Abstract: TH-PO1016

Effect of Hyperkalemia on Renal Ammonia Metabolism

Session Information

  • Acid Base: Basic
    November 02, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 701 Acid-Base: Basic


  • Harris, Autumn N, University of Florida , Gainesville, Florida, United States
  • Grimm, P. Richard, University of Maryland School of Medicine , Baltimore, Maryland, United States
  • Lee, Hyun-Wook, University of Florida , Gainesville, Florida, United States
  • Delpire, Eric J., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Welling, Paul A., University of Maryland School of Medicine , Baltimore, Maryland, United States
  • Verlander, Jill W., University of Florida , Gainesville, Florida, United States
  • Weiner, I. David, University of Florida , Gainesville, Florida, United States

Type IV Renal Tubular Acidosis (RTA) is characterized by metabolic acidosis and hyperkalemia, but the mechanism(s) through which the metabolic acidosis develops remains in question. In particular, hyperkalemia’s role in the pathogenesis of the metabolic acidosis has been unclear. This is because in vivo models testing the effects of hyperkalemia are difficult to perform because of robust renal K excretory mechanisms that limit development of chronic hyperkalemia. To obviate this limitation, we used a genetic model of hyperkalemia that does not target the proximal tubule (PT) or collecting duct, does not directly target proteins involved in ammonia metabolism and does not involve altered K intake to determine hyperkalemia’s effect on acid-base homeostasis and ammonia metabolism.


We used a recently reported DCT-specific constitutively active SPAK (DCT-CA-SPAK) mouse model and compared it with wild type (WT) littermates. We used thiazide administration to block the NCC over-activity and correct the hyperkalemia.


Under basal conditions DCT-CA-SPAK mice exhibited hyperkalemia and metabolic acidosis. Despite the metabolic acidosis, they had decreased urine ammonia excretion compared to WT mice. Titratable acid excretion was not altered. Thiazide administration, to reverse the effect of DCT-CA-SPAK on NCC, corrected the hyperkalemia and increased ammonia excretion, but had neither effect in WT mice. Phosphoenolypyruvate and phosphate-dependent glutaminase, key ammonia generating proteins, expression was significantly less in DCT-CA-SPAK PT. Glutamine synthetase, which recycles ammonia, was significantly greater in DCT-CA-SPAK cortical PT. NKCC2 and Rhbg expression were unchanged. Thus, hyperkalemia in a genetic model that does not alter K intake, does not directly involve the PT and does not directly alter proteins involved in ammonia metabolism, alters expression of multiple proximal tubule proteins involved in ammonia generation, leading to decreased ammonia excretion, which is reversible with correction of the hyperkalemia.


Hyperkalemia can directly inhibit proximal tubule ammonia metabolism, decreasing ammonia and net acid excretion, and leading to metabolic acidosis. Moreover, the effects of hyperkalemia on ammonia metabolism to suppress ammonia excretion are greater than those of metabolic acidosis to stimulate it.


  • NIDDK Support