Verena Klämbt1, Charlotte Gimpel2, Martin Bald3, Christopher Gerken4, Heiko Billing5, Sebastian Loos6, Matthias Hansen7, Jens König8, Tobias Vinke9, Carmen Montoya10, Bärbel Lange-Sperandio11, Martin Kirschstein12, Imke Hennies13, Martin Pohl1, Karsten Häffner14,15. 1. Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center, University of Freiburg, Faculty of Medicine, Mathildenstr. 1, 79106 Freiburg, Germany. 2. Department of Internal Medicine IV, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany. 3. Olga Children's Hospital, Department of Pediatric Nephrology, Klinikum Stuttgart, Stuttgart, Germany. 4. University Children's Hospital Marburg, Philipps-University, Marburg, Germany. 5. Paediatrics I, University Children's Hospital, Tübingen, Germany. 6. University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 7. KfH-Nierenzentrum für Kinder und Jugendliche beim Clementine-Kinderhospital, Frankfurt, Germany. 8. Department of General Pediatrics, University Children's Hospital, Münster, Germany. 9. Department of Pediatrics I, University Children's Hospital of Heidelberg, Heidelberg, Germany. 10. KfH Center of Pediatric Nephrology, Children's Hospital Munich Schwabing, Munich, Germany. 11. Dr. v. Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany. 12. Department of Pediatrics, General Hospital, Celle, Germany. 13. Department of Paediatric Kidney, Liver and Metabolic Diseases, Paediatric Research Center, Hannover Medical School Children's Hospital, Hannover, Germany. 14. Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center, University of Freiburg, Faculty of Medicine, Mathildenstr. 1, 79106 Freiburg, Germany. karsten.haeffner@uniklinik-freiburg.de. 15. Department of Internal Medicine IV, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany. karsten.haeffner@uniklinik-freiburg.de.
Abstract
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP). METHODS: Twenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome. RESULTS: The median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation. CONCLUSION: Our study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment.
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP). METHODS: Twenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome. RESULTS: The median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation. CONCLUSION: Our study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment.
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