Hyperkalemia across the Continuum of Kidney Function

Calcineurin inhibitors (CNIs) are immunosuppressive drugs, which are used widely to prevent rejection of transplanted organs and treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria, and acidosis often complicate their use 1,2 . These side effects resemble familial hyperkalemic hypertension (FHHt), a genetic disease characterized by overactivity of the renal sodium chloride co-transporter (NCC), and caused by mutations in WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC, and the NCC regulatory kinases WNK3, WNK4, and SPAK. The functional importance of NCC in this response was demonstrated by showing that tacrolimus did not affect blood pressure in NCC knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice over-expressing NCC. Moreover, hydrochlorothiazide reversed tacrolimus-induced hypertension. In kidney transplant recipients treated with tacrolimus, fractional chloride excretion in response to bendroflumethiazide was greater than in controls, and renal NCC abundance was also greater, extending these observations to humans. Together, these findings indicate that tacrolimus-induced hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.

The mammalian distal convoluted tubule (DCT) makes an important contribution to potassium homeostasis by modulating NaCl transport. The thiazide-sensitive Na+/Cl- cotransporter (NCC) is activated by low potassium intake and by hypokalemia. Coupled with suppression of aldosterone secretion, activation of NCC helps to retain potassium by increasing electroneutral NaCl reabsorption, therefore reducing Na+/K+ exchange. Yet the mechanisms by which DCT cells sense plasma potassium concentration and transmit the information to the apical membrane are not clear. Here, we tested the hypothesis that the potassium channel Kir4.1 is the potassium sensor of DCT cells. We generated mice in which Kir4.1 could be deleted in the kidney after the mice are fully developed. Deletion of Kir4.1 in these mice led to moderate salt wasting, low BP, and profound potassium wasting. Basolateral membranes of DCT cells were depolarized, nearly devoid of conductive potassium transport, and unresponsive to plasma potassium concentration. Although renal WNK4 abundance increased after Kir4.1 deletion, NCC abundance and function decreased, suggesting that membrane depolarization uncouples WNK kinases from NCC. Together, these results indicate that Kir4.1 mediates potassium sensing by DCT cells and couples this signal to apical transport processes.