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To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P[4.94E-20, odds ratio (OR) [1.90)

Background Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. Methods We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. Results Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in 6 the patients with heterozygous variants compared to those in patients harboring the deletion (median: 37.6 vs 58.8 ml/min/1.73 m ; p = 0.0091). Conclusion We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

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Prostaglandin E2 (PGE2) is well-known as an endogenous pro-inflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2. Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2. However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor-mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2-activated EP2 receptor-mediated signaling after PGE2 is metabolized to 15-keto-PGE2. The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a “switched agonist.” This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation, and/or maintaining homeostasis of colorectal tissues/cells functions.

Objective Sclerosing encapsulating peritonitis (SEP) is a clinical syndrome with a high mortality rate and is a serious complication of peritoneal dialysis (PD). Peritoneal sclerosis (PS) is a histological diagnosis. PS is usually observed in the peritoneal specimens of patients with SEP. Avoiding SEP is considered to be extremely important for pediatric patients who may require long-term PD. In this study, the characteristics of patients with PS were investigated to determine when to perform peritoneal biopsies and how long PD can be performed safely. Design A retrospective single-center study. Setting Tokyo Metropolitan Kiyose Children's Hospital. Patients A total of 109 children younger than 16 years have received chronic PD in our unit since 1981. Among these children, 16 patients had been on PD for more than 5 years (mean 7.4 ± 2.5 years) from May 1992 to March 1999. Peritoneal biopsies were performed in 14 of the 16 patients, who were divided into two groups based on the histological diagnoses: a PS and a peritoneal fibrosis (PF) group. Results The 14 patients were on PD for a mean of 7.8 ± 2.5 years. There were 8 patients with PS and 6 patients with PF. SEP was observed in 2 patients in the PS group. The risk of PS increased with the duration of PD: 57% (8/14) > 5 years, 80% (4/5) > 8 years, and 100% (3/3) > 10 years. All patients in the PS group showed both peritoneal calcifications on abdominal CT scan and poor ultra-filtration at the time of diagnoses. Conclusion Long-term PD was the important risk factor of SEP. If both peritoneal calcification on abdominal CT scan and poor ultrafiltration are observed in a patient on PD more than 5 years, a peritoneal biopsy should be performed. If PS is detected, PD should be discontinued.

Background Information on the epidemiology of idiopathic nephrotic syndrome (INS) in children, complications of INS and the side effects of steroid therapy is scarce. Methods The Japanese Pediatric Survey Holding Information of Nephrotic Syndrome, a nationwide cohort study, was conducted by the Japanese Study Group of Renal Disease in Children and enrolled 2099 children with newly diagnosed INS between 1 January 2010 and 31 December 2012. We conducted a follow-up study of the complications during the first onset and the patients’ prognosis in this cohort. Results We obtained follow-up data on 999 children (672 males) with a median age at onset of 4.5 years [interquartile range (IQR) 2.8–9.4] and a median follow-up period of 4.1 years (IQR 2.5–5.1). At the first onset, 24% of patients experienced severe acute kidney injury (AKI), defined as a serum creatinine increase to a level two or more times the baseline. On logistic regression analysis, age, hematuria, severe hypoalbuminemia (serum albumin <1.0 g/dL) and severe bacterial infection were not independent factors, but female sex {hazard ratio [HR] 1.5 [95% confidence interval (CI) 1.1–1.7]} and hypertension [HR 4.0 (95% CI 2.6–6.0)] were significantly related to AKI. During the observation period, ocular hypertension requiring treatment occurred in 17.4% of patients, among which 0.4% received surgical treatment. Progression to frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome in 3 years was seen in 44.2% of the patients and was shown by the Cox regression analysis to be significantly related to younger age and days until remission at the first episode, but not to sex, hematuria, the minimum serum albumin level or AKI. Two patients died during the observation period. One patient showed progression to end-stage kidney disease. Conclusion Based on the results of a multicenter questionnaire survey, the overall survival and renal survival rates were found to be excellent. However, proper management of complications, particularly in AKI and ocular hypertension, is mandatory.