#817 Genetic testing in adults with nephrocalcinosis enables precision diagnosis

Abstract Background and Aims Nephrocalcinosis (NC) refers to the parenchymal form of nephrolithiasis (NL), and could be detected by ultrasonography or computer tomography (CT), isolated or in association with NL. The etiology of NC and NL is multifactorial and includes both environmental components and genetic components. Molecular analysis in patients with NC allows an appropriate evaluation. Genetic testing for known pathogenic mutations has become more accessible due to technologic advances and decreasing of the cost. Method We report a retrospective observational study that included adults with diagnosis of nephrocalcinosis diagnosed by renal ultrasound or CT scan, on whom we performed a genetic test using nephrolithiasis panel, from two commercial genetic laboratories. The study was conducted between September 2020–December 2024 in the nephrology department, Fundeni Clinical Institute. Demographics, personal and family history, clinical and biological data were recorded at the time of genetic test performance. The estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation, and CKD stage was classified according to the KDIGO guideline. Results The study included 13 adult patients, 6 males and 7 females. The mean age at the time of genetic testing was 33.0 ± 10.3 years, but the mean age of the NC diagnosis was 20.1 ± 10.9 years. All patients presented medullary NC; in nine patients (69.2%) had NC associated with NL, and four patients (30.8%) had isolated NC. Family history was positive for NL and/or NC in 8 patients (61.5%). Also, 7 patients (53.8%) presented pediatric onset of the disease. We found a Mendelian disease in 10 patients: inherited distal renal tubular acidosis (dRTA) (SLC4A1; n = 3), Dent disease (CLCN5; n = 2), infantile hypercalcemia type 1 (CYP24A1; n = 2), familial hypomagnesaemia with hypercalciuria and NC (CLDN16; n = 1), primary hyperoxaluria (PH) type 1 (AGXT; n = 1), Bartter syndrome type 2 (KCNJ1; n = 1). One patient had a monoallelic pathogenic variant in SLC34A3 gene, another patient had a monoallelic variant of uncertain significance of SLC3A1 gene, and in one patient the genetic test was negative. Analyzing the inheritance type of the Mendelian diseases we noticed that 5 patients had an autosomal recessive genetic disease, 3 had an autosomal dominant genetic type of inheritance, and 2 patients had an X-linked disease. Considering the chronic kidney disease (CKD) stage, 6 patients had CKD G1-G2, 4 patients had CKD G3, 2 patients had CKD G4, and 1 patient had a kidney transplant. Other specific manifestations in those 12 patients with positive genetic test included, distal renal tubular acidosis (n = 4), hypercalciuria (n = 3), low intact parathormone (n = 2). Although the clinical diagnosis was concordant with the molecular diagnosis in 5 patients with Mendelian disease, another 5 patients remained clinically undiagnosed due to the association with other genetic disease (mutation of GANAB gene, n = 1), the presence of advanced kidney disease that altered the clinical phenotype, and the variability of the phenotype. Knowing the molecular diagnosis, we implemented a personalized management that included: initiating the specific treatment such as the newly introduced small interfering RNA treatment for the PH type 1 patient, avoiding vitamin D for patients with infantile hypercalcemia type 1, correction of acidosis, hypokalemia for inherited dRTA patients. Conclusion In our study, 12/13 patients tested for genetic causes of NC presented mutations of different genes, and 10/13 patients had a Mendelian disease. Our results confirm that NC is a manifestation which is frequently associated with a genetic disease. Thus, genetic testing should be considered in all patients with nephrocalcinosis. Genetic testing enables accurate diagnoses, changes in disease management, and precision medicine, that could significantly influence the long-term outcomes.