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Blood Pressure Control, Proteinuria, and the Progression of Renal Disease: The Modification of Diet in Renal Disease Study

John C. Peterson, MD; Sharon Adler, MD; John M. Burkart, MD; Tom Greene, PhD; Lee A. Hebert, MD; Lawrence G. Hunsicker, MD; Andrew J. King, MD; Saulo Klahr, MD; Shaul G. Massry, MD; Julian L. Seifter, MD; and Modification of Diet in Renal Disease (MDRD)Study Group*
[+] Article and Author Information

From the Modification of Diet in Renal Disease Study Group, Cleveland, Ohio. Grant Support: By the National Institute of Diabetes, Digestive and Kidney Diseases and the Health Care Financing Administration. Requests for Reprints: MDRD Study Data Coordinating Center, Department of Biostatistics and Epidemiology, P88, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Current Author Addresses: Dr. Peterson: University of Florida, Division of Nephrology, P.O. Box 100224, Gainesville, FL 32610-0224.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(10):754-762. doi:10.7326/0003-4819-123-10-199511150-00003
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Objective: To examine the relations among proteinuria, prescribed and achieved blood pressure, and decline in glomerular filtration rate in the Modification of Diet in Renal Disease Study.

Design: 2 randomized trials in patients with chronic renal diseases of diverse cause.

Setting: 15 outpatient nephrology practices at university hospitals.

Patients: 840 patients, of whom 585 were in study A (glomerular filtration rate, 25 to 55 mL/min·1.73 m2) and 255 were in study B (glomerular filtration rate, 13 to 24 mL/min·1.73 m2). Diabetic patients who required insulin were excluded.

Interventions: Patients were randomly assigned to a usual blood pressure goal (target mean arterial pressure, less than equals 107 mm Hg for patients less than equals 60 years of age and less than equals 113 mm Hg for patients more than equals 61 years of age) or a low blood pressure goal (target mean arterial pressure, less than equals 92 mm Hg for patients less than equals 60 years of age and less than equals 98 mm Hg for patients more than equals 61 years of age).

Main Outcome Measures: Rate of decline in glomerular filtration rate and change in proteinuria during follow-up.

Results: The low blood pressure goal had a greater beneficial effect in persons with higher baseline proteinuria in both study A (P = 0.02) and study B (P = 0.01). Glomerular filtration rate declined faster in patients with higher achieved blood pressure during follow-up in both study A (r = −0.20; P < 0.001) and study B (r = −0.34; P < 0.001), and these correlations were stronger in persons with higher baseline proteinuria (P < 0.001 in study A; P < 0.01 in study B). In study A, the association between decline in glomerular filtration rate and achieved follow-up blood pressure was nonlinear (P = 0.011) and was stronger at higher mean arterial pressure. In both studies, the low blood pressure goal significantly reduced proteinuria during the first 4 months after randomization. This, in turn, correlated with a slower subsequent decline in glomerular filtration rate.

Conclusions: Our study supports the concept that proteinuria is an independent risk factor for the progression of renal disease. For patients with proteinuria of more than 1 g/d, we suggest a target blood pressure of less than 92 mm Hg (125/75 mm Hg). For patients with proteinuria of 0.25 to 1.0 g/d, a target mean arterial pressure of less than 98 mm Hg (about 130/80 mm Hg) may be advisable. The extent to which lowering blood pressure reduces proteinuria may be a measure of the effectiveness of this therapy in slowing the progression of renal disease.

*For a list of MDRD participants, see reference 10.

Figures

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Figure 1.
Baseline proteinuria and decline in glomerular filtration rate (GFR).PP

For study A, estimated mean (± SE) rates of decline in glomerular filtration rate from baseline to 3 years based on the 2-slope model are shown. Mean (± SE) rates of decline in glomerular filtration rate estimated from the 1-slope informative censoring model are shown for study B. Closed circles designate the usual blood pressure group; open circles designate the low blood pressure group. The number in parentheses in each column is the total number of patients in both blood pressure groups who had at least one follow-up glomerular filtration rate measurement. Eight patients in study A and 24 patients in study B had no follow-up glomerular filtration rate measurements. Greater baseline proteinuria is associated with steeper mean glomerular filtration rate decline and with a greater benefit from the low blood pressure goal ( = 0.02 in study A; = 0.01 in study B).

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Figure 2.
Estimated mean decline in glomerular filtration rate (GFR) from baseline to selected follow-up times in study A.dashed linesolid line

Estimated mean (±SE) declines in glomerular filtration rate (mL/min) from baseline to follow-up points coinciding with glomerular filtration rate measurements for different levels of baseline proteinuria. The usual ( ) and low ( ) blood pressure groups are compared. B3 equals the third monthly baseline visit (before randomization); F equals follow-up visits at each given number of months. Three hundred five patients had baseline proteinuria of 0 to 0.25 g/d (mean, 0.08 g/d); 120 had baseline proteinuria of 0.25 to 1.0 g/d (mean, 0.58 g/d); 105 had baseline proteinuria of 1.0 to 3.0 g/d (mean, 1.8 g/day); and 55 had baseline proteinuria of 3 g/d or more (mean, 4.8 g/d).

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Figure 3.
Baseline proteinuria and the initial and final decline in glomerular filtration rate (GFR) in study A.P

Mean (± SE) initial (baseline to 4 months, left) and final (4 months to end of follow-up, right) rates of decline in glomerular filtration rate based on the 2-slope model. Closed circles designate the usual blood pressure group; open circles designate the low blood pressure group. Greater baseline protein excretion is associated with steeper initial and final mean rates of decline in glomerular filtration rate. Mean initial rates of decline do not differ significantly between blood pressure groups for patients with different levels of protein excretion. Greater baseline protein excretion is associated with a greater beneficial effect of the low blood pressure goal on the final mean rate of decline ( = 0.006).

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Figure 4.
Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressure in study A.

Regression lines relating the estimated mean glomerular filtration rate decline over 3 years to mean follow-up mean arterial pressure (MAP) for groups of patients defined according to baseline proteinuria. Within each group, a 3-slope model was used with break points at 92 and 98 mm Hg. Increasing mean follow-up mean arterial pressure is significantly related to steeper decline in glomerular filtration rate for mean arterial pressure greater than 98 mm Hg in patients with baseline proteinuria 0.25 to 3.0 g/d and for mean arterial pressure greater than 92 mm Hg for patients with baseline proteinuria of 3 g/d or more.

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Figure 5.
Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressure in study B.

Regression lines relating mean decline in glomerular filtration rate to mean follow-up mean arterial pressure (MAP) for groups of patients defined according to baseline proteinuria. Within both groups, a 5-slope model was used with break points at 90, 95, 100, and 105 mm Hg. Decline in glomerular filtration rate is inversely related to follow-up blood pressure for patients with baseline proteinuria of 1 g/d or more but not for patients with baseline proteinuria of less than 1 g/d.

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Figure 6.
Changes in urine protein from baseline to selected follow-up times in study A.dotted linesolid line

Comparison of changes from baseline in urine protein between patients in the usual ( ) and the low ( ) blood pressure groups within subgroups defined according to baseline proteinuria. Proteinuria was log transformed. Changes in proteinuria are expressed as percentage changes. Three hundred five patients had baseline proteinuria of 0 to 0.25 g/d (mean, 0.08 g/d); 120 had baseline proteinuria of 0.25 to 1.0 g/d (mean, 0.58 g/d); 105 had baseline proteinuria of 1.0 to 3.0 g/d (mean, 1.8 g/d); and 55 had baseline proteinuria of 3.0 g/d or more (mean, 4.8 g/d).

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