Recurrent focal glomerulosclerosis: natural course and treatment with plasma exchange
Margret B. Andresdottir1,
Nouaf Ajubi1,
Sandra Croockewit2,
Karel J. M. Assmann3,
Luuk B. Hibrands1 and
Jack F. M. Wetzels1
Department of Internal Medicine,
1 Divisions of Nephrology and
2 Haematology, and
3 Department of Pathology, University Hospital Nijmegen, The Netherlands
Correspondence and offprint requests to:
M. B. Andresdottir, MD, Department of Medicine, Division of Nephrology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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Abstract
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Background. Focal glomerulosclerosis (FGS) can recur after renal transplantation and prognosis is poor in untreated patients. A circulating plasma factor has been implicated in the pathogenesis of a recurrent FGS and treatment with plasma exchange has proven effective in decreasing proteinuria in some patients.
Methods. We retrospectively studied the course of disease in patients with recurrent FGS, transplanted in our centre. Seven patients transplanted between 1991 and 1997, received treatment with plasma exchange, whereas 10 patients, transplanted between 1973 and 1991, were left untreated and served as historical controls.
Results. The time of onset of proteinuria (>3.5 g/day) was comparable in the untreated and treated patients (9 and 10 days respectively), as was the average proteinuria at that time (5.5 and 5.8 g/day respectively). In the untreated patients, proteinuria persisted and eventually all grafts were lost, on average 43 months after the diagnosis of a recurrence. In five cases (50%) the recurrence was the single cause of graft loss. The clinical course was different in the seven patients who were treated with plasma exchange. In five of these patients, the recurrence occurred within 3 weeks after transplantation. Plasma exchange was started 114 days after onset of proteinuria in these patients. Two lost their grafts after 0.7 and 1.0 months because of untreatable rejection. In the remaining three patients the plasma exchange resulted in abrupt disappearance of the proteinuria, and the response has been lasting for 23.2 years. In these patients the only histological abnormality was foot effacement on electron-microscopy. In two patients the recurrence became manifest at 9 weeks and 5.8 years after transplantation respectively. These two patients relapsed after the initial course of plasma exchange, but responded to repeated session, and are currently being treated once a month. They have been followed for 1.7 and 1.4 years after the onset of proteinuria and their urinary protein levels are 0.23 and 1.2 g/10 mmol creatinine.
Conclusions. The prognosis of untreated recurrent FGS is poor. Treatment with plasma exchange can lead to complete remission of proteinuria and relapsing patients may respond to repeated sessions. Best results are obtained when plasma exchange is started early, when there are no visible lesions on light-microscopy.
Keywords: focal glomerulosclerosis; plasma exchange; recurrence; renal transplantation
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Introduction
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Approximately 30% of patients with focal glomerulosclerosis (FGS) experience a recurrence of the original disease after renal transplantation [15], and patients who have developed recurrent disease in their first graft are at very high risk (80%) of recurrence in subsequent grafts [4]. The following factors have been associated with an increased risk of recurrence: rapid progression of the original disease to end-stage renal disease (ESRD) [69], mesangial hypercellularity in the biopsy of the native kidney [1,5,7,9] and young age [6]. In contrast, time on dialysis is not a proven risk factor [7,9,10]. FGS can recur immediately after transplantation and fulminant nephrotic syndrome usually ensues. Immunosuppressive drug regimens are not effective in preventing the recurrence.
The pathogenesis of FGS is still unknown, although some clinical and experimental observations suggest that a circulating plasma factor is responsible for the protein leak in patients with a recurrence of FGS after transplantation. The assumption of the presence of a plasma factor has led to the use of plasma exchange for the treatment of recurrent FGS, and indeed plasma exchange was found to be effective in reducing proteinuria in anecdotal reports and small studies [4,5,1116].
In view of the strong evidence of a pathogenic plasma factor, as well as the favourable results obtained by plasma exchange in some patients with recurrent FGS, this treatment option has been used in our clinic since 1994. In this paper we describe the results of plasma exchange in seven adult kidney transplant recipients with a recurrence of nephrotic syndrome after transplantation. For comparison, the clinical course of recurrent FGS in 10 patients, who were not treated with plasma exchange, is described.
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Subjects and methods
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We analysed the clinical course of 17 adult patients with a recurrent FGS after transplantation. The patients received a renal allograft in our centre in between 1973 and 1997. Histological diagnosis of the original renal disease was available in 15 patients. In two patients without a biopsy, the diagnosis was made because heavy proteinuria developed almost immediately after transplantation, in the absence of other glomerular disease. A clinical diagnosis of a recurrent FGS was made in case of a rapid onset or firm increase of proteinuria. The day that the proteinuria exceeded 3.5 g/day was defined as the time of onset of the recurrence. In all patients a renal biopsy was performed. Biopsy findings that showed either effacement of epithelial foot processes on electron-microscopy (EM) with normal appearance on light-microscopy (LM) or segmental, focal sclerosis on LM, were considered compatible with the diagnosis of recurrent FGS.
During the study period we used different regimens of immunosuppressive therapy, as described previously [17]. In short, from 1973 to 1983 patients received prednisone and azathioprine (3 mg/kg/day) from the day of transplantation. From 1983 to 1985 patients were treated in a randomized study with either cyclosporin (CsA; starting with 17.5 mg/kg/day and tapering to 5 mg/kg/day at 3 months) and prednisone for the first 3 months followed by conversion to azathioprine and prednisone, or azathioprine and prednisone for the whole period. From 1985 to 1989 all patients received CsA and prednisone during the first 3 months and azathioprine and prednisone thereafter. In the period 19891992 patients were treated with CsA (starting with 12 mg/kg/day and tapering to 4 mg/kg/day at 3 months) and prednisone for the first 3 months and thereafter randomized for continued treatment with both azathioprine and prednisone, or CsA monotherapy. Since 1992, the combination of CsA and prednisone has been given.
During the hospital stay, the serum creatinine and urine protein levels were measured daily. Following discharge, all patients were followed weekly for the first 4 months, every 24 weeks thereafter, and at least every 3 months from 1 year on. At each visit serum creatinine level and urinary protein concentration were recorded. For the purpose of this study the medical records of the 17 patients with recurrent FGS were analysed. The following data were documented for each patient: sex, age at diagnosis of the original disease, time from diagnosis to end-stage renal failure, time on dialysis, age at transplantation, immunosuppressive therapy post transplant, time from transplantation to recurrence and time from recurrence to the start of plasma exchange therapy (when appropriate). Furthermore, proteinuria and serum creatinine were noted.
Since 1994, patients with recurrent FGS have been treated with plasma exchange. The treatment protocol consisted of daily plasma exchanges for up to 3 days. Thereafter, intensity of plasma exchange treatment was decreased depending on the clinical response. The initial cycle of plasma exchange treatment consisted of a maximum of 10 treatment sessions. Plasma exchange was performed with the CS-3000 Plus Cell Separator (Baxter, Deerfield, IL). A total of 1.5 plasma volumes were replaced per session with either fresh frozen plasma or 5% albumin.
Statistical analysis
Survival probabilities were calculated using the KaplanMeier method. Unless otherwise noted, values are given as mean±SD.
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Results
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Overall, a diagnosis of recurrent FGS was made in 17 patients. Ten patients, who received a renal allograft between June 1973 and February 1991, were not treated with plasma exchange and served as historical controls. Seven patients who received a renal allograft between May 1991 and February 1997, underwent plasma exchange for recurrent nephrotic syndrome after transplantation. The demographic characteristics of these patients are compared in Table 1
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Table 1. Characteristics of patients wth recurrent focal glomerulosclerosis with and without plasma exchange (PE) treatment
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The two patient groups were comparable with respect to sex, age at diagnosis, time from diagnosis to ESRD, age at transplantation, immunosuppressive treatment post transplantation and number of rejections. Furthermore, the time of onset of the recurrence and the level of proteinuria at this time were comparable. The interval between the onset of the recurrent proteinuria and the transplant biopsy was, however, considerably shorter in the plasma-exchange-treated patients. This difference reflects our change in attitude towards the treatment of the patients and our endeavour to start plasma exchange promptly at the onset of heavy proteinuria.
In the 10 untreated patients a renal biopsy was taken on average 1.3 months (0.224 months) after onset of the recurrent FGS. In eight patients there were characteristic changes of focal glomerulosclerosis on LM. In addition, there was evidence of an acute interstitial rejection in two patients, and of a chronic vascular rejection in one. In two patients, LM showed no evidence of FGS, but only changes compatible with acute interstitial rejection or CsA toxicity. In both patients there was evidence of foot process effacement on EM. These biopsies were taken early (0.2 and 0.9 months) after start of the recurrence. In all these 10 patients heavy proteinuria persisted during follow-up (Figure 1
) and prognosis was dismal, with graft failure occurring in all patients on average 43 months after the diagnosis of the recurrence. In five of these patients (50%) the recurrence was the single cause of graft loss. Six patients were treated with CsA at the time of the recurrence, however, in only one patient was the treatment continued beyond 3 months post transplant. In two patients, an increase in proteinuria was noted after stopping CsA. CsA was re-introduced in one patient without effect on the proteinuria. In two patients, treatment with angiotensin-converting enzyme (ACE) inhibitor was started after the development of the recurrence.

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Fig. 1. Time course of proteinuria in patients with recurrent FGS after transplantation; mean±SEM. Proteinuria persists in untreated patients (), whereas proteinuria decreases in patients treated with plasma exchange ().
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The clinical course was different in the seven patients who were treated with plasma exchange after the onset of the recurrence. Detailed information on the individual patients in this group is given in Table 2
. In all but one (no. 4) patient, recurrence occurred within 9 weeks after transplantation. In these patients a renal biopsy was performed 114 days after the onset of proteinuria. In four patients no glomerular abnormalities were found in LM, although in two of these patients (nos 1 and 7) there was evidence of interstitial rejection. In these patients there was effacement of the foot processes in EM. In one patient (no. 6), whose biopsy showed signs of acute tubular necrosis and rejection, an adhesion was found in one glomerulus, suggestive of FGS. Finally, in one patient (no. 5), who was biopsied 14 days after onset of the proteinuria, there was evidence of focal segmental sclerosis on LM. In one patient the diagnosis of recurrence was made late after transplantation (no. 4). This patient was treated with CsA monotherapy. She developed mild proteinuria and a decrease in renal function. A renal biopsy revealed vascular changes compatible with CsA toxicity and/or chronic vascular rejection. In the glomeruli there was mesangial matrix and cell proliferation with mild influx of mononuclear leucocytes. There was mild swelling of the epithelial cells. The EM showed a focal fusion of the foot processes. CsA was replaced by azathioprine and prednisone. Shortly thereafter, a tremendous increase in proteinuria occurred, without evidence of renal function deterioration. A clinical diagnosis of recurrent FGS was made, and a renal biopsy was not performed in view of the known abnormalities in the previous biopsy.
Plasma exchange was started a median of 9 days (range 050 days) after onset of the proteinuria. The clinical response could be evaluated in five patients, two lost their graft after 0.7 and 1.0 months because of untreatable rejection. In the remaining five patients the treatment with plasma exchange resulted in the abrupt disappearance of the proteinuria (Figure 2
), and in three of them the response was lasting (follow-up 23.2 years; Table 2
). In these three patients, the plasma exchange was started within 14 days after the onset of proteinuria and in all of them, the biopsy showed only foot process effacement on EM. In two patients (nos 4 and 5), the proteinuria recurred after stopping the plasma exchange treatment. In these two patients, the plasma exchange was started later, 19 and 50 days after the onset of proteinuria, and the biopsy specimens already showed abnormalities on LM in one. Both patients responded to a second course of plasma exchange and are currently being treated with one session every 4 weeks. They have been followed for 1.4 and 1.7 years after the onset of proteinuria, their serum creatinine levels are stable, and the last recorded urinary protein excretion is 0.23 and 1.2 g/10 mmol creatinine respectively (Table 2
). All patients but one developed the recurrence during CsA treatment and in one patient CsA was introduced after the onset of the recurrence. All patients are given continued treatment with CsA aiming at trough levels of 125175 ng/ml. Furthermore, in one patient, an ACE inhibitor was added to the therapy.

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Fig. 2. Time course of proteinuria after plasma exchange treatment in the individual patient with recurrent FGS after transplantation.
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Discussion
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Our study clearly demonstrates the favourable effects of plasma exchange on proteinuria in five of the seven patients with a recurrence of FGS. It was not possible to evaluate the effect of plasma exchange in the two patients with early graft loss due to rejection. Three patients remained in complete remission after the first treatment cycle. These patients all had early recurrences (<3 weeks after transplantation) and were treated within 2 weeks after the onset of the proteinuria, none of them had the characteristic lesions of FGS on LM. The other two patients relapsed after discontinuation of plasma exchange but responded to repeated sessions. These patients are currently being treated once a month. Both these patients had late recurrences (at 9 weeks and 5.8 years after transplantation respectively), and plasma exchange was started relatively late. One of these patients had evidence of FGS in the biopsy. The other had a chronic vascular rejection and transplant glomerulopathy in an earlier biopsy. Although proteinuria in this patient could have been secondary to these vascular and glomerular abnormalities, the sudden increase in proteinuria as well as the response to plasma exchange favours the clinical diagnosis of recurrent FGS.
Thus far, our patients with recurrent FGS that have been treated with plasma exchange have a favourable course, which contrasts with the course in untreated patients. All these untreated patients had persistent nephrotic range proteinuria and eventually lost their graft. The 5-year graft survival was merely 30% and half of the graft failures were due to the recurrence only. Such an unfavourable prognosis is well known in patients with recurrent FGS [6]. In view of the rapid onset of proteinuria, sometimes immediately after renal transplantation, it was suggested for many years that the recurrence of FGS was caused by a circulating plasma factor [18]. Clinical experiments demonstrating that injection of patient serum induced proteinuria in rats further strengthened this idea [19]. More recently, Savin et al. [20] developed an in vitro assay for the measurement of glomerular permeability and demonstrated that serum from patients with recurrent FGS increased the glomerular permeability. In subsequent studies it was shown that the presence of a factor that increases glomerular permeability is associated with a high risk of recurrence [20]. The presence of a plasma factor could explain the benefits of plasma exchange treatment. Thus far, the nature of the factor involved remains unknown. Both plasma exchange and absorption of serum onto a protein A column (which binds IgG) were effective in lowering proteinuria [4,5,21]. In order to identify the pathogenic molecule, Dantal et al. [21] used membrane filtration and ultracentrifugation to separate the protein A column eluates derived from patients with a recurrence according to molecular weight. Only injections of the low-molecular mass fraction (Mw<100 kDa) resulted in a significant increase in albumin excretion. Recently, Dantal et al. [22] demonstrated that the protein permeability factor could also be removed by selective absorption of human IgG. Taken together these data suggest that the putative plasma factor is not itself an immunoglobulin, but is bound to IgG.
It is evident from our data and from the literature that the effectiveness of plasma exchange treatment is quite variable; some patients do not respond at all, whereas others will experience a relapse. These differences may be explained by differences in the study population or variation in the time of onset and magnitude of proteinuria. Also, there may be differences in the level or pathogenicity of the permeability factor, or even in the sensibility of the kidney to this molecule. There is some evidence that the time of the start of the treatment is important. Best results are obtained when plasma exchange is started early after the onset of proteinuria at a time when the renal biopsy shows no abnormalities except for foot process fusion on EM. In contrast, if plasma exchange is started with delay or after the lesions of FGS are well established it is less effective (Table 3
). In most patients that did not respond to plasma exchange, there were already sclerotic lesions in the biopsy [5,6,15]. In this respect it is notable that in patients with established, idiopathic FGS in their native kidneys, plasma exchange is hardly effective. Feld et al. [23] described eight patients with primary FGS who were treated on average 12 months after the initial presentation; six of the eight patients failed to respond, whereas two patients had a partial remission, which lasted in only one.
It is possible that the type of immunosuppressive treatment influences the course of a recurrent FGS. Sharma et al. [24] studied the effects of CsA in vitro; incubation of isolated glomeruli with CsA prevented the increase in glomerular permeability that was seen with FGS sera. These studies indicated that CsA could attenuate proteinuria independent of its haemodynamic and immunologic effects. However, in vivo the beneficial effects of CsA are unproven. In a comparative study the rate of recurrence was similar in CsA- and azathioprine-treated patients [3]. Since 12 of our patients developed a recurrence under CsA treatment, it is not effective in preventing a recurrence of FGS. Furthermore, plasma exchange treatment was necessary to reduce the initial proteinuria. We cannot, however, exclude that the favourable course in the treated group is partly due to the continuation of the CsA treatment. In nearly all patients in the control group CsA was stopped at 3 months after transplantation. In two patients, an increase in proteinuria was seen. Furthermore, our experience in patient no. 4, who developed massive proteinuria after withdrawal of CsA, would fit with a protective effect of CsA. This effect has been attributed to suppression of the production of putative factor or to haemodynamic effects. One factor that might be important in interpreting the results of all these studies is the dose of CsA and it might well be that very high levels are needed to prevent a recurrence. Mowry et al. [16] and Ingulli and Tejani [10] have shown favourable effects of high-dose CsA in children with recurrent FGS, analogous to the experience in children with idiopathic FGS, where high doses of CsA are needed to induce a remission of proteinuria [25].
Recently, recurrent FGS was reported during immunosuppressive treatment which included the new immunosuppressive agent mycophenolate mofetil [22]. To our knowledge, there is, as yet, no report of a recurrent FGS under treatment with tacrolimus, which could indicate that this immunosuppressive agent either can prevent recurrent FGS or that it has not been widely used after transplantation in patients with FGS.
In conclusion, our results confirm the findings that plasma exchange, when started early can substantially reduce proteinuria in patients with a recurrent FGS. Furthermore, if a relapse of proteinuria occurs, a remission of proteinuria can be maintained by repeated cycles. Longer follow-up is needed to evaluate whether plasma exchange treatment also leads to a prolonged graft survival in patients with a recurrent FGS. The role of high-dose CsA or tacrolimus as additional therapy needs to be investigated further.
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Acknowledgments
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M.B.A. is supported by a grant from the Dutch Kidney Foundation (C96.1543).
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Received for publication: 26. 3.99
Accepted in revised form: 6. 7.99