Renal Physiology Regulation of Potassium Homeostasis

Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students. Clin J Am Soc Nephrol 10: 1050–1060, 2015. doi: 10.2215/CJN.08580813 Introduction Potassium plays a key role in maintaining cell function. Almost all cells possess an Na1-K1-ATPase, which pumps Na1 out of the cell and K1 into the cell and leads to a K1 gradient across the cell membrane (Kin. Kout) that is partially responsible for maintaining the potential difference across the membrane. This potential difference is critical to the function of cells, particularly in excitable tissues, such as nerve and muscle. The body has developed numerous mechanisms for defense of serum K1 . These mechanisms serve to maintain a proper distribution of K1 within the body as well as regulate the total body K1 content. Internal Balance of K1 The kidney is primarily responsible for maintaining total body K1 content by matching K1 intake with K1 excretion. Adjustments in renal K1 excretion occur over several hours; therefore, changes in extracellular K1 concentration are initially buffered by movement of K1 into or out of skeletal muscle. The regulation of K1 distribution between the intracellular and extracellular space is referred to as internal K1 balance. The most important factors regulating this movement under normal conditions are insulin and catecholamines (1). After a meal, the postprandial release of insulin functions to not only regulate the serum glucose concentration but also shift dietary K1 into cells until the kidney excretes the K1 load re-establishing K1 homeostasis. These effects are mediated through insulin binding to cell surface receptors, which stimulates glucose uptake in insulin-responsive tissues through the insertion of the glucose transporter protein GLUT4 (2,3). An increase in the activity of the Na-K-ATPase mediates K 1 uptake (Figure 1). In patients with the metabolic syndrome or CKD, insulin-mediated glucose uptake is impaired, but cellular K1 uptake remains normal (4,5), demonstrating differential regulation of insulin-mediated glucose and K1 uptake. Catecholamines regulate internal K1 distribution, with a-adrenergic receptors impairing and b-adrenergic receptors promoting cellular entry of K1. b2-Receptor–induced stimulation of K1 uptake is mediated by activation of the Na1-K1-ATPase pump. These effects play a role in regulating the cellular release of K1 during exercise (6). Under normal circumstances, exercise is associated with movement of intracellular K1 into the interstitial space in skeletal muscle. Increases in interstitial K1 can be as high as 10–12 mM with severe exercise. Accumulation of K1 is a factor limiting the excitability and contractile force of muscle accounting for the development of fatigue (7,8). Additionally, increases in interstitial K1 play a role in eliciting rapid vasodilation, allowing for blood flow to increase in exercising muscle (9). During exercise, release of catecholamines through b2 stimulation limits the rise in extracellular K1 concentration that otherwise occurs as a result of normal K1 release by contracting muscle. Although the mechanism is likely to be multifactorial, total body K1 depletion may blunt the accumulation of K1 into the interstitial space, limiting blood flow to skeletal muscle and accounting for the association of hypokalemia with rhabdomyolysis. Changes in plasma tonicity and acid–base disorders also influence internal K1 balance. Hyperglycemia leads to water movement from the intracellular to extracellular compartment. This water movement favors K1 efflux from the cell through the process of solvent drag. In addition, cell shrinkage causes intracellular K1 concentration to increase, creating a more favorable concentration gradient for K1 efflux. Mineral acidosis, but not organic acidosis, can be a cause of cell shift in K1. As recently reviewed, the general effect of acidemia to cause K1 loss from cells is not because of a direct K1-H1 exchange, but, rather, is because of an apparent coupling resulting from effects of acidosis on transporters that normally regulate cell pH in skeletal muscle (10) (Figure 2). Department of