5/6 Nephrectomy impairs acute kaliuretic responses and predisposes to postprandial hyperkalemia

The susceptibility of patients with chronic kidney disease to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na⁺) and potassium (K⁺) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K⁺ loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this with the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K⁺ loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K⁺ concentrations in 5/6Nx rats, which were accompanied by corresponding increases in plasma aldosterone. Acute K⁺ loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase and the sodium-chloride cotransporter both in sham and 5/6Nx rats. In contrast, the acute K⁺ load decreased the Na⁺/hydrogen exchanger 3 and increased serum- and glucocorticoid-regulated kinase 1 and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K⁺ load, which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia.<b>NEW & NOTEWORTHY</b> Rats who underwent 5/6 nephrectomy demonstrate a reduced ability to excrete an acute K⁺ load with the development of postprandial hyperkalemia. 5/6 Nephrectomy attenuates K⁺-induced natriuresis and impairs ENaC regulation despite intact NCC dephosphorylation and increased plasma aldosterone. This offers a potential explanation for why patients with chronic kidney disease are predisposed to postprandial hyperkalemia.