Predictors of proteinuria, amyloidosis and kidney failure in familial Mediterranean fever: data from the International AIDA Network Registry

Antonio Vitale^{1

2}, Valeria Caggiano^{1

2}, Jessica Sbalchiero^{1

2}, Abdurrahman Tufan³, Ezgi Deniz Batu⁴, Gaafar Ragab^{5

6}, Piero Portincasa⁷, Giovanni Conti⁸, Emma Aragona⁹, Jurgen Sota^{1

2}, Francesco Gavioli^{1

2}, Carla Gaggiano^{1

2}, Amato De Paulis^{10

11}, Ali Şahin¹², Maria Cristina Maggio¹³, Donato Rigante^{14

15}, Alma Nunzia Olivieri¹⁶, Derya Yildirim³, Hamit Kucuk³, Riza Can Kardas³, Ibrahim Vasi³, Seza Ozen⁴, Yelda Bilginer⁴, Seher Sener⁴, Hulya Ercan Emreol⁴, Ayman Abdel-Monem Ahmed Mahmoud⁵, Mahmoud Ghanema⁵, Amina Maher⁵, Moustafa Ali Saad⁵, Nour Jaber⁷, Mohamad Khalil⁷, Agostino Di Ciaula⁷, Ludovica De Palma⁸, Renata Cuzzola⁸, Andrea Affronti⁹, Fabrizio Gambino⁹, Francesca Della Casa^{10

11}, Ilaria Mormile^{10

11}, Arif Babayiğit¹², Neşe Çabuk Çelik¹², Maria Francesca Gicchino¹⁶, Karina Jahnz-Rozyk¹⁷, Francesco La Torre¹⁸, Antonella Insalaco¹⁹, Andreas Recke²⁰, Emanuela Del Giudice²¹, Patrizia Barone²², Marco Cattalini²³, Antonio Luca Brucato²⁴, Daniela Opris-Belinski²⁵, Petros P Sfikakis²⁶, Francesca Li Gobbi²⁷, Giacomo Emmi^{28

29

30}, Henrique A Mayrink Giardini³¹, José Hernández-Rodríguez³², Paola Parronchi³³, Piero Ruscitti³⁴, Stefania Costi³⁵, Samar Tharwat^{36

37}, Anastasios Karamanakos³⁸, Paolo Sfriso³⁹, Alessandro Conforti⁴⁰, Elena Verrecchia^{15

41}, Giuseppe Lopalco⁴², Benson Ogunjimi^{43

44

45

46}, Ewa Wiesik-Szewczyk¹⁷, Alberto Balistreri⁴⁷, Claudia Fabiani^{2

48}, Bruno Frediani^{1

2}, Luca Cantarini^{1

2}

Affiliations

¹ Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, University of Siena, Siena, Italy.
² Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Siena, Italy.
³ Department of Internal Medicine, Division of Rheumatology, Gazi University Hospital, Ankara, Turkey.
⁴ Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey.
⁵ Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
⁶ Faculty of Medicine, Newgiza University, 6th of October City, Egypt.
⁷ Clinica Medica "A. Murri", Division of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro, Bari, Italy.
⁸ Pediatric Nephrology and Rheumatology Unit, Azienda Ospedaliera Universitaria (AOU) "G. Martino", University of Messina, Messina, Italy.
⁹ Division of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, Palermo, Italy.
¹⁰ Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
¹¹ Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, Italy.
¹² Division of Rheumatology, Department of Internal Medicine, Sivas Cumhuriyet University Medical Faculty, Sivas, Turkey.
¹³ University Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) "G. D'Alessandro", University of Palermo, Palermo, Italy.
¹⁴ Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
¹⁵ Rare Diseases and Periodic Fevers Research Centre, Università Cattolica del Sacro Cuore, Rome, Italy.
¹⁶ Department of Woman, Child and of General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
¹⁷ Department of Internal Medicine, Pneumonology, Allergology, Clinical Immunology and Rare Diseases, Military Institute of Medicine, National Research Institute, Warsaw, Poland.
¹⁸ Department of Pediatrics, Pediatric Rheumatology Center, Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy.
¹⁹ Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Rome, Italy.
²⁰ Department of Dermatology, Allergology and Venerology, University Hospital Schleswig-Holstein, Campus Lübeck, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Lübeck, Germany.
²¹ Pediatric and Neonatology Unit, Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Latina, Italy.
²² Pediatric Rheumatology Unit, Department of integrated Maternal-Child and Reproduction Activity, AOU "Policlinico-San Marco" Catania, Italy.
²³ Department of Experimental and Clinical Sciences, Paediatrics Clinic, University of Brescia and Spedali Civili of Brescia, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Brescia, Italy.
²⁴ Department of Biomedical and Clinical Sciences, Fatebenefratelli Hospital, Università di Milano, Milan, Italy.
²⁵ Rheumatology and Internal Medicine Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
²⁶ Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Athens, Greece.
²⁷ Rheumatology Unit, Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro, Florence, Italy.
²⁸ Department of Medical, Surgical and Health Sciences, University of Trieste, Italy.
²⁹ Clinical Medicine and Rheumatology Unit, Cattinara University Hospital, Trieste, Italy.
³⁰ Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, Australia.
³¹ Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, Brazil.
³² Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic of Barcelona [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], University of Barcelona, Barcelona, Spain.
³³ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
³⁴ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
³⁵ Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Milan, Italy.
³⁶ Rheumatology and Immunology Unit, Internal Medicine Department, Mansoura University, Mansoura, Egypt.
³⁷ Department of Internal Medicine, Faculty of Medicine, Horus University, New Damietta, Egypt.
³⁸ Department of Rheumatology, "Evangelismos" General Hospital, Athens, Greece.
³⁹ Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy.
⁴⁰ Ospedale San Paolo di Civitavecchia, U.O. Medicina Generale, Civitavecchia, Rome, Italy.
⁴¹ Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
⁴² Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J) Policlinic Hospital, University of Bari, Bari, Italy.
⁴³ Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of Antwerp, Antwerp, Belgium.
⁴⁴ Antwerp Center for Translational Immunology and Virology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
⁴⁵ Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium.
⁴⁶ Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
⁴⁷ Bioengineering and Biomedical Data Science Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
⁴⁸ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

PMID: 40175882
DOI: 10.1093/rheumatology/keaf181

Predictors of proteinuria, amyloidosis and kidney failure in familial Mediterranean fever: data from the International AIDA Network Registry

Antonio Vitale et al. Rheumatology (Oxford). 2025.

. 2025 Aug 1;64(8):4776-4787.

doi: 10.1093/rheumatology/keaf181.

Authors

Affiliations

¹ Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, University of Siena, Siena, Italy.
² Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Siena, Italy.
³ Department of Internal Medicine, Division of Rheumatology, Gazi University Hospital, Ankara, Turkey.
⁴ Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey.
⁵ Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
⁶ Faculty of Medicine, Newgiza University, 6th of October City, Egypt.
⁷ Clinica Medica "A. Murri", Division of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro, Bari, Italy.
⁸ Pediatric Nephrology and Rheumatology Unit, Azienda Ospedaliera Universitaria (AOU) "G. Martino", University of Messina, Messina, Italy.
⁹ Division of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, Palermo, Italy.
¹⁰ Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
¹¹ Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, Italy.
¹² Division of Rheumatology, Department of Internal Medicine, Sivas Cumhuriyet University Medical Faculty, Sivas, Turkey.
¹³ University Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) "G. D'Alessandro", University of Palermo, Palermo, Italy.
¹⁴ Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
¹⁵ Rare Diseases and Periodic Fevers Research Centre, Università Cattolica del Sacro Cuore, Rome, Italy.
¹⁶ Department of Woman, Child and of General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
¹⁷ Department of Internal Medicine, Pneumonology, Allergology, Clinical Immunology and Rare Diseases, Military Institute of Medicine, National Research Institute, Warsaw, Poland.
¹⁸ Department of Pediatrics, Pediatric Rheumatology Center, Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy.
¹⁹ Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Rome, Italy.
²⁰ Department of Dermatology, Allergology and Venerology, University Hospital Schleswig-Holstein, Campus Lübeck, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Lübeck, Germany.
²¹ Pediatric and Neonatology Unit, Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Latina, Italy.
²² Pediatric Rheumatology Unit, Department of integrated Maternal-Child and Reproduction Activity, AOU "Policlinico-San Marco" Catania, Italy.
²³ Department of Experimental and Clinical Sciences, Paediatrics Clinic, University of Brescia and Spedali Civili of Brescia, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Brescia, Italy.
²⁴ Department of Biomedical and Clinical Sciences, Fatebenefratelli Hospital, Università di Milano, Milan, Italy.
²⁵ Rheumatology and Internal Medicine Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
²⁶ Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Athens, Greece.
²⁷ Rheumatology Unit, Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro, Florence, Italy.
²⁸ Department of Medical, Surgical and Health Sciences, University of Trieste, Italy.
²⁹ Clinical Medicine and Rheumatology Unit, Cattinara University Hospital, Trieste, Italy.
³⁰ Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, Australia.
³¹ Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, Brazil.
³² Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic of Barcelona [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], University of Barcelona, Barcelona, Spain.
³³ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
³⁴ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
³⁵ Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Milan, Italy.
³⁶ Rheumatology and Immunology Unit, Internal Medicine Department, Mansoura University, Mansoura, Egypt.
³⁷ Department of Internal Medicine, Faculty of Medicine, Horus University, New Damietta, Egypt.
³⁸ Department of Rheumatology, "Evangelismos" General Hospital, Athens, Greece.
³⁹ Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy.
⁴⁰ Ospedale San Paolo di Civitavecchia, U.O. Medicina Generale, Civitavecchia, Rome, Italy.
⁴¹ Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
⁴² Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J) Policlinic Hospital, University of Bari, Bari, Italy.
⁴³ Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of Antwerp, Antwerp, Belgium.
⁴⁴ Antwerp Center for Translational Immunology and Virology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
⁴⁵ Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium.
⁴⁶ Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
⁴⁷ Bioengineering and Biomedical Data Science Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
⁴⁸ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

PMID: 40175882
DOI: 10.1093/rheumatology/keaf181

Abstract

Objectives: Proteinuria, amyloidosis and kidney failure are the main long-term renal complications of FMF. This study assesses their risk factors, independent of ethnicity or residence.

Methods: Patients' data were drawn from the International AIDA Network registry for monogenic autoinflammatory diseases.

Results: A total of 598 FMF patients were enrolled, with 80 having proteinuria, 61 amyloidosis and 25 kidney failure. At multivariate regression analysis, proteinuria was associated with out-of-flares thrombocytosis (odds ratio [OR]: 4.78, 95% CI: 1.54-14.8, P = 0.007), increased out-of-flares ESR (OR: 2.7, 95% CI: 1.3-5.6, P = 0.008), homozygous M694V mutation (OR: 2.27, 95% CI: 1.1-4.66, P = 0.025) and heterozygous M694V mutation (OR: 0.29, 95% CI: 0.09-0.86, P = 0.026); amyloidosis was associated with the disease duration (OR: 1.034, 95% CI: 1.004-1.065, P = 0.027), during-flares anaemia (OR: 2.9, 95% CI: 1.18-7.19, P = 0.021), out-of-flares leucocytosis (OR: 7.47, 95% CI: 1.6-34.7, P = 0.01), increased out-of-flares ESR (OR: 3.6, 95% CI: 1.48-8.81, P = 0.005) and heterozygous M694V mutation (OR: 0.18, 95% CI: 0.035-0.9, P = 0.04); kidney failure was associated with the age at diagnosis (OR: 1.04, 95% CI: 1.0003-1.19, P = 0.048), the disease duration in years (OR: 1.07, 95% CI: 1.02-1.12, P = 0.005), attack frequency per year (OR: 1.04, 95% CI: 1.007-1.076, P = 0.019), anaemia out-of-flares (OR: 4.7, 95% CI: 1.004-22.1, P = 0.049) and out-of-flares leucocytosis (OR: 25.8, 95% CI: 2.75-242, P = 0.004). The intraclass correlation coefficient related to ethnicity and country of residence was 6.7% and 6.8% for amyloidosis, respectively, and 0% for proteinuria and kidney failure.

Conclusion: FMF patients with older age at diagnosis, longer disease duration, anaemia, leucocytosis, thrombocytosis, elevated ESR and homozygous M694V mutation are at higher risk of kidney complications.

Keywords: FMF; complications; kidney; outcome; prognosis.

© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Predictors of proteinuria, amyloidosis and kidney failure in familial Mediterranean fever: data from the International AIDA Network Registry

Affiliations

Predictors of proteinuria, amyloidosis and kidney failure in familial Mediterranean fever: data from the International AIDA Network Registry

Authors

Affiliations

Abstract

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous