Lifelong effect of therapy in young patients with the cOL4A5 alport missense variant p.(Gly624Asp): a prospective cohort study

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) have evolved as a first-line therapy for delaying end-stage renal failure (ESRF) in Alport syndrome. The present study tested the hypothesis of a superior nephroprotective potential of an early ACEi intervention, examining a cohort with the COL4A5 missense variant p.(Gly624Asp). METHODS: In this observational cohort study (NCT02378805), 114 individuals with the identical gene-variant were explored for "age at ESRF" and "life-expectancy" in correlation with treatment as endpoints. RESULTS: All 13 untreated hemizygous patients developed ESRF (mean age 48.9+/-13.7 years) as did three very late treated hemizygotes (51.7+/-4.2 years), with a mean life-expectancy of 59.2+/-9.6 years. All 28 earlier (eGFR 60 ml/min or higher) treated hemizygous patients were still alive and still had not reached ESRF. Therapy minimized the annual loss of their glomerular filtration rate, similar to the annual loss in healthy individuals. Out of 65 heterozygotes, 4 untreated individuals developed ESRF at an age of 53.3+/-20.7 years. None of the treated heterozygous females developed ESRF. CONCLUSIONS: For the first time, this study shows that in Alport syndrome, early therapy in individuals with missense variants might have the potential to delay renal failure for their lifetime and thus to improve life-expectancy and quality of life without the need for renal replacement therapy. Some treated patients have reached retirement age with still-functioning kidneys whereas untreated relatives have already reached ESRF at the same or younger age. Thus, in children with glomerular hematuria, early testing for Alport-related gene variants could lead to timely nephroprotective intervention