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Gender differences in responsiveness to erythropoietin: In Reply
CORRESPONDENCE
EPO resistance.3 It is therefore credible to surmise that as a result of hormonal or other metabolic differences, women on maintenance HD may display higher AcSDKP levels than matched men also on HD. Unfortunately, the study by Le Meur et al3 apparently did not examine for gender differences, if any, for AcSDKP levels in men and women both before and after initiation of maintenance HD. Another related question that arises is whether, in view of the molecular weight of AcSDKP of 487 daltons, peritoneal dialysis (PD) may remove more of the tetrapeptide than conventional HD and therefore PD patients would have lower levels of the molecule and less EPO resistance compared with HD patients. All of these questions call for further review. Macaulay Onuigbo, MD Division of Nephrology Department of Medicine University of Maryland School of Medicine Baltimore, Maryland REFERENCES 1. Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delosreyes G, Friedman EA: Gender modulates responsiveness to recombinant erythropoietin. Am J Kidney Dis 38:518522, 2001 2. Shemin D, Bostom AG, Laliberty P, Dworkin LD: Residual renal function and mortality risk in hemodialysis patients. Am J Kidney Dis 38:85-90, 2001 3. Le Meur Y, Lorgeot V, Comte L, Szelag J-C, Aldigier J-C, 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 38:510-517, 2001 © 2002 by the National Kidney Foundation, Inc. doi:10.1053/ajkd.2002.31195 In Reply: In his letter, Macaulay Onuigbo mentions the article of Ifudu et al1 and our article,2 both of which appeared in the same recent issue of the Journal. The article by Ifudu et al1 showed that gender could influence response to erythropoietin (EPO), with women having identical hematocrit levels despite a better quality of dialysis and greater doses of EPO. Our article showed that high plasma levels of N-acetyl-seryl-asparatyl-lysylproline (AcSDKP), an inhibitor of hematopoiesis, can promote EPO resistance in hemodialyzed (HD) patients. Interestingly, the influence of gender on EPO requirement was reported very recently by Hayashi et al.3 Onuigbo asked about possible differences in AcSDKP levels related to gender in our study that could contribute to this phenomenon, and he rightly noticed that we did not provide in our article plasma AcSDKP concentrations for men and women subgroups. Going back to the data showed that the mean AcSDKP levels were 1.47 pmol/mL and 1.88 pmol/mL for our 19 women and 32 men controls, respectively, and that these values were not significantly different (P = 0.28). Similarly, we did not find significant differences related to gender either in the whole population of patients with chronic renal
443
failure or in the different subgroups (predialysis patients, HD patients, HD patients treated with EPO). As suggested by Ifudu et al,1 these data reinforce the hypothesis that this difference in EPO sensitivity between women and men is largely related to the different endogenous levels of androgens and is not related to AcSDKP. Finally, Onuigbo hypothesizes that patients in peritoneal dialysis (PD) could have a better clearance of AcSDKP and consequently a better response to EPO. PD patients are known to have a lower EPO requirement,4 even if only a few studies comparing HD and PD patients are available. We did not measure AcSDKP levels in PD patients, and we agree that it could be an interesting study. However, AcSDKP has a molecular weight (MW;487 daltons) very similar to that of creatinine. PD patients are traditionally considered as having a better clearance of middle MW molecules than HD patients but a lower clearance of low MW molecules such as creatinine and AcSDKP. Consequently, it would be surprising tofindlower AcSDKP levels in PD patients. Valerie Lorgeot, PhD Laboratoire de Physiologie Faculte de Medecine Limoges, France Jean-Christophe Szelag, MD Service de Nephrologie et d'Hemodialyse Höpital Universitaire Dupuytren Limoges, France Vincent Praloran, MD, PhD Laboratoire Universitaire d'Hematologie Universite; Victor Segalen Bordeaux 2 Bordeaux, France Yannick Le Meur, MD, PhD Service de Nephrologie et d'H6modialyse Höpital Universitaire Dupuytren Limoges, France REFERENCES 1. Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delosreyes G, Friedman EA: Gender modulates responsiveness to recombinant erythropoetin. Am I Kidney Dis 38:518522,2001 2. Le Meur Y, Lorgeot V, Comte L, Szelag J-C, Aldigier J-C, 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 38:510-517, 2001 3. Hayashi K, Hasegawa K, Kobayashi S: Effects of angiotensin-converting enzyme inhibitors on the treatment of anemia with erythropoietin. Kidney Int 60:1910-1916,2001 4. House AA, Pham B, Page DE: Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities. Nephrol Dial Transplant 13:1763-1769, 1998 © 2002 by the National Kidney Foundation, Inc. doi:10.1053/ajkd.2002.32051
EPO resistance.3 It is therefore credible to surmise that as a result of hormonal or other metabolic differences, women on maintenance HD may display higher AcSDKP levels than matched men also on HD. Unfortunately, the study by Le Meur et al3 apparently did not examine for gender differences, if any, for AcSDKP levels in men and women both before and after initiation of maintenance HD. Another related question that arises is whether, in view of the molecular weight of AcSDKP of 487 daltons, peritoneal dialysis (PD) may remove more of the tetrapeptide than conventional HD and therefore PD patients would have lower levels of the molecule and less EPO resistance compared with HD patients. All of these questions call for further review. Macaulay Onuigbo, MD Division of Nephrology Department of Medicine University of Maryland School of Medicine Baltimore, Maryland REFERENCES 1. Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delosreyes G, Friedman EA: Gender modulates responsiveness to recombinant erythropoietin. Am J Kidney Dis 38:518522, 2001 2. Shemin D, Bostom AG, Laliberty P, Dworkin LD: Residual renal function and mortality risk in hemodialysis patients. Am J Kidney Dis 38:85-90, 2001 3. Le Meur Y, Lorgeot V, Comte L, Szelag J-C, Aldigier J-C, 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 38:510-517, 2001 © 2002 by the National Kidney Foundation, Inc. doi:10.1053/ajkd.2002.31195 In Reply: In his letter, Macaulay Onuigbo mentions the article of Ifudu et al1 and our article,2 both of which appeared in the same recent issue of the Journal. The article by Ifudu et al1 showed that gender could influence response to erythropoietin (EPO), with women having identical hematocrit levels despite a better quality of dialysis and greater doses of EPO. Our article showed that high plasma levels of N-acetyl-seryl-asparatyl-lysylproline (AcSDKP), an inhibitor of hematopoiesis, can promote EPO resistance in hemodialyzed (HD) patients. Interestingly, the influence of gender on EPO requirement was reported very recently by Hayashi et al.3 Onuigbo asked about possible differences in AcSDKP levels related to gender in our study that could contribute to this phenomenon, and he rightly noticed that we did not provide in our article plasma AcSDKP concentrations for men and women subgroups. Going back to the data showed that the mean AcSDKP levels were 1.47 pmol/mL and 1.88 pmol/mL for our 19 women and 32 men controls, respectively, and that these values were not significantly different (P = 0.28). Similarly, we did not find significant differences related to gender either in the whole population of patients with chronic renal
443
failure or in the different subgroups (predialysis patients, HD patients, HD patients treated with EPO). As suggested by Ifudu et al,1 these data reinforce the hypothesis that this difference in EPO sensitivity between women and men is largely related to the different endogenous levels of androgens and is not related to AcSDKP. Finally, Onuigbo hypothesizes that patients in peritoneal dialysis (PD) could have a better clearance of AcSDKP and consequently a better response to EPO. PD patients are known to have a lower EPO requirement,4 even if only a few studies comparing HD and PD patients are available. We did not measure AcSDKP levels in PD patients, and we agree that it could be an interesting study. However, AcSDKP has a molecular weight (MW;487 daltons) very similar to that of creatinine. PD patients are traditionally considered as having a better clearance of middle MW molecules than HD patients but a lower clearance of low MW molecules such as creatinine and AcSDKP. Consequently, it would be surprising tofindlower AcSDKP levels in PD patients. Valerie Lorgeot, PhD Laboratoire de Physiologie Faculte de Medecine Limoges, France Jean-Christophe Szelag, MD Service de Nephrologie et d'Hemodialyse Höpital Universitaire Dupuytren Limoges, France Vincent Praloran, MD, PhD Laboratoire Universitaire d'Hematologie Universite; Victor Segalen Bordeaux 2 Bordeaux, France Yannick Le Meur, MD, PhD Service de Nephrologie et d'H6modialyse Höpital Universitaire Dupuytren Limoges, France REFERENCES 1. Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delosreyes G, Friedman EA: Gender modulates responsiveness to recombinant erythropoetin. Am I Kidney Dis 38:518522,2001 2. Le Meur Y, Lorgeot V, Comte L, Szelag J-C, Aldigier J-C, 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 38:510-517, 2001 3. Hayashi K, Hasegawa K, Kobayashi S: Effects of angiotensin-converting enzyme inhibitors on the treatment of anemia with erythropoietin. Kidney Int 60:1910-1916,2001 4. House AA, Pham B, Page DE: Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities. Nephrol Dial Transplant 13:1763-1769, 1998 © 2002 by the National Kidney Foundation, Inc. doi:10.1053/ajkd.2002.32051