Physiology Note - Potassium Homeostasis

 

Dr. Prithwiraj Saha; MBBS, MD, DrNB ; 

Associate Consultant, Fortis Escorts Heart Institute Delhi 

Email-pitusri@gmail.com  

Phone-9830509648 

Outline: 

 Normal Homeostasis 

  Internal Homeostasis 

  External Homeostasis

o Renal handling 

o Gut handling 

o Circadian rhythm 

Introduction: 

    Plasma potassium level is maintained within a narrow range by the help of normal potassium 

hemostasis which includes matching intake, absorption, secretion and lastly ensuring proper 

distribution between extra- and intracellular fluid compartments. It is the most abundant intracellular 

cation in the body. 98 % of total potassium remains intracellular while only 2% make up for 

extracellular potassium. 

    Normal Homeostasis: 

It means maintaining total body potassium and plasma potassium within a narrow range inspite of 

wide variation in dietary intake and pathological conditions. Total Body potassium is approximately 50 

mEq/kg i.e aggregately around 3500 mEq. Out of this only 60 to 80mEq is found in extracellular fluid, 

maintaining a concentration normally ranging from 3.5 to 5.3mEq/L. 

It comprises of two concurrent processes- Internal and External Potassium balance. Internal Potassium 

balance is defined as regulation of potassium distribution between the intracellular and extracellular 

space, whereas external K+ homeostasis controls the potassium excretion (renal and gut) in balance 

to potassium intake (diet and non-diet source). 

                                                     Fig.1:  Normal K+ Homeostasis in body 

Internal Homeostasis: 

Potassium is maintained in a very narrow range in serum. Large deviation from this range is not 

compatible to life. The importance of internal homeostasis involves maintenance of an asymmetric 

distribution of total body potassium between the intracellular and extracellular fluid. This maintains 

the balance of active cellular uptake by sodium–potassium adenosine triphosphatase, an enzyme that 

pumps sodium out of cells while pumping potassium into cells (Na+/K+-ATPase pump), and passive 

potassium efflux (leak rate). This causes immediate buffering of plasma potassium level after K+ load 

followed by adjustments in renal and gut K+ excretion involving several hours. 

Post prandial release of insulin also moves potassium into the cell along with glucose. It increases the 

activity of Na+/K+-ATPase pump along with the insertion of GLUT-4 receptors in Insulin responsive 

tissues. Stimulation of Na+/K+-ATPase pump mainly drives potassium into cells. Cellular K+ uptake 

occurs normally but insulin mediated glucose uptake is compromised in various diseases indicating 

differential regulation of insulin-mediated glucose and K+ uptake. This mechanism is used in treating 

hyperkalemia, where high dose of insulin is given.  Similarly, when potassium is low in diabetic keto

acidosis (DKA) patient, introduction of insulin is delayed till it’s correction. 

Catecholamines also play a role in regulating potassium homeostasis. Beta adrenergic receptors (Beta

2) promote potassium uptake into cells by activating Na+/K+-ATPase pump while alpha adrenergic 

receptors (alpha-1) promote temporary increase in serum potassium. Increase in interstitial potassium 

causes vasodilation(especially during exercises via potassium channels) that increases blood flow. 

Increase catecholamine flow in turn decreases extracellular potassium through activation of Beta-2 

receptors. On the other hand, hypokalemia causes impaired blood flow in skeletal muscles causing 

rhabdomyolysis. Use of phenylephrine, a pure alpha agonist causes little increase in plasma potassium 

while Beta-2 agonist in nebulisation decreases serum potassium. 

Plasma tonicity and acid base balance affects internal potassium homeostasis. Hyperosmolar agents 

(such as glucose, mannitol, and sucrose) sucks water from the intracellular to the extracellular 

compartment. Thus, it increases intracellular K+, favouring efflux through K+-permeable channels. 

Normal anion gap metabolic acidosis (mineral acidosis) tends to cause more increase in plasma 

potassium than a higher anion gap acidosis (organic acidosis). Acidaemia causes loss of K+ from 

intracellular fluid not because of a direct K+/H+ exchange, but through a coupling triggered by the 

effects of acidosis on transporters regulating cell pH in skeletal muscle. (Fig 2). 

Fig 2. The decrease in extracellular pH with mineral acidosis (hyperchloremic normal anion gap acidosis) lowers the rate of Na+/H+ exchange by the Na+/H+ exchanger (NHE1) and the inward rate of cotransport of Na+ and HCO3− by electrogenic sodium bicarbonate cotransporter (NBCe) 1 and 2. As a result, the intracellular Na+ concentration will decline, lessening Na+/K+-adenosine triphosphatase (Na+/K+-ATPase) activity and leading to a net loss of cellular K+. Similarly, a lower extracellular HCO3− concentration will increase inward movement of Cl− by Cl−/HCO3− exchange, contributing to additional K+ efflux by K+/Cl− cotransport. During organic acidosis, there is inward movement of H+ and the accompanying organic anion on the monocarboxylate transporter 1 and 4 (MCT 1 and 4), results in a larger fall of cell pH in comparison to mineral acidosis. This higher acidic intracellular pH allosterically increases activity of the Na+-H+ exchanger and provides a more favourable gradient for inward Na-HCO3 cotransport. Thus, an adequate amount of intracellular Na+ is available to maintain activity of Na+-K+ ATPase, thus minimizing changes in extracellular K + concentration. 

External  Homeostasis: 

External potassium balance comprises of three systems out of which two are reactive and one is 

predictive. Reactive systems are negative-feedback mechanisms that react to changes in the plasma 

potassium level regulating the potassium balance. They are found in gut and kidney. Predictive system 

is driven by a circadian oscillator in the suprachiasmatic nucleus of the brain and is entrained to the 

ambient light–dark cycle, also known as Circadian rhythm of potassium hemostatsis. 

Renal handling of potassium: 

Potassium is freely filtered through glomerulus. Almost all potassium filtered is reabsorbed in proximal 

convoluted tubule (mainly paracellular) and thick ascending loop of Henle (mainly transcellular). While 

urinary K+ excretion results primarily from secretion along the aldosterone-sensitive distal nephron 

(ASDN), comprising the last portion of the distal convoluted tubule (DCT2), connecting tubule and 

collecting duct. 

Potassium reabsorption: 

 Proximal Convoluted tubule:  Potassium is reabsorbed in proximal tubule through 

paracellular pathway in approximation with sodium and water. A large component of filtered 

K+ is reabsorbed primarily by solvent drag. The change of lumen potential from negative to 

positive in later part of PCT also drags potassium through paracellular pathway. (Fig.3) 

                                                Fig.3 Absorption in Proximal Tubule 

 Ascending Thick Loop of Henle:  Potassium absorption here takes place both by paracellular 

and transcellular pathway. Transcellular movement is mediated by the Na+-K+-2Cl- co

transporter located on the apical membrane. A component of K+ that enters the cell back 

diffuses into the lumen through the ROMK (renal outer medullary K+) channel, leading to 

generation of a lumen positive charge which in turn, drives a component of potassium 

reabsorption through the paracellular pathway. (Fig.4) 

                                                Fig.4  Absorption in Thick Ascending Loop of Henle 

Potassium excretion:  (Fig 5) 

 Potassium excretion results from the aldosterone sensitive distal nephron. It is mediated by 

two type of apical channels- ROMK (renal outer medullary K+) , also known as Kir1.1 channel 

in principal cells and maxi-K+ or BK channels in principal and intercalated cells. It is driven 

mainly by a transepithelial voltage which is oriented in the lumen-negative direction. It is 

generated due to sodium reabsorption through the epithelial Na+ channels (ENaC) localized 

on the apical membrane. Aldosterone stimulates ENaC activity through mineralocorticoid 

receptors (MR), which increase both in number and the proportion of time that the channel 

is in its open state.  

 Maxi-K or BK channels mediates K+ secretion under conditions of increased flow. In addition 

to stimulating maxi-K+  channels, tubular  flow also augments electrogenic  K+  secretion by 

diluting luminal K+ concentration and stimulating Na reabsorption through the epithelial  Na 

channel (ENaC). This stimulatory effect can be traced to a mechanosensitive property whereby 

shear stress increases the open probability of the ENaC channel. 

 Major determinants of potassium excretion are luminal Na+ delivery and flow rate, plasma K+ 

concentration, circulating aldosterone and arginine vasopressin levels, and acid-base status. 

Increased potassium excretion following potassium rich diet or hyperkalemia is linked to 

increased sodium delivery to ASDN. It begins in the initial portion of the DCT (DCT1), where 

salt transport is driven exclusively by the thiazide-sensitive Na+/Cl− cotransporter (NCC). 

 High plasma K+ concentration sensed by Kir4.1/5.1 channels located on the basolateral 

surface of the DCT1 causes alterations in activity of WNK family of kinases and their regulatory 

proteins SPAK and OxSR1. It inhibits the activity of Na+/Cl− cotransporter (NCC) (Fig 2). As a 

result, there is greater Na+ delivery to the aldosterone-sensitive K+ secretory segments 

located in the later portions of the DCT (DCT2) and collecting duct, resulting in more K+ 

secretion. With long-term high K+ intake, the effect of plasma K+ concentration on cells of the 

DCT1 is amplified by decreased Na+ reabsorption in the thick ascending limb (Na+-K+-2Cl- co

transporter) and proximal tubule due to medullary recycling and accumulation of K+ in the 

interstitium. In contrast, decreased intake and decreased plasma K+ concentrations leads to 

increased activity of the NCC in the DCT1. This change limits K+ secretion by reducing Na+ 

delivery and flow to the ASDN. 

 The effects may be deleterious in which typically dietary Na+ intake is high and K+ intake is 

low. K+-deficient diet will reduce K+ secretion while increasing Na+ retention leading to salt

sensitive hypertension. Similarly, decreased NCC activity and natriuresis may explain the 

blood pressure–lowering effect of high K+ intake. 

Fig.5  Secretion in Aldosterone sensitive distal nephron 

DCT,distal convoluted tubule,CD, collecting duct; ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; ROMK, renal outer medullary 

potassium channel;SPAK, Ste20-related proline/alanine-rich kinase. 

Aldosterone paradox: 

Aldosterone can stimulate salt retention without potassium excretion (as in hypovolemia) and can 

excrete potassium without retaining salt (as in hyperkalemia). This phenomenon is called aldosterone 

paradox. 

 In volume depletion there is increased circulating angiotensin II (A II) along with 

Aldosterone. A II stimulates the Na+-Cl− cotransporter in DCT1, thereby reducing Na+ 

delivery to DCT2 and collecting duct. In the aldosterone sensitive distal nephron 

(ASDN), A II also exerts an inhibitory effect on renal outer medullary potassium 

channel (ROMK) and along with aldosterone stimulates epithelial Na+ channel (ENaC) 

activity. Additionally, A II leads to dephosphorylation of the mineralocorticoid 

receptors in intercalated cells, permitting aldosterone to activate the apical proton 

pumps (H+-ATPase and H+/K+-ATPases) and the Cl−/HCO3 − exchanger (pendrin) in 

intercalated cells.(Fig 6) 

 Hyperkalemia inhibits Na+-Cl− cotransport activity in DCT 1. Increased Na+ delivery to 

the ENaC leads to increased secretion of K+ through ROMK. In the presence of low 

Angiotensin II Phosphorylated mineralocorticoid receptors prevent aldosterone

mediated electroneutral NaCl transport in intercalated cells. (Fig 6) 

                                    Fig.6 Aldosterone paradox 

Role of gut in Potassium handling: 

    Gut also plays an important role in potassium hemostasis. Splanchnic sensing mechanism initiates the kaliuretic response as early as K+ entry into the gastrointestinal tract. Gastric delivery of K+ leads to 

dephosphorylation and decreased activity of the NCC in the DCT1. It results in decreased activity of 

NCC and thereby enhancing delivery of Na to the ASDN (Fig.7 and Fig.8). Finally, it leads to increased 

potassium excretion. Studies  suggest that splanchnic sensing of K can initiate the renal excretory 

response independent of change in plasma K concentration or mineralocorticoid activity. On chronic 

ingestion of high potassium diet there is also inhibition of Na reabsorption in the thick ascending limb 

and proximal tubule of the kidney, thereby facilitating increased delivery of Na to portions of the distal 

nephron responsive to mineralocorticoid activity. (Fig.7) 

 

 

                            Fig.7 Gut regulation of potassium homeostasis 

 

                                                 Fig.8 Potassium excretion after meal 

Role of Magnesium in Potassium excretion: 

Intracellular Magnesium inhibits ROMK channel in distal nephrons and prevents the potassium 

excretion. Thus, hypomagnesemia results in increased potassium excretion leading to hypokalemia. 

A magnesium deficiency can make it very difficult to treat low potassium levels with potassium 

supplements alone. The underlying magnesium deficiency must be addressed first to allow the 

ROMK channels to be properly regulated and to enable the body to retain the supplemented 

potassium. 

                                            Fig.9 Role of magnesium in potassium excretion 

Magnesium deficiency alone doesn’t increase potassium excretion much, rather an increase in distal 

sodium delivery or elevated aldosterone exacerbates potassium loss. 

                                                Fig.10 Hypokalemia in hypomagnesemia 

Circadian clock in potassium hemostasis 

Circadian rhythm in potassium hemostasis is due to a central clock in the suprachiasmatic nucleus of 

the brain and peripheral clocks present virtually in all cells. It is characterized by lower excretion at 

night and in early morning hours, thereby increasing in the afternoon, irrespective of dietary intake. 

This coincides with a circadian rhythm in the transcripts coding for kidney proteins related to K+ 

secretion. Increased gene expression of ROMK (Potassium eflux pump) during periods of activity 

during daylight is observed, whereas expression of the H-K-ATPase(Potassium influx pump) is higher 

during rest and night time, corresponding to periods when renal K excretion is greater and less, 

respectively.(Fig.11). There is also a pacemaker function regulating K transport, as indicated by 

expression of clock genes within cells of the distal nephron. 

                                            Fig.11 Circadian rhythm of Kaliuresis 

Studies have shown intravenous administration of potassium at noon (when clock-driven potassium 

excretion was near its maximum and food intake typically occurs) resulted in a smaller increase in the 

plasma potassium level than when the same amount of potassium was administered at midnight 

(when clock-driven potassium excretion was minimal). Potassium homeostasis, therefore, is not only 

due to reactive systems (Gut and Kidney) but also modulated by the central and peripheral circadian 

clocks (Predictive system). 

                                Fig.12 Summary of renal handling of Potassium 

Recommended reading

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2015;373:60-72. 

2. Palmer BF. Regulation of potassium homeostasis. Clin J Am Soc Nephrol. 2015;10:1050-1060.  

3. Palmer BF, Clegg DJ. Achieving the benefits of a high potassium,Paleolithic diet, without the 

toxicity. Mayo Clin Proc.2016;91:496-508. 

4. Preston R, Afshartous D, Rodco R, Alonso A, Garg D. Evidence for a gastrointestinal-renal kaliuretic 

signaling axis in humans. Kidney Int. 2015;88:1383-1391. 

5. Shibata S, Rinehart J, Zhang J, et al. Mineralocorticoid receptor phosphorylation regulates ligand 

binding and renal response to volume depletion and hyperkalemia. Cell Metab. 2013;18:660-671. 

6. Terker AS, Zhang C, McCormick JA, et al. Potassium modulates electrolyte balance and blood 

pressure through effects on distal cell voltage and chloride. Cell Metab. 2015;21:39-50. 

7. Veiras L, Girardi A, Curry J, et al. Sexual dimorphic pattern of renal transporters and electrolyte 

homeostasis. J Am Soc Nephrol. 2017;28:3504-3517. 

8. Weiner, ID., Linus, S., Wingo, CS. Disorders of potassium metabolism. In: Free-hally, J.Johnson, 

RJ., Floege, J., editors. Comprehensive clinical nephrology. 5th. St. Louis: Saunders; 2014. p. 118 

9. Malnic, G., Giebisch, G., Muto, S., Wang, W., Bailey, MA., Satlin, LM. Regulation of K+ excretion. 

In: Alpern, RJ.Caplan, MJ., Moe, OW., editors. Seldin and Giebisch's the kidney: physiology and 

pathophysiology. 5th. London: Academic Press; 2013. p. 1659-716. 

10. Mount, DB., Zandi-Nejad, K. Disorders of potassium balance. In: Taal, MW.Chertow, 

GM.Marsden,PA.Skorecki, KL.Yu, ASL., Brenner, BM., editors. The kidney. 9th. Philadelphia: Elsevier; 

2012. p.640-88. 

11. Biff F. Palmer and Deborah J. Clegg. Physiology and Pathophysiology of Potassium Homeostasis: 

Core Curriculum 2019. AJKD.2019;74(5):p.682-695