Persistent Hypophosphatemia in Gitelman Syndrome: A Cohort Study on Prevalence and Associated Factors

Rationale & Objective Gitelman syndrome is a rare, hereditary salt-losing tubulopathy caused by loss-of-function of the sodium chloride co-transporter (NCC) in the distal tubule characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and reduced extracellular volume. While unexpected in a distal tubular disorder, hypophosphatemia was previously reported and may contribute to symptoms. It remains unclear whether hypophosphatemia is transient or persistent, and its underlying mechanism is unknown. Study design Retrospective cohort study Setting & Population Gitelman patients at three European expertise centers. Exposure(s) or Predictor(s) Genetically proven Gitelman syndrome (biallelic SLC12A3 mutations) or a Gitelman-like phenotype and a sibling with genetically proven Gitelman syndrome Outcomes Phosphate levels Analytical approach Phosphate levels were compared to reference values and fasting phosphate levels of a historical cohort. Patients were classified as having persistent hypophosphatemia if their mean phosphate z-score was < -2 and more than 50% of z-scores were < -2. Linear mixed effect models were used to compare the persistent hypophosphatemia group to the normal phosphate group. Results Phosphate levels were lower in Gitelman syndrome compared to fasting controls (phosphate z-score -1.03 [IQR: -1.85 – -0.20] vs. -0.30 [IQR: -1.12 – 0.45]; p<0.001). Hypophosphatemia was present in 19-21% of patients and persistent in 24% of cases with available longitudinal data. Hypophosphatemia was PTH-independent. Patients with persistent hypophosphatemia were prescribed higher dosages of magnesium supplementation (mean difference 21.4 mmol/day [95% CI: 1.38 – 41.4]; p<0.05). Patients using oral contraceptives had lower phosphate levels compared to non-users (mean difference phosphate Z-score: -0.98 [-1.56 – -0.41]; p=0.001). Limitations Retrospective data collection; Phosphate levels were not measured at every outpatient visit for all patients; Paired data on key phosphate regulators (e.g vitamin D and FGF23) and phosphate excretion were largely unavailable. Conclusions Patients with Gitelman syndrome frequently have persistent hypophosphatemia. Magnesium supplementation and oral contraceptives are potentially contributing and modifiable factors.