Why is my relatively healthy elderly patient so prone to hyperkalemia?

Hyporeninemic hypoaldosteronism (HH)—without impairment of cortisol synthesis— is associated with hyperkalemic (type IV) renal tubular acidosis (RTA) and is not uncommon among older patients despite glomerular filtration rates (GFRs) >20 ml/min, and absence of diabetes mellitus or chronic tubulointerstitial disease (1-7).  

Hyperkalemia due to HH in the elderly should come as no surprise because the renin-angiotensin-aldosterone system (RAAS) function declines with age, reaching its lowest level by age 60. 1-4   In fact, older people have comparatively lower mean levels of plasma renin and aldosterone at baseline and have an impaired ability to mount appropriate responses to RAAS stimuli, such as upright posture, volume depletion, catecholamines, or potassium administration (3-5).

The impaired RAAS capacity in the elderly often becomes more obvious when they are prescribed medications that further suppress RAAS (3). These include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers, nonsteroidal anti-inflammatory agents and heparin (3,7). 

Drugs that increase aldosterone resistance, including potassium-sparing diuretics (eg, spironolactone, amiloride, triamterene, eplerenone) and certain antibiotics (eg, trimethoprim, pentamidine) may also aggravate hyperkalemia associated with HH (7). 

A variety of mechanisms leading to HH with aging have been proposed. These include impaired conversion of prorenin to renin, prostaglandin deficiency, sympathetic nervous system dysfunction and increased plasma levels of atrial natriuretic factors as found in congestive heart failure (1,7). 

Bonus pearl: Did you know that the first case of “pure hypoaldosteronism” was described in 1957 in a 71 year old non-diabetic patient with hyperkalemia in the setting of congestive heart failure? (8)

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  1. Bauer JH. Age-related changes in the renin-aldosterone system. Physiological effects and clinical implications. Drugs & Aging 1993;3:238-45. https://www.ncbi.nlm.nih.gov/pubmed/8324299
  2. Musso CG, Jauregui JR. Renin-angiotensin-aldosterone system and the aging kidney. Expert Rev Endocrinol Metab 2014;9:543-46. https://www.tandfonline.com/doi/full/10.1586/17446651.2014.956723
  3. Yoon HE, Choi BS. The renin-angiotensin system and aging in the kidney. Korean J Intern Med 2014;29:291-95. https://www.researchgate.net/publication/262530577_The_renin-angiotensin_system_and_aging_in_the_kidney
  4. Nadler JL, Lee FO, Hsueh W, et al. Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1015-20. https://www.ncbi.nlm.nih.gov/pubmed/3515183
  5. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1041-42. https://www.ncbi.nlm.nih.gov/pubmed/3515186
  6.  Block BL, Bernard S, Schwartzstein RM. Hypo-hypo: a complex metabolic disorder. Ann Am Thorac Soc 2016;13:127-133. https://www.ncbi.nlm.nih.gov/pubmed/26730868
  7. Michelis MF. Hyperkalemia in the elderly. Am J Kid Dis 1990;16:296-99.https://www.ajkd.org/article/S0272-6386(12)80005-9/pdf
  8. Hudson JB, Chobanian AV, Relman AS. Hypoaldosteronism. A clinical study of a patient with an isolated adrenal mineralocorticoid deficiency, resulting in hyperkaliemia and Stokes-Adams attack. N Engl J Med 1957;257:529-36. https://www.ncbi.nlm.nih.gov/pubmed/13464977


Why is my relatively healthy elderly patient so prone to hyperkalemia?

Does my patient on chronic prednisone need stress doses of corticosteroids perioperatively?

There are wide-ranging opinions on stress doses of corticosteroids (CS) in patients on chronic prednisone undergoing surgery, largely due to lack of adequately-sized randomized controlled studies.  Most experts seem to agree, however, that the age-old practice of routinely administering very high doses of hydrocortisone (eg, 100 mg IV every 8 hours) with prolonged taper postoperatively is excessive. 1-7

Couple of questions to consider before you decide on stress doses of CS for your patient with CS-induced (not primary) adrenal suppression. First, is your patient likely to have a suppressed adrenal function? And if so, what type of surgery is he or she about to undergo?

As for the first question, keep in mind that exogenous CS suppress the production of corticotropin (ACTH) and can induce adrenal atrophy that may persist for up to 12 months, an effect that’s dependent not only on their dose but also on their duration and may vary greatly from person to person. 2,4

Generally, a daily prednisone dose of 5 mg or less —irrespective of the duration— is considered unlikely to cause adrenal suppression (unless it’s given at bed time) and therefore should not require stress doses of CS.1 Conversely, clinical features of Cushing’s syndrome and prednisone doses of 20 mg or more daily for more than 3 weeks are likely to be associated with hyphothalamic-pituitary-adrenal (HPA) axis suppression.  Due to possible delay in the recovery of the HPA axis after discontinuation of exogenous CS, you should review not only your patient’s current dose and duration of CS but his or her regimen during the previous year. 2

When in doubt, particularly in patients receiving intermediate doses (eg, between 5 to 20 mg of prednisone daily) or duration of CS, testing the HPA axis (eg, by cosyntropin stimulation) has been suggested by some with the caveats that it’s a grade 2C (weak recommendation, low quality evidence) recommendation,7 and the results may not necessarily predict clinical adrenal insufficiency or be available before surgery. 4  

Once you have decided that your patient may be at risk of adrenal insufficiency during the perioperative period, the stress dose and duration of CS will likely depend on the type of surgery: “minor” (eg, inguinal herniorrhaphy); “moderate” (eg, total joint replacement, peripheral vascular surgery) and “major” (eg, pancreatoduodenectomy, cardiac surgery with cardiopulmonary bypass). 

A popular online resource suggests the following:4

  • Minor surgery or local anesthesia: Give only the morning maintenance dose of CS without any stress doses
  • Moderate surgery: Give the usual morning dose plus hydrocortisone IV 50 mg (or equivalent) just before the procedure followed by 25 mg IV every 8 hours for 24 hours, followed by the maintenance regimen
  • Major surgery: Give the usual morning dose plus hydrocortisone 100 mg IV before anesthesia induction, followed by 50 mg IV every 8 hours for 24 hours, tapering the dose by half each day to maintenance.

Alternatively, for minor and moderate procedures, other authors suggest usual daily dose plus hydrocortisone 50 mg IV before incision, followed by hydrocortisone 25 mg IV every 8 h for 24 h, then the usual daily dose.1  Yet others have recommended giving IV hydrocortisone 25 mg/day for 1 day for minor surgeries, 50-75 mg/day x 1-2 days for moderate surgeries, and 100-150 mg/day for 2-3 days for major surgeries.2-4 Whichever regimen you chose, make sure to give the morning maintenance dose.  

Why is less aggressive stress dosing being favored in these patients? Several reasons come to mind, including:

  •  In normal subjects, endogenous cortisol production rarely rises above 150-200 mg /day even in response to major surgery 2-4   
  • High doses of CS, particularly with long taper, may unnecessarily subject patients to adverse effects, such as hyperglycemia and poor wound healing 3,4
  • Published reports of CS-treated patients having complications such as hypotension or even death in the postoperative period have generally only implicated, not proven, adrenal insufficiency as a cause. 1-4


Bonus pearl: Did you know that the hypotension of secondary adrenal insufficiency in patients treated with CS is not caused by mineralocorticoid deficiency? Instead, it may in part be related to the action of CS in enhancing vascular responsiveness to vasopressors (eg, catecholamines).2 

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  1. Liu MM, Reidy AB, Saatee S, et al. Perioperative steroid management: Approaches based on current evidence. Anesthesiology 2017;127:166-72. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2626031
  2. Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin N Am 2003;32:367-83. http://pggweb.com/doc/glucocorticoids.pdf
  3. Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 1997;219:416-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1243159/
  4. Shaw M. When is perioperative ‘steroid coverage’ necessary? Clev Clin J Med 2002;69:9-11. https://www.ncbi.nlm.nih.gov/pubmed/11811727
  5. Urmson K. Stress dose steroids: the dogma persists. Can J Anesthe 2019;September 23. https://www.ncbi.nlm.nih.gov/pubmed/31549340
  6. Wax DB. One size fits all for stress-dose steroids. Anesthesiology 208;128:674-87. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2672525
  7. Hamrahian AH, Roman S, Milan S. The management of the surgical patient taking glucocorticoids. Uptodate 2019, accessed October 21, 2019. https://www.uptodate.com/contents/the-management-of-the-surgical-patient-taking-glucocorticoids
Does my patient on chronic prednisone need stress doses of corticosteroids perioperatively?

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

Although we may expect patients with DKA to present with hypotension due to hypovolemia, many patients with DKA may actually be hypertensive. This finding is particularly intriguing because hyperinsulinemia, not insulinopenia as found in DKA, has been associated with hypertension. 1,2

Though not proven, potential explanations for hypertension in DKA include elevated serum levels of catecholamines, pro-inflammatory cytokines, renin, angiotension II and aldosterone.3-5 Hyperosmolality may also lead to the release of antidiuretic hormone (ADH) which increases blood pressure via V2 receptors.  Another possibility is that the high insulin levels associated with the treatment of DKA suppress the catecholamine-stimulated production of vasodilative eicosanoids (eg, prostaglandins) by adipose tissue. 1 It’s possible that in any given patient, 1 or more of these mechanisms may be enough to override the potential hypotensive effect of insulin deficiency in DKA.

We should note that reports of frequent hypertension in DKA have primarily involved pediatric patients. A 2011 study found that 82% of pediatric patients with DKA had hypertension during the first 6 hours of admission with no patient having hypotension.3  

On the other extreme, refractory hypotension without obvious cause (eg, sepsis, acute adrenal insufficiency, cardiogenic causes) has also been reported in DKA.5Because insulin inhibits the production of vasodilative prostaglandins (eg, PGI2 and PGE2), severe insulin deficiency in DKA can also contribute to hypotension along with volume depletion. 

Potential genetic polymorphism in the synthesis and metabolism of prostaglandins may at least partially explain the varied blood pressure response and whether a patient with DKA presents with hypertension or hypotension. 5  

The author would like to acknowledge the valuable contribution of Lloyd Axelrod MD, Massachusetts General Hospital, to this post.

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  1. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991;40:1223-1227. https://diabetes.diabetesjournals.org/content/40/10/1223 
  2. Chatzipantelli K, Head C, Megerman J, et al. The relationship between plasma insulin level, prostaglandin productin by adipose tissue and blood pressure in normal rats and rats with diabetes mellitus and diabetic ketoacidosis. Metabolism 1996;45:691-98. https://www.sciencedirect.com/science/article/abs/pii/S002604959690133X 
  3. Deeter KH, Roberts JS, Bradford H, et al. Hypertension despite dehydration during severe pediatric diabetic ketoacidosis. Pediatr Diabetes 2011;12:295-301. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-5448.2010.00695.x 
  4. Ferris JB, O’Hare JA, Kelleher CM, et al. Diabetic control and the renin-angiotensin system, catecholamines and blood pressure. Hypertension 1985 7(Suppl II):II-58-II-63. https://www.ahajournals.org/doi/abs/10.1161/01.HYP.7.6_Pt_2.II58  
  5. Singh D, Cantu M, Marx MHM, et al. Diabetic ketoacidosis and fluid refractory hypotension. Clin Pediatrics 2016;55:182-84. https://journals.sagepub.com/doi/abs/10.1177/0009922815584549?journalCode=cpja 


Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

How does excess licorice consumption cause hypertension and hypokalemia?

The active ingredient of licorice, glycyrrhizic acid or glycyrrhizin, is first converted to glycyrrhetinic acid (GRA) in the bowel which is then absorbed. Once in the circulation, GRA inhibits activation of 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD2), an enzyme in renal tissue that converts active cortisol to inactive cortisone. Without the full action of this enzyme, proper sodium and potassium homeostasis would be difficult because cortisol is just as effective in stimulating mineralocorticoid receptors as aldosterone but with 100-1000 times higher concentration than that of aldosterone! 1-3

Other ways that GRA may cause hypertension and hypokalemia include inhibition of 5 β-reductase in the liver, an enzyme that metabolizes aldosterone and direct stimulation of mineralocorticoid receptors, though overall these mechanisms may not be as important as the effect of GRA on cortisol metabolism in renal tissue.1,2

Besides causing fluid retention, licorice ingestion has also been found to increase systemic vascular resistance possibly by increasing vascular tone and remodeling of the vascular wall, potentiating the vasoconstrictor actions of angiotensin II and catecholamines in smooth muscle, and suppressing vasodilatory systems, including endothelial nitric oxide synthase and prostacyclin synthesis.

It’s no wonder that the FDA issued a statement in 2017: “If you’re 40 or older, eating 2 ounces of black licorice a day for a day for at least two weeks could land you in the hospital with an irregular heart rhythm or arrhythmia.” 5

Bonus Pearl: Did you know that as early as 1951, extract of licorice was reported for treatment of Addison’s disease, a combination of licorice and soy sauce has been reported to be “life-saving” in a patient with Addison’s disease (2007), and GRA food supplementation may lower serum potassium in chronic hemodialysis patients (2009)? 6,7



  1. Sontia B, Mooney J, Gaudet L, et al. Pseudohyperaldosteronism, liquorice and hypertension. J Clin Hypertens (Greenwich) 2008; 10:153-57. https://www.ncbi.nlm.nih.gov/pubmed/18256580
  2. Omar HR, Komarova I, El-Ghonemi M, et al. Licorice abuse: time to send a warning message. The Adv Endocrinol Metab 2012;3:125-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498851/
  3. Penninkilampi R, Eslick EM, Eslick GD. The association between consistent licorice ingestion, hypertension and hypokalaemia: as systematic review and meta-analysis. Journal of Human Hypertension 2017;31:699-707. https://www.ncbi.nlm.nih.gov/pubmed/28660884
  4. Black licorice: trik or treat? https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm 277152.htm
  5. Hautaniemi EJ, Tahvanainen AM, Koskela JK, et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep 2017;7:10947. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591274/
  6. Groen J, Pelser H, Willebrands AF, et al. Extract of licorice for the treatment of Addison’s disease. N Engl J Med 1951;244:471-75. https://www.ncbi.nlm.nih.gov/pubmed/14806786
  7. Cooper H, Bhattacharya B, Verma V, et al. Liquorice and soy sauce, a life-saving concoction in a patient with Addison’s disease. Ann Clin Biochem 2007;44:397-99. https://www.ncbi.nlm.nih.gov/pubmed/17594790
  8. Farese S, Kruse Anja, Pasch A, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney International 2009;76:877-84. https://www.ncbi.nlm.nih.gov/pubmed/19641483
How does excess licorice consumption cause hypertension and hypokalemia?

Could constipation contribute to hyperkalemia in my patient with chronic kidney disease?

Yes! Constipation may be an important contributor to hyperkalemia in some patients with chronic kidney disease (CKD).

 Under normal conditions, 80-90% of excess dietary potassium (K+) is excreted by the kidneys, with the remainder excreted through the GI tract.1 However, in advanced CKD, particularly in the setting of end-stage kidney disease (ESKD), the GI tract assumes a much more important role in maintaining K+ balance. 

As early as 1960’s, the daily fecal excretion of K+ was found to be directly related to the wet stool weight, irrespective of creatinine clearance. Furthermore, K+ excretion in stool was as high as ~80% of dietary intake (average 37%) in some hemodialysis (HD) patients compared to normal controls (average 12%). 2

Such increase in K+ excretion in the GI tract of patients with CKD was later found to be primarily the result of K+ secretion into the colon/rectum rather than reduced dietary K+ absorption in the small intestine 1,3, was inversely related to residual kidney function, and as a consequence could serve as the main route of K+ excretion in patients with ESKD. 4

Collectively, these findings suggest that in addition to non-dietary factors such as medications, we may need to routinely consider constipation as a potential cause of hyperkalemia in patients with advanced CKD or ESKD. 1

Bonus Pearl: Did you know that secretion of K+ by the apical surface of colonic epithelial is mediated in part by aldosterone-dependent mechanisms? 5


  1. St-Jules DE, Goldfarb DS, Sevick MA. Nutrient non-equivalence: does restricting high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients? J Ren. Nutr 2016;26: 282-87. https://www.ncbi.nlm.nih.gov/pubmed/26975777
  2. Hayes CP, McLeod ME, Robinson RR. An extrarenal mechanism for the maintenance of potassium balance in severe chronic renal failure. Trans Assoc Am Physicians 1967;80:207-16.
  3. Martin RS, Panese S, Virginillo M, et al. Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis 1986;8:105-10. https://www.ncbi.nlm.nih.gov/pubmed/3740056
  4. Cupisti A, Kovesdy CP, D’Alessandro C, et al. Dietary approach to recurrent or chronic hyperkalemia in patients with decreased kidney function. Nutrients 2018, 10, 261;doi:10.3390/nu10030261. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872679/
  5. Battle D, Boobes K, Manjee KG. The colon as the potassium target: entering the colonic age of hyperkalemia treatment. EBioMedicine 2015;2: 1562-1563. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740340/pdf/main.pdf


Contributed in part by Alex Blair, MD, Mass General Hospital, Boston, MA.

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Could constipation contribute to hyperkalemia in my patient with chronic kidney disease?

Should my patient with compensated heart failure be placed on a sodium-restricted diet?

Although sodium restriction is routinely recommended for patients with heart failure (HF), the data is often conflicting with a number of studies even suggesting that it may be harmful in some patients.

Two randomized trials (by the same group) involving patients with compensated HF recently discharged from the hospital reported that “less restricted” sodium diet (2.8 gm/d) along with fluid restriction (1 L/day) and high dose furosemide (at least 125-250 mg furosemide twice daily) was associated with less rates of readmissions and improved levels of brain natriuretic peptide, aldosterone and plasma renin activity compared to patients on more restricted sodium diet (1.8 gm/d). 1,2

Analysis of data from the multihospital HF Adherence and Retention Trial enrolling New York Heart Association functional class II/III HF patients found that sodium restriction (<2.5 gm/d) was associated with significantly higher risk of death or HF hospitalization but only in patients not on an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). 3

In normal subjects who are not sodium deprived, excess sodium intake has been shown to cause expansion of intravascular volume without increasing total body water. 4 Thus, sodium restriction combined with diuretics may reduce intravascular volume and renal perfusion, further stimulating the renin-angiotensin-aldosterone system and fluid retention. 5

Bonus Pearl: Did you know that the 2013 American College of Cardiology Foundation/American Heart Association guidelines downgraded the recommendation for sodium restriction to Class IIa (reasonable) with Level of Evidence:C? 6


  1. Paterna S, Gaspare P, Fasullo S, et al. Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend? Clin Sci 2008;114:221-230. https://www.ncbi.nlm.nih.gov/pubmed/17688420
  2. Paterna S, Parrinello G, Cannizzaro S, et al. Medium term effects of different dosage of diuretic, sodium, and fluid administration on neurohormonal and clinical outcome in patients with recently compensated heart failure. Am J Cardiol 2009;103:93-102. https://www.ncbi.nlm.nih.gov/pubmed/19101237
  3. Doukky R, Avery E, Mangla A, et al.Impact of dietary sodium restriction on heart failure outcomes. J Am Coll Cariol HF 2016;4:24-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705447/
  4. Heer M, Baisch F, Kropp J et al. High dietary sodium chloride consumption may not induce body fluid retention in humans. Am J Physiol Renal Physiol 2000;278:F585-F595. https://www.ncbi.nlm.nih.gov/pubmed/10751219
  5. Rothberg MB, Sivalingam SK. The new heart failure diet: less salt restriction, more micronutrients. J Gen Intern Med 25;1136-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955483/
  6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 CCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239. https://www.ncbi.nlm.nih.gov/pubmed/23741058

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Should my patient with compensated heart failure be placed on a sodium-restricted diet?