Intensive and Prolonged Treatment of Focal and Segmental Glomerulosclerosis Recurrence in Adult Kidney Transplant Recipients: A Pilot Study

Authors


* Corresponding author: Guillaume Canaud, guillaume.canaud@nck.aphp.fr

Abstract

No treatment has consistently induced long-term remission of proteinuria in adult patients with focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation. We undertook an open-label, nonrandomized pilot trial of intensive and prolonged treatment of FSGS recurrence. Over an 18-month period, 10 adult kidney transplant recipients with FSGS recurrence received concomitantly high-dose steroids, intravenous cyclosporine for 14 days followed by oral cyclosporine therapy, and an intensive and prolonged course of plasma exchanges (PE). We compared this treatment with those of a control group of 19 patients with a FSGS recurrence transplanted between 1997 and 2005. Complete, rapid (mean 23 ± 7 days) and sustained remission was obtained in 9/10 patients (90%) as opposed to 27% in the control group. At month 3 and month 12, proteinuria was 0.16 g/day (range 0.05–0.3 g/day) and 0.19 g/day (range 0.05–1 g/day) respectively. Only one patient remained in partial remission at month 12 but he had already lost two previous grafts due to FSGS recurrence. PEs were stopped at month 9 in all patients except for the patient with a partial remission who remains PE-dependent. This small pilot study provides very encouraging results demonstrating that this treatment rapidly achieves complete and sustained remission in a high proportion of patients.

Introduction

Primary focal segmental glomerulosclerosis (FSGS) leads to end-stage renal disease in a high proportion of cases (1–6). Recurrence of FSGS after kidney transplantation is frequent (20–40%) and associated with poor graft survival (7–13). The pathophysiology of primary FSGS remains uncertain, but secretion of a circulating factor is suspected to play a key role in excessive glomerular permeability. Treatment of recurrence remains controversial. Most reports relate to use of plasma exchange (PE) in uncontrolled trials with relatively small groups of patients and conflicting results. PE or protein immunoadsorption can markedly reduce urinary protein excretion or induce complete remission in some cases, but usually fail to achieve sustained remission (14–16). Immunosuppressive drug therapy with cyclosporine (CsA), cyclophosphamide, mycophenolate mofetil or tacrolimus, either as monotherapy or in combination, has also produced inconsistent results (7,8,12,17–29). In a pediatric series, however, intravenous CsA induced sustained remission in 70% of patients who received PE and in 30% of patients without PE (21). In our experience during last 10 years, complete and sustained proteinuria remission was obtained in 27% of cases using various treatments.

We therefore conducted a nonrandomized pilot trial of intensive and prolonged multiple treatment of FSGS recurrence in adult kidney transplant recipients. As, this complex disease implicate a systemic immune dysregulation targeting podocyte, we elaborate our strategy on a concomitant theoretical association of intravenous CsA, high dose steroids for there immunosuppressive action but also podocyte cytoskeleton stabilization properties (30–32) and PE sessions. The primary end-point was induction of a complete and sustained proteinuria remission.

Material and Methods

Between September 2005 and March 2007, 286 kidney transplantations were performed at our institution. Eighteen kidney transplant recipients with primary FSGS were carefully monitored for proteinuria recurrence (Table 1). After kidney transplantation, all patients received an immunosuppressive regimen including prednisone at a starting dose of 500 mg on the first day, then gradually tapered to 10 mg/d over the first 2 months, mycophenolate mofetil 2000 mg/day, oral cyclosporine started at 6 to 8 mg/kg/day targeting a 2-h blood concentration level (C2) of 600–800 ng/mL (n = 6 in the group with recurrence, and n = 4 in the group without recurrence) or tacrolimus (C0: 8–12 ng/mL) (n = 4 in the group with recurrence, and n = 4 in the group without recurrence), and an induction with either basiliximab (n = 8 in the group with recurrence, and n = 4 in the group without recurrence) or antithymocyte globulin (Thymoglobulin®, Genzyme)(n = 3 in the group with recurrence, and n = 3 in the group without recurrence).

Table 1.  Patient characteristics according to proteinuria recurrence (p = ns)
PatientsPatients with recurrencePatients without recurrence
GenderEthnicityAge at onset of proteinuriaDelay to ESRD (years)Duration of HD (years)DonorGenderEthnicityAge at onset of proteinuriaDelay to ESRD (years)Duration of HD (years)Donor
 1MAfrican26 71LRDMCaucasian1630.8DD
 2MCaucasian19 5 3.3DDMCaucasian18 4.52.1DD
 3FCaucasian32 20LRDMAfrican19 2.64 LRD
 4MAfrican15  2.63DDFAfrican1542.8DD
 5FAfrican 3191DDMAfrican3281.6DD
 6MCaucasian54 72DDFCaucasian 774 DD
 7MAfrican 6282DDMCaucasian 612 2 LRD
 8MCaucasian12 3 5.8DDFAfrican1293.2DD
 9MAfrican11 58DD      
10MAfrican18 22DD      
Mean   19.6  8.1 2.8    15.6 6.22.5 
SD   14.8  8.6 2.4     8.1 3.31.2 

Recurrence was defined by a proteinuria >3 g/day without evidence of acute rejection, glomerulitis or allograft glomerulopathy on the biopsy. Intensive treatment was started after 3 days of permanent nephrotic range proteinuria without spontaneous improvement. Delay between transplantation and recurrence was defined according to Cameron's classification: immediate (<48 h), early (<3 months) and late recurrence (>3 months) (7).

In case of recurrence, the following standardized therapeutic strategy was applied (Figure 1):

Figure 1.

Intensive and prolonged treatment of FSGS recurrence.

  • • high dose of oral steroids (1 mg/kg/day) during the first 4 weeks tapered using the following sequence: 0.75 mg/kg/day during 2 weeks, then 0.5 mg/kg/day during 2 weeks, then 0.25 mg/kg/day during 2 weeks, then 0.2 mg/kg/day or a maximal daily dose of 10 mg thereafter;
  • • fourteen days of intravenous cyclosporine (2 mg/kg, target blood level: 200–400 ng/mL) followed by oral treatment, targeting C2 levels between 1200–1400 ng/mL. IV cyclosporine was chosen because of its reported efficacy in children (21) rather than tacrolimus that has never been demonstrated to have a superior efficacy in FSGS recurrence;
  • • PE with 5% albumin replacement: three sessions per week during 3 weeks, followed by two sessions per week during 3 weeks, one session a week until month 3, two sessions per month until month 5 and finally once a month until month 9.

Once remission was obtained, angiotensin-converting enzyme (ACE) inhibitor (ramipril) and/or angiotensin receptor blocker (ARB) (irbesartan) were introduced.

Partial remission was defined as a 50% reduction of proteinuria, complete remission as a proteinuria <0.3 g/day, and sustained remission as a prolonged remission (>12 months).

Twenty-four hour proteinuria was checked every week until month 3, then every 2 weeks until month 6 and then once a month until last follow-up.

For each patient, a kidney transplant biopsy was performed at time of recurrence and screening biopsies were performed at month 3 and month 12. Kidney biopsies were processed following the international recommendations for light microscopy. For each biopsy we defined: the number of glomerulus, FSGS variant according to the Columbia Classification (33), acute and chronic lesions graded according to the BANFF classification 2005 (34).

Results were expressed as mean ± SE. As electron microscopy is unfortunately not of current routine practice in France, we were unable to describe foot process fusion and we therefore just referred to normal light microscopy aspect in the paper.

As a control group, we studied a retrospective cohort of 19 kidney transplant recipients with FSGS recurrence during the 1997–2005 time periods (Table 2). In this group of patients, there were 12 men and 7 women, 9 African Americans and 10 Caucasians. The mean age at onset of FSGS on native kidney was 17 ± 10 years, leading to ESRD in 6.4 ± 4.4 years. Mean duration of hemodialysis was 2.6 ± 2.6 years. It was a second graft in four cases (graft loss due to recurrence of FSGS in three cases and irreversible rejection in one case). The donor was a living related donor (LRD) in four cases and a deceased donor (DD) in 15 cases. During this period, treatment of FSGS recurrence was not standardized as summarized in Table 2. Partial and complete remissions were obtained in 42% and 27% of cases, respectively, at last follow-up.

Table 2.  Patients treated for FGGS recurrence during the1997–2005 time period (control group)
PatientsTreatmentHistological findingOutcomeProteinuria remission
  1. Cyc = cyclophosphamide; FK = tacrolimus.

 1CsA IVFSGS on M12Return on dialysis on M24No
 2Cyc + PENormal kidney on light microscopyLast follow-up M80Complete and sustained
 3FK + PENormal kidney on light microscopyLast follow-up M47Complete and sustained
 4Steroids + FKFSGS on M12Last follow-up M52No
 5CsA IV + PEFSGS on M18Return on dialysis on M36No
 6Steroids + PENormal kidney on light microscopyLast follow-up M61Partial
 7CsA oral +PEFSGS on M6Return on dialysis M24No
 8Steroids + PEFSGS M12Return on dialysis on M34No
 9CsA oral + PENormal kidney on light microscopyLast follow-up M92Partial
10CsA IV + PEFSGS on M6Return on dialysis on M6No
11CsA IV + PENormal kidney on light microscopyLast follow-up M55Complete and sustained
12PE + Cyc + RituximabFSGS on M12Return on dialysis M18No
13CsA IVFSGS on M9Return on dialysis on M48No
14CsA oral + PEFSGS M18Return on dialysis on M40No
15PE + Steroids + FKFSGS M24Return on dialysis on M24No
16FK+ PENormal kidney on light microscopyLast follow-up M60Complete and sustained
17PE + Steroids + RituximabNormal kidney on light microscopyLast follow-up M38Partial
18PE + SteroidsNormal kidney on light microscopyLast follow-up M85Complete and sustained
19CsA IV + PEFSGS on M24Return on dialysis on M48No

Results

Patient characteristics (Table 1)

Out of 286 kidney transplantations performed between September 2005 and March 2007 at our institution, 18 were undertaken in patients with primary FSGS (deceased donor [n = 14], living donor [n = 4]) (Table 1). After transplantation these patients were carefully monitored for proteinuria and 10 (56%, 8 men, 2 women) exhibited recurrence. Mean age at the onset of primary FSCS on native kidneys was 19.1 ± 14.8 years, leading to end-stage renal disease 8.1 ± 8.6 years later. Mean duration of hemodialysis was 2.8 ± 2.4 years. It was a first transplant in nine cases and a third one in one patient who lost his first 2 kidneys from FSGS recurrence.

Clinical results (Table 3)

Table 3.  FSGS recurrence and treatment characteristics
PatientPrevious graftDay of recurrenceProteinuria at time recurrence (g/day)Delay to remission (day)Proteinuria month 3 (g/day)Proteinuria month 12 (g/day)Ioexhol GFR at 1 year (mL/min)Follow-up after remission (months)Total of PE sessions
 1024 180.050.05862125
 2012 5.4240.1 0.1 581925
 3055 7.1280.3 0.3 751625
 4017.9290.150.07841825
 5025.6180.200.05941725
 6047.7200.220.1 411425
 70422  100.3 0.05611625
 8218.7230.041851539
 90140  330.050.1 561325
100112  260.20.1 45 925
Mean  8.312.0 22.90.160.19 68.5 15.8 
SD  16.8 11.1  6.70.090.29 18.6  3.3 

Proteinuria occurred immediately after transplantation in six patients (60%) and early posttransplant in the remaining four patients (range 4–55 days). Recurrence was associated with massive proteinuria (mean 12 ± 11 g/day). PE was started within the first 10 days of diagnosis in all patients while high-dose steroids with intravenous cyclosporine were initiated at the time of diagnosis. Complete proteinuria remission was achieved in all patients after a mean of 23 ± 7 days postdiagnosis (Figure 2). In contrast with our and others experiences, we did not notice any proteinuria relapse at any time after beginning of the treatment in nine cases. Three months after diagnosis, all patients were still in complete remission (mean proteinuria 0.16 ± 0.09 g/day) and all but one patient remained in remission at 1-year (mean proteinuria 0.19 ± 0.29 g/day). Treatment guidelines defined in the material and methods section were carefully respected for all patients during the follow-up period. In the nine patients with complete remission, PEs was tapered gradually to month 9 and then stopped. During follow-up (mean 16 ± 3 months), none of these nine patients relapsed. At 1-year posttransplant, mean serum creatinine was 121 ± 29 μmol/L and measured iohexol GFR was 68.5 ± 18 mL/min. The patient who failed to obtain sustained proteinuria remission was the patient who had undergone a third kidney transplant. In this case, proteinuria recurred when the frequency of PE was tapered to less than once a week. Infusion with rituximab infusion was attempted, and after two doses circulating B lymphocytes were completely depleted (CD19 < 1/mm3). Proteinuria was maintained in the 1–2 g/day range with PEs administered twice per month.

Figure 2.

Course of proteinuria following multiple target therapy.

Histological findings

A kidney biopsy has been performed within 20 days of the diagnosis of FSGS recurrence. On light microscopy, we found in all cases, normal glomeruli without any segmental lesion on biopsies taken at time of proteinuria recurrence, at month 3 and at month 12. As EM is not of routine practice in our country, we were unable to describe foot process fusion. It was impossible to process the biopsy samples retrospectively for EM because of inadequate fixator. Three patients had grade I interstitial fibrosis and tubular atrophy (IF/TA) on month 3 biopsy and remained stable at month 12, two patients progressed from nonspecific lesions at month 3 biopsy to grade I IF/TA at 1 year, one patient progressed from grade II to grade III IF/TA at month 12, and four patients remained stable with nonspecific lesions at months 3 and 12. CNI toxicity was observed in five patients with arteriolar hyalinization (score 1–2) at month 3, associated with myocyte vacuolization in two cases. These lesions remained stable at month 12 in all patients.

Discussion

Results from this pilot study suggest that intensive and prolonged therapy combining high-dose steroids, intravenous cyclosporine and PEs can induce complete and prolonged remission of proteinuria after FSGS recurrence in adult kidney transplant recipients. Posttransplant recurrence of FSGS is frequent (20–40%) and associated with poor 5-year graft survival, and represents a significant cause of allograft failure (11,13,35,36). The risk of recurrence is increased following a second transplant if recurrence occurred after the first one. Performing transplantation in such patients has, indeed, been discouraged (11,13).

Despite new immunosuppressive regimens and induction therapies, the incidence of FSGS recurrence has remained unchanged (7,17,37,38). Since the first report in which PE was used to remove a putative plasma-increasing permeability factor, most authors have employed PE therapy to obtain proteinuria remission (39). However, the rate of remission is rather variable, published series have been small, and no controlled trial has ever been performed (8,12,25,27,40,41,42). Other approaches have been attempted (immunoadsorption, antihuman immunoglobulin affinity immunoadsorption, low-density lipoprotein) and have resulted in a significant reduction in proteinuria but as for PEs, many patients did not respond or experienced relapses (15,26,28,43,44). There are a small number of reports describing pre-emptive PE therapy, which have obtained 50% success in a selected group of patients at high risk of recurrence (45,46). Interestingly, intravenous cyclosporine has been shown to be effective in a cohort of children. Salomon et al. achieved an 80% remission rate, with or without concomitant PE (21,47). Consistent with these data, we have developed a strategy of intensive and prolonged treatment for FSGS recurrence posttransplant. All of our patients achieved rapid, complete and sustained remission (without recurrent flares of proteinuria) within a mean of 23 ± 7 days despite the fact that most patients experienced massive proteinuria in the first hours or days after transplantation. At 1-year follow-up, only one patient is in partial remission and is PE dependent (2 per month). Recurrence on a previous graft is known to be one of the most powerful predictors of relapse, and this patient lost his two previous grafts within a few months due to FSGS recurrence. With the current treatment regimen, he has had for the first time a significant and prolonged proteinuria reduction with good renal function. In comparison with our previous results using various sequential treatments (Table 2), we have improved significantly our rate of complete and sustained proteinuria remission. So, if CsA, PE and steroids used alone have very inconstant results, their utilization in association seems to be more efficient to induce long-term proteinuria remission. The theoretical rationale of our choice of treatment association was based on a potent action towards two distinct ways: on the immune system targeting the secretion of the permeability factor (48), and directly on the podocyte cytoskeleton stabilization, as it has ever been demonstrated for cyclosporine and steroids (30–32). We chose to use PEs over a long time period in order to taper very slowly and avoid multiple flares of proteinuria. No serious adverse events were noticed. Interestingly, histological examination found no evidence of FSGS lesions either at time of recurrence or month-3 and month-12 biopsies, with the limitation of light microscopy. Electron microscopy may have found diffuse foot process effacement. Previous observations have suggested that minimal change disease may be associated with a better prognosis than constituted FSGS variant (47). Here, the absence of constituted FSGS lesion may be due to the short delay between diagnosis and initiation of treatment, and the subsequent sustained remission.

The present pilot study, though limited by a small population size and an historical control group, provides encouraging results. In contrast to native kidneys treated by cyclosporine (49), 1-year biopsies did not show progressive interstitial fibrosis. Thus, combined intensive therapy offered a markedly beneficial effect on early proteinuria recurrence in this cohort of adult kidney transplant recipients. These preliminary results will have to be confirmed on a larger scale with an extensive follow-up.

Acknowledgment

This study received no external funding.

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