70 research outputs found

    Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment

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    Hemolytic uremic syndrome is defined by the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In children, most cases of HUS are caused by Shiga-toxin-producing bacteria, especially Escherichia coli O157:H7. Common vehicles of transmission include ground beef, unpasteurized milk, and municipal or swimming water. Shiga-toxin-associated HUS is a main cause of acute renal failure in young children. Management remains supportive as there is at present no specific therapy to ameliorate the prognosis. Immediate outcome is most often favourable but long-term renal sequelae are frequent due to nephron loss. Atypical HUS represents 5% of cases. In the past 15 years, mutations in complement regulators of the alternative pathway have been identified in almost 60% of cases, leading to excessive complement activation. The disease has a relapsing course and more than half of the patients either die or progress to end-stage renal failure. Recurrence after renal transplantation is frequent

    Pediatric Nephrology

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    NPHS2 mutation analysis shows genetic heterogeneityof steroid-resistant nephrotic syndrome and lowpost-transplant recurrence

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    NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.BackgroundMutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations.MethodsNPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS).ResultsTwenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases.ConclusionPatients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation

    Truncation of C-mip (Tc-mip), a New Proximal Signaling Protein, Induces c-maf Th2 Transcription Factor and Cytoskeleton Reorganization

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    Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH(2)-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4(+) T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon γ expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction

    A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome

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    Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues

    Nephronophthisis

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    Nephronophthisis (NPH) is an autosomal recessive disease characterized by a chronic tubulointerstitial nephritis that progress to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form). In the juvenile form, a urine concentration defect starts during the first decade, and a progressive deterioration of renal function is observed in the following years. Kidney size may be normal, but loss of corticomedullary differentiation is often observed, and cysts occur usually after patients have progressed to end-stage renal failure. Histologic lesions are characterized by tubular basement membrane anomalies, tubular atrophy, and interstitial fibrosis. The infantile form is characterized by cortical microcysts and progression to end-stage renal failure before 5 years of age. Some children present with extrarenal symptoms: retinitis pigmentosa (Senior-Løken syndrome), mental retardation, cerebellar ataxia, bone anomalies, or liver fibrosis. Positional cloning and candidate gene approaches led to the identification of eight causative genes (NPHP1, 3, 4, 5, 6, 7, 8, and 9) responsible for the juvenile NPH and one gene NPHP2 for the infantile form. NPH and associated disorders are considered as ciliopathies, as all NPHP gene products are expressed in the primary cilia, similarly to the polycystic kidney disease (PKD) proteins

    Competition and Access

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    Hemolytic uremic syndrome is defined by the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In children, most cases of HUS are caused by Shiga-toxin-producing bacteria, especially Escherichia coli O157:H7. Common vehicles of transmission include ground beef, unpasteurized milk, and municipal or swimming water. Shigatoxin-associated HUS is a main cause of acute renal failure in young children. Management remains supportive as there is at present no specific therapy to ameliorate the prognosis. Immediate outcome is most often favourable but long-term renal sequelae are frequent due to nephron loss. Atypical HUS represents 5% of cases. In the past 15 years, mutations in complement regulators of the alternative pathway have been identified in almost 60% of cases, leading to excessive complement activation. The disease has a relapsing course and more than half of the patients either die or progress to end-stage renal failure. Recurrence after renal transplantation is frequent
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