What causes elevated creatinine levels?

Causes of Elevated Creatinine

Elevated serum creatinine levels are primarily caused by decreased glomerular filtration rate (GFR), but can also result from increased creatinine production, decreased tubular secretion, or laboratory assay interference. 1

Acute Causes of Elevated Creatinine

Decreased Glomerular Filtration

• Acute Kidney Injury (AKI) - classified by stages:

  • Stage 1: Increase in creatinine ≥0.3 mg/dL or 1.5-2 fold from baseline 1
  • Stage 2: 2-3 fold increase from baseline 1
  • Stage 3: >3 fold increase, creatinine >4 mg/dL with acute increase ≥0.3 mg/dL, or requiring renal replacement therapy 1

• Prerenal causes:

  • Volume depletion (dehydration, hemorrhage, excessive diuresis) 1
  • Decreased cardiac output (heart failure, cardiogenic shock) 1
  • Systemic hypotension 1

• Intrinsic renal causes:

  • Acute tubular necrosis (ischemic or nephrotoxic) 1
  • Acute interstitial nephritis (drug-induced, autoimmune) 1
  • Glomerulonephritis 1
  • Immune checkpoint inhibitor-related nephritis 1

• Postrenal causes:

  • Urinary tract obstruction (stones, tumors, prostatic hypertrophy) 1

Medications

• Nephrotoxic drugs:

  • Aminoglycosides (gentamicin) 2
  • NSAIDs 1
  • Contrast media 1
  • Certain chemotherapeutics 1

• Drugs affecting renal hemodynamics:

  • ACE inhibitors/ARBs (especially with bilateral renal artery stenosis, volume depletion, or concomitant NSAID use) 1
  • Cyclosporine 1

• Drugs reducing tubular secretion:

  • Trimethoprim 1
  • Cimetidine 1

Other Acute Factors

• Increased creatinine production:
  • Rhabdomyolysis 1
  • Recent high protein/meat meal 1
  • Dietary creatine supplements 1

Chronic Causes of Elevated Creatinine

Decreased Glomerular Filtration

• Chronic Kidney Disease (CKD) - staged by GFR:

  • Stage 1: GFR ≥90 mL/min/1.73m² with kidney damage
  • Stage 2: GFR 60-89 mL/min/1.73m²
  • Stage 3a: GFR 45-59 mL/min/1.73m²
  • Stage 3b: GFR 30-44 mL/min/1.73m²
  • Stage 4: GFR 15-29 mL/min/1.73m²
  • Stage 5: GFR <15 mL/min/1.73m² 3

• Common causes of CKD:

  • Diabetic nephropathy 1
  • Hypertensive nephrosclerosis 1
  • Glomerular diseases 1
  • Polycystic kidney disease 1
  • Chronic interstitial nephritis 1

Physiologic/Demographic Factors

• Increased creatinine generation:

  • Male sex 4
  • Muscular body habitus 1
  • Afro-Caribbean ethnicity 1
  • High protein diet 4

• Age-related changes:

  • Decreased muscle mass in elderly (may mask renal dysfunction) 1
  • Age-related decline in GFR (approximately 1-2 mL/min/year after age 30-40) 1

Laboratory Interference

• Jaffe assay interference:

  • Hyperbilirubinemia 1
  • Ketones 1
  • Certain medications 5

• Enzymatic interference:

  • Hyperbilirubinemia 1
  • Hemolysis 1

Clinical Pearls and Pitfalls

1. Small absolute increases in creatinine can be significant:

   • Even a 0.3 mg/dL increase in creatinine can indicate AKI and is associated with increased mortality 6
   • The significance of creatinine changes depends on baseline values - a 0.3 mg/dL rise is more significant with normal baseline than with elevated baseline 1

2. Creatinine is a late marker of kidney injury:

   • GFR may decrease by 50% before serum creatinine rises above normal range 4
   • Creatinine rises more slowly than actual GFR decline, especially in acute settings

3. Medication management considerations:

   • ACE inhibitors/ARBs typically cause a small (up to 30%) rise in creatinine that stabilizes within days to weeks and is not an indication to discontinue therapy unless increase exceeds 30% or hyperkalemia develops 1
   • Temporary holding of ACE inhibitors/ARBs may be necessary during acute illness with volume depletion 1

4. Monitoring recommendations:

   • Verify elevated creatinine with repeat testing 3
   • Calculate eGFR to better assess kidney function 3
   • Monitor creatinine more frequently in high-risk patients (diabetes, hypertension, heart failure) 1
   • Consider nephrology referral for persistent unexplained elevation, rapid decline in function, or GFR <30 mL/min/1.73m² 3

Remember that serum creatinine should be interpreted in clinical context, as various factors beyond kidney function can influence its levels. An elevated creatinine level is a powerful independent risk factor for mortality 7, making proper identification of its cause crucial for appropriate management.