Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies

Alexis Werion; Pauline Storms; Ysaline Zizi; Claire Beguin; Jelle Bernards; Jean-François Cambier; Karin Dahan; Daan Dierickx; Nathalie Godefroid; Pascale Hilbert; Catherine Lambert; Elena Levtchenko; Thomas Meyskens; Xavier Poiré; Lambert van den Heuvel; Kathleen J Claes; Johann Morelle; UCLouvain TMA/HUS Network and KU Leuven TMA/HUS Network

doi:10.2215/CJN.0000000000000182

Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies

Clin J Am Soc Nephrol. 2023 Apr 21;18(7):881-891. doi: 10.2215/CJN.0000000000000182. Online ahead of print.

Authors

Alexis Werion^{1

2}, Pauline Storms³, Ysaline Zizi¹, Claire Beguin⁴, Jelle Bernards^{5

6}, Jean-François Cambier⁷, Karin Dahan⁸, Daan Dierickx³, Nathalie Godefroid^{2

9}, Pascale Hilbert⁸, Catherine Lambert^{2

10}, Elena Levtchenko¹¹, Thomas Meyskens¹², Xavier Poiré^{2

10}, Lambert van den Heuvel^{11

13}, Kathleen J Claes^{5

14}, Johann Morelle^{1

2}; UCLouvain TMA/HUS Network and KU Leuven TMA/HUS Network

Collaborators

UCLouvain TMA/HUS Network and KU Leuven TMA/HUS Network:
Selda Aydin, Charles Cuvelier, Pierre-Yves Decleire, Nathalie Demoulin, Arnaud Devresse, Ludovic Gérard, Gaëlle Gillerot, Valentine Gillion, Eric Goffin, Philippe Hantson, Michel Jadoul, Jean Jamez, Nada Kanaan, Laura Labriola, Jean-Philippe Lengelé, Lionel Mazzoleni, Yves Pirson, Jean-Michel Pochet, Nadejda Ranguelov, Marie-Astrid van Dievoet, Elliott van Regemorter, Xavier Wittebole, Bert Bammens, Greet de Vlieger, Koenraad Devriendt, Katrien de Vusser, Pieter Evenepoel, Laurent Godinas, Priyanka Koshy, Dirk Kuypers, Evelyne Lerut, Björn Meijers, Maartens Naesens, Patrick Schöffski, Ben Sprangers, Dirk Timmerman, Amaryllis van Craenenbroeck, Alexander Wilmer

Affiliations

¹ Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
² Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
³ Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
⁴ Department of Medical Informatics and Statistics, Cliniques universitaires Saint-Luc, Brussels, Belgium.
⁵ Department of Nephrology, Dialysis, and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
⁶ Department of Nephrology, ZNA Middelheim, Antwerpen, Belgium.
⁷ Department of Nephrology, Grand Hôpital de Charleroi, Gilly, Charleroi, Belgium.
⁸ Institut de Pathologie et de Génétique, Gosselies, Belgium.
⁹ Division of Pediatric Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
¹⁰ Division of Hematology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
¹¹ Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
¹² Department of Oncology, AZ Klina, Brasschaat, Belgium.
¹³ Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁴ Department of Microbiology, Immunology, and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium.

PMID: 37094330
PMCID: PMC10356144 (available on 2024-07-01)
DOI: 10.2215/CJN.0000000000000182

Abstract

Background: The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA.

Methods: In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers.

Results: During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference).

Conclusions: Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.

Trial registration: ClinicalTrials.gov NCT04743804.

Associated data

ClinicalTrials.gov/NCT04743804