1. Creatinine metabolism was studied in nine patients with severe chronic renal failure who were nevertheless in a nearly steady state with respect to their creatinine pool. Labelled creatinine was injected intravenously and the specific radioactivity of creatinine in urine was measured during the ensuing 5–7 days.
2. In each patient, the decline in specific radioactivity with time was a single exponential function after 12 h. The volume of distribution of creatinine averaged 49.1 ± 2.8% body weight. The average rate of creatinine production was 148 μmol day−1 kg−1, which is similar to predicted values for normal subjects of the same age, weight and sex. Creatinine metabolism rate/kg body weight, estimated as the difference between production rate/kg body weight, determined radioisotopically, and creatinine appearance rate (excretion plus accumulation), averaged 42 μmol day−1 kg−1.
3. Total creatinine metabolism rate/kg body weight was correlated with serum creatinine. Thus, as serum creatinine rises, an increasing fraction of the produced creatinine was metabolized rather than excreted. This relationship could account for the diminished creatinine excretion commonly seen in patients with chronic renal failure.
4. Extrarenal clearance (metabolism/serum creatinine) of this magnitude (approximately 31% of renal clearance in these patients) would be an undetectably small fraction of normal renal clearance. This could explain the absence of demonstrable creatinine metabolism in normal subjects.
5. Two pathways of metabolism were identified: a recycling of creatinine to creatine and an irreversible degradation of creatinine to products other than creatine.