Background: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. Methods: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. Results: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. Conclusions: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

1st Department of Internal Medicine Semmelweis University Budapest Hungary

1st Department of Internal Medicine University of Szeged Szeged Hungary

1st Department of Pediatrics Semmelweis University Budapest Hungary

Carol Davila Nephrology Hospital Bucharest Romania

Department of Internal Medicine 4 Nephrology and Hypertension Medical University Innsbruck Innsbruck Austria

Department of Medicine 3 Division of Nephrology and Dialysis Medical University of Vienna Vienna Austria

Department of Medicine 3 Nephrology Transplant Medicine and Rheumatology Linz Austria Geriatric Department Ordensklinikum Linz Elisabethinen Linz Austria

Department of Nephrology Arterial Hypertension Dialysis and Transplantation University Hospital Center Zagreb School of Medicine University of Zagreb Zagreb Croatia

Department of Nephrology Dubrava University Hospital Zagreb Croatia

Department of Nephrology Hypertension and Internal Medicine School of Medicine Collegium Medicum University of Warmia and Mazury Olsztyn Poland

Department of Nephrology Szent Margit Hospital Budapest Hungary

Department of Nephrology Wilhelminenspital Vienna Austria

Department of Pathology University Hospital Split Split Croatia School of Medicine University of Split Split Croatia

Department of Pediatric Nephrology Division of Pediatrics University Medical Centre Ljubljana Ljubljana Slovenia

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague University Hospital Motol Prague Czech Republic

Department of Pediatrics and Adolescent Medicine Division of Pediatric Nephrology and Gastroenterology Medical University of Vienna Vienna Austria

Department of Pediatrics Comenius University Bratislava Slovakia

Department of Pediatrics Division of Nephrology Faculty of Medicine Palacky University and Faculty Hospital in Olomouc Olomouc Czech Republic

Department of Pediatrics Faculty of Medicine Debrecen University Debrecen Hungary

Department of Pediatrics Faculty of Medicine in Pilsen Charles University Prague Pilsen Czech Republic

Department of Pediatrics Faculty of Medicine University Hospital Ostrava Czech Republic

Department of Pediatrics Medical University of Innsbruck Innsbruck Austria

Department of Pediatrics Medical University of Innsbruck Innsbruck Austria Institute of Neurology of Senses and Language Hospital of St John of God Linz Austria Research Institute for Developmental Medicine Johannes Kepler University Linz Linz Austria

Department of Pediatrics University of Pécs Pécs Hungary

Department of Pediatrics University of Szeged Szeged Hungary

FMC Center of Dialysis Miskolc Hungary

Hospital of Klagenfurt Klagenfurt Austria

Institute of Pathology Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Internal Medicine 4 Section of Nephrology Klinikum Wels Grieskirchen Wels Austria

Medimapax Center of Elimination Methods Bratislava Slovakia

Nephrology Center Santaros Klinikos Medical Faculty Vilnius University Vilnius Lithuania

Nephrology Clinic 1st Faculty of Medicine Charles University Prague Czech Republic

Pediatric Nephrology Department Fundeni Clinical Institute Bucharest Romania

Research Laboratory 3rd Department of Internal Medicine Hungarian Academy of Sciences and Semmelweis University Budapest Hungary MTA SE Research Group of Immunology and Hematology Hungarian Academy of Sciences and Semmelweis University Budapest Hungary

University Children's Hospital Medical University Sofia Bulgaria

Živile Riispere Department of Pathology Tartu University Hospital Tartu Estonia

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$a Garam, Nóra $u Research Laboratory, 3rd Department of Internal Medicine, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.

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$a Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis / $c N. Garam, Z. Prohászka, Á. Szilágyi, C. Aigner, A. Schmidt, M. Gaggl, G. Sunder-Plassmann, D. Bajcsi, J. Brunner, A. Dumfarth, D. Cejka, S. Flaschberger, H. Flögelova, Á. Haris, Á. Hartmann, A. Heilos, T. Mueller, K. Rusai, K. Arbeiter, J. Hofer, D. Jakab, M. Sinkó, E. Szigeti, C. Bereczki, V. Janko, K. Kelen, GS. Reusz, AJ. Szabó, N. Klenk, K. Kóbor, N. Kojc, M. Knechtelsdorfer, M. Laganovic, AC. Lungu, A. Meglic, R. Rus, T. Kersnik-Levart, E. Macioniene, M. Miglinas, A. Pawłowska, T. Stompór, L. Podracka, M. Rudnicki, G. Mayer, R. Rysava, J. Reiterova, M. Saraga, T. Seeman, J. Zieg, E. Sládková, T. Szabó, A. Capitanescu, S. Stancu, M. Tisljar, K. Galesic, A. Tislér, I. Vainumäe, M. Windpessl, T. Zaoral, G. Zlatanova, D. Csuka,

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$a Background: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. Methods: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. Results: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. Conclusions: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

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$a Szilágyi, Ágnes $u Research Laboratory, 3rd Department of Internal Medicine, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.

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$a Aigner, Christof $u Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.

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$a Schmidt, Alice $u Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.

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$a Gaggl, Martina $u Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.

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$a Sunder-Plassmann, Gere $u Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.

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$a Bajcsi, Dóra $u 1st Department of Internal Medicine, University of Szeged, Szeged, Hungary.

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$a Brunner, Jürgen $u Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.

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$a Dumfarth, Alexandra $u Department of Medicine III: Nephrology, Transplant Medicine and Rheumatology, Linz, Austria. Geriatric Department, Ordensklinikum Linz - Elisabethinen, Linz, Austria.

700    1_

$a Cejka, Daniel $u Department of Medicine III: Nephrology, Transplant Medicine and Rheumatology, Linz, Austria. Geriatric Department, Ordensklinikum Linz - Elisabethinen, Linz, Austria.

700    1_

$a Flaschberger, Stefan $u Hospital of Klagenfurt, Klagenfurt, Austria.

700    1_

$a Flögelova, Hana $u Department of Pediatrics, Division of Nephrology, Faculty of Medicine, Palacky University and Faculty Hospital in Olomouc, Olomouc, Czech Republic.

700    1_

$a Haris, Ágnes $u Department of Nephrology, Szent Margit Hospital, Budapest, Hungary.

700    1_

$a Hartmann, Ágnes $u Department of Pediatrics, University of Pécs, Pécs, Hungary.

700    1_

$a Heilos, Andreas $u Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Medical University of Vienna, Vienna, Austria.

700    1_

$a Mueller, Thomas $u Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Medical University of Vienna, Vienna, Austria.

700    1_

$a Rusai, Krisztina $u Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Medical University of Vienna, Vienna, Austria.

700    1_

$a Arbeiter, Klaus $u Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Medical University of Vienna, Vienna, Austria.

700    1_

$a Hofer, Johannes $u Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria. Institute of Neurology of Senses and Language, Hospital of St John of God, Linz, Austria. Research Institute for Developmental Medicine, Johannes Kepler University Linz, Linz, Austria.

700    1_

$a Jakab, Dániel $u Department of Pediatrics, University of Szeged, Szeged, Hungary.

700    1_

$a Sinkó, Mária $u Department of Pediatrics, University of Szeged, Szeged, Hungary.

700    1_

$a Szigeti, Erika $u Department of Pediatrics, University of Szeged, Szeged, Hungary.

700    1_

$a Bereczki, Csaba $u Department of Pediatrics, University of Szeged, Szeged, Hungary.

700    1_

$a Janko, Viktor $u Medimapax - Center of Elimination Methods, Bratislava, Slovakia.

700    1_

$a Kelen, Kata $u 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.

700    1_

$a Reusz, György S $u 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.

700    1_

$a Szabó, Attila J $u 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.

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$a Klenk, Nóra $u FMC Center of Dialysis, Miskolc, Hungary.

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$a Kóbor, Krisztina $u FMC Center of Dialysis, Miskolc, Hungary.

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$a Kojc, Nika $u Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

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$a Knechtelsdorfer, Maarten $u Department of Nephrology, Wilhelminenspital, Vienna, Austria.

700    1_

$a Laganovic, Mario $u Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia.

700    1_

$a Lungu, Adrian Catalin $u Pediatric Nephrology Department, Fundeni Clinical Institute, Bucharest, Romania.

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$a Meglic, Anamarija $u Department of Pediatric Nephrology, Division of Pediatrics, University Medical Centre Ljubljana, Ljubljana, Slovenia.

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$a Kersnik-Levart, Tanja $u Department of Pediatric Nephrology, Division of Pediatrics, University Medical Centre Ljubljana, Ljubljana, Slovenia.

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$a Macioniene, Ernesta $u Nephrology Center, Santaros Klinikos, Medical Faculty, Vilnius University, Vilnius, Lithuania.

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$a Miglinas, Marius $u Nephrology Center, Santaros Klinikos, Medical Faculty, Vilnius University, Vilnius, Lithuania.

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$a Pawłowska, Anna $u Department of Nephrology, Hypertension and Internal Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland.

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$a Stompór, Tomasz $u Department of Nephrology, Hypertension and Internal Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland.

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$a Podracka, Ludmila $u Department of Pediatrics, Comenius University, Bratislava, Slovakia.

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$a Rudnicki, Michael $u Department of Internal Medicine IV-Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria.

700    1_

$a Mayer, Gert $u Department of Internal Medicine IV-Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria.

700    1_

$a Rysava, Romana $u Nephrology Clinic, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

700    1_

$a Reiterova, Jana $u Nephrology Clinic, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

700    1_

$a Saraga, Marijan $u Department of Pathology, University Hospital Split, Split, Croatia. School of Medicine, University of Split, Split, Croatia.

700    1_

$a Seeman, Tomáš $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University Prague, University Hospital Motol, Prague, Czech Republic.

700    1_

$a Zieg, Jakub $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University Prague, University Hospital Motol, Prague, Czech Republic.

700    1_

$a Sládková, Eva $u Department of Pediatrics, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.

700    1_

$a Szabó, Tamás $u Department of Pediatrics, Faculty of Medicine, Debrecen University, Debrecen, Hungary.

700    1_

$a Capitanescu, Andrei $u Carol Davila Nephrology Hospital, Bucharest, Romania.

700    1_

$a Stancu, Simona $u Carol Davila Nephrology Hospital, Bucharest, Romania.

700    1_

$a Tisljar, Miroslav $u Department of Nephrology, Dubrava University Hospital, Zagreb, Croatia.

700    1_

$a Galesic, Kresimir $u Department of Nephrology, Dubrava University Hospital, Zagreb, Croatia.

700    1_

$a Tislér, András $u 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary.

700    1_

$a Vainumäe, Inga $u Živile Riispere, Department of Pathology, Tartu University Hospital, Tartu, Estonia.

700    1_

$a Windpessl, Martin $u Internal Medicine IV, Section of Nephrology, Klinikum Wels-Grieskirchen, Wels, Austria.

700    1_

$a Zaoral, Tomas $u Department of Pediatrics, Faculty of Medicine, University Hospital, Ostrava, Czech Republic.

700    1_

$a Zlatanova, Galia $u University Children's Hospital, Medical University, Sofia, Bulgaria.

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$a Csuka, Dorottya $u Research Laboratory, 3rd Department of Internal Medicine, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.

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