Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study

Abstract

Background: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies.

Methods: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN).

Results: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting.

Conclusions: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Keywords: Bartter syndrome; Gitelman syndrome; parathyroid hormone; phosphate; salt losing tubulopathies.

Graphical Abstract

FIGURE 1:

Patient cohort. NOS, not otherwise specified. Patients were grouped for analysis according to the genetic confirmation of disease (subtype). *Creatinine and PTH had to be provided. ^# 51 patients with Bartter syndrome type I and 56 patients with Bartter syndrome type II.

FIGURE 2:

Boxplots of iPTH, calcium, phosphate-SDS and TmP/GFR-SDS according to disease subtype iPTH, intact parathyroid hormone; phosphate-SDS, age-related phosphate standard deviation score; TmP/GFR-SDS, age-related ratio of tubular maximum reabsorption of phosphate to GFR standard deviation score; Boxplot graphs represent the median and IQR; the upper and lower whiskers represent data points within 25th percentile − 1.5x IQR and 75th percentile + 1,5x IQR. Outliers are plotted individually. *P < .05; **P < .01; ***P < .001. A. iPTH in pmol/L; statistically significant difference in iPTH level between patients with Bartter syndrome type I and II and patients with Bartter syndrome type III, Bartter syndrome NOS and Gitelman syndrome. B. Calcium in mmol/L, statistically significant difference in calcium level between patients with Bartter syndrome type I and II and patients with Gitelman syndrome. C. Phosphate-SDS; statistically significant difference in age-adjusted phosphate level between patients with Bartter syndrome type III and patients with Bartter syndrome type I and II and Gitelman syndrome. D. TmP/GFR-SDS; statistically significant difference between Bartter syndrome type I and II and Bartter syndrome NOS and Gitelman syndrome.

FIGURE 3:

Scatterplots of calcium, urinary calcium/creatinine ratio, phosphate-SDS, TmP/GFR-SDS and alkaline phosphatase-SDS with iPTH of patients with Bartter syndrome type I and II. iPTH, intact parathyroid hormone; phosphate-SDS, age-related phosphate standard deviation score; alkaline phosphatase-SDS, age-related alkaline phosphatase standard deviation score; TmP/GFR-SDS: age-related ratio of tubular maximum reabsorption of phosphate to GFR standard deviation score; A. Scatterplot of calcium with iPTH. B. Scatterplot of urinary calcium/creatinine ratio with iPTH. C. Scatterplot of phosphate-SDS with iPTH. D. Scatterplot of TmP/GFR-SDS with iPTH. E. Scatterplot of alkaline phosphatase-SDS with iPTH.

FIGURE 4:

Scatterplots of TmP/GFR with age-adjusted phosphate Phosphate-SDS, age-related phosphate standard deviation score; TmP/GFR-SDS, age-related ratio of tubular maximum reabsorption of phosphate to GFR standard deviation score; A. Scatterplot of TmP/GFR with age-adjusted phosphate of all patients. B. Scatterplot of TmP/GFR with age-adjusted phosphate of patients with Bartter syndrome type III. C. Scatterplots of TmP/GFR with age-adjusted phosphate of patients with Gitelman syndrome.