The Modification of Diet in Renal Disease (MDRD) Study is a multicenter, randomized, controlled trial to determine acceptance, safety, and efficacy of low protein and phosphorus diets in patients with progressive renal disease. During the feasibility phase, 96 patients aged 18 to 75 years, with previously declining reciprocal serum creatinine concentration (1/PCr) and current glomerular filtration rate (GFR) from 7.5 to 80 ml/min/1.73 m2, were randomly assigned four study diets. After randomization, 91 patients were followed for a mean duration of 14.1 months. GFR, 1/PCr and creatinine clearance (CCr) were measured every three months. In an earlier report, we demonstrated relatively weak correlations of rates of change in GFR and 1/PCr during the feasibility phase; the proportion of variability in 1/PCr slopes that was explained by variability in GFR slopes (r2) was only 0.49 to 0.55. In this study, we examined the relationship of GFR and 1/PCr to other determinants of the serum creatinine concentration, including filtration (GFCr), secretion (TSCr), and total renal excretion (UCrV) of creatinine. Our results show that these parameters varied widely among individuals and changed over time. These findings may explain, in part, the relatively weak correlations. These results strengthen our previous suggestion that the rate of change in 1/PCr may not be an accurate index of the rate of change in GFR and raise questions about the validity of conclusions from other studies in which the efficacy of dietary modification in retarding the progression of renal disease was based principally on measurements of 1/PCr.