Can Ranolazine Cause Kidney Failure?
Ranolazine does not directly cause kidney failure, but it requires significant dose reduction or avoidance in patients with existing renal impairment because plasma levels increase substantially (up to 2-fold) as kidney function declines, leading to potential toxicity and worsening of pre-existing renal dysfunction. 1, 2
Mechanism of Renal Involvement
Ranolazine undergoes extensive hepatic metabolism via CYP3A enzymes but is primarily excreted by the kidneys. 3 The critical issue is not that ranolazine damages healthy kidneys, but rather:
- Accumulation in renal impairment: Plasma concentrations increase 1.72-fold in mild, 1.80-fold in moderate, and 1.97-fold in severe renal impairment compared to patients with normal kidney function. 2
- Less than 7% of ranolazine is excreted unchanged, indicating that factors beyond reduced glomerular filtration rate contribute to drug accumulation—likely reduced tubular secretion and altered metabolism. 2
- Creatinine clearance correlates negatively with both AUC and maximum concentration, meaning worse kidney function leads to higher drug levels. 2
FDA-Mandated Warnings and Contraindications
The FDA label explicitly warns about renal failure risk:
- "Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60mL/min). If acute renal failure develops, discontinue Ranolazine Extended-Release Tablets." 1
- This warning indicates that while ranolazine doesn't typically cause kidney failure de novo, it can precipitate acute renal failure in vulnerable patients with pre-existing dysfunction. 1
Clinical Evidence of Renal Complications
Case Reports Documenting Renal Deterioration
A 2019 case report described an 88-year-old woman who developed bradycardia, hyperkalemia, and acute renal injury while taking ranolazine, representing a variant of BRASH syndrome (Bradycardia, Renal failure, AV nodal blockade, Shock, Hyperkalemia). 4 Key findings:
- Her serum creatinine rose to 1.6 mg/dL with potassium of 6.8 mEq/L. 4
- After discontinuing ranolazine, renal function returned to baseline within 48 hours. 4
- The authors concluded that ranolazine contributed to renal failure-induced hyperkalemia, creating a cascade of metabolic derangements. 4
Another case in 2013 documented severe neurologic toxicity in an 81-year-old woman with baseline renal impairment who received ranolazine, demonstrating how drug accumulation from impaired renal clearance leads to serious adverse effects. 5
Drug Interaction Complications
A 2019 case involving dabigatran-ranolazine interaction in a patient with renal failure (CrCL 45.22 mL/min) resulted in an INR of 7.03, illustrating how ranolazine's P-glycoprotein inhibition exacerbates problems in renal impairment. 6 After discontinuing dabigatran, creatinine clearance improved to 64.39 mL/min, suggesting the drug combination worsened renal function. 6
Guideline Recommendations for Chronic Kidney Disease
Expert consensus from Nature Reviews Cardiology (2018) explicitly states: "Ranolazine should not be prescribed when glomerular filtration rate is <30 ml/min/1.73 m². Plasma levels increase up to 50–60% in patients with moderate hepatic or renal impairment. These drugs should not be used in patients with chronic stable angina and chronic kidney disease, because they carry the risk of further complications." 7
This represents a contraindication rather than just a caution, distinguishing ranolazine from many other cardiovascular medications that can be dose-adjusted in CKD. 7
Practical Clinical Algorithm
For Patients with Normal Renal Function (CrCL ≥60 mL/min):
- Standard dosing: 500 mg twice daily, titrate to 1000 mg twice daily based on symptoms. 1
- Monitor renal function periodically, especially in elderly patients (>80 years). 5
For Patients with Moderate Renal Impairment (CrCL 30-60 mL/min):
- Maximum dose: 500 mg twice daily—do not exceed this dose. 1, 5
- Monitor renal function closely after initiation and monthly thereafter. 1
- Watch for signs of drug accumulation: dizziness, neurologic changes, bradycardia. 5, 4
For Patients with Severe Renal Impairment (CrCL <30 mL/min):
- Avoid ranolazine entirely—select alternative antianginal therapy. 7, 1
- If inadvertently prescribed, discontinue immediately if acute renal failure develops. 1
For Elderly Patients (>80 years):
- Do not exceed 500 mg twice daily regardless of calculated CrCL, as age-related decline in renal function may not be captured by creatinine-based estimates. 5
Common Pitfalls to Avoid
Overlooking mild baseline renal impairment: Many elderly patients have CrCL 40-60 mL/min despite "normal" serum creatinine due to reduced muscle mass—always calculate CrCL before prescribing. 2, 5
Combining with other P-glycoprotein inhibitors: Ranolazine inhibits P-gp, and when combined with other P-gp substrates (like digoxin or dabigatran) in patients with renal impairment, creates a dangerous synergy of drug accumulation. 1, 6
Ignoring drug-drug interactions with CYP3A inhibitors: Moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin) require limiting ranolazine to 500 mg twice daily, and strong inhibitors (ketoconazole, clarithromycin) are absolute contraindications. 1 In renal impairment, these interactions become even more dangerous.
Failing to recognize BRASH syndrome variant: The combination of bradycardia, worsening renal function, and hyperkalemia should prompt immediate consideration of ranolazine discontinuation. 4
Alternative Antianginal Options in CKD
When ranolazine is contraindicated due to renal impairment, consider:
- Beta-blockers (particularly bisoprolol, which is well-tolerated and does not require renal dose adjustment). 7
- Calcium channel blockers (amlodipine, diltiazem) for patients with preserved ventricular function. 7
- Long-acting nitrates (isosorbide mononitrate) with appropriate nitrate-free intervals. 7
- Ivabradine (only 20% renally excreted, no known renal pathology associations). 7