Effectiveness of renin–angiotensin–aldosterone system blockers in patients with Alport syndrome: a systematic review and meta-analysis

Abstract

Background Though renin-angiotensin-aldosterone system (RAAS) blockers have been considered the primary treatment for patients with Alport syndrome (AS) for a decade, there is no comprehensive review with evidence-based analysis evaluating the effectiveness of RAAS blockers in AS. Methods A systematic review and meta-analysis was performed of published studies that compared outcomes related to disease progression between patients with AS receiving RAAS blockers with those taking non-RAAS treatment. Outcomes were meta-analyzed using the random effects models. Cochrane risk-of-bias, Newcastle-Ottawa Scale and GRADE assessment determined the certainty of evidence. Results A total of eight studies (1182 patients) were included in the analysis. Overall, the risk of bias was low to moderate. Compared with non-RAAS treatment, RAAS blockers could reduce the rate of progression to end-stage kidney disease (ESKD) (four studies; HR: 0.33; 95% CI: 0.24–0.45; moderate certainty evidence). After stratified by genetic types, a similar benefit was detected: male X-linked Alport syndrome (XLAS) (HR: 0.32; 95% CI: 0.22–0.48), autosomal recessive Alport syndrome (HR: 0.25; 95% CI: 0.10–0.62), female XLAS and autosomal dominant Alport syndrome (HR: 0.40; 95% CI: 0.21–0.75). In addition, RAAS blockers showed a clear gradient of benefit depending on the stage of disease at the initiation of treatment. Conclusion This meta-analysis suggested that RAAS blockers could be considered as a specific therapy to delay of ESKD for AS with any genetic type, especially at the early stage of the disease, and every further more-effective-therapy would be advised to be applied on top of this standard of care.

WITHDRAWN: Disrupting the Genetic Code: The Impact of a novel homozygous/heterozygous Splicing Mutation on COL4A3 with mild phenotype in an autosomal recessive Alport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.…”

Case report: A case report of Alport syndrome caused by a novel mutation of COL4A5

“…There is currently no specific treatment for AS. ACEI and ARB are often used to treat AS and delay renal failure ( Yamamura et al, 2020b ; Zhang et al, 2021 ; Boeckhaus et al, 2022 ; Zeng et al, 2023 ). Recently, many studies have demonstrated the protective effect of SGLT-2 inhibitors in kidney disease ( Perkovic et al, 2019 ; Heerspink et al, 2020 ), and their therapeutic effects are still being investigated ( Mabillard and Sayer, 2020 ).…”

SGLT2 Inhibitors are Blockbusters in Adults - But Not Studied in Children with Kidney Disease due to Industry Conflicts of Commercial Interest: A Call for Help To Regulators

“…"Genotype-phenotype" correlation and "genotype-response to therapy (Angiotensinconverting enzyme (ACE)-inhibition) correlation" have been described in hundreds of patients with Alport syndrome worldwide. 4 A previous investigator-initiated randomized Placebocontrolled trial in children two years and older, EARLY PRO-TECT Alport, 5 registry data, 6 trial concepts discussed with the FDA, 7 a case series, 8 as well as a recent meta-analysis,4 cumulated high quality good clinical practice (ICH-GCP) conform clinical data from children with Alport syndrome and chronic kidney disease, a unique tool to plan the first Pediatric randomized controlled trial in chronic kidney disease with SGLT2-inhibitors. The world's first pediatric randomized controlled trial, DOUBLE PRO-TECT Alport, is a proof of concept showing that -if a high unmet medical need meets academia -combined efforts of patient alliances and physicians can make things happen after a five-year planning phase: very positively, the idea for a Pediatric chronic kidney disease trial with SGLT2-inhibitors originates from industry.…”

“…In Alport syndrome, the international therapy recommendations recommend ACE-inhibitors, especially Ramipril, 19 as a specific therapy for oligo-symptomatic small children from the age of 2 years, because observational studies in Europe and Asia show a clear therapeutic effect and a randomized controlled trial also shows the safety in small children, as was recently the case summarized in a meta-analysis. 4 From a scientific point of view, the evidence for the off-label use of ACE-inhibitors such as ramipril in children with Alport syndrome in terms of delaying dialysis and improving life expectancy is far better than the evidence for the -approved -enzyme replacement therapy in Fabry disease. Nevertheless, ACE-inhibitors such as ramipril are not approved, quite the opposite of enzyme replacement therapy for Fabry disease.…”

“…If it comes to use of ACE-inhibitor in children with chronic kidney disease, we do not want to make a profit with a drug, but use it safely and effectively with the help of a Benefit-risk assessment by the European Medicines Agency EMA and the Food and Drug Administration FDA, which is absolutely possible due to the wide range of data for ACE-inhibitors in Alport syndrome. 2,[4][5][6][7]12,13,19 Now that ACE-inhibitors are and will remain standard of care anyway, why do we need advice by regulatory authorities? An assessment by the European Medicines Agency EMA and the Food and Drug Administration FDA would be extremely helpful, because the regulatory authorities have global expertise and an overall view of the data situation that is outstanding worldwide.…”