Factors other than the glomerular filtration rate (GFR) can affect creatinine clearance (Ccr) and serum creatinine concentration (Pcr). The effect of dietary protein and antihypertensive therapy on Ccr the reciprocal of the Pcr (1/Pcr). and their determinants (GFR, creatinine clearance from tubular secretion (CTScr), and creatinine excretion (UcrV) values) was assessed in patients participating in the Modification of Diet in Renal Disease (MDRD) Study. This study compared the effects of assignment to a low versus usual-protein diet and to a low versus usual-blood pressure goal on the decline in these measurements over 3 yr in 585 patients with baseline GFR of 25 to 55 mL/min per 1.73 m2 (Study A). This study also assessed correlations and associations of these measurements with each other and with protein intake, blood pressure, class of antihypertensive agents, and renal diagnosis in 840 patients with baseline GFR of 13 to 55 mL/min per 1.73 m2 (Studies A and B). In Study A, the estimated mean decline in GFR at 3 yr did not differ significantly between the low and usual-protein diet groups (-10.9 versus -12.1 mL/min). In contrast, CTScr declined more in the low-protein diet group (-7.8 versus -3.6 mL/min, P < .05). Consequently, the low-protein diet group had a greater decline in Ccr (-17.6 versus -14.4 mL/min, P < .05). The low-protein diet group also had a greater decline in UcrV (-306 versus -92 mg/day, P < .05). The decline in UcrV was proportionately greater than the decline in CTScr hence the decline in 1/Pcr was less in the low-protein diet group (-0.091 versus -0.122 dl/mg, P < .05). Similarly, in Study A, there was no significant difference in the decline in GFR at 3 yr between the low and usual-blood pressure groups (-10.7 versus -12.3 mL/ min). However, there was a lesser decline in CTScr in the low blood pressure group (-4.7 versus -6.7 mL/ min, P < .05). Consequently, the decline in Ccr was less in the low blood pressure group (-14.2 versus -17.8 mL/min, P < .05). There was no significant difference in UcrV between the blood pressure groups (-192 versus -205 mg/day). Hence, the decline in 1/Pcr paralleled the decline in Ccr; it was less in the low blood pressure group (-0.091 versus -0.122 dL/mg, P < .05). In Studies A and B, correlations of rates of decline in Ccr and GFR were 0.64 and 0.79, respectively (P < 0.001). Correlations of rates of decline in 1/Pcr and GFR were 0.79 and 0.85, respectively (P < 0.001). In Studies A and B combined, baseline GFR, CTScr and UcrV correlated significantly with protein intake (r = 0.45, 0.47, and 0.36, respectively; P < 0.001), but not with blood pressure. Baseline CTScr was significantly lower in patients with polycystic kidney disease and tubulointerstitial diseases or urinary tract diseases, compared with glomerular and other diseases (P < 0.05). It was also lower in patients who were taking calcium channel blockers, compared with patients not taking these agents, and in patients not taking diuretics, compared with patients taking diuretics (P < 0.05). These results show that creatinine secretion and excretion are affected by protein intake. Creatinine secretion is also affected by antihypertensive therapy and renal diagnosis. In the MDRD Study, the low-protein diet reduced creatinine secretion and excretion, and the low blood pressure goal slowed the decline in creatinine secretion. These effects caused differences between the diet groups and between the blood pressure groups in Ccr and 1/Pcr that were not the result of differences in GFR. Studies assessing the effects of these interventions on the progression of renal disease should measure GFR in addition to Ccr and Pcr.