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The Effect of a Lower Target Blood Pressure on the Progression of Kidney Disease: Long-Term Follow-up of the Modification of Diet in Renal Disease Study

Mark J. Sarnak, MD; Tom Greene, PhD; Xuelei Wang, MS; Gerald Beck, PhD; John W. Kusek, PhD; Allan J. Collins, MD; and Andrew S. Levey, MD
[+] Article and Author Information

From Tufts-New England Medical Center, Boston, Massachusetts; Cleveland Clinic Foundation, Cleveland, Ohio; National Institute of Health, Bethesda, Maryland; and U.S. Renal Data System, Minneapolis, Minnesota.


Presented in part at the 2003 Annual Meeting of the American Society of Nephrology, San Diego, California, 14 to 17 November 2003.

Grant Support: By grants K23 DK 02904 and UO1 DK 35073 from the National Institutes of Diabetes and Digestive and Kidney Diseases.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Mark J. Sarnak, MD, Box 391, Division of Nephrology, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111; e-mail, msarnak@tufts-nemc.org.

Current Author Addresses: Drs. Sarnak and Levey: Division of Nephrology, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111.

Drs. Greene, Wang, and Beck: Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Kusek: National Institutes of Health, Room 617, 6707 Democracy Boulevard, Bethesda, MD 20817.

Dr. Collins: U.S. Renal Data System, 914 South 8th Street, D-206, Minneapolis, MN 55404.

Author Contributions: Conception and design: M.J. Sarnak, T. Greene, G. Beck, J.W. Kusek, A.J. Collins, A.S. Levey.

Analysis and interpretation of the data: M.J. Sarnak, T. Greene, X. Wang, G. Beck, J.W. Kusek, A.S. Levey.

Drafting of the article: M.J. Sarnak, T. Greene, A.S. Levey.

Critical revision of the article for important intellectual content: M.J. Sarnak, T. Greene, G. Beck, J.W. Kusek, A.S. Levey.

Final approval of the article: M.J. Sarnak, T. Greene, X. Wang, G. Beck, J.W. Kusek, A.J. Collins, A.S. Levey.

Provision of study materials or patients: A.J. Collins, A.S. Levey.

Statistical expertise: T. Greene, X. Wang, G. Beck.

Obtaining of funding: M.J. Sarnak, G. Beck, J.W. Kusek, A.S. Levey.

Administrative, technical, or logistic support: M.J. Sarnak, G. Beck, A.S. Levey.

Collection and assembly of data: M.J. Sarnak, T. Greene, G. Beck, J.W. Kusek, A.J. Collins.


Ann Intern Med. 2005;142(5):342-351. doi:10.7326/0003-4819-142-5-200503010-00009
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The outcomes observed after long-term follow-up of the MDRD Study show that participants in the low target blood pressure group took longer to develop kidney failure and the composite outcome of kidney failure or all-cause mortality. The benefit of the low target blood pressure was observed in participants with various types of kidney disease, including polycystic kidney disease, and may extend to participants with proteinuria less than 1 g/d.

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Figure 1.
Mean arterial blood pressure during the Modification of Diet in Renal Disease Study (1989 to 1993).

The bars extend from the 25th to the 75th percentiles, and the dotted and solid lines connect the medians. F = month of follow-up; n1 = participants in the usual target blood pressure group for whom a blood pressure measurement was available at the indicated follow-up time point; n2 = participants in the low target blood pressure group for whom a blood pressure measurement was available at the indicated follow-up time point; phase V = 9 months after completion of the trial.

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Figure 2.
Outcomes during the Modification of Diet in Renal Disease Study (1989 to 1993) and during long-term follow-up (1993 to 2000).

*The number of deaths include only those that occurred before kidney failure. †“Alive” refers to participants who did not develop kidney failure or who died during the period of interest. BP = blood pressure.

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Figure 3.
Cumulative probability of kidney failure (top) and cumulative probability of the composite of kidney failure or all-cause mortality before kidney failure (bottom).

“Low blood pressure” and “usual blood pressure” refer to a target mean arterial pressure of less than 92 mm Hg and less than 107 mm Hg, respectively. Numbers in parentheses are numbers of participants. For the top panel, there were 554 events (unadjusted  = 0.0056; adjusted  = 0.00003). For the bottom panel, there were 624 events (unadjusted  = 0.0502; adjusted  = 0.0024). BP = blood pressure.

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Figure 4.
Adjusted hazard ratios in the low target blood pressure group and the usual target blood pressure group, by subgroup.

The P value for interaction of target blood pressure with proteinuria was 0.09 for kidney failure and 0.08 for the composite outcome. The P value for interaction of target blood pressure with kidney disease diagnosis was 0.97 for kidney failure and 0.94 for the composite outcome. The P values for the interaction of target blood pressure with study (A versus B) were 0.08 for kidney failure and 0.07 for the composite outcome. All analyses are adjusted for the following baseline variables: log urinary protein, log urinary protein × duration of follow-up, polycystic kidney disease, polycystic kidney disease × duration of follow-up, black ethnicity, transferrin level, high-density lipoprotein cholesterol level, mean arterial pressure, glomerular filtration rate, age, and dietary protein group assignment. The analysis is stratified by clinical center and study. The composite outcome is kidney failure or all-cause mortality before kidney failure. The percentages in parentheses are the proportion of patients in each subgroup with kidney failure or the composite outcome.

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blood pressure and kidney disease
Posted on March 18, 2005
Yujiro Kida
Department of AnatomyII, Tsurumi University, School of Dental Medicine
Conflict of Interest: None Declared

Sarnak MJ et al. concluded that a low target blood pressure slowed the progression of nondiabetic kidney disease (1). However, Ruggenenti P et al. recently reported that no additional benefit from further blood-pressure (BP) reduction by felodipine (dihydropyridine calcium-channel blockers) could be shown in patients with non-diabetic proteinuric nephropathies receiving backgroud ACE-inhibitor therapy (2). As Sarnak MJ pointed out, more participants in the low target blood pressure group received angiotensin converting enzyme (ACE)-inhibitors in their study (1). ACE inhibitors are known to slow progression of kidney disease independent of their BP-lowering effect (3). In the AASK study, targeting antihypertensive therapy at a mean BP of 92 mmHg, compared with usual targets of 102-107 mmHg, did not slow progression of hypertensive nephrosclerosis (4). In that study, an identical proportion of patients in the usual or lower BP group was on ACE-inhibitor therapy (4). In the study by Ruggenenti P, the proportion of participants receiving ramipril in both conventional (diastolic <90 mmHg) and intensified (target BP=130/80 mmHg) BP control group was dared to set identical in order to the pure effect of lowering BP by felodipine on the progression of kidney disese (2). Therefore, though the sensitivity analysis did not affect their results, the conclusion that the additional renoprotective effect of BP reduction led by Sarnak MJ et al. remains questionable.

References (1) Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease. Ann Intern Med 2005; 142: 342-351 (2) Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2). Lancet 2005; 365: 939-946 (3) Jafer TH, Schmid CH, Landa M, et al. Angiotensin- converting enzyme inhibitors and progression of nondiabetic renal disease. Ann Intern Med 2001; 135: 73-87 (4) Wright JT, Barkis G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288: 2421-2431

Conflict of Interest:

None declared

MDRD Revisited: What about death?
Posted on March 30, 2005
Chester B Good
VA Pittsburgh Healthcare System
Conflict of Interest: None Declared

Sarnak and colleagues present an observational follow-up of the Modification of Diet in Renal Disease (MDRD) Study (1). After a total of 10 years, they report that the hazard ratio for time to progression to kidney failure in the low, compared to usual blood pressure group, was 0.68 (CI, 0.57-0.82). However, in presenting this optomistic report, they seem to ignore the 10-ton gorilla in the living room. 10.1% of patients in the low blood pressure group died, compared to 6.3% in the usual blood pressure arm, a result that is statistically significant. Yet, there is no mention of increased deaths, and no attempt to explain why this finding occurred. Perhaps death is outweighed by the clinical benefit of a delay in dialysis, although it would be interesting to see how patients would accept that reality in a "shared decision making" process. In any event, I would ask that the authors provide an additional graph to Figure 3, which would detail the cumulative probability of death over time, with the appropriate statistical analysis for this outcome. 1) Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, Levey AS. The effect of a lower target blood pressure on the progression of kidney disease: Long-term follow-up of the Modification of Diet in Renal Disease Study. Ann Intern Med. 2005;142:342-351.

Conflict of Interest:

None declared

No Title
Posted on May 2, 2005
Mark J. Sarnak
Tufts-New England Medical Center
Conflict of Interest: None Declared

Dr. Good raises the concern that deaths may be higher in the lower blood pressure target. It is important to note however that the deaths to which Dr. Good refers only include those prior to development of kidney failure (see legend to figure 2) (1). Consideration of deaths only prior to kidney failure may result in an informative censoring bias. That is, those patients who reach kidney failure first, may be more likely to die; however the deaths post kidney failure are not included in the comparison. The figure also does not provide data on follow-up time, which limits the comparison. In fact, median follow-up time was longer in the lower blood pressure group because of a delay in reaching kidney failure (1). A longer follow-up time will of course allow more deaths to occur.

Without censoring for kidney failure, there were 101 and 107 deaths in the low and usual blood pressure targets, respectively. Using cox regression analyses the adjusted hazard ratio (HR) for mortality was 0.97 (p=0.81) for the low blood pressure target compared with the usual blood pressure target. Thus there is no evidence to support the contention that the low blood pressure target results in a higher death rate.

Of note, we presented the results of the composite of kidney failure and mortality. This incorporates the competing risk of death into the kidney failure models. The results were consistent with the kidney failure models, and demonstrated a benefit of the lower blood pressure target.

We agree with Dr. Kida that we cannot disprove the fact that angiotensin converting enzyme (ACE) inhibitor use may have had an effect on the outcome. As noted we however believe this is unlikely for the following reasons. 1). Adjustment for ACE inhibitor use did not diminish the benefit of the lower blood pressure target. 2). The benefit achieved in the low blood pressure target (HR of 0.68 with only a 19% difference in use of ACE inhibitors) is much greater than one would expect if one compared the results to other non-diabetic ACE inhibitor trials in which a similar risk reduction was observed with a 100% difference in use of ACE inhibitors (2).

We believe two important differences of the MDRD Study from the studies mentioned by Dr. Kida are longer follow-up and more kidney failure outcomes. We propose that it may take time for the benefit of a lower blood pressure goal to be appreciated.

References. 1) Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, Levey AS. The effect of a lower target blood pressure on the progression of kidney disease: Long-term follow-up of the Modification of Diet in Renal Disease Study. Ann Intern Med. 2005;142:342-351. 2) Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med. 2001;135(2):73-87.

Conflict of Interest:

None declared

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Summary for Patients

A Low Blood Pressure Target Prevented Kidney Failure in Patients with Chronic Kidney Disease

The summary below is from the full report titled “The Effect of a Lower Target Blood Pressure on the Progression of Kidney Disease: Long-Term Follow-up of the Modification of Diet in Renal Disease Study.” It is in the 1 March 2005 issue of Annals of Internal Medicine (volume 142, pages 342-351). The authors are M.J. Sarnak, T. Greene, X. Wang, G. Beck, J.W. Kusek, A.J. Collins, and A.S. Levey.

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