Explore the vast range of titles available.

X-linked Alport syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain (α5(IV)). Complete absence of α5(IV) in the renal basal membrane is considered a pathological characteristic in male patients; however, positive α5(IV) staining has been found in over 20% of patients. We retrospectively studied 52 genetically diagnosed male X-linked Alport syndrome patients to evaluate differences in clinical characteristics and renal outcomes between 15 α5(IV)-positive and 37 α5(IV)-negative patients. Thirteen patients in the α5(IV)-positive group had non-truncating mutations consisting of nine missense mutations, three in-frame deletions, and one splice-site mutation resulting in small in-frame deletions of transcripts. The remaining two showed somatic mutations with mosaicism. Missense mutations in the α5(IV)-positive group were more likely to be located before exon 25 compared with missense mutations in the α5(IV)-negative group. Furthermore, urinary protein levels were significantly lower and the age at onset of end-stage renal disease was significantly higher in the positive group than in the negative group. These results help to clarify the milder clinical manifestations and molecular characteristics of male X-linked Alport syndrome patients expressing the α5(IV) chain.

Background In 2009, the Oxford classification of IgA nephropathy was published. However, its validity has not been fully examined in children. This study aimed to assess this system in an independent large-scale cohort of children. Methods We analyzed 161 consecutive children with newly diagnosed IgA nephropathy from 1977 to 1989 retrospectively. We examined the ability of each variable in the Oxford classification as a predictor of renal outcome defined as ≥ stage III chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 ) using Cox regression analysis. Results The mean mesangial score, and ratios of segmental glomerulosclerosis, endocapillary hypercellularity, tubular atrophy, and crescents were 0.49, 0.8%, 13.1%, 3.3%, and 9.2% respectively. Seven cases reached ≥ stage III CKD. In univariate analyses, mesangial hypercellularity score, endocapillary hypercellularity, tubular atrophy, and crescents were significant predictors of renal outcome. In a multivariate analysis, only mesangial hypercellularity score, tubular atrophy, and crescents were significant though, depending on models. Segmental glomerulosclerosis was not a significant predictor of renal outcome. Although the significance of crescents was not addressed in the Oxford classification, crescents were important predictors of outcome. Conclusions The Oxford classification appears to be valid for predicting renal outcome in children.

Background Autosomal recessive Alport syndrome (ARAS) is a rare hereditary disease caused by homozygous or compound heterozygous mutations in either the COL4A3 or COL4A4 genes. Failure to diagnose ARAS cases is common, even if detailed clinical and pathological examinations are carried out. As the mutation detection rate for ARAS is unsatisfactory, we sought to develop more reliable diagnostic methods and provide a better description of the clinicopathological characteristics of this disorder. Methods A retrospective analysis of 30 genetically diagnosed patients with ARAS in 24 pedigrees was conducted. The mutation detection strategy comprised three steps: (1) genomic DNA analysis using polymerase chain reaction (PCR) and direct sequencing; (2) mRNA analysis using reverse transcription (RT)-PCR to detect RNA processing abnormalities; (3) semi-quantitative PCR using capillary electrophoresis to detect large heterozygous deletions. Results Using the three-step analysis, we identified homozygous or compound heterozygous mutations in all patients. Interestingly, 20 % of our ARAS patients showed normal expression of α5 in kidney tissue. The median age of developing end-stage renal disease was 21 years. Conclusions The strategy described in this study improves the diagnosis for ARAS families. Although immunohistochemical analysis of α5 can provide diagnostic information, normal distribution does not exclude the diagnosis of ARAS.

The management of Henoch-Schönlein purpura nephritis (HSPN) is controversial. It has been revealed that some patients develop end-stage renal disease and aggressive treatment with drugs such as steroids is increasing, and some of them may be overzealous. At our institutes, our treatment decisions are based on the clinical and pathological severity of the case in an attempt to limit the indications for aggressive therapies such as steroids and immunosuppressive agents. Here, we retrospectively examined the efficacy of treatment for HSPN. Renal biopsy was performed in patients with nephrotic syndrome or persistent proteinuria for more than 3 months and patients were classified by treatment. Patients ( n  = 31) with moderately severe HSPN (histological grade I–III and serum albumin [Alb] >2.5 g/dl) were treated with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. Patients ( n  = 19) with HSPN exceeding grade III or Alb ≤ 2.5 g/dl received combination therapy comprising prednisolone, immunosuppressants, warfarin, and dipyridamole. All patients showed resolution of proteinuria without renal dysfunction during the observation period (3.76 ± 0.37 years). Our findings support those of some earlier reports that treatment strategies for HSPN should depend on the histological and clinical severity. Furthermore, aggressive therapies, particularly combination therapies, are unnecessary for moderate–severe HSPN.

Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25–0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. Japan Agency for Medical Research and Development (grant CCT-B-2503).

Post-operative hyponatremia is a common complication in children which results from hypotonic fluid administration in the presence of arginine vasopressin (AVP) excess. We evaluated the relationship between the change in serum sodium and AVP levels following percutaneous renal biopsy in children receiving either hypotonic or isotonic fluids. This study was prompted after we encountered a patient who developed near-fatal hyponatremic encephalopathy following a renal biopsy while receiving hypotonic fluids. The relationship between the change in serum sodium and AVP levels was evaluated prior to (T0) and at 5 h (T5) following a percutaneous renal biopsy in 60 children receiving either hypotonic (0.6% NaCl, 90 mEq/L) or isotonic fluids (0.9% NaCl, 154 mEq/L). The proportion of patients with elevated AVP levels post-procedure was similar between those receiving 0.6 or 0.9% NaCl (30 vs. 26%). Patients receiving 0.6% NaCl with elevated AVP levels experienced a fall in serum sodium of 1.9 ± 1.5 mEq/L, whereas those receiving 0.9% NaCl had a rise in serum sodium of 0.85 ± 0.34 mEq/L with no patients developing hyponatremia. There were no significant changes in serum sodium levels in patients with normal AVP concentrations post-procedure in either group. In conclusion, elevated AVP levels were common among our patients following a percutaneous renal biopsy. Isotonic fluids prevented a fall in serum sodium and hyponatremia, while hypotonic fluids did not.

Autosomal dominant pseudohypoaldosteronism type 1 (PHA1) is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (MR), but it is a matter of debate whether MR mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD) and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations. We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products. mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.

Alport syndrome is the most common form of hereditary nephritis, and the majority of cases are caused by mutations in the COL4A5 gene. However, direct sequencing by polymerase chain reaction (PCR), from genomic DNA, or reverse transcriptase-polymerase chain reaction (RT-PCR), from mRNA, or polymerase chain reaction–single-strand conformation polymorphism (PCR-SSCP) has reportedly resulted in detection rates of 31% to 84%, but of only 20% to 71% when restricted to female patients. This report concerns two female patients with X-linked Alport syndrome. Although mutational analysis of the COL4A5 gene was conducted with direct sequencing using genomic DNA and mRNA extracted from leukocytes, the results were negative for detection of mutations. Semi-quantitative PCR using genomic DNA was therefore conducted to detect large heterozygous deletions. The results were that the first patient showed complete loss of the COL4A5 gene and the second patient showed deletion from exons 37 to 51. Our patients possessed large heterozygous deletions in the COL4A5 gene that could not be detected with the standard direct sequencing method and were identified with semi-quantitative PCR. Previously reported mutation detection rates for female patients have been lower than overall rates. Our findings indicate that this difference may, in part, be due to failure to detect this type of mutation with conventional analytical methods.

Several studies have suggested that T cell-producing permeability factors might lead to proteinuria in minimal change nephrotic syndrome (MCNS). However, it is still unclear whether T-cell abnormalities cause MCNS. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulation system, which leads to severe autoimmune phenomena including autoimmune enteropathy, atopic dermatitis with high levels of serum immunoglobulin E (IgE), type 1 diabetes mellitus (T1DM), and severe infection such as sepsis, which frequently result in death within the first 2 years of life. This disease is caused by mutations in the FOXP3 gene that result in the defective development of regulatory T (Treg) cells. This report describes a 5-year-old boy with IPEX syndrome with a 3 bp deletion in the FOXP3 gene (c.748–750delAAG, p.250K.del) and a paucity of CD4 + CD25 + FOXP3 + T cells. The boy’s condition was complicated by MCNS in addition to many IPEX-related manifestations, such as atopic dermatitis, T1DM, enteropathy, sepsis and hemolytic anemia. This is the first report of IPEX syndrome complicated by MCNS, and our findings imply that Treg cell dysfunction may be crucial for the development of MCNS.

Type I Bartter syndrome (BS), an inherited salt-losing tubulopathy, is caused by mutations of the SLC12A1 gene. While several intronic nucleotide changes in this gene have been detected, transcriptional analysis had not been conducted because mRNA analysis is possible only when renal biopsy specimens can be obtained or occasionally when mRNA is expressed in the leukocytes. This report concerns a type I BS patient due to compound heterozygosity for the SLC12A1 gene. Genomic DNA sequencing disclosed the presence of two novel heterozygous mutations of c.724 + 4A > G in intron 5 and c.2095delG in intron 16, but it remains to be determined whether the former would be likely to influence the transcription. In this report, we conducted both in vivo assay of RT-PCR analysis using RNA extracted from the proband's urinary sediments and in vitro functional splicing study by minigene construction, and obtained evidence that this intronic mutation leads to complete exon 5 skipping. To the best of our knowledge, this is the first study to use non-invasive methods for both an in vivo assay and an in vitro functional splicing assay of inherited kidney disease. These analytical assays could be adapted for all inherited kidney diseases.