P0058THE ROLE OF GENETICS IN INCOMPLETE DISTAL RENAL TUBULAR ACIDOSIS IN NEPHROLITHIASIS

Background and Aims Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in a hyperchloremic non-anion gap metabolic acidosis, hypokalemia and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis and recurrent nephrolithiasis, impaired renal function and bone demineralization due to reabsorption of bicarbonate and phosphate complexed with calcium from the bone as a buffer for metabolic acidosis. Distal RTA is therefore a well-defined entity that can be diagnosed by genetic testing of five genes known to be disease-causative (ATPV1B1 and ATPV0A4, FOXi1, SLC4A1 and WDR72). Incomplete distal renal tubular acidosis (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or other acid load tests. It is observed in 10-20% of calcium stone formers. It is still uncertain whether idRTA represents a distinct entity or it is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. Heterozygous ATP6V1B1 pathogenic variants have been linked to idRTA, as well as mutations in SLC4A1. Method In this cross-sectional study we investigated a group of 23 stone formers whose clinical features were suspicious of idRTA: a history of nephrolithiasis or nephrocalcinosis with morning urinary pH > 5.8 in the absence of overt metabolic acidosis. They therefore underwent a simplified NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 4 genes: SLC4A1, ATP6V1B1, ATP6V0A4 and FOXi1. Results Two unrelated individuals were found to have mutations in SLC4A1: 2 different variants in heterozygosis that had never been described before. The first patient was a 47-year old man, recurrent stone former (mainly apatite, but also some calcium oxalate), with hypercalciuria but normal bone mineral density (BMD). His family history revealed 1 uncle with kidney stones. The second patient was a 56-year old woman with a diagnosis of osteogenesis imperfecta, a history of reduced BMD and severe restrictive ventilation disorder and passed 1 stone (35% apatite, 65% CaOx). She was found to have bilateral nephrocalcinosis and hypocitraturia. Her family history revealed a sister with kidney stones. Conversely, 21 patients did not show any mutations for the genes sequenced, leading to a prevalence of genetic mutations of 8.7%. This is a much lower figure compared with overt dRTA, in which only 30% of patients with a clinical diagnosis of hereditary dRTA have no identified causative mutations in the currently known genes. Conclusion This suggests the involvement of other genes (WDR72 or others) or non-genetic tubular dysfunction in the pathogenesis of idRTA in stone formers.