At what levels of creatinine (creatinine) and alanine transaminase (ALT) should medications such as statins (e.g. atorvastatin), angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and metformin be held in a patient with impaired renal function and elevated liver enzymes?

Medication Hold Thresholds Based on Creatinine and ALT Levels

ACE Inhibitors/ARBs: Creatinine-Based Hold Criteria

ACE inhibitors and ARBs should be held if creatinine rises to ≥3.5 mg/dL (310 μmol/L), or if creatinine increases by more than 50% from baseline when baseline is already ≥3.0 mg/dL (265 μmol/L). 1

Specific Creatinine Thresholds for ACE Inhibitors/ARBs:

• Continue therapy: Creatinine rise up to 50% from baseline OR absolute value <3.0 mg/dL (265 μmol/L), whichever is lower 1
• Reduce dose by 50%: Creatinine 3.0-3.5 mg/dL (265-310 μmol/L) with close monitoring 1
• Discontinue immediately: Creatinine ≥3.5 mg/dL (310 μmol/L) 1
• Temporary hold during acute illness: Any serious intercurrent illness (sepsis, dehydration, hypotension) in patients with GFR <60 mL/min/1.73 m² 2, 3

Important Context for ACE Inhibitor Creatinine Rises:

• An initial 25% rise in creatinine within the first 2-4 weeks is expected and acceptable, representing beneficial hemodynamic effects rather than kidney injury 1, 4
• The rise typically occurs as 15% in the first 2 weeks, then an additional 10% in weeks 3-4, with stabilization thereafter 4
• Do not discontinue for rises <30% above baseline during the first 2 months, as this early moderate rise is associated with long-term renoprotection 4

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Metformin: Creatinine-Based Hold Criteria

Metformin must be discontinued immediately when creatinine corresponds to eGFR <30 mL/min/1.73 m² (typically creatinine ≥2.0 mg/dL in elderly women or ≥2.5 mg/dL in men), due to severe risk of fatal lactic acidosis. 1, 2, 5

Specific eGFR/Creatinine Thresholds for Metformin:

• Contraindicated (stop immediately): eGFR <30 mL/min/1.73 m² 5
• Do not initiate: eGFR 30-45 mL/min/1.73 m² 5
• Reduce dose by 50%: eGFR 30-44 mL/min/1.73 m² if already on therapy 2
• Continue same dose: eGFR 45-59 mL/min/1.73 m² 2
• Gender-specific creatinine cutoffs: Stop if creatinine ≥1.5 mg/dL in men or ≥1.4 mg/dL in women 1

Critical Temporary Hold Situations for Metformin:

• Before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73 m² 5
• During any serious intercurrent illness causing dehydration, hypotension, or sepsis 3, 5
• During surgical procedures with restricted food/fluid intake 5

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NSAIDs: Creatinine-Based Hold Criteria

NSAIDs should be avoided entirely when eGFR <30 mL/min/1.73 m² (CKD stages 4-5) and used with extreme caution when eGFR 30-60 mL/min/1.73 m² (CKD stage 3). 6, 3

Specific Thresholds for NSAIDs:

• Absolute contraindication: eGFR <30 mL/min/1.73 m² 6
• Avoid prolonged use: eGFR <60 mL/min/1.73 m² 6
• Never combine with ACE inhibitors/ARBs: At any level of renal impairment, as this "triple therapy" (NSAID + RAAS blocker + diuretic) dramatically increases acute kidney injury risk 6, 3

High-Risk Scenarios Requiring Immediate NSAID Discontinuation:

• Volume depletion or dehydration 6
• Concurrent use with ACE inhibitors, ARBs, or diuretics 6
• Heart failure (Class III recommendation for harm by European Society of Cardiology) 6
• Any acute illness increasing AKI risk 6

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Statins: ALT-Based Hold Criteria

Statins should be held when ALT rises to >5× ULN, or when ALT >3× ULN occurs with concurrent total bilirubin elevation >2× ULN (Hy's Law criteria indicating severe hepatocellular injury). 1

Specific ALT Thresholds for Statins:

• Continue with increased monitoring: ALT 3-5× ULN without bilirubin elevation 1
• Hold therapy: ALT >5× ULN 1
• Permanent discontinuation: ALT ≥3× ULN with total bilirubin ≥2× ULN (Hy's Law) 1
• Life-threatening injury: ALT >20× ULN 1

Important Nuances for Statin Hepatotoxicity:

• Statins can be used safely in patients with renal disease, including those with creatinine >3 mg/dL, as atorvastatin is completely metabolized by the liver 7
• The magnitude of ALT elevation correlates poorly with severity of liver injury; clinical indicators (INR, albumin, bilirubin) are more important than ALT degree alone 1
• Monitor liver enzymes at baseline, then periodically during therapy 1

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Common Pitfalls to Avoid

Critical Drug Combinations to Never Use:

• NSAIDs + ACE inhibitors/ARBs + diuretics in any patient with renal impairment creates a "perfect storm" for acute kidney injury 6, 3
• Metformin + contrast dye without appropriate hold periods in patients with eGFR 30-60 mL/min/1.73 m² 5

Monitoring Errors to Avoid:

• Do not rely solely on serum creatinine to assess renal function, especially in elderly patients or those with reduced muscle mass, as creatinine may appear normal despite significantly reduced eGFR 2, 3
• Do not panic with early ACE inhibitor creatinine rises <30% above baseline in the first 2 months, as these represent beneficial hemodynamic effects 4
• Check eGFR, not just creatinine, as the same creatinine level represents much worse kidney function in elderly patients (e.g., creatinine 2.0 mg/dL may indicate eGFR <30 in an 80-year-old woman) 5

Temporary vs. Permanent Discontinuation:

• Temporary holds are appropriate for ACE inhibitors, ARBs, and metformin during acute illnesses, with reinitiation once the patient stabilizes 2, 3, 5
• Permanent discontinuation is required for metformin when eGFR falls below 30 mL/min/1.73 m² in stable patients 5
• NSAIDs should be permanently avoided in advanced CKD (eGFR <30), not just temporarily held 6, 3