Johanna Stock1, Johannes Kuenanz1, Niklas Glonke1, Joseph Sonntag1, Jenny Frese1, Burkhard Tönshoff2, Britta Höcker2, Bernd Hoppe3, Markus Feldkötter3, Lars Pape4, Christian Lerch4, Simone Wygoda5, Manfred Weber6, Gerhard-Anton Müller1, Oliver Gross7. 1. Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany. 2. Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany. 3. Division of Pediatric Nephrology, University Children's Hospital Bonn, Bonn, Germany. 4. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany. 5. Clinic for Children and Adolescents, Hospital St. Georg, Leipzig, Germany. 6. Cologne General Hospital Merheim, University Witten-Herdecke, Cologne, Germany. 7. Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany. gross.oliver@med.uni-goettingen.de.
Abstract
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.
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.
Authors: Mir Reza Bekheirnia; Berenice Reed; Martin C Gregory; Kim McFann; Alireza Abdollah Shamshirsaz; Amirali Masoumi; Robert W Schrier Journal: J Am Soc Nephrol Date: 2010-04-08 Impact factor: 10.121
Authors: A T Tiebosch; P M Frederik; P J van Breda Vriesman; J M Mooy; H van Rie; T W van de Wiel; J Wolters; E Zeppenfeldt Journal: N Engl J Med Date: 1989-01-05 Impact factor: 91.245
Authors: Katherine A Benson; Susan L Murray; Ross Doyle; Brendan Doyle; Anthony M Dorman; Denise Sadlier; Eoin Brennan; Margaret Large; Gianpiero L Cavalleri; Catherine Godson; Peter J Conlon Journal: Cold Spring Harb Mol Case Stud Date: 2020-10-07
Authors: Majid Moshirfar; David F Skanchy; Aaron T Gomez; Yasmyne C Ronquillo; Benjamin Buckner; Phillip C Hoopes Journal: World J Clin Cases Date: 2019-10-06 Impact factor: 1.337