I became an instant fan of Dr. Biff Palmer after the ASN Kidney Week Acid Base & Electrolytes pre-course in 2017. This course definitely adds a new dimension to your understanding on the subject, but certainly as the old adage goes- there’s still so much to learn. This time I came across one of Dr. Palmer’s articles on potassium homeostasis, and was struck by how potassium (K+) load in the gut could influence channels in the kidney.
This ‘feed-forward’ (no pun intended) mechanism, or quick control of kidney K+ excretion in anticipation of increased plasma K+ during oral intake, was first described by Rabanowitz via studies in sheep in which meal induced kaliuresis was not accompanied by significant change in plasma aldosterone secretion. It was then postulated that there might be a signal that originates from the K+ sensing receptors in the splanchnic bed that leads to the kaliuresis. This axis was further supported by a study in which intraportal potassium chloride infusion in anesthetized rats increased hepatic afferent nerve activity and urinary K+ excretion in the absence of increases in plasma K+.
In humans, various studies have been performed to demonstrate this important physiological link. Effects of systemic, intraportal, and intragastric potassium infusion during simultaneous feeding with a potassium-deficient diet have been studied, with a subsequent observation that the intragastric potassium infusion combined with a potassium-deficient meal was associated with marked enhancement of clearance of the potassium infused and an increase in renal efficiency of potassium excretion compared with systemic or portal infusion. Similarly, there is evidence that a gastrointestinal potassium load increased potassium excretion more than an equal increase in plasma potassium. Kaliuresis following oral intake of potassium citrate in healthy human volunteers occurred despite no change in the plasma potassium or significant increases in plasma aldosterone levels.
An interesting study showed that kaliuresis post oral K+ load persisted despite aldosterone blockade via eplerenone – suggesting that the gut mediated K+ excretion appears to be independent from aldosterone and serum potassium.
With regards to mechanism of this gut driven kaliuresis, a few mechanisms have been proposed:
- A high K+ diet upregulates the mRNA of the With No Lysine kinases (WNK), which in turn act as regulators of the sodium-chloride symporter (NCC) in the distal convoluted tubule (DCT). These kinases switch off the NCC in response to K+ intake. This leads to higher solute delivery to the distal tubule, which in turn, leads to enhanced K+ excretion.
It is important to note that K+ does have variable effects of different types of WNK. With respect to WNK4, high plasma K+ leads to a higher intracellular chloride (Cl-), which inhibits WNK4 and leads to inability to activate NCC(Figure 1).
- Mild reduction of NCC abundance and phosphorylation (in mice kept on a high K+ diet compared to those on low K+ diet).
- K+ intake induces dephosphorylation of the NCC and upregulation of the epithelial sodium channel (ENaC) in the collecting tubule.
This down regulation of the NCC, can further enhance sodium excretion and in turn, aid in lowering of blood pressure. This in line with established evidence that potassium supplementation is associated with reduction in blood pressure.
The effort to elucidate this axis further has spawned many studies, and it remains to be seen what we will uncover in this story. One fact is for certain – we will definitely keep you posted.
Post by Sam Kant, MD (@kantsmd)
Chief Resident, Internal Medicine
University of Maryland Medical Center, Midtown Campus
