Der langfristige Effekt einer RAAS-Blockade auf den Krankheitsverlauf bei heterozygoten Mutationsträgern des Alport-Syndroms

Eine prospektive Vier-Jahres-Auswertung des Europäischen Alport-Registers

The long-term effect of RAAS blockade on the progression of disease in heterozygous mutation carriers of Alport syndrome

A prospective four-year evaluation of the European Alport Register

by Johannes Künanz
Doctoral thesis
Date of Examination:2020-02-19
Date of issue:2020-02-11
Advisor:Prof. Dr. Oliver Gross
Referee:Prof. Dr. Oliver Gross
Referee:PD Dr. Hendrik Rosewich
Persistent Address: http://dx.doi.org/10.53846/goediss-7834

 

 

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Abstract

English

Alport Syndrome (AS) is a hereditary disease that leads to a progressive loss of glomerular basement membrane function due to mutations in collagen IV, but AS is also associated with extra renal symptoms such as hearing loss and ocular changes. Due to the predominant X-chromosomal inheritance pattern, AS in its full manifestation is mainly diagnosed in male patients. Nevertheless, patients with the heterozygous mutations (carrier), therefore all are at risk of developing terminal renal failure. The progression of renal failure can be reduced by ACE inhibitor (ACEi) therapy and thus the onset of terminal renal failure can be significantly delayed. While this therapy has been well studied in the predominantly males, data on the effect of this therapy in carriers of the heterozygous mutation are still scarce. Therefore, I conducted a prospective analysis of 65 heterozygous mutation carriers over a representative period of more than four years based on data from the European Alport Registry to perform. I investigated the effect of ACEi therapy by comparing a group of carriers treated with ACEi and a group of carriers without any treatment. I showed that the therapy group exhibited no disease progression and in a few cases an improvement in renal function was observed. For the first time, it could be prospectively confirmed that therapy with ACEi leads to a stabilization of AS progression in carriers. Consequently, I found that the onset of terminal renal failure under ACEi therapy was delayed significantly. In order to ensure an early start of therapy, it is crucial to make the diagnosis in time. The data I collected show that the time between the first symptom and the final diagnosis is too long for timely therapy, regardless of the patient’s age. Problems are, among others, the insufficient evaluation of extra renal manifestations and the transition from pediatric to adult medicine. In order to improve patient care, I suggest improved cooperation between pediatricians, nephrologists, ophthalmologists and ear specialists. Also, it is essential to include heterozygous carriers in the diagnostic algorithm. Putting these suggestions into action, it can be assumed that terminal renal failure can be prevented in the vast majority of carriers.
Keywords: Alport syndrome; RAAS blockade; ACE inhibitor; European Alport Registry; heterozygous mutations
 
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