Achieving the Benefits of a High-Potassium, Paleolithic Diet, Without the Toxicity  Biff F. Palmer, MD, Deborah J. Clegg, PhD  Mayo Clinic Proceedings  Volume 91, Issue 4, Pages 496-508 (April 2016) DOI: 10.1016/j.mayocp.2016.01.012 Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 Older studies suggest that high dietary K+ intake inhibits Na+ reabsorption in the proximal nephron and thick ascending limb of Henle, causing increased flow and delivery of Na+ to the aldosterone-sensitive distal nephron, resulting in increased K+ excretion. More recent studies suggest that this process is more regionalized to the distal nephron and implicates the distal convoluted tubule (DCT) as a renal K+ sensor. The proximal portion of the DCT (DCT1) reabsorbs NaCl in an electroneutral fashion via the Na+-Cl− cotransporter (NCC). High dietary intake achieved through changes in plasma K+ concentration leads to an inhibitory effect on NCC activity. As a result, Na+ delivery and flow are increased to the aldosterone-sensitive K+ secretory segments located in the later portions of the DCT (DCT2) and collecting duct (CD). Increased plasma K+ concentration stimulates aldosterone release from the adrenal gland, which, in turn, facilitates electrogenic K+ secretion through the renal outer medullary K+ (ROMK) channel. Both increased flow and aldosterone stimulate K+ secretion through the maxi-K channel. Increased K+ secretion may begin upon K+ entry into the gastrointestinal tract before any change in plasma K+ concentration through an enteric sensing mechanism, which leads to an inhibitory effect on NCC activity. ENaC = epithelial Na+ channel. Mayo Clinic Proceedings 2016 91, 496-508DOI: (10.1016/j.mayocp.2016.01.012) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Effect of decreased dietary K+ on Na+ transport in the distal tubule. Decreased dietary K+ achieved through a decrease in plasma K+ concentration hyperpolarizes cells in the proximal portion of the distal convoluted tubule (DCT1), leading to decreased intracellular Cl− concentration, which, in turn, activates WNK lysine-deficient protein kinase 4 (WNK4). K+ deficiency is associated with increases in the ratio of long WNK lysine-deficient protein kinase 1 (WNK1) to kidney specific (KS)-WNK1. An increase in this ratio (L-WNK1/KS-WNK1) leads to an increased retrieval of renal outer medullary K+ (ROMK) from the apical membrane, thereby minimizing K+ secretion, which would be an appropriate response to the K+-deficient diet. Increased L-WNK1/KS-WNK1 also alters WNK4 activity such that activity of the thiazide-sensitive Na+-Cl− cotransporter (NCC) is increased. In addition, increased L-WNK1 leads to an increased activity of the epithelial Na+ channel (ENaC). These last 2 effects lead to salt retention and thus could explain the genesis of salt-sensitive hypertension in patients ingesting K+-deficient diets. Mayo Clinic Proceedings 2016 91, 496-508DOI: (10.1016/j.mayocp.2016.01.012) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions