In reply:

Abstract

In their letter to the editor, Abu-Alfa and Perazella questioned the results of our recent article1Le Meur Y Lorgeot V Comte L Szelag JC Aldigier JC Leroux-Robert C Praloran V Plasma levels and metabolism of AcSDKP in patients with chronic renal failure: Relationship with erythropoietin requirements.Am J Kidney Dis. 2001; 38: 510-517Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar showing a relationship between angiotensin-converting enzyme (ACE) inhibitors and erythropoiesis. Two recent studies2Abu-Alfa AK Cruz D Perazella MA Mahnensmith RL Simon D Bia MJ ACE inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients.Am J Kidney Dis. 2000; 35: 1076-1082Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 3Hayashi K Hasegawa K Kobayashi S Effects of angiotensin-converting enzyme inhibitors on the treatment of anemia with erythropoietin.Kidney Int. 2001; 60: 1910-1916Crossref PubMed Scopus (39) Google Scholar failed to find resistance to recombinant human erythropoietin (rHuEPO) in hemodialysis (HD) patients, but others provided opposite results.4Macdougall IC The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin.Nephrol Dial Transplant. 1999; 14: 1836-1841Crossref PubMed Scopus (104) Google Scholar The important anemia recently evidenced in ACE knockout mice5Cole J Ertoy D Lin H Sutliff RL Ezan E Guyene TT Capecchi M Corvol P Bernstein KE Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice.J Clin Invest. 2000; 106: 1391-1398Crossref PubMed Scopus (137) Google Scholar shows that angiotensin II stimulates erythropoiesis in vivo and thus reinforces the hypothesis that ACE inhibitors and angiotensin II receptor blockers participate together with other endogenous factors to produce the rHuEPO resistance observed in some HD patients. We proposed that N-acetyl-seryl-lysyl-proline (AcSDKP), a natural inhibitor of hematopoiesis, could be a missing link between ACE inhibitors and rHuEPO resistance in HD patients.1Le Meur Y Lorgeot V Comte L Szelag JC Aldigier JC Leroux-Robert C Praloran V Plasma levels and metabolism of AcSDKP in patients with chronic renal failure: Relationship with erythropoietin requirements.Am J Kidney Dis. 2001; 38: 510-517Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar AcSDKP is eliminated (as creatinine) by glomerular filtration and degraded in vivo by ACE.6Comte L Lorgeot V Volkov L Allegraud A Aldigier JC Praloran V Effect of the angiotensin-converting enzyme inhibitor enalapril on blood haematopoietic progenitors and acetyl-N-Ser-Asp-Lys-Pro concentrations.Eur J Clin Invest. 1997; 27: 788-790Crossref PubMed Scopus (44) Google Scholar It accumulated in all patients with chronic renal failure (CRF), and AcSDKP plasma levels were even higher when these patients are treated with an ACE inhibitor. In HD patients, those with AcSDKP concentration above 24 pmol/mL (value approximately 12-fold higher than controls) required the highest doses of rHuEPO. Only a minority of HD patients reached a level of AcSDKP high enough to inhibit erythropoiesis, because plasma AcSDKP concentration depends on at least two intricate factors: (1) residual renal function and/or quality of dialysis and (2) the degree of ACE inhibition, which is dependent on the dose and the type of ACE inhibitor used. Thus, we think that the results of Hayashi et al3Hayashi K Hasegawa K Kobayashi S Effects of angiotensin-converting enzyme inhibitors on the treatment of anemia with erythropoietin.Kidney Int. 2001; 60: 1910-1916Crossref PubMed Scopus (39) Google Scholar showing that low doses of ACE inhibitors had no effect on rHuEPO requirement do not contradict our data. Interestingly, Cole et al5Cole J Ertoy D Lin H Sutliff RL Ezan E Guyene TT Capecchi M Corvol P Bernstein KE Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice.J Clin Invest. 2000; 106: 1391-1398Crossref PubMed Scopus (137) Google Scholar showed that the anemia of tissue ACE knockout mice is corrected by infusion of angiotensin II, a result that demonstrates the physiological role of angiotensin II in erythropoiesis. Due to a normal renal function and a partially conserved plasma ACE activity, the high plasma AcSDKP levels observed in these mice were elevated only 3-fold instead of 24-fold in our HD patients treated with an ACE inhibitor, a difference that could explain the good correction of the anemia of these mice by angiotensin II administration. These experimental data support our hypothesis that the rHuEPO resistance observed in a minority of HD patients is due to the association of very high AcSDKP and low angiotensin II concentrations, respectively, above and below a critical threshold. Consequently, the publications mentioned by Abu-Alfa and Perazella in their letter cannot be considered as contradicting our results because neither the AcSDKP nor the angiotensin II levels were explored in these papers.