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Original Investigation |

Effects of Blood Pressure Level on Progression of Diabetic Nephropathy:  Results From the RENAAL Study FREE

George L. Bakris, MD; Matthew R. Weir, MD; Shahnaz Shanifar, MD; Zhongxin Zhang, PhD; Janice Douglas, MD; David J. van Dijk, MD; Barry M. Brenner, MD ; for the RENAAL Study Group
[+] Author Affiliations

From the Department of Preventive Medicine, Rush Presbyterian/St Luke's Medical Center, Rush Medical College, Chicago, Ill (Dr Bakris); Department of Medicine, University of Maryland Medical Center, Baltimore (Dr Weir); Division of Renal Research, Merck and Co, Blue Bell, Pa (Drs Shanifar and Zhang); Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio (Dr Douglas); Institute of Hypertension and Kidney Diseases, Rabin Medical Center, Petach Tikwa, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Dr van Dijk); and Department of Medicine, Renal Division, Brigham's and Women's Hospital, Harvard Medical School, Boston, Mass (Dr Brenner). A complete listing of the RENAAL Study Group members was published previously (N Engl J Med. 2001;345:861-869). The authors have no relevant financial interest in this article.


Arch Intern Med. 2003;163(13):1555-1565. doi:10.1001/archinte.163.13.1555.
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Published online

Background  Clinical trials of nephropathy in people with type 2 diabetes mellitus have not examined the effects of systolic blood pressure (SBP) or pulse pressure (PP) on the time to end-stage renal disease (ESRD) or death.

Objectives  To evaluate the impact of baseline and treated SBP, diastolic blood pressure (DBP), and PP on composite and individual outcomes including doubling of serum creatinine, ESRD, or death in participants of the Reduction of Endpoints in NIDDM (non–insulin-dependent diabetes mellitus) With the Angiotensin II Antagonist Losartan (RENAAL) Study; to assess the specific effect of the angiotensin receptor blocker losartan potassium on composite and renal outcomes; and to explore the implications of dihydropyridine calcium channel blockers as concurrent therapy on composite and renal outcomes.

Design  A Cox proportional hazards regression model was used to assess the hazard risk profile of baseline SBP (categories: <130, 130-139, 140-159, 160-179, and ≥180 mm Hg), DBP (categories: <70, 70-79, 80-89, 90-99, and ≥100 mm Hg), and PP (categories: <60, 60-69, 70-79, 80-89, and ≥90 mm Hg) on renal outcomes.

Participants  The study comprised 1513 participants with established nephropathy and hypertension associated with type 2 diabetes.

Interventions  The RENAAL study was a randomized, placebo-controlled study of losartan vs placebo, with other agents added to achieve the goal of a trough BP (ie, BP immediately prior to the next dosing) below 140/90 mm Hg, and had a mean follow-up of 3.4 years.

Main Outcome Measures  The primary analysis was time to composite end point of doubling of serum creatinine, ESRD, or death.

Results  A baseline SBP range of 140 to 159 mm Hg increased risk for ESRD or death by 38% (P = .05) compared with those below 130 mm Hg. In a multivariate model, every 10–mm Hg rise in baseline SBP increased the risk for ESRD or death by 6.7% (P = .007); the same rise in DBP decreased the risk by 10.9% (P = .01) when adjusting for urinary albumin-creatinine ratio, serum creatinine, serum albumin, hemoglobin, and hemoglobin A1c. Those randomized to the losartan group with a baseline PP above 90 mm Hg had a 53.5% risk reduction for ESRD alone (P = .003) and a 35.5% risk reduction for ESRD or death (P = .02) compared with the placebo group.

Conclusions  Baseline SBP is a stronger predictor than DBP of renal outcomes in those with nephropathy resulting from type 2 diabetes. Those with the highest baseline PP have the highest risk for nephropathy progression but also garner the greatest risk reduction with SBP lowered to less than 140 mm Hg.

Figures in this Article

POST HOC ANALYSES of clinical trials that involve participants with type 2 diabetes mellitus as well as longitudinal follow-up studies of people with hypertension without diabetes demonstrate a clear association between the degree of systolic blood pressure (SBP) elevation and cardiovascular risk.13 Additionally, long-term follow-up data involving more than 10 000 men from a Veterans Administration study showed that SBP was an independent risk factor for renal disease progression.4 Until recently, no clinical trial has recruited participants with predominately systolic hypertension to evaluate the impact of SBP on renal outcomes.

In the recent Reduction of Endpoints in NIDDM (non–insulin-dependent diabetes mellitus) With the Angiotensin II Antagonist Losartan (RENAAL) Study, randomization to an angiotensin receptor blocker (ARB)-based regimen to achieve blood pressure (BP) reduction resulted in a significant decrease in risk of doubling of serum creatinine, end-stage renal disease (ESRD), and death compared with the placebo group.5 In the present study, baseline BP values were assessed on current antihypertensive medications being taken by the participants. Systolic hypertension (mean BP, 152/82 mm Hg) was prominent in the entire group at entry, since 73% of participants had predominantly systolic hypertension by the criteria put forth in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).6 Thus, the RENAAL Study is the first clinical trial to formally evaluate participants with predominately isolated systolic hypertension at baseline with regard to renal disease progression and time to ESRD.

In the present article, a number of questions are addressed: What is the optimal BP range to slow progression of renal disease in participants with type 2 diabetes with nephropathy? What is the relative importance of baseline and "on treatment" (while receiving randomized antihypertensive therapy during the trial) SBP, diastolic BP (DBP), or pulse pressure (PP) with regard to progression to ESRD associated with type 2 diabetes? What is the effect of ARB use on outcomes as a function of achieved BP? Finally, in a predefined analysis, we address differences in renal outcomes in the presence of dihydropyridine calcium channel blockers (DHPCCBs) with and without an ARB.

STUDY DESIGN

The study design and description of the patient population have been published previously.5 Briefly, the RENAAL Study was a multinational, double-blind, randomized, placebo-controlled study designed to evaluate the renoprotective effects of losartan potassium in 1513 participants with type 2 diabetes and nephropathy. The mean length of follow-up was 3.4 years (range, 2.3-4.6 years). Nephropathy was defined by the presence on 2 occasions of a ratio of urinary albumin (measured in milligrams per liter) to urinary creatinine (measured in grams per liter) from a first morning specimen of at least 300 mg/g, (about 800 mg/d), and a serum creatinine range between 1.3 and 3.0 mg/dL (115 and 265 µmol/L), with a lower limit of 1.5 mg/dL (133 µmol/L) for male participants weighing more than 60 kg.

During the 6-week screening phase, participants with hypertension continued to receive their standard antihypertensive therapy. If they had been taking angiotensin I–converting enzyme (ACE) inhibitors or ARBs, however, therapy with these medications was discontinued and replaced by alternative open-label medications (ie, diuretics, calcium channel antagonists, α- or β-blockers, centrally acting agents, or some combination of these types of medication). About half of the participants (400 [53.3%] of 751 participants in the losartan group and 376 [49.3%] of 762 participants in the placebo group) were receiving an ACE inhibitor or ARB at study entry. Use of these agents was stopped in all participants to allow for randomization to agents that block the angiotensin II receptor vs placebo and use of other agents that do not inhibit this receptor. Participants were stratified according to their baseline level of proteinuria (a urinary albumin-creatinine ratio <2000 mg/g or ≥2000 mg/g) and randomly assigned to receive either losartan potassium (50 mg initially and titrated to 100 mg if BP was not at goal) or placebo once daily, along with conventional antihypertensive therapy. No mandate for specific additional medications was stated in the protocol; however, diuretics were strongly encouraged as second-line agents with the addition of other agents as needed to achieve a BP goal of below 140/90 mm Hg.

Trough sitting BP measurements, defined within 22 to 26 hours of the last dose, were taken at every visit during the screening and treatment phases. Participants were instructed not to take their antihypertensive medications on the morning of every clinic visit, but were administered those medications after BP measurements were obtained. A standard mercury sphygmomanometer was used to measure BP; random zero sphygmomanometers or automated devices were not used. All BP measurements were taken after at least a 5-minute period in the sitting position. Three consecutive BP measurements at 1-minute intervals in the same arm were measured. The mean value of the 3 SBP and DBP readings was recorded for each visit. None of the 3 consecutive DBP readings could have differed from the mean by more than 5 mm Hg. If a greater difference occurred, additional readings were obtained until 3 consecutive DBP readings met this requirement.

After randomization, target trough BP was below 140/90 mm Hg. If the target BP was not achieved after the first 4 weeks of therapy or at any phase during the study, the dose of losartan potassium (or placebo) was increased to 100 mg/d. However, if the 100-mg losartan potassium dose was not sufficient to reduce trough BP below target values, additional open-label antihypertensive medications (described previously) were added.

The primary composite end point was time to doubling of serum creatinine, ESRD, or death, whichever occurred first. Every participant was counted only once even if he or she had multiple primary events. For ESRD or death analysis, time to ESRD or death, whichever occurred first, was analyzed. For analysis of ESRD or time to ESRD, regardless of whether a patient had doubling of serum creatinine, was taken into consideration, and participants who died were considered censored. End-stage renal disease was defined by the need for long-term dialysis or renal transplantation.

STATISTICAL ANALYSIS

All randomized participants (N = 1513) were included from randomization through the study termination date, regardless of any protocol violations or adherence to study medication. Using a JNC VI–defined BP goal, the BP values were categorized for SBP (<130, 130-139, 140-159, 160-179, and ≥180 mm Hg) and DBP (<70, 70-79, 80-89, 90-99, and ≥100 mm Hg). Pulse pressure was categorized as below 60, 60 to 69, 70 to 79, 80 to 89, and 90 mm Hg or above. Baseline BP for each patient was defined as the last BP value prior to randomization. Chronic kidney disease stages were determined by estimated glomerular filtration rate at baseline.7 A 1-sample t test was used to explore the impact of ACE inhibitor or ARB therapy being stopped in participants during the screen phase; the BP at trial entry was compared with the baseline BP under the antihypertensive therapy participants were receiving at trial entry.

To assess the relationship of SBP, DBP, and PP, a Cox regression model was used with categorical variables as covariates to determine the hazard ratio of each category over a selected reference and 95% confidence interval (CI) for hazard ratio. The relationship was explored for both baseline and last observed BP prior to end points of interest. The group with the lowest BP was treated as the reference for hazard ratio. No comparison was intended for hazard ratios between the 2 BP measurements, since patients may go from one BP group at baseline to another BP group prior to end points.

To study the relative importance of SBP, DBP, or PP with regard to progression to ESRD associated with type 2 diabetes mellitus, pairwise comparisons among the 3 pressures were made. Multivariate Cox regression models including pairs of the 3 pressures as covariates were used to determine which variable contributed the most to outcomes. The variable with the smaller P value was deemed relatively more important with respect to an end point.

To explore SBP as an independent risk factor, a multivariate Cox model, including DBP and SBP as well as additional baseline covariates (eg, age, body mass index, race, smoking, DHPCCB use, insulin use, baseline albuminuria level, hemoglobin, serum albumin, serum uric acid, hemoglobin A1c, total cholesterol, serum triglycerides, serum calcium, and phosphorus) were used to determine the hazard ratio of SBP and DBP at 10–mm Hg increments, adjusting for these risk factors. The assumption of proportionality for the Cox analysis was tested, and the criteria were met. The backward selection method was used to eliminate covariates having a P value of .05 or greater. The BP measurements prior to the composite end point of ESRD or death were summarized between the 2 treatment groups. The risk reduction of losartan compared with placebo for ESRD alone and for ESRD or death was explored by post–BP control using a Cox model with region, time-varying BP groups, and interactions of treatment by time-varying BP group as covariates and baseline urinary albumin-creatinine ratio level as strata (<2000 mg/g and ≥2000 mg/g).

Lastly, given previous trials documenting less protective effects of DHPCCBs on renal outcomes, this article presents an analysis of the primary composite end point for participants with and without use of DHPCCBs at baseline. In addition, the impact of between-group differences for those receiving DHPCCBs randomized to placebo vs losartan was examined by adding on-treatment DHPCCB as a time-varying covariate in the Cox model and comparing the estimated effect of losartan from this model with that from the primary analysis.

The statistical package SAS version 8 (SAS Institute Inc, Cary, NC) was used for this analysis. A P value of less than .05 was considered statistically significant. All statistical tests were 2-sided.

We specifically sought answers to the following questions in this post hoc analysis: What was the optimal BP range to slow progression to ESRD? Was there greater predictability of progression to ESRD by baseline and on treatment SBP, DBP, or PP values? What was the treatment effect of losartan based on achieved BP values in the range of the different JNC VI stages? Was there a difference in renal outcomes when DHPCCBs were used in combination with ARBs?

BASELINE BP

At baseline, 93.5% of the participants (92.3% in the losartan group and 94.6% in the placebo group) were receiving antihypertensive therapy. An additional 3% of participants had hypertension but were not receiving antihypertensive therapy. The baseline demographic characteristics of participants, defined by JNC VI SBP and DBP stages, as well as the classes of antihypertensive medications prescribed, is summarized in Table 1 and Table 2. The distribution of baseline BP values in relation to stage of chronic kidney disease are summarized in Table 3. It is clear from Table 3 that more than three fourths of the participants in the trial had stage 3 or 4 nephropathy at baseline. The baseline distribution, by JNC VI staging, of those receiving ACE inhibitors or ARBs at study entry is summarized in Table 4. Lastly, the breakdown of all antihypertensive medications at study entry, by both SBP and DBP, is provided in Table 5. Note that SBP increased significantly only among the group that was receiving DHPCCBs when therapy with ACE inhibitors and ARBs was stopped. This suggests that in this group BP is more difficult to control. Additionally, those with a higher SBP were receiving more ACE inhibitors, calcium channel blockers, and diuretics at baseline than were people with an elevated DBP, who were more likely to receive α-blockers and central agents (Table 1 and Table 2).

Table Graphic Jump LocationTable 1. Baseline Characteristics Stratified by Baseline Systolic BP Stage*
Table Graphic Jump LocationTable 2. Baseline Characteristics Stratified by Baseline Diastolic BP Stage*
Table Graphic Jump LocationTable 3. Distribution of Baseline Sitting BP Values in Relation to CKD Stages Using JNC VI and Kidney Disease Stages*
Table Graphic Jump LocationTable 4. Distribution of Participants Taking ACEIs or ARBs at Study Entry by JNC VI Sitting BP Stages*
Table Graphic Jump LocationTable 5. Summary of Sitting SBP by Antihypertensive Medications During Washout Period*

The trough BP declined progressively during the course of the study. The mean trough BP at baseline was 152/82 mm Hg in the losartan group and 153/82 mm Hg in the placebo group (P = .15/.93); the mean arterial pressure was 105.5 mm Hg in the losartan group and 106.0 mm Hg in the placebo group (P = .39); and the PP was 69.4 mm Hg in the losartan group and 70.8 mm Hg in the placebo group (P = .13).

BP AND PRIMARY OUTCOMES

To establish the relationship with baseline BP, the renal outcomes considered for the following analyses are (1) primary composite end point of doubling serum creatinine, ESRD, or death; (2) ESRD alone, and (3) the composite of ESRD or death.

BASELINE SBP

At baseline, SBP was stratified by categories outlined in the JNC VI (<130, 130-139, 140-159, 160-179, and ≥180 mm Hg). Table 6 gives the hazard ratio for each category compared with the recommended guideline of an SBP below 130 mm Hg. It is clear that the risk (including all-cause death) increases with SBP, with a significant increased risk for renal outcomes at all BP levels above 140 mm Hg (Table 6). The risk for achieving ESRD increases by 37% at a baseline SBP in the 140 to 159 mm Hg category vs the below 130 mm Hg category (P<.01) and more than doubles at SBP levels of 160 mm Hg or above (P<.001). The Kaplan-Meier curves for the primary outcome of doubling of serum creatinine, ESRD, or death as well as the outcome of ESRD alone, based on those with a baseline BP below 140 mm Hg vs 140 mm Hg or above, are shown in Figure 1.

Table Graphic Jump LocationTable 6. Outcomes Based on Baseline and Last SBP Prior to End Points for Pooled Treatment Groups*
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Figure 1.

A, Event rate for the primary composite end point by baseline systolic blood pressure (SBP). B, Event rate for end-stage renal disease alone by baseline SBP.

Graphic Jump Location
BASELINE DBP

The DBP was stratified as follows: below 70, 70 to 79, 80 to 89, 90 to 99, and 100 mm Hg or above. In contrast to SBP, Table 7 shows no significant increase in risk of a renal end point at any level of baseline DBP. Like SBP, however, there was a strong relationship between JNC VI stage of last BP measured and development of an end point (Table 6 and Table 7).

Table Graphic Jump LocationTable 7. Outcomes Based on Baseline and Last DBP for Pooled Treatment Groups*
BASELINE PP

The PP is the difference between SBP and DBP. The baseline PP was stratified as below 60, 60 to 69, 70 to 79, 80 to 89, and 90 mm Hg or above. Table 8 gives the hazard ratio of each category over baseline PP relative to the below 60–mm Hg category. For every end point, a baseline PP level of 70 mm Hg or above increased the risk of all renal end points including ESRD and death.

Table Graphic Jump LocationTable 8. Outcomes Based on Baseline and Last PP for Pooled Treatment Groups*
RELATIONSHIP OF BASELINE SBP, DBP, AND PP ON RENAL OUTCOMES

As previously noted, baseline SBP and PP are risk factors for renal outcomes without the adjustment of other risk factors. This increased risk for the renal outcomes with either the SBP or PP is diminished, however, after adjusting for other risk factors. In a multivariate model, every 10– mm Hg rise in baseline SBP increased the risk for ESRD or death by 6.7% (P = .007), the same rise in DBP decreased the risk by 10.9% (P = .01), when adjusting for urinary albumin-creatinine ratio (on the log scale), serum creatinine, serum albumin, hemoglobin A1c, and hemoglobin. With the use of a multivariate Cox model with baseline BP categories, the adjusted risk for the primary composite end point increased with ascending baseline SBP, with a hazard ratio of 1.82 (95% CI, 1.36-2.42) (P<.001) for those in 160 to 179–mm Hg category compared with those in the below 130–mm Hg category. In this same SBP range, the adjusted risk for ESRD or death increased with a hazard ratio of 1.96 (95% CI, 1.40-2.74) (P<.001). Baseline PP showed similar trends for all renal end points in those in the 70–mm Hg or above category compared with those in the below 60–mm Hg category.

PROGRESSION TO ESRD: RELATIVE IMPORTANCE OF BASELINE SBP, DBP, OR PP

We previously explored the relative importance of baseline BP after adjustment for other baseline risk factors. However, among SBP, DBP, or PP, the question of which is more important for determination of renal outcomes was not addressed. Since the PP is the difference between SBP and DBP, the only way to answer this question is to make pair-wise comparisons among the 3 BP measurements. For the primary composite, ESRD alone, and ESRD or death outcomes, a multivariate Cox model was applied with terms including each pair of the 3 BP variables. A statistical comparison for each pair of the BP variables was performed and validated to evaluate the relative importance of each with respect to a given end point (Table 9). The results of this analysis demonstrate that, when not correcting for other risk factors, for every increase of 10 mm Hg, BP, SBP, and PP are relatively more important than DBP for each outcome. Systolic BP is equivalent to PP with respect to the primary end point and ESRD alone; however, for the combined outcome of ESRD or death, PP was a more powerful predictor than SBP.

Table Graphic Jump LocationTable 9. Relative Importance Between Pair of BP Measurements*
ON TREATMENT BP

Figure 2 summarizes the data for the length of the trial for mean, trough, annual, achieved BP, SBP, PP, and DBP. Note that some differences between groups occurred at specific time points throughout the trial in SBP and PP but not DBP.

Place holder to copy figure label and caption
Figure 2.

A, The annual, mean, trough systolic blood pressure (SBP) and diastolic blood pressure (DBP). B, The annual, mean, trough pulse pressure (PP). Error bars indicate SD.

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EFFECT OF ARB ON OUTCOMES AS A FUNCTION OF ON TREATMENT, TIME-VARYING BP

Based on an analysis of the BP prior to an end point using a Cox model with terms including region, time-varying BP category, treatment by time-varying BP category as covariates, and baseline proteinuria level (<2000 mg/g and ≥2000 mg/g) as strata, the following were observed. Treatment with losartan in those who achieved an SBP below 140 mm Hg (losartan [n = 361] vs placebo [n = 317]) was associated with a risk reduction of 22.7% (95% CI, 0.1%-40.2%) (P = .049) compared with placebo for the primary composite outcome. Moreover, those randomized to losartan who achieved both an SBP below 140 mm Hg and a DBP below 90 mm Hg (n = 353) had a 25.2% (95% CI, 2.9%-42.3%) (P = 0.03) risk reduction compared with placebo (n = 307) for the primary composite outcome and a 25.8% (95% CI, 0.3%-44.7%) (P = .048) risk reduction for ESRD or death. For ESRD alone, the data were more compelling for those with lower BP levels who received losartan, Figure 3.

Place holder to copy figure label and caption
Figure 3.

Comparison of end-stage renal disease outcomes in the groups randomized to losartan (given as losartan potassium) vs placebo at different achieved mean blood pressures (BPs) up until a primary composite event. SBP indicates systolic BP; DBP, diastolic BP. Asterisk indicates data are number of events/total number of patients.

Graphic Jump Location
ANTIHYPERTENSIVE MEDICATIONS

A mean of 3.5 different antihypertensive medications were used in addition to the randomized drug to achieve the BP goal of below 140/90 mm Hg. A prespecified analysis assessed the effect of different classes of BP medications being taken at study entry with regard to the primary composite outcome (ie, starting dialysis, death, or doubling of serum creatinine). This analysis demonstrated that use of either ACE inhibitors or β-blockers at baseline did not affect the primary outcome. However, use of DHPCCBs at study entry was associated with higher risk of primary composite events throughout the trial (ie, participants who were receiving DHPCCBs at study entry had a higher risk [hazard ratio = 1.38] of reaching the primary composite outcome than participants who did not receive this subclass of calcium channel blockers). Approximately 54% of participants were receiving a DHPCCB at study entry, 94.6% of whom continued to receive a DHPCCB for a minimum of 2 weeks or more throughout the study (Table 10).

Table Graphic Jump LocationTable 10. Summary of Patient Use of DHPCCBs at Baseline and During the Study*

There were 247 participants (losartan, 113; placebo, 134) who did not use DHPCCBs at baseline but used DHPCCBs during the study. A predefined intention-to-treat analysis showed that after adjustment for use of DHPCCBs during the study, a 16.1% risk reduction (P = .02) was present for the primary outcome of time to doubling of serum creatinine, ESRD, or death in the losartan group compared with placebo. This risk reduction is similar to that seen for the entire losartan cohort in the study.5 Since the use of non-DHPCCBs was low (21%) relative to DHPCCB use, an evaluation between the 2 calcium channel blocker subgroups on renal outcomes was not possible. It should be noted that ACE inhibitor or β-blocker use prior to randomization at baseline had no impact on primary composite outcomes.

The RENAAL study demonstrates that BP reduction with an ARB significantly reduced the time to ESRD.5 Analyses of the BP data from this study demonstrate that baseline SBP is an independent risk factor for ESRD or death and that SBP and PP have similar predictive ability for ESRD alone. Baseline elevations in DBP failed to predict poor renal outcome in this cohort of participants with type 2 diabetes and nephropathy. Moreover, at any level of SBP above 140 mm Hg, significant risk was seen for renal disease progression compared with levels below 130 mm Hg. The current analyses are also unique in that it documents a relationship between elevated baseline PP and renal outcomes in a cohort of participants with nephropathy from type 2 diabetes mellitus, that is, those with the highest baseline PPs garner the greatest benefit for slowing nephropathy progression from treatment. Conversely, in this older population of participants with nephropathy from type 2 diabetes, DBP provided little to no useful information with regard to renal outcomes. Thus, to our knowledge, we present the first evidence in nephropathy from type 2 diabetes to support the concept that baseline and SBP and PP are strong risk factors for nephropathy progression. Moreover, treated SBP values of 140 mm Hg or above in those with nephropathy from type 2 diabetes significantly increases risk of nephropathy progression compared with values below 130 mm Hg.

Retrospective, epidemiological analyses of participants with type 2 diabetes from observational studies have demonstrated that lowering SBP levels to below 150 mm Hg and DBP levels to below 85 mm Hg reduce the risk of cardiovascular outcomes811; however, similar data for declines in renal outcomes have only been appreciated for mean arterial pressure.9 Guidance for a BP goal to reduce renal outcomes has been derived exclusively from retrospective analyses of generally underpowered clinical trials that largely involve participants with nondiabetic renal disease.9,12 Thus, to our knowledge, these are the first data from an adequately powered clinical trial on time to ESRD, albeit post hoc, that help establish meaningful BP goals to preserve renal function in those with nephropathy associated with type 2 diabetes.

To slow progression of diabetic nephropathy, the JNC VI recommends that an SBP goal of below 130 mm Hg be achieved.6 This goal has been supported by other organizations such as the National Kidney Foundation, American Diabetes Association, and the Canadian Hypertension Society.9,1315 Data for this goal, however, were derived from a small number of generally underpowered studies in people who had nephropathy from either diabetic or nondiabetic causes and reflect more a benefit garnered on cardiovascular rather than renal outcomes.9,16 While a number of additional trials in people with diabetes have been completed and resulted in better refinement of a DBP goal for cardiovascular disease, the SBP goal remains to be supported from an adequately powered study, even in a retrospective analysis for renal outcomes.9

The actual percentage of people in the United States who achieve the recommended BP goal by the JNC VI is 11%.17,18 This is in part due to the reluctance of physicians to achieve such goals, perhaps because of the lack of aggressive therapy or lack of its acceptance by patients as well as many other factors.19 The analysis from the present study is the first, to our knowledge, to support a treated SBP goal in the range recommended by guidelines in people with both nephropathy and isolated systolic hypertension. Additionally, no J-curve for either renal outcomes or relationship between adverse effects was noted in the group that achieved lower BP levels.

Baseline PP values above 70 mm Hg are associated with high cardiovascular risk in the Systolic Hypertension in the Elderly Program (SHEP) trial and Framingham study.20,21 No data on renal outcomes exist with regard to baseline PP in these analyses. In the RENAAL Study, participants with baseline PPs of above 70 mm Hg had higher risk for renal disease progression to ESRD compared with those with lower levels. Moreover, those who garnered the greatest benefit from treatment were those with a baseline PP above 90 mm Hg. Thus, our observations about baseline PP and treatment benefit to slow progression of kidney disease are consistent with those of cardiovascular disease risk reduction.

Diastolic BP is a useful predictor of renal outcomes in younger people with nondiabetic renal disease and type 1 diabetes.12,2224 However, once arterial compliance starts to fall, as in our cohort, DBP loses its power to predict events, much as it does for cardiovascular risk after the age of 55 years.20,25 In our small group of participants with a DBP above 90 mm Hg at baseline, it served as a better predictor of renal disease progression; however, it was still not as powerful as SBP. This suggests that increases in PP may be associated with reduced intrarenal autoregulation and, hence, a loss of the kidney's ability to adjust to changes in BP.26,27

Angiotensin receptor blockers have been shown in the present and one other trial to slow the time to doubling of serum creatinine and attenuate increases in proteinuria, while the RENAAL Study showed a significant slowing of progression to ESRD and death.5,28,29 However, it is also clear from trials of participants with established proteinuric nephropathy, regardless of cause, that, compared with initial therapy with either an ARB or ACE inhibitor, initial therapy with a DHPCCB does not slow renal disease progression to the same extent in spite of similar levels of BP control.28,30 In the RENAAL Study, the prespecified analysis supports the aforementioned observation in that those who were receiving a DHPCCB at baseline or received them during the trial in the placebo group had worse renal outcomes compared with those who did not (Table 10). The reasons for these poorer renal outcomes may be related to more advanced renal disease or relatively more difficult to lower BP, unlike those who did not receive DHPCCBs. Thus, this subgroup may be at higher risk for progression to ESRD. The failure of DHPCCB use to protect against renal disease progression has been shown in animal models of either diabetic or nondiabetic renal disease and may relate to the abolishment of renal autoregulation.31,32

In contrast, the combined use of either an ACE inhibitor or an ARB with a DHPCCB has been shown in animal studies and small, short-term, human studies to prevent worsening of proteinuria and stabilize renal function.6,3235 The RENAAL Study, however, is the first long-term study to demonstrate in a prespecified analysis that use of a DHPCCB taken at baseline or throughout the study in those randomized to an ARB manifested a slower rate of progression to ESRD compared with that observed for the entire cohort randomized to losartan. Thus, in the presence of antihypertensive agents that lower BP and block the renin-angiotensin system, DHPCCBs can provide a benefit of lowering BP and not reduce efficacy of agents shown to reduce renal end points such as ESRD.

There are some limitations to the prespecified analyses outlined in the present article. First, there may be bias inherent in the method of BP measurement, since a random zero device was not used, although this trial was meant to mirror clinic practice. Additionally, the analyses are retrospective in nature and thus fraught with some bias. The analyses focus not only on baseline BP values but also on achieved levels of BP on treatment prior to a clinical event; thus, it is subject to a greater degree of interpretation bias. An analysis of the annual BP values demonstrate a significantly lower BP at years 1 and 3 in the losartan group; thus, while we statistically accounted for this, we cannot totally eliminate the possibility that the benefit on renal outcomes was, in part, related to better BP control during these periods. Lastly, the comparator groups for the achieved BP analyses, the below 130/80–mm Hg category had relatively fewer individuals achieve such goals compared with higher treated BP values, thus, reducing power of the analyses. We, however, tried to reduce the risk of bias in such analyses by using specific statistical approaches.

We conclude that participants with type 2 diabetes mellitus and nephropathy clearly manifest a slowing of nephropathy progression and specifically postpone dialysis longer by achieving an SBP goal of below 130 mm Hg. Achieving this goal requires a mean of 3.5 different antihypertensive medications plus study medications in moderate to high doses as documented in this and many other trials.36,37 This BP goal should be achieved in type 2 diabetes using initial therapy known to slow diabetic nephropathy progression such as an ARB in such patients. Diuretics are useful second agents for reducing cardiovascular risk, especially since individuals with nephropathy from type 2 diabetes are frequently volume expanded.3840 Additional BP-lowering agents including β- and α/β-blockers, calcium channel blockers, and centrally acting agents are frequently needed to achieve the BP goal. Moreover, when BP-lowering agents (shown to have placebolike effects on renal disease progression, eg, DHPCCBs) are used in combination with an ARB to further reduce BP, a slowed progression to ESRD similar to that observed in the entire ARB cohort is observed. Hence, the effects of ARBs on renal disease progression are not minimized. Our findings provide strong support for aggressive BP reduction for people with nephropathy from type 2 diabetes. Hopefully, these data will better equip physicians to slow the epidemic of ESRD.

Corresponding author and reprints: George L. Bakris, MD, Rush Medical Center, 1700 W Van Buren St, Suite 470, Chicago, IL 60612 (e-mail: gbakris@earthlink.net).

Accepted for publication December 20, 2002.

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Black  HR Isolated systolic hypertension in the elderly: lessons from clinical trials and future directions. J Hypertens. 1999;17 ((suppl 5)) S49- S54
PubMed
Kannel  WB Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol. 2000;85251- 255
PubMed
Perry  HM  JrMiller  JPFornoff  JR  et al.  Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension. 1995;25587- 594
PubMed Link to Article
Brenner  BMCooper  MEDeZeeuw  D  et al.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345861- 869
PubMed Link to Article
Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;1572413- 2446
PubMed Link to Article
Levey  ASBosch  JPLewis  JBGreene  TRogers  NRoth  Dfor the Modification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130461- 470
PubMed Link to Article
Hansson  LZanchetti  ACarruthers  SG  et al. HOT Study Group, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;3511755- 1762
PubMed Link to Article
Bakris  GLWilliams  MDworkin  L  et al. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group, Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36646- 661
PubMed Link to Article
UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317703- 713
PubMed Link to Article
Staessen  JAWang  JGThijs  L Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;3581305- 1315
PubMed Link to Article
Jafar  THSchmid  CHLanda  M  et al.  Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med. 2001;13573- 87
PubMed Link to Article
American Diabetes Association, Clinical Practice Recommendations 2002. Diabetes Care. 2002;25 ((suppl 1)) S1- 147
PubMed Link to Article
Kidney Disease Outcome Quality Initiative, K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39 ((suppl 1)) S1- S231
PubMed
McAlister  FACampbell  NRZarnke  KLevine  MGraham  ID The management of hypertension in Canada: a review of current guidelines, their shortcomings and implications for the future. CMAJ. 2001;164517- 522
PubMed
Dillon  JJ The quantitative relationship between treated blood pressure and progression of diabetic renal disease. Am J Kidney Dis. 1993;22798- 802
PubMed Link to Article
Coresh  JWei  GLMcQuillan  G  et al.  Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med. 2001;1611207- 1216
PubMed Link to Article
Berlowitz  DRAsh  ASHickey  EC  et al.  Inadequate management of blood pressure in a hypertensive population. N Engl J Med. 1998;3391957- 1963
PubMed Link to Article
Hyman  DJPavlik  VN Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med. 2001;345479- 486
PubMed Link to Article
Franklin  SSKhan  SAWong  NDLarson  MGLevy  D Is pulse pressure useful in predicting risk for coronary heart Disease? the Framingham Heart Study. Circulation. 1999;100354- 360
PubMed Link to Article
Celis  HFagard  RHStaessen  JAThijs  L Risk and benefit of treatment of isolated systolic hypertension in the elderly: evidence from the Systolic Hypertension in Europe Trial. Curr Opin Cardiol. 2001;16342- 348
PubMed Link to Article
Peterson  JCAdler  SBurkart  JM  et al.  Blood pressure control, proteinuria, and the progression of renal disease: the Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123754- 762
PubMed Link to Article
Lewis  JBBerl  TBain  RPRohde  RDLewis  EJCollaborative Study Group, Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Am J Kidney Dis. 1999;34809- 817
PubMed Link to Article
Klag  MJWhelton  PKRandall  BL  et al.  Blood pressure and end-stage renal disease in men. N Engl J Med. 1996;33413- 18
PubMed Link to Article
Franklin  SSGustin  WWong  ND  et al.  Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation. 1997;96308- 315
PubMed Link to Article
Mourad  JJPannier  BBlacher  J  et al.  Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension. Kidney Int. 2001;591834- 1841
PubMed Link to Article
Christensen  PKHommel  EEClausen  PFeldt-Rasmussen  BParving  HH Impaired autoregulation of the glomerular filtration rate in patients with nondiabetic nephropathies. Kidney Int. 1999;561517- 1523
PubMed Link to Article
Lewis  EJHunsicker  LGClarke  WR  et al.  Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345851- 860
PubMed Link to Article
Brenner  BMCooper  MEde Zeeuw  D  et al.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345861- 869
PubMed Link to Article
Agodoa  LYAppel  LBakris  GL  et al. for the African-American Study of Kidney Disease and Hypertension Study, Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;2852719- 2728
PubMed Link to Article
Griffin  KAPicken  MMBakris  GLBidani  AK Class differences in the effects of calcium channel blockers in the rat remnant kidney model. Kidney Int. 1999;551849- 1860
PubMed Link to Article
Koshy  SBakris  GL Therapeutic approaches to achieve desired blood pressure goals: focus on calcium channel blockers. Cardiovasc Drugs Ther. 2000;14295- 301
PubMed Link to Article
Bakris  GLGriffin  KAPicken  MMBidani  AK Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury. J Hypertens. 1997;151181- 1185
PubMed Link to Article
Ruggenenti  PBrenner  BMRemuzzi  G Remission achieved in chronic nephropathy by a multidrug approach targeted at urinary protein excretion. Nephron. 2001;88254- 259
PubMed Link to Article
Herlitz  HHarris  KRisler  T  et al.  The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study. Nephrol Dial Transplant. 2001;162158- 2165
PubMed Link to Article
Bakris  GL Maximizing cardio-renal benefits: achieve blood pressure goals. J Clin Hypertens (Greenwich). 1999;1141- 148
PubMed
Bakris  GL A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med. 2001;1612661- 2667
PubMed Link to Article
Curb  JDPressel  SLCutler  JA  et al.  Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension: Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA. 1996;2761886- 1892
PubMed Link to Article
O'Hare  JPAnderson  JVMillar  ND  et al.  Hormonal response to blood volume expansion in diabetic subjects with and without autonomic neuropathy. Clin Endocrinol (Oxf). 1989;30571- 579
PubMed Link to Article
Giles  TDSander  GE Beyond the usual strategies for blood pressure reduction: therapeutic considerations and combination therapies. J Clin Hypertens (Greenwich). 2001;3346- 353
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

A, Event rate for the primary composite end point by baseline systolic blood pressure (SBP). B, Event rate for end-stage renal disease alone by baseline SBP.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

A, The annual, mean, trough systolic blood pressure (SBP) and diastolic blood pressure (DBP). B, The annual, mean, trough pulse pressure (PP). Error bars indicate SD.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Comparison of end-stage renal disease outcomes in the groups randomized to losartan (given as losartan potassium) vs placebo at different achieved mean blood pressures (BPs) up until a primary composite event. SBP indicates systolic BP; DBP, diastolic BP. Asterisk indicates data are number of events/total number of patients.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics Stratified by Baseline Systolic BP Stage*
Table Graphic Jump LocationTable 2. Baseline Characteristics Stratified by Baseline Diastolic BP Stage*
Table Graphic Jump LocationTable 3. Distribution of Baseline Sitting BP Values in Relation to CKD Stages Using JNC VI and Kidney Disease Stages*
Table Graphic Jump LocationTable 4. Distribution of Participants Taking ACEIs or ARBs at Study Entry by JNC VI Sitting BP Stages*
Table Graphic Jump LocationTable 5. Summary of Sitting SBP by Antihypertensive Medications During Washout Period*
Table Graphic Jump LocationTable 6. Outcomes Based on Baseline and Last SBP Prior to End Points for Pooled Treatment Groups*
Table Graphic Jump LocationTable 7. Outcomes Based on Baseline and Last DBP for Pooled Treatment Groups*
Table Graphic Jump LocationTable 8. Outcomes Based on Baseline and Last PP for Pooled Treatment Groups*
Table Graphic Jump LocationTable 9. Relative Importance Between Pair of BP Measurements*
Table Graphic Jump LocationTable 10. Summary of Patient Use of DHPCCBs at Baseline and During the Study*

References

Adler  AIStratton  IMNeil  HA  et al.  Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321412- 419
PubMed Link to Article
Black  HR Isolated systolic hypertension in the elderly: lessons from clinical trials and future directions. J Hypertens. 1999;17 ((suppl 5)) S49- S54
PubMed
Kannel  WB Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol. 2000;85251- 255
PubMed
Perry  HM  JrMiller  JPFornoff  JR  et al.  Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension. 1995;25587- 594
PubMed Link to Article
Brenner  BMCooper  MEDeZeeuw  D  et al.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345861- 869
PubMed Link to Article
Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;1572413- 2446
PubMed Link to Article
Levey  ASBosch  JPLewis  JBGreene  TRogers  NRoth  Dfor the Modification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130461- 470
PubMed Link to Article
Hansson  LZanchetti  ACarruthers  SG  et al. HOT Study Group, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;3511755- 1762
PubMed Link to Article
Bakris  GLWilliams  MDworkin  L  et al. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group, Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36646- 661
PubMed Link to Article
UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317703- 713
PubMed Link to Article
Staessen  JAWang  JGThijs  L Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;3581305- 1315
PubMed Link to Article
Jafar  THSchmid  CHLanda  M  et al.  Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med. 2001;13573- 87
PubMed Link to Article
American Diabetes Association, Clinical Practice Recommendations 2002. Diabetes Care. 2002;25 ((suppl 1)) S1- 147
PubMed Link to Article
Kidney Disease Outcome Quality Initiative, K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39 ((suppl 1)) S1- S231
PubMed
McAlister  FACampbell  NRZarnke  KLevine  MGraham  ID The management of hypertension in Canada: a review of current guidelines, their shortcomings and implications for the future. CMAJ. 2001;164517- 522
PubMed
Dillon  JJ The quantitative relationship between treated blood pressure and progression of diabetic renal disease. Am J Kidney Dis. 1993;22798- 802
PubMed Link to Article
Coresh  JWei  GLMcQuillan  G  et al.  Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med. 2001;1611207- 1216
PubMed Link to Article
Berlowitz  DRAsh  ASHickey  EC  et al.  Inadequate management of blood pressure in a hypertensive population. N Engl J Med. 1998;3391957- 1963
PubMed Link to Article
Hyman  DJPavlik  VN Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med. 2001;345479- 486
PubMed Link to Article
Franklin  SSKhan  SAWong  NDLarson  MGLevy  D Is pulse pressure useful in predicting risk for coronary heart Disease? the Framingham Heart Study. Circulation. 1999;100354- 360
PubMed Link to Article
Celis  HFagard  RHStaessen  JAThijs  L Risk and benefit of treatment of isolated systolic hypertension in the elderly: evidence from the Systolic Hypertension in Europe Trial. Curr Opin Cardiol. 2001;16342- 348
PubMed Link to Article
Peterson  JCAdler  SBurkart  JM  et al.  Blood pressure control, proteinuria, and the progression of renal disease: the Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123754- 762
PubMed Link to Article
Lewis  JBBerl  TBain  RPRohde  RDLewis  EJCollaborative Study Group, Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Am J Kidney Dis. 1999;34809- 817
PubMed Link to Article
Klag  MJWhelton  PKRandall  BL  et al.  Blood pressure and end-stage renal disease in men. N Engl J Med. 1996;33413- 18
PubMed Link to Article
Franklin  SSGustin  WWong  ND  et al.  Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation. 1997;96308- 315
PubMed Link to Article
Mourad  JJPannier  BBlacher  J  et al.  Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension. Kidney Int. 2001;591834- 1841
PubMed Link to Article
Christensen  PKHommel  EEClausen  PFeldt-Rasmussen  BParving  HH Impaired autoregulation of the glomerular filtration rate in patients with nondiabetic nephropathies. Kidney Int. 1999;561517- 1523
PubMed Link to Article
Lewis  EJHunsicker  LGClarke  WR  et al.  Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345851- 860
PubMed Link to Article
Brenner  BMCooper  MEde Zeeuw  D  et al.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345861- 869
PubMed Link to Article
Agodoa  LYAppel  LBakris  GL  et al. for the African-American Study of Kidney Disease and Hypertension Study, Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;2852719- 2728
PubMed Link to Article
Griffin  KAPicken  MMBakris  GLBidani  AK Class differences in the effects of calcium channel blockers in the rat remnant kidney model. Kidney Int. 1999;551849- 1860
PubMed Link to Article
Koshy  SBakris  GL Therapeutic approaches to achieve desired blood pressure goals: focus on calcium channel blockers. Cardiovasc Drugs Ther. 2000;14295- 301
PubMed Link to Article
Bakris  GLGriffin  KAPicken  MMBidani  AK Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury. J Hypertens. 1997;151181- 1185
PubMed Link to Article
Ruggenenti  PBrenner  BMRemuzzi  G Remission achieved in chronic nephropathy by a multidrug approach targeted at urinary protein excretion. Nephron. 2001;88254- 259
PubMed Link to Article
Herlitz  HHarris  KRisler  T  et al.  The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study. Nephrol Dial Transplant. 2001;162158- 2165
PubMed Link to Article
Bakris  GL Maximizing cardio-renal benefits: achieve blood pressure goals. J Clin Hypertens (Greenwich). 1999;1141- 148
PubMed
Bakris  GL A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med. 2001;1612661- 2667
PubMed Link to Article
Curb  JDPressel  SLCutler  JA  et al.  Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension: Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA. 1996;2761886- 1892
PubMed Link to Article
O'Hare  JPAnderson  JVMillar  ND  et al.  Hormonal response to blood volume expansion in diabetic subjects with and without autonomic neuropathy. Clin Endocrinol (Oxf). 1989;30571- 579
PubMed Link to Article
Giles  TDSander  GE Beyond the usual strategies for blood pressure reduction: therapeutic considerations and combination therapies. J Clin Hypertens (Greenwich). 2001;3346- 353
PubMed Link to Article

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