Yuko Shima

糸球体疾患の診療において腎病理組織所見は，診断および病態理解の中核を担うが，個々の所見の評価に偏ると疾患全体像を見失う危険がある．本総説では「木を見て森を見る」という視点から，腎病理組織所見を臨床情報と統合して解釈する重要性を概説した．小児IgA腎症およびIgA血管炎関連腎炎（紫斑病性腎炎）を題材に，Oxford分類の長所と限界，腎生検のタイミングが予後因子の解釈に与える影響を整理した．さらに，発症年齢による免疫応答の違いが形成される所見や治療反応性に影響する可能性を示し，腎病理組織診断において臨床医が積極的に関わり，臨床像と病理像を結びつけて理解を深めることの重要性を強調した．

Background Angiotensin-converting enzyme inhibitors such as lisinopril have long been used for childhood IgA Nephropathy (cIgAN). A two-year combined regimen including prednisolone + mizoribine + warfarin + dipyridamole was shown in our previous randomized control trial to be better for severe cIgAN than prednisolone + mizoribine (without warfarin or dipyridamole) in proteinuria remission. However, to avoid warfarin nephropathy and to shorten the duration of prednisolone use, we consider a new two-year combined regimen of prednisolone + mizoribine + lisinopril. Methods Between July 1976 and December 2022, among 567 biopsy-proven cases of cIgAN, there were 93 cases of severe cIgAN treated with prednisolone + mizoribine. We investigated clinicopathological differences between the 77 cases of cIgAN (82.8%) with the previous treatment and the other 16 patients with the new treatment regimen. After 1:1 propensity score matching was performed to account for between-group differences (amount of proteinuria, eGFR, and the percentage of patients with C0, C1, and C2), we analyzed 15 matched pairs. Results Clinicopathological presentations did not significantly differ between the groups. Kaplan-Meier analysis of proteinuria remission showed that the patients with the new treatment achieved significantly higher (90.0 vs. 64.1% at 11 yrs, p = 0.01), and faster (1.0 vs. 4.0 yrs, p = 0.03) proteinuria remission than those with the previous treatment. Proteinuria recurrence was not significantly different between the groups. Conclusions We suggested the superiority of 2-year combined regimen of prednisolone + mizoribine + lisinopril for severe cIgAN in achieving early proteinuria remission and shortening prednisolone use without recurrence of proteinuria.

Background: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. Methods: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2–5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. Results: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. Conclusions: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Background Proteinuria remission is the most significant predictive factor for kidney outcome in childhood IgA nephropathy (c-IgAN). Even if proteinuria remission can be obtained, some patients have recurrence of proteinuria in the long-term. Methods This is a retrospective analysis of 312 cases of proteinuria remission among 538 consecutive children with biopsy-proven IgAN from 1976 to 2013. To elucidate the incidence and factors related to recurrence of proteinuria in c-IgAN, we compare clinical and pathological findings between patients with and without recurrence of proteinuria. Results Among 312 patients with remission of proteinuria, 91 (29.2%) had recurrence of proteinuria within the observation period (median 8 years). Using a multivariate Cox regression analysis, significant factors associated with recurrence of proteinuria were onset age (HR 1.13 [95%CI: 1.05–1.22], P = 0.002) and presence of hematuria after proteinuria remission (HR 2.11 [95%CI: 1.30–3.45], P = 0.003). The Kaplan–Meier analysis showed significant differences in CKD G3a-G5-free survival between the patients with no-recurrence of proteinuria, recurrence of proteinuria and non-proteinuria remission (P < 0.0001, log-rank test). Kidney survival was 100% in no-recurrence of proteinuria, 92.2% in recurrence of proteinuria, and 65.6% in non-proteinuria remission at 15 years. Cox analyses adjusted by proteinuria remission showed that recurrence of proteinuria (HR 03.10e⁹ [95%CI: NA], P = 0.003) was a significant factor associated with progression to CKD G3a-G5 in all patients with c-IgAN. Conclusions Approximately 30% of patients with proteinuria remission had recurrence of proteinuria regardless of treatment. Both remission and recurrence of proteinuria are significant prognostic factors for kidney outcome. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Nephronophthisis is an autosomal-recessive kidney disease that is caused by abnormalities in primary cilia. Nephronophthisis-related ciliopathies (NPHP-RCs) are a common cause of end-stage kidney disease (ESKD) in children and adolescents. NPHP-RCs are often accompanied by extrarenal manifestations, including intellectual disability, retinitis pigmentosa, or polydactyly. Although more than 100 causative genes have been identified, its diagnosis is difficult because the clinical features of each mutation often overlap. From September 2010 to August 2021, we performed genetic analysis, including next-generation sequencing (NGS), in 574 probands with kidney dysfunction and retrospectively studied cases genetically diagnosed with NPHP-RCs. Results We detected mutations related to NPHP-RCs in 93 patients from 83 families. Members of 60 families were diagnosed using NGS, and the mutations and the corresponding number of families are as follows: NPHP1 (24), NPHP3 (10), OFD1 (7), WDR35 (5), SDCCAG8 (4), BBS10 (3), TMEM67 (3), WDR19 (3), BBS1 (2), BBS2 (2), IFT122 (2), IFT140 (2), IQCB1 (2), MKKS (2), SCLT1 (2), TTC21B (2), ALMS1 (1), ANKS6 (1), BBS4 (1), BBS12 (1), CC2D2A (1), DYNC2H1 (1), IFT172 (1), and MAPKBP1 (1). A total of 39 cases (41.9%) progressed to ESKD at the time of genetic analysis, whereas 58 cases (62.3%) showed extrarenal manifestations, the most common being developmental delay, intellectual disability, and autism spectrum disorder in 44 patients. Comprehensive genetic analysis using NGS is useful for diagnosing patients with NPHP-RCs.

Background Cases of Henoch–Schönlein purpura nephritis (HSPN) with moderate severity were demonstrated to achieve good prognosis after treatment with renin-angiotensin system (RAS) inhibitors. However, some patients required additional treatment for recurrence after remission. This study aimed to clarify the effect of RAS inhibitors in HSPN cases with moderate severity, including the proportion of cases with recurrence and their response to additional treatment. Methods Among 126 patients diagnosed with HSPN between 1996 and 2019, 71 patients with clinicopathologically diagnosed HSPN of moderate severity, defined as ISKDC grade II–IIIa and serum albumin ≥ 2.5 g/dL, were investigated. Results Proteinuria became negative after RAS inhibitor treatment alone in all 71 cases. However, 16 (22.5%) had recurrence. Eleven recurrent cases achieved negative proteinuria again following additional treatment. At the last follow-up (median 46.5 months; IQR, 23.2–98.2), 5 patients had persistent mild proteinuria; no patients had estimated glomerular filtration rate < 90 mL/min/1.73 m². The pathological findings in all recurrent cases were ISKDC grade IIIa. The 16 recurrent cases had significantly higher proportions of glomeruli with global/segmental sclerosis (25.0 vs. 0%, P < 0.001) and tubular atrophy/interstitial fibrosis (37.5 vs. 12.7%, P =0.0 24) than 55 cases without recurrence. Conclusions Japanese childhood HSPN cases with moderate severity had good outcomes without need for corticosteroids or immunosuppressants, when prescribed RAS inhibitor treatment. Even in recurrent cases, abnormal proteinuria was transient, and prognosis was excellent. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Background Pathological findings in Alport syndrome frequently show mesangial proliferation and sometimes incidental IgA deposition, in addition to unique glomerular basement membrane (GBM) changes including thin basement membrane and/or lamellation. However, similar GBM abnormalities are also often observed in IgA nephropathy. Both diseases are also known to show hematuria, proteinuria, and sometimes macrohematuria when associated with viral infection. Therefore, it can be difficult to make a differential diagnosis, even based on clinical and pathological findings. Some recent articles demonstrated that galactose-deficient IgA1 (Gd-IgA1)-specific monoclonal antibody (KM55) could potentially enable incidental IgA deposition to be distinguished from IgA nephropathy. Methods We performed comprehensive gene screening and glomerular Gd-IgA1 and type IV collagen α5 chain immunostaining for five cases with both IgA deposition and GBM changes to confirm that Gd-IgA1 can help to distinguish these two diseases. Results Four of the cases were genetically diagnosed with Alport syndrome (Cases 1–4) and one was IgA nephropathy with massive GBM changes, which had a negative gene test result (Case 5). In Cases 1–4, glomerular Gd-IgA1 deposition was not detected, although there was positivity for IgA in the mesangial area. In Case 5, glomerular Gd-IgA1 deposition was observed. Conclusion Gd-IgA1 expression analysis could clearly differentiate these two disorders. This approach can be applied to identify these two diseases showing identical clinical and pathological findings.