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Hyperkalemia
Hyperkalemia
CME LEARNING OBJECTIVE: Readers will assess, find the cause of, and treat hyperkalemia
CREDIT
BIFF F. PALMER, MD DEBORAH J. CLEGG, PhD
Professor of Internal Medicine, Professor of Internal Medicine, Biomedi-
Department of Internal Medicine, cal Research Department, Diabetes and
University of Texas Southwestern Obesity Research Division, Cedars-Sinai
Medical Center, Dallas, TX Medical Center, Los Angeles, CA
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PALMER AND CLEGG
gastrointestinal tract. Red clay or river bed In contrast, organic acidosis (due to lactic,
clay, on the other hand, is enriched in potas- beta-hydroxybutyric, or methylmalonic acid)
sium (100 mmol of potassium in 100 g of clay) tends not to cause a potassium shift, since most
and can cause life-threatening hyperkalemia organic anions readily cross the cell mem-
in patients with chronic kidney disease.8 brane along with hydrogen. Lactic acidosis is
Eating burnt match heads. Some indi- often associated with potassium shift, but this
viduals chew and ingest burnt match heads, effect is due to loss of cell integrity as a result
a condition called cautopyreiophagia. In one of cell ischemia. The hyperkalemia typically
reported case,9 this activity contributed an ad- present on admission in patients with diabetic
ditional 80 mmol of daily potassium intake in ketoacidosis is the result of insulin deficiency
a dialysis patient, resulting in a plasma potas- and hypertonicity and not the underlying or-
sium concentration of 8 mmol/L. ganic acidosis.10
Hypertonic states can cause hyperkalemia
Is the hyperkalemia the result due to cell shift. For example, hyperglycemia,
of a cellular shift? as in diabetic ketoacidosis, pulls water from
Acute hyperkalemia can be the result of re- the intracellular into the extracellular com-
distribution of cellular potassium. Shifting of partment, thereby concentrating intracellu-
as little as 2% of the body’s potassium from lar potassium and creating a more favorable
the intracellular to the extracellular space can gradient for potassium efflux through mem-
double the plasma potassium concentration. brane channels. This same effect can occur in
Tissue injury. Hyperkalemia frequently neurosurgical patients given large amounts of
occurs in diseases that cause tissue injury such hypertonic mannitol. Repetitive doses of im-
as rhabdomyolysis, trauma, massive hemolysis, munoglobulin can lead to extracellular accu-
and tumor lysis. mulation of sorbitol, maltose, or sucrose, since
Insulin deficiency. Insulin and catechol- these sugars are added to the preparations to
amines are major regulators of potassium prevent immunoglobulin aggregation.11
distribution within the body. After a meal,
The Paleolithic release of insulin not only regulates the plas- Is a disturbance in renal potassium
ma glucose concentration, it also causes po- excretion present?
diet contained tassium to move into cells until the kidneys Sustained hyperkalemia is more commonly as-
4 times as much have had sufficient time to excrete the dietary sociated with decreases in renal potassium ex-
potassium potassium load and reestablish total-body po- cretion than with a cellular shift. In most in-
tassium content. stances the clinician can distinguish between
as ours Exercise, beta-blockers. During exercise, cell shift and impaired renal excretion based
potassium is released from skeletal muscle on the available clinical data.
cells and accumulates in the interstitial com- The transtubular potassium gradient has
partment, where it exerts a vasodilatory effect. been used to determine whether there is a dis-
The simultaneous increase in circulating cat- turbance in renal potassium excretion and to
echolamines regulates this release by promot- assess renal potassium handling.12
ing cell potassium uptake through beta-adren-
ergic receptor stimulation. Transtubular potassium gradient =
Metabolic acidosis can facilitate exit (ie, [urine potassium concentration /
shift) of potassium from cells, but this effect (urine osmolality / serum osmolality)] /
depends on the type of acidosis. Hyperchlo- serum potassium concentration
remic normal anion gap acidosis (mineral
acidosis) most commonly causes this effect This calculation is based on the assump-
due to the relative impermeability of the cell tion that only water is reabsorbed past the
membrane to the chloride anion. As hydrogen cortical collecting duct, and not solutes. It has
ions move into the cell due to accumulation fallen out of favor since we have found this
of ammonium chloride or hydrogen chloride, assumption to be incorrect; a large amount
electrical neutrality is maintained by potas- of urea is reabsorbed daily in the downstream
sium exit. medullary collecting duct as a result of intra-
936 C L E V E L A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 8 4 • N U M B E R 1 2 D E C E M B E R 2 0 1 7
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PALMER AND CLEGG
Angiotensin-converting
enzyme inhibitors Angiotensin II receptor
Direct renin inhibitor blockers
NSAIDs
Beta-blockers
Cyclosporine, tacrolimus Angiotensin I Angiotensin II Adrenal gland
Diabetes
Elderly
Renin
Impaired release Impaired aldosterone
of renin metabolism
Adrenal disease
Heparin
Collecting Ketoconzaole
duct
(–)
Aldosterone
(–) +
Na+
+
+ +
(–) + +
+ Aldosterone receptor
+
+ blockers
+
Na+ channel (–) +
+
Spironolactone
blockers Eplerenone
K+ +
Amiloride Drospirenone
K+
+
Triamterene Aldosterone
Trimethoprim K+ K+
K+
receptor
Pentamidine (–)
K+ K+ CCF
K+ ©2017
Medical Illustrator: David Schumick
Figure 1. A number of pharmacologic agents and conditions can interfere with the renin-angiotensin-
aldosterone system, altering renal potassium excretion. Reabsorption of sodium in the collecting duct
increases the luminal electronegativity, providing a more favorable gradient for potassium secretion.
Aldosterone is critical for this reabsorptive process. A number of drugs and conditions interfere with the
production of aldosterone and, as a result, reduce renal potassium secretion. In some patients, more than
1 disturbance may be present. NSAIDs = nonsteroidal anti-inflammatory drugs.
Based on information in Palmer BF. A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis 2010; 56:387–393.
culating levels of both angiotensin I and II.16 Calcineurin inhibitors impair potassium
The syndrome of hyporeninemic hypoal- secretion by suppressing renin release and by
dosteronism is a common cause of hyperkale- direct tubular effects.19
mia in patients who have a glomerular filtra- Beta-blockers. Beta-1 and to a lesser ex-
tion rate between 40 and 60 mL/min. Diabetic tent beta-2 receptor blockade can also result
nephropathy and interstitial renal disease are in a hyporeninemic state.
the most common clinical entities associated
with this syndrome.10 Other causes include Distal tubular defect
analgesic nephropathy, urinary tract obstruc- Hyperkalemia can result from interstitial renal
tion, sickle cell disease, systemic lupus erythe- diseases that specifically affect the distal neph-
matosus, and amyloidosis. ron. In this setting, the glomerular filtration
Nonsteroidal anti-inflammatory drugs can rate is only mildly reduced, and circulating al-
cause hyperkalemia by suppressing renin re- dosterone levels are normal.
lease and reducing delivery of sodium to the Renal transplant, lupus erythematosus,
distal nephron.18 amyloidosis, urinary obstruction, and sickle
938 C L E V E L A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 8 4 • N U M B E R 1 2 D E C E M B E R 2 0 1 7
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PALMER AND CLEGG
TABLE 2
Reducing the risk of hyperkalemia when using
renin-angiotensin-aldosterone system blockers
Assess renal function to define overall risk of hyperkalemia
Discontinue medications that can impair renal potassium excretion, including herbal preparations and over-
the-counter nonsteroidal anti-inflammatory drugs
Reduce potassium in diet, avoid salt substitutes containing potassium
Ensure effective diuretic therapy (loop diuretics should be used if the estimated glomerular filtration rate
is < 30 mLmin/1.73 m2)
Correct metabolic acidosis when present
Start with low doses of renin-angiotensin-aldosterone system blockers and monitor closely
citability but does not alter the plasma potas- may be a hidden source of dietary potassium.
sium concentration. Dietary counseling. Patients should be
Insulin lowers the plasma potassium con- instructed to reduce their dietary intake of po-
centration by promoting its entry into cells. tassium and to avoid salt substitutes that con-
To avoid hypoglycemia, 10 units of short-act- tain potassium.
ing insulin should be accompanied by a 50-g Diuretic therapy is beneficial in minimiz-
infusion of glucose, increased to 60 g if 20 ing hyperkalemia in patients with chronic
units of insulin are given.24 kidney disease. Thiazide and loop diuretics en-
Beta-2 receptor agonists produce a similar hance renal potassium excretion by increasing
effect. The shift of potassium into cells with flow and delivery of sodium to the collecting
insulin and beta-2-adrenergic receptor stimu- duct. Thiazide diuretics are effective when the
Acute lation is brought about by increases in sodium- estimated glomerular filtration rate is greater
treatment potassium ATPase pump activity, primarily in than 30 mL/min, while loop diuretics should
is indicated skeletal muscle cells. be used in patients with more severe renal in-
Sodium bicarbonate, in the absence of sufficiency (Table 2).
for marked acidosis, lowers the plasma potassium con- Sodium bicarbonate is an effective agent
electrocardio- centration only slightly. It should be reserved to minimize increases in the plasma potassium
for hyperkalemic patients who have coexist- concentration in patients with chronic kidney
graphic ing metabolic acidosis after the patient has disease and metabolic acidosis. This drug in-
changes and received insulin and glucose, an adrenergic creases renal potassium excretion by increas-
agent, and calcium. ing distal sodium delivery and shifts potassium
severe muscle into cells as the acidosis is corrected. The
These acute treatments need to be fol-
weakness lowed by therapies designed to lower the to- likelihood of developing volume overload as
tal body potassium content such as diuretics, a complication of sodium bicarbonate admin-
potassium-binding drugs, and dialysis. istration can be minimized with effective di-
uretic therapy.
■■ TREATMENT OF CHRONIC HYPERKALEMIA
Avoiding hyperkalemia if renin-angiotensin-
Review medications. Once the diagnosis of aldosterone system blockers are needed
hyperkalemia has been made, the initial ap- Renin-angiotensin-aldosterone system block-
proach should be to review the patient’s medi- ers can be problematic, as these drugs cause
cations and make every effort to discontinue hyperkalemia, often in the very patients who
drugs that can impair renal potassium excre- derive the greatest cardiovascular benefit from
tion.16 Patients should be asked about their use them.16 A number of steps can reduce the risk
of over-the-counter nonsteroidal anti-inflam- of hyperkalemia and allow these drugs to be
matory drugs and herbal remedies, since herbs used.
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PALMER AND CLEGG
The initial dose should be low and the plasma potassium concentration in the setting
plasma potassium should be measured within of ongoing use of renin-angiotensin-aldoste-
1 to 2 weeks after drug initiation. If the potas- rone system blockers.
sium level is normal, the dose can be titrated Patiromer is a nonabsorbed polymer ap-
upwards with remeasurement of the plasma proved for clinical use to treat hyperkalemia.
potassium after each dose titration. If the The drug binds potassium in exchange for
plasma potassium concentration rises to 5.5 calcium in the gastrointestinal tract, predomi-
mmol/L, in some cases lowering the dose will nantly in the colon, and lowers the plasma
reduce the potassium concentration and allow potassium concentration in a dose-dependent
the patient to remain on the drug. manner, with the greatest reduction in those
In patients at risk of hyperkalemia, angio- with higher starting values.27,28
tensin II receptor blockers and direct renin in- Patiromer effectively controlled plasma
hibitors should be used with the same caution potassium concentrations in a 1-year ran-
as angiotensin-converting enzyme inhibitors. domized trial in high-risk patients on renin-
If the plasma potassium concentration ex- angiotensin-aldosterone system blockers.29
ceeds 5.5 mmol/L despite the above precau-
The main adverse events in clinical trials
tions, one can consider using a potassium-bind-
have been constipation and hypomagnesemia,
ing drug (see below) before deciding to avoid
which required magnesium replacement in a
renin-angiotensin-aldosterone system blockers.
Sodium polystyrene sulfonate binds small number of patients, but overall, the drug
potassium in the gastrointestinal tract in is well tolerated.
exchange for sodium and has been used to Sodium zirconium cyclosilicate is a non-
manage hyperkalemia. This drug is most absorbed microporous compound that binds
commonly given along with sorbitol as a potassium in exchange for sodium throughout
therapy for acute hyperkalemia. Although the gastrointestinal tract. It has been found ef-
the drug is widely used, most of the potas- fective in lowering plasma potassium concen- Use loop
sium-lowering effect is due to an increase in tration in a dose-dependent fashion in high- diuretics,
stool volume caused by sorbitol.25,26 In addi- risk patients, most of whom were receiving
tion, long-term use is poorly tolerated, and renin-angiotensin-aldosterone system block- not thiazides,
the drug has been linked to gastrointestinal ers.30–32 Adverse events were generally com- if the estimated
toxicity in rare cases. parable to those with placebo in clinical tri- glomerular
Patiromer and sodium zirconium cyclosili- als; however, edema occurred more frequently
cate are two new potassium-binding drugs that when higher doses were used. This drug is not filtration rate
have been shown to be effective in reducing yet approved for clinical use. ■ is < 30 mL/min
■■ REFERENCES JAMA 1975; 234:738–740.
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Nephrol 2015; 10:1050–1060. tients with diabetes mellitus. N Engl J Med 2015; 373:548–559.
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4. Sebastian A, Frassetto LA, Sellmeyer DE, Morris RC Jr. The evolu- nous immunoglobulin therapy. Nephron Clin Pract 2007; 106:c143–
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greatly exceeds current and recommended intakes. Semin Nephrol 12. Choi M, Ziyadeh F. The utility of the transtubular potassium gradi-
2006; 26:447–453. ent in the evaluation of hyperkalemia. J Am Soc Nephrol 2008;
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leolithic diet, without the toxicity. Mayo Clin Proc 2016; 91:496–508. 13. Palmer BF. A physiologic-based approach to the evaluation of a
6. Liamis G, Liberopoulos E, Barkas F, Elisaf M. Spurious electrolyte patient with hyperkalemia. Am J Kidney Dis 2010; 56:387–393.
disorders: a diagnostic challenge for clinicians. Am J Nephrol 2013; 14. Stanton BA. Renal potassium transport: morphological and func-
38:50–57. tional adaptations. Am J Physiol 1989; 257:R989–R997.
7. Mansoor S, Holtzman N, Emadi A. Reverse pseudohyperkalemia: an 15. Hayes CP Jr, McLeod ME, Robinson RR. An extravenal mechanism
important clinical entity in chronic lymphocytic leukemia. Case Rep for the maintenance of potassium balance in severe chronic renal
Hematol 2015; 2015:930379. failure. Trans Assoc Am Physicians 1967; 80:207–216.
8. Gelfand M, Zarate A, Knepshield J. Geophagia. A cause of life- 16. Palmer BF. Managing hyperkalemia caused by inhibitors of the
threatening hyperkalemia in patients with chronic renal failure. renin-angiotensin-aldosterone system. N Engl J Med 2004; 351:585–
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