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.
2 randomized trials in patients with chronic renal diseases of diverse cause.
15 outpatient nephrology practices at university hospitals.
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.
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.
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.
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.
- 1. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982; 307:652-9. Google Scholar
- 2. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med. 1988; 318:1657-66. Google Scholar
- 3. William JD, Coles GA. Proteinuria—a direct cause of renal morbidity? Kidney Int. 1994; 45:443-50. Google Scholar
- 4. Klahr S. The kidney in hypertension—villain and victim [Editorial]. N Engl J Med. 1989; 320:731-3. Google Scholar
- 5. Brazy PC, Stead WW, Fitzwilliam JF. Progression of renal insufficiency: role of blood pressure. Kidney Int. 1989; 35:670-4. Google Scholar
- 6. Alvestrand A, Gutierrez A, Bucht H, Bergstrom J. Reduction of blood pressure retards the progression of chronic renal failure in man. Nephrol Dial Transplant. 1988; 3:624-31. Google Scholar
- 7. Williams PS, Fass G, Bone JM. Renal pathology and proteinuria determine progression in untreated mild/moderate chronic renal failure. Q J Med. 1988; 67:343-54. Google Scholar
- 8. Apperloo AJ, deZeeuw D, deJong PE. The initial antiproteinuric effect of antihypertensive treatment predicts the effect of treatment on long-term renal function outcome [Abstract]. J Am Soc Nephrol. 1992; 3:279(A). Google Scholar
- 9. Remuzzi G, Bertani T. Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? [Editorial] Kidney Int. 1990; 38:384-94. Google Scholar
- 10. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994; 330:877-84. Google Scholar
- 11. Beck GJ, Berg RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluchter MD, et al. Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group. Control Clin Trials. 1991; 12:566-86. Google Scholar
- 12. Hunsicker L, Adler S, Caggiula A, England B, Greene T, Kusek J, et al. Relationship among baseline proteinuria, mean arterial blood pressure during follow-up, and decline in glomerular filtration rate in the Modification of Diet in Renal Disease Study [Abstract]. J Am Soc Nephrol. 1993; 4:254. Google Scholar
- 13. Greene T, Bourgoignie JJ, Habwe V, Kusek JW, Snetselaar LG, Soucie JM, et al. Baseline characteristics in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol. 1993; 4:1221-36. Google Scholar
- 14. Frisancho AR. Anthropometric Standards for the Assessment of Growth and Nutritional Status. Ann Arbor: Univ of Michigan Pr; 1990. Google Scholar
- 15. Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, et al. Association of increased protein intake with progression of renal disease in patients with advanced renal insufficiency [Abstract]. Proceedings of the Third Annual Spring Clinical Nephrology Meetings. National Kidney Foundation. 1994:A-14. Google Scholar
- 16. Kusek JW, Coyne T, de Velasco A, Drabik M, Finlay RA, Gassman JJ, et al. Recruitment experience in the full-scale phase of the Modification of Diet in Renal Disease Study. Control Clin Trials. 1993; 14:538-57. Google Scholar
- 17. “The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83.” Google Scholar
- 18. Perrone RD, Steinman TI, Beck GJ, Skibinski CI, Royal HD, Lawlor M, et al. Utility of radioisotopic filtration markers in chronic renal insufficiency: simultaneous comparison of 125I-iothalamate, 169Yb-DTPA, 99mTc-DTPA, and inulin. The Modification of Diet in Renal Disease Study. Am J Kidney Dis. 1990; 16:224-35. Google Scholar
- 19. Levey AS, Greene T, Schluchter MD, Cleary PA, Teschan PE, Lorenz RA, et al. Glomerular filtration rate measurements in clinical trials. Modification of Diet in Renal Disease Study Group and the Diabetes Control and Complications Trial Research Group. J Am Soc Nephrol. 1993; 4:1159-71. Google Scholar
- 20. Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int. 1985; 27:58-65. Google Scholar
- 21. Pesce MA, Strande CS. A new micromethod for determination of protein in cerebrospinal fluid and urine. Clin Chem. 1973; 19:1265-7. Google Scholar
- 22. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982; 38:963-74. Google Scholar
- 23. Schluchter MD. Methods for the analysis of informatively censored longitudinal data. Stat Med. 1992; 11:1861-70. Google Scholar
- 24. Lazarus J, Buckalew V, Bourgoignie J, Greene T, Milas C, Paranandi L, et al. Blood pressure compliance and safety in the MDRD Study [Abstract]. Proceedings of the Third Annual Spring Clinical Nephrology Meetings. National Kidney Foundation. 1994:A-4. Google Scholar
- 25. Parving HH, Andersen AR, Hommel E, Smidt U. Effects of long-term antihypertensive treatment on kidney function in diabetic nephropathy. Hypertension. 1985; 7(6 Pt 2):II114-7. Google Scholar
- 26. Parving HH, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PA. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. BMJ. (Clin Res Ed). 1987; 294:1443-7. Google Scholar
- 27. Praga M, Hernandez E, Montoyo C, Andres A, Ruilope LM, Rodicio JL. Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis. 1992; 20:240-8. Google Scholar
- 28. Stenvinkel P, Alvestrand A, Bergstrom J. Factors influencing progression in patients with chronic renal failure. J Intern Med. 1989; 226:183-8. Google Scholar
- 29. Gordge MP, Leaker BR, Rylance PB, Neild GH. Haemostatic activation and proteinuria as factors in the progression of chronic renal failure. Nephrol Dial Transplant. 1991; 6:21-6. Google Scholar
- 30. Hunt LP, Short CD, Mallick NP. Prognostic indicators in patients presenting with the nephrotic syndrome. Kidney Int. 1988; 34:382-8. Google Scholar
- 31. Williams PS, Fass G, Bone JM. Renal pathology and proteinuria determine progression in untreated mild/moderate chronic renal failure. Q J Med. 1988; 67:343-54. Google Scholar
- 32. Perrone RD. Means of clinical evaluation of renal disease progression. Kidney Int Suppl. 1992; 36:S26-32. Google Scholar
Author, Article, and Disclosure Information
John C. Peterson,
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.
Corresponding Author: 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.