What are the possible causes of a persistently elevated serum creatinine in an otherwise healthy adult with no known medical history?

Causes of Persistently Elevated Creatinine in Otherwise Healthy Adults

In an otherwise healthy adult with no known medical history, persistently elevated creatinine most commonly results from pre-renal causes (dehydration, volume depletion), intrinsic kidney diseases (chronic kidney disease from undiagnosed diabetes or hypertension, glomerulonephritis), medication effects, or factitious elevation from dietary creatine supplements or certain drugs that interfere with creatinine measurement or secretion. 1

Pre-Renal Causes (Decreased Kidney Perfusion)

Dehydration and volume depletion are the most common reversible causes of elevated creatinine in otherwise healthy individuals 1:

• A BUN/creatinine ratio >20:1 strongly suggests pre-renal causes like dehydration 1
• If dehydration is the cause, improvement should be seen within 24-48 hours of adequate fluid repletion 1
• Check for orthostatic hypotension, decreased skin turgor, dry mucous membranes, and recent weight loss 1
• Serum osmolality >300 mOsm/kg confirms dehydration 1

Heart failure with reduced cardiac output can cause pre-renal azotemia, typically with BUN/creatinine ratio >20:1 1

Intrinsic Renal Causes (Direct Kidney Damage)

Chronic Kidney Disease from Undiagnosed Conditions

Diabetic nephropathy is the leading cause of end-stage renal disease in the U.S. 1:

• In type 2 diabetes, kidney disease may be present at diagnosis due to delayed recognition of diabetes onset 2
• Screening should begin at diagnosis of type 2 diabetes 2
• Diagnosis requires macroalbuminuria or microalbuminuria plus retinopathy 2

Hypertensive nephrosclerosis from undiagnosed hypertension is a common cause of chronic kidney disease 1:

• Hypertensive individuals are at increased risk for elevated creatinine even at low blood lead levels 2
• Blood pressure should be monitored at every clinical contact 2

Glomerulonephritis should be suspected if there is significant proteinuria or microhematuria 2:

• Urine microscopy has excellent negative predictive value for ruling out clinically important intrinsic kidney injury 1
• Parenchymal renal diseases may require renal biopsy for diagnosis 2

Plasma Cell Disorders

Multiple myeloma with light chain cast nephropathy should be considered, especially with unexplained renal dysfunction accompanied by hypercalcemia, anemia, or bone pain 1, 3:

• Light chain cast nephropathy occurs when monoclonal free light chains precipitate in distal tubules with Tamm-Horsfall protein, causing tubular obstruction 3
• Diagnosis requires serum protein electrophoresis, serum immunofixation, 24-hour urine protein electrophoresis, and serum free light chain assay 3
• Bone marrow biopsy showing ≥20% plasma cells definitively establishes clonal plasma cell disorder 3

Medication-Related Causes

Drugs That Interfere with Creatinine Secretion

Several medications cause elevated creatinine without reducing GFR by inhibiting tubular secretion 4:

• Trimethoprim inhibits creatinine secretion by proximal tubules 4
• Cimetidine blocks tubular secretion of creatinine 4
• Salicylates can inhibit creatinine secretion 4

Drugs That Cause Hemodynamic Changes

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 1:

• These increases reflect reduced intraglomerular pressure, not true kidney injury 2
• Do not discontinue for creatinine increases ≤30% in the absence of volume depletion 2
• Discontinuation should only be considered when creatinine rise exceeds 30% or hyperkalemia develops 1

Diuretics can cause pre-renal azotemia through volume depletion, with BUN/creatinine ratio >20:1 1:

• Diuretic-induced volume depletion is the most common avoidable reason for creatinine elevation in patients on RAS-modulating drugs 1

Nephrotoxic Medications

Cyclosporine and tacrolimus (immunosuppressants) commonly cause nephrotoxicity 5, 6:

• Nephrotoxicity was reported in approximately 59% of heart transplant patients receiving tacrolimus 6
• Frequency and severity of creatinine elevations increase with dose and duration 5

NSAIDs should be avoided or discontinued when elevated creatinine is detected 1

Factitious Elevation (Pseudo-Renal Failure)

Dietary Creatine Supplements

Creatine supplements (including creatine ethyl ester) can elevate serum creatinine without true kidney dysfunction 7, 8:

• Creatine is metabolized to creatinine, directly increasing serum levels 7
• Abnormalities reverse after discontinuation of the supplement 7
• Excessive dietary creatine intake (e.g., from beef liver or bodybuilding supplements) can mimic advanced renal failure 8
• Creatinine can normalize within 12 hours of stopping high-creatine sources 8

Drugs That Increase Creatinine Production

Corticosteroids and vitamin D metabolites modify creatinine production rate and release 4

Diagnostic Approach

Initial Evaluation

Assess volume status and recent medication changes 1:

• Look for orthostatic hypotension, decreased skin turgor, dry mucous membranes, recent weight loss 1
• Review use of diuretics, NSAIDs, trimethoprim, ACE inhibitors, ARBs 1
• Obtain detailed nutritional history, including supplements and homemade formulas 8

Obtain urinalysis to check for proteinuria or hematuria indicating intrinsic kidney damage 1:

• Urine albumin-to-creatinine ratio with persistent albuminuria (≥30 mg/g) indicates kidney damage 1
• Active urine sediment (red blood cells or cellular casts) suggests non-diabetic kidney disease 2

Screen for diabetes and hypertension, the leading causes of chronic kidney disease 1:

• Screening should begin at diagnosis of type 2 diabetes 2
• Type 1 diabetes screening should begin 5 years after diagnosis 2

Distinguishing True Kidney Injury from Hemodynamic Changes

Perform urine microscopy to distinguish between hemodynamic creatinine rise and true tubular injury 1:

• Worsening renal function is often not associated with tubular injury in heart failure patients undergoing aggressive diuresis 1

Calculate estimated GFR using appropriate equations 9:

• The MDRD equation systematically underestimates GFR in healthy persons by 29% 9
• At the same serum creatinine level, age, and sex, GFR is on average 26% higher in healthy persons than in patients with chronic kidney disease 9

Follow-Up Testing

Repeat BUN, creatinine, and calculate GFR in 3-6 months to determine if kidney disease is chronic 1:

• If values remain elevated despite adequate hydration for 2 days, intrinsic kidney disease should be considered 1
• A GFR <60 mL/min/1.73 m² indicates Stage 3 chronic kidney disease if persistent 1

Monitor serum creatinine and potassium levels periodically when ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists are used 2

Common Pitfalls and Caveats

Do not confuse modest creatinine increases (up to 30%) with ACE inhibitors/ARBs as acute kidney injury 2:

• Analysis of the ACCORD BP trial demonstrates that those with up to 30% increase in serum creatinine did not have increased mortality or progressive kidney disease 2
• Markers for AKI showed no significant increase with increased creatinine 2

Serum creatinine alone is unreliable for assessing kidney function, as it can be normal even when GFR has decreased by 40% 1

Serum creatinine may underestimate kidney dysfunction if the patient has decreased muscle mass 1

Always evaluate hydration status when encountering elevated creatinine, as simple rehydration may correct pre-renal causes 1

Consider multiple myeloma in patients with unexplained renal dysfunction, especially when accompanied by hypercalcemia, anemia, or bone pain 1

When to Refer to Nephrology

Immediate referral to nephrology is recommended for 1:

• eGFR <30 mL/min/1.73 m²
• Uncertainty about the etiology of kidney disease
• Difficult management issues
• Rapidly progressing kidney disease

Consider nephrology referral based on the risk stratification grid incorporating both eGFR and albuminuria 2:

• Green (normal eGFR and albumin-to-creatinine ratio): annual follow-up
• Yellow: measurements at least once per year
• Orange: measurements twice per year
• Red: measurements three times per year
• Dark red: measurements four times per year and nephrology referral