Molecular aspects and long-term outcome of patients with primary distal renal tubular acidosis.

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.

Efficacy and safety of cinacalcet for the treatment of secondary hyperparathyroidism in patients with advanced chronic kidney disease before initiation of regular dialysis.

AIM: To evaluate the compassionate use of cinacalcet for the management of secondary hyperparathyroidism in patients who are not on dialysis. METHODS: Patients with stage 4-5 chronic kidney disease (CKD) who were not on dialysis, had an intact parathyroid hormone (iPTH) level greater than 300 pg/mL, and had not responded satisfactorily to treatment with phosphate binders and vitamin D were prospectively studied. Patients received 6 months of compassionate treatment with cinacalcet, which was initiated at a dose of 30 mg/day orally and flexibly dosed thereafter based on iPTH levels. RESULTS: Twenty-six patients with a mean age±standard deviation (SD) of 58.8±16.1 years were enrolled in the study and included in the statistical analysis. The mean percentage change in iPTH levels from baseline after 6 months of treatment was -67.9±17.0%, with 92.3% (95% confidence interval (CI), 75.9-97.9) of patients showing an iPTH level within the limits recommended by Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. The mean serum calcium concentrations had decreased significantly at the end of the study (-8.0±6.9%), while the mean serum phosphorus concentration had significantly increased (+8.3±17.0%). CONCLUSION: Our results suggest that cinacalcet may be a useful alternative for the treatment of secondary hyperparathyroidism in pre-dialysis patients who are unresponsive to other treatments. The hypocalcemia and hyperphosphatemia reported in previous studies may not occur if a moderate dose of calcimimetics is used in patients with marginal glomerular filtration rates, especially if combined with vitamin D analogues and calcium-based phosphate binders.