Familial hyperkalemia and hypertension and a hypothesis to explain proximal renal tubular acidosis

Familial hyperkalemia and hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension, and hyperchloremic acidosis (1, 2). The primary defect is a hyperactive sodium chloride cotransporter (NCC), expressed exclusively in renal distal convoluted tubule (DCT). FHHt is caused by a mutation in 1 of 4 genes, WNK1, WNK4, KLHL3, and Cul3, which leads to activation of NCC (2). A recent publication in PNAS (3) shows that a mutation of WNK4 prevents specific modulation by Cl− ions, inhibits its activity, and produces a FHHt phenotype. This emphasizes the significant role of WNK4 in renal Cl− handling in pathogenesis of FHHt and the question of the mechanism of hyperchloremic metabolic acidosis (4). Is hyperchloremia in FHHt a primary abnormality … [↵][1]1To whom correspondence may be addressed. Email: farfel{at}post.tau.ac.il. [1]: #xref-corresp-1-1