Diagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN
Roser Torrá, Beata S. Lipska‐Ziętkiewicz, Frederic Acke, Corinne Antignac, Jan U. Becker, Émilie Cornec-Le Gall, Albertien M. van Eerde, Nicolas Feltgen, Rossella Ferrari, Daniel P. Gale, Susie Gear, Oliver Groß, Stefanie Haeberle, Laurence Heidet, Rachel Lennon, Laura Massella, Kristina Pfau, María del Prado Venegas, Rezan Topaloğlu, Tanja Wlodkowski, Heidi Zealey, ERKNet, ERA Genes&Kidney and ESPN Inherited renal disorders working group, Oana Ailioaie, Marina Aksenova, Peter Bárány, Moumita Barua, Elisa Benetti, Lisa Bonebrake, Olivier Bonny, Antonia Bouts, Olivia Boyer, Gianluca Caridi, Cristina Castro-Alonso, Kathleen Claes, Peter J. Conlon, George Claudiu Costea, Stéphane Decramer, Constantinos Deltas, Erol Demir, Nathalie Demoulin, Mark Eijgelsheim, Francesco Emma, Frances Flinter, Mónica Furlano, Danica Galešić Ljubanović, Valentine Gillion, Ana Marta Gomes, Dieter Haffner, Julia Hoefele, Svetlana Jovicic Pavlovic, Clifford E. Kashtan, Stefan Kohl, Martin Konrad, Matjaž Kopač, Sandrine Lemoine, Max Christoph Liebau, Francesca Lugani, A. Madrid, Andrew Mallett, Antonio Mastrangelo, Anamarija Meglič, Esther Meijer, Jeffrey H. Miner, Sevgı Mır, Kar Hui Ng, João Paulo Oliveira, Maria Vanessa Perez Gomez, Anna Maria Pinto, Ann Raes, Michelle N. Rheault, Judy Savige, Christoph Schwarz, Angel Manuel Sevillano Prieto, Ekamol Tantisattamo, Velibor Tasic, Kálmán Tory, Neil Turner, André Weinstock, Izabela Zakrocka
Abstract
Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies. Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children. As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world. Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation. This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes.