Forms Of Idiopathic Nephrotic Syndrome Research Articles

A novel flow cytometry panel to identify prognostic markers for steroid-sensitive forms of idiopathic nephrotic syndrome in childhood.

The clinical evolution of steroid-sensitive forms of pediatric idiopathic nephrotic syndrome (INS) is highly heterogeneous following the standard treatment with prednisone. To date, no prognostic marker has been identified to predict the severity of the disease course starting from the first episode. In this monocentric prospective cohort study we set up a reproducible and standardized flow cytometry panel using two sample tubes (one for B-cell and one for T-cell subsets) to extensively characterized the lymphocyte repertoire of INS pediatric patients. A total of 44 children with INS at disease onset were enrolled, sampled before and 3 months after standard induction therapy with prednisone and followed for 12 months to correctly classify their disease based on relapses. Age-matched controls with non immune-mediated renal diseases or with urological disorders were also enrolled. Demographical, clinical, laboratory and immunosuppressive treatment data were registered. We found that children with INS at disease onset had significantly higher circulating levels of total CD19+ and specific B-cell subsets (transitional, mature-naïve, plasmablasts/plasmacells, CD19+CD27+, unswitched, switched and atypical memory B cells) and reduced circulating levels of Tregs, when compared to age-matched controls. Prednisone therapy restored most B- and T-cell alterations. When patients were subdivided based on disease relapse, relapsing patients had significantly more transitional, CD19+CD27+ memory and in particular unswitched memory B cells at disease onset, which were predictive of a higher risk of relapse in steroid-sensitive patients by logistic regression analysis, irrespective of age. In accordance, B-cell dysregulations resulted mainly associated with steroid-dependence when patients were stratified in different disease severity forms. Of note, Treg levels were reduced independently from the disease subgroup and were not completely normalized by prednisone treatment. We have set up a novel, reproducible, disease-specific flow cytometry panel that allows a comprehensive characterization of circulating lymphocytes. We found that, at disease onset, relapsing patients had significantly more transitional, CD19+CD27+ memory and unswitched memory B cells and those who are at higher risk of relapse had increased circulating levels of unswitched memory B cells, independently of age. This approach can allow prediction of clinical evolution, monitoring of immunosuppression and tailored treatment in different forms of INS.

Proteomics of Plasma and Plasma-Treated Podocytes: Application to Focal and Segmental Glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a severe form of idiopathic nephrotic syndrome (INS), a glomerulopathy of presumably immune origin that is attributed to extrarenal pathogenic circulating factors. The recurrence of FSGS (rFSGS) after transplant occurs in 30% to 50% of cases. The direct analysis of patient plasma proteome has scarcely been addressed to date, mainly due to the methodological difficulties associated with plasma complexity and dynamic range. In this study, first, we compared different methods of plasma preparation, second, we compared the plasma proteomes of rFSGS and controls using two preparation methods, and third, we analyzed the early proximal signaling events in podocytes subjected to patient plasma, through a combination of phosphoproteomics and lipid-raft proteomics (raftomics). By combining immunodepletion and high pH fractionation, we performed a differential proteomic analysis of soluble plasma proteins and of extracellular vesicles (EV) obtained from healthy controls, non-INS patient controls, and rFSGS patients (n = 4). In both the soluble- and the EV-protein sets from the rFSGS patients, we found a statistically significant increase in a cluster of proteins involved in neutrophil degranulation. A group of lipid-binding proteins, generally associated with lipoproteins, was found to be decreased in the soluble set from the rFSGS patients. In addition, three amino acid transporters involved in mTORC1 activation were found to be significantly increased in the EV from the rFSGS. Next, we incubated human podocytes for 30 min with 10% plasma from both groups of patients. The phosphoproteomics and raftomics of the podocytes revealed profound differences in the proteins involved in the mTOR pathway, in autophagy, and in cytoskeleton organization. We analyzed the correlation between the abundance of plasma and plasma-regulated podocyte proteins. The observed changes highlight some of the mechanisms involved in FSGS recurrence and could be used as specific early markers of circulating-factor activity in podocytes.

Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD.NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.

Infrequent tacrolimus-induced nephrotoxicity in French patients with steroid-dependent nephrotic syndrome.

Chronic nephrotoxicity with potentially irreversible lesions is a major concern regarding calcineurin inhibitor (CNI) treatment in children with severe forms of idiopathic nephrotic syndrome (INS). We retrospectively included all children on CNI for steroid-dependent INS with a duration of CNI treatment of more than 1year. Only patients in whom CNI could not be replaced by mycophenolate mofetil were included. All included patients underwent a kidney biopsy. All results were expressed as median and range. Twenty-one children (6 girls) were included. Age at disease onset was 49 (29-66) months and treatment duration on CNI was 30 (20-45) months. Age at kidney biopsy was 108 (78-170) months. Number of relapses was 7 (3-9) since disease onset. Serum creatinine level was transiently and moderately increased in two patients. Kidney biopsy revealed minimal change disease in 20/21 patients and focal segmental glomerulosclerosis in 1/21. Evidence for chronic CNI nephrotoxicity was found in one patient revealed by arteriolar hyalinosis and fibrosis in 50% of glomeruli. CNI-induced chronic nephrotoxicity was infrequent. In patients who require long-term and/or high-dose CNI treatment, kidney biopsies might be useful to exclude chronic CNI-induced lesions.

Quality of life in children with severe forms of idiopathic nephrotic syndrome in stable remission-A cross-sectional study.

Severe forms of idiopathic nephrotic syndrome (INS) require immunosuppressive therapy: oral treatment or intravenous therapy (rituximab, RTX). The main objective was to describe quality of life (QOL) in these specific patients. Cross-sectional, multicentre, observational study analysed QOL using a standardised questionnaire in children from 7 to 17years, with a steroid-dependent or steroid-resistant INS in stable remission. The questionnaire consisted of 30 questions concerning physical and emotional well-being, self-esteem, family, friends, school and disease resulting in a global score of 0-100. A total of 110 patients with a mean age of 11.6years from three French paediatric nephrology centres were included. A total of 71 patients had oral immunosuppressive treatment, 27 had RTX, and 12 had both. 13.6% of patients had a steroid-resistant INS. The mean number of relapses was 5.8. Seventy-eight patients answered the questionnaire. The global score in the whole study population was 74.7; 72.6 in the RTX group, 76.2 in the oral drugs group, (P=0.49). The results of sub-dimension 'school' were statistically lower in RTX group (61.6±19.5) compared with oral drugs group (71.4±16; P=0.02). Global QOL score was high in 'difficult-to-treat' patients with INS in stable remission on oral immunosuppressive or RTX treatment.

Idiopathic Nephrotic Syndrome: Characteristics and Identification of Prognostic Factors.

There are various histopathological forms of idiopathic nephrotic syndrome, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Whereas some relapse predictor factors have been identified in renal transplantation, the clinical future of idiopathic nephrotic syndrome in the native kidney remains uncertain. We designed a multicentric retrospective descriptive cohort study including all patients aged 15 years and over whose renal biopsy confirmed MCD or FSGS between January 2007 and December 2014. We studied 165 patients with idiopathic nephrotic syndrome; 97 with MCD and 68 with FSGS. In the MCD cohort, 91.7% of patients were treated with corticosteroids for a median total duration of 13 months. During 45 months of follow-up, 92.8% of patients achieved remission and 45.5% experienced relapse. In this cohort, 5% of patients experienced terminal kidney disease. With respect to FSGS patients, 51.5% were treated with corticosteroids for a median total duration of 15 months. During 66 months of follow-up, 73.5% of patients achieved remission and 20% experienced relapse. In this cohort, 26.5% of patients experienced terminal kidney disease. No statistical association was observed between clinical and biological initial presentation and relapse occurrence. This study describes the characteristics of a cohort of patients with the nephrotic idiopathic syndromes of MCD and FSGS from the time of renal biopsy and throughout follow-up.

CD80 and CTLA-4 as diagnostic and prognostic markers in adult-onset minimal change disease: a retrospective study.

BackgroundMinimal change disease (MCD) is a form of idiopathic nephrotic syndrome. Compared to children, adult-onset MCD patients are reported to have delayed responses to glucocorticoid treatment. Several studies of children have suggested detecting urinary CD80 levels to diagnose MCD. There are no effective diagnostic methods to distinguish steroid-sensitive MCD from steroid-resistant MCD unless treatments are used.MethodsIn a total of 55 patients with biopsy-proven MCD and 26 patients with biopsy-proven idiopathic membranous nephropathy, CD80 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) levels in serum, urine and renal tissue were analyzed.ResultsSteroid-sensitive MCD patients in remission had lower urinary CD80 levels and higher CTLA-4 levels than patients in relapse (156.65 ± 24.62 vs 1066.40 ± 176.76 ng/g creatinine; p < 0.0001), (728.73 ± 89.93 vs 151.70 ± 27.01 ng/g creatinine; p < 0.0001). For MCD patients in relapse, mean urinary CD80 level was higher, and CTLA-4 level was lower for those who were steroid-sensitive than those who were steroid-resistant (1066.40 ± 176.76 vs. 203.78 ± 30.65 ng/g creatinine; p < 0.0001), but the mean urinary CTLA-4 level was lower (151.70 ± 27.01 vs. 457.83 ± 99.45 ng/g creatinine; p < 0.0001). CD80 expression in glomeruli was a sensitive marker to diagnose MCD. The absent or minimal expression of CTLA-4 in glomeruli could distinguish steroid-sensitive MCD from steroid-resistant MCD.ConclusionsGlucocorticoid treatment may result in complete remission for only MCD patients with strongly positive CD80 expression and negative CTLA-4 expression in glomeruli, or higher urinary CD80 level and lower CTLA-4 level.

Changes in Steroid Response pattern in Childhood Idiopathic Nephrotic Syndrome in Sohag

Background and aim of work: Nephrotic syndrome (NS) is a common chronic kidney disease in childhood and it is mostly idiopathic. Steroid response pattern remains the most important issue in prognosis of NS. Increase in steroid resistant nephrotic syndrome (SRNS) frequency over years was documented in some studies. This work aimed to demonstrate the change in steroid response pattern of idiopathic nephrotic syndrome (INS) over years in our locality at Sohag in Upper Egypt. Patients and Methods: Combined retrospective and prospective studies were done; including 280 children with INS, aged from 1 to 15 years, diagnosed and followed in our pediatric renal unit in Sohag University Hospital, Egypt in the period from January 2000 to December 2014. The patients' demographic features, steroid response pattern in both groups were studied. Results: A total of 280 patients (203 in the retrospective group and 77 in the prospective group) with INS were included with mean age at disease onset 4.60±2.58 (range 1-15) years and male/female ratio 1.8/1. Mean follow up duration was 4.44±3.24 (range 1-15) years. Steroid was given to all patients. 94.1% and 79.2% of patients in the retrospective and the prospective groups respectively were steroid sensitive, and the rest of patients were steroid resistant. Renal biopsy was done in 36 and 26 patients in the retrospective and prospective studies respectively. Biopsy results revealed minimal change disease (MCD) in 55.6% and 38.5%, focal segmental glomerulosclerosis (FSGS) in 22.2% and 42.3%, mesangioproliferative glomerulonephritis (MesPGN) in 22.2% and 19.2% of biopsied patients in the retrospective and prospective groups respectively. End stage renal disease (ESRD) was developed in 4 patients all of them were steroid and other immunosuppressive therapies resistant and with FSGS histopathology. Death occurred in 5 patients. Conclusion: Steroid sensitive NS is the most common form of INS in children but there is increase in the frequency of SRNS over years in our locality.

Pathogenesis of minimal change nephrotic syndrome: an immunological concept.

Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia. Minimal change nephrotic syndrome (MCNS) is the most common form of INS in children. The pathogenesis of MCNS still remains unclear, however, several hypotheses have been recently proposed. For several decades, MCNS has been considered a T-cell disorder, which causes the impairment of the glomerular filtration barrier with the release of different circulating factors. Increased levels of several cytokines are also suggested. Recently, a "two-hit" theory was proposed that included the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory functions of the podocyte. In contrast to the well-established involvement of T cells, the role of B cells has not been clearly identified. However, B-cell biology has recently gained more attention, because rituximab (a monoclonal antibody directed against CD20-bearing cells) demonstrated a very good therapeutic response in the treatment of childhood and adult MCNS. Here, we discuss recent insights into the pathogenesis of MCNS in children.

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.

Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor–dependent idiopathic nephrotic syndrome

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice

Oxidative stress, inflammation, and fibrosis are involved in the development and progression of focal segmental glomerulosclerosis (FSGS), a common form of idiopathic nephrotic syndrome that represents a therapeutic challenge because it has a poor response to steroids. Antroquinonol (Antroq), a purified compound, is a major active component of a mushroom, namely Antrodia camphorata, that grows in the camphor tree in Taiwan, and it has inhibitory effects on nitric oxide production and inflammatory reactions. We hypothesized that Antroq might ameliorate FSGS renal lesions by modulating the pathogenic pathways of oxidative stress, inflammation, and glomerular sclerosis in the kidney. We demonstrate that Antroq significantly (1) attenuates proteinuria, renal dysfunction, and glomerulopathy, including epithelial hyperplasia lesions and podocyte injury; (2) reduces oxidative stress, leukocyte infiltration, and expression of fibrosis-related proteins in the kidney; (3) increases renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; and (4) inhibits renal nuclear factor-κB (NF-κB) activation and decreases levels of transforming growth factor (TGF)-β1 in serum and kidney tissue in a mouse FSGS model. Our data suggest that Antroq might be a potential therapeutic agent for FSGS, acting by boosting Nrf2 activation and suppressing NF-κB-dependent inflammatory and TGF-β1-mediated fibrosis pathways in the kidney.

A Molecular Profile of Focal Segmental Glomerulosclerosis from Formalin-Fixed, Paraffin-Embedded Tissue

Focal segmental glomerulosclerosis (FSGS) is a common form of idiopathic nephrotic syndrome defined by the characteristic lesions of focal glomerular sclerosis and foot process effacement; however, its etiology and pathogenesis are unknown. We used mRNA isolated from laser-captured glomeruli from archived formalin-fixed, paraffin-embedded renal biopsies, until recently considered an unsuitable source of mRNA for microarray analysis, to investigate the glomerular gene expression profiles of patients with primary classic FSGS, collapsing FSGS (COLL), minimal change disease (MCD), and normal controls (Normal). Amplified mRNA was hybridized to an Affymetrix Human X3P array. Unsupervised (unbiased) hierarchical clustering revealed two distinct clusters delineating FSGS and COLL from Normal and MCD. Class comparison analysis of FSGS + COLL combined versus Normal + MCD revealed 316 significantly differentially regulated genes (134 up-regulated, 182 down-regulated). Among the differentially regulated genes were those known to be part of the slit diaphragm junctional complex and those previously described in the dysregulated podocyte phenotype. Analysis based on Gene Ontology categories revealed overrepresented biological processes of development, differentiation and morphogenesis, cell motility and migration, cytoskeleton organization, and signal transduction. Transcription factors associated with developmental processes were heavily overrepresented, indicating the importance of reactivation of developmental programs in the pathogenesis of FSGS. Our findings reveal novel insights into the molecular pathogenesis of glomerular injury and structural degeneration in FSGS.

How should microemulsified Cyclosporine A (Neoral®) therapy in patients with nephrotic syndrome be monitored?

Cyclosporine A (CyA) has been used empirically for almost two decades in the treatment of severe forms of idiopathic nephrotic syndrome (NS), in both children and adults [1]. The mechanism of CyA’s action remains unclear. It may be related to immunosuppressive or haemodynamic properties, or have an effect on heparan sulfate, the main component of the glomerular charge barrier [2]. Initially, the therapy was performed with ‘classic’ Cyclosporine (Sandimmune ). Because of substantial interand intra-patient variability and a narrow therapeutic window, therapeutic drug monitoring of Cyclosporine therapy is mandatory [3,4]. With ‘classic’ CyA, trough level monitoring was recommended. In the mid-1990s a microemulsified (ME) formulation of Cyclosporine (Neoral ) became available and many patients were converted because of more predictable pharmacokinetics—not always without problems [5]. Similar to renal transplant patients, patients with NS were often converted from the classic Cyclosporine to the microemulsified formulation (CyA ME). There is growing evidence that CyA ME should be monitored using the 2 h post-intake concentration (C2) rather than the preor post-dose trough level. This has been studied extensively in patients receiving a solid organ transplant, both in adults [6] and in children [7]. Targeting of C2 concentration as part of a post-transplantation treatment strategy is leading to excellent outcomes in adult transplantation with the ME Cyclosporine [8]. As CyA ME is used increasingly in patients with NS, the question arises whether C2 monitoring is also beneficial in patients with NS. However, even recent studies have not addressed this question in detail [9].

Genetics of the nephrotic syndrome.

There are a large number of glomerular diseases that may be responsible for a nephrotic syndrome, the most frequent in childhood being minimal change disease. In the past few years, the molecular genetic basis of several conditions that may cause a nephrotic syndrome have been identified. Denys-Drash syndrome and Frasier syndrome are related diseases caused by mutations in the WT1 gene. Familial forms of idiopathic nephrotic syndrome with focal and segmental glomerular sclerosis/hyalinosis have been identified with an autosomal dominant or recessive mode of inheritance and linkage analysis have allowed to localize several genes on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital nephrotic syndrome has been identified. This gene, named NPHS1, codes for nephrin, which is located at the slit diaphragm of the glomerular podocytes and is thought to play an essential role in the normal glomerular filtration barrier.

Cyclosporine treatment of glomerular diseases.

Cyclosporine-A is primary therapy for organ transplantation. Its immunosuppressive effect might suggest a therapeutic role in autoimmune diseases, including several idiopathic and secondary glomerular conditions. Various forms of idiopathic nephrotic syndrome, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy (MN), may respond well to cyclosporine in selected patients. However, frequent relapse limits its use to those who have failed to respond to, or were intolerant of, steroids or cytotoxics. Cyclosporine's efficacy in other glomerulopathies, such as IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) remains poorly studied and, given the risk of nephrotoxicity, cannot be recommended for treatment of these entities until further data are available. Cyclosporine demonstrates some efficacy in treating proliferative lupus nephritis and, based on pilot study data, membranous lupus as well. Again, given relapse rates and potential nephrotoxicity, it should be used only in combination with azathioprine and steroids, assuming cytotoxic therapy has failed. Finally, cyclosporine toxicity is briefly reviewed.

New insight into the pathogenesis of the ‘idiopathic nephrotic syndrome’

The incidence of idiopathic nephrotic syndrome (INS) is estimated to be 20-30 cases per million children and three cases per million adults per year. Different histological patterns are associated with the disease such asminimal-change glomerulonephritis (MCGN) and focal segmental glomerulosclerosis (FSGS), which can both be associated with various degrees of mesangial cell proliferation. Whether these two pathological forms of INS are two extremes of a single disease with different evolutions or represent two unique diseases remains a point of discussion. MCGN is a more benign glomerulonephritis which is largely sensitive to glucocorticoids and/or to other immunosuppressive drugs (cyclophosphamide, cyclosporin A), while FSGS is poorly responsive to these drugs and usually progresses to end-stage renal failure. Nevertheless, the prognosis associated with FSGS can be influenced by more aggressive and/or prolonged treatments [1]. In addition, the histologically apparent recurrence of FSGS after kidney transplantation demonstrates that early MCGN can result in FSGS within a few weeks or months [2].

Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis.

Idiopathic nephrotic syndrome (INS) in childhood is characterized by massive proteinuria and minimal glomerular changes. Most patients with INS respond to steroid therapy. INS is generally regarded as a sporadic disease with favorable outcome. We investigated a distinct subgroup of nephrosis--the familial form of steroid resistant INS (SRN). These patients always progress to end-stage renal failure within a few years and show absence of recurrence of the disease after renal transplantation. The occurrence of the disorder in siblings and the high incidence of inbreeding in these families made an autosomal recessive mode of inheritance very likely. We performed whole genome linkage analysis in nine multiplex families of European or Northern African origin. Our results allowed us to assign a disease locus (SRN1) to a defined chromosomal region on 1q25-1q31, thus confirming the existence of a distinct entity of autosomal recessive nephrosis. Exclusion of linkage to the entire region in one family proves genetic heterogeneity.

Relapsing nephrotic syndrome

Relapsing nephrotic syndrome is the most frequent form of idiopathic nephrotic syndrome in children. Children with relapsing nephrotic syndrome respond to corticosteroids but relapse when corticosteroid dosage is decreased or soon after it is stopped. Idiopathic nephrotic syndrome is defined by the association of a nephrotic syndrome and minimal changes on renal biopsy with foot process fusion of epithelial cells on electron microscopy. No immunoglobulin or complement fraction deposits are seen on immunofluorescence examination.’ Patients with minimal change disease most often respond to corticosteroids. As renal biopsy is not usually performed when the patient responds to corticosteroids, minimal change disease (MCD) has become synonymous with steroid sensitive nephrotic syndrome. However, in some patients, histological examination shows diffuse mesa&al proliferation and/or focal and segmental glomerular sclerosis (FSGS). In addition, IgM deposits are frequently found. Several authors believe that MCD is a distinct disease and that diffuse mesangial proliferation, FSGS and IgM nephropathy are also distinct entities. There is no doubt that patients with diffuse mesangial proliferation or FSGS are more frequently resistant to corticosteroids and have a significant propensity for progression to renal failure. However, there is an overlap between these histological variants and a significant proportion of patients with FSGS respond to corticosteroids, whereas some patients with MCD are resistant to corticosteroids.’ Experience has shown that response to steroid therapy carries a greater prognostic weight than the histological features seen on the initial biopsy. Therefore, two types of nephrosis can be described