The antiproteinuric effect of these drugs is an excellent surrogate marker and a predictor of the beneficial influences on the progression of renal failure. The type of renal disease, an inadequate control of blood pressure, and the presence of obesity may counteract the beneficial influences of RAS inhibition, whereas early treatment of all patients with significant proteinuria before the appearance of renal insufficiency and combined therapy with an ACEI and an ARA may augment it. Dietary protein restriction is a classic treatment of chronic renal insufficiency whose effectiveness has been validated by multicentric studies. However, a poor compliance of the patient and the risk of malnutrition with very strict protein restriction could limit the benefits of this treatment. Treatment of hyperlipidemia, prevention of obesity, avoidance of smoking, and regular physical exercise are interventions whose therapeutic potential is progressively recognized, particularly in type 2 diabetic nephropathy. Early correction of anemia may contribute to the slowing of renal disease progression. Although further studies are required, the accumulated evidence and the likelihood of additive beneficial effect of these therapeutic measures advise their combined implementation in patients with chronic renal diseases. A large number of experimental studies have demonstrated that renal diseases share pathogenic mechanisms that play a fundamental role in the progression toward end-stage renal failure, independently of the original etiology. In recent years a number of therapeutic measures that can halt or slow these common, harmful pathogenic ways have emerged. In this article, we review some of the most relevant new insights in the field of general renoprotective measures. There is compelling clinical evidence that the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitors (ACEI) or with angiotensin II subtype 1 receptor antagonists (ARA) slow the progression of renal failure in many chronic nephropathies. Several large, multicentric, and prospective studies have shown a significant reduction in the risk of doubling baseline serum creatinine or progression toward end-stage renal failure in patients with type 1 and type 2 diabetic nephropathy treated with ACEI or ARA, in comparison with control patients1.Lewis E.J. Hunsicker L. Bain R.P. Rhode R.P. for the Collaborative Study Group The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (4783) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. for the Collaborative Study Group et al.Renoprotective effect of the angiotensin-receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Brenner B.M. Cooper M.E. De zeeuw D. for the Renal Study Investigators et al.Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 4.Parving H.H. Lehnert H. Bröchner-Mortensen J. The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar. Similarly, these drugs have shown a clear renoprotective effect in proteinuric non-diabetic chronic nephropathies5.Maschio G. Alberti D. Janin G. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1619) Google Scholar,6.The GISEN Group Randomised placebo-controlled trial of effect of ramipril on declining in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar. The accumulating evidence of the beneficial effects offered by ACEI and AT1RA has led to the generalized use of these drugs in both diabetic and non-diabetic nephropathies. Some patients may exhibit a clear beneficial response, with dramatic proteinuria decrease and stabilization of GFR over the years. However, a review of the referred multicentric trials1.Lewis E.J. Hunsicker L. Bain R.P. Rhode R.P. for the Collaborative Study Group The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (4783) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. for the Collaborative Study Group et al.Renoprotective effect of the angiotensin-receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Brenner B.M. Cooper M.E. De zeeuw D. for the Renal Study Investigators et al.Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 4.Parving H.H. Lehnert H. Bröchner-Mortensen J. The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar, 5.Maschio G. Alberti D. Janin G. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1619) Google Scholar, 6.The GISEN Group Randomised placebo-controlled trial of effect of ramipril on declining in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar shows that the number of patients that reach the most commonly analyzed primary outcome (doubling of baseline SCr) is still considerably high. Thus, in the AIPRI and REIN studies, which included preferably non-diabetic nephropathies, 10–30% of the patients treated with ACEI had doubled the baseline serum creatinine (SCr) after 2–3 years of follow up5.Maschio G. Alberti D. Janin G. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1619) Google Scholar,6.The GISEN Group Randomised placebo-controlled trial of effect of ramipril on declining in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar. In the studies performed with diabetic patients1.Lewis E.J. Hunsicker L. Bain R.P. Rhode R.P. for the Collaborative Study Group The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (4783) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. for the Collaborative Study Group et al.Renoprotective effect of the angiotensin-receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Brenner B.M. Cooper M.E. De zeeuw D. for the Renal Study Investigators et al.Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 4.Parving H.H. Lehnert H. Bröchner-Mortensen J. The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar, the number of patients doubling baseline SCr reached 20–40% among those treated with ACEI and ARA, after 2.5–3.5 years of follow up. Although the number of patients reaching primary outcomes was significantly higher in control groups, these results indicate that RAS inhibition with ACEI or ARA should not be considered, unfortunately, as the definitive defeat of renal failure progression. The antiproteinuric effect of ACEI is well known after numerous studies performed in the past 15 years7.Gansevoort R.T. Sluiter W.J. Hemmelder M.H. Antiproteinuric effect of blood-pressure–lowering agents: A meta-analysis of comparative trials.Nephrol Dial Transplant. 1995; 10: 1963-1974PubMed Google Scholar. More recently, ARA have demonstrated a similar effect. A review of the mechanisms implicated in this beneficial effect, shared so far by all classes of ACEI and ARA so far, is beyond the scope of this article. In 1992 we reported, for the first time, that in those captopril-treated patients showing a substantial proteinuria decrease, a clear slowing in the progression of renal insufficiency was observed. On the contrary, those patients also treated with captopril but in whom no significant proteinuria decrease was observed, continued to show a progressive loss of renal function8.Praga M. Hernández E. Montoyo C. Long-term beneficial effects of ACE inhibition in patients with nephrotic proteinuria.Am J Kidney Dis. 1992; 20: 240-248Abstract Full Text PDF PubMed Scopus (156) Google Scholar. Interestingly, the proteinuria decrease was unrelated to blood pressure changes in our study, and several studies have confirmed our results later. Very importantly, in all the above-cited multicentric landmark studies1.Lewis E.J. Hunsicker L. Bain R.P. Rhode R.P. for the Collaborative Study Group The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (4783) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. for the Collaborative Study Group et al.Renoprotective effect of the angiotensin-receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Brenner B.M. Cooper M.E. De zeeuw D. for the Renal Study Investigators et al.Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 4.Parving H.H. Lehnert H. Bröchner-Mortensen J. The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar, 5.Maschio G. Alberti D. Janin G. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1619) Google Scholar, 6.The GISEN Group Randomised placebo-controlled trial of effect of ramipril on declining in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar, the slowing in the progression of renal insufficiency has always strongly been related to proteinuria decrease induced by ACEI or ARA, whereas it appears to be largely independent of the blood-pressure lowering effects induced by these drugs. Because the proteinuria decrease is already observed within the fist weeks or months of treatment, it should be considered as an excellent clinical predictor of the long-term renoprotective effects of RAS inhibition. Therefore, there is mounting evidence that the level of proteinuria is of paramount importance in order to monitor the effectiveness of ACEI and/or ARA in proteinuric nephropathies. Some authors have suggested that the definitions of partial or complete remissions (proteinuria decreases to <2.5 g/24 h and <0.5 g/24 h, respectively), commonly used to define the responses to immunosuppressive drugs in many glomerular diseases, should also be applied to evaluate the response of chronic proteinuric nephropathies when ACEI/ARA are introduced. On the other hand, the absence of a significant antiproteinuric response should be considered as a resistance to the beneficial effects of these drugs. In this case, an analysis of those factors that may contribute to the resistance should be performed. A significant number of patients treated with ACEI/ARA did not show a clear antiproteinuric response, and this failure heralds a progressive loss of renal function in most cases1.Lewis E.J. Hunsicker L. Bain R.P. Rhode R.P. for the Collaborative Study Group The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (4783) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. for the Collaborative Study Group et al.Renoprotective effect of the angiotensin-receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Brenner B.M. Cooper M.E. De zeeuw D. for the Renal Study Investigators et al.Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 4.Parving H.H. Lehnert H. Bröchner-Mortensen J. The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar, 5.Maschio G. Alberti D. Janin G. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1619) Google Scholar, 6.The GISEN Group Randomised placebo-controlled trial of effect of ramipril on declining in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar, 7.Gansevoort R.T. Sluiter W.J. Hemmelder M.H. Antiproteinuric effect of blood-pressure–lowering agents: A meta-analysis of comparative trials.Nephrol Dial Transplant. 1995; 10: 1963-1974PubMed Google Scholar, 8.Praga M. Hernández E. Montoyo C. Long-term beneficial effects of ACE inhibition in patients with nephrotic proteinuria.Am J Kidney Dis. 1992; 20: 240-248Abstract Full Text PDF PubMed Scopus (156) Google Scholar. The factors that may contribute to this resistance are largely unknown, but their identification and correction should have an obvious clinical importance to slow the progression of renal insufficiency more effectively in proteinuric renal diseases. Some clinical studies have brought forward interesting data in this field. Although the number of clinical studies concerning this issue is relatively scarce, the antiproteinuric response to RAS inhibition appears to be influenced by the type of renal disease. Thus, we have reported that those renal diseases defined as "hyperfiltration disorders" (reflux nephropathy, significant reductions of functioning renal mass whatever the cause, healed crescentic glomerulonephritis) show a striking proteinuria decrease after the introduction of an ACEI, with reductions of 55–65% of the baseline values8.Praga M. Hernández E. Montoyo C. Long-term beneficial effects of ACE inhibition in patients with nephrotic proteinuria.Am J Kidney Dis. 1992; 20: 240-248Abstract Full Text PDF PubMed Scopus (156) Google Scholar. In the same study, we observed an also satisfactory response among patients with IgA nephropathy (43%) and benign nephroangiosclerosis (58%). On the contrary, patients with idiopathic focal and segmental glomerulosclerosis (FSG) and membranous glomerulonephritis showed a less evident response, with proteinuria decreases oscillating between 24% and 27%8.Praga M. Hernández E. Montoyo C. Long-term beneficial effects of ACE inhibition in patients with nephrotic proteinuria.Am J Kidney Dis. 1992; 20: 240-248Abstract Full Text PDF PubMed Scopus (156) Google Scholar. However, it is important to remark that a striking variability in the response was also observed within each specific diagnosis group. Thus, some patients with membranous GN or idiopathic FSG showed proteinuria decreases higher than 50%. Given the results obtained in the Modification of Diet in Renal Disease Study (MDRD), blood pressure control should be targeted to values 1 g/24 h, regardless of blood pressure and renal function status. We have analyzed recently the evolution of those patients that started treatment when SCr was 0.5–1 g/24 h) regardless of blood pressure and preferably before the appearance of renal insufficiency. From a theoretical point of view, the combined use of an ACEI and an ARA would augment the beneficial influences of both classes of agents: ARA would provide a complete blocking of AT1 receptors of angiotensin II, not guaranteed by ACEI, whereas the later would contribute with an increased synthesis of bradykinin. In clinical practice, a greater antiproteinuric effect of the combination ACEI+ARA in comparison with single therapy with an ACEI or an ARA has been reported in patients with IgAnephropathy16.Russo D, Pisani A, Balletta MM, et al: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851–856Google Scholar. In the last two meetings of the ASN, more than 20 studies have analyzed the antiproteinuric effect of the combination ACEI+ARA, and nearly all have found it significantly greater than the one observed with just ACEI or ARA, although the doses of these drugs were increased when used alone. Interestingly, no differences in blood pressure that could explain the greater antiproteinuric effect of the combination were observed. Although other published studies have not confirmed the superiority of the combination17.Agarwal R. Add-on angiotensin receptor blockade with maximized ACE inhibition.Kidney Int. 2001; 59: 2282-2289https://doi.org/10.1046/j.1523-1755.2001.0590062282.xCrossref PubMed Scopus (117) Google Scholar, prospective multicentric studies including a larger number of patients should be performed in order to evaluate definitely the indication of the ACEI+ARA combination in proteinuric diseases. An in-depth review of the beneficial effects of low protein diets on the progression of renal failure is beyond the scope of this article, but several meta-analyses and secondary analyses of randomized trials have demonstrated that protein restriction slows the progression of renal diseases18.Levey A. Greene T. Beck G. Dietary protein restriction and the progression of chronic renal disease: What have all the results of the MDRD study shown?.J Am Soc Nephrol. 1999; 10: 2426-2439PubMed Google Scholar,19.Kasiske B. Lakatua J. Ma J. A meta-analysis of the effects of dietary protein restrictions on the rate of decline in renal function.Am J Kidney Dis. 1998; 31: 954-961Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar. Protein intakes of 0.6–0.7 g/kg/day are the most commonly recommended in patients with GFR 27 kg/m2) with proteinuric renal diseases of several etiologies. One half of the cases had type 2 diabetic nephropathy. We have found that a moderate weight loss (4.1 ± 3% of the baseline values) by hypocaloric normoproteic diet induced a significant proteinuria decrease higher than 30% of baseline together with stable GFR. On the contrary, a tendency to body weight and proteinuria increases together with significant GFR decrease was observed in control group patients, who maintained their dietary habits (abstract; Moraleset al,J Am Soc Nephrol 12:231, 2001). These results indicate that treatment of obesity should be an important target in chronic proteinuric nephropathies. Taking into account the increasing prevalence of obesity in the general population and the fact that a great majority of patients with type 2 diabetic nephropathy (the leading cause of end-stage renal disease) are obese, further studies are required to confirm these results. The influence of obesity on the progression of renal diseases could be related to the emerging hypothesis that emphasizes the importance of intrauterine/congenital factors in the predisposition to suffer some diseases in adulthood. Experimental studies have demonstrated that an inadequate protein intake in pregnant experimental animals leads to the birth of animals with a reduced number of nephrons and endocrine pancreatic tissue24.Zeman F.J. Effects of maternal protein restriction on the kidneys of the newborn young of rats.J Nutr. 1968; 94: 111-116PubMed Google Scholar,25.De Prins F.A. van Assche F.A. Intrauterine growth retardation and development of endocrine pancreas in the experimental rat.Biol Neonate. 1982; 41: 16-21Crossref PubMed Scopus (75) Google Scholar. Some autopsy studies performed in dead neonates support the validity of these findings for the human being, because the number of glomeruli was significantly lower among neonates with a birth weight <2500 g compared with neonates with normal birth weight26.Mañalich R. Reyes L. Herrera M. Relationship between weight at birth and the number and size of renal glomeruli in humans: A histomorphometric study.Kidney Int. 2000; 58: 770-773Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar. Epidemiologic studies coming from Britain, US, China, and other countries have confirmed an inverse relationship between weight at birth and the risk to develop hypertension, type 2 diabetes mellitus and renal insufficiency in adulthood27.Forsen T. Eriksson J. Tuomilehto J. The fetal and childhood growth of persons who develop type 2 diabetes.Ann Intern Med. 2000; 133: 176-182Crossref PubMed Scopus (551) Google Scholar. In addition, a disproportionate tendency to the development of hypertension, type 2 diabetes, and end-stage renal disease has been repeatedly reported in social groups such as Native Americans or Australian aborigines28.Muneta B. Newman J. Stevenson J. Eggers P. Diabetic end-stage renal disease among Native Americans.Diabetes Care. 1993; 16: 346-348Crossref PubMed Scopus (14) Google Scholar. The prevalence of prematurity and low birth weight is high among these groups, as well as the prevalence of obesity in adulthood. Therefore, it could be hypothesized that the presence of a reduced number of nephrons and pancreatic islets, determined by intrauterine factors mainly related to maternal nutrition, facilitates the development of hypertension, type 2 diabetes and renal insufficiency. The development of obesity and a sedentary lifestyle in adulthood could be the crucial factors to precipitate the appearance of these diseases. According to this hypothesis, an adequate maternal nutrition during pregnancy, and regular physical exercise and avoidance of obesity in adulthood, should decrease the risk of progressive renal failure in the general population. Several recently published retrospective studies have stressed the role of smoking in the progression of both diabetic and non-diabetic nephropathies29.Orth S. Stockmann A. Conradt C. Smoking as a risk factor for end-stage renal failure in men with primary renal disease.Kidney Int. 1998; 54: 926-931Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar. Direct harmful effects of smoking on kidney vascular beds have been demonstrated by other studies. Therefore, avoidance of smoking should be strongly recommended to all patients with renal diseases. Although some experimental studies had suggested that anemia correction could hasten the progression of renal failure, clinical studies have shown that erythropoietin improves anemia in predialysis patients and does not accelerate the rate of renal failure progression30.Roth D. Smith R.D. Schulman G. Effects of recombinant human erythropoietin on renal function in chronic renal failure in predialysis patients.Am J Kidney Dis. 1994; 24: 777-784Abstract Full Text PDF PubMed Scopus (166) Google Scholar. Furthermore, recent studies have suggested that early correction of anemia may induce a beneficial influence retarding the progression of renal failure31.Jungers P. Choukroun G. Oualim Z. Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients.Nephrol Dial Transplant. 2001; 16: 307-312Crossref PubMed Scopus (180) Google Scholar. Hypoxia stimulates the progression of renal interstitial fibrosis32.Fine L. Orphanides C. Norman J. Progressive renal disease: The chronic hypoxia hypothesis.Kidney Int. 1998; 53: S74-S78Google Scholar, and erythropoietin could counteract these harmful pathways. Prospective studies are warranted in order to assess these important implications of erythropoietin therapy. Several therapeutic interventions, briefly reviewed in this article, have demonstrated a beneficial effect slowing the progression of renal diseases, and they are likely to have additive beneficial influences. Therefore, as it has been recently proposed33.Hebert L.A.Q. Wilmer W.A. Falkenhain M.E. Renoprotection: One or many therapies?.Kidney Int. 2001; 59: 1211-1226https://doi.org/10.1046/j.1523-1755.2001.0590041211.xAbstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, a multiple-risk-factor intervention including all these possibilities appears to be the most plausible approach in patients with chronic nephropathies.
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