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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 4  |  Page : 497-502
Cyclosporine Utilization in Idiopathic Nephrotic Syndrome in Children


1 Pediatric nephrology department, Surgical Kidney Hospital, Ibn Alnafis Medical Complex, Syria
2 Nephrology unit, Al-Assad University Hospital, Damascus University, Damascus, Syria

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   Abstract 

The treatment of steroid-resistant focal segmental glomerulosclerosis (FSGS) imposes one of the most perplexing and frustrating problems on nephrologists. Cyclosporine A (CsA) is widely considered as the treatment of choice for steroid-resistant or dependent nephrotic children. We reviewed the clinical outcome in children with idiopathic nephrotic syndrome (INS) under CsA treatment. A total of 22 children presented with either steroid­resistant nephrotic syndrome (SRNS) (14 children), or steroid-dependent nephrotic syndrome (SDNS) (8 children) during the period from August 2002 to February 2005; the mean age for both groups was 7.6 years (range: 23months -15 years). Renal histology showed FSGS in 14(63%) patients, minimal change disease (MCD) in 4(18%), diffuse mesangial glomerulonephritis (MesGN) in three (13.6%), and membranous glomerulonephritis (MGN) in two (6.8%). Treatment with CsA in combination with alternate-day prednisolone induced remission in 15(68%) patients; 9(60%) patients had complete remission and six (40%) had partial remission. Seven (50 %) patients in the SRNS group responded to CsA treatment; two (14.2%) patients had complete remission and 5 (35.7%) had partial remission. Seven (87.5%) children in the SDNS group had complete remission and one (13.5%) had partial remission. We conclude that this study demonstrates the efficacy of CsA in inducing remission in the steroid dependent is higher than in the steroid resistant nephrotic children We believe that CsA is probably a good alternative therapy in this population.

Keywords: Children, Nephrosis, Cyclosporine, steroid, Focal, Glomerulosclerosis, Minimal change disease.

How to cite this article:
Saeed B, Ossman M, Sheriff S. Cyclosporine Utilization in Idiopathic Nephrotic Syndrome in Children. Saudi J Kidney Dis Transpl 2006;17:497-502

How to cite this URL:
Saeed B, Ossman M, Sheriff S. Cyclosporine Utilization in Idiopathic Nephrotic Syndrome in Children. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2019 Nov 13];17:497-502. Available from: http://www.sjkdt.org/text.asp?2006/17/4/497/32486

   Introduction Top


Although most children with idiopathic nephrotic syndrome (INS) respond to cortico­steroid therapy, 40%-90% of respondents have subsequent relapses. One of the major problems in the management of children who have frequent relapses is the serious side effects resulting from continuous steroid therapy. Cytotoxic agents sustain remission when there is steroid-dependency, but are less efficacious when there is steroid-resistance, and also have serious side effects. [1] Therefore, cytotoxic agents do not seem to benefit patients with steroid-resistant focal segmental glomerulo­sclerosis (FSGS), as emphasized by the controlled study of the International Study of Kidney Disease in Children (ISKDC). [2]

Calcineurin inhibitors may be a useful alter­native to cytotoxic agents with less toxicity. Cyclosporine A (CsA) was shown to be effective in randomized controlled studies of steroid-dependent (SDNS) and steroid­resistant nephrotic syndrome (SRNS), and it was recommended as the first choice treatment for SRNS with either minimal change disease (MCD) or FSGS. [3],[4],[5]

We aimed, in this study, to investigate the effect of CsA therapy on the clinical outcome of steroid dependent and steroid resistant nephrotic children.


   Patients and Methods Top


We retrospectively analyzed the data of 22 children with primary nephrotic syndrome who were treated with CsA during the period from August 2002 to February 2005. There were 17 boys (77%) and 5 girls (23%).The age of the patients ranged from 23 months to 15 years with a mean of 7.6 years. The mean duration of illness was 3 years (it ranged from 2 months to 13.5 years). The studied patients were divided into two groups according to their steroid responsiveness; 14 (64%) children were in the SRNS group, and 8 (36%) were in the SDNS group.

The definition and criteria for nephrotic syndrome were the same as those used by the ISKDC. [6],[7] Relapse was defined as the reappearance of proteinuria (C40mg/h per m²) for three consecutive days. A frequently relapsing course was defined as two or more relapses in the preceding six months or three or more relapses in the preceding year.

Patients were considered as SDNS if they had two consecutive relapses, or if two of four relapses in any 6-month period occurred while a (usually reducing) dose of steroid was still being given, or within 14 days of dis­continuing steroid therapy. The eight SDNS patients were further classified as either highly steroid-dependent whenever they were dependent on a steroid dose of 01 mg/kg per day, or low steroid-dependent if they were dependent on a steroid dose of < 1 mg/kg per day; four patients were highly steroid-dependent and four patients were low steroid-dependent. All SDNS cases in this study previously received a trial of cyclophsphamide (CPO). CsA therapy was administered because CPO had failed to induce or sustain remission of the nephrotic syndrome in this group.

Patients were considered as "steroid-resistant" if remission did not occur after 4 weeks of continuous steroid (prednisolone) treatment followed by another 4 weeks of intermittent treatment.

The initial attack and relapses were treated with 60mg/m² (not to exceed 80 mg per day) of prednisolone in two or three divided doses daily. This dose was maintained for four weeks irrespective of the response. At the end of four weeks, the dose was reduced to 40 mg/ m², given every other day, and continued for four more weeks, at the end of which the predni­solone was abruptly discontinued. Steroid toxicity was considered to be an indication for the withdrawal of steroid group (either high or low steroid-dependent cases) and initiation of CsA therapy in the SDNS if two of the following features of steroid toxicity were present: a gross cushingoid appearance, hypertension, growth suppression, cataract, diabetes, and glaucoma.

We performed renal biopsy for all of the four-teen patients with SRNS and for seven out of eight patients with SDNS. The renal biopsies were examined with light micro­scopy. Hepatitis B and C were excluded by serological tests in all patients before treatment with CsA. The patients were not analyzed for podocin mutations, but their subsequent response to CsA makes these unlikely.

CsA was started at a dosage of 5 - 6 mg/kg per day given in two divided doses. The dose of CsA was adjusted to achieve and maintain 10- to 12-hour trough levels of 100 to 200 ng/ml (whole-blood monoclonal immunoassay). The patients received prednisolone in combination with CsA for the total duration of treatment as such a combination usually results in an increased remission rate. [5] Prednisolone was started at a dose of 30mg/m² per day in two divided doses for the first month of CsA therapy, followed by a dosage of 15 mg/ m² on alternate days for the total duration of therapy. The duration of CsA therapy depended on the renal histological findings, as was shown by Ponticelli et al [8] who advised more than 18 months of CsA therapy for FSGS. The CsA regimen for MCD and MesGN is shown in [Table - 1]. The CsA regimen for FSGS and MGN is shown in [Table - 2].

Complete remission was defined as a redu­ction in the urinary excretion of protein to less than 4 mg/hr/m² for 3 consecutive days, while partial remission was defined as normal serum albumin and a reduction of the 24­hour total protein excretion by at least 50% but with a level which remained above 4 mg/hr/m². The patients with MCD or MesGN were not considered as non-responders to CsA therapy before being treated for four months with a full dose (5-6 mg/kg / day); for those with FSGS or membranous glomerulonephritis (MGN), a full dose of CsA therapy was conti­nued for at least a 6-month period before consi­dering it ineffectiveness in inducing remission.


   Results Top


Nine patients (41%) out of 22 had received CPO prior to CsA therapy, including all of the SDNS cases and one case from the SRNS group; only one patient went into remission, and the remaining 8 patients were CPO­resistant. We have noticed steroid toxicity in the majority of the study group (i.e. 17 patients (77%)). Pre-existing low-glomerular filtration rate (GFR) was present in 4 (18%) patients; however, there was no further decline in their GFR throughout follow-up.

The mean required dose of CsA needed to maintain a 10-12 hour trough level of 100-200 ng/ml was 6 mg/kg/day ranging from 3.5 to 8 mg/kg/day. Of the 21 biopsies performed, the histological findings included 12 (57%) FSGS, 4(19%) MCD, 3(14%) MesGN, and two (10%) MGN. The patterns and frequencies of the different histological findings are shown in [Table - 3]. In addition, [Figure - 1] shows an example of the FSGS cases.

Fifteen patients out of 22 (68%) responded to CsA therapy; 9 (41%) patients had complete remission, and 6 (27%) patients had a partial remission. The outcome of CsA therapy in both steroid-resistant and steroid-dependent nephrotic patients is shown in [Table - 4].

Seven patients (58%) with FSGS, all patients with MCD and MGN, and one patient (30%) of the MesGN responded to CsA therapy. The outcome of CsA therapy in these four histological findings is shown in [Table - 5].


   Discussion Top


The treatment of INS has not substantially changed over the last decade. Corticosteroids and CsA remain the mainstay of therapy. Steroid toxicity was present in the majority of our patients due to the prolonged courses of steroid therapy, which was the main reason to initiate CsA. The potential CsA toxicity was

a concern, but so were the potential compli­cations of the steroid resistant-dependent nephrotic syndrome in our patients. We did not observe in this study the deterioration of renal function during the follow up period that might raise suspicion of the CsA nephro­toxicity. Nevertheless, since none of our patients underwent protocol renal biopsy to detect subclinical CsA toxicity, one cannot be sure of the long-term nephrotoxicity of this drug. In a study of the long-term effect of CsA on patients with FSGS, the number of FSGS lesions on biopsy increased in some patients, irrespective of whether CsA induced remission, and interstitial fibrosis was most remarkable in those with progressive glomerulopathy. [9] Nonetheless, the number of cases was small and the follow-up was short, precluding definite conclusions about the long-term tolerability of CsA. However, the very low dose of CsA, such as that used in our protocol, most probably imposes very little risk of long-term toxicity. [10] The randomized study by Cattran et al [11] showed that long-term CsA treatment improved renal function in FSGS. This finding, unexpected for a drug with potential nephrotoxicity, might be interpreted as an indication of a favorable effect on the natural course of the disease.

CsA was an effective form of therapy for both SDNS and SRNS patients in this study. In the steroid-dependent group, the results were very comparable to those reported by Niaudet, [5] while the results in the steroid resistant group were comparable to those of the study of the French Society of Pediatric Nephrology, though they could attain a higher percentage of complete remission than [12] ours.

We have noticed that the CsA response rate differs significantly between the different groups of patients when classified according to their histopathological findings. There are three randomized controlled trials of CsA in steroid-resistant patients with FSGS; the percentage of complete remission ranged from 12 to 33% and partial remission ranged from 40 to 66%, while it was 33 and 25% respect­ively in our study. [4],[11],[13] All the four cases with MCD in our study had responded to CsA therapy, though the nephrotic syndrome due to MesGN tends to be associated with relatively high incidence of steroid resistance and progression to renal insufficiency. [14],[15]

The high proportion of non-responders to steroid therapy among patients with MesGN suggests that these patients differ clinically as well as histopathologically from those with MCD. [14],[16],[17] Only one patient with MesGN in this study had partially responded to CsA therapy, while the remaining 2 were CsA­resistant. Hymes [18] treated seven patients with MesGN with CsA; one patient developed renal failure, and only two patients had complete remission.

Finally, published reports are fairly consi­stent in showing that relapse is almost invariable when the CsA is withdrawn. There­fore, it is very important to emphasize to the patient and parents that CsA dependence will substitute for steroid dependence, it will not cure the disease. [19]

We conclude that the results of this retro­spective study show that the use of CsA in combination with steroids is effective for the treatment of INS, and that it is more effective in inducing remission in SDNS than in SRNS, which probably makes CsA a good alternative of therapy for these patients.


   Acknowledgement Top


We would like to thank the staff of our pediatric nephrology department whose care and attention to detail has been a major con­tribution to this work.

 
   References Top

1.Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis 1994;23:773-83.  Back to cited text no. 1  [PUBMED]  
2.Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr. Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis. A report of the International Study of Kidney Disease in Children. Pediatr Nephrol 1996;10:590-3.  Back to cited text no. 2    
3.Ponticelli C, Edefonti A, Ghio L, et al. Cyclosporine versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial. Nephrol Dial Transplant 1993;8:1326-32.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Ponticelli C, Rizzoni G, Edefonti A, et al. A randomized trial of Cyclosporine in steroid­resistant idiopathic nephrotic syndrome. Kidney Int 1993;43:1377-84.  Back to cited text no. 4  [PUBMED]  
5.Niaudet P. Treatment of childhood steroid­resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J Pediatr 1994;125:981-6.  Back to cited text no. 5    
6.Early identification of frequent relapsers among children with minimal change nephrotic syndrome. A report of the Inter­national Study of Kidney Disease in Children. J Pediatr 1982;101:514-8.  Back to cited text no. 6  [PUBMED]  
7.Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A report of the International Study of Kidney Disease in Children. Kidney Int 1981;20:765-71.  Back to cited text no. 7  [PUBMED]  
8.Ponticelli C, Villa M, Banfi G, et al. Can prolonged treatment improve the prognosis in adults with focal segmental glomerulo­sclerosis? Am J Kidney Dis 1999;34:618-25.  Back to cited text no. 8  [PUBMED]  
9.Meyrier A, Noel LH, Auriche P, Callard P. Long-term renal tolerance of cyclosporine A treatment in adult idiopathic nephrotic syndrome. Kidney Int 1994;45:1446-56.  Back to cited text no. 9  [PUBMED]  
10.Meyrier A. Nephrotic focal segmental glomerulosclerosis in 2004: an update. Nephrol Dial Transplant 2004;19:2437-44.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Cattran DC, Appel GB, Hebert LA, et al. A randomized trial of cyclosporine in patients with steroid resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int 1999; 56:2220-6.  Back to cited text no. 11    
12.Niaudet P, Habib R. Cyclosporine in the treatment of idiopathic nephrosis. J Am Soc Nephrol 1994;5:1049-56.  Back to cited text no. 12  [PUBMED]  
13.Lieberman KV, Tejani A. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. J Am Soc Nephrol 1998;9:1333-40.  Back to cited text no. 13    
14.Joh K, Matsuyama N, Kanetsuna, Y, et al. Nephrotic syndrome associated with diffuse mesangial hypercellularity: is it a hetero­geneous disease entity. Am J Nephrol 1998; 8:214-20.  Back to cited text no. 14    
15.Ji-Yun Y, Melvin T, Sibley R, Michael AF. No evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome. Kidney Int 1984;25:100-6.  Back to cited text no. 15  [PUBMED]  
16.Primary nephrotic syndrome in children. Clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int 1981;20:765-71.  Back to cited text no. 16    
17.Report of the Southwest Pediatric Nephro­logy Study Group. Childhood nephrotic syndrome associated with diffuse mesangial hypercellularity. Kidney Int 1983;24:87-94.  Back to cited text no. 17    
18.Hymes LC. Steroid resistant cyclosporin responsive, relapsing nephrotic syndrome. Pediatr Nephrol 1995;9:137-9.  Back to cited text no. 18  [PUBMED]  
19.Hulton SA, Neuhaus TJ, Dillon MJ, Barratt TM. Long-term Cyclosporin A treatment of minimal-change nephrotic syndrome of childhood. Pediatr Nephrol 1994;8:401-3.  Back to cited text no. 19  [PUBMED]  

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Correspondence Address:
Bassam Saeed
Pediatric Nephrology Department Surgical Kidney Hospital, Ibn Alnafis Medical Complex, P.O. Box 8292, Damascus
Syria
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PMID: 17186683

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