BACKGROUND: To develop a test that would disclose subclinical impairment in renal function, we studied the increment in tubular secretion of creatinine (TS(Cr)) induced by intravenous creatinine administration. METHODS: Studies were done in 14 normal individuals, 7 kidney donors (KDs), and 11 transplant recipients (Tx), all of whom had normal creatinine levels (P(Cr) <133 micromol/L). Creatinine infusion studies determined that maximal stimulation of TS(Cr) resulted from P(Cr) levels of 500 to 700 micromol/L. Therefore, in the tubular stress test, clearances, urinary excretion of creatinine (U(Cr)V) and TS(Cr) were determined before and after (15 to 105 min) a single bolus injection of 88.4 mmol/kg body wt, which resulted in the target P(Cr) levels. RESULTS: Baseline determinations of P(Cr), U(Cr)V, and TS(Cr) were not significantly different in the study groups. Stimulated U(Cr)V (nmol/kg/min) was higher in normals (426 +/- 82) than in KDs (338 +/- 72, P < 0.05) and Tx patients (311 +/- 66, P < 0.01). Similarly, TS(Cr) (nmol/kg/min) was higher (P < 0.001) in normals (180 +/- 60) than in KDs (155 +/- 54) and Tx patients (86 +/- 35). Furthermore, the transplanted kidney responded worse than the solitary normal kidney (P < 0.05), despite having similar levels of glomerular filtration rate (GFR). The tubular stress test increased TS(Cr) 11.3 +/- 6.2 times in normals, 4.3 +/- 1.2 times in KDs (P < 0.01), and 2.5 times in Tx (P < 0.001). CONCLUSIONS: Impaired tubular secretory response to a creatinine load is a more sensitive index of reduced functioning renal mass than levels of P(Cr) and GFR. The tubular stress test may be useful in following the natural history of kidney disease and the results of therapeutic interventions.