Plasmapheresis for Recurrent Posttransplant Focal Segmental Glomerulosclerosis

Plasmapheresis for Recurrent Posttransplant Focal Segmental Glomerulosclerosis C.D. Garcia, V.B. Bittencourt, A. Tumelero, J.S. Antonello, D. Malheiros, and V.D. Garcia ABSTRACT The high recurrence rate of focal segmental glomerulosclerosis (FSGS) in kidney transplant recipients suggests that such patients have a circulating factor that alters glomerular capillary permeability. Serum from patients with FSGS increases glomerular permeability to albumin. This permeability factor has been partially identified as a protein. The removal of this protein by plasmapheresis (PP) decreases proteinuria. In this study we report data on the therapeutic effects of PP in FSGS children with recurrence in the transplanted kidney. Three hundred pediatric (age ⬍19 years) renal transplants were performed, including 21 patients (24 transplants) with FSGS as a cause of renal failure. Fourteen (58.3%) subjects experienced disease recurrence (proteinuria ⬎1 g/m2 per day) within 1 month after transplantation. Mean age patient was 12 ⫾ 4.3 years, including 83.3% Caucasians and 70.2% recipients of living donor grafts. Nine were treated with 10 cycles of PP (3 cycles/weekly), initiated immediately after recurrence (⬍48 hours). Immunosuppression included high doses of cyclosporine (C2 levels of 1700 –1800 ng/mL), mycophenolate sodium or mofetil, and prednisone. Thirteen patients were induced with anti-IL2 receptor monoclonal antibody (daclizumab/basiliximab). Among the patients who underwent PP, five (55.5%) achieved a complete remission and one (12%), a partial remission (1 g/24 hours). There were no cases of remission among the five patients who were not treated with PP. Those who achieved remission after PP experienced no recurrences during the 2.6 ⫾ 1.4 years follow-up. PP appears to be effective to treat recurrent FSGS following kidney transplantation. It should be started as soon as possible.

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HE CLINICAL COURSE of primary focal segmental glomerulosclerosis (FSGS) is frequently complicated by nephrotic range proteinuria and progression to renal failure.1 Recurrence of FSGS in the transplanted kidney is a severe condition associated with graft loss. The high recurrence rate of the disease in transplanted kidneys suggests that such patients have a circulating factor that alters glomerular capillary permeability.2 In recent years some authors have observed that sera from patients with FSGS increase glomerular permeability to albumin. The permeability factor has been partially identified as a 30 to 50 Kd protein.3,4 The removal of this protein by plasmapheresis (PP) decreases the proteinuria. In this report we provide preliminary data on the therapeutic effect of PP in children with recurrent posttransplant FSGS. PATIENTS AND METHODS From 1977 to 2005, 300 pediatric (age ⬍19 years) renal transplants were performed, including 21 patients (24 transplants) who had

FSGS as the cause of renal failure as confirmed by pretransplant biopsy. Fourteen (58.3%) of these subjects experienced recurrences (proteinuria ⬎1 g/m2 per day) within 1 month of transplantation. The patients displayed a mean age of 12 ⫾ 4.3 years, 83.3% were Caucasians, 70.2% had received a graft from a living donor. Since 2001, patients who presented with recurrent FSGS were treated with 10 cycles of PP (3 cycles/weekly), initiated immediately postrecurrence (⬍48 hours). For financial reasons, the number of sessions had to be limited to 10. In each session, 50 to 75 mL/kg of patient plasma was exchanged with 5% to 8% albumin. Immunosuppressive therapy consisted of high doses of cyclosporine (C2 levels of 1700 –1800 ng/mL), mycophenolate sodium or mofetil (until 1997 azathioprin was used), and prednisone. Thirteen paFrom Santo Antônio Children’s Hospital, Santa Casa Hospital Complex, Faculdade de Ciencias Medicas de Porto Alegre (FFFCMPA), Porto Alegre, Brazil. Address reprint requests to Clotilde Druck Garcia, Correa Lima 1493 - Porto Alegre, 90850-250, Brazil. E-mail: cdgarcia1@ uol.com.br

0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.069

© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

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Transplantation Proceedings, 38, 1904 –1905 (2006)

PLASMAPHERESIS FOR POST-TRANSPLANT FSGS tients received induction with an anti-IL2 receptor monoclonal antibody (daclizumab/basiliximab).

RESULTS

Twenty-four transplants were performed in 21 children with FSGS, 14 (58.3%) of whom showed recurrences. Of these, nine (64.3%) were treated with PP. Five of the nine (55.5%) patients treated with PP went into complete remission (⬍0.2 g/m2 per day) and one (12%) into partial remission (1 g/ 24 hours) after receiving a total of 10 sessions. There was no recurrence during the 2.6 ⫾ 1.4 years follow-up. Infectious complications were observed in three patients after PP: one cytomegalovirus disease and two varicella. There were no cases of remission among the five patients who were not treated with PP. All untreated patients had persistent nephrotic proteinuria range losing their grafts at 3.2 ⫾ 2.3 years after the transplant. DISCUSSION

Steroid-resistant nephrotic syndrome with FSGS is one of the most common lesions leading to renal transplantation in children.5,6 The recurrence rate is approximately 30% with half of the grafts lost. Several therapeutic regimens have been proposed, although with conflicting results.7,8 The rapid onset of proteinuria, in general, immediately after renal transplantation, led to the hypothesis that recurrence of FSGS was caused by a circulating plasma factor.5,9 Clinical experiments demonstrated that injection of patient serum induced proteinuria in rats.3 This circulating factor is associated with increased glomerular permeability to albumin in recurrent FSGS.10,11 The presence of a plasma factor may explain the benefits of plasma exchange treatment.4,12,13 It is evident from our data and from the literature that the effectiveness of PP treatment is quite variable; some patients do not respond at all, whereas others experience a relapse. These differences may be explained by variations in the study population or in the time of onset and magnitude of proteinuria. Also, there may be differences in the level or pathogenicity of the permeability factor, or even in the sensitivity of the kidney to this molecule. There is some evidence that the starting time of treatment is important. Better results are obtained when plasma exchange is started early after the onset of proteinuria when the the renal biopsy shows no abnormalities, except for foot process fusion on electronic microscopy. In contrast, if PP is delayed or after the FSGS lesions are well established, it is less effective.6,14 –17 Our study demonstrated favorable effects of plasma exchange on proteinuria in six of nine patients with FSGS recurrence, who remained in remission after the treatment.

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In conclusion, early PP treatment for recurrent posttransplant FSGS was successful in the majority of this series of cases without a definite adverse event. PP appeared to be effective when started as soon as possible. REFERENCES 1. Hubsch H, Montane B, Abitbol C, et al: Recurrent focal glomerulosclerosis in pediatric renal allografts: the Miami experience. Pediatr Nephrol 20:210, 2005 2. Moriconi L, Lenti C, Puccini R, et al: Proteinuria in focal segmental glomerulosclerosis: role of circulating factors and therapeutic approach. Ren Fail 23:533, 2001 3. Zimmerman SW: Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol 22:32, 1984 4. Dantal J, Bigot E, Bogers W, et al: Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 330:7, 1994 5. Hoyer JR, Vernier RL, Najarian JS, et al: Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet 2:343, 1972 6. Cheong HI, Han HW, Park HW, et al: Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis. Nephrol Dial Transplant 15:78, 2000 7. Cochat P, Kassir A, Colon S, et al: Recurrent nephrotic syndrome after transplantation: early treatment with plasmaphaeresis and cyclophosphamide. Pediatr Nephrol 7:50, 1993 8. Vincenti F, Ghiggeri GM: New insights into the pathogenesis and the therapy of recurrent focal glomerulosclerosis. Am J Transplant 5:1179, 2005 9. Ghiggeri GM, Artero M, Carraro M, et al: Glomerular albumin permeability as an in vitro model for characterizing the mechanism of focal glomerulosclerosis and predicting posttransplant recurrence. Pediatr Transplant 8:339, 2004 10. Savin VJ, Sharma R, Sharma M, et al: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334: 878, 1996 11. McCarthy ET, Sharma M, Sharma R, et al: Sera from patients with collapsing focal segmental glomerulosclerosis increase albumin permeability of isolated glomeruli. J Lab Clin Med 143:225, 2004 12. Jungraithmayr TC, Bulla M, Dippell J, et al: Primary focal segmental glomerulosclerosis—long-term outcome after pediatric renal transplantation. Pediatr Transplant 9:226, 2005 13. Valdivia P, Gonzalez Roncero F, Gentil MA, et al: Plasmapheresis for the prophylaxis and treatment of recurrent focal segmental glomerulosclerosis following renal transplant. Transplant Proc 37:1473, 2005 14. Rao PS, Bakir AA: The role of plasmapheresis in the treatment of focal segmental glomerulosclerosis (FSGS). Int J Artif Organs 23:798, 2000 15. Ohta T, Kawaguchi H, Hattori M, et al: Effect of pre- and postoperative plasmapheresis on posttransplant recurrence of focal segmental glomerulosclerosis in children. Transplantation 71:628, 2001 16. Greenstein SM, Delrio M, Ong E, et al: Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts. Pediatr Nephrol 14:1061, 2000 17. Pradhan M, Petro J, Palmer J, et al: Early use of plasmapheresis for recurrent post-transplant FSGS. Pediatr Nephrol 18:934, 2003