The Answer is D: Cushing's Syndrome
Cushing's syndrome causes hypokalemia, not hyperkalemia, making it the exception among the listed options. All other choices are well-established causes of hyperkalemia.
Why Cushing's Syndrome Causes Hypokalemia (Not Hyperkalemia)
Cushing's syndrome produces hypercortisolism, which activates mineralocorticoid receptors and causes renal potassium wasting, leading to hypokalemia—not hyperkalemia 1.
Patients with Cushing's syndrome typically present with hypokalemia and hypertension due to excessive cortisol's mineralocorticoid effects 1.
The glucocorticoid excess in Cushing's syndrome mimics aldosterone activity, promoting urinary potassium excretion and resulting in low serum potassium levels 2.
Why the Other Options DO Cause Hyperkalemia
Excessive Physical Exercise (Option A)
Intense physical exercise causes transcellular shift of potassium from intracellular to extracellular space, producing profound hyperkalemia 2.
During vigorous muscle activity, potassium is released from skeletal muscle cells into the bloodstream, temporarily elevating serum levels 2.
Oliguric Acute Renal Failure (Option B)
Acute kidney injury dramatically impairs renal potassium excretion and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis 3, 4.
The kidneys are the primary regulators of potassium homeostasis, and impaired renal excretion is the dominant cause of sustained hyperkalemia 5.
Hyperkalemia incidence increases dramatically with severity of renal impairment, occurring in up to 73% of patients with advanced chronic kidney disease 4, 6.
Administration of Spironolactone (Option C)
Spironolactone is a potassium-sparing diuretic that can cause hyperkalemia by blocking aldosterone-mediated potassium excretion in the distal nephron 3, 4, 7.
The FDA drug label explicitly warns that spironolactone can cause hyperkalemia, with risk increased by impaired renal function or concomitant use of RAAS inhibitors 7.
In patients taking spironolactone with ACE inhibitors or ARBs, the prevalence of hyperkalemia is 11.2%, with higher doses (>25 mg/day) significantly increasing risk 8.
Spironolactone use is identified as a specific risk factor for repeated hyperkalemia episodes within 6 months 3.
Cyclosporine (Option E)
Cyclosporine is a calcineurin inhibitor that impairs renal potassium excretion and is recognized as a drug that increases potassium levels 3, 4.
Drug-induced hyperkalemia from cyclosporine is increasingly common in clinical practice, particularly in transplant recipients 5.
Clinical Context and Key Distinctions
The fundamental distinction is that Cushing's syndrome causes mineralocorticoid excess (leading to potassium loss), while the other conditions either impair renal excretion, cause transcellular shifts outward, or block aldosterone activity 2, 1.
Hyporeninemic hypoaldosteronism (the opposite of Cushing's) is actually an overlooked cause of hyperkalemia, characterized by suppressed renin and aldosterone responses 9.
In contrast, primary aldosteronism (like Cushing's) causes hypokalemic alkalosis with low-renin hypertension due to excessive mineralocorticoid activity 2.