Impact of early initiation of cysteamine on renal and extra-renal outcomes in cystinosis: a retrospective international multicentric cohort study in cystinosis siblings

Presented by Dr Koenraad Veys, Department of Pediatrics, Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium

Authors: Koenraad R.P. Veys*¹, Ward Zadora*¹, Martine Besouw², Mirian Janssen³, Dieter Haffner⁴, Gema Ariceta⁵, Pape Lars⁶, Katharina Hohenfellner⁷, Erik Harms⁸, Detlef Bockenhauer⁹, Patrick Niaudet¹⁰, Robert Novo¹¹, Elke Wühl¹², Przemyslaw Sikora¹³, Rezan Topaloglu¹⁴, Atif Awan¹⁵, Bert van den Heuvel¹⁶, Elena Levtchenko¹

* Both authors contributed equally

Background Cystinosis is a lysosomal storage disorder caused by dysfunction of cystinosin due to various bi-allelic mutations in CTNS, characterized by lysosomal cystine accumulation. Cysteamine, a cystine-depleting agent and the only available disease-modifying treatment, has shown to slow down the progression of chronic kidney disease, and to reduce the incidence of extra-renal manifestations if initiated early and continued lifelong. However, the potential confounding effect of the genetic background on both outcomes remains unknown.

Aims We aimed to investigate the effect of early initiation of cysteamine on the natural course of the renal and extra-renal manifestations in cystinosis patients showing a similar genetic background and exposed to similar environmental conditions.

Materials & Methods An international multicentric retrospective cohort study of cystinosis siblings was set up, and lifelong clinical data was collected to compare the clinical course of index patients with their siblings.

Results Siblings were initiated on cysteamine treatment at the median age of 10 months (1.3 – 18.0), compared to the median age of 23 months (21.0 – 45.0) in the index patients. Index patients and siblings showed a similar compliance based on WBC cystine levels. Siblings showed a significant slower progression towards end-stage renal disease (mean age 13 ± 2.8 years versus 10 ± 3.1 years), and event-free survival curves for several stages of chronic kidney disease and kidney transplantation showed a significant difference. However, upon correction for the kidney function at the age of diagnosis, no significant difference could be demonstrated in renal outcome. No significant difference of extra-renal complications could be observed between siblings and index patients.

Conclusion Early diagnosis and initiation of cysteamine treatment constitutes a major determinant for the progression of chronic kidney disease in cystinosis, irrespective of the genetic background. In contrast, a determining effect of the genetic background on the occurrence of extra-renal manifestations cannot be excluded.

Authors’ Affiliations

1 Department of Pediatrics, Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium

2 Department of Pediatric Nephrology, University Medical Center Groningen, Groningen, The Netherlands

3 Department of Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands

4 Department of Pediatric Kidney, Liver, and Metabolic disease, Hannover Medical School, Hannover, Germany

5 Service of Pediatric Nephrology, University Hospitals Vall d’Hebron Barcelona, Spain

6 Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany

7 Pediatric Nephrology, Rosenheim Kliniken, Rosenheim, Germany

8 Children’s University Hospital, Muenster, Germany

9 Department of Pediatric Nephrology, Great Ormond Street Hospital for Sick Children (GOSH), London, United Kingdom

10 Department of Hereditary Nephropathies and Renal Development, Hôpital Necker-Enfants Malades, Paris, France

11 Department of Pediatrics, CHRU Jeanne de Flandre, Lille, France

12 Department of Pediatric Nephrology, Universitätsklinikum Heidelberg, Heidelberg, Germany

13 Department of Pediatrics, Lublin Medical University, Lublin, Poland

14 Department of Pediatric Nephrology and Rheumatology, Hacettepe Ihsan Dogramaci Children’s Hospital, Ankara, Turkey

15 Pediatric Nephrology and Transplantation, Temple Street Children’s University Hospital, Dublin, Ireland

16 Pediatric Nephrology, University Medical Center Nijmegen, Nijmegen, The Netherlands

Correspondence

Elena Levtchenko, University Hospitals Leuven, KU Leuven, Herestraat 49, Box 817, 3000 Leuven, Belgium, Phone +3216343822, E-mail: [email protected]