Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study

Abstract

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.

WITHDRAWN: Disrupting the Genetic Code: The Impact of a novel homozygous/heterozygous Splicing Mutation on COL4A3 with mild phenotype in an autosomal recessive Alport Syndrome’s family

“…Unfortunately, AS does not yet have a cure. Numerous research studies have substantiated the efficacy of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) as therapeutic interventions for individuals with AS, effectively delaying the onset of failure of the kidneys in these individuals [26][27][28][29][30] . The proband in our study is treated with ACEI by oral administration, and her urine protein and red blood cells decreased compared with the previous treatment.…”

Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome

“…AS is characterized by renal fibrosis with progression to end-stage renal disease in young adult life ( Barker et al, 1990 ; Grünfeld, 2000 ; Williamson, 1961 ). Though early treatment with angiotensin-converting enzyme inhibitors (ACEi) was shown to reduce proteinuria and delay disease progression in both retrospective ( Gross et al, 2012 ) and prospective ( Boeckhaus et al, 2022 ) studies, there is no specific treatment to prevent renal failure in patients with AS.…”

Empagliflozin reduces renal lipotoxicity in experimental Alport syndrome

“…AS is characterized by renal fibrosis with progression to end-stage renal disease in young adult life (Barker et al, 1990; Grunfeld, 2000; Williamson, 1961). Though early treatment with angiotensin-converting enzyme inhibitors (ACEi) was shown to reduce proteinuria and delay disease progression in both retrospective (Gross et al, 2012) and prospective (Boeckhaus et al, 2022) studies, there is no specific treatment to prevent renal failure in patients with AS.…”