Gut Microbiota Dysbiosis in Children with Relapsing Idiopathic Nephrotic Syndrome.

BACKGROUND: While the etiology of idiopathic nephrotic syndrome (idiopathic nephrotic syndrome [INS]; characterized by repeated relapses and comorbid allergic conditions) remains unknown, recent evidence suggests that dysfunction in regulatory T cells (Tregs) plays an important role in the development of INS as well as allergic diseases. We hypothesized that dysbiosis involving decreased butyric acid-producing gut microbiota leads to defective induction and differentiation of peripherally induced Tregs, resulting in INS relapse. METHODS: Study subjects were 12 children with INS, 8 classified as relapsing (R group; median age: 3.0 years) and 4 as non-relapsing (NR group; median age: 4.3 years), and 11 healthy children (HC group; median age: 5.1 years) serving as normal controls. Measurement of microbiota was performed using 16S ribosomal RNA metagenomic analysis, and fecal butyric acid was measured using high performance liquid chromatography. Flow-cytometric analysis of Tregs and CD4-positive (CD4+) cells in peripheral blood was also performed. RESULTS: Metagenomic analysis of gut microbiota using feces showed that the proportion of butyric acid-producing bacteria was significantly lower in R (median 6.36%) than HC (median 18.84%; p = 0.0013), but no different between NR (median 16.71%) and HC (p = 0.29). Fecal organic acid analysis revealed significantly lower butyric acid quantities in R than HC (medians: 0.48 vs. 0.99 mg/g, p = 0.042). Circulating Tregs as a proportion of CD4+ cells were decreased in 75% of R and NR. CONCLUSION: Pediatric relapsing INS patients show gut microbiota dysbiosis, characterized by a decreased proportion of butyric acid-producing bacteria and lower fecal butyric acid quantities, concomitant with reduced circulatory Tregs.

Urinary C-megalin for screening of renal scarring in children after febrile urinary tract infection.

BackgroundFebrile urinary tract infection (fUTI) in children may cause renal scarring. This study aimed to investigate the usefulness of urinary biomarkers for diagnosing renal scarring after fUTI.MethodsThirty-seven children (median age: 1.36 years, range: 0.52-12.17 years, 25 boys) with a history of fUTI, who underwent renal scintigraphy for 4 months or longer after the last episode of fUTI, were analyzed. A spot urine sample was obtained on the day of renal scintigraphy to measure levels of total protein, N-acetyl-ß-D-glucosaminidase (NAG), ß2-microglobulin (BMG), neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid binding protein (L-FABP), and C-megalin (full-length megalin). Results were corrected for urinary creatinine (Cr) and compared between the group with renal scarring (n=23) and that without scarring (n=14). Urinary levels of C-megalin were also measured in healthy control subjects.ResultsNo significant differences in total protein, NGAL, L-FABP, NAG, and BMG levels were found between the groups. However, C-megalin levels were significantly higher in the renal scarring group than in the non-renal scarring group and healthy controls (P<0.001). A cutoff value of 6.5 pmol/nmol of urinary C-megalin/Cr yielded 73.9% of specificity and 92.9% of sensitivity.ConclusionUrinary C-megalin is useful for diagnosing renal scarring caused by fUTI.

The Effect of Family Assistance to Wake Children with Monosymptomatic Enuresis in Alarm Therapy: A Pilot Study.

PURPOSE: Alarm therapy is widely used as first line treatment for nocturnal enuresis. However, some children do not wake when nocturnal urination activates the alarm. It is currently unclear whether waking the child when the alarm is activated improves the efficacy of alarm therapy. In this study we investigated the efficacy of alarm therapy for nocturnal enuresis when children do not wake in response to the sound and their parents do not wake them. MATERIALS AND METHODS: Detailed information regarding incontinence was retrospectively obtained from 78 of 112 patients who underwent alarm therapy between 2006 and 2016, and completed a questionnaire and a 14-day bladder diary. The enrolled patients were divided into 2 groups. In the family assisted group (44) the children were awakened by family members when the alarm sounded. In the alarm control group (34) the children were self-responsible for waking to the alarm. The groups were compared to investigate differences at 16 weeks after alarm therapy began. The efficacy rate was calculated using the International Children's Continence Society criteria. RESULTS: The efficacy was similar between the groups. Full response and partial response were observed in 36.4% and 20.5% of patients in the family assisted group, and 26.5% and 29.4% of patients in the alarm control group (p = 1.00), respectively. There was no significant difference in the percentage of children who woke spontaneously to the alarm in the 2 groups (56.7% and 64.0%, respectively). CONCLUSIONS: Family assisted alarm therapy and self-responsible alarm therapy are equally efficacious in the treatment of childhood nocturnal enuresis.

Effect of cesarean section on relapse of childhood idiopathic nephrotic syndrome.

In parallel with the increase in the prevalence of childhood chronic diseases, the rate of cesarean delivery has risen during the past decades. This study tested the hypothesis that children delivered by cesarean section (CS) have a higher risk of relapse of idiopathic nephrotic syndrome (INS). Fifty-six children with INS were categorized into three groups. Group A consisted of patients with INS who had no relapses after the onset of INS; group B consisted of patients with INS who had infrequent relapse; and group C consisted of patients with INS who had frequent relapse. The number of enrolled patients in groups A, B, and C was 10, 14, and 32, respectively. The ratio of neonates delivered via CS was significantly higher in group C (37.5%, P < 0.001) than in groups A (0%) and B (7.1%). This study shows that CS is associated with an increased risk of relapse of childhood INS.

Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome.

The pathogenesis of idiopathic nephrotic syndrome (INS) remains unknown. Recently, it was postulated that suppression of regulatory T cells (Treg) leads to massive proteinuria in INS, although there is some controversy. Considering the important role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in Treg-mediated immune suppression, the aim of this study was therefore to clarify the involvement of Treg and CTLA-4 in the pathogenesis of INS. Fifteen patients with INS were enrolled. Their blood was sampled twice, once at onset and once at remission induced by glucocorticoid. Although median Treg number was significantly lower at onset than in healthy children, it increased at remission. Similarly, serum CTLA-4 concentration significantly increased at remission compared with onset. Furthermore, a positive significant correlation was observed between Treg number and serum CTLA-4 level. This suggests that Treg and CTLA-4 are involved in the induction of remission in INS.

Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations.

BACKGROUND: The oculocerebrorenal syndrome of Lowe gene (OCRL) is located on chromosome Xq25-26 and encodes an inositol polyphosphate-5-phosphatase (OCRL-1). Mutations in this gene cause Lowe syndrome (LS) or type 2 Dent disease, of which low-molecular-weight (LMW) proteinuria is a characteristic feature. Megalin is considered to play an important role in the development of renal tubular proteinuria. Two forms of megalin are excreted into the urine: full-length megalin (C-megalin) and megalin ectodomain (A-megalin). We have explored the role of megalin in the development of LMW proteinuria in patients with OCRL mutations by determining urinary megalin fractions. METHODS: We measured A- and C-megalin in spot urine samples from five male patients with OCRL mutations (median age 9 years), using sandwich enzyme-linked immunosorbent assays, and adjusted the obtained values for excreted creatinine. The results were compared with those of 50 control subjects and one patient with type 1 Dent disease (T1D). RESULTS: All patients demonstrated normal levels of urinary C-megalin. However, patients with OCRL mutations or T1D showed abnormally low levels of urinary A-megalin, with the exception of one 5-year-old boy with LS, who was the youngest patient enrolled in the study. CONCLUSIONS: Decreased excretion of urinary A-megalin in four out of five patients with OCRL mutations suggests that LMW proteinuria may be caused by impaired megalin recycling within the proximal tubular cells. Homologous enzymes, similar to inositol polyphosphate-5-phosphatase B in mice, may help to compensate for defective OCRL-1 function during early childhood.