letter to the editor
ACKNOWLEDGMENTS
This study was supported by grants from the Japan Osteoporosis Foundation, Japanese Kidney Foundation, Kochi Organization for Medical Reformation and Renewal (YT), and a grant from the Ministry of Education, Science, Culture and Sports of Japanese government (YS, SF, and YT).
roles of suPAR as a pathological factor or as a diagnostic marker in CKD are ambiguous. 1.
2. 1.
2.
3. 4.
Wada T, Nangaku M, Maruyama S et al. A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease. Kidney Int 2014; 85: 641–648. Meijers B, Maas RJ, Sprangers B et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int 2014; 85: 636–640. Wei C, El Hindi S, Li J et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17: 952–960. Shankland SJ, Pollak MR. A suPAR circulating factor causes kidney disease. Nat Med 2011; 17: 927–927.
1
1
Yoshinori Taniguchi , Yoshiko Shimamura , Taro Horino1, Shimpei Fujimoto1 and Yoshio Terada1 1
Department of Endocrinology, Metabolism and Nephrology, Kochi University School of Medicine, Nankoku, Japan Correspondence: Yoshinori Taniguchi or Yoshio Terada, Department of Endocrinology, Metabolism and Nephrology, Kochi University School of Medicine, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. E-mail: [email protected] or [email protected]
3.
4.
Taniguchi Y, Shimamura Y, Horino T et al. Serum levels of soluble urokinase plasminogen activator receptor in Japanese patients with chronic kidney disease. Kidney Int 2014; 86: 209–210. Wada T, Nangaku M, Maruyama S et al. A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease. Kidney Int 2014; 85: 641–648. Huang J, Liu G, Zhang YM et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int 2013; 84: 366–372. Meijers B, RJH Maas, Sprangers B et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int 2014; 85: 636–640.
Takehiko Wada1, Masaomi Nangaku1, Shoichi Maruyama2 and Seiichi Matsuo2 1
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan and 2Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan Correspondence: Masaomi Nangaku or Takehiko Wada, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected] or [email protected] Kidney International (2014) 86, 210; doi:10.1038/ki.2014.138
Kidney International (2014) 86, 209–210; doi:10.1038/ki.2014.136
The Authors Reply: We thank Taniguchi et al.1 for their interest in our recent paper. In their cohort of 487 Japanese patients with chronic kidney disease (CKD), several interesting and important findings came to light. Their study included CKD patients regardless of underlying renal diseases, and it should be noted that a significant number of their patients had severe CKD. Moreover, unlike our cross-sectional study,2 they collected follow-up data from 208 patients. Their first finding was the inverse correlation at baseline between serum soluble urokinase plasminogen activator receptor (suPAR) levels and estimated glomerular filtration rate (eGFR), which supports our data2 and others.3,4 Next they showed that serum levels of suPAR were positively associated with urinary protein excretion, whereas we did not find any association between serum suPAR levels and proteinuria in our multi-center national cohort. A potential explanation for this discrepancy is that urinary protein excretion and renal function could be potential confounding factors for each other in the study population including severe CKD patients. Finally, they demonstrated that suPAR levels were inversely associated with the progression rate of kidney function, DeGFR, in year 1 as well as in year 2. Although a potential role of suPAR levels as a predictive factor of CKD progression seems fascinating, we cannot exclude the possibility that eGFR at baseline affected their data, given that mild CKD patients should have lower levels of suPAR and that the proportion of stable patients may be larger in a mild CKD population. The 210
Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies To the Editor: MacDougall et al.1 provided a comprehensive review of pure red-cell aplasia (PRCA) induced by antibodies directed against erythropoietin (EPO) and its treatments (steroids, cyclosporin A (CsA), or cyclophosphamide). However, they have overlooked evidence for treatment by rituximab (RTX), a monoclonal antibody directed against CD20 þ B cells. In May 2012, we made a diagnosis of antibody-mediated PRCA in a 69-year-old male followed for short bowel syndrome, and requiring total parenteral nutrition. For the last 36 months, he had received epoetina to treat anemia related to mild myelodysplastic syndrome (MDS) and moderate renal failure (glomerular filtration rate 47 ml/min per 1.73 m2). As short bowel syndrome precluded adequate enteric absorption of steroids and CsA and cyclophosphamide was contraindicated because of underlying MDS, intravenous RTX was deemed the most appropriate therapy. RTX was administered intravenously (1 g at days 1 and 15; June 2012). One month after RTX, antiEPO antibody levels decreased substantially from 69 to 5 IU/ ml (o0.1 IU/ml at month 14 despite CD19 þ B-cell recovery). From June to August 2012, patient received iterative RBC transfusion (Figure 1), while one transfusion was required thereafter. Consistent with previous reports, including one of successful re-treatment by EPO,2,3 the very short delay Kidney International (2014) 86, 208–213
letter to the editor
Ab titers
69
0.58
5
Rituximab rHu-EPO
8 7
12
6
Hb (g/dl)
10
5 8 PRBC units
6
Hb level (g/dl)
4
4 3
PRBC units
14
2 1
0
0
N ov D em ec be em r1 Ja be 1 n rFe ua 11 br ryua 12 M ryar 12 ch Ap -12 ri M l-12 ay Ju -12 ne Ju -12 A Se ug ly-1 pt us 2 em t1 O be 2 N cto r-1 ov be 2 D em r-1 ec be 2 em r1 Ja be 2 n rFe ua 12 br ryua 13 M ryar 13 ch Ap -13 ri M l-13 ay Ju -13 ne Ju -13 A Se ug ly-1 pt us 3 em tbe 13 r-1 3
2
Figure 1 | Hemoglobin level and requirement for red blood cell transfusion in a patient with rHu-EPO-related PRCA successfully treated by rituximab. Ab, anti-rHu-EPO antibody; EPO, erythropoietin; Hb, hemoglobin; PRBC, pure red blood cell; PRCA, pure red-cell aplasia.
between rituximab and reticulocyte recovery strongly argues for a specific effect of the compound rather than natural history. RTX is a safe and efficient alternative to steroids and CsA to treat PRCA. 1.
2.
3.
Macdougall IC, Roger SD, de Francisco A et al. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int 2012; 81: 727–732. Behler CM, Terrault NA, Etzell JE et al. Rituximab therapy for pure red cell aplasia due to anti-epoetin antibodies in a woman treated with epoetin-alfa: a case report. J Med Case Rep 2009; 3: 7335. Mandreoli M, Finelli C, Lopez A et al. Successful resumption of epoetin alfa after rituximab treatment in a patient with pure red cell aplasia. Am J Kidney Dis 2004; 44: 757–761.
Thibault Comont1, Barbara Bournet2, Nicole Casadevall3, Dominique Chauveau1,4 and Stanislas Faguer1,4 1
De´partement de Ne´phrologie et Transplantation d’Organes , Centre Hospitalo-Universitaire de Rangueil, Toulouse, France; 2Service de Gastroente´rologie, Centre Hospitalo-Universitaire de Rangueil, Toulouse, France; 3Laboratoire d’He´matologie, Centre Hospitalo-Universitaire Saint-Antoine (AP/HP), Paris, France and 4Universite´ Toulouse-III, Toulouse, France Correspondence: Stanislas Faguer, De´partement de Ne´phrologie et Transplantation d’Organes , Centre Hospitalier Universitaire Toulouse, Hoˆpital Rangueil, 1 Avenue Jean Poulhes, 31059, Toulouse Cedex 09, France. E-mail: [email protected] Kidney International (2014) 86, 210–211; doi:10.1038/ki.2014.144
mediated pure red-cell aplasia (PRCA) following rituximab therapy. Although I agree that the case reports described contribute significantly to our knowledge base on the treatment of this condition, I would suggest more cautious optimism than is exhibited in the above letter. In the largest series of antibody-mediated PRCA ever published (47 cases), which myself and one of the coauthors of the above letter (Professor Casadevall) reported in 2004,2 two cases were treated with rituximab (see Table 3 from the report), and neither of them responded to the treatment. One also has to take heed of positive publication bias, in that it is highly unlikely that any single case of PRCA unresponsive to rituximab therapy would ever be published, in contrast to cases with a positive outcome to this treatment. Thus, I agree with Comont et al.1 that rituximab therapy may be worth trying in patients who develop antibody-mediated PRCA, but for the two reasons noted above I would be more cautious in interpreting the likelihood of a successful outcome with this monoclonal antibody. 1.
2.
Comont T, Bournet B, Casadevall N et al. Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies. Kidney Int 2014; 86: 210–211. Verhelst D, Rossert J, Casadevall N et al. for the Pure Red Cell Aplasia Study Group. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet 2004; 363: 1768–1771.
Iain C. Macdougall1 The Author Replies: Sir, I note the reports by Comont et al.,1 documenting the possible recovery of antibodyKidney International (2014) 86, 208–213
1 Renal Unit, King’s College Hospital, London, UK Correspondence: Iain C. Macdougall, Renal Unit, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. E-mail: [email protected]
Kidney International (2014) 0, 000–000. doi:10.1038/ki.2014.150
211
ACKNOWLEDGMENTS
This study was supported by grants from the Japan Osteoporosis Foundation, Japanese Kidney Foundation, Kochi Organization for Medical Reformation and Renewal (YT), and a grant from the Ministry of Education, Science, Culture and Sports of Japanese government (YS, SF, and YT).
roles of suPAR as a pathological factor or as a diagnostic marker in CKD are ambiguous. 1.
2. 1.
2.
3. 4.
Wada T, Nangaku M, Maruyama S et al. A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease. Kidney Int 2014; 85: 641–648. Meijers B, Maas RJ, Sprangers B et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int 2014; 85: 636–640. Wei C, El Hindi S, Li J et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17: 952–960. Shankland SJ, Pollak MR. A suPAR circulating factor causes kidney disease. Nat Med 2011; 17: 927–927.
1
1
Yoshinori Taniguchi , Yoshiko Shimamura , Taro Horino1, Shimpei Fujimoto1 and Yoshio Terada1 1
Department of Endocrinology, Metabolism and Nephrology, Kochi University School of Medicine, Nankoku, Japan Correspondence: Yoshinori Taniguchi or Yoshio Terada, Department of Endocrinology, Metabolism and Nephrology, Kochi University School of Medicine, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. E-mail: [email protected] or [email protected]
3.
4.
Taniguchi Y, Shimamura Y, Horino T et al. Serum levels of soluble urokinase plasminogen activator receptor in Japanese patients with chronic kidney disease. Kidney Int 2014; 86: 209–210. Wada T, Nangaku M, Maruyama S et al. A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease. Kidney Int 2014; 85: 641–648. Huang J, Liu G, Zhang YM et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int 2013; 84: 366–372. Meijers B, RJH Maas, Sprangers B et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int 2014; 85: 636–640.
Takehiko Wada1, Masaomi Nangaku1, Shoichi Maruyama2 and Seiichi Matsuo2 1
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan and 2Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan Correspondence: Masaomi Nangaku or Takehiko Wada, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected] or [email protected] Kidney International (2014) 86, 210; doi:10.1038/ki.2014.138
Kidney International (2014) 86, 209–210; doi:10.1038/ki.2014.136
The Authors Reply: We thank Taniguchi et al.1 for their interest in our recent paper. In their cohort of 487 Japanese patients with chronic kidney disease (CKD), several interesting and important findings came to light. Their study included CKD patients regardless of underlying renal diseases, and it should be noted that a significant number of their patients had severe CKD. Moreover, unlike our cross-sectional study,2 they collected follow-up data from 208 patients. Their first finding was the inverse correlation at baseline between serum soluble urokinase plasminogen activator receptor (suPAR) levels and estimated glomerular filtration rate (eGFR), which supports our data2 and others.3,4 Next they showed that serum levels of suPAR were positively associated with urinary protein excretion, whereas we did not find any association between serum suPAR levels and proteinuria in our multi-center national cohort. A potential explanation for this discrepancy is that urinary protein excretion and renal function could be potential confounding factors for each other in the study population including severe CKD patients. Finally, they demonstrated that suPAR levels were inversely associated with the progression rate of kidney function, DeGFR, in year 1 as well as in year 2. Although a potential role of suPAR levels as a predictive factor of CKD progression seems fascinating, we cannot exclude the possibility that eGFR at baseline affected their data, given that mild CKD patients should have lower levels of suPAR and that the proportion of stable patients may be larger in a mild CKD population. The 210
Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies To the Editor: MacDougall et al.1 provided a comprehensive review of pure red-cell aplasia (PRCA) induced by antibodies directed against erythropoietin (EPO) and its treatments (steroids, cyclosporin A (CsA), or cyclophosphamide). However, they have overlooked evidence for treatment by rituximab (RTX), a monoclonal antibody directed against CD20 þ B cells. In May 2012, we made a diagnosis of antibody-mediated PRCA in a 69-year-old male followed for short bowel syndrome, and requiring total parenteral nutrition. For the last 36 months, he had received epoetina to treat anemia related to mild myelodysplastic syndrome (MDS) and moderate renal failure (glomerular filtration rate 47 ml/min per 1.73 m2). As short bowel syndrome precluded adequate enteric absorption of steroids and CsA and cyclophosphamide was contraindicated because of underlying MDS, intravenous RTX was deemed the most appropriate therapy. RTX was administered intravenously (1 g at days 1 and 15; June 2012). One month after RTX, antiEPO antibody levels decreased substantially from 69 to 5 IU/ ml (o0.1 IU/ml at month 14 despite CD19 þ B-cell recovery). From June to August 2012, patient received iterative RBC transfusion (Figure 1), while one transfusion was required thereafter. Consistent with previous reports, including one of successful re-treatment by EPO,2,3 the very short delay Kidney International (2014) 86, 208–213
letter to the editor
Ab titers
69
0.58
5
Rituximab rHu-EPO
8 7
12
6
Hb (g/dl)
10
5 8 PRBC units
6
Hb level (g/dl)
4
4 3
PRBC units
14
2 1
0
0
N ov D em ec be em r1 Ja be 1 n rFe ua 11 br ryua 12 M ryar 12 ch Ap -12 ri M l-12 ay Ju -12 ne Ju -12 A Se ug ly-1 pt us 2 em t1 O be 2 N cto r-1 ov be 2 D em r-1 ec be 2 em r1 Ja be 2 n rFe ua 12 br ryua 13 M ryar 13 ch Ap -13 ri M l-13 ay Ju -13 ne Ju -13 A Se ug ly-1 pt us 3 em tbe 13 r-1 3
2
Figure 1 | Hemoglobin level and requirement for red blood cell transfusion in a patient with rHu-EPO-related PRCA successfully treated by rituximab. Ab, anti-rHu-EPO antibody; EPO, erythropoietin; Hb, hemoglobin; PRBC, pure red blood cell; PRCA, pure red-cell aplasia.
between rituximab and reticulocyte recovery strongly argues for a specific effect of the compound rather than natural history. RTX is a safe and efficient alternative to steroids and CsA to treat PRCA. 1.
2.
3.
Macdougall IC, Roger SD, de Francisco A et al. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int 2012; 81: 727–732. Behler CM, Terrault NA, Etzell JE et al. Rituximab therapy for pure red cell aplasia due to anti-epoetin antibodies in a woman treated with epoetin-alfa: a case report. J Med Case Rep 2009; 3: 7335. Mandreoli M, Finelli C, Lopez A et al. Successful resumption of epoetin alfa after rituximab treatment in a patient with pure red cell aplasia. Am J Kidney Dis 2004; 44: 757–761.
Thibault Comont1, Barbara Bournet2, Nicole Casadevall3, Dominique Chauveau1,4 and Stanislas Faguer1,4 1
De´partement de Ne´phrologie et Transplantation d’Organes , Centre Hospitalo-Universitaire de Rangueil, Toulouse, France; 2Service de Gastroente´rologie, Centre Hospitalo-Universitaire de Rangueil, Toulouse, France; 3Laboratoire d’He´matologie, Centre Hospitalo-Universitaire Saint-Antoine (AP/HP), Paris, France and 4Universite´ Toulouse-III, Toulouse, France Correspondence: Stanislas Faguer, De´partement de Ne´phrologie et Transplantation d’Organes , Centre Hospitalier Universitaire Toulouse, Hoˆpital Rangueil, 1 Avenue Jean Poulhes, 31059, Toulouse Cedex 09, France. E-mail: [email protected] Kidney International (2014) 86, 210–211; doi:10.1038/ki.2014.144
mediated pure red-cell aplasia (PRCA) following rituximab therapy. Although I agree that the case reports described contribute significantly to our knowledge base on the treatment of this condition, I would suggest more cautious optimism than is exhibited in the above letter. In the largest series of antibody-mediated PRCA ever published (47 cases), which myself and one of the coauthors of the above letter (Professor Casadevall) reported in 2004,2 two cases were treated with rituximab (see Table 3 from the report), and neither of them responded to the treatment. One also has to take heed of positive publication bias, in that it is highly unlikely that any single case of PRCA unresponsive to rituximab therapy would ever be published, in contrast to cases with a positive outcome to this treatment. Thus, I agree with Comont et al.1 that rituximab therapy may be worth trying in patients who develop antibody-mediated PRCA, but for the two reasons noted above I would be more cautious in interpreting the likelihood of a successful outcome with this monoclonal antibody. 1.
2.
Comont T, Bournet B, Casadevall N et al. Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies. Kidney Int 2014; 86: 210–211. Verhelst D, Rossert J, Casadevall N et al. for the Pure Red Cell Aplasia Study Group. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet 2004; 363: 1768–1771.
Iain C. Macdougall1 The Author Replies: Sir, I note the reports by Comont et al.,1 documenting the possible recovery of antibodyKidney International (2014) 86, 208–213
1 Renal Unit, King’s College Hospital, London, UK Correspondence: Iain C. Macdougall, Renal Unit, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. E-mail: [email protected]
Kidney International (2014) 0, 000–000. doi:10.1038/ki.2014.150
211
