Sara Gómez-Conde1, Alejandro García-Castaño1,2, Mireia Aguirre1,3, María Herrero1,3, Leire Gondra1,3,4, Nélida García-Pérez1,4,5, Paula García-Ledesma6, Luis Martín-Penagos7, Cecilia Dall'Anese8, Gema Ariceta9, Luis Castaño1,2,4, Leire Madariaga10,11,12,13. 1. Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. 2. CIBERDEM, CIBERER, Endo-ERN, Madrid, Spain. 3. Pediatric Nephrology Department, Cruces University Hospital, Barakaldo, Spain. 4. Pediatric Department, University of the Basque Country UPV/EHU, Leioa, Spain. 5. Pediatric Nephrology Department, Basurto University Hospital, Bilbao, Spain. 6. Nephrology Department, Galdakao-Usansolo Hospital, Galdakao, Spain. 7. Nephrology Department, Marqués de Valdecilla University Hospital, Santander, Spain. 8. Nephrology Department, San Pedro Hospital, Logroño, Spain. 9. Pediatric Nephrology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 10. Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. LEYRE.MADARIAGADOMINGUEZ@osakidetza.eus. 11. CIBERDEM, CIBERER, Endo-ERN, Madrid, Spain. LEYRE.MADARIAGADOMINGUEZ@osakidetza.eus. 12. Pediatric Nephrology Department, Cruces University Hospital, Barakaldo, Spain. LEYRE.MADARIAGADOMINGUEZ@osakidetza.eus. 13. Pediatric Department, University of the Basque Country UPV/EHU, Leioa, Spain. LEYRE.MADARIAGADOMINGUEZ@osakidetza.eus.
Abstract
BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal mechanisms of urinary acidification. Most cases are secondary to pathogenic variants in ATP6V0A4, ATP6V1B1, and SLC4A1 genes, which encode transporters regulating acid-base balance in the collecting duct. METHODS: Retrospective study of molecular and clinical data from diagnosis and long-term follow-up (10, 20, and 40±10 years) of 16 patients with primary dRTA diagnosed in childhood. RESULTS: Molecular analyses revealed nine patients had ATP6V0A4 pathogenic variants, five in ATP6V1B1, and two in SLC4A1. A novel intragenic deletion and a common ATP6V0A4 gene variant (c.1691 + 2dupT) in ATP6V0A4 occurred in two-thirds of these patients, suggesting a founder effect. Median age at diagnosis was 3.25 months (IQR 1, 13.5), which was higher in the SLC4A1 group. Median SDS height at diagnosis was -1.02 (IQR -1.79, 0.14). Delayed clinical diagnosis was significantly related to growth failure (P = 0.01). Median SDS height at 20 years follow-up was -1.23 (IQR -1.71, -0.48), and did not significantly improve from diagnosis (P = 0.76). Kidney function declined over time: at last follow-up, 43% had moderate to severe chronic kidney disease (CKD). Adequate metabolic control was not related to CKD development. Incidence of sensorineural hearing loss (SNHL) was high in ATP6V1B1 patients, though not universal. Patients harboring ATP6V0A4 variants also developed SNHL at a high rate (80%) over time. CONCLUSIONS: Patients with dRTA can develop moderate to severe CKD over time with a high frequency despite adequate metabolic control. Early diagnosis ameliorates long-term height prognosis.
BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal mechanisms of urinary acidification. Most cases are secondary to pathogenic variants in ATP6V0A4, ATP6V1B1, and SLC4A1 genes, which encode transporters regulating acid-base balance in the collecting duct. METHODS: Retrospective study of molecular and clinical data from diagnosis and long-term follow-up (10, 20, and 40±10 years) of 16 patients with primary dRTA diagnosed in childhood. RESULTS: Molecular analyses revealed nine patients had ATP6V0A4 pathogenic variants, five in ATP6V1B1, and two in SLC4A1. A novel intragenic deletion and a common ATP6V0A4 gene variant (c.1691 + 2dupT) in ATP6V0A4 occurred in two-thirds of these patients, suggesting a founder effect. Median age at diagnosis was 3.25 months (IQR 1, 13.5), which was higher in the SLC4A1 group. Median SDS height at diagnosis was -1.02 (IQR -1.79, 0.14). Delayed clinical diagnosis was significantly related to growth failure (P = 0.01). Median SDS height at 20 years follow-up was -1.23 (IQR -1.71, -0.48), and did not significantly improve from diagnosis (P = 0.76). Kidney function declined over time: at last follow-up, 43% had moderate to severe chronic kidney disease (CKD). Adequate metabolic control was not related to CKD development. Incidence of sensorineural hearing loss (SNHL) was high in ATP6V1B1 patients, though not universal. Patients harboring ATP6V0A4 variants also developed SNHL at a high rate (80%) over time. CONCLUSIONS: Patients with dRTA can develop moderate to severe CKD over time with a high frequency despite adequate metabolic control. Early diagnosis ameliorates long-term height prognosis.
Authors: Sergio Camilo Lopez-Garcia; Francesco Emma; Stephen B Walsh; Marc Fila; Nakysa Hooman; Marcin Zaniew; Aurélia Bertholet-Thomas; Giacomo Colussi; Kathrin Burgmaier; Elena Levtchenko; Jyoti Sharma; Jyoti Singhal; Neveen A Soliman; Gema Ariceta; Biswanath Basu; Luisa Murer; Velibor Tasic; Alexey Tsygin; Stéphane Decramer; Helena Gil-Peña; Linda Koster-Kamphuis; Claudio La Scola; Jutta Gellermann; Martin Konrad; Marc Lilien; Telma Francisco; Despoina Tramma; Peter Trnka; Selçuk Yüksel; Maria Rosa Caruso; Milan Chromek; Zelal Ekinci; Giovanni Gambaro; Jameela A Kari; Jens König; Francesca Taroni; Julia Thumfart; Francesco Trepiccione; Louise Winding; Elke Wühl; Ayşe Ağbaş; Anna Belkevich; Rosa Vargas-Poussou; Anne Blanchard; Giovanni Conti; Olivia Boyer; Ismail Dursun; Ayşe Seda Pınarbaşı; Engin Melek; Marius Miglinas; Robert Novo; Andrew Mallett; Danko Milosevic; Maria Szczepanska; Sarah Wente; Hae Il Cheong; Rajiv Sinha; Zoran Gucev; Stephanie Dufek; Daniela Iancu; Robert Kleta; Franz Schaefer; Detlef Bockenhauer Journal: Nephrol Dial Transplant Date: 2019-06-01 Impact factor: 5.992