Can Renal Issues Cause Elevated Cortisol?
Yes, impaired renal function can cause falsely elevated cortisol measurements and alter cortisol metabolism, but this represents altered clearance and measurement artifacts rather than true hypercortisolism. The kidney is the major site of cortisol-to-cortisone conversion, and renal dysfunction disrupts this process, leading to accumulation of cortisol metabolites and altered test interpretation.
Mechanisms of Cortisol Elevation in Renal Disease
Moderately impaired renal function (eGFR 30-60 mL/min/1.73 m²) significantly increases both morning cortisol levels and cortisol levels during dexamethasone suppression testing in patients with adrenal adenomas. Patients with moderately impaired renal function showed cortisol levels of 541 vs 456 nmol/L (p=0.02) and post-dexamethasone cortisol of 62 vs 37 nmol/L (p=0.001) compared to those with eGFR >60 mL/min/1.73 m² 1. Importantly, mildly impaired renal function (eGFR 60-90 mL/min/1.73 m²) does not produce this effect 1.
The kidney serves as the major site of cortisone production in humans through 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme activity 2. Anephric patients demonstrate plasma cortisone levels of only 6±1 nmol/L compared to 62±3 nmol/L in controls (p<0.001), confirming the kidney's central role 2. In chronic kidney disease, impaired conversion of cortisol to cortisone results in a reversed tetrahydrocortisone/tetrahydrocortisol ratio of 0.7±0.4 in CKD patients versus 1.9±0.9 in controls (p<0.001), with this ratio correlating inversely with serum creatinine 3.
Impact on Diagnostic Testing
The dexamethasone suppression test has reduced specificity for diagnosing subclinical hypercortisolism in patients with moderately impaired renal function. Cortisol levels ≥50 nmol/L after 1 mg overnight dexamethasone occurred in 76% of patients with eGFR 30-60 mL/min/1.73 m² versus only 30% with eGFR >60 mL/min/1.73 m² (p<0.001), while ACTH suppression rates remained similar 1. This indicates that the elevated post-dexamethasone cortisol represents altered clearance rather than autonomous cortisol production.
For screening tests in patients with renal impairment (CrCl <60 mL/min), late-night salivary cortisol may be preferred over 24-hour urinary free cortisol (UFC). Urine volume and glomerular filtration rate strongly predict UFC levels, making UFC interpretation unreliable in renal dysfunction 4. The guideline explicitly recommends considering alternative screening tests for patients with significant renal impairment 4.
False Positives and Measurement Artifacts
Decreased corticosteroid-binding globulin (CBG) and albumin levels in nephrotic syndrome can produce falsely low total cortisol values during dexamethasone suppression testing. This occurs because total cortisol measurements include both bound and free cortisol, and reduced binding proteins lower the total cortisol despite potentially normal free cortisol levels 4.
Chronic kidney disease produces a pattern of subclinical hypercortisolism characterized by blunted diurnal cortisol decline, impaired negative feedback regulation, and reduced cortisol clearance 5. However, this represents dysregulation of cortisol metabolism rather than true Cushing's syndrome.
Clinical Implications and Diagnostic Approach
When evaluating suspected hypercortisolism in patients with renal impairment, measure ACTH levels alongside cortisol to distinguish true autonomous cortisol production from altered clearance. In the study of patients with moderately impaired renal function and elevated post-dexamethasone cortisol, ACTH levels remained similar to those with normal renal function (4.1 vs 2.9 pmol/L, p=0.21), and the prevalence of suppressed ACTH (<2 pmol/L) was comparable (24% vs 31%, p=0.51) 1. This indicates that elevated cortisol without ACTH suppression suggests altered clearance rather than autonomous production.
For patients with CKD and suspected Cushing's syndrome, use late-night salivary cortisol as the primary screening test rather than UFC or dexamethasone suppression testing. Late-night salivary cortisol measures free cortisol and is independent of CBG changes, renal function, and urine collection accuracy 4.
Important Caveats
The relationship between cortisol and mortality in CKD remains under investigation, with associations reported in end-stage renal disease but requiring further research in earlier CKD stages 5. Acute intrarenal cortisol administration does not affect renal blood flow or vascular resistance in hypertensive patients, suggesting that cortisol's effects on blood pressure in CKD operate through mechanisms other than direct renal vasoconstriction 6.
Never rely solely on elevated cortisol levels or abnormal dexamethasone suppression test results to diagnose hypercortisolism in patients with eGFR <60 mL/min/1.73 m². Require additional confirmatory evidence such as suppressed ACTH, elevated late-night salivary cortisol, or clinical features strongly suggestive of Cushing's syndrome before pursuing further evaluation 4, 1.