What dose adjustments are necessary for patients with Chronic Kidney Disease (CKD)?

Dose Adjustments in Chronic Kidney Disease

Consider GFR when dosing medications cleared by the kidneys, using validated eGFR equations based on serum creatinine for most clinical settings, with dose reductions or interval extensions required for renally eliminated drugs when eGFR falls below drug-specific thresholds. 1

General Principles for Medication Dosing in CKD

Assessment of Renal Function

• Obtain an estimated glomerular filtration rate (eGFR) before initiating medications that require renal dose adjustment 1, 2
• For most clinical settings, validated eGFR equations using serum creatinine are appropriate for drug dosing 1
• Where more accuracy is required (narrow therapeutic window, drug toxicity concerns, or unreliable eGFRcr estimates), use equations combining both creatinine and cystatin C, or measured GFR 1
• In patients with extremes of body weight, eGFR non-indexed for body surface area may be indicated, especially for medications with narrow therapeutic ranges 1

Monitoring Requirements

• Monitor eGFR, electrolytes, and therapeutic medication levels when indicated in patients with CKD receiving medications with narrow therapeutic windows, potential adverse effects, or nephrotoxicity 1
• Obtain eGFR at least annually in all patients taking renally cleared medications 2
• In patients at risk for developing renal impairment (e.g., elderly), assess renal function more frequently 2

Drug-Specific Dosing Adjustments

Metformin

Metformin is contraindicated when eGFR is less than 30 mL/min/1.73 m² due to risk of lactic acidosis 2

• Do not initiate metformin in patients with eGFR between 30-45 mL/min/1.73 m² 2
• No dose adjustment needed if eGFR >45 mL/min/1.73 m² 1, 2
• In patients taking metformin whose eGFR falls below 45 mL/min/1.73 m², assess benefit versus risk of continuing therapy 2
• Metformin is substantially excreted by the kidney, and renal clearance is approximately 3.5 times greater than creatinine clearance, indicating tubular secretion as the major elimination route 2

Antiplatelet Agents (for Acute Coronary Syndromes)

No specific dose adjustments are required for clopidogrel, prasugrel, or ticagrelor in CKD patients 1

• Clopidogrel: Loading dose 300-600 mg, maintenance dose 75 mg daily—no adjustment needed 1
• Prasugrel: Loading dose 60 mg, maintenance dose 10 mg daily (5 mg if <60 kg or ≥75 years)—no adjustment needed 1
• Ticagrelor: Loading dose 180 mg, maintenance dose 90 mg twice daily—no adjustment needed 1

Antiretroviral Medications

Nucleoside reverse-transcriptase inhibitors (NRTIs) require dose adjustment based on creatinine clearance, while protease inhibitors and non-nucleoside reverse-transcriptase inhibitors generally do not 1

Lamivudine Dosing:

• CrCl ≥50 mL/min: 150 mg twice daily or 300 mg once daily 1
• CrCl 30-49 mL/min: 150 mg once daily 1
• CrCl 15-29 mL/min: 150 mg first dose, then 100 mg once daily 1
• CrCl 5-14 mL/min: 150 mg first dose, then 50 mg once daily 1
• Hemodialysis: 50 mg first dose, then 25 mg once daily 1

Zidovudine Dosing:

• CrCl ≥15 mL/min: No adjustment needed 1
• CrCl <15 mL/min or hemodialysis: 100 mg every 6-8 hours 1

Protease Inhibitors and NNRTIs:

• No dose adjustment required for indinavir, ritonavir, lopinavir/ritonavir, atazanavir, nevirapine, efavirenz, or delavirdine in CKD 1
• Exception: Administer 200 mg nevirapine after dialysis sessions 1

Antidiabetic Agents

DPP-IV Inhibitors:

Sitagliptin requires dose reduction based on eGFR 1:

• eGFR >50 mL/min/1.73 m²: 100 mg daily 1
• eGFR 30-50 mL/min/1.73 m²: 50 mg daily 1
• eGFR <30 mL/min/1.73 m²: 25 mg daily 1

Linagliptin requires no dose adjustment at any level of renal function 1

Sulfonylureas:

• Avoid glyburide in CKD—it is contraindicated 1
• Glipizide: No adjustment if eGFR >50 mL/min/1.73 m²; use conservative initial dose (2.5 mg daily) with caution in advanced CKD 1

Insulin:

• Reduce total daily insulin dose by 25-30% for patients with CKD stage 3 1
• Reduce total daily insulin dose by 35-50% for patients with CKD stage 5 1
• Reduce basal insulin by 25% on pre-hemodialysis days 1

Lipid-Lowering Agents

Most statins require no dose adjustment in mild to moderate CKD 1

• Rosuvastatin: Initiate at 5 mg daily and do not exceed 10 mg daily when CrCl <30 mL/min/1.73 m² 1
• Simvastatin: Initiate at 5 mg daily in severe kidney disease 1
• Lovastatin: Use doses >20 mg daily cautiously when CrCl <30 mL/min 1
• Fenofibrate: Initiate at 54 mg daily and minimize doses when CrCl <50 mL/min, as drug clearance is greatly reduced 1

Fluconazole

Reduce fluconazole maintenance dose by 50% after loading dose when CrCl ≤50 mL/min 3

• CrCl >50 mL/min: Standard dosing (200-800 mg daily depending on indication) 3
• CrCl ≤50 mL/min: Full loading dose on Day 1, then 50% maintenance dose starting Day 2 3
• Hemodialysis: Administer 100% of recommended dose after each dialysis session 3
• Approximately 50% of fluconazole is removed during a 3-hour hemodialysis session 3

Special Considerations

Medications to Avoid or Use with Extreme Caution

• NSAIDs should be avoided in CKD due to nephrotoxic effects 1, 4
• Review and limit over-the-counter medicines and dietary/herbal remedies that may be harmful 1
• Consider potential nephrotoxicity when prescribing any medication, always weighing benefits versus harms 1

Perioperative Management

Consider planned discontinuation of metformin, ACE inhibitors, ARBs, and SGLT2 inhibitors 48-72 hours prior to elective surgery as a precautionary measure 1

• Communicate a clear plan for when to restart discontinued medications to the patient and healthcare providers 1
• Document the restart plan in the medical record to prevent unintentional harm from failure to resume these medications 1

Contrast Imaging Procedures

Stop metformin at the time of or prior to iodinated contrast imaging in patients with eGFR 30-60 mL/min/1.73 m² 2

• Also stop in patients with hepatic impairment, alcoholism, heart failure, or those receiving intra-arterial contrast 2
• Re-evaluate eGFR 48 hours after the procedure before restarting metformin 2

Medication Review and Transitions of Care

Perform thorough medication review periodically and at all transitions of care to assess adherence, continued indication, and potential drug interactions 1

• Patients with CKD often have complex medication regimens and see multiple specialists 1
• Adapt drug dosing when GFR, non-GFR determinants of filtration markers, or volume of distribution are not in steady state 1

Common Pitfalls to Avoid

• Dosage adjustment based solely on GFR may not always be appropriate, as net renal excretion involves glomerular filtration, tubular secretion, and tubular reabsorption 5
• Inappropriate dosing in renal dysfunction can cause toxicity or ineffective therapy 5, 6
• Even when dosage adjustments are carefully followed, adverse drug reactions remain common in CKD 5
• Plasma protein binding of drugs may be significantly reduced in CKD, influencing distribution and elimination 5
• The activity of drug-metabolizing enzymes and drug transporters is impaired in chronic renal failure 5