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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 [...]

Objectives Crescentic IgA nephropathy (C-IgAN) is defined as IgAN with more than 50% of glomeruli showing crescents. C-IgAN in children is rare; we investigate in detail for the first time. Methods We retrospectively analyzed the 515 consecutive children who were newly diagnosed with biopsy-proven IgAN between June 1976 and May 2010. We compared clinical and pathological findings between C-IgAN and non-C-IgAN. Results Among 515 cases of childhood IgAN, 25 children (4.9%) had C-IgAN. Of these 25, 16 children (64%) were referred to hospitals by annual school screening. Clinical findings showed significant differences in gross hematuria (76 vs. 50%, p = .03), excretion of proteinuria (1.9 vs. 0.5 g/day/m.sup.2, p < .0001), eGFR (102 vs. 108 ml/min/1.73 m.sup.2, p = .03), and duration from onset to renal biopsy (4.0 vs. 8.0 months, p = .04) between groups. Pathological findings showed significant differences in M1 (88 vs. 55%, p = .02), E1 (83 vs. 53%, p = .008), and presence of tubular atrophy/interstitial fibrosis (88 vs. 53%, p < .0001) between groups. The 16 children with C-IgAN were treated with prednisolone and immunosuppressant. Four cases (16%) reached chronic renal failure (eGFR < 60) at the latest observation (mean observation period: 6.0 ± 3.6 years). Patients with C-IgAN had significantly lower renal survival curve than non-C-IgAN patients according to Kaplan-Meier analysis (77.1% vs. 92.6% at 13 years, p < .0001). Compared with previous reports, however, they had better renal outcome. Conclusions We confirmed the importance of school screening to find C-IgAN. Although most crescents (mean: 98.1%) of C-IgAN were cellular/fibrocellular, and acute lesions were well modified with combination therapy, the presence of tubular atrophy in C-IgAN may be the reason for poorer prognosis., Author(s): Yuko Shima [sup.1] , Koichi Nakanishi [sup.2] , Taketsugu Hama [sup.1] , Hironobu Mukaiyama [sup.1] , Masashi Sato [sup.1] , Yu Tanaka [sup.1] , Ryojiro Tanaka [sup.3] , Hiroshi [...]

Background Although rituximab effectively prevents relapses of complicated frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS), data of long-term outcomes and safety are limited. Methods Fifty-one patients (age, 3-38 years) with childhood-onset complicated FRNS or SDNS, who received rituximab in investigator-initiated multicenter prospective trials were enrolled. Rituximab was administered at 375 mg/m.sup.2 once weekly for 4 weeks, and immunosuppressive agents were discontinued according to the study protocol. We investigated relapses, re-administration of immunosuppressive agents, additional rituximab treatment, body height, renal function, and late adverse events during the observation period. Results Forty-eight patients (94%) developed relapses during the observation period (median, 59 months) and the 50% relapse-free survival was 261 days. Thirty patients (59%) developed SDNS, 44 (86%) required re-administration of immunosuppressive agents, and 22 (43%) received additional rituximab treatment. All patients who were receiving immunosuppressive agents at rituximab treatment required either immunosuppressive agents or additional rituximab treatment. On the contrary, 5 of the 13 patients without immunosuppressive agents at rituximab treatment required neither immunosuppressive agents nor additional rituximab treatment and 3 of them did not develop relapse during observation period. Growth failure due to steroid toxicity did not progress and none of the patients developed chronic renal insufficiency. None of the patients suffered from rituximab-related late adverse events. Conclusions As most patients suffer from relapses after B-cell recovery, long-term immunosuppressive agents or additional rituximab treatment is necessary. However, some patients who can discontinue immunosuppressive agents before rituximab treatment may achieve long-term remission after rituximab treatment without immunosuppressive agents., Author(s): Koichi Kamei [sup.1] , Kenji Ishikura [sup.1] , Mayumi Sako [sup.2] , Kunihiko Aya [sup.3] , Ryojiro Tanaka [sup.4] , Kandai Nozu [sup.5] , Hiroshi Kaito [sup.5] , Koichi [...]

Background Despite a low incidence, nephrotic syndrome (NS) can present with IgA nephropathy (IgAN). The clinical characteristics and long-term outcomes of pediatric patients with IgAN presenting with NS (NS-IgAN) at onset have not been fully elucidated. Methods We retrospectively analyzed 426 patients, and compared clinical and pathological (Oxford) findings between those with NS-IgAN and those with non-NS-IgAN. Results Among 426 patients, 30 (7.0 %) had NS-IgAN. Logistic analyses showed that male sex (OR: 7.6, p = 0.0002), M1 (OR: 10.3, p = 0.002), and E1 (OR: 15.2, p = 0.0001) were significantly related to NS. The mean observation period was 6.2 ± 3.2 years. Although NS-IgAN was associated with significantly lower renal survival than non-NS-IgAN according to Kaplan-Meier analysis (p = 0.02), renal survival of NS-IgAN was good (92.4 % at 10 years). The most significant prognostic factor for renal survival was remission of proteinuria after treatment, and NS at onset is also a significant prognostic factor for renal survival after adjusting for remission of proteinuria. Twenty children with NS-IgAN were treated with prednisolone alone, or prednisolone and immunosuppressant. Remission of proteinuria occurred in 21 patients. Three cases of NS-IgAN progressed to stage III-V chronic kidney disease at the most recent observation. They all demonstrated heavy proteinuria after the 2-year initial treatment. The significant factor for persistent proteinuria at 5 years was S1 in NS-IgAN. Conclusions The most significant factor for renal survival was responsiveness to treatment, not NS itself. As modifiable acute lesions are the dominant pathological findings in NS-IgAN, histological improvements achieved by appropriate treatments can result in a favorable prognosis., Author(s): Yuko Shima [sup.1] , Koichi Nakanishi [sup.1] , Masashi Sato [sup.1] , Taketsugu Hama [sup.1] , Hironobu Mukaiyama [sup.1] , Hiroko Togawa [sup.1] , Ryojiro Tanaka [sup.2] , Kandai [...]

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 Some patients with IgA nephropathy (IgAN) achieve spontaneous remission even when not receiving medication. However, details on such remissions remain unknown. The aim of our study was to clarify this information in the clinical setting of childhood IgAN with minor glomerular abnormalities or focal mesangial proliferation (MGA/FMP). Methods This study was a retrospective analysis of 96 children with MGA/FMP who did not receive medication from among the 555 patients with newly diagnosed childhood IgAN treated between January 1972 and December 2000. The Kaplan-Meier method and Cox proportional hazard model were used for the analysis. Results Of the 96 pediatric patients who did not receive medication, 57 (59.4%) achieved spontaneous remission. The cumulative spontaneous remission rates among these patients were 57.5 and 77.4% at 5 and 10 years, respectively, from onset. The mean time from onset to remission was 5.9 ± 0.4 years. Clinical and histological findings were similar between the remission and non-remission groups. Of the 57 patients with spontaneous remissions, ten (17.5%) also developed a recurrence of urinary abnormalities. The cumulative recurrence-free rates were 79.9 and 67.9% at 5 and 10 years, respectively, after remission. Conclusions The spontaneous remission rate in childhood IgAN with MGA/FMP was higher than expected. Our results suggest that physicians should consider the potential for spontaneous remission and refrain from very aggressive treatment in IgAN patients with MGA/FMP. Keywords Minor glomerular abnormality * Focal mesangial proliferation * Recurrence * Kaplan-Meier method * Cox proportional hazard model, Introduction Immunoglobulin A nephropathy (IgAN) is currently the most common type of primary glomerulonephritis worldwide. Long-term follow-up studies have revealed that the disease progresses to renal failure in 20-50% of [...]