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NDT Advance Access published online on May 15, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm092
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated

Jochen H. H. Ehrich1, Christoph Geerlings1, Miroslav Zivicnjak1, Doris Franke1, Heinz Geerlings2 and Jutta Gellermann3

1Department of Paediatric Nephrology, Children's Hospital, 2Department of Medical Statistics, Hannover Medical School and 3Department of Paediatric Nephrology, Charité Children's Hospital Berlin, Germany

Correspondence and offprint requests to: Children's Hospital, Hannover Medical School, Carl Neuberg str. 1, 30625 Hannover, Germany, Tel. +49 511 3212 Email: ehrich.jochen{at}mh-hannover.de



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. The rate of complete remission after induction therapy for steroid-resistant nephrotic syndrome (SRNS) due to either focal segmental glomerulosclerosis (FSGS) or minimal change nephrotic syndrome (MCNS) has been reported to be <50%. The present retrospective study investigated 86 children with SRNS due to FSGS and MCNS and found improved rates of complete remission in children with idiopathic FSGS and MCNS after combination therapies using ciclosporin A (CSA) and prednisolone (PRED).

Methods. Eighty-six children with FSGS or MCNS and with SRNS receiving standard oral PRED therapy were analysed in a retrospective, non-randomized study. Fifty-two patients had idiopathic FSGS (group 1), 14 patients had MCNS (group 2), and 20 patients had genetic FSGS or syndrome-associated FSGS (group 3). In group 1A (n = 25), induction therapy consisted of CSA (initial dose 150 mg/day/m2 divided into two doses) given in combination with intravenous methylprednisolone (IV-MPRED 300–1000 mg/day/m2 for 3–8 days) and oral PRED. In group 1B (n = 27), CSA was combined with oral PRED (40 mg/m2 on alternate days).

Results. In group 1, patients with idiopathic FSGS receiving IV-MPRED + oral PRED + CSA had a significantly better outcome than patients treated with oral PRED + CSA (84 vs 64% cumulative proportion of sustained complete remission, respectively; P = 0.02, log-rank test). Sixteen (40%) out of 40 children entering complete remission had a first relapse after a median interval of 1 year. All relapses were successfully treated with IV-MPRED + oral PRED + CSA or oral PRED + CSA. Three out of forty responding children developed stage 2 chronic kidney disease (CKD), and none advanced to stage 3–5; in contrast, 9 out of 12 children with persistent nephrotic syndrome (NS) developed CKD stage 2–5 (8 vs 75%, respectively; P < 0.001, Fisher's exact test). In group 2, all 14 children with steroid-resistant MCNS went into remission after receiving PRED + CSA (n = 11) or IV-MPRED + oral PRED + CSA (n = 3). No patient developed CKD. In group 3, NS persisted in all 20 children having a genetic or syndromic type of FSGS receiving either PRED + CSA (n = 9) or PRED alone (n = 11). Seventeen out of 20 patients entered stage 5 CKD and were successfully transplanted; one patient developed recurrent NS.

Conclusion. Prolonged and intensified treatment of children with idiopathic non-genetic SRNS (FSGS or MCNS) with combined PRED + CSA therapy including IV-MPRED pulses resulted in a higher rate of remission when compared with previous reports on using CSA mono-therapy or other immunosuppressive combination therapies.

Keywords: ciclosporin A; focal and segmental glomerular sclerosis; methylprednisolone pulses; minimal change nephrotic syndrome; remission; steroid-resistant nephrotic syndrome



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Children having steroid-resistant nephrotic syndrome (SRNS) with focal and segmental glomerular sclerosis (FSGS) or minimal change nephrotic syndrome (MCNS) run a high risk of resistance to immunosuppressive therapy. In addition, children not showing clinical remission of nephrotic syndrome (NS) have a 50% risk of developing end-stage renal failure within 5 years. One-third of children with FSGS relapse after renal transplantation and show a poor graft survival rate. The present retrospective study showed that the outcomes may be better than previously reported if children receive a combined immunosuppressive therapy using intravenous methylprednisolone (IV-MPRED) + oral PRED + ciclosporin A (CSA) for induction of remission followed by long-term maintenance immunotherapy. The tolerability of intensified immunosuppressive therapy was also examined and did not show unacceptable side effects.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The course of SRNS with FSGS or MCNS was retrospectively studied in 86 Caucasian children treated between 1991 and 2005 at the Children's Hospitals of Hannover Medical School and of Charité University Hospital in Berlin. In group 1, 52 children had idiopathic FSGS. In group 2, 14 children had steroid-resistant MCNS, and in group 3, 20 children had FSGS of the genetic, familial or syndrome-associated type. The mean age and SD at onset of the disease were 7 ± 4 years, and the mean follow-up was 5 ± 3.6 years. Initial PRED therapy was given continuously for 6 weeks, and then for 6 weeks on alternate days (Figure 1) [1]. The mean age at the final examination was 13 ± 5 years (range 2–20). All patients fulfilled the criteria of an NS and of steroid-resistance as described by the International Study for Kidney Diseases in Children (ISKDC) [2] and the study group of Paediatric Nephrology (Arbeitsgemeinschaft fuer Paediatrische Nephrologie) (APN) [1]. At onset of the disease, all patients had a serum albumin below 25 g/l and mean serum cholesterol was 11.6 ± 4.7 mmol/l. Proteinuria was above 3 g/l in all children. The NS was unresponsive to treatment after a 6-week course of continuous PRED, followed by 6 weeks of alternate day PRED.


Figure 1
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  		Fig. 1. Treatment protocol for patients with idiopathic steroid-resistant nephrotic syndrome and FSGS (Group 1).

 
Definitions
Paediatric definitions for NS in children are presented in Table 1 [3]. Early steroid resistance was defined as no response of proteinuria to initial PRED therapy. Late steroid resistance was defined as no response of a relapsing proteinuria to PRED in a patient who had initially responded to PRED. Complete remission of NS was defined as a proteinuria <166 mg/1.73 m2/day for more than 3 days and serum albumin >35 g/l. Arterial hypertension was defined as an elevated blood pressure measurement above the 95th percentile for age-matched occasional blood pressure measurements. Chronic renal failure (CRF) was classified into five CKD stages according to Levey et al. [4].


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  		Table 1. Paediatric definitions used for the diagnosis and treatment of idiopathic nephrotic syndrome in children

 
Histology
All patients underwent a renal biopsy which was studied by light, immune and electron microscopy. The mean number of glomeruli studied was 19 (range 3–49) glomeruli in children with idiopathic FSGS and 18 (range 3–60) glomeruli in children with genetic or syndromic FSGS. The histological types of FSGS were classified according to D’Agati et al. [5] into five subtypes: NOS variant, perihilar variant, cellular variant, tip variant and collapsing variant.

Molecular genetics
Forty-seven out of 78 children with FSGS were analysed for genetic defects including NPHS2 (n = 32), WT1 (n = 6) or SMARCAL (n = 7).

Treatment
In the late 1980s, the standard protocol in our two children's hospitals for treatment of steroid-resistant NS with FSGS was a combination of oral PRED plus CSA. The allocation of patients into two different treatment groups, 1A and 1B, in our study was based on the fact that in the early 1990s, one of the two teams introduced a new protocol using IV-MPRED pulses in addition to oral PRED and CSA Neoral, and found good results in their pilot phase. When one member of the team moved in 1997 from one hospital to the other hospital, the old CSA + oral PRED protocol (group 1B) was replaced by the new protocol using IV-MPRED + oral PRED + CSA (group 1A). The criteria for choosing the intensified protocol were resistance of SRNS to previous imunosuppresssive therapies such as cyclophosphamide (CYC) (n = 3), and absence of poorly controlled arterial hypertension or severe steroidal side effects.

In group 1 children having idiopathic FSGS, induction therapy in group 1A (25 out of 52 children consisted of CSA (initial dose 150 mg/day/m2) in combination with IV-MPRED (300–1000 mg/day/m2 for 3–8 days) and oral PRED (40 mg/m2/day during IV-MPRED-free days followed by alternate days of PRED (40 mg/m2) which was tapered and withdrawn after 6 months (Figure 1) (Table 2). Induction therapy for the 27 children of group 1B included CSA (initial dose 150 mg/day/m2) in combination with oral PRED (40 mg/m2) given on alternate days until it was tapered and withdrawn after 6 months. All patients showing partial remission were treated with another course of IV-MPRED and increasing dosages of CSA and PRED until complete remission was achieved.


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  		Table 2. Allocation of children with steroid-resistant nephrotic syndrome according to different immunosuppressive treatment protocols for induction of remission (A) and for rescue therapy (B), and results of treatment

 
Groups 1A and 1B were comparable in age and gender, as well as in histological subtypes of FSGS.

Rescue immunosuppressive therapy for induction of remission in unresponsive patients (n = 14) or partially responsive (n = 1) to PRED and CSA in groups 1A and 1B included mycophenolate mofetil (MMF) (n = 3), tacrolimus (TAC) (n = 2) or plasmapheresis (n = 5) (Table 2). One patient was treated with peritoneal dialysis because of acute renal failure. Four unresponsive patients did not receive a rescue therapy because of CRF.

Maintenance CSA therapy (Neoral 150 mg/m2/day) was given continuously to all 52 patients during the first year and initial CSA target trough levels were aimed at 120–140 ng/ml. Target levels for long-term CSA maintenance therapy were 80–100 ng/ml. Maintenance alternate day PRED began with 40 mg/m2/48 h and was continuously tapered to 10 mg/m2/48 h within 12 weeks, and stopped after 6 months. MMF was given to the children in addition to CSA when CSA was tapered or when the patients had experienced a relapse. Indications for a switch from CSA to TAC were either repeated relapses or severe side effects with CSA [6].

In group 2, 11 out of 14 children with steroid-resistant MCNS were treated with PRED + CSA and three children received IV-MPRED + oral PRED + CSA (Table 2).

In group 3, 9 of 20 patients with genetic or syndromic FSGS were diagnosed before 1999 and were treated with PRED + CSA (Table 2). Eleven patients with syndromic SRNS were withheld from further immunosuppressive therapy after steroid resistance and the genetic cause of FSGS had been diagnosed (eight patients with Schimke's disease, two with Frasier syndrome and one with NPHS2 mutation).

Statistics
Study groups were analysed descriptively with means, medians, SD, minimum and maximum and absolute and relative frequencies. Cumulative remission rates were calculated according to Kaplan–Meier and groups were compared using the log-rank test. Comparison of frequencies were analysed with the exact Fisher's test because of small patient numbers.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Idiopathic FSGS
In group 1, 40 (77%) of 52 children with idiopathic FSGS showed complete remission of SRNS. Of the 52, 37 had remission after the first course of combined induction immunosuppression using CSA and PRED and three had remission after a second course with rescue therapy. Forty-six out of 52 children were found to have an early resistance to oral PRED mono-therapy and six had a late steroid resistance. All six late non-responders to oral PRED monotherapy entered remission after combined induction therapy. The median interval between the end of oral PRED monotherapy qualifying patients for entry into the study and the start of combination therapy induction was 4 months, with a range of 0–75 months. In the 40 responsive children, the median interval between the start of induction therapy and remission was 4 months (range 0.2–41 months). All six patients with a partial remission after 6 months entered complete remission within 3 weeks to 6 months after increasing the CSA dosage and/or repeating IV-MPRED pulses. In those five children who already presented with CRF on admission (with a serum creatinine above 100 µmol/l, receiving IV-MPRED + oral PPRED + CSA (n = 2), or PRED + CSA (n = 3)) there was no remission of NS.

When comparing the different treatment schedules, the 25 patients in group 1A with IV-MPRED + oral PPRED + CSA had a significantly better outcome than the 27 patients treated with CSA + oral PRED (84 vs 64%, P = 0.02, log-rank test) (Figure 2). However, two patients entered remission after addition of plasmapheresis to the treatment protocol (group 1B), and one patient entered partial remission while on peritoneal dialysis, and a subsequent repeated course of IV-MPRED + CSA led to complete remission (group 1A) (Table 2). Three children were unresponsive to rescue therapy with plasmapheresis. Two non-responders in groups 1A and 1B were switched from CSA to TAC, and three non-responders received MMF in addition to CSA; however, none of these five patients went into remission after changing immunosuppression. Four children with CRF did not receive a rescue therapy. All three patients with prior CYC resistance of NS responded to CSA.


Figure 2
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  		Fig. 2. Remission rate after initiation of two different immunosuppressive therapies in children with idiopathic steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis (FSGS) (group 1A = 25 patients, group 1B = 27 patients) CSA, ciclosporin A; PRED, prednisolone. The arrows indicate the response to rescue therapy: PD, peritoneal dialysis; TPE, therapeutic plasma exchange.

 
The mean number of IV-MPRED pulses was 4.1 ± 1, the median dosage of one pulse was 400 mg/day/m2, and the median cumulative IV-MPRED dosage per patient was 1.7 g/m2. The mean cumulative alternate day oral PRED dosage was not calculated because of a lack of documented data. The maximum mean CSA dosage was 176 ± 44 mg/day/m2 during induction therapy, and the median CSA trough level was 131 ng/ml.

Relapses and follow-up in patients with idiopathic FSGS
Sixteen (40%) of 40 children entering remission had a first relapse after a median interval of 1 year (5 out of 16 patients had been taken off maintenance therapy with CSA) (Figure 3). All relapses were successfully treated with IV-MPRED + oral PRED + CSA or PRED + CSA in 15 patients and additional plasmapheresis in one child. Two out of 16 patients had frequent relapses defined as four or more relapses per year. Mean CSA trough levels during maintenance therapy were 90 ± 58 ng/ml. In addition to CSA maintenance therapy, MMF was given to 14 of the 40 responders during long-term follow-up, and CSA dosage was subsequently reduced to achieve trough levels between 80–100 ng/ml. Median MMF dosage was 1000 mg/day/m2. Three of these 14 patients were treated with MMF in addition to CSA when serum creatinine had increased to values between 80 and 120 µmol/l. Fifteen of 40 responders underwent a repeat renal biopsy; 10 of these showed CSA nephrotoxicity, one patient with elevated serum creatinine had tubulointerstitial fibrosis without CSA nephrotoxicity, and four had no toxic lesions.


Figure 3
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  		Fig. 3. Percentage of 40 patients with SRNS and FSGS remaining in remission after combined induction therapy with CSA + PRED. Two-thirds of patients were still on a maintenance immunosuppression during relapse, and one-third had been taken off any immnuosuppression when the relapse occurred.

 
At the most recent investigation, all responders had a serum albumin above 36 g/l, and median serum cholesterol was 5.7 mmol/l. Three out of 40 responsive children (8%) developed stage 2 CKD and none went into stage 5. In contrast, 9 out of 12 children (75%) with persistent NS developed CKD at stage 2 or higher (P < 0.001, Fisher's exact test), and 6 out of 12 entered stage 5 requiring transplantation in five patients. Of those five transplanted children, four had a relapse of FSGS in the graft which was successfully brought transiently into remission in three children by plasmapheresis and/or IV-MPRED plus high dose CSA aiming at CSA trough levels of 160–180 ng/ml.

Mean age at last examination was 13.5 ± 5 years (range 2–20 years). At the most recent investigation, 30 out of 40 responsive children were still on immunosuppressive maintenance therapy, and one quarter had been weaned off all immunosuppression. None of the responsive patients suffered growth failure whereas 7 out of 18 non-responsive children developed growth failure with a body height SDS below -2SD (Figure 4). Haematuria was found in one-quarter of patients at onset of NS and persisted in 1 out of 40 responders. Arterial hypertension was found in 69% of patients during the early phase of the disease. It persisted in half the patients at the end of induction therapy and persisted thereafter until last examination in half the patients. At last examination, hypertension was found in 11 out of 40 responsive children (28%) which was significantly rarer than in 14 out of 18 non-responders (88%) (P < 0.001, Fisher's exact test). Angiotensin-converting enzyme inhibitors were given to one-third of responsive children until last follow-up, and to all resistant patients.


Figure 4
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  		Fig. 4. Body height in children with steroid-resistant nephrotic syndrome in all children from groups 1–3 (cross-sectional and longitudinal data; open circles, patients achieving remission; triangles, patients achieving no remisson; stars, patients with genetic and syndromic FSGS; Fit line, regression line; R Sq Linear, regression coefficient r2).

 
Side effects of treatment were striae, hypertrichosis and gingival hyperplasia in 8 patients each out of 40, and a cataract was found in one patient. Body mass indices for responding patients were within normal limits in 90% of children responding to combined immunosuppressive therapy (Figure 5). All 52 children survived.


Figure 5
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  		Fig. 5. Body mass index of patients of groups 1–3 with steroid-resistant nephrotic syndrome (BMI SDS, Z score of body mass index, cross-sectional data; Fit line, 0 regression line; R Sq Linear, regression coefficient r2).

 
The analysis of renal biopsies in 52 children with idiopathic FSGS revealed 17 (33%) with the NOS type, 6 (12%) with perihilar variant, 8 (16%) with cellular variant, 7 (14%) with tip variant, 4 (8%) collapsing variant, 1 (1%) completely sclerosed glomeruli, and 9 (18%) with unclear FSGS subtype. All children with the tip variant entered remission, 88% entered remission with NOS type, 83% with perihilar variant, 71% with cellular variant, 20% with collapsing type, none with completely sclerosed glomeruli, and 45% of those with an unclear subtype of FSGS entered remission.

MCNS
In group 2, all 14 patients with steroid-resistant MCNS receiving either PRED + CSA (n = 11) or IV-MPRED + oral PRED + CSA (n = 3) went into complete remission after a median period of 4 months (range 1–24 months). Three of these 14 patients had been unresponsive to a previous CYC therapy. Four of 14 responsive patients had one or more relapses, which were successfully treated with IV-MPRED + oral PRED + CSA or PRED + CSA. Arterial hypertension was found in one-third of the patients during induction therapy and persisted in 20% during maintenance therapy.

Genetic and syndromic FSGS
In group 3, 7 out of 20 patients with genetic or syndromic FSGS had a SMARCAL defect and Schimke's disease, five had a homozygous NPHS2 mutation, four a WT1 mutation (Frasier syndrome), two had a familial NS without a known genetic defect, one had a mitochondriopathy, and one had an unclassifiable syndromic disorder. The NS persisted in all 20 children having genetic or syndromic type of FSGS. Nineteen out of 20 children went into chronic kidney disease, two children developed stage 2 CKD, and 17 developed stage 5 CKD (one child was on peritoneal dialysis and 16 were transplanted; one of 16 children had a relapse after renal transplantation). Half of the children suffered growth failure (Figure 4). No child died.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
SRNS with FSGS or MCNS as assessed by renal biopsy shows a complex podocytopathy [7], and is ‘not a disease entity in terms of pathogenesis and clinical picture, but instead is a lesion of obscure pathophysiology that is treated with drugs of which the mechanism of action is poorly understood’ [modified from 8]. Trachtman [9] wrote in 2007 that ‘if we are honest and evaluate the literature critically, then most everyone will agree that there is no good therapy for this disease.’

Overdiagnosis and undertreatment
In fact, it is a disease group which includes patients with SRNS due to either: (i) genetic defects leading to podocyte dysfunction, such as NPHS2 mutations [10], (ii) genetic defects leading to complex syndromic disorders involving extrarenal manifestations such as SMARCAL mutations [3], or (iii) idiopathic SRNS which suggests acquired immunological defects, such as circulating proteinuric factors which may cause podocyte dysfunction and heavy proteinuria in native and transplanted kidneys [11,12]. Among the 67 reports on treatment of SRNS and FSGS listed in PUBMED between 1980 and 2005, less than 10% of therapeutic studies in children took the heterogeneity of FSGS into consideration, and none differentiated between patients with genetic and non-genetic types of SRNS. Because children with genetic SRNS do not respond to immunosuppressive agents [13,14], the overall remission rates published thus far may have been severely biased by varying proportions of genetic cases included in the study groups.

Further limitations of the hitherto published studies on SRNS and FSGS include the low numbers of patients studied; in fact, two-thirds of 50 retrospective studies had fewer than 10 patients. Half of these 50 publications included both patients with steroid resistance and steroid sensitivity. Half of the articles lacked a follow-up period of more than 2 years after the start of immunosuppressive therapy. Data on comorbidity, including growth, was rarely reported [15]. Fifty-five percent of the articles did not differentiate between the efficacy of induction therapy to achieve remission and of maintenance therapy to sustain remission. Finally, there have been only six randomized prospective trials on SRNS and FSGS [16].

The homogeneity of the initial manifestation of SRNS is in contrast to the heterogeneity of the clinical course in nephrotic patients with FSGS [17]. The clinical course of FSGS may vary from early steroid resistance (classical clinical variant) to early partial or complete steroid response, or to late steroid resistance [17,18]. Some patients have a persistent steroid sensitivity, and may suffer from frequent relapses and steroid dependence [19]. Mildly proteinuric FSGS without NS occurs in 11–18% of children and adults with FSGS [20], and it is unclear whether this represents a different entity. All our patients with idiopathic FSGS had a SRNS according to the definitions of ISKDC and APN. It is unclear whether the ISKDC definition of steroid resistance indicates that patients will not respond to steroids at all; for example, it is not known how many children with FSGS would respond to an increased dosage or to prolonged treatment. Using the 6 + 6 weeks PRED protocol for our patients and extending the ISKDC standard PRED protocol by another 4 weeks, 46 patients had an early and 6 a late steroid resistance. This suggests that almost 15% of our children with FSGS had initially responded to an intensified PRED therapy. Other authors have suggested that PRED monotherapy may induce remission in 30% of patients [21] if given for a long enough period, because steroid response may occur even after 6 months of PRED therapy. Nakyama et al. [22] showed a relatively greater interstitial oedema in late rather than in early responders. However, due to the increased risk of irreversible steroidal side effects (cataract, striae) with long-term courses of PRED, we and others [23] do not recommend that long-term daily PRED should be given to children. It is possible that the response rates in SRNS to other immunosuppressants may vary according to the type of steroid resistance. For example, all of our FSGS patients with late PRED resistance (six out of six) responded to IV MPRED pulses + CSA whereas only 34 out of 46 patients (74%) with early resistance entered remission (statistically non-significant difference). In summary, the well-known diagnostic definitions of ISKDC—including steroid resistance—should be changed in order to improve the policy for treatment decisions for children with FSGS.

There is also a need for changing the concepts of treatment strategies for children with SRNS and FSGS. Undertreatment, such as underdosage, monotherapy and delay of immunosuppressive therapy, must be avoided in children with idiopathic FSGS. In the past, the treatment policies for SRNS with FSGS varied extensively, and Vehaskari [24] described at least 10 different treatment schedules performed by 181 US paediatric nephrologists in 1998. In addition, the previous therapeutic approach for the initial attack on SRNS included a variety of substances which were used either singularly or in combination. These included TAC, MMF, mizoribine, vincristine, CYC, chlorambucil, amongst others. More than 90% of our patients who were treated with our protocol had received no other immunosuppressive agents other than PRED before the start of therapy.

Long-term combination therapy of steroid resistant FSGS and MCNS with ciclosporin A and prednisolone
Our retrospective, non-randomized study is able to exclude some, but not all, of the critical aspects mentioned above. It is most unlikely that the idiopathic FSGS was overdiagnosed in our study. Twenty-eight percent of all 72 children with FSGS had a genetic or syndromic type and were excluded from the analysis following response to two different treatment schedules. We also wanted to avoid undertreatment because our findings extend previous reports by adding a ‘new’ intensified treatment protocol, ‘IV-MPRED pulses + oral PRED + CSA’ which was positively tested against a known induction therapy, ‘oral PRED + CSA’. Furthermore, we aimed at stratifying the groups of patients into different aetiologies and histological categories [18]. The subsequent clinical course of disease was analysed during and after maintenance therapy. It was shown that children with idiopathic SRNS had better kidney function outcomes than children with a genetic type of NS. This data supports the findings of Ruf et al. [14], which showed a lack of complete response to immunosuppressive therapies in children with podocin mutations, as well as the findings of Boerkoel et al. [25] which showed a lack of complete response in children with Schimke's immuno-osseous dysplasia.

We additionally found that children with idiopathic SRNS and MCNS or FSGS in biopsy had similarly good outcomes if FSGS patients were treated with a combination of IV-M-PRED + oral PRED + CSA. A good response to CSA alone has only previously been shown for steroid-dependent MCNS and not for SRNS [20]. In patients with FSGS, it had been suggested that the prognosis may correlate with the subtype of glomerular lesion, such as the tip lesion, classical type, perihilar, cellular or collapsing variant [5,26]. Chun et al. [27] showed that the rates of remission in treated nephrotic patients could not be predicted by variants of FSGS. Our data showed a better response to the two treatment schedules in children with the tip lesion, classical type, perihilar and cellular type when compared with children with the collapsing type or a totally sclerosed glomeruli, which supported the findings of Stokes et al. [28]. We found no correlation between histological subtype and the response rate to a specific type of treatment. Apart from the collapsing subtype, the other histological variants of FSGS seem to be of minor prognostic value. In contrast, a comparison of our FSGS data with our MCNS data supports the concept that the type of underlying glomerular lesion in idiopathic SRNS may influence the response to treatment. Patients (11 out of 11) with steroid-resistant MCNS receiving PRED + CSA showed a statistically significant higher remission rate (100 vs 63%, P = 0.01, Fisher's exact test) than patients (17 out of 27) with FSGS receiving PRED + CSA. Using the ‘more intensive’ immunosuppression with IV-MPRED + oral PRED + CSA, patients with FSGS also showed a high response rate comparable to that of patients with MCNS and CSA + PRED. This supports the idea that intensity of immunosuppression may have to be adapted to the underlying findings in renal biopsy. However, our findings do not answer the question of whether all children with steroid-resistant MCNS need to be treated with PRED + CSA. Because of a lack of efficacy and because of the risk of severe side effects of cytotoxic drugs including gonadal toxicity, our current experience does not indicate that children should be treated for steroid-resistant MCNS with CYC.

Renal function at the start of immunosuppressive treatment may be an important predictive factor for outcome. None of our five children with stage 2 CKD or greater responded to treatment. The start of immunosuppressive treatment in these five patients was delayed due to late referrals. The response rate of all 47 out of 52 FSGS patients with initial absence of CKD was 85%, and 21 out of 23 children receiving IV-MPRED + oral PRED + CSA came into remission, compared with 17 out of 24 with oral PRED + CSA. We recommend that induction treatment in children with steroid-resistant FSGS should start early and that any delays must be avoided.

There were a number of limitations to our study. For example, molecular genetic testing was only possible in 47 out of 72 children. However, 7 out of 12 non-responders were negative for NPHS2 mutations, leaving only five non-responders in the idiopathic FSGS group, which may theoretically have a NPHS2 mutation. Due to the young age of our patients, it is most unlikely that our study group included children with mutations of alfa-actinin, TRPC6, or CD2AP.

As a second limitation, there were deviations from the study protocol caused by doctor and patient non-compliance. In actual fact, the number of IV-MPRED pulses ranged from 3 to 9, and their dosage ranged from 300–1000 mg/day/m2. The duration of alternate day PRED ranged from 4 to 8 months, and during maintenance therapy CSA trough levels were not always above 80 ng/ml as was indicated in the protocol. Nevertheless, the overall remission rates were good and the side effects of treatment were regarded as acceptable in view of the poor prognosis of untreated patients. Treatment of relapses was not a problem, however, repeated relapses in 2 out of 16 patients led to stage 2 CKD.

Repeat biopsies were performed in 15 responders. Mild CSA nephrotoxicity was found in two-thirds of biopsied patients after a maintenance treatment period that ranged from 3 to 14 years. None of these showed incipient FSGS on histology. All patients with CSA toxicity received additional MMF maintenance therapy and CSA dosage was reduced. Two of these seven patients—having had repeated relapses—developed stage 2 CKD. One patient had been on CSA for 15 years because of five relapses. Interestingly, glomerular filtration rate (GFR) decreased during his last three relapses and nephrotoxicity was ruled out in two repeat biopsies.

Our data show that more than two-thirds of patients with SRNS and FSGS responded with a complete remission to a combined therapy of CSA with PRED, and that use of IV-MPRED + oral PRED + CSA further increased the response rate to 84%. Only one previous study has reported a similar response rate, however, their study group included patients having both steroid resistance and steroid sensitivity with steroid dependence, and only five patients had FSGS on renal biopsy [29].

Using the Cochrane analysis, Habashy et al. [16] showed from the few randomized controlled clinical trials in children that CSA increased the number of children achieving remission (RR = 0.64; 95% CI = 0.47 – 0.88). Oral CYC did not increase response rates when compared with PRED alone. IV-CYC was not superior to oral CYC and azathioprine + PRED was not superior to PRED alone. In the uncontrolled trials, a partial or complete remission was found in about 30% of children treated with CSA, and in up to 60% in those treated with IV-MPRED pulses and CYC or chlorambucil [16].

As most articles differentiated poorly between patients with genetic and non-genetic types of SRNS and between steroid-resistant FSGS and MCNS, it can be argued that the favourable results in our patients were due to our patient selection. This is only partly true. With the estimation that about 20% of the previously reported children with SRNS may have had genetic, familial or syndromic types of FSGS, our response rate of over 80% is still considerably higher than what has been previously published. There is, however, the exception of the Mendoza protocol, which showed similarly good results. Their findings, may be due to three factors, which include, treatment with IV-MPRED [30–32], combined immunosuppressive therapy [33], and finally, long-term immunosuppression [34]. In fact, our data shows that the combination of IV-MPRED + oral PLRED + CSA was superior to CSA + oral PRED, and remission was achieved not only during the early phase but also after 6 months when the PRED dosage had already been tapered, thus supporting the Mendoza concept of long-term treatment.

In an unpublished study from the APN (Plank C, personal communication) comparing CSA + oral PRED after three IV-MPRED pulses with IV-CYC + oral PRED after three IV-MPRED pulses, the proportion of complete or partial remissions after CSA + oral PRED was 60% compared with 18% after IV-CYC + PRED, thus supporting the concept that the combination of CSA + PRED may play a key role in the induction of remission. The response rate of 60% after IV MPRED followed by CSA + oral PRED was similar to the 70% response rate in a previous study using CSA + oral PRED [35]. However, pooled data from seven open clinical studies dating from 1992 comprising a total of 341 patients treated with CSA with the aim of inducing remission of idiopathic NS showed that 39% of patients with FSGS and 70% of patients with MCNS benefited from CSA treatment [20].

Induction therapy must be given for a long enough period because short-term treatment with immunosuppressive agents was often ineffective in steroid-resistant patients [19]. The question is, how long should the treatment be continued? Based on published data and our own findings, we conclude that the combination therapy may have to be given for at least 6 months. In fact, approximately 30% of our patients receiving IV-MPRED did not respond during induction therapy, but responded only after 6 months of maintenance therapy. Remission can be induced if the immunosuppressive attack is continued long enough to halt the underlying unknown pathogenetic mechanisms. It is also unclear whether and which rescue therapies should be offered to those patients who did not respond to IV-MPRED + oral PRED + CSA pulses after 6 months. The addition of plasmapheresis has been shown to be effective in FSGS [36,37]. Alternatively, it may be possible to increase the intensity of immunosuppression by adding MMF [38] or switching to other drugs such as TAC [6,39]. We are not aware of any studies that have answered these questions.

Maintenance therapy sustained remission efficiently in 63% of 54 responding children with FSGS and MCNS, corresponding to the 40% relapse rate published by Cattran et al. [35], and secondary CSA resistance did not occur [40]. However, a treatment over 15 years with CSA was necessary in one patient, who developed five relapses while on CSA, and 3 out of 5 relapses were associated with a 10% decrease in GFR that led to stage 2 CRF at the age of 18 years; nevertheless, the young man was always brought back into NS remission. Pooled data of four published reports [38,41–43] and our own observations showed a benefit in MMF maintenance therapy in 15 out of 22 patients, which indicates a PRED and CSA sparing effect to sustain remission.

Long-term kidney function and side effects of treatment
Long-term kidney function in our patients was good when NS responded to treatment. Of our 52 patients with idiopathic FSGS, 23% developed CKD stage 2+ or persistent proteinuria after a mean follow-up period of 5 years. This compares with 83% of 75 unselected patients with FSGS entering CKD or having proteinuria after a similar timescale [44]. The progression of FSGS in our patients was unrelated to age, sex, or the presence of haematuria or hypertension, which is in accordance with Korbet [45].

Arterial hypertension was a frequent finding in our patients during induction therapy. This was also found by Ponticelli et al. [46,47]. Hypertension persisted, though well-controlled, in 29% of our patients during maintenance therapy and may be due to CSA toxicity.

Growth in patients with SRNS depends on the preservation of GFR, the cumulative dosage of steroids applied, and the severity of hypoalbuminaemia [15]. All of our responsive children grew normally, and body mass index was within the normal range, thus supporting the findings of O’Regan et al. [48] who described an increased growth velocity after CSA response in eight children with SRNS. In contrast, those children entering renal failure developed growth failure, and almost half our children with syndromic FSGS had severe disproportionate growth failure.

Patients with unresponsive SRNS had a poor outcome and 28 out of 32 patients (85%) had entered CKD 2+ after a mean period of 5 years. Recurrence of NS after renal transplantation was observed in four children with idiopathic FSGS and in one child with genetic FSGS [49]. Patients with partial response had a better outcome than patients with no response to immunosuppression [50]. We conclude for our results that patients with partial response may enter a complete remission after an intensified rescue therapy, which may further improve long-term outcome of global kidney function.

In conclusion, treatment of children with idiopathic, non-genetic, SRNS with FSGS produced a 77% rate of complete remission using combined PRED plus CSA induction therapy, and these results were even better when immunosuppression was intensified by IV-MPRED pulses and when MPRED was started before onset of CKD. The remission rate of 84% is substantially higher compared with previous reports using CSA monotherapy. Remission may, however, be delayed for several months and relapses may occur in up to 40% of patients. The greatest limitation to our study was its retrospective nature. These findings may, however, produce a stimulus for future randomized trials.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 21.12.05
Accepted in revised form: 31. 1.07


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S.-W. Kengne, L. Massella, F.-C. Diomedi, A. Gianviti, M. Vivarelli, M. Greco, G. S. Rita, and F. Emma
Risk Factors for Cyclosporin A Nephrotoxicity in Children with Steroid-Dependant Nephrotic Syndrome
Clin. J. Am. Soc. Nephrol., September 1, 2009; 4(9): 1409 - 1416.
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