| Abstract|| |
A 12-year-old girl with a history of steroid and cyclosporine (CsA) resistant nephrotic syndrome owing to focal and segmental glomerulosclerosis (FSGS) has progressed to end-stage renal disease (ESRD) for which she underwent hemodialysis for 18 months before she successfully received a fully matched kidney transplant from her sister at the age of nine years. The post transplantation (Tx) period was marked by an early and massive proteinuria indicating recurrent FSGS for which she received 12 sessions of plasmapheresis (PP); unfortunately, she did not appear to have any response to the PP therapy; thereafter, a conservative management comprising essentially enalapril and losartan has been initiated and was also not successful during the first four months, however, a very gradual response has been noticed to occur after five months of conservative therapy and ultimately, the patient attained complete remission after 21 months of treatment. Amazingly, 15 months after discontinuation of enalapril and losartan, she remained in a complete and sustained remission with a good renal allograft function. To the best of our knowledge, this is the first case ever reported in the literature of a "spontaneous" remission of post transplant recurrent FSGS.
|How to cite this article:|
Saeed B, Mazloum H, Askar M. Spontaneous remission of post-transplant recurrent focal and segmental glomerulosclerosis. Saudi J Kidney Dis Transpl 2011;22:1219-22
|How to cite this URL:|
Saeed B, Mazloum H, Askar M. Spontaneous remission of post-transplant recurrent focal and segmental glomerulosclerosis. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2014 Dec 22];22:1219-22. Available from: http://www.sjkdt.org/text.asp?2011/22/6/1219/87238
| Introduction|| |
Focal segmental glomerulosclerosis (FSGS) is the primary renal disease in approximately one-tenth of pediatric patients receiving a renal allograft. Recurrence of proteinuria after renal transplantation is observed in approximately 30% of patients and negatively impacts graft survival.  The management of FSGS following renal transplantation remains controversial. Following the assumption of a putative permeability factor, several studies have suggested the efficacy of plasmapheresis in inducing remission, preferably in conjunction with highdose cyclosporine A or cyclophosphamide.  Its long-term prognosis and the likelihood of late remission have rarely been studied.
| Case Report|| |
A 12-year-old girl known to have a long history of nephrotic syndrome that started at the age of three years and proved later to be a steroid-resistant case with FSGS diagnosed using a kidney biopsy. The family screening for affected siblings with similar condition was negative. The patient received a six month course of cyclosporine (CsA), which ended-up by a complete failure to induce remission. Thereafter, CsA was stopped and the patient was started on conservative management comprising an angiotensin converting enzyme inhibitor (ACEi), diuretics, statin, and other supportive therapies. At age of five years, she developed progressive chronic kidney disease (CKD) that reached end-stage renal disease (ESRD) at age of 7.5 years, when she was started on hemodialysis that lasted for 18 months before she received a kidney transplant from her fully matched sister. The immunosuppressive protocol consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. The surgery was uneventful with an immediate post transplant diuresis and the serum creatinine in the very next day was 0.6 mg/dL, though she was completely anuric before she got transplanted. The first week that followed transplantation was unremarkable with no evidence of recurrent proteinuria.
During the second week of post operation, she started to have pitting edema in the lower limbs associated with massive proteinuria of 2.5 g per day (127 mg/m²/hour), hypoalbuminemia, and hypercholesterolemia indicating an early recurrence of FSGS. Her parents were reluctant to consenting for an allograft kidney biopsy, we asked for, to confirm the diagnosis. The patient has been managed as recurrent FSGS and a course of plasmapheresis (PP) was initiated at day 14, post transplantation. This course comprised a total of 12 PP sessions within a period of eight weeks. The PP was initially performed every other day for four treatments, thereafter, twice weekly for four additional treatments and then weekly for the last four treatments. The dosage of TAC was kept within the recommended levels between 10-15 mg/d during the first month, 7-10 during the rest of the first six months post transplantation, and 5-7 thereafter. Response to therapy was assessed by measuring urine protein to creatinine ratios as well as by measuring total protein excretion in timed collections. By the end of the PP course, the patient did not appear to have any response to PP therapy. At that time, the patient was started on conservative management comprising essentially enalapril with a starting dose of 5 mg daily then gradually increased to 20 mg on two divided doses in addition to diuretics and statin. Given the absence of any evidence of response at one month of conservative management, losartan (angiotensin receptor blocker) (ARB) was added with a starting dose of 25 mg once daily then increased to 50 mg. The patient did remain non responsive to this combined ACEi and ARB treatment for several months before the edema started to very gradually disappear five months after the end of the PP therapy. However, the nephrotic range 24-hour proteinuria has persisted for nine months of conservative therapy and ranged from 1.6 to 2.1 grams (81-106 mg/m²/hour) before getting decreased below the nephrotic range, but well above the upper normal limits at 13 months post-transplantation, and finally to attain a complete remission at 21 months post-transplantation with a 24-hour urinary protein of 38 mg. Thereafter, although the conservative therapy was discontinued, the patient remained in a complete and sustained remission after 15 months of discontinuation of the antiproteinuric therapy. Her renal allograft function was always maintained around a glomerular filtration rate of 75 mL/min. Three years after transplantation, she was on a minimal immunosuppressive therapy comprising one mg twice daily of TAC, 250 mg twice daily of MMF, and 5 mg of prednisolone on alternate day.
| Discussion|| |
Since FSGS was the original disease causing renal failure in our index case, recurrence occurs in 14% to 60% of first transplants. , Our case is probably a sporadic form of FSGS, given the absence of similar case in her family. However, the mutational studies for the several genes encoding slit diaphragm proteins including podocin were not performed in order to exclude the possibility of structural alterations in podocyte proteins of the native kidneys, where one could not predict recurrence of disease. However, there have been recent reports of high rates of recurrent FSGS in patients with a certain NPHS2 mutation and resultant abnormal expression of podocin, the rate of recurrence in these reports may be comparable to that for idiopathic FSGS. ,, The questions regarding the importance of identifying mutations of podocyte proteins in anticipating the risk of recurrence of FSGS and regarding the pathogenic mechanisms that result in the development of proteinuria and FSGS are raised and need further examination. In our case, FSGS was presumably idiopathic and not due to structural alteration in podocyte protein. As such, one would predict recurrence of FSGS. There are several risk factors for the development of recurrent FSGS such as:
As for our case, although she did not have most of these risk factors except the race factor, she experienced recurrence of FSGS in her graft.
- Aggressive clinical course of primary FSGS,,,
- The age at presentation between six and 15 years 
- Previous recurrence of FSGS in a renal transplant 
- Renal histopathology demonstrating diffuse mesangial proliferation 
- The race of children, white children are at higher risk than African American children 
The timing of recurrence was during the second week post-transplantation and that is consistent with 78% of cases that reveal recurrence during the first month after transplantation. , The diagnosis of recurrent FSGS was almost certain although not confirmed histologically because nothing else could explain such a severe recurrent nephrotic syndrome that appeared shortly after transplantation in a patient with ESRD due to FSGS.
Because FSGS can be related to a "circulating permeability factor" that increases glomerular permeability to protein, therapies aimed at removing this factor such as PP may be beneficial. , The PP was started in our case within less than a week of recognition of nephrotic range proteinuria as recommended in most reports;  however, some centers recommend prophylactic use of PP even before the nephrotic syndrome develops,  such a prophylactic PP was not used in our case given the absence of most risk factors for recurrence of FSGS. The outcome of the PP in recurrent FSGS may be linked to the number of sessions performed, typically ranging from five to 13 treatments. We consider the 12 PP sessions we applied for this case as a relatively intensive course. The time to remission is highly variable and ranges from five to 27 days after initiation of the PP. ,, Unfortunately, that was not the case for our patient who, despite this "intensive" course of the PP therapy, did not respond even two months after initiation of the PP. Thus, the outcome of PP therapy in this case was considered as a complete failure. The efficacy of calcinurin inhibitors in inducing remission of recurrent post-transplant FSGS is quite debatable. Several case reports have suggested benefits of CsA at high doses. , As for our case, the dose of TAC was not increased given the limited experience with the use of TAC in recurrent nephrotic syndrome after transplantation. 
The efficacy of ACEi in decreasing proteinuria associated with different patterns of glomerular diseases is well established; captopril was reported to dramatically decrease nephrotic range proteinuria in secondary FSGS.  A decrease in proteinuria and even complete remission have also been observed in patients with chronic glomerulopathies being treated with ACEi.  In recurrent FSGS, ACEi may also help diminish protein excretion. , Our case has been treated first with enalapril and then in combination with losartan; however, this combined therapy did not succeed in diminishing the nephrotic range proteiuntria during the first eight months of treatment. Interestingly, the further follow up of this patient revealed a very gradual decrease of proteinuria that started during the 9 th month of conservative therapy and continued till the patient attained complete remission after 17 months of conservative therapy; such a very long time to attain remission would raise legitimate question about the cause-effect relationship. We tend to consider this favorable and wonderful outcome as a spontaneous remission rather than being the result of combined ACE and ARB therapy.
To the best of our knowledge, this is the first case ever reported in the literature of a "spontaneous" remission of post transplant recurrent FSGS.
| References|| |
|1.||Weber S, Tonshoff B. Recurrence of focalsegmental glomerulosclerosis in children after renal transplantation: Clinical and genetic aspects. Transplantation 2005;80:S128-34. |
|2.||Artero M, Brava C, Amend W, et al. Recurrent focal glomerulosclerosis: Natural history and response to therapy. Am J Med 1992;92:375-83. |
|3.||Tejani A, Stablein D. Recurrence of focal segmental glomerulosclerosis posttransplantation: A special report of the North American Pediatric Renal Transplant Cooperative Study, J Am Soc Nephrol 1992;2(12):S258-63. |
|4.||Billing H, Mueller D, Ruf R, et al. NPHS2 mutation associated with recurrence of proteinuria after transplantation. Pediatr Nephrol 2004;19:561-64. |
|5.||Bertelli R, Ginevri F, Caridi G, et al. Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin. Am J Kidney Dis 2003; 41:1314-21. |
|6.||Newstead C. Recurrent disease in renal transplant. Nephrol Dial Transplant 2003;18:vi68-74. |
|7.||Seikaly M. Recurrence of primary disease in children after renal transplantation: An evidence-based update. Pediatr Transplant 2004;8:113-9. |
|8.||Baum M. Outcomes after renal transplantation for FSGS in children. Pediatr Transplant 2004; 8:329-33. |
|9.||Rizzoni G, Ehrich J, Brunner F, et al. Combined report on regular dialysis and trans-plantation of children in Europe, 1990. Nephrol Dial Transplant 1991;6(4):31-42. |
|10.||Cameron J. Recurrent primary disease and de novo nephritis following renal transplantation. Pediatr Nephrol 1991;5:412-21. |
|11.||Savin V, Artero M, Sharma R. Risk of recurrence of focal segmental glomerulosclerosis (FSGS) after transplantation can be assessed using an in vitro assay of serum. J Am Soc Nephrol 1993;4:125-9. |
|12.||Benchimol C. Focal segmental glomerulosclerosis: Pathogenesis and treatment. Curr Opin Pediatr 2003;15:171-80. |
|13.||Pradhan M, Petro J, Palmer J, et al. Early use of plasmapheresis for recurrent post-transplant FSGS. Pediatr Nephrol 2003;18:934-8. |
|14.||Ohta T, Kawaguchi H, Hattori M, et al. Effect of pre and postoperative plasmapheresis on post-transplant recurrence of focal segmental glomerulosclerosis in children. Transplantation 2001;71:628-33. |
|15.||Cochat P, Schell M, Ranchin B, et al. Management of recurrent nephrotic syndrome after kidney transplantation in children. Clin Nephrol 1996;46:17-20. |
|16.||Shariatmadar S, Noto T. Therapeutic plasma exchange in recurrent focal segmental glomerulosclerosis following transplantation. J Clin Apheresis 2002;17:78-83. |
|17.||Mowry J, Marik J, Cohen A, et al. Treatment of recurrent focal segmental glomerulosclerosis with high-dose cyclosporine A and plasmapheresis. Transplant Proc 1993;25:1345-46. |
|18.||MacCauley J, Shapiro R, Jordan M, et al. FK506 in the management of nephrotic syndrome after renal transplantation. Transplant Proc 1993;25:1351-4. |
|19.||Martinez-Vea A, Garciaruiz C, Carrera M, et al. Effect of captopril in nephrotic range proteinuria due to renovascular hypertension. Nephron 1987;45:162-3. |
|20.||Ferder LF, Inserra F, Daccordi H, Smith RD. Enalapril improved renal function and proteinuria in chronic glomerulonephritis. Nephron 1990;55:S90-5. |
Pediatric Nephrology Department, Kidney Hospital, P.O. Box 8292, Damascus