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Review
. 2015 Jul 2;373(1):60-72.
doi: 10.1056/NEJMra1313341.

An Integrated View of Potassium Homeostasis

Michelle L Gumz, Lawrence Rabinowitz, Charles S Wingo
Review

An Integrated View of Potassium Homeostasis

Michelle L Gumz et al. N Engl J Med. .

Erratum in

No abstract available

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Conflict of interest statement

Dr. Wingo reports receiving consulting fees from ZS Pharma. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Overview of Potassium Homeostasis
Shown are the known mechanisms that regulate external potassium balance and the pathways for net potassium movement associated with meal-driven potassium intake (Panel A) and with between-meal fasting (Panel B). Meal-driven potassium intake initiates both an increase in potassium excretion and sequestration of potassium in liver and skeletal muscle. Increased excretion is driven by reactive mechanisms, which can be either dependent on the plasma potassium level (negative-feedback regulation) or independent of the plasma potassium level (feed-forward regulation) initiated at splanchnic receptors. The circadian rhythm drives a predictive regulation of the tubule mechanisms responsible for potassium excretion, generated by a central clock and transmitted to circadian clocks in the tubule cells responsible for variations in potassium excretion. This rhythm enhances excretion during the active daylight phase and diminishes it during the inactive nighttime phase. In combination, these components provide maintenance of total body potassium levels within narrow limits without appreciable changes in the plasma potassium level. Between periods of meal intake, potassium is released from intracellular stores (primarily liver and skeletal muscle) for excretion.
Figure 2
Figure 2. Model of the Major Cell Types of the Cortical Collecting Duct
Shown are important potassium ion (K+) transport proteins of the principal cell and the α-intercalated cell, illustrating the mechanism of active potassium secretion and active potassium reabsorption. In principal cells, potassium is actively pumped into the cell from the peritubular fluid by basolateral sodium-potassium adenosine triphosphatase (Na+/K+-ATPase, also called sodium-potassium pump) and is secreted at the apical membrane by potassium channels and by functional potassium chloride (K+/Cl−) cotransporters. (The sodium-potassium pump moves out three sodium ions [3NA+] and moves in two potassium ions [2K+], thus removing one positive charge.) In the α-intercalated cell, potassium is actively absorbed from the lumen and can exit the cell apically during potassium-replete states or basolaterally during conditions of potassium deficiency. The collecting duct is part of the aldosterone-sensitive distal nephron, which also includes the distal convoluted tubule and connecting segment. These segments also have the capacity for substantial net potassium secretion.
Figure 3
Figure 3. Circadian Rhythm of Urinary Potassium Excretion in Humans during Two Levels of Potassium Intake
Shown is the approximate hourly rate of urinary potassium excretion (based on urine collections every 6 hours) in multiple patients receiving four identical meals every 6 hours, with a normal amount of potassium (100 mmol per day) for the first 2 days, a high-potassium diet (400 mmol per day) for the next 6 days, and a normal amount of potassium for the next 4 days. Rapid renal potassium adaptation occurs in response to either an increase or a decrease in potassium intake. The hourly rate of potassium excretion over a 24-hour period varies from noon, when the largest rate of potassium excretion typically occurs (midpoint of the white bar on the x axis), to midnight, when it is typically the least (midpoint of the black bar). This circadian variation is approximately 40% in persons consuming a high-potassium diet and by approximately 300% in persons consuming a normal level of potassium. This circadian rhythm occurs despite evenly spaced meals every 6 hours during a 24-hour period. Data are adapted from Rabelink et al.
Figure 4
Figure 4. Molecular Mechanism of the Mammalian Circadian Clock
The core cycle is shown on the right, with an increase in the amount of period circadian clock proteins 1 through 3 (PER1–3) and cryptochrome proteins 1 and 2 (CRY1–2) throughout the day, which acts to suppress their transcription. The red diamonds represent repressor proteins, and the blue ovals, activator proteins. Both activators and repressors are transcription factors or transcription regulators. The rectangles represent genes that encode the respective proteins. CSNK1E encodes casein kinase 1 epsilon, a kinase that is known to alter the period of the circadian oscillator through the phosphorylation (P) of core clock proteins, as shown. CSNK1E (also called CK1ε) is shown in gray because it is neither a transcriptional activator nor a repressor. BMAL1 (also called ARNTL) denotes aryl hydrocarbon receptor nuclear translocator-like protein 1, CLOCK clock circadian regulator, NR1D1 (also called REV-ERBα) nuclear receptor subfamily 1 group D member 1, and ROR retinoic acid receptor–related orphan receptor.
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