Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations
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Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1–20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1–4) with/without nephroprotective therapy.
This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan–Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed.
The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2–18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0–52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy.
Treatment with blockers of the renin–angiotensin–aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most—if not all—AS patients with heterozygous mutations in the causal genes.
KeywordsChronic kidney disease Renal insufficiency Fibrosis Collagen Alport syndrome Thin basement membrane disease Familial benign hematuria
The authors wish to thank the patients and relatives and the German patients advocacy group (Alport Selbsthilfe e.V.) for their contributions. Original data acquisition of the European Alport Registry was supported 2006 to 2010 by the Association pour l’Information et la Recherche sur les Maladies Rénales Génétiques (AIRG). Parts of the registry data were made public in abstract form at the annual meetings of the German and the European Renal Association in 2015.
The first and the last author JS and OG had full access to all the data in the study and take responsibility for the content of the manuscript, including the data and analysis. JS and OG contributed to the conception and design of the study, analysis and interpretation of data, drafting the article, revising the paper and final approval of the manuscript. All other authors contributed to the acquisition of data, revision of the manuscript and final approval. All authors have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Compliance with ethical standards
The authors declare that they have no competing interests.
The registry and data storage, in conformity with GCP guidelines, were approved by the Ethics Committee of the University Medical Center Göttingen. For ethical and data safety reasons, we only re-contacted patients from German-speaking countries and only patients who contacted us previously by email, facsimile or personally. Informed consent was obtained for all participants.
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