Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy

Abstract

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Outcomes of Male Patients with Alport Syndrome Undergoing Renal Replacement Therapy

“…It is conceivable that increasing use of renoprotective therapy with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers over the past two decades may have been beneficial in adolescents with Alport syndrome (12,20). In addition, earlier diagnosis and increased awareness of possible therapeutic options for Alport syndrome in recent years may have delayed the onset of RRT and improved outcome.…”

“…Until the late 1990s, no therapy could be offered to patients with Alport syndrome to delay onset of kidney failure. Angiotensin-converting enzyme inhibitor therapy may delay disease progression, according to studies in both animal models (19) and humans (20).…”

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

“…Accurate genetic counseling and reasonable estimation of prognosis in patients and families with persistent hematuria require precise diagnosis, which is especially important, because early therapeutic intervention has recently been shown to be effective in AS. 23 Comprehensive clinical evaluation and pedigree analysis (including testing of relatives for hematuria) combined with histopathology and study of type IV collagen expression in skin and kidney BM are sometimes sufficient to firmly establish a diagnosis and determine the risk of transmission. However, in many cases, molecular analysis is necessary to achieve the desired level of diagnostic accuracy.…”

Feasibility of Repairing Glomerular Basement Membrane Defects in Alport Syndrome

“…2 A progression of hematuria, proteinuria, and glomerulosclerosis leads to ESRD, usually by adolescence or young adulthood. Angiotensin-converting enzyme (ACE) inhibition slows progression to proteinuria and ESRD, 6 but there is no cure for Alport syndrome.…”