Mechanism of hyperkalemia-induced metabolic acidosis

Autumn N. Harris, P. Richard Grimm, Hyun Wook Lee, Eric Delpire, Lijuan Fang, Jill W. Verlander, Paul A. Welling, I. David Weiner

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Abstract

Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), themost common RTA observed, but themolecularmechanisms underlying the associatedmetabolic acidosis are incompletely understood.We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. Methods We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)- specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). Results DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H+ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression inDCT-CA-SPAKmice. In wild-typemice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Conclusions Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.

Original languageEnglish (US)
Pages (from-to)1411-1425
Number of pages15
JournalJournal of the American Society of Nephrology
Volume29
Issue number5
DOIs
Publication statusPublished - May 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Nephrology

Cite this

Harris, A. N., Grimm, P. R., Lee, H. W., Delpire, E., Fang, L., Verlander, J. W., ... Weiner, I. D. (2018). Mechanism of hyperkalemia-induced metabolic acidosis. Journal of the American Society of Nephrology, 29(5), 1411-1425. https://doi.org/10.1681/ASN.2017111163