Steroid-resistant Nephrotic Syndrome In Children Research Articles

Rituximab for childhood refractory nephrotic syndrome

Several therapies including immunosuppressive agents have been shown to be effective and safe for frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS) and steroid-resistant nephrotic syndrome in children. It is evident, however, that a substantial number of children are still refractory to treatment despite these therapies. Rituximab is a chimeric monoclonal antibody, which inhibits CD20-mediated B-cell proliferation and differentiation. It was first introduced for the treatment of B-cell non-Hodgkin's lymphoma and was subsequently administered to patients with autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, or immunocomplex glomerulonephritis. Recently, a number of case reports and non-controlled clinical trials have suggested that rituximab may be effective for children with refractory nephrotic syndrome. Controlled prospective trials, however, are required to establish the value of rituximab in refractory nephrotic syndrome. The purpose of the present study was therefore to evaluate the efficacy and safety of rituximab in childhood-onset refractory nephrotic syndrome. The Research Group of Childhood-onset Refractory Nephrotic Syndrome (RCRNS) conducted a randomized, double-blind, placebo-controlled, multi-center clinical trial (RCRNS-01) and an open-label, multi-center, pharmacokinetic clinical trial (RCRNS-02). These two trials were investigator-initiated, registration-directed clinical trials designed to apply Ministry of Health, Labour and Welfare approval for the use of rituximab for childhood-onset refractory FRNS/SDNS in Japan. RCRNS-01 could be the first study to clarify whether rituximab is effective and safe for childhood-onset refractory FRNS/SDNS.

Broad and unexpected phenotypic expression in Greek children with steroid-resistant nephrotic syndrome due to mutations in the Wilms’ tumor 1 (WT1) gene

Mutations in the Wilms' tumor suppressor gene 1 (WT1), most commonly within exons 8 or 9 or intron 9, are found in cases with the overlapping conditions of Denys-Drash and Frasier syndromes, as well as in patients with steroid-resistant nephrotic syndrome (SRNS). This study investigated the presence of WT1 gene mutations in cases with childhood SRNS, along with an evaluation of their clinical outcome. Twenty-seven Greek children with sporadic (19 cases) and familial (8 cases) SRNS were tested. Four phenotypically female patients with sporadic SRNS were found to carry de novo WT1 mutations, including two cases with p.R394W, and one case each with p.R366H, or n.1228+5G>A. Karyotype analysis found 46XX in three cases, but 46XY in one. No phenotype-genotype correlations were apparent in the WT1 gene positive cases since their clinical presentation varied broadly. Interestingly, one patient with a pathological WT1 nucleotide variation responded fully to combined therapy with cyclosporine A and corticosteroids. This study further illustrates that investigation of WT1 gene mutations is clinically useful to support definitive diagnosis in children presenting with SRNS in order to direct the most appropriate clinical management.

MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children

The putative genetic regulation of multidrug resistance gene-1 (MDR-1) gene expression and P-glycoprotein function has not yet been clearly delineated in patients with nephrotic syndrome (NS). We undertook this study to examine the distribution of three most frequent MDR-1 exonic polymorphisms G3435C, G2677T/A and C1236T in patients with NS and control children to investigate their usefulness as markers of responsiveness of the disease to steroids. Two hundred and sixteen children with NS and 216 healthy controls were genotyped for three exonic MDR-1 polymorphisms (G3435C, G2677T/A and C1236T) by using the polymerase chain reaction-restriction fragment length polymorphism technique. The frequency distribution of genotypes/alleles was compared between patients with NS and controls and also between steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) patients. Of the total 216 cases of NS (median age of onset 5 years, 165 males), 137 had SSNS, and 79 had SRNS. Homozygous mutants of C3435T (TT versus CC, P = 0.034) and G2677T/A (TT + AA versus GG), P = 0.030) were significantly higher in patients with NS compared to controls. The frequency distribution of homozygous mutant TT + AA compared to wild genotype GG was significantly higher in SRNS than SSNS patients (P = 0.011) for G2677T/A, while the mutant genotypes for C3435T and C1236T were not different between SRNS and SSNS patients. The combination-bearing mutant genotype either of C3435T or G2677T/A exhibited a significantly higher frequency of mutant genotypes distribution in SRNS patients. MDR-1 haplotypes did not differ significantly between SSNS and SRNS patients. Patients with NS carrying homozygous mutants of single nucleotide polymorphism (SNP) G2677T/A are prone to develop SRNS. The synergistic effect of mutant genotypes of SNPs G2677T/A and C3435T in different combinations increase the risk of developing steroid resistance in patients with NS.

Renalradar – a model for studying rare disease in the UK

AimTo develop a mechanism for optimising the study of rare renal disease in the UK. To maximise the potential by building UK-wide patient cohorts and identifying centres of laboratory and...

El Síndrome Nefrótico y el Diagnóstico Genético en Pediatría

Steroid-Resistant Nephrotic Syndrome (SRNS) is found in approximately 20% of patients with Nephrotic Syndrome (NS). Podocyte-gen mutations are diagnosed in a half of these children. Nephrin (NPHS1), podocin (NPHS2) and Wilms tumor suppressor gene (WT1) are the most frequently founded mutations. These patients usually progress to End Stage Renal Disease (ESRD). Objective: Current concepts in genetic diagnostic of NS in pediatrics are presented. A local experience is analyzed. In Chilean pediatric patients with SRNS, a mutational analysis of the NPHSl and NPHS2 gene was carried out by direct sequencing of the coding regions following polymerase chain reaction (PCR) amplification of genomic leukocyte DNA with flanking intronic primers. For WTl (exon 8 and exon 9), PCR of these fragments were done. Thirty-three patients were included, 17 males, 11,1 ± 6.8 years. 54% of them developed ESRD, 12 patients were transplanted at the time of the analysis, 5 were under dialysis therapy, and 16 children correspond to ESRD Stage 3 and 4. Genetic analysis showed a gen mutation in 9 patients, NPHSl in 3 and NPHS2 in 6 of them. All genetic NS patients were cyclosporine-resistant. Post transplant relapse of NS was lower in genetic patients (p < 0.05). Conclusion: SRNS in children should be always evaluated from a genetic approach in order to avoid long-term immunosuppression, and to anticipate a clinical evolution after kidney transplantation.

Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome

The literature on the clinical effectiveness of treatments for steroid-resistant nephrotic syndrome (SRNS) is very limited. The available evidence suggests a beneficial effect of cyclosporine on remission rates. Mycophenolate mofetil (MMF) represents a promising therapeutic alternative without nephrotoxicity. The purpose of the present study was to evaluate the efficacy and tolerance of MMF therapy in children with SRNS. Six patients with SRNS were treated with MMF combined with oral prednisolone at a dosage of 1 mg/kg per day. The initial dosage of MMF was 600 mg/m² per 12 hours, adjusted to maintain levels of mycophenolic acid at 2.5-5 µg/mL. The planned duration of study to assess treatment efficacy was 12 weeks. All patients had a pathological renal study. The treatment with MMF was started at a median age of 11 years (range 9-13). Pathological patterns were 4 patients with focal segmental glomerulosclerosis (FSGS), 1 patient with minimal change disease (MCD) and 1 patient with diffuse mesangial proliferation glomerulonephritis (DMP). Only 1 patient, who had MCD, achieved complete remission. One patient went into partial remission. However, the subgroup with no response to MMF appeared to have a reduction in proteinuria and an increase of serum albumin. There were no significant beneficial effects on the level of glomerular filtration. In this small, single-center study, a therapeutic response to MMF was obtained only in one third of patients. This response rate, though it is low, encourages us to use MMF in some patients who are resistant to conventional therapy for SRNS.

Cyclosporine A and steroid therapy in childhood steroid-resistant nephrotic syndrome

Background:In children, idiopathic nephrotic syndrome (INS) is primarily treated using corticosteroids. When remission is not achieved, the coadministration of potent immunosuppressant therapy becomes imperative. Cyclosporine A (CsA) is reportedly associated with a higher incidence of remission in comparison with other immunosuppressive agents.Methods:The present study investigated the response of combination therapy using CsA and prednisolone in 30 Tunisian children with idiopathic steroid-resistant nephrotic syndrome (ISRNS). Renal histopathology was compatible with focal segmental glomerular sclerosis (FSGS) in 15 children, minimal change disease (MCD) in nine children, and diffuses mesangiale proliferation (DMP) in six children.Results:The therapy protocol produced a complete remission of proteinuria in 15 patients (50%) and a partial remission in nine patients (30%). Six patients (20%) showed no response to therapy. Progression to end stage renal disease occurred in five CsA-resistant children and in four CsA-responsive patients. CsA-related nephrotoxicity was detected by renal biopsy in one patient.Conclusions:CsA remains the primary cytotoxic treatment for childhood steroid-resistant nephrotic syndrome. Its use in combination with corticosteroids provides optimum efficiency without high risk of nephrotoxicity.

Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations

Several genes have been implicated in genetic forms of nephrotic syndrome occurring in children. It is now known that the phenotypes associated with mutations in these genes display significant variability, rendering genetic testing and counselling a more complex task. This review will focus on the recent clinical findings associated with those genes known to be involved in isolated steroid-resistant nephrotic syndrome in children and, thereby, propose an approach for appropriate mutational screening. The recurrence of proteinuria after transplantation in patients with hereditary forms of nephrotic syndrome will also be discussed.

Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus

We report the outcome of our single-center, long-term follow-up study of tacrolimus therapy in children with steroid-resistant nephrotic syndrome (SRNS). All cases of nephrotic syndrome (NS) with kidney biopsies treated at our center between January 2000 and July 2008 were reviewed. Children with systemic lupus erythematosus and steroid-dependent NS were excluded. Nineteen children with SRNS received tacrolimus. Histopathological analysis of the biopsy revealed the underlying conditions of these 19 patients to be focal segmental glomerulosclerosis (ten patients), C1q nephropathy (four), membranous nephropathy (two), minimal change disease (one), membranoproliferative glomerulonephritis (one), and immunoglobulin A nephropathy (one). The mean follow-up was 55 months, and the median age of the patient cohort was 10 years. We observed complete remission in 11 (58%) patients, partial remission in six (32%), and failure to respond in two (9%). The median time to response was 8 weeks. Side effects were mild and transient (one case of acute kidney injury and three cases of hyperglycemia). The initial rate for combined partial and complete remission of the NS in children with SRNS was 81%, which was sustained in 58% of the patients on follow-up. Among children with FSGS, the sustained remission rate was 50%, while 40% progressed to end-stage renal disease (ESRD) (mean time 52 months). Based on the results of this study, we conclude that tacrolimus is an effective and well-tolerated therapeutic option for the treatment of SRNS in children. However, the occurrence of relapses of the NS with progression to ESRD during the long-term follow-up indicates the need for careful monitoring of such patients.

Histopathology of steroid-resistant nephrotic syndrome in children living in the Kingdom of Saudi Arabia

Steroid resistant nephrotic syndrome (SRNS) is believed to be associated with a high risk of developing chronic renal failure (CRF). The underlining histopathology usually affects the course of the disease and the response to treatment . Focal segmental glomerulosclerosis (FSGS) was reported as the main cause of SRNS in western countries as well as many other parts of the world . However, in black South Africans membranous nephropathy associated with hepatitis B infection was reported as a main cause of SRNS and minimal change nephrotic syndrome (MCD) was reported as the main cause in Kuwaiti children. In this study we report the pattern of the histopathology of SRNS in children presented to King AbdulAziz University Hospital (KAUH).

Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie.

First line immunosuppressive treatment in steroid-resistant nephrotic syndrome in children is still open to discussion. We conducted a controlled multicentre randomized open label trial to test the efficacy and safety of cyclosporin A (CSA) versus cyclophosphamide pulses (CPH) in the initial therapy of children with newly diagnosed primary steroid-resistant nephrotic syndrome and histologically proven minimal change disease, focal segmental glomerulosclerosis or mesangial hypercellularity. Patients in the CSA group (n = 15) were initially treated with 150 mg/m(2) CSA orally to achieve trough levels of 120-180 ng/ml, while patients in the CPH group (n = 17) received CPH pulses (500 mg/m(2) per month intravenous). All patients were on alternate prednisone therapy. Patients with proteinuria >40 mg/m(2) per hour at 12 weeks of therapy were allocated to a non-responder protocol with high-dose CSA therapy or methylprednisolone pulses. At week 12, nine of the 15 (60%) CSA patients showed at least partial remission, evidences by a reduction of proteinuria <40 mg/h per m(2). In contrast, three of the 17 (17%) CPH patients responded (p < 0.05, intention-to-treat). Given these results, the study was stopped, in accordance with the protocol. After 24 weeks, complete remission was reached by two of the 15 (13%) CSA and one of the 17 (5%) CPH patients (p = n.s.). Partial remission was achieved by seven of the 15 (46%) CSA and two of the 15 (11%) CPH patients (p <0.05). Five patients in the CSA group and 14 patients in the CPH group were withdrawn from the study, most of them during the non-responder protocol. The number of adverse events was comparable between both groups. We conclude that CSA is more effective than CPH in inducing at least partial remission in steroid-resistant nephrotic syndrome in children.

Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephrotic syndrome.

In African American (AA) children, focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome (NS). It has been shown that AA children suffer from FSGS and steroid-resistant nephrotic syndrome (SRNS) at a higher frequency and with a more severe renal outcome in comparison with Caucasian children. Previous mutation analysis of large cohorts revealed that a high percentage of childhood SRNS is monogenic and that mutations in podocin (NPHS2) and Wilms' tumor gene 1 (WT1) account for approximately 30% of SRNS in children. To test whether AA children with SRNS have a similar or a higher mutation rate, we performed mutation analysis of NPHS2 and WT1 in a cohort of AA children with SRNS. Direct sequencing was carried out for all exons of NPHS2 and for exons 8 and 9 of WT1. We ascertained 18 children of AA descent in whom renal biopsy findings showed FSGS in 13 patients (72%) and minimal-change disease in five patients (28%). In both NPHS2 and WT1, no disease-causing mutations were detected. Our data strongly suggest that in AA children with SRNS, the frequency of NPHS2 mutations is much lower than in large cohorts of pediatric SRNS patients in the general population. Knowledge of mutation rate of NPHS2 in different populations of SRNS patients facilitates the physician in planning a suitable genetic screening strategy for patients.

Nephrin Mutations Can Cause Childhood-Onset Steroid-Resistant Nephrotic Syndrome

Classically, infants with mutations in NPHS1, which encodes nephrin, present with nephrotic syndrome within the first 3 mo of life (congenital nephrotic syndrome of the Finnish-type), and children with mutations in NPHS2, which encodes podocin, present later with steroid-resistant nephrotic syndrome. Recently, however, NPHS2 mutations have been identified in children with congenital nephrotic syndrome. Whether NPHS1 mutations similarly account for some cases of childhood steroid-resistant nephrotic syndrome is unknown. In this study, 160 patients who belonged to 142 unrelated families and presented with nephrotic syndrome at least 3 mo after birth were screened for NPHS1 variants once mutations in NPHS2 had been excluded. Compound heterozygous NPHS1 mutations were identified in one familial case and nine sporadic cases. Mutations included protein-truncating nonsense and frameshift mutations, as well as splice-site and missense variants. Mutations were classified as "severe" or "mild" using prediction algorithms and functional assays. Most missense variants trafficked normally to the plasma membrane and maintained the ability to form nephrin homodimers and to heterodimerize with NEPH1, suggesting retained function. The presence of at least one "mild" mutation in these patients likely explains the later onset and milder course of disease. These results broaden the spectrum of renal disease related to nephrin mutations.

Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children

This study was conducted to evaluate the safety and efficacy of tacrolimus (TAC) in children with SRNS. The study group comprised of 22 consecutive children with steroid-resistant nephrotic syndrome (SRNS) who were studied prospectively. TAC was initiated with a dose of 0.10 mg/kg/day, and the dose was increased to attain a trough level of 5.0-10.0 g/l. These patients were treated with concomitant prednisone, which was subsequently tapered off and stopped. The primary outcome variable was the number of patients who attained a complete remission (CR) or partial remission (PR). The mean age of onset was 7.33 +/- 5.9 years, and there were 20 boys and 2 girls. Of the 22 children, 9 had minimal change disease, 11 had focal segmental glomerulosclerosis and the other 2 had diffuse mesangial hypercellularity on histopathology. TAC had to be withdrawn in 3 children because of its side effects. Of the remaining 19 children who received adequate therapy and were able to achieve target levels, CR was seen in 16 (84%) children, 2 (10.5%) attained PR and 1 was nonresponsive. The mean time to achieve remission was 63.2 +/- 44 days and the mean dose of TAC was 0.18 +/- 0.07 mg/kg. The mean urine spot protein/creatinine ratios were significantly lower (0.33 +/- 0.58 vs. 13.5 +/- 21.9 mg/mg, p = 0.002) and the mean serum albumin levels were significantly higher (3.92 +/- 0.35 g/dl vs. 2.39 +/- 0.56 g/dl, p = 0.00005), as compared to those prior to starting TAC. The mean glomerular filtration rate values at the end of the study were similar to those prior to starting TAC (97.9 +/- 21.2 ml/min/1.73 m(2) vs. 96.4 +/- 18.4 ml/min/1.73 m(2), p = 0.30). The mean duration of follow-up was 290 +/- 126 days. This is the largest study so far on the safety and efficacy of TAC therapy in SRNS. Our results suggest that TAC is an effective therapeutic modality for SRNS, including the subgroup of children who are nonresponsive to the current therapeutic modalities like cyclophosphamide and cyclosporine.

The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review

To assess the clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome (SRNS). Electronic databases from inception to February 2006, bibliographies of studies, and experts in the field. Studies were selected, quality assessed and data were extracted using recognised methods agreed a priori. Meta-analysis was undertaken where appropriate using the random effects model. Where data allowed, subgroup analysis was undertaken according to renal histopathology. Two systematic reviews and 11 trials were included in the clinical effectiveness review; however, the quality of reporting and methodology of the included studies was generally poor. No economic evaluations were identified. No statistically significant difference in remission rates was found between cyclophosphamide plus prednisone and prednisone alone for all children or those with focal segmental glomerulosclerosis (FSGS), also the time to response was statistically significantly less with cyclophosphamide (38.4 days versus 95.5 days). Remission rates were not statistically significantly different between intravenous and oral cyclophosphamide. Vomiting was common with intravenous cyclophosphamide, while pneumonia and alopecia occurred in the oral group. Ciclosporin statistically significantly increased the number of children with complete remission compared with placebo or supportive treatment, but not for the FSGS subgroup, adverse effects including infection and hypertension differed little between groups. No differences were found between azathioprine and placebo, with about 13% of each group having remission. Complete or partial remission occurred in six out of seven patients on the 18-month methylprednisolone regimen and three out of five patients on the 6-month regimen, for both groups renal function improved and adverse events such as hypertension and frequent infections occurred. Intravenous dexamethasone and methylprednisolone produced similar complete remission rates, partial remission rates, median time to response (about 10 days) and total number of adverse events, with hypertension as the most common. Six-hour urinary albumin and urinary albumin to creatinine ratio decreased statistically significantly with high-dose but not low-dose enalapril. Tuna fish oil was not associated with any statistically significant improvements in proteinuria, creatinine clearance, serum creatinine or lipid profiles compared with placebo. A very limited literature was found on costs associated with SRNS in children. The pharmaceutical cost of treatment varied considerably: an 8-week course of cyclophosphamide cost less than 6 pounds, while a course of ciclosporin cost almost 900 pounds per year. Treatment with tacrolimus, an alternative to ciclosporin, was estimated to cost in excess of 3400 pounds per year. Healthcare medical management costs were estimated; varying by treatment strategy, they ranged from 250 pounds to 930 pounds per year in patients not experiencing complications. Other longer term costs may also be incurred. Lack of data meant that cost-effectiveness modelling was not feasible. The clinical effectiveness literature on treatments for idiopathic SRNS in children is very limited. The available evidence suggests a beneficial effect of ciclosporin on remission rates and of cyclophosphamide on time to remission; however, the strength of the conclusions drawn is limited by the poor quality of the included studies. The other treatments included in this review were each evaluated by only one study, and none found a statistically significant effect. There is insufficient evidence to determine whether or not there is a clinically significant difference. The available data on costs and outcomes are sparse and do not permit the reliable modelling of the cost-effectiveness of treatments for SRNS at present. A modelling framework is suggested, should more relevant data become available. A well-designed adequately powered randomised controlled trial comparing ciclosporin with other treatments in children with SRNS without genetic mutation is required.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

The majority of children, who present with their first episode of nephrotic syndrome, achieve remission with corticosteroid therapy. Children who fail to respond to corticosteroids may be treated with immunosuppressive agents such as cyclophosphamide, chlorambucil or cyclosporin or with non-immunosuppressive agents such as ACE inhibitors. Optimal combinations of these agents with least toxicity remain to be determined. The aims of this systematic review are to assess the benefits and harms of interventions used to treat idiopathic steroid resistant nephrotic syndrome (SRNS) in children. We aimed to evaluate the benefits and harms of all interventions for children with SRNS. Published and unpublished randomised controlled trials (RCTs) were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of articles and abstracts from conference proceedings. RCTs and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged 3 months to 18 years with SRNS. Two reviewers independently searched the literature, determined trial eligibility, assessed quality, extracted data and entered it in RevMan. For dichotomous outcomes, results were expressed as relative risk (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model. Nine RCTs involving 225 children were included. Cyclosporin when compared with placebo or no treatment significantly increased the number of children who achieved complete remission (three trials, 49 children: RR for persistent nephrotic syndrome 0.64, 95% CI, 0.47 to 0.88). There was no significant difference in the number of children who achieved complete remission between oral cyclophosphamide with prednisone and prednisone alone (two trials, 91 children: RR 1.01, 95% CI 0.74 to 1.36), between intravenous cyclophosphamide and oral cyclophosphamide (one study, 11 children: RR 0.09, 95% CI 0.01 to 1.39) and between azathioprine with prednisone and prednisone alone (one trial 31 children: RR 1.01, 95% CI 0.77 to 1.32). No RCTs were identified comparing combination regimens comprising high dose steroids, alkylating agents or cyclosporin with single agents, placebo or no treatment. Further adequately powered and well designed RCTs are needed to confirm the efficacy of cyclosporin and to evaluate other regimens for idiopathic SRNS including high dose steroids with alkylating agents or cyclosporin.

Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.

Nephrotic syndrome and mizoribine in children.

The treatment of nephrotic syndrome (NS) has recently made dramatic progress. The ultimate purpose of treatment is that patients can lead a normal, disease-free life with no adverse effects from treatment. However, clear treatment guidelines remain to be established in the children with frequent relapsing NS (FRNS) and steroid-resistant NS (SRNS). The frequent use or large dose of steroids may lead to a serious adverse effect. Immunosuppressive drugs including cyclophosphamide and cyclosporin have been used to induce lasting remission, thereby sparing patients from further exposure to steroids. However, these drugs have both acute and chronic side-effects. Mizoribine is a relatively safe and effective immunosuppressant. The report discusses the role of mizoribine in FRNS and SRNS in children. The papers in experimental and clinical studies about mizoribine in NS were reviewed. Our experiences of mizoribine were also added. Mizoribine has been reported as an effective and safe drug for patients with FRNS. However, the efficacy of mizoribine has differed among various reports, depending on the dose given. There have yet to be any conclusive reports on the effects of mizoribine in SRNS in children. Better results might be obtained if the doses of mizoribine increased in children with FRNS. When 5 mg/kg was used, no serious adverse effects were seen, therefore this dose may be safe and effective. An investigation of appropriate, effective and safe doses of mizoribine should be examined in the future. In patients with SRNS, large doses of mizoribine of more than 5 mg/kg might be effective, while the combined use of mizoribine and cyclosporin or methylprednisolone pulse therapy might also be even more effective. Further studies are called for to examine the use of large doses of mizoribine.

Sodium dodecyl sulphate polyacrylamide gel electrophoresis of urinary proteins in steroid-responsive and steroid-resistant nephrotic syndrome in children.

Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS PAGE) of urinary proteins was performed in 56 children with nephrotic syndrome during relapse, of whom 31 had their urines tested within 2 months of the onset of disease. The urines of all 32 steroid-sensitive [presumed minimal change nephrotic syndrome (MCNS)] patients revealed albumin and transferrin bands only; whereas 19 steroid-resistant children with focal glomerular sclerosis showed additional excretion of IgG and low molecular weight proteins (lysozyme, beta 2-microglobulin). This mixed pattern of proteinuria was also detected in 5 other steroid-resistant patients, 3 of whom were Africans with MCNS on biopsy and 2 who were Indians and not biopsied. Findings in patients studied within 2 months of presentation were identical to those investigated later in the course of the disease. SDS PAGE analysis of urine, which appears to distinguish steroid-responsive from steroid-resistant patients may provide a valuable adjunct to the management of childhood nephrotic syndrome.

Ultrastructural studies in the nephrotic syndrome of childhood.

The ultrastructural abnormalities of the kidney were studied in 14 cases of steroid-resistant nephrotic syndrome in children. It is emphasized that none of the individual glomerular alterations is distinctive of any typical process. When, however, considered in their entire pattern, they permit to distinguish two well-defined types. The cases revealing alterations of the epithelium and of the basement membrane correspond clinically to the nephrotic syndrome and histologically to membranous glomerulonephritis. In contradistinction to this type, the group where the mesangium and the endothelial cells are prevalently affected may be associated with the clinical syndrome of nephrosis or nephritis and with the histological features of membranous or membranoproliferative glomerulonephritis. The membrano-epithelial type responds favourably to immunosuppressive treatment, in contrast to the mesangio-endothelial type which is generally unresponsive.