Search

IgA nephropathy (IgAN) is the most common chronic primary glomerulonephritis in both children and adults, and 20-30% of patients with persistent hematuria/proteinuria progress to kidney failure within 20 years. In Japan, most cases of childhood IgAN are detected by school screening programs during the early onset of the disease when hematuria/proteinuria are asymptomatic and kidney function is normal. Therefore, it is possible to follow the detailed clinical course and appropriate therapeutic interventions from early onset of the disease. Data on non-immunosuppressive therapies for children with IgAN are highly limited. The Japanese Pediatric IgA Nephropathy Treatment Study Group was organized in 1989 to conduct clinical trials and accumulate data on treatments for childhood IgAN. In this review, we focus on non-immunosuppressive therapies, notably with renin-angiotensin-aldosterone system (RAAS) inhibitors for childhood IgAN and related clinical trials conducted primarily in Japan. We also describe the anti-inflammatory and antiproteinuric effects of RAAS inhibitors in IgAN, differences in treatment regimens because of the acute and active pathological features of childhood IgAN, adverse events of RAAS inhibitors, other non-immunosuppressive treatment options, and future directions., Author(s): Yuko Shima [sup.1] , Koichi Nakanishi [sup.2] , Norishige Yoshikawa [sup.3] Author Affiliations: (1) grid.412857.d, 0000 0004 1763 1087, Department of Pediatrics, Wakayama Medical University, , Wakayama City, Wakayama, [...]

Author(s): Yosuke Inaguma [sup.1] , Hiroshi Kaito [sup.1] , Tomoko Horinouchi [sup.1] , Yoshiharu Ogawa [sup.2] , Makiko Yoshida [sup.3] , Norishige Yoshikawa [sup.4] , Ryojiro Tanaka [sup.1] Author Affiliations: [...]

Background IgA nephropathy (IgAN) is characterized by predominant mesangial IgA deposition. Some patients with IgAN demonstrate IgA deposition in glomerular peripheral capillaries (cap-IgA). The clinicopathological significance of cap-IgA remains incompletely investigated in children. Methods We retrospectively analyzed 503 consecutive cases of biopsy-proven childhood IgAN between July 1976 and June 2013 to compare clinical and pathological features between IgAN patients with and without cap-IgA. Results Among the 503 patients, 30 (6.0%) had cap-IgA. We found significant differences in proteinuria (2.0 vs. 0.5 g/day/m.sup.2, p < 0.0001), time from onset to kidney biopsy (2.2 vs. 8.3 months, p < 0.0001), and rate of proteinuria remission after treatment (23.3% vs. 48.0%, p = 0.007) between both groups. Pathological analysis revealed significant differences in M1 (83.3% vs. 56.0%, p = 0.002), ratio of subendothelial electron dense deposits (EDDs, 58.6% vs. 16.5%, p < 0.0001) and subepithelial EDDs (48.3% vs. 16.5%, p = 0.0001), and glomerular basement membrane (GBM) lysis (58.6% vs. 27.1%, p = 0.0006) between both groups. More than half of cap-IgA patients (17/30, 56.7%), whereas only 26.2% of non-cap-IgA patients (124/473), were treated with immunosuppressive treatments. Six of 30 cases (20%) with cap-IgA reached glomerular filtration rate (GFR) categories G3a-G5 (estimated GFR < 60 ml/min/1.73 m.sup.2) at most recent observation (mean observation period: 7.0 ± 4.0 years). According to Kaplan-Meier analysis, patients with cap-IgA had significantly lower kidney survival curves than non-cap-IgA patients (72.8% vs. 97.2% at 10 years, p < 0.0001). Conclusions Cap-IgA is associated with acute inflammation with GBM changes, resulting in refractory heavier proteinuria. Cap-IgA may represent a poor prognostic factor., Author(s): Yuko Shima [sup.1] , Koichi Nakanishi [sup.2] , Hironobu Mukaiyama [sup.1] , Yu Tanaka [sup.1] , Takuzo Wada [sup.1] , Ryojiro Tanaka [sup.3] , Hiroshi Kaito [sup.3] , Kandai [...]

Background Although a 2-year combination therapy is effective for severe childhood immunoglobulin A (IgA) nephropathy, proteinuria persists in some patients even after the treatment. Methods Seventy-nine patients aged 80 % of glomeruli showed mesangial proliferation were enrolled in the study. Risk factors for persistent proteinuria after combination therapy were investigated using multivariate logistic regression analysis. Results Proteinuria ([greater than or equal to]0.2 g/1.73 m.sup.2/day) persisted in 27 patients (34 %) after the combination therapy. Twenty-four-hour urinary protein excretion, rate of glomeruli with crescents, rate of glomeruli with segmental sclerosis and rate of glomeruli with global sclerosis at diagnosis were higher in patients with persistent proteinuria than those without. In the multivariate analysis, 24-h urinary protein excretion [odds ratio (OR) 6.9; 95 % confidence interval (CI) 2.1-27.8; p = 0.001] and rate of glomeruli with crescents (OR 3.8; 95 % CI 1.1-13.9; p = 0.03) were independent risk factors for persistent proteinuria. Analysis of the receiver operating characteristic curve demonstrated that the most accurate cut-off values to detect persistent proteinuria were a urinary protein excretion of 1.32 g/1.73 m.sup.2/day and a 14 % rate of glomeruli with crescents. Conclusions In our cohort, urinary protein excretion and rate of glomeruli with crescents at diagnosis were independent risk factors for persistent proteinuria after the combination therapy., Author(s): Koichi Kamei[sup.1] , Koichi Nakanishi[sup.2] , Shuichi Ito[sup.1] , Kenji Ishikura[sup.3] , Hiroshi Hataya[sup.3] , Masataka Honda[sup.3] , Kandai Nozu[sup.4] , Kazumoto Iijima[sup.4] , Yuko Shima[sup.2] , Norishige Yoshikawa[sup.2] [...]

Background To investigate the long-term outcome in children with frequently relapsing nephrotic syndrome (FRNS) we conducted a follow-up of a previous randomized controlled trial (RCT) 10 years after the initiation of the treatment protocol. Methods We previously conducted an RCT on the efficacy of cyclosporine for treating children with FRNS. After 2 years of treatment, a recommended a management protocol of steroids, and immunosuppressants was provided. Results Valid information was available for 46 of the 56 patients (82.1%) enrolled in the original RCT. The median follow-up period was 10.3 years from the start of protocol treatment with cyclosporine. At last follow-up (mean age 18.7 years), only ten patients (21.7%) showed disease-free remission (no relapse for at least 2 years). In contrast, 23 (50.0%) continued to relapse frequently or were on immunosuppressants, eight patients (17.4%) had infrequent relapses without immunosuppressants. Adverse effects attributable to treatment included short stature (6 patients), osteoporosis (six patients), obesity (4 patients), cataracts (3 patients) and hypertension (3 patients). No lethal event or renal dysfunction occurred during follow-up. Conclusions This 10-year follow-up study shows that most children with FRNS experience relapses after 2 years of cyclosporine treatment, in adolescence and into adulthood. Outcomes in terms of life expectancy and renal function are favorable. Keywords Children * Follow-up * Long-term * Nephrotic syndrome * Randomized * Controlled trial * Non-remission, Introduction The use of immunosuppression therapy in children with frequently relapsing nephrotic syndrome (FRNS), a severe form of nephrotic syndrome which affects about half of patients, has been established [1-5]. [...]

Background The criterion for performing a renal biopsy in children with idiopathic nephrotic syndrome (NS) showing microscopic hematuria at onset remains controversial. Methods To determine an adequate renal biopsy criterion in children with NS showing hematuria, the optimal cutoff for the maximum red blood cell (RBC) range in urine sediment to separate minimal change disease (MCD) from other glomerular changes was obtained by receiver operating characteristic analysis. We studied 29 children with NS showing hematuria who were screened from 1,320 patients who underwent renal biopsies between January 2001 and September 2011. Patients were divided into two groups according to the cutoff value to verify its validity. Results The optimal maximum RBC range was 30-49/high-power field (HPF). In group 1 (RBC [less than or equal to] 29/HPF, n = 14), 3 patients showed nephritis and the other 11 patients showed MCD. In group 2 (RBC [greater than or equal to] 30/HPF, n = 15), 1 patient showed focal segmental glomerulosclerosis, 12 showed nephritis, and the other 2 showed MCD. These findings indicated that the ratio of non-MCD/MCD was significantly higher in group 2 than in group 1 (P < 0.01). Conclusions The use of maximum RBC range (30-49/HPF) for a criterion of renal biopsy in patients with NS showing hematuria may be reasonable for clinical practice. Keywords Minimal change disease * Focal segmental glomerulosclerosis * IgA nephropathy * Membranoproliferative glomerulonephritis * Receiver operating characteristic analysis, Introduction Idiopathic nephrotic syndrome (NS) is defined as NS in the absence of systemic disease. This category is divided into two types of entities according to histopathological findings: minimal change [...]

Background Although the Oxford classification of IgA nephropathy appears valid, we found crescents were significantly related to renal outcome in our cohort, whereas segmental glomerulosclerosis (S) was not. The timing of renal biopsy may significantly affect the variables in the Oxford classification. Method The relationship between biopsy timing and pathological variables (mesangial hypercellularity score [M], endocapillary hypercellularity [E], S, tubular atrophy/ interstitial fibrosis [T], crescents, and global glomerulosclerosis [G]) was analyzed retrospectively in 250 children with IgA nephropathy. Results The median time from disease onset to renal biopsy was 5.1 months (interquartile range, 2.7-15.4). M ([rho] = -0.26, P < 0.0001), E ([rho] = -0.34, P < 0.0001), and crescents ([rho] = -0.14, P = 0.023) showed significant negative correlations, and S([rho] = 0.15, P = 0.018) and G([rho] = 0.25, P < 0.0001) showed significant positive correlations with time to biopsy (Spearman test). M, E, and crescents differed significantly in renal biopsies obtained before and after 3 years from onset (Wilcoxon test). Most crescents (92.9%) were cellular/ fibrocellular and were acute lesions. As crescents formed early after disease onset and decreased over time, they may be prognostic for acute phase, but not for chronic phase disease. Conclusions Renal biopsy timing may alter the significance of variables used in the Oxford classification. Keywords Glomerulosclerosis * Crescents * Correlation * Onset * Diagnosis, Introduction IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and the main cause of end-stage renal disease in patients of all ages with primary glomerular disease [1, 2]. Pathological [...]

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. Keywords Autosomal recessive Alport syndrome * COL4A3 * COL4A4 * Type IV collagen alpha5, Introduction Alport syndrome is a hereditary disorder that generally runs a progressive course. It usually presents in children as hematuria and proteinuria associated with neurosensory deafness and progresses to end-stage [...]

Background: Little is known about the epidemiology of Henoch–Schönlein purpura nephritis (HSPN). Methods: We conducted a nationwide epidemiological survey of Japanese children aged 1 to 15 years with HSPN. Children who were newly diagnosed with HSPN by biopsy between January 2013 and December 2015 were eligible for the survey to clarify the incidence of HSPN. We also conducted an institutional survey on kidney biopsy criteria and treatment protocols. Results: A total of 353 of 412 institutions (85.7%) responded to the questionnaire. Of the 353 institutions, 174 reported to perform kidney biopsies at their institutions, and 563 children were diagnosed with HSPN. Considering the collection rate, the estimated incidence of biopsy-proven HSPN was 1.32 cases/100,000 children per year. The median age at biopsy was 7.0 years, and the male-to-female ratio was 1.2:1. The kidney biopsy criteria and treatment protocols for HSPN were as follows. Patients with acute kidney injury underwent biopsy at least one month after onset. For patients without kidney dysfunction, the timing for biopsy was determined by the amount of proteinuria. Regarding the treatment of HSPN, there were certain commonalities among the treatment protocols, they eventually differed depending on the institutions involved. Conclusions: The incidence of biopsy-proven HSPN was 1.32 cases/100,000 children per year in Japan. The male-to-female ratio and date of diagnosis of HSPN were similar to those in previous studies. The kidney biopsy criteria and treatment protocols for HSPN varied among institutions. Further studies are warranted to establish an optimal treatment policy based on the prognosis. [ABSTRACT FROM AUTHOR]

Background A possible mechanism of cyclosporine (CsA) nephrotoxicity is tubular apoptosis. Endoplasmic reticulum (ER) stress has been shown to be an apoptosis activator. Glucose-regulated proteins 78 and 94 (GRP78, GRP94, respectively) are ER stress-induced chaperones. Eukaryotic translation initiation factor 2α (EIF2α) attenuates protein synthesis. If stress is prolonged, cells undergo apoptosis, inducing the production of GADD153, a transcription factor, which in turn downregulates anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). Methods Endoplasmic reticulum stress-related molecules were evaluated by real-time polymerase chain reaction (PCR) using renal biopsy tissues from 17 children with frequently relapsing nephrotic syndrome before and after 2 years of CsA therapy. Results GRP78, GRP94, eIF2α, and Bcl-2 were significantly upregulated in renal biopsy tissues from children 2 years post-CsA treatment. However, there was almost no change in GADD153. Mean ratios of post- to pre-CsA expression of GRP78, GRP94, eIF2α and Bcl-2 were 2.53, 1.80, 2.38 and 1.92, respectively. Post-CsA administration, GRP78 and eIF2α were upregulated by up to sixfold, and GRP94 and Bcl-2 were upregulated by up to fourfold compared with the respective pre-CsA levels. There were significant correlations between GRP78, GRP94, eIF2α, and Bcl-2 levels. These findings suggest that CsA induced an unfolded protein response due to ER stress, but did not cause apoptosis. Conclusions An unfolded protein response due to ER stress induced by CsA may function in a defensive manner, with less apoptosis occurring under low-dose conditions. This finding is important for the rationale for CsA administration. Keywords Cyclosporine A * Endoplasmic reticulum stress * Frequently relapsing nephrotic syndrome * Nephrotoxicity * Unfolded protein response, Introduction Idiopathic nephrotic syndrome (NS) is a common disease in children. More than 80 % of children with idiopathic NS have steroid-sensitive NS (SSNS) [1]. However, approximately 60 % of [...]