Begin typing your search above and press return to search.
EPUB Before Print

FULL TEXT

ARTICLE
Rituximab as a Preemptive Treatment to Prevent Recurrence of Primary Focal Segmental Glomerulosclerosis: A Novel Approach

Objectives: Primary idiopathic focal segmental glomerulo-sclerosis is a serious disease, frequently progressing to end-stage kidney failure. Management of recurrence after kidney transplant is challenging despite multiple proposed therapeutic approaches. Available treatment for focal segmental glomeru-losclerosis recurrence is plasma exchange, intravenous cyclosporine, and rituximab. In this study, we investigated kidney transplant recipients with focal segmental glomerulosclerosis who were at high risk for recurrence. Patients were given preemptive rituximab at day 0 posttransplant.

Materials and Methods: Between January 2013 and June 2017, our center had 8 patients with primary focal segmental glomerulosclerosis at high risk for recurrence who were scheduled for kidney transplant. These patients received a single rituximab infusion of 375 mg/m2 on day 0 posttransplant. Recurrence of focal segmental glomerulosclerosis posttransplant was defined as repeated proteinuria > 2 g/day, without evidence of clinical or biopsy-proven rejection.

Results: Follow-up showed that none of our patients had immediate posttransplant proteinuria. Only 1 patient developed proteinuria at almost 4 months posttransplant. Mean follow-up duration was 8 months. With regard to complications, 2 patients had serious bacterial infections and 1 patient had cytomegalovirus infection.

Conclusions: Rituximab at day 0 posttransplant may be used safely to prevent focal segmental glomeru-losclerosis recurrence in the graft in the early posttransplant period. However, longer follow-up studies with larger series are needed.


Key words : End-stage kidney disease, Proteinuria, Renal transplant

Introduction

Primary idiopathic focal segmental glomerulosclerosis (FSGS) is a serious disease, which frequently progresses to end-stage kidney disease (ESKD). Apart from its congenital forms, its exact cause is still not completely understood. The diagnosis is based on severe proteinuria along with typical histologic findings, which include diffuse foot process effacement of podocytes on electron microscopy.1 Little is known about its rate of recurrence after kidney transplant (KT), its treatment response, and long-term graft outcomes.2

Management of recurrent disease after KT is challenging. Despite multiple proposed therapeutic approaches, none has proven to be optimal. Published data have suggested an FSGS recurrence rate of 20% to 52% after the first KT, with up to 80% after receiving a second graft.3,4 Risk factors for recurrence include early age of onset (< 6 years), fast disease progression with a short period between the onset of illness and the occurrence of ESKD (typically < 3 years), heavy proteinuria before KT, diffuse mesangial proliferation in the native kidney, FSGS in prior transplanted grafts, and steroid sensitivity.5,6 Available therapies for FSGS recurrence include plasma exchange, intravenous cyclosporine, rituximab, and multiple target treatments as detailed by Canaud and associates.7 However, these lines of treatment achieve partial or complete remission in only some cases. In most cases, graft loss ensues. Rituximab is an anti-CD20 monoclonal antibody that has been used in FSGS recurrence after KT.8,9 Proposed mechanisms of action of rituximab include either nonimmunologic effects on podocytes or as a B-cell-depleting agent (B-lymphocyte depletion is thought to restore T-regulatory cells, which are deficient in nephrotic syndromes).10-13

In this study, we identified FSGS KT recipients who were at high risk for recurrence and who were pretreated with a single preemptive infusion of rituximab on day 0 posttransplant. We investigated whether this treatment could prevent or delay the development of FSGS recurrence in the graft.

Materials and Methods

The study was conducted in accordance with the ethical standards of our institution and in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

This prospective short-term observational study was carried out in the KT unit at New Kasr El Aini Teaching Hospital, Cairo University (Cairo, Egypt). Between January 2013 and June 2017, 8 patients with primary FSGS and who had high risk for recurrence were scheduled for KT and were enrolled in this study. An informed consent was obtained from all patients. Criteria for primary FSGS were proteinuria, typical histology, fast progression, and no other underlying detectable cause; criteria for high recurrence risk were rapid disease progression (< 3 years between diagnosis and ESKD), heavy pro-teinuria pretransplant of > 2 g, or diffuse mesangial proliferation in the native kidney. None of the 8 patients had prior KT.

According to our center’s standard practice, our patients initially received a triple immunosuppressive protocol (calcineurin inhibitor, mycophenolate, and steroids). Tapering of steroids was undertaken over the first year, if no rejection episodes had occurred. No induction therapy was used; instead, a single rituximab infusion of 375 mg/m2 was administered to all patients on day 0 posttransplant. Recurrence of FSGS after KT was defined as repeat proteinuria of > 2 g/day without evidence of clinical or biopsy-proven rejection. The diagnosis was confirmed by histopathologic changes consistent with FSGS on examination with light and electron microscopy.

The following data were recorded: age, date of transplant, postoperative immunosuppressive regi-men, patient and graft survival, occurrence of acute rejection episodes, infections, causes of graft loss, and patient death. In case of recurrence, intensive treatment was administered, which included plasma exchange together with high-dose steroid and calcineurin. Complete response was defined as proteinuria less than 0.3 g/day, and partial response was defined as a 50% decrease in proteinuria with respect to baseline level and less than 3 g/day.

Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 22, IBM Corporation, Armonk, NY, USA). Significance level was set at P < .05.

Results

Demographics of study patients are presented in Table 1. Regarding the recurrence of FSGS, close follow-up of our patient proteinuria levels showed that no patients had immediate posttransplant proteinuria (that is, within the first 72 h post-transplant) and no patients had premature proteinuria (that is, within 2 to 3 wk posttransplant). Only 1 patient developed proteinuria, which occurred almost 4 months posttransplant. The proteinuria level of that patient was around 4 g/day, and graft biopsy revealed areas of focal segmental sclerosis with no evidence of rejection or drug toxicity. The patient was started on plasma exchange and high-dose steroids immediately after diagnosis. In addition, the patient received another infusion of rituximab at the same dosage, with partial remission (proteinuria around 1.5 g/day) shown after about 6 weeks. The patient was followed up for 6 more months with no relapse of proteinuria after plasma exchange treatment had stopped. Our mean follow-up duration was 8 months, with a minimum follow-up duration of 6 months.

None of our patients had graft loss. Mean serum creatinine level was of 1.2 g/dL. The patient with FSGS recurrence had increased serum creatinine that stabilized after remission to 1.8 g/dL. With regard to acute rejection episodes, 2 patients had biopsy-proven single acute rejection episodes, which were successfully treated with pulsed steroids. With regard to other complications, serious bacterial infections were diagnosed and treated in 2 patients and cytomegalovirus (CMV) infection was noted in 1 patient. No other surgical or medical complications were shown in our patients.

Discussion

To the best of our knowledge, this is the first case series of preemptive treatment with rituximab infusion to prevent FSGS recurrence in KT recipients. Recurrence rate of FSGS in our study was 12.5% (1 patient) compared with recurrence rates of 25% to 50% reported in previous series.3,4 Our patient achieved partial remission with plasma exchange, high-dose steroids, and oral cyclosporine. His remission was sustained at the 6-month follow-up.

Rituximab is an anti-CD20 monoclonal antibody, the successful use of which in treatment of steroid-dependent or steroid-resistant nephrotic syndromes has been previously shown.14,15 Encouraging results have also been reported in its use in FSGS recurrence after KT in several retrospective studies.8,9 With plasma exchange, with or without cyclosporine, 70% of children and 63% of adult KT recipients achieved remission of proteinuria.2 In a recent study that evaluated remission rates associated with different treatment strategies for post-KT FSGS recurrence, 66% of patients achieved remission, whether partial or complete, when rituximab was given with plasma exchange at time of recurrence. In the same study, 50% of resistant cases achieved remission when rituximab was given after no response to standard treatment. Rituximab was also successful in maintaining partial and complete remission in patients with difficult weaning from plasma exchange.16 With these results taken into consideration, we attempted to use rituximab as a preemptive agent that might prevent, rather than treat, the recurrence of FSGS in the graft. We believe that the proposed mechanisms of action that would treat could also prevent recurrence.17,18

Rituximab is believed to bind with sphingomyelin-phosphodiesterase acid-like 3b, which is expressed by podocytes and aids in protection of the actin cytoskeleton.10 In addition, rituximab acts as a B-cell-depleting agent, thereby reducing the numerous antibodies incriminated in the pathogenesis of FSGS recurrence. The binding of rituximab to CD20 causes a depletion of B lymphocytes through 3 mechanisms: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and induction of apoptosis.11-13 B-lymphocyte depletion possibly also restores T-regulatory cells deficient in nephrotic syndromes.18

We noticed a moderate rate of infections, mainly bacterial, in 25% of patients (shown as pyelonephritis and gastroenteritis in 2 patients). Another patient developed CMV enteritis, which was treated by valganciclovir. A significantly higher rate of severe bacterial infection was previously reported in a study of rituximab for treatment of FSGS recurrence, which reached 75%.16 Other studies have also previously associated rituximab with increased risk of severe infections, particularly pyogenic or herpes virus infections, including CMV, and pneumonitis caused by Pneumocystis jiroveci.19,20 The role of rituximab in the high occurrence of infectious diseases in these highly immunosuppressed patients is still to be determined. We believe that preemptive use of rituximab could reduce the risk and severity of these infections by reducing the need for plasma exchange therapy. However, such deductions require a larger number of patients and a longer follow-up before being ascertained.

Our study had several limitations. First, this study was performed in an adult care center and did not include any pediatric patients. Factors known to be associated with FSGS response to rituximab in the literature are normal serum albumin rate during infusion and age younger than 18 years at the time of KT.8 Indeed, rates of remission observed after use of rituximab have been shown to be 80% in pediatric patients and 50% in adults.9 A second limitation was the lack of monitoring of CD19 as an indicator of B-lymphocyte depletion; this has been proposed as a guide for defining the efficacy of treatment with rituximab. Finally, the small number of patients and the short follow-up were additional limitations that would prevent us from drawing definite conclusions. However, this work may be considered as a pilot study, guiding further research to help with man-agement of this challenging group of patients.

Conclusions

Our results suggest that rituximab on day 0 post-transplant may be used safely to prevent or limit FSGF recurrence in the graft after a first KT in the early posttransplant period. Longer follow-up and larger numbers of patients in future prospective studies are needed to confirm these highly encouraging results.


References:

  1. Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol. 2004;15(8):2169-2177.
    CrossRef - PubMed
  2. Ponticelli C. Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation. Nephrol Dial Transplant. 2010;25(1):25-31.
    CrossRef - PubMed
  3. Ingulli E, Tejani A. Incidence, treatment, and outcome of recurrent focal segmental glomerulosclerosis posttransplantation in 42 allografts in children—a single-center experience. Transplantation. 1991;51(2):401-405.
    CrossRef - PubMed
  4. Pardon A, Audard V, Caillard S, et al. Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients. Nephrol Dial Transplant. 2006;21(4):1053-1059.
    CrossRef - PubMed
  5. Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review. Pediatr Transplant. 2010;14(3):314-325.
    CrossRef - PubMed
  6. Cravedi P, Kopp JB, Remuzzi G. Recent progress in the pathophysiology and treatment of FSGS recurrence. Am J Transplant. 2013;13(2):266-274.
    CrossRef - PubMed
  7. Canaud G, Zuber J, Sberro R, et al. Intensive and prolonged treatment of focal and segmental glomerulosclerosis recurrence in adult kidney transplant recipients: a pilot study. Am J Transplant. 2009;9(5):1081-1086.
    CrossRef - PubMed
  8. Araya CE, Dharnidharka VR. The factors that may predict response to rituximab therapy in recurrent focal segmental glomerulosclerosis: a systematic review. J Transplant. 2011;2011:374213.
    CrossRef - PubMed
  9. Kumar J, Shatat IF, Skversky AL, et al. Rituximab in post-transplant pediatric recurrent focal segmental glomerulosclerosis. Pediatr Nephrol. 2013;28(2):333-338.
    CrossRef - PubMed
  10. Fornoni A, Sageshima J, Wei C, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med. 2011;3(85):85ra46.
    CrossRef - PubMed
  11. Alachkar N, Gupta G, Montgomery RA. Angiotensin antibodies and focal segmental glomerulosclerosis. N Engl J Med. 2013;368(10):971-973.
    CrossRef - PubMed
  12. Delville M, Sigdel TK, Wei C, et al. A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med. 2014;6(256):256ra136.
    CrossRef - PubMed
  13. Musante L, Candiano G, Bruschi M, et al. Circulating anti-actin and anti-ATP synthase antibodies identify a sub-set of patients with idiopathic nephrotic syndrome. Clin Exp Immunol. 2005;141(3):491-499.
    CrossRef - PubMed
  14. Guitard J, Hebral AL, Fakhouri F, et al. Rituximab for minimal-change nephrotic syndrome in adulthood: predictive factors for response, long-term outcomes and tolerance. Nephrol Dial Transplant. 2014;29(11):2084-2091.
    CrossRef - PubMed
  15. Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014;384(9950):1273-1281.
    CrossRef - PubMed
  16. Garrouste C, Canaud G, Buchler M, et al. Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: clinical outcomes. Transplantation. 2017;101(3):649-656.
    CrossRef - PubMed
  17. Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. 2015;11(2):76-87.
    CrossRef - PubMed
  18. Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients' management. Nat Rev Nephrol. 2013;9(3):154-169.
    CrossRef - PubMed
  19. Kamar N, Milioto O, Puissant-Lubrano B, et al. Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients. Am J Transplant. 2010;10(1):89-98.
    CrossRef - PubMed
  20. Bomback AS, Derebail VK, McGregor JG, Kshirsagar AV, Falk RJ, Nachman PH. Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol. 2009;4(4):734-744.
    CrossRef - PubMed


DOI : 10.6002/ect.2018.0027


PDF VIEW [153] KB.

From the 1Department of Internal Medicine and Nephrology and the 2Department of Urology, Cairo University, Cairo, Egypt
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Sahier El Khashab, 29 Omar ibn khattab tower, Maadi, Cairo, Egypt
Phone: +201117145521
E-mail: sahieee7@yahoo.com