title: Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Stock
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kuenanz
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Glonke
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sonntag
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Frese
authors.affiliation: Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
authors.affiliation: Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Höcker
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Bonn, Bonn, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoppe
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Feldkötter
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Pape
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lerch
authors.affiliation: Clinic for Children and Adolescents, Hospital St. Georg, Leipzig, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Wygoda
authors.affiliation: Cologne General Hospital Merheim, University Witten-Herdecke, Cologne, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Weber
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
authors.forename: Gerhard-Anton
authors.initials: GA
authors.lastname: Müller
authors.affiliation: Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany. gross.oliver@med.uni-goettingen.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
mesh_terms: 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 / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016896:Treatment Outcome; D055815:Young Adult
keywords: Alport syndrome; Chronic kidney disease; Collagen; Familial benign hematuria; Fibrosis; Renal insufficiency; Thin basement membrane disease