The Unappreciated Role of Extrarenal and Gut Sensors in Modulating Renal Potassium Handling: Implications for Diagnosis of Dyskalemias and Interpreting Clinical Trials

Abstract

In addition to the classic and well-established "feedback control" of potassium balance, increasing investigative attention has focused on a novel and not widely recognized complementary regulatory paradigm for maintaining potassium homeostasis-the "feed-forward control" of potassium balance. This regulatory mechanism, initially defined in rumen, has recently been validated in normal human subjects. Studies are being conducted to determine the location for this putative potassium sensor and to evaluate potential signals, which might increase renal potassium excretion. Awareness of this more updated integrative control mechanism for potassium homeostasis is ever more relevant today, when the medical community is increasingly focused on the challenges of managing the hyperkalemia provoked by renin-angiotensin-aldosterone system inhibitors (RAASis). Recent studies have demonstrated a wide gap between RAASi prescribing guidelines and real-world experience and have highlighted that this gap is thought to be attributable in great part to hyperkalemia. Consequently we require a greater knowledge of the complexities of the regulatory mechanisms subserving potassium homeostasis. Sodium polystyrene sulfonate has long been the mainstay for treating hyperkalemia, but its administration is fraught with challenges related to patient discomfort and colonic necrosis. The current and imminent availability of newer potassium binders with better tolerability and more predictive dose-response potassium removal should enhance the management of hyperkalemia. Consequently it is essential to better understand the intricacies of mammalian colonic K⁺ handling. We discuss colonic transport of K⁺ and review evidence for potassium (BK) channels being responsible for increased stool K⁺ in patients with diseases such as ulcerative colitis.

Keywords: chronic kidney disease; potassium.

Figure 1

Summary of potassium transport along the nephron. Following filtration, potassium is extensively reabsorbed along the proximal tubule and the loop of Henle. Potassium is secreted along the initial and cortical collecting tubules. Net secretion can be replaced by net reabsorption in states of potassium depletion. Also shown are the 2 cell types lining the distal tubule and cortical collecting duct. (a) A cell model for K⁺ transport in the proximal tubule. K⁺ reabsorption in the proximal tubule primarily occurs through the paracellular pathway. Active Na⁺ reabsorption drives net fluid reabsorption across the proximal tubule, which, in turn, drives K⁺ reabsorption through a solvent drag mechanism. As fluid flows down the proximal tubule, the luminal voltage shifts from slightly negative to slightly positive. The shift in transepithelial voltage provides an additional driving force favoring K⁺ diffusion through the low-resistance paracellular pathway. Experimental studies suggest that there may be a small component of transcellular K⁺ transport; however, the significance of this pathway is not known. K⁺ uptake through the Na⁺-K⁺-ATPase pump can exit the basolateral membrane through a conductive pathway or coupled to Cl^–. An apically located K⁺ channel functions to stabilize the cell negative potential, particularly in the setting of Na⁺-coupled cotransport of glucose and amino acids, which has a depolarizing effect on cell voltage. (b) A cell model for K⁺ transport in the thick ascending limb of Henle. K⁺ reabsorption occurs by both paracellular and transcellular mechanisms. The basolateral Na⁺-K⁺-ATPase pump maintains intracellular Na⁺ at a low level, thus providing a favorable gradient to drive the apically located Na⁺-K⁺-2Cl^– cotransporter (an example of secondary active transport). The apically located renal outer medullary K⁺ (ROMK) channel provides a pathway for K⁺ to recycle from cell to lumen, and ensures an adequate supply of K⁺ to sustain Na⁺-K⁺-2Cl^– cotransport. This movement through ROMK creates a lumen-positive voltage, providing a driving force for passive K⁺ reabsorption through the paracellular pathway. Some of the K⁺ entering the cell through the cotransporter exits the cell across the basolateral membrane, accounting for transcellular K⁺ reabsorption. K⁺ can exit the cell through a conductive pathway or in cotransport with Cl^–. ClC-Kb is the primary pathway for Cl^– efflux across the basolateral membrane. (c) A cell model for K⁺ transport in the distal convoluted tubule (DCT). In the early DCT, luminal Na⁺ uptake is mediated by the apically located thiazide-sensitive Na⁺-Cl^– cotransporter. The transporter is energized by the basolateral Na⁺-K⁺-ATPase, which maintains low intracellular Na⁺ concentration, thus providing a favorable gradient for Na⁺ entry into the cell through secondary active transport. The cotransporter is abundantly expressed in the DCT1 but progressively declines along the DCT2. ROMK is expressed throughout the DCT and into the cortical collecting duct. Expression of the epithelial Na⁺ channel (ENaC), which mediates amiloride-sensitive Na⁺ absorption, begins in the DCT2 and is robustly expressed throughout the downstream connecting tubule and cortical collecting duct. The DCT2 is the beginning of the aldosterone-sensitive distal nephron as identified by the presence of both the mineralocorticoid receptor and the enzyme 11β-hydroxysteroid dehydrogenase II. This enzyme maintains the mineralocorticoid receptor free to only bind aldosterone by metabolizing cortisol to cortisone, which has no affinity for the receptor. Electrogenic-mediated K⁺ transport begins in the DCT2 with the combined presence of ROMK, ENaC, and aldosterone sensitivity. Electroneutral K⁺-Cl^– cotransport is present in the DCT and collecting duct. Conditions that promote a low luminal Cl^– concentration increase K⁺ secretion through this mechanism, which occurs with delivery of poorly reabsorbable anions, such as sulfate, phosphate, or bicarbonate. (d) The cell that is responsible for K⁺ secretion in the initial collecting duct and the cortical collecting duct is the principal cell. This cell possesses a basolateral Na⁺-K⁺-ATPase that is responsible for the active transport of K⁺ from the blood into the cell. The resultant high cell K⁺ concentration provides a favorable diffusion gradient for movement of K⁺ from the cell into the lumen. In addition to establishing a high intracellular K⁺ concentration, the activity of this pump lowers intracellular Na⁺ concentration, thereby maintaining a favorable diffusion gradient for movement of Na⁺ from the lumen into the cell. The movements of both Na⁺ and K⁺ across the apical membrane occur through well-defined Na⁺ and K⁺ channels. (e) Reabsorption of HCO₃ in the distal nephron is mediated by apical H⁺ secretion by the α-intercalated cell. Two transporters secrete H⁺, a vacuolar H⁺-ATPase and an H⁺-K⁺-ATPase. The H⁺-K-ATPase uses the energy derived from ATP hydrolysis to secrete H⁺ into the lumen and reabsorb K⁺ in an electroneutral fashion. The activity of the H⁺-K⁺-ATPase increases in K⁺ depletion and thus provides a mechanism by which K⁺ depletion enhances both collecting duct H⁺ secretion and K⁺ absorption. ADH, antidiuretic hormone; ALDO, aldosterone; ASDN, aldosterone-sensitive distal nephron; ATPase, adenosine triphosphatase; CCT, cortical collecting tubule; Cl, chloride; ClC-Kb, chloride channel Kb; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; HCO₃, bicarbonate; ICT, initial connecting tubule; MCD, medullary collecting duct; PT, proximal tubule; R, reabsorption; ROMK, renal outer medullary potassium; S, secretion; TAL, thick ascending limb. Courtesy of Murray Epstein.

Figure 2

A schematic depicting the complementary roles of the classic feedback and “feed-forward” control mechanisms for maintaining potassium homeostasis. An increase in plasma potassium evokes an array of responses that promote a kaliuresis. In contrast, the “feed-forward” control mechanism is engaged when dietary potassium is sensed by K⁺ sensors in the gastrointestinal tract in the absence of perceptible changes in plasma potassium. Courtesy of Murray Epstein.

Figure 3

Summary of the integrated roles of the kidney, extrarenal mechanisms, and gastrointestinal effectors in modulating potassium homeostasis. It demonstrates that the undamped increase in plasma K⁺ in response to potassium administration is progressively attenuated by the adaptive responses by the kidney, by a hierarchy of nonrenal mechanisms including participation by insulin and glucose, and by gastrointestinal mechanisms evoked by gastrointestinal potassium sensors. Courtesy of Murray Epstein.