Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.
BACKGROUND
Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy.


METHODS
This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed.


RESULTS
The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy.


CONCLUSIONS
Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most-if not all-AS patients with heterozygous mutations in the causal genes.
['Stock|Johanna|J|', 'Kuenanz|Johannes|J|', 'Glonke|Niklas|N|', 'Sonntag|Joseph|J|', 'Frese|Jenny|J|', 'Tönshoff|Burkhard|B|', 'Höcker|Britta|B|', 'Hoppe|Bernd|B|', 'Feldkötter|Markus|M|', 'Pape|Lars|L|', 'Lerch|Christian|C|', 'Wygoda|Simone|S|', 'Weber|Manfred|M|', 'Müller|Gerhard-Anton|GA|', 'Gross|Oliver|O|']
D000293:Adolescent D000328:Adult D017668:Age of Onset D002648:Child D002675:Child, Preschool D018450:Disease Progression D005260:Female D005500:Follow-Up Studies D005838:Genotype D006579:Heterozygote D006801:Humans D007223:Infant D007231:Infant, Newborn D053208:Kaplan-Meier Estimate D007676:Kidney Failure, Chronic D008297:Male D008875:Middle Aged D009154:Mutation D009394:Nephritis, Hereditary D011446:Prospective Studies D051436:Renal Insufficiency, Chronic D012084:Renin-Angiotensin System D016896:Treatment Outcome D055815:Young Adult
Alport syndrome Collagen Chronic kidney disease Familial benign hematuria Fibrosis Renal insufficiency Thin basement membrane disease