Measurable Urinary Albumin Predicts Cardiovascular Risk Among Normoalbuminuric Patients With Type 2 Diabetes

Measurable Urinary Albumin Predicts Cardiovascular Risk among Norm...
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458466/?report=printable
J Am Soc Nephrol. 2012 Sep 28; 23(10): 17171724.
Published online 2012 Aug 30. doi: 10.1681/ASN.2012030252
PMCID: PMC3458466
Measurable Urinary Albumin Predicts Cardiovascular Risk among

Normoalbuminuric Patients with Type 2 Diabetes
Piero Ruggenenti,* Esteban Porrini,* Nicola Motterlini,* Annalisa Perna,* Aneliya Parvanova Ilieva,* Ilian Petrov Iliev,*
Alessandro Roberto Dodesini, Roberto Trevisan, Antonio Bossi, Giuseppe Sampietro, Enrica Capitoni, Flavio
Gaspari,* Nadia Rubis,* Bogdan Ene-Iordache,* Giuseppe Remuzzi, * and for the BENEDICT Study Investigators
*Clinical Research Center for Rare Diseases, Aldo & Cele Dacc, Mario Negri Institute for Pharmacological Research, Bergamo, Italy;
Units of Nephrology and

Diabetology and
Research Foundation, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy;

Unit of Diabetology, Treviglio Hospital, Treviglio, Italy; and
Epidemiological Observatory, Azienda Sanitaria Locale della Provincia di Bergamo, Bergamo, Italy
Corresponding author.
P.R. and E.P. contributed equally to this work.
Correspondence: Dr. Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori Science and
Technology Park, Kilometro Rosso Via Stezzano, 87. 24126 Bergamo, Italy., Email: Giuseppe.remuzzi@marionegri.it, Email:
manuela.passera@marionegri.it
Received 2012 Mar 9; Accepted 2012 Jul 11.

Copyright 2012 by the American Society of Nephrology
Abstract
Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with
type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is
unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208
hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes
Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI)
therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to
the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery
revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a
main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently
predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.021.08). Second-degree
polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and
events without thresholds. Considering the entire study population, even albuminuria at 12 g/min was
significantly associated with increased risk compared with albuminuria <1 g/min (HR, 1.04; 95% CI,
1.021.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI
therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and
was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with
type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The
association with risk is continuous but is lost with early ACEI therapy.
Patients with type 2 diabetes mellitus and micro- or macroalbuminuria (i.e., a urinary albumin excretion
[UAE] rate of 20200 g/min or >200 g/min, respectively) have a risk for cardiovascular death that is
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212 times that observed in patients with less albuminuria.1,2 This largely accounts for the excess
cardiovascular mortality observed in patients with diabetes compared with age-matched persons without
the disease.1,3,4 Conversely, diabetic patients with UAE <20 g/min (the upper limit of what is generally
considered the normal range) are supposed to have a cardiovascular risk close to that of the general
population.57 However, this cutoff was introduced a priori in clinical use and research based on the
observation that 95% of normal individuals had excretion rates below that limit.8 Whether this value
reflects a real threshold for cardiovascular risk or whether any measurable amount of albuminuria bears a
significant risk, even within the normal range, is unknown, particularly in the diabetic population. Whether
there is a level for albuminuria that differentiates patients who need cardioprotective intervention from
those with a low risk who are unlikely to be affected by any treatment is also elusive. This is a major health
issue because persons with normoalbuminuria account for the large majority of the diabetic population, and
promptly identifying those at risk and providing them with preventive strategies before they progress to
more severe and possibly irreversible stages of the disease might have major clinical implications.
To address the above issues, we evaluated a large cohort of patients with type 2 diabetes and baseline UAE
<20 g/min who were included in the BErgamo NEphrologic Diabetes Complication Trial
(BENEDICT-A)9 and eventually followed for approximately 10 years. In BENEDICT, at similar BP
control, angiotensin-converting enzyme inhibitor (ACEI) treatment with trandolapril alone or in
combination with the nondihydropyridine calcium-channel blocker verapamil halved the incidence of
microalbuminuria compared with verapamil alone or placebo.9,10
We primarily sought to address whether and to what extent baseline albuminuria was associated with
long-term incidence of fatal and nonfatal cardiovascular events in the above population. Secondarily, we
explored whether earlier treatment with an ACEI translated into more effective cardioprotection in the long
term and whether there was a threshold for baseline albuminuria above which this effect became apparent.
Results
Baseline Characteristics
Median UAE at inclusion was 5.24 (range, 0.4419.85) g/min. UAE exceeded 14 g/min in only 10% of
participants (Table 1). Baseline characteristics of study participants were similar to those of the 139 patients
who did not enter the BENEDICT extension study, with the exception of a higher prevalence of men, lower
hemoglobin A1c (HbA1c), and lower LDL-to-HDL cholesterol ratio in included participants (Supplemental
Table 1). A similar proportion of patients originally randomly assigned in BENEDICT to trandolapril or
non-ACEI therapy was receiving ACEI (87.5%) or statin (50.5%) therapy during the extension study.
Outcomes
During a median follow-up of 9.12 (interquartile range, 6.169.86) years, 168 patients died, 37 (22%) of
cardiovascular causes. Overall, 212 major cardiovascular events were observed in 189 patients.
Primary Composite End-Point Overall,
first onset of a component of the composite end point of major

cardiovascular events was observed in 189 of the 1208 randomly assigned participants (15.6%). In 24 cases
(12.7%), the event was fatal. In addition to 3 sudden-death events (1.6%), there were 105 (55.6%), 39
(20.6%), and 31 (16.4%) events related to coronary, cerebrovascular, or peripheral artery disease,
respectively, and 11 hospitalizations (5.8%) due to worsening of congestive heart failure (Table 2).
Throughout the whole observation period, there were 2.14 patients with the end point event every 100
patients per year. Overall, there were 55 end point events (4 fatal) during BENEDICT-A and 133 (20 fatal)
during the extension study.
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Compared with patients without cardiovascular events, those progressing to the end point were older and
more frequently male, more frequently reported a cardiovascular event before study inclusion, and had
more albuminuria and higher HbA1c and serum LDL-to-HDL cholesterol ratio (Table 1). Other baseline
characteristics (including BP; concomitant antihypertensive, antidiabetic, and lipid-lowering treatment; and
whether patient was allocated to ACEI therapy) were similar between groups with or without end point
events.
Baseline Characteristics and Cardiovascular Risk At
univariable Cox proportional hazards regression

analysis, older age; male sex; a longer duration of diabetes; previous cardiovascular events; and higher
LDL-to-HDL cholesterol ratio, creatinine levels, and albuminuria levels were significantly associated with
a higher risk for new-onset cardiovascular events (Table 3). At multivariable analysis, albuminuria was
significantly associated with risk for cardiovascular events (hazard ratio [HR], 1.06; 95% confidence
interval [CI], 1.021.08). On average, for 1 g/min excess of albuminuria at baseline there was a 6% risk
for progression to the end point on follow-up. Other independent predictors of events were older age, male
sex, previous cardiovascular events, higher HbA1c levels, and higher LDL-to-HDL cholesterol ratio. No
significant interaction between albuminuria and the other baseline covariates was observed. The
assumption of proportionality was not violated (Schoenfeld residuals: P=0.26).
The second-degree polynomial transformation of albuminuria described the relationship with the
cardiovascular end point with lower deviance (best goodness of fit) than the first degree (logarithmic)
transformation (931.32 versus 934.27, respectively). Modeling baseline albuminuria by second-degree
polynomial transformation in the multivariable analysis showed a continuous nonlinear relationship
between albuminuria and cardiovascular events (Figure 1). A significant excess risk for progression to the
end point was already evident for a UAE ranging from 1 to 2 g/min compared with an excretion <1
g/min (HR, 1.04; 95% CI, 1.021.07) taken as the reference value. The risk for events compared with the
reference albuminuria level tended to plateau (HR, 2.49; 95% CI, 1.564.00) between albuminuria values
of 13 and 14 g/min (Figure 1 and Supplemental Table 2). Results were similar when baseline albuminuria
was modeled with a spline function (data not shown). Cardiovascular risk at higher levels of albuminuria
was not considered because of the too small number of patients and events.
Sensitivity Analyses Relationships
between albuminuria and outcomes similar to those described in the

whole study group were observed when the analyses were restricted to low-risk patients without a history
of cardiovascular events at inclusion or with persistent normoalbuminuria throughout BENEDICT, as well
as when cardiovascular events were considered independent of revascularizations and amputations or when
only coronary events were analyzed (data not shown). Unlike BP, albuminuria at the end of
BENEDICTthat is, at baseline of the extension studypredicted cardiovascular events on subsequent
follow-up at univariate or multivariable analyses (odd ratios, 1.41 [95% CI, 1.151.74], P=0.001, and 1.29
[95% CI, 1.041.60], P=0.001, respectively). Consistently, patients with persistent low-range compared
with those with persistent high-range normoalbuminuria (i.e., albuminuria <1 SD or >1 SD of the mean at
baseline or at BENEDICT last visit, respectively) had a three-fold lower incidence of cardiovascular events
during the extension study (8% versus 24%; P=0.027).
Baseline characteristics of patients who had been originally

allocated to ACEI therapy with trandolapril alone or combined with verapamil in BENEDICT were similar
to those of patients randomly assigned to non-ACEI therapy with verapamil alone or placebo.11 Eighty-four
of the 603 patients (13.9%) originally randomly assigned to ACEI therapy had at least one major
cardiovascular event compared with 105 of the 605 patients (17.4%) randomly assigned to non-ACEI
therapy (P=0.08). During BENEDICT, 27 (4.5%) participants receiving ACEI therapy progressed to the
end point compared with 28 (4.6%) receiving non-ACEI therapy (P=0.49). During the extension study,
however, 57 patients receiving ACEI therapy progressed to the end point compared with 77 receiving
Cardiovascular Risk According to ACEI Therapy
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non-ACEI therapy, and the incidence of events was significantly lower in those with ACEI (9.5% versus
12.7%; P=0.043).
As in the study group considered as a whole, a continuous significant incremental risk for cardiovascular
events for each 1 g/min increase in albuminuria at baseline was observed in patients originally randomly
assigned to non-ACEI therapy considered separately. Again, in this group a significant increase was already
evident for a UAE ranging from 1 to 2 g/min compared with <1 g/min (HR, 1.02; 95% CI, 1.011.074)
taken as the reference value. The risk for events tended to plateau (HR, 3.15; 95% CI, 1.765.63) between
albuminuria values of 13 and 14 g/min (Figure 2 and Supplemental Table 2). Of note, however, in patients
originally randomly assigned to ACEI therapy, the risk for major cardiovascular events was uniformly low
at any considered level of albuminuria at baseline, and no significant association was observed between any
increment in albuminuria and cardiovascular events during the whole study period (Figure 2 and
Supplemental Table 2).
Discussion
In this longitudinal observational study of >1000 patients with type 2 diabetes and normoalbuminuria, we
found a continuous relationship between UAE rate at inclusion and incidence of major cardiovascular
events during approximately 10 years of follow-up. For each 1 g/min excess in baseline albuminuria, there
was a progressive incremental risk for cardiovascular events up to a UAE of 1314 g/min. Above this
level, the number of patients was too small to evaluate any relationship between albuminuria and events.
The incremental risk for events, compared with the reference risk observed with a UAE <1 g/min, was
already evident at an excretion rate ranging from 1 to 2 g/min. The incremental incidence of
cardiovascular events observed for each 1 g/min excess in baseline UAE was significant in the study
group as a whole as well as in the subgroup of patients who had been originally randomly assigned in
BENEDICT to non-ACEI therapy with verapamil alone or placebo. Of note, however, the association
between albuminuria and events was not significant in patients who had been randomly assigned to ACEI
therapy with trandolapril alone or in combination with verapamil. Actually, in this subgroup the risk for
events was uniformly low, independent of the extent of albuminuria at baseline.
The above findings were not explained by differences in patient characteristics or concomitant treatments
because demographic, clinical, and laboratory variables at baseline, as well as targets for antihypertensive,
antidiabetic, and lipid-lowering therapy throughout the whole observation period, were similar between
treatment groups. Thus, the finding that patients originally randomly assigned to trandolapril during
BENEDICT tended to have fewer cardiovascular events than those who received the same treatment only
after inclusion in the extension study was consistent with the hypothesis that early ACEI therapy is more
cardioprotective than late intervention. These datawhich require confirmation in ad hoc prospective
studiesextend previous evidence of sustained long-term benefit of early intensified metabolic control in
an extension study of the Diabetes Control and Complications Trial12 and suggest that the same memory
effect could apply also to ACEI, as already observed in the Heart Outcomes Prevention Evaluation (HOPE)
study extension.13
A qualifying aspect of the present study was that for the first time evidence for a continuous relationship
between albuminuria and risk was formally provided in patients with normoalbuminuria to start with. The
HOPE study14 found that in patients at increased cardiovascular risk, the relationship between albuminuria
and cardiovascular events extended to as low as 0.5 mg of urinary albumin for 1 mmol of urinary
creatinine, while the Losartan Intervention For End-point reduction in hypertension (LIFE) study15 found a
similar relationship between albuminuria and events among patients with left ventricular hypertrophy. The
Framingham Heart Study showed that 6-year risk for cardiovascular disease was three-fold higher in
nonhypertensive, nondiabetic persons with a urinary albumin-to-creatinine ratio above the sex-specific
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median (3.9 mg/min for men and 7.5 mg/min for women) than in those with a ratio below that level.16
Consistently, the Prevention of Renal and Vascular End Stage Disease (PREVEND) study found that
independent of the effects of other cardiovascular risk factors, UAE was a predictor of cardiovascular
mortality in the general population; the excess cardiovascular risk was already apparent at levels currently
considered to be normal.7 All the preceding studies, however, included patients with a UAE ranging from
very low levels, in the so-called normoalbuminuric range, to the micro- and even macroalbuminuric ranges.
Thus, those results were largely driven by the well known association between micro- or macroalbuminuria
and excess cardiovascular risk. Conversely, the present study allows us to conclude that, as for BP, the
concept of a threshold level to define normality is inconsistent with available data17 and that any degree of
measurable albuminuriathat is, a urinary albumin concentration close to the detection limit (12 g/ml)
of the methods commonly used to measure urinary albumin (such as nephelometry or immunoturbidimetry)
bears a significant risk for cardiovascular events.
The preceding findings may have practical implications because albuminuria can be reduced by
amelioration of insulin sensitivity,18 weight loss,19 BP, and blood glucose reduction20 and reninangiotensin system inhibitor therapy.9,21 In the long run, these interventions are expected to prevent or
delay end-organ damage.22 However, whether the above interventions are uniformly beneficial throughout
the whole range of normoalbuminuria (or, rather, whether there is a threshold below which specific
intervention is not associated with appreciable benefits) is unknown.
In this regard, it is noteworthy that in this study, the relationship between albuminuria and cardiovascular
events was not appreciable in patients allocated to ACEI therapy during BENEDICT. Actually, in this
treatment group baseline albuminuria was no longer predictive of cardiovascular events throughout the
whole observation period. This was probably explained by a trend toward a progressively larger
cardioprotective effect of trandolapril for progressively increasing levels of albuminuria. Independent of the
above, during the extension study we observed fewer events in patients who had been originally randomly
assigned to ACEI therapy at inclusion in BENEDICT than in those who started ACEI therapy only after
conclusion of the trial. These findings extend previous and more robust data from HOPEThe Ongoing
Outcomes study showing that the protective effect of ACEI therapy against cardiovascular events observed
during the HOPE trial was sustained during 2.6 years extended follow-up, while all patients were receiving
the same ACEI therapy.13 These findings led the authors to suggest that the 4.5 years of initial earlier use
of ramipril therapy during the HOPE trial provided greater cardioprotection compared with later
initiation,13 possibly because of benefits on endothelial or vascular structure and function that persisted
beyond the blinded treatment period of the trial.23 Conceivably, the above considerations could apply also
to our study population.
The major limitation of this study is that this was an extension of a clinical trial originally designed for
other purposes. Thus, study findings are hypothesis generating and need to be tested in ad hoc prospective
studies. However, extension data could be recorded on the basis of preplanned monitoring guidelines in
almost 90% of patients completing BENEDICT, and exhaustive survival data could be obtained by the
Health Authorities Registry. Moreover, baseline characteristics of patients with or without extension data
were similar, as well as their original allocation to ACE or non-ACEI therapy. A major strength is the
centralized measurement of albuminuriaalong with all other laboratory variablesby gold standard
procedures in triplicate overnight urine collections.9,10,24 Study findings may be widely generalizable
because outcome data were observed in patients with type 2 diabetes with normoalbuminuria and
hypertension, a type of patient representing at least 90% of the whole diabetic population. In addition, the
follow-up was the longest among similar studies thus far reported that considered the relationship between
baseline albuminuria and cardiovascular outcomes in patients with or without diabetes. Finally, consistency
of the results obtained by using fractional polynomial models or spline functions provided additional
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evidence of the robustness of the study findings. Another unique strength was that, unlike data from
previous series in the general population7,16 or in patients with left ventricular hypertrophy15 or increased
cardiovascular risk14 that included also patients with micro- or macroalbuminuria (who most likely drove
the study findings), our present data definitely confirmed the independent predictive value of albuminuria
in a pure population of patients with type 2 diabetes and normoalbuminuria. Whether the above findings
can be generalized to nonwhite populations or to persons without diabetes is matter of investigation.
In conclusion, in patients with type 2 diabetes and normoalbuminuria, any degree of measurable urinary
albumin bears a significant risk for cardiovascular events. The association between albuminuria and risk is
continuous, and there is no threshold level that distinguishes patients at risk from those who are protected
from cardiovascular disease. This incremental risk almost fully dissipates with early ACEI therapy. Future
randomized trials are needed to identify levels of albuminuria above which cardioprotective therapy is
appreciably beneficial in this population.
Concise Methods
The BENEDICT Extension Study
BENEDICT-A has been described elsewhere.9,10,24 In brief, from 1997 to 2000, a total of 1209 patients
with type 2 diabetes and hypertension, normoalbuminuria, creatinine <1.5 mg/dl, and HbA1c <11% were
randomly assigned to trandolapril, verapamil, their combination, or placebo in order to prevent
microalbuminuria. The current study was a preplanned extension study of BENEDICT-A that consisted of
clinical, laboratory, and case record evaluations until December 31, 2008. Finally, the Registry of the
Health District provided fatal events and causes of deaths. On the basis of BENEDICT results, after the
trial (January 2004), all patients received an ACEI. Overall, outcome data from BENEDICT with or
without extension data were available for 1056 of the 1208 patients (87.4%) (Supplemental Figure 1).
Definitions and Measurements
Baseline normoalbuminuria was defined as UAE <20 g/min for two of three overnight urine collections,
and the median of the three measurements was used for analysis. Progression to microalbuminuria was
diagnosed in patients with UAE 20 g/min and <200 g/min in two of three measurements.
Cardiovascular Outcomes
The main outcome was the first onset of a component of a composite end point of fatal (including sudden
death) or nonfatal major cardiovascular events, such as coronary (acute myocardial infarction, unstable
angina pectoris, or coronary revascularization by bypass grafting or percutaneous angioplasty),
cerebrovascular (stroke, transient ischemic attack, precerebral artery revascularization), or peripheral
vascular (amputation, revascularization) disease and hospitalizations due to congestive heart failure. All
events were defined a priori and were adjudicated under blind conditions by P.R. and E.P.
Secondary outcomes were spontaneous components of the composite end point and coronary events.
Statistical Analyses
The relationships between baseline albuminuria and cardiovascular events were evaluated by Cox
proportional hazards models. Confounders included baseline variables with a proven or possible
association with the outcome, such as age, sex, duration of diabetes, smoking, history of cardiovascular
events, body mass index, serum creatinine, HbA1c levels, randomization to ACEI therapy during the core
trial, mean arterial pressure, LDL-to-HDL cholesterol ratio, triglyceride and uric acid levels, and treatment
with lipid-lowering therapy. Continuous variables, including albuminuria, were kept continuous.
Colinearity was tested by Pearson correlation coefficient; when colinearity was found, only one variable
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(HbA1c instead of glucose, LDL cholesterol instead of total cholesterol) or a surrogate (mean for systolic or
diastolic BP and the LDL-to-HDL ratio for both components of the ratio) was used. Variables with a
nonlinear association with risk (LDL-to-HDL ratio, albuminuria, and HbA1c and creatinine levels) were
log-transformed. The proportionality assumption was assessed using the log-rank and the weighted
Schoenfeld residuals, and model goodness of fit was assessed by the Hosmer-Lemeshow test.
Multivariable analysis was also performed by modeling baseline albuminuria with the fractional
polynomial algorithm method (first and second degree), or a spline function, two flexible and informative
approaches for the evaluation of possible nonlinear relationships between continuous variables and
outcomes.25,26 In preplanned sensitivity analyses, multivariable models were restricted to low-risk patients:
those without previous cardiovascular events (n=1156) and those persistently normoalbuminuric
throughout BENEDICT (n=1107). Finally, analyses separately considered data from BENEDICT and the
extension study and from patients originally randomly assigned to ACEI therapy or not. Data were
analyzed using SPSS software, version 17.0.1, for Windows (SPSS, Inc., Chicago, IL) and Stata software,
version 11.0 (fracpoly command; Stata Corp., Cary, NC).
Disclosures
None.
Supplementary Material
Supplemental Data:
Acknowledgments
The authors are indebted to the staff of the Diabetology Units and of the Clinical Research Center for Rare
Diseases Aldo & Cele Dacc of the Mario Negri Institute for their assistance in the selection of and care
for the patients in this study; to Diletta Valsecchi for monitoring the data handling; and to Manuela Passera
for assistance with the preparation of the manuscript.
Abbott (Ludwigshafen, Germany) sponsored BENEDICT. E.P. is the recipient of a long-term fellowship
from the European Renal AssociationEuropean Dialysis Transplant Association, which allowed him a
postdoctoral position in the Mario Negri Institute.
This study was an academic, internally funded study. No sponsor or company was involved in the data
recording; study design, analysis, interpretation, and reporting; manuscript preparation; or decision to
submit the article for publication. For a complete list of study investigators, see the Supplemental Material.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
See related editorial, Urinary Albumin: How Low Is Normal?, on pages 16051607.
This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681

/ASN.2012030252/-/DCSupplemental.
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Figures and Tables
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Table 1.
Baseline characteristics of the overall study group and of patients with or without major cardiovascular
events during follow-up
Characteristic
Patients, n (%)
Age (yr)
Men, n (%)
History of cardiovascular events

Known duration of diabetes (yr)
Overall
Without Events
With Events
P Valuea
62.338.05
61.858.12
64.927.15
<0.001
34 (3.3)
18 (9.5)
<0.001
0.20
1208
638 (52.8)
52 (4.3)
1019 (84.4)
521 (51.1)
189 (15.6)
117 (61.9)
6 (311)
6 (211)
7 (312)
Never smoked
700 (57.9)
600 (58.9)
100 (52.9)
Current smoker
146 (12.1)
117 (11.5)
29 (15.3)
Smoking status, n (%)

Former smoker
2
Body mass index (kg/m )
362 (30.0)
302 (29.6)
60 (31.7)
0.004
0.18
29.084.72
29.164.72
28.664.68
0.19
Systolic
150.8214.16
150.7714.17
151.1014.16
0.77
Mean
108.588.35
108.668.21
108.179.07
Glucose (mg/dl)
161.3447.05
Total
LDL
Trough BP (mmHg)
Diastolic
Glycosylated hemoglobin (%)

Cholesterol (mg/dl)
HDL
Triglycerides
Serum creatinine (mg/dl)

Uric acid (mg/dl)
Albuminuria (g/min)
Allocation to study treatments, n (%)

Placebo
Verapamil
Trandolapril
Verapamil plus trandolapril
Use of antihypertensive agents, n (%)b

Number of antihypertensive agentsc
87.467.63
86.608.44
0.13
160.0046.67
6.161.37
168.5248.57
<0.001
209.7836.74
209.0537.21
213.6733.93
0.11
162.7536.05
161.6036.36
168.8233.81
0.900.16
0.900.15
0.930.17
5.791.37
46.9412.06
125 (91181)
4.091.18
87.607.47
5.731.36
47.2912.11
124 (91177)
5.011.19
0.03
45.0611.65
0.02
134 (91194)
0.12
5.001.13
0.90
0.01
0.02
5.24 (3.59.3)
5.09 (3.58.7)
7.08 (3.711.6)
<0.001
302 (25.0)
258 (25.3)
44 (23.3)
0.15
302 (25)
259 (25.4)
43 (22.8)
664 (55.0)
556 (54.6)
108(57.1)
303 (25.1)
301 (24.9)
2 (12)
243 (23.8)
259 (25.4)
2 (12)
60 (31.7)
42 (22.2)
2 (13)
Antilipidemic agents, n (%)
138 (11.4)
119 (11.7)
19 (10.0)
Duration of follow-up (yr)
9.12 (6.169.86)
9.09 (6.09.81)
9.28 (7.710.10)
Aspirin, n (%)
0.45
28 (2.3)
17 (1.7)
11 (5.8)
0.32
0.28
0.30
0.002
0.03
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Data are numbers, percent values, mean SD, or median (interquartile range).
aWith versus without events.

b
Different from the study treatments.

Including the study treatments.
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Table 2.
Patients with first-onset fatal or nonfatal major cardiovascular events (primary end point)
Event
Coronary heart disease (n=105)
Patients (n)
Unstable angina pectoris
14
Acute myocardial infarction
46
Unstable angina pectoris + stenting/revascularization

Acute myocardial infarction + stenting/revascularization
40
5
Congestive heart failure
11
Stroke
24
Sudden death
Stroke or transient ischemic attack (n=39)

Transient ischemic attack
Peripheral vascular disease (n=31)
15
Severe carotid obstruction
Severe peripheral obstruction
Severe carotid obstruction + stenting or angioplasty

Severe peripheral obstruction + stenting or bypass surgery
Total
10
189
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Table 3.
Univariate and multivariable Cox proportional hazards regression analysis of covariates versus the primary
end point (major cardiovascular events)
Covariates
Age
Female versus male
Duration of diabetes
History of cardiovascular disease
Univariate Analysis
HR (95% CI)
P Value
1.46 (1.091.96)
0.01
1.05 (1.031.07)
1.02 (1.0021.043)
0.11
1.25 (0.811.92)
0.16
HbA1ca
2.87 (1.565.27)
0.001
a
LDL-to-HDL cholesterol ratio
Triglycerides
Serum creatinine
UAE
Uric acid
Allocation to ACEI
Use of lipid-lowering therapy
0.31
1.93 (1.26 2.94)
0.002
2.54 (1.105.85)
0.03
1.001 (0.9991.003)
0.02
0.99 (0.971.02)
0.96 (0.951.009)
0.99 (0.971.008)
1.58 (1.072.32)
0.03
Body mass index

Mean BP
P Value
1.06 (1.041.08)
<0.001
1.38 (0.932.04)
OR (95% CI)
<0.001
3.02 (1.854.91)
Smoker status
Multivariable Analysis
<0.001
0.88
2.97 (1.794.93)
<0.001
0.99 (0.961.03)
0.65
0.98 (0.961.00)
3.17 (1.556.48)
0.31
0.05
0.002
2.03 (1.213.39)
0.007
0.86 (0.312.42)
0.78
0.07
1.00 (0.991.002)
1.055 (1.0261.086)
<0.001
1.05 (1.021.08)
0.002
0.818 (0.6141.089)
0.17
0.84 (0.631.13)
0.25
1.002 (0.8911.127)
0.857 (0.5331.377)
0.97
0.52
1.01 (0.881.16)
0.79 (0.481.29)
0.90
0.90
0.34
OR, odds ratio.
Variables log-transformed.
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Figure 1.
Adjusted HRs for major cardiovascular events according to baseline albuminuria. Solid line shows estimated relation when
logarithmic hazard is modeled as linear function of log (UAE). The reference value (HR = 1) is set at UAE = 1 g/min.
The shaded area includes the 95% CIs for more general functional relation, as estimated by P-splines. The HRs are
adjusted for age, sex, duration of diabetes, history of cardiovascular events, smoking habit, body mass index, mean BP,
logarithms of HbA1c, LDL-to-HDL cholesterol ratio, triglyceride and serum creatinine levels, and whether patient was
allocated to ACEI therapy. CVD, cardiovascular disease.
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Figure 2.
Adjusted HRs for major cardiovascular events according to baseline albuminuria in patients who during the BENEDICT
trial had been randomly allocated to ACEI therapy with trandolapril alone or combined to verapamil (solid line) or to
non-ACEI therapy with verapamil alone or placebo (dashed line). The lines show estimated relation when logarithmic
hazard is modeled as linear function of log (UAE). The reference value (HR = 1) is set at UAE = 1 g/min. The HRs are
adjusted for age, sex, duration of diabetes, history of cardiovascular events, smoking habit, body mass index, mean BP,
logarithms of HbA1c, LDL-to-HDL cholesterol ratio, triglyceride and serum creatinine levels, and whether patient was
allocated to ACEI therapy. CVD, cardiovascular disease.
Articles from Journal of the American Society of Nephrology : JASN are provided here courtesy of American
Society of Nephrology
7/08/2015 2:52 a. m.

Measurable Urinary Albumin Predicts Cardiovascular Risk Among Normoalbuminuric Patients With Type 2 Diabetes

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J Am Soc Nephrol. 2012 Sep 28; 23(10): 17171724.

Published online 2012 Aug 30. doi: 10.1681/ASN.2012030252