{"title":"分级聚类揭示了免疫复合物介导的特发性MPGN和C3肾小球病变的疾病模式和进一步解开的复杂性。","authors":"Ariela Benigni,Erica Daina,Henry Löffler-Wirth,Rossella Piras,Miriam Rigoldi,Maria Schmidt,Camillo Carrara,Roberta Donadelli,Zahra Imanifard,Caterina Mele,Marta Alberti,Maddalena Marasà,Carolina Martinatto,Elena Bresin,Sara Gamba Res,Lisa Quadri,Giliane Nanchen,Marina Vivarelli,Francesco Emma,Gaetano La Manna,Enrico Vidal,Andrea Pasini,Andrea Ranghino,Gabriele Donati,Enrico Verrina,Andrea Angeletti,Giuliano Brunori,Mario Giordano,Federico Alberici,Umberto Maggiore,Gabriele Malgieri,Giuseppe Remuzzi,Matteo Breno,Marina Noris, ","doi":"10.1016/j.kint.2025.08.035","DOIUrl":null,"url":null,"abstract":"INTRODUCTION\r\nMembranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate.\r\n\r\nMETHODS\r\nHere, we applied hierarchical clustering to a much larger cohort of patients with C3G/ICMPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable.\r\n\r\nRESULTS\r\nFive clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches.\r\n\r\nCONCLUSION\r\nOur proposed strategy may possibly guide anti-complement treatment.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"13 1","pages":""},"PeriodicalIF":12.6000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hierarchical clustering uncovered disease patterns and further untangled complexities in immune complex-mediated idiopathic MPGN and C3 glomerulopathy.\",\"authors\":\"Ariela Benigni,Erica Daina,Henry Löffler-Wirth,Rossella Piras,Miriam Rigoldi,Maria Schmidt,Camillo Carrara,Roberta Donadelli,Zahra Imanifard,Caterina Mele,Marta Alberti,Maddalena Marasà,Carolina Martinatto,Elena Bresin,Sara Gamba Res,Lisa Quadri,Giliane Nanchen,Marina Vivarelli,Francesco Emma,Gaetano La Manna,Enrico Vidal,Andrea Pasini,Andrea Ranghino,Gabriele Donati,Enrico Verrina,Andrea Angeletti,Giuliano Brunori,Mario Giordano,Federico Alberici,Umberto Maggiore,Gabriele Malgieri,Giuseppe Remuzzi,Matteo Breno,Marina Noris, \",\"doi\":\"10.1016/j.kint.2025.08.035\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"INTRODUCTION\\r\\nMembranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate.\\r\\n\\r\\nMETHODS\\r\\nHere, we applied hierarchical clustering to a much larger cohort of patients with C3G/ICMPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable.\\r\\n\\r\\nRESULTS\\r\\nFive clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches.\\r\\n\\r\\nCONCLUSION\\r\\nOur proposed strategy may possibly guide anti-complement treatment.\",\"PeriodicalId\":17801,\"journal\":{\"name\":\"Kidney international\",\"volume\":\"13 1\",\"pages\":\"\"},\"PeriodicalIF\":12.6000,\"publicationDate\":\"2025-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Kidney international\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.kint.2025.08.035\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney international","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.kint.2025.08.035","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
Hierarchical clustering uncovered disease patterns and further untangled complexities in immune complex-mediated idiopathic MPGN and C3 glomerulopathy.
INTRODUCTION
Membranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate.
METHODS
Here, we applied hierarchical clustering to a much larger cohort of patients with C3G/ICMPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable.
RESULTS
Five clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches.
CONCLUSION
Our proposed strategy may possibly guide anti-complement treatment.
期刊介绍:
Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide.
KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics.
The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.