Crohn's disease following rituximab treatment in a patient with refractory nephrotic syndrome.

Rituximab (RTX) is increasingly used for the treatment of refractory nephrotic syndrome due to its inhibitory effect on B cells which extends the period of remission, while lowering the dose of steroids needed for disease management. However, RTX can lead to various side effects, including Crohn's disease. Herein, we describe a case of a 15-year-old boy with refractory nephrotic syndrome diagnosed at age 9 years who developed Crohn's disease following RTX treatment. RTX was initiated in this patient at the age of 13 years 6 months due to occurrence of 12 relapses of nephrotic syndrome over a 4-year period, despite treatment using cyclosporine, steroid pulse therapy, and mycophenolate mofetil. The patient received 4 doses of RTX over a 2-year period (dose, 375 mg/m2). Although the treatment was effective in extending the disease-free duration up to 6 months, at the age of 15 years 9 months, the patient developed abdominal pain, associated with frequent watery stools and rapid weight loss. Based on clinical and endoscopic findings, he was diagnosed with Crohn's disease and treated using infliximab. Remission of Crohn's disease was achieved with this treatment, with no further relapse of nephrotic syndrome. Infliximab is thought to extend the remission period of nephrotic syndrome. In this case, we propose that Crohn's disease was caused by an abnormal immune tolerance, secondary to the use of RTX, although the exact underlying mechanism remains to be clarified. Therefore, inflammatory bowel disease should be considered if severe abdominal symptoms with weight loss following RTX administration are observed.

Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome.

X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.

Epidemiological survey and clinical investigation of pediatric IgA nephropathy.

BACKGROUND: Since school urinalysis screening was introduced in 1974, the number of cases requiring initiation of dialysis due to glomerulonephritis has been steadily decreasing and school urinalysis screening has been praised for contributing to the early detection and treatment of glomerulonephritis. However, the lack of nationwide epidemiological surveys is also a problem. METHODS: We conducted an epidemiological survey focusing on the frequency of occurrence of pediatric IgA nephropathy in Nishinomiya City. Subjects comprised 374,846 children who underwent school urinalysis screening from 2003 to 2012. Renal biopsy findings and clinical findings of these pediatric IgA nephropathy cases were retrospectively investigated. RESULTS: There were 37 (mean 3.7/year) newly diagnosed cases of pediatric IgA nephropathy in Nishinomiya City. The IgA nephropathy onset rate per 100,000 children who underwent school urinalysis screening was 9.9 cases/year. Compared to the histologic low grade group, the histologic high grade group had significantly higher urinary P/C ratio (P < 0.001). In the histologic high grade group, the number of cases of proteinuria remission 3 years after starting treatment was significantly higher in the group treated with steroids (P = 0.045). CONCLUSIONS: Our study found that 9.9 cases of pediatric IgA nephropathy were diagnosed per 100,000 in the pediatric population, which is equivalent to or slightly more than past reports. IgA nephropathy, which poses a high histologic risk, presents with heavy proteinuria; but the proteinuria remission rate following steroid therapy is high 3 years after treatment, which suggests that administration of steroids results in an improved clinical outcome.

Low prevalence and incidence of Helicobacter pylori infection in children: a population-based study in Japan.

BACKGROUND: Infection of Helicobacter pylori mainly occurs in childhood. In Japan, incidence of gastric cancer is still high in the senior citizen population, but little is known about the current H. pylori infection status among children or their family members. METHODS: As a population-based study, the prevalence of H. pylori infection and change in infection status over a 1-year interval in children were determined. Family members of some participants were also invited to participate in the study to determine their infection status. All children of specific ages attending 16 schools in Sasayama, Hyogo Prefecture, were invited to participate. H. pylori infection was determined by the stool antigen test and diagnosis confirmed by polymerase chain reaction and the urea breath test. RESULTS: Helicobacter pylori prevalence was 1.9% among 689 children aged 0-8 years in 2010 and 1.8% among 835 children aged 0-11 in 2011. No feco-conversion was observed in 430 children aged 0-8 years (170 were aged 0-4 years) who provided follow-up stool samples after 1 year. The prevalence of infection was 6% (2 of 33) and 38% (6 of 16) in mothers of negative and positive probands (p = .04), respectively, and 12% (3 of 25) and 50% (8 of 16) (p = .01), respectively, in fathers. CONCLUSION: Helicobacter pylori prevalence in Japanese children is approximately 1.8%, which is much lower than that reported in Japanese adults. New infection may be rare. Parent-to-child infection is thought to be the main infection route of the infrequent infection for children in Japan.

[Clinical usefulness of CD68 staining in children with various glomerular diseases].

PURPOSE: Glomerular macrophage accumulation is a common feature of proliferative forms of human glomerulonephritis and kidney injury. Our present study was designed to investigate the role of macrophages in pediatric kidney diseases by using CD68 staining. MATERIAL AND METHODS: Seventy-four patients (39 boys and 35 girls) with pediatric kidney disease yielding 81 specimens were investigated. A monoclonal anti-human CD68 mouse antibody (KP1) was used as a macrophage marker in this study. Paraffin-embedded renal biopsy specimens were stained for immunohistochemical analysis. The average number of macrophages per glomerulus in each patient was calculated as the total number of CD68 (+) cells within all glomeruli divided by the total number of glomeruli in a single section and the average number of observed interstitial macrophages was calculated in 3-5 high power fields. RESULTS: Glomerular macrophage accumulations were increased with crescentic proliferative glomerulonephritis, mesangial proliferative glomerulonephritis, and focal segmental glomerulosclerosis. Glomerular and interstitial macrophage accumulations were correlated with hematuria, proteinuria and renal function (eGFR). In particular, activity and chronicity index, as well as the severity of glomerular IgA, C3, and fibrinogen deposition were correlated with glomerular macrophage accumulation. CONCLUSIONS: Macrophage accumulation observed by CD68 staining was a useful marker in providing a deeper understanding of the clinicopathologic state of children with chronic kidney diseases, and was effective in the selection of treatment.

Genetic heterogeneity among bovine leukemia viruses in Japan and their relationship to leukemogenicity.

Bovine leukemia virus (BLV) infection in cattle causes persistent lymphocytosis, and a few percent of infected animals develop lymphoid tumors, namely enzootic bovine leukosis (EBL). In this study, a 440-bp fragment of the env gene was amplified from 204 tumor samples collected from different regions of Japan and analyzed by restriction fragment length polymorphism (RFLP) to determine the association of BLV with EBL. Of the seven RFLP types defined, types I, II, and III were dominant and found in 12.7, 75.0, and 8.3% of tumor samples, respectively. Cattle harboring type III virus were significantly older than other animals at the time of diagnosis of EBL. Type III viruses were found in approximately 33% and 5.5% of Japanese Black and Holstein cattle, respectively, with EBL. These findings indicate that genetically distinct BLV was associated with EBL in Japan and that the genetic profile may influence the leukemogenicity of the virus.