Principles of Renal Dose Adjustment

Renal dose adjustment keeps drug exposure equal to that seen with normal kidney function. It is needed when a drug or an active metabolite is mainly cleared by the kidney (over 40 to 50 percent excreted unchanged), and either the therapeutic index is narrow or toxicity is dose related.

Loading and maintenance. The loading dose depends on volume of distribution and is usually not reduced. The maintenance dose depends on clearance and is reduced.

Method. Lower the dose, lengthen the interval, or both. Lengthen the interval for concentration-dependent drugs that need a high peak, such as aminoglycosides. Lower the dose or modestly lengthen the interval for time-dependent drugs such as beta-lactams.

Calculation. Adjustment factor Q = 1 minus [fe × (1 minus KF)], where fe is the fraction excreted unchanged and KF is the patient's clearance divided by 120 mL/min. New dose = usual dose × Q, or new interval = usual interval divided by Q. For fe 0.8 and clearance 30 mL/min, KF is 0.25 and Q is 0.4, so give 40 percent of the dose or lengthen the interval 2.5 times.

Active metabolites. Morphine, pethidine, allopurinol and glibenclamide produce metabolites that accumulate and prolong effect.

Prefer drugs with non-renal clearance when equal efficacy exists: linagliptin, ceftriaxone, atorvastatin, amlodipine, doxycycline, clindamycin and fentanyl.

Usually avoid in advanced disease. Nitrofurantoin, NSAIDs, metformin, pethidine, lithium, glibenclamide and sodium phosphate preparations.

Special groups.

• Children: calculate by mg/kg using an age-appropriate estimate of function.

• Older adults: start low, because a normal creatinine can conceal a clearance under 50 mL/min.

• Pregnancy: filtration rises, so normal-range doses may be needed despite a creatinine in the usual range for non-pregnant adults.

• Liver disease: do not assume a kidney-based adjustment is sufficient.

Clearance is Cockcroft-Gault in mL/min.

• Gabapentin: 30 to 59, total 400 to 1400 mg daily in 2 doses. 15 to 29, 200 to 700 mg once daily. Under 15, 100 to 300 mg once daily.

• Pregabalin: 30 to 59, 75 to 300 mg daily in 2 or 3 doses. 15 to 29, 25 to 150 mg daily in 1 or 2 doses. Under 15, 25 to 75 mg once daily.

• Aciclovir intravenous (10 mg/kg every 8 hours normally): 25 to 50, every 12 hours. 10 to 25, every 24 hours. Under 10, 5 mg/kg every 24 hours.

• Amoxicillin oral: 10 to 30, at most 500 mg every 12 hours. Under 10, at most 500 mg every 24 hours.

• Fluconazole: give the usual loading dose, then 50 percent of the daily dose when clearance is 50 or under.

• Co-trimoxazole: full dose over 30, half dose at 15 to 30, avoid under 15 unless levels are available.

• Enoxaparin: prophylaxis 20 mg once daily and treatment 1 mg/kg once daily if clearance is under 30.

• Metformin: maximum 1 g daily at eGFR 30 to 44, stop under 30.

Monitoring. Reassess the dose whenever kidney function changes. Measure levels for aminoglycosides, vancomycin, lithium and digoxin. Check clinical signs of accumulation at each review.

Stop and reduce signs. Myoclonus or confusion (gabapentinoids, morphine, cefepime), tremor and ataxia (lithium), bradycardia (digoxin, sotalol), hypoglycaemia (sulphonylureas, insulin) and seizures (cefepime, imipenem) mean the dose is too high for current clearance.

Referral and escalation. Involve a pharmacist or nephrologist for narrow index drugs in clearance under 30 mL/min, for patients on dialysis, and when no published adjustment exists.

Common errors. Reducing the loading dose, using eGFR for a drug labelled by Cockcroft-Gault clearance, ignoring active metabolites, and failing to raise doses again after recovery.