Clinical Science Articles
Independent and Additive Impact of Blood Pressure Control
and Angiotensin II Receptor Blockade on Renal Outcomes in
the Irbesartan Diabetic Nephropathy Trial: Clinical
Implications and Limitations
Marc A. Pohl,* Samuel Blumenthal,†Daniel J. Cordonnier,‡Fernando De Alvaro,§
Giacomo DeFerrari,?Gilbert Eisner,¶Enric Esmatjes,#Richard E. Gilbert,** Lawrence G. Hunsicker,††
Jose B. Lopes de Faria,‡‡Ruggero Mangili,§§Jack Moore, Jr.,??Efrain Reisin,¶¶Eberhard Ritz,##
Guntram Schernthaner,*** Samuel Spitalewitz,†††Hilary Tindall,‡‡‡Roger A. Rodby,§§§and
Edmund J. Lewis;§§§for the Collaborative Study Group§§§a
*Department of Nephrology and Hypertension, Cleveland Clinic Foundation, Cleveland, Ohio;†Department of Medicine, Medical
College of Wisconsin, Milwaukee, Wisconsin;‡Department of Medicine, University of Grenoble, Grenoble, France;§Department of
Medicine, Hospital la Paz, Madrid, Spain;?Department of Internal Medicine, University of Genova, Genova, Italy;¶Department
of Internal Medicine, Washington Hospital Center, Washington, DC;#Hospital Clinicoy Provincial, Barcelona, Spain; **Department
of Medicine, University of Melbourne, Fitzroy, Victoria, Australia;††Department of Medicine, University of Iowa, Iowa City, Iowa;
‡‡Department of Medicine, University of Campinas, Campinas, Brazil;§§Department of Medicine, Hospital Bolognini, Seriate, Italy;
??Department of Medicine, Washington Hospital Center, Washington, DC;¶¶Department of Medicine, Louisiana State University
Medical Center, New Orleans, Louisiana;##Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany;
***Department of Internal Medicine, Rudolphstiftung Hospital, Vienna, Austria;†††Department of Internal Medicine, Brookdale
Hospital Medical Center, Brooklyn, New York;‡‡‡Department of Diabetes, North Middlesex Hospital, London, United Kingdom;
and§§§Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial
pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in
the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics
worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of
assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed.
concentration up to 266 ?mol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 ? 20/11 mmHg. Median
patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a
mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold,
all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120
mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg,
in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.
J Am Soc Nephrol 16: 3027–3037, 2005. doi: 10.1681/ASN.2004110919
atients with type 2 diabetes and hypertension have a
two- to four-fold greater risk for developing cardiovas-
cular sequelae such as myocardial infarction, stroke, or
death and have a seven-fold greater likelihood for developing
renal failure compared with age-matched control subjects (1,2).
Patients with type 2 diabetes now constitute the single largest
group of patients who enter ESRD programs in the United
States (3). This report, presenting an analysis of the impact of
BP control on clinical outcomes in a large cohort of hyperten-
sive adults with overt type 2 diabetic nephropathy, was under-
taken with the purpose of determining (1) the optimal targets
for the component(s) of arterial pressure most closely associ-
ated with renal deterioration as well as all-cause mortality and
Received November 8, 2004. Accepted July 9, 2005.
Published online ahead of print. Publication date available at www.jasn.org.
aSee Appendix 2 for a list of study group members.
Copyright © 2005 by the American Society of NephrologyISSN: 1046-6673/1610-3027
(2) to examine the interaction between the renoprotective action
of the antihypertensive agents tested, the level of BP achieved,
and renal outcomes.
Materials and Methods
This study is based on analysis of data from the Irbesartan in Diabetic
Nephropathy Trial (IDNT) (4) (Appendix 1); some of the information in
this article has been referred to in previous publications (4,5). Methods
and baseline characteristics of the 1715 participants and the primary
outcome of the IDNT have been published (4–6). Entry criteria in-
cluded age between 30 and 70 yr; documented type 2 diabetes; and
hypertension defined as any of the following: seated office systolic BP
(SBP) ?135 mmHg, seated office diastolic BP (DBP) ?85 mmHg, or
documented treatment with antihypertensive agents. All participants
had established diabetic nephropathy with overt proteinuria (?900
mg/24 h) and mild to moderate renal insufficiency (serum creatinine
between 88 and 266 ?mol/L [1.0 and 3.0 mg/dl] in women and be-
tween 106 and 266 ?mol/L [1.2 and 3.0 mg/dl in men]). The institu-
tional review board or appropriate ethics committee at each center
approved the study protocol.
Consenting eligible patients were randomized 1:1:1 into one of three
treatment arms: irbesartan 300 mg/d, amlodipine 10 mg/d, or placebo.
mmHg or less; (2) 10 mmHg below the baseline SBP when baseline SBP
was between 146 and 170 mmHg; (3) 160 mmHg, the maximum allowable
for all participants was ?85 mmHg. To achieve these goals, patients were
prescribed additional antihypertensive therapy. The use of other angio-
tensin receptor blockers, angiotensin-converting enzyme inhibitors, or cal-
cium channel blockers was excluded. The primary outcome for the IDNT
was the time to a composite end point of doubling of the baseline serum
creatinine, ESRD (defined as a serum creatinine ?530 ?mol/L [6 mg/dl]
or renal replacement therapy), or all-cause mortality. For the purposes of
this study, the term renal end point refers to patients who reached a
doubling of serum creatinine (SCr) or end-stage renal failure. Analysis for
each end point was on an intention-to-treat basis. Patients who reached an
end point stopped coded medication but continued to be followed until
the closing date of the trial.
Patients were seen in routine hypertension clinic settings at specified
study visit intervals: Screening, enrollment, randomization, week 1, week
death, or administrative censoring of the study (December 31, 2000). SBP
and DBP were determined at baseline and throughout the trial per study
protocol. Proper technique for BP measurement was detailed in the Man-
ual of Operations and reviewed with study coordinators at the investiga-
tors’ meetings before study initiation. Briefly, the BP cuff bladder was
centered over the brachial artery and inflated to 30 mmHg above the
pressure at which the radial pulse could no longer be palpated. Air in the
blood cuff was released so that pressure fell at a rate of 2 mmHg/s. SBP
was taken when two consecutive beats were audible, read to the nearest 2
mmHg. DBP was taken as the phase V Korotkoff sounds. Office BP
measurements were performed 1 min apart in triplicate after the patient
remained quiet in a seated position for 10 min, followed by triplicate
measurements after remaining in a standing position for 2 min. More
frequent visits were required when, at any regularly scheduled visit, the
recorded BP was not at treatment goal. These return visits to bring BP
under control were generally at 2-wk intervals until goal BP was reached.
A Clinical Management Committee (CMC) reviewed achieved BP and
therapeutic regimens on any participant who did not meet his or her
respective BP goal on a quarterly basis after the eighth study week. The
with Sixth Report of the Joint National Committee on Prevention, Detec-
tion, Evaluation and Treatment of High Blood Pressure (JNC VI) (7). More
frequent study visits were scheduled as deemed necessary by the inves-
tigator, either for BP management or for other aspects of medical care.
Direct telephone contact and written correspondence occurred regularly
between the CMC and individual investigators or centers that seemed to
have difficulty meeting goal BP in their patients. Serum for determination
of creatinine and 24-h urine collections for creatinine and albumin were
obtained twice at baseline from all patients and analyzed in central labo-
Baseline BP were taken as the average of seated BP during two
prerandomization visits. Patients in each treatment group achieved
stable BP by the 6-mo scheduled visit, and average BP in each group
varied little over the subsequent mean study follow-up of 2.6 yr (4).
Therefore, mean follow-up BP in each patient were calculated as the
average of the recorded seated BP at scheduled visits from 6 mo to the
end of the study. Of the 1715 patients in the original study cohort, 123
patients had no scheduled visit BP recorded after the 3-mo visit (60
reached either a primary or a secondary study end point, and 63
stopped regular study follow-up for other reasons). These patients and
two additional patients in whom time to doubling of SCr (a renal end
point) could not be ascertained were excluded from further analysis.
The remaining 1590 patients are the subjects of this report. In these
patients, seated BP were recorded at an average of 9 ? 4 scheduled
visits. Ninety-one percent of these patients had BP recorded at four or
more follow-up visits at and after 6 mo. Fewer than 10 patients were
lost to follow-up. GFR at baseline was estimated from the mean of the
two baseline serum creatinine values, using the four-variable Modifi-
cation of Diet in Renal Disease formula (8). Proteinuria was expressed
as the ratio of albumin to creatinine concentration in the two baseline
24-h urine collections and was log-transformed to obtain an approxi-
mately normal distribution for use in statistical analyses.
We used SAS for Windows Version 8 (Cary, NC) for data manage-
ment and S-Plus for Windows Version 6.1 (Insightful, Seattle, WA) for
most data analysis and generation of graphics. Kaplan-Meier methods
were used to plot survival over time in strata corresponding to approx-
imate quartiles of baseline and mean follow-up seated SBP and DBP.
For other analyses, we grouped patients into strata by 10-mmHg bands
of seated BP. Relative risks were estimated in univariate and multivar-
iate models using Cox proportional hazards methods. Validity of the
proportionality of hazards assumption was confirmed for all models
using the cox.zph function in S-Plus (9).
Baseline BP (mean ? SD) for the 1590 patients was 159/87 ?
20/11 mmHg and was similar among treatment groups. BP was
controlled during the course of the trial in the irbesartan group
to a mean of 141/78 ? 14/8 mmHg (n ? 537), in the amlodipine
group to 142/77 ? 13/8 mmHg (n ? 523), and in the placebo
(usual care) group to 144/80 ? 13/8 mmHg (n ? 530). Thirty
percent of participants achieved an SBP ?135 mmHg; 82% of
patients achieved their DBP goal of 85 mmHg. The use of
nonstudy drugs to achieve target BP was similar in the three
cohorts: The placebo group received an average of 3.3 nonstudy
3028Journal of the American Society of NephrologyJ Am Soc Nephrol 16: 3027–3037, 2005
drugs; the other two groups received an average of 3.0 non-
study drugs (4,10). There was a significantly greater use of
sympathetic depressant agents in the placebo group. There was
no statistically significant difference in the use of thiazide or
loop diuretics among the three study cohorts (10).
Baseline SBP correlated significantly with the renal outcomes
(doubling of SCr or ESRD) in univariate analysis (Figure 1A). The
risk for reaching a renal end point increased progressively with
higher baseline SBP (P ? 0.0001), with 36% of patients in the
highest quartile (baseline SBP ?170 mmHg) reaching a renal end
point compared with 18% of patients in the lowest SBP quartile
(SBP ?145 mmHg) over the 4 yr of the study. Baseline DBP was
weakly correlated with the renal outcome (P ? 0.065). There was
no correlation of DBP with renal outcome among the 152 patients
with baseline DBP ?100 mmHg. When baseline SBP and DBP
were included in the same model (Table 1), only SBP was inde-
pendently correlated with outcome.
The impact of achieved follow-up SBP on renal outcomes is
Figure 1. (A) Cumulative proportions of patients who reached a renal end point (doubling of baseline serum creatinine [SCr] or
ESRD, defined as SCr ?6.0 mg/dl or renal replacement therapy) by quartile of baseline systolic BP (SBP). The number of patients
who were at risk for reaching a renal end point is tabulated for each period during follow-up. (B) Cumulative proportions of
patients who reached a renal end point (doubling of baseline SCr or ESRD, defined as SCr ?6.0 mg/dl or renal replacement
therapy) by quartile of achieved SBP. The number of patients who were at risk for reaching a renal end point is tabulated for each
period during follow-up.
J Am Soc Nephrol 16: 3027–3037, 2005Blood Pressure Management in Diabetic Nephropathy 3029
illustrated in Figure 1B. The best renal outcome was observed in
patients who achieved SBP ?134 mmHg, among whom only 17%
(63 of 379) reached a renal end point during the course of follow-
up. In contrast, the risk for a renal end point was 2.2-fold higher
of whom reached a doubling of their SCr or ESRD. After account-
ing for this impact of achieved SBP, the achieved DBP did not
correlate significantly with renal outcome (Table 1).
We determined whether baseline or achieved SBP was more
closely associated with renal outcome by examining the simul-
taneous impact of these variables on the risk for renal end
points in a multivariate model. The results (Table 1) demon-
strated that achieved follow-up SBP is an independent predic-
tor of the risk for an adverse renal outcome irrespective of the
baseline SBP. A decrease of 20 mmHg in achieved SBP was
associated with a 47% decrease in the risk for developing a
renal end point. Although baseline SBP was an independent
predictor of renal outcome, this relationship was lost when
achieved SBP was taken into account.
These results indicate that the renal outcomes in the IDNT were
better at lower quartiles of follow-up SBP but do not exclude the
possibility of an adverse effect on renal outcomes or all-cause
mortality at the lowest follow-up SBP (10). We therefore examined
renal outcomes and mortality of patients with mean follow-up
seated SBP grouped in 10-mmHg increments. Renal outcomes
(Figure 2A) in patients with a follow-up SBP ?120 mmHg were
not substantially better than in patients with follow-up SBP be-
tween 120 and 130 mmHg. The association of achieved SBP with
all-cause mortality among patients in these same SBP categories is
shown in Figure 2B; average follow-up SBP and risk for all-cause
mortality are essentially linear from SBP of 120 mmHg to SBP
?180 mmHg. However, patients with the lowest follow-up SBP
(?120 mmHg) had sharply higher mortality, and a test of the
shape of the entire relationship depicted in Figure 2B demon-
strated significant nonlinearity (P ? 0.001).
The relationship of follow-up BP to renal outcomes that
might be attributable to differences in baseline renal function
was investigated. Baseline estimated GFR (eGFR) and albu-
min/creatinine ratio (ACR) both were linearly and significantly
correlated with both mean follow-up BP and with the risk for a
renal end point (11,12). The assessed risk for a renal outcome
associated with lower follow-up SBP after adjustment for base-
line eGFR and ACR continued to reveal a relationship between
SBP and the likelihood of a renal event. Uncorrected, each
Figure 2. (A) Natural log of the relative risk for reaching a renal
end point by level of achieved follow-up SBP. The number of
patients who were at risk for reaching a renal end point is
tabulated for each level of achieved follow-up SBP. (B) Natural
log of the relative risk for all-cause mortality by level of
achieved follow-up SBP. The number of patients who were at
risk for death by any cause is tabulated for each level of
achieved follow-up SBP.
Table 1. Simultaneous impact of SBP and DBP on risk for subsequent renal end point (doubling of SCr or ESRD)a
decrease of 20 mmHg in SBP
decrease of 20 mmHg in DBP
decrease of 20 mmHg in SBP
decrease of 20 mmHg in DBP
Baseline and achieved
decrease of 20 mmHg in baseline SBP
decrease of 20 mmHg in achieved SBP
0.71 to 0.88
0.85 to 1.22
0.45 to 0.60
0.84 to 1.35
0.87 to 1.07
0.46 to 0.64
aSBP, systolic BP; DBP, diastolic BP; SCr, serum creatinine; RR, relative risk; CI, confidence interval.
3030Journal of the American Society of Nephrology J Am Soc Nephrol 16: 3027–3037, 2005
20-mmHg decrease in SBP was associated with a 47% decrease
in the risk for a renal outcome (P ? 0.0001). After correction for
eGFR and ACR, each 20-mmHg decrease in SBP was still asso-
ciated with a 30% reduction in the risk for a renal event (P ?
0.0001), independent of these two baseline renal covariates.
Figure 3 presents the renal outcomes among the follow-up
SBP quartiles, further divided by treatment assignment (irbe-
sartan, amlodipine, or placebo). In each treatment group, renal
outcomes improved progressively at lower follow-up SBP lev-
els. Furthermore, in all SBP strata, patients who were assigned
to irbesartan had better renal outcomes than patients who were
assigned to the other treatments. Renal outcomes in patients
who were assigned to amlodipine and to placebo did not differ
significantly. Table 2 presents the crude event rate and relative
renal risk reduction for quartiles of achieved SBP and for irbe-
sartan versus the two other treatment groups combined. Over-
all, assignment to irbesartan resulted in a 33% reduction in risk
(P ? 0.001) for reaching a renal end point beyond that achieved
by lowering the SBP. Even in patients who achieved a SBP ?134
mmHg, adverse renal outcomes were significantly reduced
with irbesartan (12%) compared with amlodipine plus placebo
(20%; relative risk ? 0.55, P ? 0.034). These two effects, lower
SBP and treatment with irbesartan, were completely indepen-
dent (P ? 0.61 for interaction) and therefore additive.
We conclude that there is a direct relationship between control
nephropathy, independent of baseline renal function. We also
conclude that angiotensin receptor blockade is renoprotective
across a wide range of SBP. Both of these results are consistent
course of diabetic nephropathy (13,14) and current theories re-
garding pathophysiology of diabetic glomerulosclerosis (15,16).
The glomerulus in the diabetic kidney seems to be particularly
vulnerable to the barotrauma caused by systemic arterial hyper-
tension. The explanation for this sensitivity of the glomerular
capillary bed to elevated systemic BP has been explored in exper-
imental models of diabetes and may reside in the fact that the
glomerular capillary bed is part of an arteriolar portal system.
Thus, in diabetes, the hemodynamic determinants of altered hy-
Figure 3. Simultaneous impact of quartile of achieved SBP and treatment modality on the relative risk for reaching a renal end
point (doubling of baseline SCr or ESRD, defined as SCr ?6.0 mg/dl or renal replacement therapy).
Table 2. Renal risk reduction (doubling of SCr or ESRD) by level of achieved seated SBP and assigned treatment
?134134 to 140141 to 149
No. of patients
No. of events (%)
irbesartan versus amlodipine
irbesartan (%) versus amlodipine
? placebo (%)
irbesartan versus amlodipine
18/151 versus 45/228 27/128 versus 54/229 28/122 versus 97/306 42/136 versus 122/290115/537 versus 318/1053
12 versus 20 21 versus 24 23 versus 32 31 versus 4221 versus 30
0.55 (P ? 0.034) 0.92 (P ? 0.71)0.66 (P ? 0.05) 0.70 (P ? 0.05)0.67 (P ? 0.0002)
J Am Soc Nephrol 16: 3027–3037, 2005Blood Pressure Management in Diabetic Nephropathy3031
draulic pressure in the glomerulus may be associated with both
relative arteriolar dilation and efferent arteriolar constriction (16,17).
It is known that a loss of autoregulatory function occurs in
various experimental nephropathies and is manifest as afferent
arteriolar dilation (18). Morphologic correlates of this func-
tional abnormality of the afferent arteriole have also been de-
scribed in the aging human kidney (19). Inability to autoregu-
late afferent arteriolar tone in response to changes in renal
perfusion pressure has been shown in diabetic rats (20). De-
creased afferent arteriolar resistance increases glomerular
blood flow while simultaneously exposing glomerular capillar-
ies to the elevated systemic pressures of the hypertensive state
(16). This pathophysiologic abnormality may explain the vul-
nerability of the diabetic glomerulus to elevated SBP. The ac-
tion of agents that can inhibit the renin-angiotensin system and
dilate the efferent arteriole provides a second, independent
mechanism for relieving the potential traumatic effects of ele-
vated glomerular capillary hydraulic pressure (17).
The data presented herein indicate that it is SBP achieved dur-
in patients with progressive nephropathy as a result of type 2
diabetes. Although the level of SBP at baseline predicts renal
outcome in these patients, the ability to alter significantly renal
prognosis according to the SBP that is achieved emphasizes the
importance of antihypertensive therapy in caring for this patient
findings of other investigators (21–23), DBP (even DBP ?100
mmHg), whether baseline or follow-up, were not significant pre-
dictors of renal outcomes. Mean arterial pressure and pulse pres-
sure also were not independent predictors of adverse renal out-
comes; any relationship between these two BP calculations and
renal outcomes in this study were merely reflections of their
dependent relationship upon SBP (24).
Our data indicate continuous renal protection with reduction
of SBP to levels down to 120 mmHg. Limited data from patients
whose SBP was reduced below 120 mmHg preclude definitive
statements about the course of renal function below this level.
However, our data do suggest that the risk for mortality in-
creases when SBP is reduced below this threshold (25). This
observation, referred to as a J-curve phenomenon, was evident
in all three treatment groups and in patients with and without
a history of cardiovascular disease at entry into the trial. Bouti-
tie et al. (26), in a recent meta-analysis, also noted the presence
of higher cardiovascular and all-cause mortality in elderly in-
dividuals with hypertension and with SBP ?120 mmHg. Sim-
ilarly, Hasebe et al. (27) noted increased cardiovascular events
in patients with angina pectoris and SBP ?124 mmHg. In our
study, the reasons for increased mortality at follow-up SBP
levels ?120 mmHg are not clear and may reflect severe preex-
isting intrinsic cardiac disease, adverse effects of multiple an-
tihypertensive agents, a tendency to orthostatic hypotension, or
some combination of these clinical factors.
These analyses of the relationship of BP with renal outcomes,
with data collected prospectively but analyzed retrospectively,
are observational in nature and not based on a randomized
assignment to BP goal. As such, they show only a correlation of
follow-up SBP to outcomes. There is a possibility of confound-
ing by some unmeasured baseline factor that might fully ac-
count for the effect of follow-up BP. The only way to examine
the impact of lower achieved BP on renal outcomes with com-
plete confidence would be with a controlled clinical trial in
which patients are randomized to different BP goals. Unfortu-
nately, there are no such trials in patients with advanced dia-
betic kidney disease. Furthermore, the correlation of risk for
progression with higher achieved SBP that we have observed is
independent of baseline renal function and is consistent with
current understanding of the underlying pathophysiology of
progressive renal injury. We believe, therefore, that this study
has important implications for antihypertensive therapy guide-
lines for the practicing physician.
Our observation that achieved SBP during follow-up has a
stronger correlation with renal and mortality outcomes than
does SBP at entrance into the study indicates that the course of
renal disease in this vulnerable patient population can be al-
tered to the benefit of the patient. The SBP targets are consistent
with data from other clinical trials and retrospective observa-
tions (23,28–30). Furthermore, these data emphasize the impor-
tance of additional renoprotection by blockade of the renin-
angiotensin system (4,30–32). Irbesartan therapy reduced the
risk for reaching a renal end point at all BP levels, and its
renoprotective effect was independent of level of BP control.
Thus, the concomitant treatment goals of reducing SBP and use
of angiotensin receptor blockade with irbesartan are both crit-
ical in slowing the progression of renal disease in individuals
with type 2 diabetes. These observations are also consistent
with previous observations in type 1 diabetic nephropathy with
use of the angiotensin-converting enzyme inhibitors captopril
or ramipril (30,33).
Although the benefits of decreasing SBP in proteinuric
renal disease are supported in other reports, there are sparse
data about an appropriate lower limit for SBP (28,34,35). We
found evidence for renoprotection down to an SBP level of 120
mmHg, but all-cause mortality rose below this threshold. Jafar et
al. (13), in a recent meta-analysis in nondiabetic renal disease,
noted an increased incidence of renal failure when SBP fell below
110 mmHg. The recently published JNC VII recommends that BP
in patients with chronic kidney disease be reduced to at least
130/80 and suggests an even lower limit as appropriate for indi-
viduals with diabetes (36). JNC VII also notes that a SBP ?115
mmHg is associated with increased cardiovascular risk. Because
our data describe an increase in mortality below 120 mmHg, we
believe that treating individuals with diabetes and nephropathy
to the suggested lower limits of the JNC be undertaken only
with the utmost care. We recommend a SBP target between 120
and 130 mmHg, in conjunction with blockade of the renin-angio-
tensin system, to provide optimal protection from progressive
renal insufficiency in patients with type 2 diabetic nephropathy.
Caution should be exercised in reducing SBP below 120 mmHg,
even with the use of renin-angiotensin system blockade, as this
treatment approach may not offer additional renoprotection and
may be associated with increased mortality in this patient popu-
3032 Journal of the American Society of NephrologyJ Am Soc Nephrol 16: 3027–3037, 2005
The Collaborative Study Group
Clinical Coordinating Center.
ical Center, Chicago, IL; Principal Investigator and Director: Edmund J.
Lewis, MD; Co-Principal Investigator and Associate Director: Tomas
Berl, MD, University of Colorado Health Science Center, Denver, CO;
Project Coordinator and Director of Central Laboratory: Richard D.
Rush-Presbyterian-St. Luke’s Med-
Rohde, BS, Chicago, IL; Associate Project Coordinator: Elizabeth
Muskwe, Chicago, IL.
European Clinical Coordinating Center.
berg, Heidelberg, Germany; Director: Professor Eberhard Ritz, MD;
Associate Director: Luis Ruilope, MD, Hospital 12 de Octubre, Madrid,
Spain; Medical Consultant: Pieter Klooker, MD, Heidelberg, Germany;
Project Coordinator: Beatrix Spiller, Pharm.D, Heidelberg, Germany.
University of Heidel-
J Am Soc Nephrol 16: 3027–3037, 2005 Blood Pressure Management in Diabetic Nephropathy3033
Pacific Clinical Coordinating Center.
Clayton, Victoria, Australia; Director: Professor Robert Atkins, MD;
Associate Director: George Jerums, MD, Austin & Repatriation Medical
Center, Heidelberg, Victoria, Australia; Project Coordinator: Raphael
Bartholomeusz, PhD, Clayton, Victoria, Australia.
European Country Coordinators.
Sweden, Denmark and Finland—Lennart Hulthen, MD, Staffan Bjo ¨rck,
MD; France—Daniel J. Cordonnier, MD; Italy—Giacomo DeFerrari,
MD; Spain—Luis Ruilope, MD; Hungary—Gyula Tamas, MD, PhD;
Belgium and Netherlands—Luc F. Van Gaal, MD.
Biostatistical Coordinating Center.
pitals and Clinics, Iowa City, IA; Principal Investigator: Lawrence G.
Hunsicker, MD; Co-Principal Investigator: William R. Clarke, PhD,
Iowa City, IA.
Edmund J. Lewis, MD, Robert Atkins, MD,
Eberhard Ritz, MD, Tomas Berl, MD, George Jerums, MD, Luis Ruilope,
MD, Rudolf Bilous, MD, Samuel Blumenthal, MD, William Clarke,
PhD, Daniel J. Cordonnier, MD, Donald Hricik, MD, Lawrence G.
Hunsicker, MD, Pieter Klooker, MD, Julia Lewis, MD, Otegbola Ojo,
MD, Marc Pfeffer, MD, Marc A. Pohl, MD, Jerome G. Porush, MD,
Itamar Raz, MD, Roger A. Rodby, MD, Thomas B. Wiegmann, MD.
Clinical Management Committee.
Daniel J. Cordonnier, MD (Co-chair), Staffan Bjorck, MD, Samuel Blu-
menthal, MD, William Clarke, PhD, Fernando De Alvaro, MD, Gia-
como Deferrari, MD, Richard Gilbert, MD, Lawrence G. Hunsicker,
MD, Pieter Klooker, MD, Jose ´ B. Lopes de Faria, MD, Ruggero Mangili,
MD, Efrain Reisin, MD, Roger A. Rodby, MD, Guntram Schernthaner,
MD, Samuel Spitalewitz, MD, Hilary Tindall, MD.
Outcomes Confirmation and Classification Committee.
Berl, MD (Chair), Paul Drury, MD, Enric Esmatjes, MD, Donald Hricik,
MD, Julia Lewis, MD, Francesco Locatelli, MD, Jerome G. Porush, MD,
Itamar Raz, MD, Luis Ruilope, MD, Krzysztof Strojek, MD, Robert Toto,
MD, Phillppe Vanhille, MD, Thomas B. Wiegmann, MD, Bernard M.
Tomas Berl, MD, Samuel Z. Goldhaber,
MD, Andrew Levey, MD, Julia Lewis, MD, Marc Pfeffer, MD, Jerome G.
Porush, MD, Jean-Lucien Rouleau, MD.
Monash Medical Center,
UK—Rudolf W. Bilous, MD;
The University of Iowa Hos-
Marc A. Pohl, MD (Chair),
Veterans Affairs Medical Center and Creighton University,
Omaha, NE: R.J. Anderson, MD; Oregon Health Sciences University,
Portland, OR: S. Anderson, MD; Research Institute of Dallas, Dallas,
TX: S. Aronoff, MD; Cedars Sinai Medical Center, Los Angeles, CA: P.
Barnett, MD; University of Colorado Health Science Center, Denver,
CO: T. Berl, MD; Radiant Research of Phoenix, Phoenix, AZ: M. Block,
MD, L. Nelson, MD; Medical College of Wisconsin, Milwaukee, WI: S.
Blumenthal, MD, B. Bresnahan, MD; Renal Research Baystate Medical
Center, Springfield, MA: G.L. Braden, MD, E.M. Benjamin, MD, M.H.
O’Shea, MD; Vanderbilt University Medical Center, Nashville, TN: J.
Lewis, MD, G. Schulman, MD; Thomas Jefferson University, Philadel-
phia, PA: J.F. Burke, Jr., MD, K. Sharma, MD; Charlotte Clinical Re-
search, Charlotte, NC: G. Collins, MD; Louisville Metabolic & Athero-
sclerosis Research Center, Louisville, KY: J. Cyrus, MD; Maricopa
Medical Center, Phoenix, AZ: W. Dachman, MD; Diabetes Center of
Western New York, Buffalo, NY: P. Dandona, MD; Marshfield Clinic,
Marshfield, WI: R.A. Dart, MD; Veterans Administration Medical Cen-
ter, Northport, NY: T. Dixon, MD; Beaumont Nutritional Clinic, Bir-
mingham, MI: M. Doyle, MD; Theodore Duncan & Associates, Phila-
delphia, PA: T. Duncan, MD; Rhode Island Hospital, Providence, RI: L.
Dworkin, MD; Diabetes, Endocrinology & Metabolic Disorders, San
Diego, CA: D. Einhorn, MD; Washington Hospital Center, Washington,
DC: G. Eisner, MD, J. Moore Jr, MD; University Hospital Clinic Ohio
State University, Columbus, OH: M. Falkenhain, MD; Cardiovascular
Research Center of South Florida, Miami, FL: J. Fialkow, MD; Hill Top
Research, Portland, OR: P. Fisher, MD; Veterans Administration Med-
ical Center, Spokane, WA: E. Fishman, MD; New York Medical College
and Nephrology Associates of Westchester, Hawthorne, NY: R. Gar-
rick, MD; Veterans Administration Hospital, Tucson, AZ: S. Goldman,
MD; Florida West Coast Clinical Research Group, Tampa, FL: R. Gold-
stein, MD, J. Navarro, MD; University of Iowa Hospitals & Clinics,
Iowa City, IA: R. Hegeman, MD; Rochester General Hospital, Roches-
ter, NY: R.E. Heinig, MD; University Hospitals of Cleveland, Cleve-
land, OH: D. Hricik, MD; East Bay Clinical Trial Center, Concord, CA:
R. Kaplan, MD; Boston Veterans Administration Medical Center, Bos-
ton, MA: J. Kaufman, MD; Indiana University Medical Center, India-
napolis, IN: S. Kirkman, MD; Lehigh Valley Hospital, Allentown, PA:
N. Kopyt, DO; Mecklenberg Medical Group, Charlotte, NC: N. Kramer,
MD; Veterans Administration Medical Center, Los Angeles, CA: B.
Levine, MD; Encompass Clinical Research, Spring Valley, CA: R. Li-
petz, MD; Diabetes Care Research Center, Birmingham, AL: P.
Lodewick, MD; Veterans Administration Medical Center, Buffalo, NY:
J. Lohr, MD; Oklahoma Medical Research Foundation, Oklahoma City,
OK: C. Manion, MD; Greater Baltimore Medical Center, Baltimore, MD:
J.H. Mersey, MD, J.B. Tyzack, MD, J.A. Dicke, MD; Nephron Associates,
Southfield, MI: R. Michaels, MD; University of Texas Southwestern
Medical Center, Dallas, TX: J. Middleton, MD, R. Toto, MD; Danville
Urologic Clinic, Danville, VA: M. Moore, MD; Internal Medicine Me-
morial Clinic, Lacey, WA: C. Ott, MD; Cleveland Clinic Foundation,
Cleveland, OH: M. Pohl, MD; Brookdale Hospital Medical Center,
Brooklyn, NY: J. Porush, MD, S. Spitalewitz, MD; Endocrinology &
Metabolism, Santa Rosa, CA: D. Price, MD; University of Texas Health
Science Center, Houston, TX: S.N. Rahman, MD; Louisiana State Uni-
versity Medical School, New Orleans, LA: E. Reisin, MD; Rush-Presby-
terian-St. Luke’s Medical Center, Chicago, IL: R.A. Rodby, MD, J.
Rydel, MD; Radiant Research, Greer, SC: F.D. Rogoff, MD, V.A. Klimas,
MD, W.T. Ellison, MD, W.J. Henry, III, MD, J.M. Milas, MD; WJB Dorn
Veterans Hospital, Columbia, SC: S.J. Rosansky, MD; Veterans Admin-
istration Medical Center, Bronx, NY: C. Rosendorff, MD; University of
Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical
School, New Brunswick, NJ: M. Ruddy, MD; Graduate Hospital, Phil-
adelphia, PA: M. Rudnick, MD; Health Care Discoveries, San Antonio,
TX: D. Ruff, MD; Allegheny University Hospital-Hahnemann, Phila-
delphia, PA: A. Schwartz, MD; Diabetes & Glandular Disease Clinic,
San Antonio, TX: S. Schwartz, MD; Washington Nephrology Associa-
tion, Washington, DC: K. Sethi, MD; Rockland Renal Associates, West
Nyack, NY: K. Shapiro, MD; Northern Michigan Hospital-Nisus Re-
search, Petoskey, MI: G. Shaw, MD; VA Puget Sound Health Care
System, Seattle, WA: D. Sherrard, MD, C. Stehman-Breen, MD; Medical
College of Virginia, Richmond, VA: D. Sica, MD; Physicians Research
Center, Toms River, NJ: H.J. Simon, MD, R.T. Simon, MD; Wake Forest
University Baptist Medical Center, Winston-Salem, NC: R. Smith, MD;
Health Care Plan, West Seneca, NY: B. Snyder, MD; Nephrology &
Hypertension Specialists, Liverpool, NY: N. Tolchin, DO; The Heart
Institute of Spokane, Spokane, WA: K. Tuttle, MD; George Washington
University, Washington, DC: M. Velasquez, MD; King Drew Medical
Center, Los Angeles, CA: H. Ward, MD; Internal Medicine Group, P.C.,
Cheyenne, WY: E. Wedell, MD; University of Maryland Hospital, Bal-
timore, MD: M. Weir, MD; Veterans Administration Medical Center,
Kansas City, MO: T. Wiegmann, MD; Georgetown University Medical
Center, Washington, DC: C. Wilcox, MD; Medical Plaza I, Kansas City,
MO: B. Wood, MD; Northern California Research Corp., Fair Oaks, CA:
D. Young, MD; University of California San Diego Medical Center, San
3034 Journal of the American Society of NephrologyJ Am Soc Nephrol 16: 3027–3037, 2005
Diego, CA: M. Ziegler, MD; Hunter Holmes McGuire Veterans Admin-
istration Medical Center, Richmond, VA: F.J. Zieve, MD.
The Bailey Clinic, Red Deer: G.R. Bailey, MD; Univer-
sity Health Network-Toronto General Hospital, Toronto: D. Cattran,
MD; Hotel-Dieu de Montreal, Montreal: P. Hamet, MD; Atlantic
Health Science Centre, Saint John: S.P. Handa, MD; Canadian Insti-
tute of Stress Medicine & Cardiovascular Performance Evaluation,
Oshawa, ON: O. Ojo, MD, P. Tam, MD, R. Ting, MD; Saskatoon
District Health Board, SK: G. Pylypchuk, MD; Calgary Metabolic
Education & Research Centre, Calgary, AL: S.A. Ross, MD; Endo-
crine Research Society, Vancouver, BC: H. Tildesley, MD, W. Vlahos,
MD, R. Bebb, MD, G. Bondy, MD; London Health Science Centre
University, London, ON: B.M. Wolfe, MD.
Instituto Investigaciones Cardiolo ´gical, Buenos Aires:
L.F. Ferder, MD; Hospital Argerich, Buenos Aires: F. Margulis, MD;
Instituto De Investigaciones Medicas, Buenos Aires: A. Zucchini, MD.
Faculdade de Ciencias Medicas de Sorocaba, Sorocaba: F.A.
de Almeida, MD; Universidade Estadual de Campinas, Campinas: J.B.
Lopes de Faria, MD, V. Pavan, MD; Universidade Federal de Minas
Gerais, Belo Horizonte, Minas Gerais: R. Milagres, MD; UERJ Pedro
Ernestro, Rio de Janiero: W. Oigman, MD; Escola Paulista de Medicina,
Sao Paulo: M.T. Zanella, MD; Facultade de Medicina, Sao Paulo: R.
Instituto Nacional de la Nutricio ´n, Salvador Zubira ´n, Mex-
ico City, DF: R. Correa-Rotter, MD, M. Sieiro-Muradas, MD.
San Juan Veterans Administration Medical Center,
San Juan: J. Benabe, MD; San Juan Bautista School of Medicine, Caguas:
J.L. Cangiano, MD.
Europe, United Kingdom, and Israel
General Hospital Linz, Linz: G. Biesenbach, MD; Kran-
kenanstalt Rudolf-Stiftung, Wien: G. Schernthaner, MD; Universita ¨-
tsklinik AKII, Wien: W. Waldha ¨ausl, MD.
Akademisch Ziekenhuis VUB, Brussels: B. Keymeulen,
MD; Universitaire Instelling Antwerpen, Egedem: L. Van Gaal, MD;
Centre Hospitalie Regionale de la Citadelle, Liege: X. Warling, MD.
Bispebjerg Hospital, Copenhagen: H. Perrild, MD.
Helsinki University Central Hospital, Helsinki: C. Gro ¨n-
Academic Hospital, Groningen: K. Hoogenberg,
MD; TweeSteden Ziekenhuis, Tilburg: P.F.M.J. Spooren, MD; Zieken-
huis Centrum Apeldoorn, Apeldoorn: R.P. Verhoeven, MD.
Hospital du Dr Duchenne, Boulogne S/Mer: P. Bataille,
MD; Maison Blanche Hospital, Reims: J. Chanard, MD; Hospital de
Corbeil, Corbeil Essonnes: G. Charpentier, MD; Saint-Quentin Hospital
Center, Saint Quentin: B. Coevoet, MD; Centre Hospitalier Universita-
ire, Grenoble: D.J. Cordonnier, MD, C. Maynard, MD, P. Zaoui, MD;
C.H.U. de Nancy Hospital Jeanne d’Arc, Toul: P. Drouin, MD; C.H.U.
Amiens Hospital, Amiens: A. Fournier, MD, El Esper, MD; C.H.R.U.
Hospices Civils, Strasbourg: T. Hannedouche, MD, F. Chantrel, MD;
C.H.U. Nancy Hospital Brabois, Vandoeuvre: M. Kessler, MD; Centre
Hospitalier Beauvais, Beauvais: G. Lambrey, MD; C.H.U. de Caen,
Caen: J. Mahoudeau, MD; BICHAT Hospital, Paris: F. Mignon-Henrion,
MD; Hospital Center, Valenciennes: P. Vanhille, MD.
Buergerhospital, Stuttgart: W. Beischer, MD; Diabetes-
Zentrum Bad Mergentheim, Bad Mergentheim: K. Bergis, MD, C. Ham-
mermeister, MD; Internal Medicine, Aschaffenburg: G.P. Dragoun,
MD; Bielefeld: H.H. Echterhoff, MD; Gemeinschaftspraxis Karlstrasse,
Du ¨sseldorf: W. Kleophas, MD; Ernst-Moritz-Arndt-Universita ¨t, Greif-
swald: G. Kraatz, MD; Universita ¨tsklinik Go ¨ttingen, Go ¨ttingen: G.A.
Mu ¨ller, MD; Institute of Diabetes Research, City Hospital Schwabing,
Munich: E. Standl, MD; Klinik fu ¨r Innere Medizin IV, Jena: G. Stein,
MD; Medizinisiche Universita ¨tsklinik, Wu ¨rzburg: C. Wanner, MD;
Metabolic Research Munich, Munich: P. Weisweiler, MD.
Bajcsy-Zsilinszky Hospital, Budapest: G. Jermendy, MD,
K. Farkas, MD; University Medical School of Debrecen, Debrecen: G.
Kakuk, MD; St. Istva ´n Hospital, Budapest: L. Kammerer, MD; Univer-
sity Medical School of Pecs, Pecs: J. Nagy, MD; Semmelweis University,
Budapest: G. Tamas, MD, G. Bibok, MD.
Hadassah University Hospital, Jerusalem: I. Raz, MD.
Nuovo Policlinico, Naples: V.E. Andreucci, MD; Universita ´
degli Studi La Sapienza, Rome: G.A. Cinotti, MD; Policlinico Universi-
tario, Padova: G. Crepaldi, MD; Universita ´ degli Studi di Pavia, Pavia:
A. Dal Canton, MD, C. Esposito, MD, N. Bellotti, MD; Universita ´ degli
Studi di Genova, Genova: G. DeFerrari, MD; Ospedale S. Maria della
Croci, Ravenna: E. Degli Esposti, MD; Ospedale di Lecco, Lecco: F.
Locatelli, MD; Ospedale E. Agnelli, Pinerolo: U. Malcangi, MD; Osped-
ale Civile Maggiore, Verona: G. Maschio, MD; Ospedale di Cisanello,
Pisa: R. Navalesi, MD, S. Bandinelli, MD, G. Penno, MD; Ospedale
Luigi Sacco, Milan: G. Norbiato, MD; Ospedale S. Giovanni Battista
LeMolinette, Torino: G. Piccoli, MD; Instituto Scientifico S. Raffaele,
Milan: G. Pozza, MD, R. Mangili, MD; Ospedale Giovanni Bosco,
Torino: F. Quarello, MD; Ospedale Mauriziano Umberto Primo, Torino:
A. Ramello, MD; Ospedaliero Mutizonale, Bari: F. Paolo Schena, MD;
Vimercate Hospital, Vimercate: A. Sessa, MD; Policlinico Universitario
S. Orsola, Bologna: S. Stefoni, M.D; Clinia CNR, Reggio Calabria: C.
Kliniika Endokrinology Akademii Mediczne, Szczecin: S.
Czekalski, MD, H. Fuchs, MD, K. Pynka, MD; Medical University of
Lodz, Lodz: J. Drezwoski, MD; Department of Internal Diseases &
Diabetology, Zabrze: W. Grzeszczak, MD, K. Strojek, MD, M. Snit, MD;
Medical Academy, Bialystok: I. Kinalska, MD; Klinika Chorob Meta-
bolicznych, Krakow: J. Sieradzki, MD.
Hospital Distrital de Faro, Faro: P.L. Neves, MD; Hospi-
tal Espirito Santo, Evora: C. Pires, MD.
Hospital La Paz, Madrid: F. De Alvaro, MD; Hospital
Clinico y Provincial, Barcelona: E. Esmatjes, MD; Hospital Coua-
donga, Oviedo: R. Marin Iranzo, MD; Dr. J. Trueta Hospital, Girona:
J.M. Mauri, MD; Hospital Universitari Germans Trias I Pujol, Bada-
lona, Barcelona: R. Romero, MD, J. Bonet, MD; Hospital 12 de
Octubre, Madrid: L. Ruilope, MD; Hospital de Cruces, Cruces: J.A.
Universiterssjukhuset, Linko ¨ping: H. Arnqvist, MD; Sahl-
grenska sjukhuset, Gotenburg: S. Bjo ¨rck, MD; Malmo ¨ University Hos-
pital, Malmo ¨: L. Hulthen, MD.
South Cleveland Hospital, Middlesbrough: R.
Bilous, MD; Hope Hospital, Manchester: T.L. Dornan, MD, J. New, MD;
Leeds General Infirmary, Leeds: P. Grant, MD; Central Middlesex
Hospital, London: D. Hopkins, MD, A. Grenfell, MD; Maelor Hospital,
Wrexham: J.N. Harvey, MD; Northern General Hospital, Sheffield: S.R.
Heller, MD; St. Georges Hospital, London: A. Panahloo, MD, N.W.
Oakley, MD; New Cross Hospital, Wolverhampton: P.B. Rylance, MD;
Royal Berkshire Hospital, Reading: H. Simpson, MD; North Middlesex
Hospital, London: H. Tindall, MD; Royal Sussex County Hospital, East
Sussex: N.J.A. Vaughn, MD; Royal Liverpool Hospital, Liverpool: J.P.
Australia, New Zealand, and South East Asia
Monash Medical Center, Clayton: R. Atkins, MD, P.
Kerr, MD; Royal Melbourne Hospital, Parkville: P.J. Champion de
Crespigny, MD; Royal Brisbane Hospital, Brisbane, Queensland: M.C.
D’Emden, MD, D. Saltissi, MD; Northern Hospital, Epping, Victoria: B.
Jackson, MD; Austin & Repatriation Medical Centre, Victoria: G.
Jerums, MD, R. Gilbert, MD; Westmead Hospital, Westmead, NSW: P.
O’Connell, MD; The Queen Elizabeth Hospital, Woodville South, SA: P.
J Am Soc Nephrol 16: 3027–3037, 2005Blood Pressure Management in Diabetic Nephropathy3035
Phillips, MD; Gosford Hospital, Gosford, NSW: S. Roger, MD; The St.
George Hospital, Kogarah, NSW: J. Kelly, MD, J. Whitworth, MD;
Royal Prince Alfred Hospital, Camperdown, NSW: D. Yue, MD.
Auckland Diabetes Centre, Auckland: P. Drury, MD,
G. Braatvedt, MD, W. Bagg, MD; Dunedin Hospital, Dunedin: P. Man-
ning, FRACP; Middlemore Hospital, Auckland: J. Baker, MD, D. Sim-
Prince of Wales Hospital, Hong Kong: J. Chan, MD;
Queen Mary Hospital, Hong Kong: T.M.D. Chan, MD.
National University of Malaysia Hospital, Kuala Lum-
pur: N. Kong, MD
National University Hospital, Singapore: A.C. Thai, MD.
Veterans General Hospital, Taipei: W.C. Yang, MD.
This study was funded by Bristol-Myers Squibb Pharmaceutical Re-
search Institute and Sanofi-Synthelabo. Funding sources were involved
in the data collection but not in the analysis or interpretation of data, or
in the decision to submit the manuscript for publication.
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Access to UpToDate on-line is available for additional clinical information
J Am Soc Nephrol 16: 3027–3037, 2005 Blood Pressure Management in Diabetic Nephropathy 3037