Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis

Hae Ii Cheong1, Hye Won Han1, Hye Won Park2, Ii Soo Ha1, Kyu Sup Han4, Hyun Soon Lee5, Sang Joon Kim3 and Yong Choi1

1 Departments of Pediatrics, 3 General Surgery, 4 Clinical Pathology and 5 Pathology, Seoul National University Children's Hospital, Seoul and 2 Department of Pediatrics, Seoul City Boramae Hospital, Seoul, Korea

Correspondence and offprint requests to: Hae II Cheong MD, Department of Pediatrics, Seoul National University Children's Hospital, 28 Yongon-Dong, Chongro-Gu, Seoul, 110-744, Korea.



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. We analysed risk factors to predict the recurrence of nephrotic syndrome and the therapeutic efficacy of plasmapheresis combined with oral cyclophosphamide (PE+CPM) in early recurrent nephrotic syndrome after transplantation in children with focal segmental glomerulosclerosis (FSGS).

Methods. Medical records after 1990 of 16 children with biopsy-proven idiopathic FSGS and renal transplantation before the age of 18 years were reviewed.

Results. Early recurrence of nephrotic syndrome developed in six cases (37.5%). While early kidney graft biopsies, performed within the first week after the onset of recurrence, revealed diffuse effacement of foot process only, late biopsies contained segmentally sclerosed glomeruli as well. Among several possible risk factors, the mean duration from onset of original nephrotic syndrome to development of end-stage renal disease was shorter in the recurrent group (P=0.045) and the percentage of globally sclerosed glomeruli was higher in the non-recurrent group (P=0.001). PE+CPM therapy resulted in complete remission of nephrotic syndrome if it was started early and if there was no evidence of accompanying acute rejection.

Conclusion. These results support more liberal use of living-related donors for renal transplantation of children with FSGS and ESRD, considering the shortage of cadaveric donors in our society and relatively good efficacy of the early and intensive PE+CPM therapy for early recurrent nephrotic syndrome.

Keywords: acute rejection; cyclophosphamide; FSGS; plasmapheresis; recurrent nephrotic syndrome; renal transplantation



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Early recurrent nephrotic syndrome after renal transplantation is mainly seen in children with FSGS [1,2]. It is a worrisome complication for paediatric nephrologists because of its high rate of incidence, the subsequent graft loss, and inability to predict its occurrence [39]. At present, early diagnosis and adequate treatment are the only practical things we can do. Although there are some controversies about the effectiveness, plasmapheresis (PE) is widely used for the treatment of recurrent nephrotic syndrome [913].

Living-related donors are not recommended for renal transplantation in children with FSGS in many centres because of the high incidence of recurrence and its grave outcome [14,15]. However, in our society, there is no other choice than living-related donors because of the shortage of cadaveric donors.

We analysed risk factors to predict the recurrence and therapeutic efficacy of PE+CPM in early post-transplant recurrent nephrotic syndrome in children with grafts mostly from living-related donors.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Sixteen consecutive patients after 1990, including 13 males and three females, with biopsy-proven idiopathic FSGS in the native kidney who had renal transplantation in our hospital before 18 years of age were included in this study. A cyclosporin-based regimen was used for immunosuppression in all patients.

Early recurrence of the nephrotic syndrome was clinically defined as the development of massive proteinuria (>40 mg/m2/day) and hypoalbuminaemia (<2.5 g/dl) within 3 months after transplantation, and the pathological findings of diffuse foot process effacement and/or glomerulosclerosis in the graft kidney.

We followed the therapeutic protocol for recurrent nephrotic syndrome recommended by Cochat et al. [10] with a few minor modifications. Ten sessions of PE were conducted over 2 weeks, then one session per week for 2 months. One and a half plasma volumes were replaced with 4% albumin per session. Intravenous immunoglobulins (100–150 mg/kg) were substituted following each session in some patients. Bolus methylprednisolone (250 mg/m2/day) was given for the first 3 days and then the previous dose of steroid was used. Azathioprine was replaced by CPM (2 mg/kg/day) for 3 months. Whole blood trough levels of cyclosporin A were maintained between 150–200 ng/ml.

The mean values are described with ±1 standard deviation. Statistical analysis was carried out with the Student t-test and chi-square analysis when appropriate. A P value of <=0.05 was considered significant.



   Results
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 Abstract
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 Subjects and methods
 Results
 Discussion
 References
 
The mean age of the 16 patients at the onset of original nephrotic syndrome was 6.5±3.4 years (1–12 years). Mesangial hypercellularity was observed in the native kidney of six patients (37.5%), and segmental and global glomerulosclerosis involved 25±15% and 15±16% of total glomeruli respectively. The mean duration of original nephrotic syndrome prior to reaching ESRD was 62±40 months, and all patients except one were dialysed before transplantation for a mean duration of 15±10 months. The mean age at transplantation was 12.7±3.9 years. Grafts were from 12 living-related, two living-unrelated, and two cadaveric donors. The average number of mismatched HLA-A, -B, and -DR antigens was three.

Early recurrent nephrotic syndrome developed in six patients (37.5%), and all recurrences developed within 3 days after renal transplantation. Kidney graft biopsy was performed seven times in six cases with recurrence of nephrotic syndrome. While diffuse effacement of foot processes was the only finding in all of the five early biopsies performed at 2–7 days after the onset of recurrence, FSGS was detected in two late biopsies performed at 2 and 10 months respectively, after transplantation. FSGS was also confirmed in one graft removed at 5 months after transplantation due to severe persistent nephrotic syndrome and graft failure. In two early biopsies, findings of acute cellular rejection were mixed with those of recurrence.

Among several possible risk factors compared between recurrent and non-recurrent groups, the mean duration of original nephrotic syndrome prior to ESRD was shorter in the recurrent group (P=0.045) and the percentage of globally sclerosed glomeruli was higher in the non-recurrent group (P=0.001) (Table 1Go).


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Table 1. Possible risk factors compared between recurrent and non-recurrent groups
 
All cases with recurrent nephrotic syndrome were treated with PE+CPM immediately, except one case in which the treatment was delayed for 2 months. In two cases with accompanying acute rejection did not respond to 3 days of bolus methylprednisolone therapy, a 2-week course of antilymphocytic globulin (ALG) therapy was performed simultaneously. The responses to the PE+CPM therapy and the clinical courses are summarized in Figure 1Go. Immediate early therapy resulted in three complete and two partial remissions of early recurrent nephrotic syndrome, and the latter were complicated with acute rejection. In one case showing complete remission, proteinuria recurred at 1 month after completion of the therapy and did not respond to the second course of PE. Graft function was well maintained without oedema through the last follow-up in four cases with recurrent or persistent proteinuria, although the proteinuria had persisted in the nephrotic range.



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Fig. 1. Clinical courses of six cases with early recurrent nephrotic syndrome after transplantation.

 


   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Steroid-resistant nephrotic syndrome with FSGS is one of the most common lesions leading to renal transplantation in children. This lesion has a tendency to recur in renal allografts with the overall recurrence rate of 20–40%, and graft failure follows in 40–50% of patients with recurrence [39].

An additional difficulty in managing recurrent FSGS is that it is hard to predict and, therefore, hard to prevent. There have been many studies [1,2,47] focusing on the predictability of possible risk factors for recurrence such as the age at onset of the nephrotic syndrome, the duration of disease, the interval on dialysis, the presence of diffuse mesangial proliferation in the native kidneys, and multiple transplants. However, the results have not always been consistent with each other. Recently, albumin permeability of patient's serum measured in isolated rat glomeruli has been studied as a relatively accurate predictor of recurrence in some centres [11,16,17], but we could not measure it. One unexpected finding in this study was that the proportion of glomeruli with global sclerosis was higher in the non-recurrent group. The mean duration of original nephrotic syndrome prior to renal biopsy was not different between the recurrent and non-recurrent groups. There has been no report of global sclerosis as a possible predictor of recurrence. Although it is hard to explain this finding, there is a possibility that the high percentage of globally sclerosed glomeruli indicates a chronic, quiescent disease process. If this is true, longer interval on dialysis may be helpful by providing more time for suppression of the disease activity. However, the intervals on dialysis in the recurrent and non-recurrent groups in this study were not different from each other. Therefore, a correlation study between the presence of global sclerosis and the albumin permeability should be interesting.

PE is one of the therapeutic modalities applicable to recurrent nephrotic syndrome [913,18,19]. Although there is some controversy regarding the effectiveness of PE, it can induce remission of nephrotic syndrome in some patients with recurrence. In this study, treatment with PE+CPM was very effective if it was started as early as within a few days after recurrence and there was no accompanying acute rejection. PE may not offer any therapeutic efficacy if sclerotic change, an irreversible lesion, has already occurred, in the glomeruli and therefore only early treatment may be beneficial [18]. Although we did not try it in this study, high-dose cyclosporin with or without PE, has been reported to induce remission of recurrent nephrotic syndrome in several papers [2022]. The goal of high-dose cyclosporin is to overcome lipid binding of the molecule. Some prefer intravenous route of administration to achieve a steady-state blood level.

There was a report [9] from Minnesota that recurrent FSGS was associated with an increased incidence of acute renal failure, and both acute renal failure and recurrence were associated with greater risk of acute rejection. Those workers concluded that increased graft loss in recurrence was primarily due to acute rejection. Similarly in our study, two patients with recurrence accompanied by acute rejection responded only partially to the PE+CPM therapy, and one of them lost his graft. If recurrent nephrotic syndrome is suspected clinically, an immediate graft biopsy is essential to confirm the recurrence and possible accompanying acute rejection. Aggressive anti-rejection therapy should also be started for patients experiencing graft rejection.

Living-related transplants are not recommended for children with FSGS in many centres, because of the high rate of recurrence that is hard to predict, and the following high rate of graft loss [14,15]. Nevertheless, most of the grafts in this study were from living-related donors because of shortage of cadaveric donors in our society. Although this is an uncontrolled retrospective study, the results encourage us to cautiously use more living-related donors for renal transplantation of children with FSGS and ESRD due to the shortage of cadaveric donors and relatively good efficacy of the early and intensive PE+CPM therapy for recurrent FSGS.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 26. 3.99
Accepted in revised form: 22. 7.99