Background and hypothesis Gordon syndrome (also pseudohypoaldosteronism type II (PHAII) or Familial Hyperkalemia with Hypertension (FHHt)) is a genetic condition characterised by hypertension, hyperkalaemia, hyperchloraemic metabolic acidosis and hypercalciuria caused by an activation of the thiazide-sensitive sodium-chloride cotransporter (NCC, encoded by SLC12A3) in the distal convoluted tubule of the kidney. Thiazides rescue the electrolyte and metabolic abnormalities however, it is not known whether they decrease urinary calcium excretion, nephrolithiasis and low bone mineral density. Methods We examined a cohort of 11 patients with genetically confirmed FHHt. Biochemical, radiological, and clinical data was obtained in patients before and after thiazide treatment. All patients gave informed consent. Results Among the FHHt cohort 5 of the 11 patients were female. 7 patients had heterozygous pathogenic variants in KLHL3, 3 patients had variants in WNK4, and one had a variant in WNK1. At baseline, only 1 patient was hypertensive, all patients were hyperkalemic, whereas only 40% of patients had low serum bicarbonate and increased urinary calcium excretion. 50% of patients also had low bone mineral density (either osteopenia or osteoporosis) and 1 patient had bilateral nephrolithiasis. 6 patients were treated with thiazide diuretic and therefore were suitable for comparison between pre and post treatment biochemistry and imaging data. While both serum and urinary biochemistry was completely reverted after thiazide treatment, bone mineral density had a worsening trend. 1 patient presented with bilateral nephrolithiasis after thiazide treatment. Conclusion We demonstrate that thiazide treatment normalizes serum and urinary biochemistry. Thiazide treatment therefore has clinical utility even if hypertension or hyperkalaemia are not problematic. According to our study, thiazide treatment does not seem to revert loss of bone mineral density, however, whether thiazides have an impact in nephrolithiasis is less clear and our results may require larger samples.

SBW has received honoraria from Advicenne Pharmaceuticals. VDA received consultant fees from Allena Pharmaceuticals. PMF received consultant fees and grant/other support from Allena Pharmaceuticals, Alnylam, Amgen, AstraZeneca, Bayer, Gilead, Novo Nordisk, Otsuka Pharmaceuticals, Rocchetta, Vifor Fresenius, and royalties as an author for UpToDate.

This research was funded in whole, or in part by the Wellcome Trust [Grant number 110282/Z/15/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

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