|Year : 2018 | Volume
| Issue : 3 | Page : 193-198
Recurrent focal segmental glomerulosclerosis after kidney transplant in adults: A report on various treatment regimens
Joyita Bharati1, Krishan Lal Gupta1, Deepesh Benjamin Kenwar2, Ritambhra Nada3, Manish Rathi1, Harbir Singh Kohli1, Raja Ramachandran1
1 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Renal Transplant Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||28-Sep-2018|
Dr. Raja Ramachandran
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Aim: Recurrence of focal segmental glomerulosclerosis (FSGS) in the post-transplant setting is variable with high rates of graft loss. Risk factors of recurrence include young age and Caucasian race. Data on outcome of recurrent FSGS from South Asia is scanty. We describe our experience of managing adults with recurrent FSGS with different therapies. Settings and Design: The study was conducted at the Department of Nephrology and Renal transplant surgery, Post Graduate Institute of Medical education and Research Institute, Chandigarh, India, and this was an observational study. Methods: We analyzed outcomes of patients with biopsy-proven recurrent FSGS over the last 5 years (2012–2017). Recurrence was defined as significant proteinuria (albuminuria ≥ 3+) and a demonstrable FSGS lesion on light microscopy and/or electron microscopy suggestive of diffuse foot process effacement. Results: Thirteen patients with 14 recurrences of FSGS post-renal transplant were identified. Mean age of the patients was 33.15 (±8.32) years. Median time to recurrence of FSGS was 45 days. Plasma exchange (PLEX) alone was used in two patients with 50% in remission. Combined PLEX and rituximab were used in six recurrences with remission in 83.3% of them. Five recurrences were treated with only angiotensin-converting enzyme inhibitor/angiotensin receptor blockade (ACEi/ARB) due to financial constraints. Of them, 4 (80%) achieved remission in proteinuria. One patient did not receive any therapy and expired in the 1st month of follow-up. Conclusion: The present series is one of the largest reports of recurrent FSGS from South Asia. Furthermore, the current report strengthens the use of ACEi/ARB in patients with recurrent FSGS.
Keywords: Focal segmental glomerulosclerosis, plasma exchange, rituximab, recurrence, renin–angiotensin–aldosterone system blockade
|How to cite this article:|
Bharati J, Gupta KL, Kenwar DB, Nada R, Rathi M, Kohli HS, Ramachandran R. Recurrent focal segmental glomerulosclerosis after kidney transplant in adults: A report on various treatment regimens. Indian J Transplant 2018;12:193-8
|How to cite this URL:|
Bharati J, Gupta KL, Kenwar DB, Nada R, Rathi M, Kohli HS, Ramachandran R. Recurrent focal segmental glomerulosclerosis after kidney transplant in adults: A report on various treatment regimens. Indian J Transplant [serial online] 2018 [cited 2018 Dec 11];12:193-8. Available from: http://www.ijtonline.in/text.asp?2018/12/3/193/242434
| Introduction|| |
Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome in adults and the commonest glomerular disease in patients on maintenance dialysis. About 40%–50% progress to end-stage renal disease (ESRD) after diagnosis, with renal survival of approximately 30% in patients who do not achieve remission with therapy as compared to 90% in those who achieve remission. Recurrence of FSGS occurs in 20%–40% of patients after the first renal transplant and in approximately 70% after subsequent transplants. Recurrent FSGS was found to be the cause of graft loss in 18.7% of living donor recipients and 7.8% of cadaveric recipients in the United States Renal Data Registry analysis. Moreover, 10-year graft loss due to recurrent FSGS was reported to be 12.7% in the Australia and New Zealand Dialysis and Transplant Registry analysis.
Although the best modality of treatment is still not tested in controlled trials, plasma-exchange (PLEX) with or without immunosuppressive agents such as high-dose steroids, high-dose cyclosporine, and rituximab is being widely used worldwide. Successful use of only angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEi) has been described in few reports. We report our experience on managing recurrent FSGS in adults with various therapies including plasmapheresis with or without rituximab and ACEi/ARBs only.
| Methods|| |
We analyzed the course of 13 patients (case series) with biopsy-proven recurrent FSGS (all screened with electron microscopy) over the last 5 years (2012-2017) in the Department of Nephrology and Department of Renal Transplant Surgery, respectively, at our Institute. Recurrence was defined as significant proteinuria (albuminuria ≥ 3+) and either consistent light microscopy (LM) for FSGS or in case of normal morphology on LM, an electron microscopy suggestive of diffuse foot process effacement. The clinical characteristics, which included age, sex, onset of basic disease, histopathology of native kidney biopsy, steroid responsiveness, time taken to progress to ESRD, nature of renal transplant (living or cadaveric donor), relation to donor, age of the donor, post-transplant immunosuppression used, onset of recurrence after transplant, histopathology of graft biopsy, treatment given for recurrent FSGS, and the outcome were all noted from medical records and history provided by the patient/relatives after informed consent. The characteristics were then analyzed using IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY:IBM Corp. Cox proportional hazard method was used to analyze the difference in the time to recurrence between the three groups of treatment.
| Results|| |
Thirteen patients had 14 recurrences of FSGS over the last five years. The mean age of patients was 33.15 (±8.32) years. The native kidney disease was biopsy-proven FSGS in 11 cases and in 2 patients; the kidneys were contracted at the diagnosis of ESRD. All except one were living donor allografts. The baseline immunosuppression was a combination of calcineurin inhibitors (11 received tacrolimus and 2 received cyclosporine as the initial therapy), mycophenolate mofetil, and steroids in all patients. The treatment included only PLEX, rituximab with PLEX, and only ACEi/ARB in 2 (15.38%), 6 (46.15%), and 5 (38.46%) patients, respectively, and were based on the discretion of the treating physician and patient affordability. The median time to recurrence of FSGS was 45 (interquartile range [IQR]:12.25–97.50, range: 2–360) days. The median time to recurrence was 60, 14, and 30 days in the ARB/ACEi only group, PLEX + rituximab group and PLEX only group, respectively (P = 0.607). The median serum creatinine at the onset of recurrence was 1.45 (IQR: 1.15–2.17, range: 0.9–10.2) mg/dl, with only 2 patients requiring dialysis at presentation. Of 12 patients who received treatment, all received ACEi/ARBs as adjunctive therapy. The schedule followed for PLEX (40 ml/kg plasma replaced every session) using membrane filtration technique comprised at least 7 sessions (overall 7–10 sessions in all except one, patient #5) over 2 weeks. Fresh frozen plasma and 5% albumin with saline were used as replacement fluid in 6 and 2 patients, respectively. Maintenance PLEX every fortnightly was given for one patient (Patient # 5) for relapsing disease. One patient who received PLEX for recurrence had graft loss within 6 months and received only ARB for the subsequent recurrence in the second allograft. One patient did not receive any treatment and succumbed to severe sepsis in the immediate posttransplant period. Of the 5 patients on only ACEi/ARB therapy, 4 achieved either partial or complete remission. The reason for treating with only ACEi/ARB therapy in all the patients was monetary constraints for alternative plasma or rituximab therapy. PLEX combined with rituximab therapy was most frequently used (46.15%) in our patients with 5 out of 6 achieving remission. Rituximab, single dose (375 mg/m2), was given after completion of PLEX sessions in all the 6 patients. Four out of total 8 patients who underwent PLEX developed transient hypotension which resolved immediately with intravenous fluids. The summary of baseline characteristics, treatment, and outcome of all the patients is outlined in [Table 1].
| Discussion|| |
In the current report, we highlight the outcome of recurrent FSGS in a cost-limited setting. Recurrence of FSGS after transplant has been described to be early (within hours to days) or late (within months to years), with late recurrences usually associated with bad outcomes. Most of the recurrences in our patients were reported in the early posttransplant period (<60 days). All our patients were of Indian origin and South Asian ethnicity. Three-fourth of the patients treated with PLEX with or without rituximab and adjunctive ACEi/ARBs responded to treatment.
Recurrence of FSGS in the post-transplant depends on a number of factors, which includes age at onset of disease, being more frequent in patients with younger age at onset, steroid responsiveness at presentation, rapid progression of FSGS to ESRD in the native kidney, historical recurrence in the previous allograft, and Caucasians.
Recurrent FSGS is usually a disease of childhood, but all the patients in our study were adults, as our transplant program is predominately for adult population. Native disease was biopsy-proven FSGS in 11 of the 13 patients. Rapid-onset massive proteinuria characterizes recurrent FSGS in the early posttransplant period as early as within hours of transplant. Although severe graft dysfunction is not frequent at presentation, children with recurrent FSGS were found to have higher incidence of acute tubular necrosis requiring dialysis than those with other primary diagnosis. In the present series, only 2 patients had advanced graft dysfunction requiring dialysis at presentation.
Ding et al. reported recurrence of FSGS in 46% of the children with FSGS and observed that recurrence occurred in 93% of the patients with initial steroid sensitivity compared to 30% with initial steroid resistance. Similarly, we found that 50% of our patients with recurrent FSGS were steroid sensitive at onset. The mean time to recurrence of FSGS was around 3 months in the current series, with 6 of 13 (46.2%) patients having recurrence within 1 month of transplant. Early recurrences (<4 weeks) were reported in three-fourth of the patients by Deegens et al.
Commonly used therapies in recurrent FSGS are plasmapheresis/PLEX, rituximab, and renin–angiotensin–aldosterone system (RAAS) blockade., Presence of a circulating factor in the plasma of patients with recurrent FSGS remains a mechanistic hypothesis in light of the immediate recurrence of proteinuria within hours after transplantation. This plasma “factor” was reported to directly lead to increased glomerular permeability and proteinuria by Savin et al. in isolated rat glomeruli in 1996. Success of plasmapheresis in inducing remission of recurrent FSGS supported this hypothesis of proteinuria by a putative humoral “factor,” the exact molecular structure of which is not identified. Universally, plasmapheresis with replacement with 5% albumin or plasma (PLEX) is the standard therapy for recurrent FSGS. Ponticelli compiled 10 studies on plasmapheresis in recurrent FSGS and reported a remission rate of 63% in adults and 70% in pediatric patients. In addition, plasmapheresis is also used successfully in preventing recurrence of FSGS in those with high risk of recurrence. Gohh et al. reported reduction of recurrence by 50% with the use of preemptive perioperative plasmapheresis (8 sessions) in adults with high risk of recurrence, defined as, rapid progression to ESRD (≤3 years of diagnosis) or first graft loss to recurrent FSGS. The best response with plasmapheresis results from its early start (within 2 weeks of relapse) and repeated sessions till remission, sometimes requiring therapy over months and years. The limitations with plasmapheresis procedure are the associated side-effects (hypotension, bleeding, infections, and allergic reactions to plasma), finances involved and its frequent transient effect on proteinuria causing relapse on discontinuation. The long-term outcome of plasmapheresis therapy is scarcely reported worldwide. The short follow-up after discontinuation of PLEX in our patients restricts us to conclude on its long-term efficacy. Moroni et al. reported good graft function in 80% of patients treated with plasmapheresis for variable periods in long-term follow-up (15 years). Furthermore, Belson et al. described the reversal of massive proteinuria and better allograft survival, but, progressive glomerular sclerosis on repeat biopsies in a plasmapheresis-dependent child with early recurrent FSGS.
Efficacy of rituximab was first noted incidentally in a child with PLEX-resistant recurrent FSGS, who, after receiving rituximab infusions for treatment of lymphoma, which occurred after 5 months of the diagnosis of recurrent FSGS, went into complete remission of proteinuria. Following that, various authors have reported conflicting results on the efficacy of rituximab (used at 375 mg/m2/dose for 2–6 doses), usually with combined PLEX either at outset or after initial resistance to PLEX.,,, The efficacy of rituximab in recurrent FSGS points toward altered B-cell-mediated antibody production or antigen presentation to T-cells in these patients. In addition, rituximab was shown to reduce podocyte dysfunction caused by sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein downregulation in patients with recurrent FSGS through its direct binding to SMPDL-3b and preserves cytoskeleton alteration. Five of 6 (83.3%) patients treated with PLEX and rituximab had remission in proteinuria in our study. All these patients were given 3 sessions of PLEX per week initially for a total of 7–10 sessions and one patient (Patient #5) is maintained on PLEX every 2 weekly in view of PLEX-dependent disease. Single-dose (375 mg/m2) rituximab therapy was preplanned after completion of 7–10 sessions of plasmapheresis in all the 6 patients.
Artero et al. first described the use of ACEi therapy in 9 patients with biopsy-proven recurrent FSGS with 7 out of 9 patients receiving only ACEi therapy. They showed marked reduction in proteinuria without a decrease in creatinine clearance in patients on ACEi therapy, although, without any effect on short-term (mean follow-up: 28.7 months) allograft survival. Interestingly, Freiberger et al. reported remission of proteinuria in a young man with recurrent FSGS being treated with triple blockade of renin–angiotensin system which included ARB, ACEi, and direct renin inhibitor over 12 months. Furthermore, Bansal et al. described effective use of high-dose ARB (telmisartan 120 mg/day) in a patient with recurrent FSGS with sustained remission of proteinuria at 4 years after transplantation. Of note, the authors made a mention on the progression of glomerular sclerosis and interstitial fibrosis on repeat biopsy despite clinical remission with ARB. However, this finding is contrary to the effect of ARB or ACEi therapy which is likely due to its hemodynamic effect of decreasing efferent arteriolar resistance to relieve glomerular hyperfiltration. The reduction in glomerular filtration prevents capillary wall damage and attenuates glomerulosclerosis. Nonetheless, in the setting of transplantation, progressive glomerular sclerosis and interstitial fibrosis are known consequences of multiple other insults such as chronic rejection and CNI therapy. In our series, 5 patients were treated with only ACEi/ARBs for financial constraints in using standard therapy. Four out of 5 (80%) patients had sustained remission till last visit (mean follow-up of 16.2 months). Repeat biopsy was not done in our patients to demonstrate histological status. The possibility of spontaneous remission of proteinuria and an equivocal late response to prior therapies used in these patients makes the conclusion on efficacy of RAAS blockade monotherapy blurred. Furthermore, none of the patients treated with RAAS blockade had moderate/severe renal dysfunction (serum creatinine >2 mg/dl). Therefore, although the role of monotherapy with RAAS blockade in treating recurrent FSGS is unclear at present, its combination with established therapies such as plasmapheresis or prednisolone has been found very effective., Our report points toward usefulness of RAAS blockade monotherapy in resource-poor settings and possibly in patients with allergies to plasma therapy. The response rate to various therapies is summarized in [Table 2].,,,,
|Table 2: Therapies for recurrent focal segmental glomerulosclerosis in adults: Comparison of various studies|
Click here to view
| Conclusion|| |
The present series, although limited by its small number of patients, is one of the largest reports of recurrent FSGS (all screened by electron microscopy) from South Asia. PLEX combined with rituximab at the outset resulted in remission in over three-fourth of the patients with recurrent FSGS. There were no serious adverse effects of plasma exchange noted. The current report also strengthens the use of ACEi/ARBs monotherapy in patients with recurrent FSGS who cannot receive standard therapy such as plasmapheresis and rituximab.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 2004;44:815-25.
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;15:2169-77.
Choy BY, Chan TM, Lai KN. Recurrent glomerulonephritis after kidney transplantation. Am J Transplant 2006;6:2535-42.
Abbott KC, Sawyers ES, Oliver JD 3rd
, Ko CW, Kirk AD, Welch PG, et al.
Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the united states. Am J Kidney Dis 2001;37:366-73.
Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. N
Engl J Med 2002;347:103-9.
Ponticelli C. Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation. Nephrol Dial Transplant 2010;25:25-31.
Hickson LJ, Gera M, Amer H, Iqbal CW, Moore TB, Milliner DS, et al.
Kidney transplantation for primary focal segmental glomerulosclerosis: Outcomes and response to therapy for recurrence. Transplantation 2009;87:1232-9.
Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula MK, Dudley JA, et al.
Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol 2014;25:1342-8.
Kang HG, Ha IS, Cheong HI. Recurrence and treatment after renal transplantation in children with FSGS. Biomed Res Int 2016;2016:6832971.
Tejani A, Stablein DH. Recurrence of focal segmental glomerulosclerosis posttransplantation: A special report of the North American pediatric renal transplant cooperative study. J Am Soc Nephrol 1992;2:S258-63.
Kaplan-Pavlovcic S, Ferluga D, Hvala A, Chwatal-Lakic N, Bren AF, Vizjak A, et al.
Recurrent focal segmental glomerulosclerosis after renal transplantation: Is early recurrent proteinuria always a surrogate marker for recurrence of the disease? Transplant Proc 2002;34:3122-4.
Baum MA. Outcomes after renal transplantation for FSGS in children. Pediatr Transplant 2004;8:329-33.
Deegens JK, Andresdottir MB, Croockewit S, Wetzels JF. Plasma exchange improves graft survival in patients with recurrent focal glomerulosclerosis after renal transplant. Transpl Int 2004;17:151-7.
Dello Strologo L, Guzzo I, Laurenzi C, Vivarelli M, Parodi A, Barbano G, et al.
Use of rituximab in focal glomerulosclerosis relapses after renal transplantation. Transplantation 2009;88:417-20.
Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, et al.
Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N
Engl J Med 1996;334:878-83.
Gohh RY, Yango AF, Morrissey PE, Monaco AP, Gautam A, Sharma M, et al.
Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients. Am J Transplant 2005;5:2907-12.
Moroni G, Gallelli B, Quaglini S, Banfi G, Montagnino G, Messa P, et al.
Long-term outcome of renal transplantation in adults with focal segmental glomerulosclerosis. Transpl Int 2010;23:208-16.
Belson A, Yorgin PD, Al-Uzri AY, Salvatierra O, Higgins J, Alexander SR, et al.
Long-term plasmapheresis and protein A column treatment of recurrent FSGS. Pediatr Nephrol 2001;16:985-9.
Pescovitz MD, Book BK, Sidner RA. Resolution of recurrent focal segmental glomerulosclerosis proteinuria after rituximab treatment. N
Engl J Med 2006;354:1961-3.
Garrouste C, Canaud G, Büchler M, Rivalan J, Colosio C, Martinez F, et al.
Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Clinical outcomes. Transplantation 2017;101:649-56.
Kumar J, Shatat IF, Skversky AL, Woroniecki RP, Del Rio M, Perelstein EM, et al.
Rituximab in post-transplant pediatric recurrent focal segmental glomerulosclerosis. Pediatr Nephrol 2013;28:333-8.
Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, et al.
Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 2011;3:85ra46.
Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F. Recurrent focal glomerulosclerosis: Natural history and response to therapy. Am J Med 1992;92:375-83.
Freiberger V, Amann K, Heemann U, Frank H. Effect of a triple blockade of the renin-angiotensin-system in recurrent focal segmental glomerulosclerosis after kidney transplantation. Transpl Int 2009;22:1110-3.
Bansal SB, Sethi SK, Jha P, Duggal R, Kher V. Remission of post-transplant focal segmental glomerulosclerosis with angiotensin receptor blockers. Indian J Nephrol 2017;27:154-6.
] [Full text]
Anderson S, Rennke HG, Brenner BM. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 1986;77:1993-2000.
Ponticelli C, Campise M, Tarantino A. The different patterns of response to plasmapheresis of recurrent focal and segmental glomerulosclerosis. Transplant Proc 2002;34:3069-71.
Canaud G, Zuber J, Sberro R, Royale V, Anglicheau D, Snanoudj 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;9:1081-6.
Rodríguez-Ferrero M, Ampuero J, Anaya F. Rituximab and chronic plasmapheresis therapy of nephrotic syndrome in renal transplantation patients with recurrent focal segmental glomerulosclerosis. Transplant Proc 2009;41:2406-8.
Tsagalis G, Psimenou E, Nakopoulou L, Laggouranis A. Combination treatment with plasmapheresis and rituximab for recurrent focal segmental glomerulosclerosis after renal transplantation. Artif Organs 2011;35:420-5.
Yabu JM, Ho B, Scandling JD, Vincenti F. Rituximab failed to improve nephrotic syndrome in renal transplant patients with recurrent focal segmental glomerulosclerosis. Am J Transplant 2008;8:222-7.
[Table 1], [Table 2]