An update on current and potential genetic insights and diagnosis of Alport syndrome

ABSTRACT

Introduction

This review presents an approach to early diagnosis and treatment of Alport syndrome, an important genetic cause of kidney failure, with the goal of delaying the need for dialysis and kidney transplantation. This approach is based on an expansive genetic definition of Alport syndrome designed to maximize the identification of affected individuals who may benefit from early intervention.

Areas covered

The areas discussed include the definition of Alport syndrome, estimating the risk and velocity of progression to kidney failure , the impact of early intervention on kidney outcomes, improving early diagnosis and treatment and hearing loss in Alport syndrome. The recommendations in this review are based on the author's reading and interpretation of approximately 1000 papers published on Alport syndrome since 2000 and archived on PubMed.

Expert opinion

It is by now clear that the natural history of Alport kidney disease can be substantially modified by angiotensin-converting enzyme (ACE) inhibition, and that optimal kidney outcomes are achieved by the initiation of treatment while kidney function is still normal. In the coming decade enhanced early diagnosis and treatment will continue to increase the age at onset of kidney failure in the Alport population. Novel therapies that can be added on to ACE inhibition will provide further benefit. Safe and effective curative therapies are not out of reach but there are significant hurdles to overcome to make such approaches a reality.

KEYWORDS:

• Alport syndrome
• basement membranes
• chronic kidney disease
• collagen IV variants
• kidney failure
• sensorineural hearing loss

Article highlights

• Alport syndrome is an important genetic cause of kidney failure resulting from pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that affect the collagen IV alpha345 network of basement membranes.

• Treatment with angiotensin-converting enzyme inhibitors delays the onset of kidney failure in patients with Alport syndrome, with the greatest benefit accruing to those who start treatment while kidney function is still normal.

• An aggressive diagnostic approach in patients with glomerular hematuria, combined with an expansive molecular genetic definition of Alport syndrome, will enhance early diagnosis and initiation of treatment.

This box summarizes the key points contained in the article.

Declaration of interest

C Kashtan is a consultant for Retrophin, Daiichi Sankyo and Ono; has received research funding from Novartis, Reata and Genzyme (Sanofi). He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.