The kidney is the primary route of elimination for a large proportion of drugs and their active metabolites. Understanding the mechanisms by which the kidney processes drugs — glomerular filtration, tubular secretion, and tubular reabsorption — is foundational to safe prescribing in patients with impaired renal function.
Key mechanisms
For drugs that are primarily renally cleared (renal fraction fe > 0.5), any reduction in GFR leads to proportional drug accumulation if the dose is not adjusted. The clinical consequence depends on whether the drug or its metabolite is pharmacologically active and whether it has a narrow therapeutic index.
A drug's renal fraction (fe) tells you how much of your dose adjustment problem is determined by the kidney. If fe is 0.9 and your patient's GFR is halved, plasma levels of unchanged drug will roughly double without adjustment.
Active metabolites are a common clinical trap. Morphine-6-glucuronide (M6G), the active metabolite of morphine, accumulates in renal impairment and can cause prolonged respiratory depression at standard doses. Similarly, the active metabolite of allopurinol — oxypurinol — accumulates and increases the risk of hypersensitivity reactions.
Always check whether a drug's metabolites are renally cleared and pharmacologically active. Key examples: morphine (M6G), codeine (morphine), allopurinol (oxypurinol), metformin (unchanged drug — renal clearance is the drug itself).
A patient with CKD stage 4 (eGFR 22 mL/min/1.73 m²) is prescribed morphine for post-operative pain. What is the primary pharmacokinetic concern?