Treatment Outcome in Childhood Steroid Resistant Nephrotic Syndrome with Different Therapeutic Regimens

1. Muhammad Imran 2. Zulfiqar Ali 3.Waqas Imran Khan 4. Hashim Raza

1. Asstt. Prof. of Paediatric Nephrology, 2. Asstt. Prof. of Paediatric Oncology, 3. Asstt. Prof. of Paediatric Endocrinology, 4. Medical Officer, Paediatrics; The Children's Hospital & the Institute of Child Health, Multan

ABSTRACT

Objective: To determine the efficacy of different  treatment strategies in children with steroid resistant nephrotic syndrome (SRNS)  and to find the impact of histopathological lesions on the treatment outcome.

Study Design: Retrospective observational

Place and Duration of Study: This study was conducted at Paediatric Nephrology Department, the Children's Hospital and the Institute of Child Health, Multan from January, 2006 to July, 2014.

Materials and methods: Medical record of 77 patients with SRNS was reviewed. For the purpose of treatment patients were divided into two groups depending upon the initial renal function tests (RFTs). Group 1 included patients with normal RFTs. They received cyclosporine A (CsA), mycophenolate mofetil (MMF), combined CsA and MMF, and intravenous methylprednisolone (MP) pulses as step 1, 2, 3, and 4 respectively. Group 2 included patients with deranged RFTs and they were given either MMF, or MP pulses. Long-term follow up was done ranging from 1-5 years. Treatment outcome with different  therapeutic regimens was determined. The role of histopathology in predicting final outcome was also evaluated.

Results: In group 1, 44/61(72%) patients achieved complete remission with successive treatment steps1-4.Two (3.4%) patients were partial responders whilst 15(24.6%) patients failed to respond to all treatment regimens. Out of the 16 patients in group 2, only 02 (12.5%) achieved  remission. Patients with focal segmental glomerulosclerosis (FSGS) were least likely to respond to treatment (12/28;42.8%),followed by mesangioproliferative glomerulonephritis (MesPGN)(15/23;65.2%), and minimal change disease (MCD)(14/18;77.8%).

Conclusion: SRNS patients with normal initial RFTs are much more likely to respond to immunosuppressives than those with deranged RFTs at  presentation. FSGS is  more difficult lesion to treat compared with non-FSGS lesions.

Key Words: Steroidresistant nephrotic syndrome, children, renal function tests, histopathological lesions

 

INTRODUCTION

The nephrotic syndrome (NS) is a common renal disorder with an  incidence of 90-100/million population/year in the Indian sub-continent.1,2 It is characterized by heavy proteinuria (40mg/m2/hour), hypoal buminemia (< 2.5G/dl), edema, and hypercholes trolemia (> 250mg/dl).3 Nephrotic syndrome in children may be primary/idiopathic or it may be secondary to some underlying cause. Idiopathic nephrotic syndrome may be steroid sensitive (SSNS) , or steroid resistant (SRNS). Resistance to steroid therapy accounts for about 10% of idiopathic nephrotic syndrome at first presentation whilst about 1-3% of initially steroid-sensitive patients become steroid resistant subsequently, and are called late non-responders.3 This response to steroids is the primary determinant of the final outcome of the disease, with >60% of those resistant to steroids going to develop chronic kidney disease (CKD).4,6,7  Treatment of these SRNS patients continues to pose a therapeutic challenge with considerable variety of strategies.7 A number of medications such as cyclosporine A (CsA), mycophenolate mofetil (MMF), cyclophosphamide (CPM), methylprednisolone (MP), and others have been used with varying results.8-11 Recent reports have shown remission rates ranging from 20% to 70% using these drugs in SRNS.11 The underlying histopathology usually affects the course of disease and the response to treatment.12 Main histopathological lesions in SRNS include focal segmental glomerulosclerosis (FSGS), mesangiopro-liferative glomerulonephritis (MesPGN), and minimal change disease (MCD)and are treated with a common steroid protocol.13 Gulati S et al14,15 showed that following immunosuppressive therapy, patients with MCD had significantly greater remission rates compared to those with non-MCD. They concluded that kidney biopsy is of significant prognostic value in SRNS.  A recent meta-analysis, however, failed to show any difference in the efficacy of immunosuppressive agents in inducing remission in SRNS children with MCD versus FSGS.16  So,there is still controversy over the role of renal biopsy in the management of children with SRNS.15 Recent guidelines for childhood SRNS by the Kidney Disease: Improving Global Outcome (KDIGO) state that the kidney function measured at the time of diagnosis is a predictor of the long-term risk for kidney failure.9

The present study was designed to determine the effectiveness of different therapeutic regimens in children with SRNS coming to our institute. We, also, evaluated the impact of initial deranged renal function and the underlying histopathologic lesion on the final patient outcome.

MATERIALS AND METHODS

A retrospective analysis was done in 77 children with SRNS, with onset age between 1-15 years, referred to our institute over the last 8.5 years. Renal biopsy was performed in 69 patients whilst it was refused in 8 patients. Inclusion criteria were: (1) steroid resistance, either initial or late, (2) MCD, MesPGN, and FSGS on renal biopsy, and (3) follow up period >1 year. Exclusion criteria were: (1) Secondary NS, (2) membranous nephropathy (MN), mesangiocapillary glomerolonephritis (MCGN), or immunoglobulin A nephropathy (IgAN) on renal biopsy, (3) Familial SRNS, and (4) infantile or congenital onset NS.7

Nephrotic syndrome (NS) was defined as edema, proteinuria > 40mg/m2/hour or spot urine protein: creatinine > 2 (mg : mg), and hypoalbuminemia < 2.5 G/dl.1,3 Remission was defined as 3 consecutive days' nil or trace proteinuria on reagent strip (UrocolorTM). Steroid resistance was defined as not achieving remission following 4 weeks' prednisolone (PDN)(60mg/m2/day in three divided doses) plus 3 alternate day pulses of  intravenous methylprednisolone (MP) (30mg/kg/dose) given over 4 hours.3 Late non-responder were the patients who were initially steroid sensitive but became steroid resistant over the course of the disease. Partial remission was defined as the absence of edema and proteinuria + or ++ by reagent strip. Relapse was defined as 3 consecutive days' ++ proteinuria, or single +++ or ++++ proteinuria on reagent strip, with or without edema.3 Deranged renal function at presentation was defined as serum creatinine level above the upper limit of the normal for age.7 The estimated glomerular filtration rate (eGFR) was calculated by Schwartz formula.5 Chronic kidney disease (CKD) was labeled when serum creatinine was persistently high for a period of 3 months or more.  CKD 5 was taken when patient needed chronic regular dialysis for survival.7

For the purpose of treatment, SRNS patients were divided into two groups depending upon the initial RFTs in the steady state condition. Group 1 patients had normal RFTs and the Group 2 patients had deranged RFTs. Patients were subjected to sequential treatment steps. Partial responders and non-responders to a treatment regimen were put on to the next step treatment and so on. For all the group 1 patients, cyclosporin A (CsA) was used as the first line agent (step 1; S1), regardless of the biopsy report. It was given according to the recommendation of French Society of Pediatric Nephrology 8, in a dose of 150mg/m2/day in 2 divided doses along with oral prednisolone (PDN) in a dose of 30mg/m2/day, also in 2 divided doses. After 1 month of treatment, PDN was switched to alternate day 30mg/m2/dose as a single morning dose after breakfast for the next 5 months; CsA was continued in the same daily dose for  6 months in the responding patients. Regular monitoring of RFTs with serum electrolytes was advised  to avoid nephrotoxicity and hyperkalemia. CsA trough levels could not be done routinely due to high cost. Repeat renal biopsy was done after 1 year of treatment to look for any histopathologic evidence of nephrotoxicity. Patients not responding to this regimen (i.e CsA resistant) were the candidates for step 2 (S2) treatment with mycophenolate mofetil (MMF) in a dose of 1200mg/m2/day in 2 divided doses along with steroids.22-24 Patients not responding to either CsA or MMF were given a combination of CsA and MMF as step 3 (S3) treatment, while withdrawing steroids, as practiced by Nikibakhsh AA et al in Iran,25 and novel multidrug therapy in children with CsA-resistant NS by Aizawa-Yashiro et al.26  Patients resistant to combined CsA and MMF were, as step4 (S4), treated with the aggressive Mendoza protocol28 in a final attempt to achieve remission.The SRNS patients in the group 2 ( with deranged RFTs) were given either MMF plus steroids or methylprednisolone (MP) intravenous pulses plus oral PDN + CPM as proposed by Mendoza et al (Table I).

Table No.I:Mendoza Protocol for Treatment of SRNS

Weeks

Intravenous Methylprednisolone Pulse   (30mg/kg)

Oral  Prednisolone

1-2

 3 times/week

None

3-10

 Once every week

2mg/kg qod

11-18

 Once every other week

With/without taper

19-50

 Once every 4 weeks

Slow taper

51-82

Once every 8 weeks

Slow taper

Note: Oral cyclophosphamide (2.5mg/kg/ day)was added to the treatment regimen when there was no remission despite IV methylprednisolone and oral prednisolone, and was continued for 3 months.

All the patients were regularly followed up for a period ranging from 1-5 years, regarding clinical response, complications of the disease and the drugs, and were properly counseled at the start of treatment and during each follow up visit to maintain good compliance with treatment and follow up. Fast track hospitalization was available in case of any complications.

Data were statistically analyzed using SPSS-19.  Descriptive statistics were applied to analyze the data. The quantitative variables were calculated by mean and standard deviation and qualitative variables by percentages and frequencies. Effectiveness of different treatment regimens in terms of remission, partial remission, no remission and progression to CKD, and the impact of initial status of renal function and that of different histopathologic lesions on these outcome variables were analyzed.

RESULTS

The study group comprised of 77 patients with SRNS; 72 (93.5%) were initial steroid resistant and 5 (6.5%) were late non-responders. Gender distribution showed 49 (63.6%) males and 28 (36.4%)females with a ratio of 1.75. Age range of patients was 1-15 years with a mean of 8.11 +3.58 years. Sixty nine (89.6%) patients underwent renal biopsy (Table 2).

Table No.2:  Demography of 77 SRNS patients

Category

Number (%age)

Biopsied

69(89.6%)

Unbiopsied

08(10.4%)

Initial SR

72(93.5%)

Late SR

05(6.5%)

Males

49(63.6%)

Females

28(36.4%)

Age(Years)

 

<4

22(28.6%)

4-10

31(40.2%)

>10

24(31.2%)

SR=Steroid resistant

The histopathologic subtypes revealed FSGS (n=31; 40.3%), MesPGN (n=25; 32.5%), MCD (n=21; 27.3%) in decreasing order of frequency. Eight patients (10.4%) could not be biopsied as their parents refused consent. Group 1 comprised of 61 (79.2%) patients with normal RFTs. Group 2 included 16 (20.8%) patients with deranged initial RFTs. The patients in group 1 received CsA  plus PDN, MMF plus PDN, combined CsA and MMF plus PDN, and intravenous MP pulses + oral PDN and CPM as S1,S2, S3, and S4 treatment respectively. Following S1, 31/61 patients (50.8%) achieved complete remission, 5/61 (8.2%) were partial responders, and 25/61 (41%) were non-responders. Three patients (4.9%), who were resistant to both steroids and CsA, went into remission with MMF plus steroids (S2). Six patients (9.8%) got remission with S3. After three steps of treatment, 40/61 (65.6%) children went into remission. Mendoza protocol28 (Table 2) (S4) was effective in inducing remission in further 4/61 (06.6%) patients  who did not respond to S1- S3. In group1, 02/61 (3.3%)  patients were partial responders and 15/61 (24.6%) were non-responders to  any immunosuppressive treatment (Table 3). These 17 (27.9%) patients in group1 went on to develop CKD.

 

 

Table.No.3: Group 1: Step wise treatment of 61 SRNS patients with normal RFTs.

Sequential Treatment Step

Drugs

Number of Patients

Complete Remission

Partial Remission

No Remission

Step 1

CsA + PDN

61 (79.2%)

31 (50.8%)

05 (8.2%)

25 (41%)

Step 2

MMF + PDN

30 (49.2%)

03 (4.9%)

07 (11.5%)

20 (32.8%)

Step 3

CsA + MMF +PDN

27 (44.3%)

06 (9.8%)

09 (14.8%)

12 (19.7%)

Step 4

IVMP + PDN + CPM

21 (34.4%)

04 (6.6%)

02 (3.3%)

15 (24.6%)

Total: Steps 1-4

 

61 (100%)

44 (72%)

02 (3.3%)

15 (24.6%)

RFTs= Renal function tests, CsA= Cyclosporin A, PDN= Prednisolone, MMF= Mycophenolate mofetil,
IVMPP= Intravenous methylprednisolone, CPM= Cyclophosphamide

Table No.4: Group 2: Treatment of 16 SRNS patients with impaired RFTs

Treatment Option

Drugs

Number of Patients

Complete Remission

Partial Remission

No Remission

Option 1

IVMP+PDN +CPM

12 (75%)

02 (16.7%)

02 (16.7%)

08 (66.7%)

Option 2

MMF + PDN

04 (25%)

None

None

04 (100%)

Total

 

16 (100%)

02 (12.5%)

02 (12.5%)

12 (75%)

RFTs= Renal function tests, IVMPP= Intravenous methylprednisolone, PDN= Prednisolone,
CPM= Cyclophosphamide, MMF= Mycophenolate mofetil

Table No.5: Impact of Histopathology on treatment outcome in SRNS patients (n=77)

Histopathological Lesion

Number of Patients

Complete Remission

Partial Remission

No Remission

FSGS

28(36.4%)

12(15.6%)

02(2.6%)

12(15.6%)

MesPGN

23(29.9%)

15(19.5%)

01(1.3%)

08(10.4%)

MCD

18(23.4%)

14(18.2%)

01(1.3%)

04(5.2%)

No biopsy done

08(10.4%)

05(6.5%)

00

03(3.9%)

Total

77(100%)

46(59.7%)

04(5.2%)

27(35.1%)

FSGS= Focal segmental glomerulosclerosis, MesPGN= Mesangioproliferative glomerulonephritis,
MCD= Minimal change disease

 

 

 

Out of the 16 patients in group 2, 12 (75%) were given treatment trial according to the Mendoza protocol. Only 2/16 (12.5%) got complete remission; 02 (12.5%) were partial responders and 08 (66.7%) were non-responders. Four patients (25%) in this group were treated with MMF plus steroids but none achieved complete remission. Thus, 14 (83.3%) patients in this group were non-responders or partial responders (Table 4) and they ultimately developed CKD. Overall, 31/77 (40.3%) patients, in our study, progressed to different CKD stages.

To find the impact of histopathological lesions on the treatment outcome, our analysis  revealed that out of the 28 children with FSGS 12 (42.9%) achieved complete remission, 02 (7.1%) were partial responders and 12 (42.9%) were resistant to all immunosuppressives. Amongst the MesPGN group 15/23 (65.2%) patients went into complete remission, 01 (4.3%) was partial responder, and 08 (34.8%) were non-responders. Out of the 18 children with MCD 14 (77.8%) got complete remission, 01 (5.5%) was partial responder, and 04 (22.2%) were non responders. Out of the eight unbiopsied patients, 04 achieved remission with
CsA and PDN, 01 responded to MMF plus PDN,
and 03 were unresponsive to all immunosuppressives (Table 5). Overall, 46/77 (59.7%) achieved complete remission, 04/77 (5.2%) were partial responders, and 27/77 (35.1%) patients with SRNS were resistant to all treatment trials.

DISCUSSION

Treatment of SRNS in children continues to pose a therapeutic challenge to the pediatric nephrologists. The lack of large-scale randomized controlled trials leads to a paucity of strong evidence to inform treatment decisions.9 The treatment strategies are heterogeneous with variable efficacy and side effects' profile. Optimal strategies with least toxicity remain to be determined.7 Without effective treatment, progression to the end-stage kidney disease is very likely.We have been treating our SRNS childrenemploying a sequential stepwise approach using different immunosuppressive therapies. Failure to respond to any step of treatment  or intolerance/toxicity to any drug was the criterion to use the next treatment step. Patients were broadly divided into 2 groups depending upon the initial RFTs because: 1) the SRNS patients who present with deranged renal function are less likely to respond to treatment, 2) calcineurin inhibitors should be avoided in these patients because of their inherent nephrotoxicity, and   3) because they are more likely to progress to kidney failure.6,9 Group 1 SRNS patients, in our study, had normal RFTs at the time of starting treatment. CsA was used as first line (S1) treatment for these patients regardless of the histopathology. In the literature, many studies reported that CsA is beneficial to the SRNS patients. However, the risk of relapse is high after therapy withdrawal, with the risk of nephrotoxicity.7-10 Regular monitoring of trough levels is not essential, unless there is non-response, sudden elevation of serum creatinine, or likelihood of non compliance.1 Long-term use of low dose CsA has been reported beneficial in reducing proteinuria, with a low risk of nephrotoxicity.20,21 Plank et al18 reported on a randomized, controlled, multicenter trial involving initial non-responders that CsA had a significantly higher rate of response than CPM pulse therapy.We used CsA along with low dose of PDN  as practiced by the French Society of Pediatric Nephrology 8 and achieved complete remission in about 51% patients. Long-term low dose (2-3mg/kg/d) of  CsA was continued to maintain remission in most of these responders for 1-2 years if there was no evidence of nephrotoxicity on renal function monitoring and on repeat renal biopsy after one year of treatment. Only three patients developed deranged RFTs during CsA therapy; but on stopping CsA, further RFTs monitoring showed reversal to the normal. MMF was substituted in the patients showing any evidence of nephrotoxicity or in those who relapsed on withdrawing or tapering CsA. It was also used as S2 treatment in those patients resistant to both steroids and CsA and in combination with CsA as S3 treatment.  Our three (4.9%) patients responded to S2 treatment  and another six (9.8%) patients achieved complete remission with S3. The combination of CsA and MMF has a synergistic immunosuppressive effect and, as a result , may induce remission in patients with steroid- and CsA- resistant FSGS.25 Combined CsA and MMF therapy and other multidrug therapy is being increasingly employed both in children and adults with SRNS at many centers with promising results.25,26  MMF seems to be safe for children with SRNS in terms of side effects as well as disease control, at least in the short term.However, it is less effective in SRNS than CsA and has not been recommended as first-line agent in such patients.9 CPM was not used alone with steroids in our patients with SRNS. Bajpai et al19, in a prospective study, administered intravenous CPM pulses. They concluded that the efficacy of this treatment was limited in inducing sustained remission in initial non-responders. The International Study of Kidney disease in Children (ISKDC) reported no benefit of orally administered CPM and prednisone compared with prednisone alone.27 Reported toxicity of CPM also limits its role in SRNS.10  However, in our study, CPM was added to those SRNS patients who were given intravenous MP pulses and oral PDN according to the Mendoza protocol28 and still did not achieve complete remissionA few studies showed efficacy of CPM in SRNS, but the frequency of side effects was high.11

Group 2 patients, in our study, had initial deranged RFTs. The SRNS patients who have already progressed to any stage of CKD are very less likely to achieve remission with any treatment modality.9 Abeyaguna-wardena et al6 reported that renal impairment at presentation and extensive FSGS were independent predictors for poor outcome in children with SRNS. Paik et al29 have also reported that initial impaired renal function and resistance to treatment were independent risk factors for poor renal outcome. Mekhali D et al7, however, demonstrated that initial renal impairment was not a predictor of poor renal outcome. According to them, only age >10 years at onset of SRNS was an independent factor of end stage renal disease. In our study , only two patients (12.5%), out of 16 SRNS patients with deranged RFTs,  responded to intravenous MP pulse therapy; rest 14 (87.5%) went on to progress to higher CKD stages. These SRNS patients also failed to respond to MMF. CsA was not employed in these already renal compromised patients due to its further risk of nephrotoxicity. Comparing group 1 and 2, about 28% patients in group 1 and 83% patients in group 2 developed progressive CKD. Overall, 59.7% patients achieved remission in our study, and 40.3% patients developed progressive CKD and were further treated by supportive CKD treatment, or dialysis as required.

Our study lacks employment of other  therapeutics like chlorambucil, vincristine, and tacrolimus. Latest effective drug reported in the literature, rituximab,  is not still available in our country. We hope to have prospective trials with these drugs in future.

Taking into consideration the impact of histopathology, in 69 biopsied patients, on the treatment outcome,  patients with FSGS were  less likely to attain remission (42.8%) compared with MCD (77.8%) and MesPGN (65.2%). FSGS with chronic sclerosing glomerulone-phritis was the lesion with no response to any treatment modality, and was also associated with either initial deranged RFTs or subsequent development of progressive CKD. Literature review shows similar results in patients with  collapsing FSGS.4,6,7,29,30 MCD  proved to be the most benign lesion in our SRNS patients with about 78% achieving complete remission with S1 or S2 treatment. Gulati S et al14 also showed that prognosis in children with SRNS with MCD is much better than non-MCD. They concluded that it is difficult to differentiate clinically MCD from non-MCD and that renal biopsy is of prognostic value in these children.

CONCLUSION

We conclude that SRNS in children is a difficult disease with significant morbidity. However, remission is achievable in majority of patients with cyclosporine and other immunosuppressive agents. Combination therapy with cyclosporine and mycophenolate mofetil has encouraging results in patients unresponsive to either drug alone.  However further prospective trials are needed in this regard. Deranged renal function at the outset and FSGS with chronic sclerosing glomerulonephritis carry poor prognosis.

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29.    Paik KH, Lee BH, Cho HY, Kang HG, Ha IS, Cheong HI, et al. Primary focal segmental glomerular sclerosis in children: clinical course and prognosis. Pediatr Nephrol 2007;22:389-395.

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Address for Corresponding Author:

Dr. Muhammad Imran,

Assistant Professor of Paediatric Nephrology,
The Children's Hospital & the Institute of Child

Health, Abdali Road, Multan, Pakistan.

Cell No. +92-300-6323860.

 

Email: This email address is being protected from spambots. You need JavaScript enabled to view it.