What causes elevated creatinine (a measure of impaired renal function) in the blood?

Causes of Elevated Creatinine in Blood

Elevated creatinine results from three main categories: pre-renal causes (decreased kidney perfusion), intrinsic renal causes (direct kidney damage), and post-renal causes (urinary obstruction), plus medication-induced elevations that may not reflect true kidney injury.

Pre-renal Causes (Decreased Kidney Perfusion)

Volume depletion and decreased cardiac output are the most common pre-renal causes, typically presenting with a BUN/creatinine ratio >20:1 1.

• Dehydration or volume depletion reduces renal perfusion and elevates both BUN and creatinine, with BUN rising disproportionately (BUN/creatinine ratio >20:1) 1
• Heart failure with reduced cardiac output decreases kidney perfusion, causing pre-renal azotemia with characteristic BUN/creatinine ratio >20:1 1
• Diuretic-induced volume depletion is the most common avoidable cause of creatinine elevation, particularly in patients on ACE inhibitors or ARBs 2

Intrinsic Renal Causes (Direct Kidney Damage)

Intrinsic kidney disease causes creatinine elevation through actual nephron damage, typically with a BUN/creatinine ratio <20:1.

• Diabetic nephropathy is the leading cause of end-stage renal disease in the U.S., developing after 10 years in type 1 diabetes but potentially present at diagnosis in type 2 diabetes 2, 1
• Hypertensive nephrosclerosis from chronic uncontrolled hypertension causes progressive kidney damage and elevated creatinine 1
• Acute tubular necrosis results from ischemic or toxic injury to kidney tubules 1
• Contrast-induced nephropathy can cause acute kidney injury following contrast administration 1
• Glomerulonephritis causes inflammation of the glomeruli, elevating creatinine 1
• Multiple myeloma can cause cast nephropathy, particularly when accompanied by hypercalcemia, anemia, or bone pain 1

Medication-Related Causes

Medications Causing True Kidney Injury

• NSAIDs should be avoided or discontinued when elevated creatinine is detected, as they reduce renal perfusion 1

Medications Causing Spurious Creatinine Elevation Without True Kidney Damage

Several medications elevate creatinine by blocking its tubular secretion rather than reducing GFR—this is a critical distinction to avoid unnecessary drug discontinuation 3, 4, 5.

• Trimethoprim blocks tubular secretion of creatinine, causing spuriously elevated levels without affecting actual kidney function 3, 4, 5
• Cimetidine inhibits creatinine secretion by proximal tubules without reducing GFR 4
• ACE inhibitors and ARBs cause modest creatinine increases (up to 30% or <266 μmol/L [3 mg/dL]) through hemodynamic changes that are acceptable and don't require discontinuation unless the rise exceeds 30% 2, 1
• Corticosteroids may modify creatinine production rate and release 4

Post-renal Causes (Urinary Obstruction)

• Urinary tract obstruction from prostatic hypertrophy, stones, or tumors can elevate creatinine by preventing urine flow

Critical Clinical Pearls

Always evaluate hydration status first—simple rehydration may correct pre-renal causes within 24-48 hours 1.

• Do not discontinue ACE inhibitors or ARBs for creatinine increases <30% in the absence of volume depletion, as these medications provide long-term kidney and cardiovascular protection 2, 1
• Consider temporarily discontinuing NSAIDs, but continue ACE inhibitors/ARBs when elevated creatinine is detected 1
• Diuretic-induced volume depletion is the most common avoidable reason for creatinine elevation in patients on RAS-modulating drugs 2
• Multiple myeloma should be considered in patients with unexplained renal dysfunction, especially with hypercalcemia, anemia, or bone pain 1
• Serum creatinine alone is unreliable for assessing kidney function, as it can remain normal even when GFR has decreased by 40% 1
• Creatinine supplements may transiently raise serum creatinine and mimic kidney disease without causing actual renal damage 6

Diagnostic Approach

• Check BUN/creatinine ratio: >20:1 suggests pre-renal causes (dehydration, heart failure); <20:1 suggests intrinsic kidney disease 1
• Assess volume status and recent medication changes (diuretics, NSAIDs, trimethoprim) 2, 1
• Monitor for improvement with rehydration: If dehydration is the cause, improvement should occur within 24-48 hours of adequate fluid repletion 1
• Screen for diabetes, hypertension, and proteinuria with urinalysis and urine albumin-to-creatinine ratio 2
• Obtain renal ultrasound to assess kidney size (small kidneys suggest chronic disease) and rule out obstruction 7
• Refer to nephrology immediately for eGFR <30 mL/min/1.73 m², uncertainty about etiology, or rapidly progressing kidney disease 1