Microalbuminuria as a marker of cardiovascular and

renal risk in type 2 diabetes mellitus: a temporal

perspective
James T. Lane
Am J Physiol Renal Physiol 286:F442-F450, 2004. ;
doi: 10.1152/ajprenal.00247.2003

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 Am J Physiol Renal Physiol 286: F442–F450, 2004;
Invited Review 10.1152/ajprenal.00247.2003.

Microalbuminuria as a marker of cardiovascular and renal risk

in type 2 diabetes mellitus: a temporal perspective
James T. Lane
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-3020

Lane, James T. Microalbuminuria as a marker of cardiovascular and renal risk

in type 2 diabetes mellitus: a temporal perspective. Am J Physiol Renal Physiol 286:
F442–F450, 2004; 10.1152/ajprenal.00247.2003.—Microalbuminuria is a marker
for diabetic nephropathy. It also signifies cardiovascular disease, as well as
nephropathy, in type 2 diabetes (DM2). Microalbuminuria may precede DM2,
occurring with the insulin resistance syndrome and its components, including
obesity and hypertension. Other indicators of cardiovascular risk, such as markers
of inflammation, are associated with microalbuminuria in populations of patients
with and without diabetes. With the rising prevalence of DM2 in minority youth,

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especially in Native Americans, a marker for future disease risk would allow earlier
prevention strategies to be tested. Before microalbuminuria can be used in a
prevention strategy, more needs to be known about the mechanism(s) of the
association between elevated excretion, its relationship to glucose intolerance, and
its relative contribution to cardiovascular and renal disease. These questions are
especially applicable as we begin to observe the long-term complications of
diabetes in youth.
insulin resistance; American Indians; young adults

MICROALBUMINURIA IS A MARKER for diabetic nephropathy and
cardiovascular disease in patients with type 1 (DM1) and type
2 (DM2) diabetes mellitus (12, 81–83, 91, 119). Microalbu-
minuria refers to the excretion of albumin in the urine at a rate
that exceeds normal limits but is less than the detection level
for traditional dipstick methods (4). Microalbuminuria has
been utilized as a screening test for the presence of diabetes-
related kidney disease in patients with DM1. Results are
expressed as milligrams per 24-h urine specimen, micrograms
per minute in a timed urine specimen, or as micrograms per
milligram creatinine in a random spot urine test (4). Detection
of microalbuminuria is important from a clinical standpoint
because, once detected, it is an indication for the initiation of
anti-angiotensin II therapy with the purpose of preventing or
delaying the advance of progressive diabetic nephropathy (4,
10, 70, 79, 89, 90). Although the positive predictive value of
microalbuminuria for progressive diabetic nephropathy is less
than once thought, it remains a standard clinical test with
important ramifications for patient management (12).
As noted below, the development of diabetes-related kidney
disease is similar in patients with DM1 and DM2 (88). How-
ever, issues involving the time course of the process are blurred
by the insidious onset of DM2. In patients with DM2, it has
become evident that microalbuminuria is also a predictor of
cardiovascular death (81). However, the presence of mi-
croalbuminuria in DM2 may be more reflective of generalized
vascular disease than diabetic glomerulopathy.
The past 10 years have seen a troubling increase in the
prevalence of DM2 in youth (29, 34, 71, 102, 114). This
epidemic of DM2 in youth has preferentially affected ethnic
Address for reprint requests and other correspondence: J. T. Lane, Dept. of
Medicine, Nebraska Medical Center, Omaha, NE 68198-3020 (E-mail:
jtlane1@unmc.edu).
F442 0363-6127/04 $5.00 Copyright © 2004 the American Physiological Society
minorities (29, 71). The long-term implications for micro- and
macrovascular disease and quality of life are enormous. In an
effort to understand the development of DM2 in youth, high-
risk populations are being closely monitored with emphasis on
early markers of disease. The goal is the development of
treatment strategies that will prevent or change the natural
history of diabetes and its complications.
The goal of this review is to summarize the evidence
supporting an association of microalbuminuria with conditions
that may occur before the development of DM2 in high-risk
populations, including obesity, the insulin resistance syn-
drome, and impaired glucose tolerance. First Nation (Canadian
North American Indians) and American Indians in North
America are highlighted as an example of a high-risk popula-
tion, but similar data exist for other ethnic groups at high-risk
for DM2, including African Americans and Hispanics (36). It
is clear that cardiovascular risk and disease begin before the
diagnosis of DM2 in patients with insulin resistance and can be
accelerated in young adults. The challenge is to learn more
about the temporal pattern of disease markers that reflect
disease evolution and why they occur, choose appropriate
strategies for intervention, and conduct clinical trials that will
prevent both cardiovascular and renal disease in patients at
risk.
NATURAL HISTORY OF MICROALBUMINURIA
IN DM1 DIABETES
Microalbuminuria is not usually a presenting finding at the
onset of DM1. After a 5- to 10-yr duration of diabetes,
susceptible patients develop intermittent microalbuminuria be-
fore having persistent microalbuminuria (84). Improved blood
glucose control (23a, 110, 117a), antihypertensive therapy, and
anti-angiotensin II therapy (10, 27a, 67, 70, 74, 77, 80a, 90,
120) have been shown to delay or prevent the progression of
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MICROALBUMINURIA AND CV/RENAL RISK
microalbuminuria and the development of nephropathy. In
DM1, microalbuminuria is a strong risk factor for the devel-
opment of nephropathy. The development of microalbuminuria
is associated with established extracellular matrix expansion in
the glomerular and tubulointerstitial compartments of the kid-
ney (69). The natural history results in progressive glomerulo-
sclerosis, increasing proteinuria, and chronic renal failure. The
long period between the onset of microalbuminuria and chronic
renal failure (in years) offers a substantial window for thera-
peutic intervention (117).
Recent data suggest that microalbuminuria in DM1 may
regress over time. Perkins et al. (94) reported data from the
Joslin Clinic on 386 patients with DM1 who were followed for
8 yr (Table 1). Regression was defined as a 50% decrease in
albumin excretion from one 2-yr study period to the next 2-yr
study period and occurred in 58% of the patients (94). Inter-
Invited Review
F443
estingly, regression was not associated with angiontensin-
converting enzyme inhibitor use but was associated with gly-
cosylated hemoglobin levels of ⬍8%, systolic blood pressure
of ⬍115 mmHg, and low levels of cholesterol and triglycer-
ides. If regression occurs with this frequency, it brings into
question the underlying mechanism(s) and true specificity for
microalbuminuria as a marker for progressive renal impair-
ment.
NATURAL HISTORY OF MICROALBUMINURIA IN DM2
Because of the insidious onset of DM2, the true duration of
the disease is often not known. It has been reported that a
duration of ⬎6 yr of diabetes may have existed before diag-
nosis (46). Because of the variable duration of disease at
diagnosis, subjects often present with microalbuminuria at that

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Table 1. Human clinical studies of microalbuminuria
Study/Ref. No. Study Question Study Group Design Results

Perkins et al. Determine the rate of DM1 patients with MA: 386 Prospective measurement of As defined by 50% reduction in MA
(84) regression of MA patients MA with retrospective from one 2-yr period to the next,
analysis 58% of patients had regression.
Framingham Determine the relationship Population study with DM2 OGGT, clinical characteristics, MA was associated with
Offspring between insulin excluded, age 28–82 yr; 1,592 and MA determinations were hyperinsulinemia and other CV
Study (70) resistance and MA subjects made as part of a larger risk factors.
study
Groop et al. Determine the impact of DM2 and controls; 52 DM2 and Euglycemic glucose clamp, Insulin sensitivity was indirectly
(33) MA and hypertension 19 healthy controls AER, and BP measurements related to MA, hypertension, or
on insulin sensitivity both.
Botnia Study Determine the CV risk Family study of DM2 in Finland Assessment of CV mortality CV death rate was three fold higher
(50) associated with the and Sweden; 4,483 subjects over time in subjects with the metabolic
metabolic syndrome (1,697 DM2, 798 IGT, and syndrome. MA was the strongest
1,988 NGT) risk for CV death.
Mexico City Determine whether MA Nondiabetic subjects studied for Cross-sectional study of OGTT, Parental DM2 and IGT were
Diabetes defines the prediabetic CV risk factors; 1,298 MA determinations on associated with MA. Subjects with
Study (23a) state subjects subjects MA more likely to be
hypertensive, dyslipidemic.
Insulin Determine the relationship Nondiabetic subjects; 982 Cross-sectional population Insulin resistance is related to MA
Resistance between MA and subjects, 40–69 yr old study where individuals had and is dependent on blood
Atherosclerosis insulin sensitivity IVGTT with minimal model pressure, glucose level, and
Study (77) and determination of AER obesity.
Hoom Study Determine whether MA is General population of Cross-sectional population MA was associated with
(51) part of the insulin Caucasians, age 50–75 yr; study with OGTT, AER hypertension but not the other
resistance syndrome 622 subjects determinations parts of the metabolic syndrome.
DESIR- Determine whether MA is Population study, age 30–64 yr; Study of baseline parameters MA is associated with CV risk and
Study(117a) associated with CV risk 3,878 subjects from a prospective study insulin resistance in men but not
and insulin resistance in consistently in women.
men and women
Inter-Tribal Determine the association Native Americans attending A cross-sectional survey from MA was found in 15% of subjects.
Heart between MA and Indian Health Service clinics; three reservations, including Components of the insulin
Project (47) insulin resistance 934 subjects history, exam, and AER resistance syndrome are associated
syndrome among with MA.
nondiabetic Native
Americans
Nurses’ Health Determine whether the Female nurses free of CV Prospective follow-up over 20 Risk for CV disease began 15 yr
Study (48) risk of CV disease is disease at baseline, age 30–55 years before the diagnosis of DM2.
elevated before yr; 117,629 subjects
diagnosis of DM2 in
women
HOPE Study Determine the predictive Subgroup of total HOPE cohort, Retrospective analysis of AER People with and without DM2 at risk
(65) value of MA for with and without DM2; 7,674 in participants with baseline for CV disease are at risk for
advancing proteinuria subjects and follow-up AER. increasing albuminuria, and this
and renal insufficiency Randomized to ramapril or can be prevented by ramipril.
placebo
MA, microalbuminuria; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes mellitus; OGTT, oral glucose tolerance test; CV, cardiovascular; IGT, impaired
glucose tolerance; NGT, normal glucose tolerance; AER, albumin excretion rate; DESIR, Data from an Epidemiological Study on the Insulin Resistance
Syndrome; HOPE, Heart Outcomes and Prevention Evaluation.

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Invited Review
F444 MICROALBUMINURIA AND CV/RENAL RISK
point. However, diabetic nephropathy in DM2 is similar to
nephropathy in DM1 with similar pathology, response to in-
terventions of glucose control and anti-angiotensin II therapy,
and progression to chronic renal failure (12, 99). DM2 with
nephropathy involves a similar proportion of patients, com-
pared with DM1 (49). At present, there is not a similar
long-term study evaluating regression in DM2 as described
above for DM1. However, data taken from recent intervention
studies using angiotensin II receptor antagonists demonstrate
some regression. Lewis et al. (70) reported on the use of
irbesartan in patients with DM2 and nephropathy. A 33%
decrease in proteinuria was seen over 2.6 yr, whereas the
placebo group decreased 10%. A similar study using losartan
in DM2 and nephropathy found a reduction of 35%, whereas
the placebo group had a rise in proteinuria (10). Parving et al.
(90) reported on the use of irbesartan in a population of
hypertensive patients with DM2 and microalbuminuria and
found that microalbuminuria was decreased by 38% over 2 yr
with only a change of 2% in the controls. Attempts at preven-
tion of nephropathy in DM2 have focused on the prevention of
microalbuminuria, the earliest clinical hallmark of nephropa-
thy, or its progression to macroalbuminuria (89, 99). In gen-
eral, the evolution of nephropathy in DM2 is similar to what is
found with DM1.
MICROALBUMINURIA IS ASSOCIATED
WITH CARDIOVASCULAR DISEASE
Microalbuminuria has been associated with increased car-
diovascular mortality in populations of both diabetic and non-
diabetic subjects (43, 57, 81, 125). In fact, microalbuminuria
has been used as a marker of cardiovascular disease, along with
other risk factors found in the insulin resistance syndrome.
Data from the Framingham Offspring Study suggest that mi-
croalbuminuria is more likely to be present with additional
cardiovascular risk factors (78). The premise is that microalbu-
minuria is a marker of generalized endothelial dysfunction.
Microalbuminuria has been linked to increased transcapillary
albumin leakage and increased von Willebrand factor and other
markers of endothelial dysfunction (59, 106). In survivors of
myocardial infarction, both albuminuria and the transvascular
escape rate of albumin are increased (58). Albuminuria has
also been shown to predict the severity of atherosclerosis (86,
116). Others have suggested that the elevated insulin levels that
occur with insulin resistance increase glomerular hemody-
namic pressures that increase albumin excretion (16, 115). The
relative contribution of underlying vascular disease vs. diabetic
nephropathy toward microalbuminuria is not clear. However, a
large body of evidence suggests that microalbuminuria is an
indicator of both micro- and macrovascular disease.
Cross-sectional studies have clearly demonstrated the pres-
ence of microalbuminuria with other markers of the insulin
resistance syndrome. Using clamp studies, hypertension alone
was found to associate with a decrease in glucose disposal by
27% (37). However, the combination of microalbuminuria and
hypertension was associated with the greatest decrease in
glucose disposal. The highest triglycerides and the lowest
HDL-C levels, additional markers of the insulin resistance
syndrome, were associated with patients having hypertension
and microalbuminuria. In the Botnia Study, 84% of those with
DM2 had elements of the insulin resistance syndrome (obesity,
AJP-Renal Physiol • VOL
hypertension, dyslipidemia, or microalbuminuria) (55). If
present, the insulin resistance syndrome increased the risk for
coronary artery disease and stroke threefold. However, mi-
croalbuminuria was the strongest risk for cardiovascular death.
Of those with normal glucose tolerance, 10% had microalbu-
minuria, suggesting the potential for microalbuminuria as a
marker for the risk of coronary artery disease in nondiabetic
individuals. This is such an important association that the
World Health Organization has included microalbuminuria in
its definition of the metabolic syndrome (2).
MICROALBUMINURIA AS A RISK FACTOR
IN NONDIABETIC PEOPLE
A number of studies have demonstrated that microalbumin-
uria occurs in individuals without diabetes. In the Mexico City
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Diabetes Study, nondiabetic people with microalbuminuria
were more likely to have a family history of diabetes (42).
Similar findings were reported by in the Botnia study, where
first-degree relatives of patients with DM2 demonstrated insu-
lin resistance in association with elevated albumin excretion
rates (32). In the Insulin Resistance Atherosclerosis Study,
patients with microalbuminuria were more insulin resistant and
had higher fasting insulin concentrations compared with pa-
tients without microalbuminuria (87). However, the relation-
ship was also partially dependent on blood pressure and obe-
sity. Although the bulk of the data supports microalbuminuria
as being a component of the insulin resistance syndrome, not
all results support this contention (56). The Hoorn Study
evaluated a homogenous Caucasian population and found that
microalbuminuria was associated with hypertension, DM2, and
waist-hip ratio. It did not, however, associate with other com-
ponents of the insulin resistance syndrome. This raises the
alternative view that microalbuminuria is associated with hy-
pertension but not the insulin resistance syndrome. In Data
from an Epidemiological Study on the Insulin Resistance
Syndrome findings, the cardiovascular events were greater in
subjects with microalbuminuria (45). However, in contrast to
men, women did not show the same increased cardiovascular
risk with the addition of microalbuminuria. A similar trend was
seen in the Inter-Tribal Heart Project, where nondiabetic Na-
tive Americans with microalbuminuria often had the insulin
resistance syndrome (52). Thus hormonal differences may play
a role in the expression of the increased cardiovascular risk in
patients with insulin resistance and microalbuminuria. Al-
though this may suggest that estrogen may have some protec-
tive effect, when women are administered estrogen in the pre-
or postmenopausal setting, it is associated with increases in
microalbuminuria in a dose- and time-dependent fashion (85).
In addition, in women high levels of microalbuminuria, when
present, are still predictive of cardiovascular disease, as dem-
onstrated in an epidemiological study from The Netherlands in
which women with the highest quintile of microalbuminuria
were at increased risk of cardiovascular death (101).
Such terms as the “ticking clock” or the “common soil”
hypothesis have been used to suggest that the time course for
the development of cardiovascular disease begins before the
onset of clinical diabetes (44, 107). The common factors for the
development of cardiovascular disease may represent genetic
or environmental factors that are present before the clinical
manifestations of disease. Indeed, in the Nurses’ Health Study,
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MICROALBUMINURIA AND CV/RENAL RISK
the risk for cardiovascular disease was found to be elevated at
least 15 yr before the diagnosis of diabetes (53). Whether the
common factors for onset of microalbuminuria and diabetes are
preventable is of great interest for future therapy. The Heart
Outcomes and Prevention Evaluation study provided powerful
data along these lines (73). The use of the ACE inhibitor
ramipril reduced the progression of albuminuria, whether this
was new albuminuria or the progression of microalbuminuria
to macroalbuminuria. This study also demonstrated that
ramipril was effective in decreasing cardiovascular death in
patients with known heart disease or DM2 patients without
established heart disease. The benefits of ramipril were greatest
on preventing cardiovascular events in patients with DM2 and
in nondiabetic patients with albuminuria.
DM2 IS INCREASING IN YOUTH
Over the past 20 years, the prevalence of DM2 has increased
18% in the United States (3). Not only is DM2 more prevalent,
but it often begins at a younger age (71, 102). This has serious
consequences for long-term health as these patients are also at
increased risk for cardiovascular disease, end-stage renal dis-
ease, blindness, amputation, and the associated personal and
economic losses at earlier ages. The younger onset of patients
with DM2 suggests that those patients will live with compli-
cations for a larger percentage of their lifetime.
Prevalence rates for diagnosed DM2 in children have been
estimated at between 2 and 50/1,000, depending on the popu-
lation studied, whereas that for the general adult population is
30/1,000 (29). Those children and young adults with the
highest prevalence rates of DM2 are from racial and ethnic
minorities, including African Americans, Hispanics, and Na-
tive Americans (29, 71). The increased prevalence of DM2 in
children has been attributed to increasing obesity, a sedentary
lifestyle, and increased intrauterine exposure to a diabetic
environment (8, 29, 34, 71, 114). The degree of obesity is
significant, as most published studies have found that affected
children with DM2 have a mean body mass index (BMI)
exceeding the 95th percentile for age (29, 71). Because of the
increased prevalence of DM2, DM1 may no longer represent
the most common form of diabetes in youth, as up to 50%
of new cases of diabetes in youth are DM2 in some popu-
lations (71).
DM2 IS INCREASED IN NATIVE AMERICANS,
INCLUDING YOUTH
DM2 is epidemic in American Indian populations (3, 11).
Data from the Indian Health Service suggest that the preva-
lence rate is 8.0%, over double the rate for the population as a
whole (14). There is also a female predominance, with
prevalence rates 25% higher in American Indian females
(13). The prevalence rates for other minorities, including
African Americans and Hispanics, are similar to those of
American Indians (3).
Similar to national trends, American Indian children and
youth are also experiencing an increased prevalence of DM2
(20, 21, 29, 47). Numbers for American Indians across the U.S.
vary from 1.3/1,000 for children 0–14 yr of age to 4.5/1,000 for
youth aged 15–19 yr (29). Recent Indian Health System data
indicate the prevalence rate has risen to 5.4/1,000 for ages
15–19 yr, an increase of 68% over a decade (1, 7). Population-
AJP-Renal Physiol • VOL
Invited Review
F445
based studies demonstrate that DM2 occurs in African Amer-
icans at a rate of 7.2/1,000, in contrast to 4.1/1,000 for all U.S.
adolescents aged 12–19 yr (29). Without a plateau in the
increasing prevalence, DM2 will be expected to increase into
the future.
MICROALBUMINURIA IN AMERICAN INDIAN CHILDREN
AND ADULTS
The prevalence of microalbuminuria amongst all American
Indian tribes is not known. However, the Strong Heart Study
recently revealed the prevalence of microalbuminuria in Ari-
zona, Oklahoma, and Dakota Indians to be 28.3, 15.2, and
13.8%, respectively (100). However, these subjects were all
adults and may not represent the prevalence of microalbumin-
uria in young American Indians.
Fagot-Campagna et al. (28) reported on the prevalence of
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cardiovascular risk factors, including microalbuminuria, in
Pima children age 5–19 yr. The group included 4,092 10- to
19-yr-old patients with normal glucose tolerance. At baseline,
6% had microalbuminuria, whereas 8% with impaired glucose
tolerance had microalbuminuria. After more than 5 yr, 33% of
the entire cohort had developed microalbuminuria. This is in
contrast to the rates of microalbuminuria in other healthy
ethnic groups. For African Americans, 7.7% of men and 10.5%
of women aged 6–19 yr have microalbuminuria (60). Non-
Hispanic whites (5.7/9.7, men/women) and Hispanics (5.4/9.5,
men/women) have lower rates of microalbuminuria. After age
19, in all ethnic groups the rate of microalbuminuria falls in the
third decade to rates roughly one-half those seen at ages 6–19
yr. If microalbuminuria serves as a marker of future cardio-
vascular and renal disease, efforts to define its prevalence in
high-risk populations are an essential first step to a prevention
strategy.
ROLE OF PUBERTY IN DEVELOPMENT
OF MICROALBUMINURIA
Puberty is normally associated with complex changes in
renal hemodynamics, somatic growth, and changes in sex
hormones that may have important interactions with hypergly-
cemia and insulin resistance (68). These changes may, in turn,
affect microalbuminuria during puberty. It is rare to develop
microalbuminuria before puberty in DM1. In fact, there has
been a suggestion that diabetic nephropathy does not occur
before puberty (24, 65). Although patients may not have
microalbuminuria, histological changes indicative of diabetic
nephropathy occur in association with duration of diabetes, not
pubertal stage (25). However, with DM2, pathological insulin
resistance may interact with developmental changes to accel-
erate the onset of microalbuminuria.
Puberty is associated with changes in insulin sensitivity (5,
9, 17, 95). Tanner staging characterizes pubertal development,
according to physical findings utilizing examination of pubic
hair and genitalia in boys and pubic hair, breast size, and
menarche in girls (75, 76). Tanner stages range from stages 1
(preadolescent) to 5 (fully mature). Several studies have dem-
onstrated that insulin sensitivity decreases early in puberty in
nondiabetic children as well as patients with diabetes, begin-
ning between Tanner stages 1 and 2 and decreasing throughout
puberty. Insulin sensitivity improves to normal after linear
growth is complete in adults. Body fat also increases in early
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Invited Review
F446 MICROALBUMINURIA AND CV/RENAL RISK
puberty, but BMI does not change with Tanner stage in
adolescents.
No clear association between insulin sensitivity and rising
sex steroid concentrations has been found in men (123). How-
ever, polycystic ovary syndrome with its proatherosclerotic
effects (123) often includes increased androgens. It has been
recently reported that higher free androgen levels in children
with DM1 were associated with the development of microalbu-
minuria (6).
Several studies have implicated a relationship between in-
sulin sensitivity and the growth hormone-IGF-1 axis, suggest-
ing increased tissue growth hormone effect as the cause (9, 17).
One study found a significant association among IGF-1, renal
hypertrophy, and microalbuminuria (19). However, others did
not confirm this relationship (104). To date, studies evaluating
microalbuminuria during puberty have been cross sectional.
Additional prospective studies are needed to more closely
characterize the changes that occur with puberty and the
development of microalbuminuria.
ASSOCIATION OF CARDIOVASCULAR DISEASE WITH
MARKERS OF INFLAMMATION
The use of the highly-sensitive C-reactive protein (CRP)
assay, a sensitive marker of inflammation, has been shown in
a number of studies to predict the risk of cardiovascular disease
events (15, 51, 64, 66, 93, 96–98, 112, 113, 128). An active
role for elevated CRP levels in the pathophysiology of vascular
disease has been suggested but not definitively proven (23, 92,
122, 129). Because microalbuminuria, CRP, and other markers
of inflammation have been shown to be associated with car-
diovascular disease, the question arises as to whether the
inflammatory process causes the microalbuminuria.
A large cross-sectional study has demonstrated an associa-
tion between microalbuminuria and CRP (31). Festa et al. (31)
reported on 1,281 subjects from the Insulin Resistance Athero-
sclerosis Study. The study population contained patients with
and without DM2. There was a positive association between
microalbuminuria and elevated CRP and fibrinogen. The asso-
ciation was similar across gender and ethnic groups. The
authors suggest that the association may arise from three
possibilities: the independent development of atherosclerosis
and microalbuminuria, the direct or indirect effect of cytokines
on the glomerulus, or the presence of both from a common
preexisting condition. However, a retrospective analysis of the
Risk Factors in Impaired Glucose Tolerance for Atherosclero-
sis and Diabetes study did not demonstrate an association
between microalbuminuria and CRP levels in a population at
high risk for DM2 (111).
Stehouwer et al. (105) prospectively followed markers of
chronic inflammation and endothelial dysfunction in 328 pa-
tients with DM2 for 9.0 yr. Markers for both endothelial
dysfunction and chronic inflammation, as well as microalbu-
minuria, were found to be interrelated, to have developed in
parallel, progressed with time, and were related to death.
Stuveling et al. (108) reported on 7,317 patients without
diabetes. CRP was associated with microalbuminuria and de-
creased renal filtration as measured by creatinine clearance.
CRP was also associated with hyperfiltration (defined by an
elevated creatinine clearance and seen before a decrease in
creatinine clearance in patients with diabetic nephropathy),
AJP-Renal Physiol • VOL
although this relationship was primarily related to BMI and has
been described previously (80, 118). These data raise the point
that inflammatory processes may negatively impact renal func-
tion, as well as cardiovascular end points. This may be espe-
cially true in individuals who progress from obesity to predi-
abetes to diabetes. No prospective data exist in patients with
diabetes to provide insight into this question.
Obesity, especially visceral obesity, has been previously
associated with plasma inflammatory markers, including IL-6,
CRP, and TNF-␣ (18, 50, 62, 121, 126, 127). BMI and
hemoglobin A1C have also been associated with inflammatory
markers (105). Acute hyperglycemia has been shown to in-
crease IL-6, TNF-␣, and IL-18 (27). Low levels of adiponectin
that occur with obesity are associated with increased IL-6 and
CRP plasma levels (26). Visceral obesity is also associated
with increased free fatty acid release into the portal vein (33).
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This leads to increased hepatic glucose output with resultant
hyperglycemia and decreased hepatic insulin extraction with
resultant hyperinsulinemia (30, 109). Glowinska et al. (35)
reported that traditional risk factors for cardiovascular disease,
such as hypertension and dyslipidemia, are also associated with
nontraditional risk factors, such as decreased fibrinolytic ac-
tivity and homocysteinemia, and lipoprotein (a) levels in obese,
diabetic adolescents.
These findings suggest that prevention of obesity, prevention
of hyperglycemia, use of antioxidants, and other anti-inflam-
matory treatments may be beneficial in addressing the early
progressive inflammatory response associated with diabetes
and vascular disease. Indeed, glutathione has been shown to
prevent the rise of cytokine levels (27). The increase in oxi-
dative stress from obesity was further supported in a commu-
nity-based cohort in the Framingham Heart Study (61). Thia-
zolidinediones increase adiponectin levels (72, 124). Salicy-
lates may improve fat-induced insulin resistance (63). Exercise
is associated with decreased CRP levels (54). These are in
addition to lifestyle changes to lose weight.
Fig. 1. Model for the development of cardiovascular and renal disease in
patients with a variety of disorders surrounding insulin resistance and glucose
intolerance. It should be noted that microalbuminuria has been found as a
marker of these conditions, evident before diabetes, and may serve as a marker
of disease activity.
286 • MARCH 2004 • www.ajprenal.org

MICROALBUMINURIA AND CV/RENAL RISK
CLINICAL USE OF THE MICROALBUMIN ASSAY
Although there are clear recommendations for the measure-
ment of microalbumin excretion in the urine, the test is not
universally employed (48). Factors contributing to this include
lack of availability, confusion with units of measure, increased
turnaround time for the assay, and the sense by clinicians that
such measurements are not needed provided patients are placed
on an angiotensin-converting enzyme inhibitor or angiotensin
II blocker. The latter point is incorrect for several reasons.
Despite therapy with one of the renoprotective agents, there is
now evidence that simultaneous use of both agents may further
decrease microalbuminuria, and prospective testing needs to be
performed to titrate the medications (103). The above review
has also indicated that microalbuminuria is a marker of vascu-
lar disease and can be used to support further therapy directed
at this complication. For the stated reasons, the recommenda-
tions for microalbuminuria testing need to be emphasized and
the obstructions to its use removed.
SUMMARY
There is generally a long lag time between the initiation of
atherogenesis and the first cardiac event, which provides an
opportunity to intervene with preventive therapy in insulin
resistance. However, before a prevention treatment can be
devised and tested, more needs to be known about the temporal
development of DM2, vascular disease, and renal disease.
Evidence already exists of the terrible toll of diabetes and its
complications occurring earlier in youth who develop diabetes.
Dean and Flett (22) reported a high mortality rate of 9% after
15 yr of diabetes in First Nation populations in Manitoba and
Ontario, Canada. These patients were diagnosed with DM2
before 18 yr of age and were only in their third decade of life
when they died. As insulin resistance and diabetes become
more prevalent, its complications loom threateningly on the
horizon for these patients.
The pathophysiology of insulin resistance and diabetes-
related vascular disease likely begins before the diagnosis of
DM2 (Fig. 1). Inflammatory markers begin to increase with the
presence of visceral obesity. Microalbuminuria is another
marker of endothelial dysfunction, which may occur with early
cardiovascular and renal disease. While microalbuminuria is
also a marker of early diabetic nephropathy and may not
always predict progression, it appears to also predict significant
cardiovascular disease. Further understanding of these issues is
critical to prevent mortality from cardiovascular and renal
disease in diabetes, especially in young adults with DM2.
REFERENCES
1. Acton K, Burrows N, Moore K, Querec L, Geiss L, and Engelgau M.
Trends in diabetes prevalence among American Indian and Alaska native
children, adolescents, and young adults. Am J Public Health 92: 1485–
1490, 2002.
2. Alberti K and Zimmet P for the WHO Consultation. Definition,
diagnosis and classification of diabetes mellitus and its complications.
Part 1: diagnosis and classification of diabetes mellitus provisional report
of a WHO consultation. Diabet Med 15: 539–553, 1998.
3. American Diabetes Association. Diabetes statistics. In: Diabetes 2001;
Vital Statistics, edited by Raynor J. Alexandria, VA: American Diabetes
Assoc., 2001, p. 13–27.
4. American Diabetes Association. Diabetic nephropathy. Diabetes Care
26, Suppl 1: S94–S98, 2003.
AJP-Renal Physiol • VOL 286 • MARCH 2004 •
Invited Review
F447
5. Amiel S, Sherwin R, Simonson D, Lauritano A, and Tamborlane W.
Impaired insulin action in puberty: a contributing factor to poor glycemic
control in adolescents with diabetes. N Engl J Med 315: 215–219, 1986.
6. Amin R, Schultz C, Ong K, Frystyk J, Dalton R, Perry L, Orskov H,
and Dunger D. Low IGF-I and elevated testosterone during puberty in
subjects with type 1 diabetes developing microalbuminuria in compari-
son to normoalbuminuric control subjects. Diabetes Care 26: 1456–
1461, 2003.
7. Arslanian S. Type 2 diabetes in children; clinical aspects and risk
factors. Horm Res 57, Suppl 1: 19–28, 2002.
8. Blair S and Brodney S. Effects of physical inactivity and obesity on
morbidity and mortality: current evidence and research issues. Med Sci
Sports Exerc 31, Suppl 11: S646–S662, 1999.
9. Bloch C, Clemons P, and Sperling M. Puberty decreases insulin
sensitivity. J Pediatr 110: 481–487, 1987.
10. Brenner E, Cooper M, de Zeeuw D, Keane W, Mitch W, Parving H,
Remuzzi G, Snapinn S, Zhang Z, and Shahinfar S. Effects of losartan
on renal and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med 345: 861–869, 2001.
Downloaded from http://ajprenal.physiology.org/ by guest on June 14, 2013
11. Burrows N, Geiss L, Engelgau M, and Acton K. Prevelance of diabetes
among Native Americans and Alaska natives. Diabetes Care 23: 1786–
1790, 2000.
12. Caramori M, Fioretto P, and Mauer M. The need for early predictors
of diabetic nephropathy risk: is albumin excretion rate sufficient? Dia-
betes 49: 1399–1408, 2000.
13. Centers for Disease Control and Prevention. Diabetes Surveillance,
1999. Atlanta, GA: Dept. of Health and Human Services, Public Health
Service, 1999.
14. Centers for Disease Control and Prevention. Prevalence of selected
risk factors for chronic disease and injury among American Indians and
Alaska Natives—United States, 1995–1998. MMWR 49: 79–82, 91,
2000.
15. Cermak J, Key N, Bach R, Balla J, Jacob H, and Vercellotti G.
C-reactive protein induces human peripheral blood monocytes to synthe-
size tissue factor. Blood 82: 513–520, 1993.
16. Cohen A, McCarthy D, and Stoff J. Direct hemodynamic effect of
insulin in the isolated perfused kidney. Am J Physiol Renal Fluid
Electrolyte Physiol 257: F580–F585, 1989.
17. Cook J, Hoffman R, Stene M, and Hansen J. Effects of maturational
stage on insulin sensitivity during puberty. J Clin Endocrinol Metab 77:
725–730, 1993.
18. Corica F, Allegra A, Corsonella A, Buemi M, Calapai G, Ruello A,
Mauro VN, and Ceruso D. Relationship between plasma leptin levels
and the tumor necrosis factor-alpha system in obese subjects. Int J Obes
23: 355–360, 1999.
19. Cummings E, Sochett E, Dekker M, Lawson M, and Daneman D.
Contribution of growth hormone and IGF-I to early diabetic nephropathy
in type 1 diabetes. Diabetes 47: 1341–1346, 1998.
20. Dabelea D, Hanson R, Bennett P, Roumain J, Knowler W, and Pettitt
D. Increasing prevalence of type II diabetes in American Indian children.
Diabetologia 41: 904–910, 1998.
21. Dabelea D, Pettitt D, Hanson R, Imperatore G, Bennett P, and
Knowler W. Birth weight, type 2 diabetes, and insulin resistance in Pima
Indian children and young adults. Diabetes Care 22: 944–950, 1999.
22. Dean H and Flett B. Natural history of type 2 diabetes diagnosed in
childhood: long term follow-up in young adult years. Diabetes 51, Suppl
2: A25–A26, 2002.
23. Devaraj S, Xu D, and Jialal I. C-reactive protein increases plasminogen
activator inhibitor-1 expression and activity in human aortic endothelial
cells. Implications for the metabolic syndrome and atherothrombosis.
Circulation 107: 398–404, 2003.
23a.Diabetes Control and Complications Research Group. The effect of
intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N Engl
J Med 329: 977–986, 1993.
24. Donaghue K, Fairchild J, Craig M, Chan A, Hing S, Cutler L,
Howard N, and Silink M. Do all prepubertal years of diabetes duration
contribute equally to diabetes complications? Diabetes Care 26: 1224-
1229, 2003.
25. Drummond K, Kramer M, Suiissa S, Levy-Marchal C, Dell’Aniello
S, Sinaiko A, and Mauer M. Effects of duration and age at onset of type
1 diabetes on preclinical manifestations of nephropathy. Diabetes 52:
1818–1824, 2003.
www.ajprenal.org
Invited Review
F448 MICROALBUMINURIA AND CV/RENAL RISK
26. Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke
J, Mohlig M, Pfeiffer A, Luft F, and Sharma A. Association between
adiponectin and mediators of inflammation in obese women. Diabetes
52: 942–947, 2003.
27. Esposito K, Nappo F, Marfella R, Giujgliano G, Giugliano F, Ciotola
M, Quagliaro L, Ceriello A, and Giugliano D. Inflammatory cytokine
concentrations are acutely increased by hyperglycemia in humans: role of
oxidative stress. Circulation 106: 2067–2072, 2002.
27a. The Euclid Study Group. Randomised placebo-controlled trial of
lisinopril in normotensive patients with insulin-dependent diabetes and
normoalbuminuria or microalbuminuria. Lancet 349: 1787–1792, 1997.
28. Fagot-Campagna A, Knowler W, and Pettitt D. Type 2 diabetes in
Pima Indian children: cardiovascular risk factors at diagnosis and 10
years later (Abstract). Diabetes 47, Suppl 1: A155, 1998.
29. Fagot-Campagna A, Pettitt D, Engelgau M, Burrows N, Geiss L,
Valdez R, Beckles G, Saaddine J, Gregg E, Williamson D, and
Narayan KV. Type 2 diabetes among North American children and
adolescents: an epidemiologic review and a public health perspective.
J Pediatr 136: 664 – 672, 2000.
30. Ferrannini E, Barrett E, Bevilacqua S, and DeFronzo R. Effect of
fatty acids on glucose production and utilization in man. J Clin Invest 72:
1737–1747, 1983.
31. Festa A, D’Agonstino R, Howard G, Mykkanen L, Tracy R, and
Haffner S. Inflammation and microalbuminuria in nondiabetic and type
2 diabetic subjects: the Insulin Resistance Atherosclerosis Study. Kidney
Int 58: 1703–1710, 2000.
32. Forsblom C, Eriksson J, Ekstrand A, Teppo A, Taskinen M, and
Groop L. Insulin resistance and abnormal albumin excretion in non-
diabetic first degree relatives of patients with IDDM. Diabetologia 38:
363–369, 1995.
33. Frayn K. Visceral fat and insulin resistance: causative or correlative?
Br J Nutr 83: S71–S77, 2000.
34. Glaser N. Non-insulin dependent diabetes mellitus in childhood and
adolescence. Pediatr Clin North Am 44: 307–337, 1997.
35. Glowinska B, Urban M, Koput Q, and Galar M. New atherosclerosis
risk factors in obese, hypertensive and diabetic children and adolescents.
Atherosclerosis 167: 275–286, 2003.
36. Goran M, Ball G, and Cruz M. Obesity and risk of type 2 diabetes and
cardiovascular disease in children and adolescents. J Clin Endocrinol
Metab 88: 1417–1427, 2003.
37. Groop L, Ekstrand A, Forsblom C, Widen E, Groop P, Teppo A, and
Eriksson J. Insulin resistance, hypertension and microalbuminuria in
patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabeto-
logia 36: 642–647, 1993.
42. Haffner S, Gonzales C, Valdez R, Mykkanen L, Hazuda H, Mitchell
B, Monterrosa A, and Stern M. Is microalbuminuria part of the
prediabetic state? The Mexico City Diabetes Study. Diabetologia 36:
1002–1006, 1993.
43. Haffner S, Stern M, Gruber M, Hazuda H, Mitchell B, and Patterson
J. Potential marker for increased cardiovascular risk factors in non-
diabetic subjects? Arteriosclerosis 10: 727–731, 1990.
44. Haffner S, Stern M, Hazuda H, Mitchell B, and Patterson J. Cardio-
vascular risk factors in confirmed prediabetic individuals. Does the clock
for coronary heart disease start ticking before the onset of clinical
diabetes? JAMA 263: 2893–2898, 1990.
45. Halimi J, Forhan A, Balkau B, Novak M, Wilpart E, Tichet J, and
Marre M. Is microalbuminuria an integrated risk marker for cardiovas-
cular disease and insulin resistance in both men and women? J Cardiovas
Risk 8: 139–146, 2001.
46. Harris M, Klein R, Welborn T, and Knuiman M. Onset of NIDDM
occurs at least 4–7 years before clinical diagnosis. Diabetes Care 15:
815–819, 1992.
47. Harwell T, McDowall J, Moore K, Fagot-Campagna A, Helgerson S,
and Gohdes D. Establishing surveillance for diabetes in American
Indian youth. Diabetes Care 24: 1029–1032, 2001.
48. Harwell T, Nelson R, Little R, McDowall J, Helgerson S, and Gohdes
D. Testing for microalbuminuria in 2002: barriers to implementing
current guidelines. Am J Kidney Dis 42: 245–248, 2003.
49. Hasslacher C, Ritz E, Wahl P, and Michael C. Similar risks of
nephropathy in patients with type 1 or type 2 diabetes mellitus. Nephrol
Dial Transplant 4: 859–863, 1989.
50. Hauner H, Bender M, Haastert B, and Hube F. Plasma concentrations
of soluble TNF-␣ receptors in obese subjects. Int J Obes 22: 1239–1243,
1998.
AJP-Renal Physiol • VOL 286 • MARCH 2004 •
51. Haverkate F, Thompson S, Pyke S, Gallimore J, Pepys M, and The
European Concerted Action on Thrombosis and Disabilities Angina
Pectoris Study Group. Production of C-reactive protein and risk of
coronary events in stable and unstable angina. Lancet 349: 462–466,
1997.
52. Hoehner C, Greenlund K, Rith-Najarian S, Casper M, and McClel-
lan W. Association of the insulin resistance syndrome and microalbu-
minuria among nondiabetic Native Americans. The Inter-Tribal Heart
Project. J Am Soc Nephrol 13: 1626–1634, 2002.
53. Hu F, Stampfer M, Haffner S, Solomon C, Willett W, and Manson J.
Elevated risk of cardiovascular disease prior to clinical diagnosis of type
2 diabetes. Diabetes Care 25: 1129–1134, 2002.
54. Isasi C, Deckelbaum R, Tracy R, Starc T, Berglund L, and Shea S.
Physical fitness and C-reactive protein level in children and young adults:
the Columbia University BioMarkers Study. Pediatrics 111: 332–338,
2003.
55. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M,
Taskinen M, and Groop L. Cardiovascular morbidity and mortality
associated with the metabolic syndrome. Diabetes Care 24: 683–689,
Downloaded from http://ajprenal.physiology.org/ by guest on June 14, 2013
2001.
56. Jager A, Kostense P, Nijpels G, Heine R, Bouter L, and Stehouwer C.
Microalbuminuria is strongly associated with NIDDM and hypertension,
but not with the insulin resistance syndrome: the Hoorn Study. Diabe-
tologia 41: 694–700, 1998.
57. Jarrett J, Viberti G, Argyropoulos A, Hill R, Mahmud U, and
Murrells T. Microalbuminuria predicts mortality in non-insulin-depen-
dent diabetes. Diabet Med 1: 17–19, 1984.
58. Jensen J. Renal and systemic transvascular albumin leakage in severe
atherosclerosis. Arteriolscler Thromb Vasc Biol 15: 1324–1329, 1995.
59. Jensen T, Bjerre-Kundsen J, Feldt-Rasmussen B, and Deckert T.
Features of endothelial dysfunction in early diabetic nephropathy. Lancet
1: 461–463, 1989.
60. Jones C, Francis M, Eberhardt M, Chavers B, Coresh J, Engelgau
M, Kusek J, Byrd-Holt D, Narayan K, Herman W, Jones C, Salive
M, and Agodoa L. Microalbuminuria in the US Population: Third
National Health and Nutrition Examination Survey. Am J Kidney Dis 39:
445–459, 2002.
61. Keaney J, Larson M, Vasan R, Wilson P, Lipinska I, Corey D,
Massaro J, Sutherlaned P, Vita J, and Benjamin E. Obesity and
systemic oxidative stress. Clinical correlates of oxidative stress in The
Framingham Study. Arteriolscler Thromb Vasc Biol 23: 434–439, 2003.
62. Kern P, Ranganathan S, Li C, Wood L, and Ranganathan G. Adipose
tissue tumor necrosis factor and interleukin-6 expression in human
obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:
E745–E751, 2001.
63. Kim J, Kim Y, Filmore J, Chen Y, Moore I, Lee J, Yuan M, Li Z,
Karin M, Perret P, Shoelson S, and Shulman G. Prevention of
fat-induced insulin resistance by salicylate. J Clin Invest 108: 437–446,
2001.
64. Koenig W, Sund M, Rohlich M, Fischer HG, Lowel H, Doring A,
Hutchinson W, and Pepys M. C-reactive protein, a sensitive marker of
inflammation, predicts future risk of coronary heart disease in initially
healthy middle-aged men. Circulation 99: 237–242, 1999.
65. Krolewski A, Warram J, Christlieb A, Busick E, and Kahn C. The
changing natural history of nephropathy in type I diabetes. Am J Med 78:
785–794, 1985.
66. Kuller L, Tracy R, Shaten J, Meilahn E, and the Multiple Risk
Factor Intervention Trial Research Group. Relationship of C-reactive
protein and coronary heart disease in the MRFIT nested case-control
study. Am J Epidemiol 144: 537–547, 1996.
67. Laffel L, McGill J, and Gans J. The beneficial effect of angiotensin-
converting enzyme inhibition with captopril on diabetic nephropathy in
normotensive IDDM patients with microalbuminuria. Am J Med 99:
497–504, 1995.
68. Lane P. Diabetic kidney disease: impact of puberty. Am J Physiol Renal
Physiol 283: F589–F600, 2002.
69. Lane P, Steffes M, Fioretto P, and Mauer S. Renal interstitial expan-
sion in insulin-dependent diabetes mellitus. Kidney Int 43: 661–667,
1993.
70. Lewis E, Hunsicker L, Clarke W, Berl T, Pohl M, Lewis J, Ritz E,
Atkins R, Rohde B, and Raz I. Renoprotective effect of the angiotensin-
receptor antagonist irbesartan in patients with nephropathy due to type 2
diabetes. N Engl J Med 345: 851–860, 2001.
www.ajprenal.org

MICROALBUMINURIA AND CV/RENAL RISK
71. Ludwig D and Ebbeling C. Type 2 diabetes mellitus in children:
primary care and public health considerations. JAMA 286: 1427–1430,
2001.
72. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H,
Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Jyru-
tana G, Gitta J, Nakmura T, Shimomura I, and Matsuzawa Y.
PPAR␥ ligands increase expression and plasma concentrations of adi-
ponectin, and adipose-derived protein. Diabetes 50: 2094–2099, 2001.
73. Mann J, Gerstein H, Yi Q, Lonn E, Hoogwerf B, Rashkow A, and
Yusuf S. Development of renal disease in people at high cardiovascular
risk: results of the HOPE Randomized Study. J Am Soc Nephrol 14:
641–647, 2003.
74. Marre M, Leblanc H, Suarez L, Guyenne T, Menard J, and Passa P.
Converting enzyme inhibition and kidney function in normotensive
diabetic patients with persistent microalbuminuria. BMJ 294: 1448–
1452, 1987.
75. Marshall W and Tanner J. Variation in the pattern of pubertal changes
in boys (Abstract). Arch Dis Child 45: 13, 1970.
76. Marshall W and Tanner J. Variation in the pattern of pubertal changes
in girls. Arch Dis Child 44: 291, 1969.
77. Mathiesen E, Hommel E, Giese J, and Parving H. Efficacy of captro-
pril in postponing nephropathy in normotensive diabetic patients with
microalbuminuria. BMJ 303: 81–87, 1991.
78. Meigs J, Jacques P, Selhub J, Singer D, Nathan D, Rifai N,
D’Agostino R, and Wilson P. Fasting plasma homocysteine levels in the
insulin resistance syndrome. The Framiningham Offspring Study. Dia-
betes Care 24: 1403–1410, 2001.
79. Meltzer S, Leiter L, Daneman D, Gerstein H, Lau D, Ludwig S, Yale
J, Zinman B, and Lillie D. Clinical practice guidelines for the manage-
ment of diabetes in Canada: Canadian Diabetes Association. Can Med
Assoc J 159, Suppl 8: S1–S29, 1998.
80. Mendall M, Patel P, Ballam L, Strachan D, and Northfield TC.
C-reactive protein and its relation to cardiovascular risk factors: a
population based cross sectional study. BMJ 312: 1061–1065, 1996.
80a.Microalbuminuria Collaborative Study Group. Intensive therapy and
progressive to clinical albuminuria in patients with insulin dependent
diabetes mellitus and microalbuminuria. BMJ 311: 973–977, 1995.
81. Mogensen C. Microalbuminuria predicts clinical proteinuria and early
mortality in maturity-onset diabetes. N Engl J Med 310: 356–360, 1984.
82. Mogensen C, Chachati A, Christensen C, Close C, Deckert T, Hom-
mel E, Kastrup J, Lefebvre P, Mathiesen E, Feldt-Rasmussen B,
Schmitz A, and Viberti G. Microalbuminuria: an early marker of renal
involvement in diabetes. Uremia Invest 9: 85–95, 1985.
83. Mogensen C and Christensen C. Predicting diabetic nephropathy in
insulin-dependent patients. N Engl J Med 311: 89–93, 1984.
84. Mogensen C, Christensen C, and Vittinghus E. The stages in diabetic
renal disease. With emphasis on the stage of incipient diabetic nephrop-
athy. Diabetes 32: 64–78, 1983.
85. Monster T, Janssen W, Jong PD, and de Jong-van den Berg LTW.
Oral contraceptive use and hormone replacement therapy are associated
with microalbuminuria. Arch Intern Med 161: 2000–2005, 2001.
86. Mykkanen L, Zaccaro D, O’Leary D, Howard G, Robbins D,
Haffner S, and the Insulin Resistance Atherosclerosis Study Group.
Microalbuminuria and carotid artery intima-media thickness in nondia-
betic and NIDDM subjects. Stroke 28: 1710–1716, 1997.
87. Mykkanen L, Zaccaro D, Wagenknecht L, Robbins D, Gabriel M,
and Haffner S. Microalbuminuria is associated with insulin resistance in
nondiabetic subjects. The Insulin Resistance Atherosclerosis Study. Di-
abetes 47: 793–800, 1998.
88. Nelson R, Meyer T, Meyers B, and Bennett P. Course of renal disease
in Pima Indians with non-insulin-dependent diabetes mellitus. Kidney Int
52, Suppl 63: S45–S48, 1997.
89. Parving H. Renoprotection in diabetes: genetic and non-genetic risk
factors and treatment. Diabetologia 41: 745–759, 1998.
90. Parving H, Lehnert H, Rochner-Mortensen J, Gomis R, Andersen S,
and Arner P. The effect of irbesartan on the development of diabetic
nephropathy in patients with type 2 diabetes. N Engl J Med 345:
870–878, 2001.
91. Parving H, Oxenboll B, Svendsen P, Christiansen J, and Andersen A.
Early detection of patients at risk of developing diabetic nephropathy: a
longitudinal study of urinary albumin excretion. Acta Endocrinol 100:
550–555, 1982.
AJP-Renal Physiol • VOL 286 • MARCH 2004 •
Invited Review
F449
92. Pasceri V, Willerson J, and Yeh E. Direct proinflammatory effect of
C-reactive protein on human endothelial cells. Circulation 102: 2165–
2168, 2000.
93. Pepys M, Rowe I, and Baltz M. C-reactive protein: binding to lipids and
lipoproteins. Int Rev Exp Pathol 27: 83–111, 1982.
94. Perkins B, Ficociello L, Silva K, Finkelstein D, Warram J, and
Krolewski A. Regression of microalbuminuria in type 1 diabetes. N Engl
J Med 348: 2285–2293, 2003.
95. Potau N, Ibanez L, Tique S, and Carrascosa A. Pubertal changes in
insulin secretion and peripheral insulin sensitivity. Horm Res 48: 219–
226, 1997.
96. Ridker P, Cushman M, Stampfer M, Tracy R, and Hennekens C.
Inflammation, aspirin, and the risk of cardiovascular disease in appar-
ently healthy men. N Engl J Med 336: 973–979, 1997.
97. Ridker P, Cushman M, Stapfer M, Tracy R, and Hennekens C.
Plasma concentration of C-reactive protein and risks of developing
peripheral vascular disease. Circulation 97: 425–428, 1998.
98. Ridker P, Glynn R, and Hennekens C. C-reactive protein adds to the
predictive value of total and HDL cholesterol in determining risk of first
Downloaded from http://ajprenal.physiology.org/ by guest on June 14, 2013
myocardial infarction. Circulation 97: 2007–2011, 1998.
99. Ritz E. Nephropathy in type 2 diabetes. J Intern Med 245: 111–126,
1999.
100. Robbins D, Knowler W, Lee E, Yeh J, Go O, Welty T, Fabsitz R, and
Howard B. Regional differences in albuminuria among American Indi-
ans: an epidemic of renal disease. Kidney Int 49: 557–563, 1996.
101. Roest M, Banga J, Janssen W, Grobbee D, Sixma J, Jong PD, Zeeuw
DD, and van der Schouw YT. Excessive urinary albumin levels are
associated with future cardiovascular mortality in postmenopausal
women. Circulation 103: 3057–3061, 2001.
102. Rosenbloom A, Joe J, Young R, and Winter W. Emerging epidemic of
type 2 diabetes in youth. Diabetes Care 22: 345–354, 1999.
103. Rossing K, Jacobsen P, Pietraszek L, and Parving H. Renoprotective
effects of adding angiotensin II receptor blocker to maximal recom-
mended doses of ACE inhibitor in diabetic nephropathy. Diabetes Care
26: 2268–2274, 2003.
104. Sen A and Buyukgebiz A. Albumin excretion rate, serum insulin-like
growth factor-I and glomerular filtration rate in type I diabetes mellitus
at puberty. J Pediatr Endocrinol Metab 10: 209–215, 1997.
105. Stehouwer C, Gall M, Twisk J, Knudsen E, Emeis J, and Parving H.
Increased urinary albumin excretion, endothelial dysfunction, and
chronic low grade inflammation in type 2 diabetes: progressive, interre-
lated, and independently associated with risk of death. Diabetes 51:
1157–1165, 2002.
106. Stehouwer C, Nauta J, Zeldenrust G, Hackeng W, Donker A, and
Ottolander G. Urinary albumin excretion, cardiovascular disease, and
endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lan-
cet 340: 319–323, 1992.
107. Stern M. Diabetes and cardiovascular disease: the “common soil”
hypothesis. Diabetes 44: 369–374, 1995.
108. Stuveling E, Hillege H, Bakker S, Gans R, Jong PD, and Zeeuw DD.
Creactive protein is associated with renal function abnormalities in a
non-diabetic population. Kidney Int 63: 654–661, 2003.
109. Svedberg J, Bjorntorp P, and Lonnroth P. Free-fatty acid inhibition of
insulin binding, degradation, and action in isolated rat hepatocytes.
Diabetes 39: 570–574, 1990.
110. Tanaka Y, Atsumi Y, Matsuoka K, Onuma T, Tohjima T, and
Kawamori R. Role of glycemic control and blood pressure in the
development and progression of nephropathy in elderly Japanese
NIDDM patients. Diabetes Care 21: 116–120, 1988.
111. Temelkova-Kurktschiev T, Siegert G, Bergmann S, Henkel E,
Koehler C, Jarob W, and Hanefeld M. Subclinical inflammation is
strongly related to insulin resistance but not to impaired insulin secretion
in a high risk population for diabetes. Metabolism 51: 743–749, 2002.
112. Torzewski J, Torzewski M, Bowyer D, Frohlich M, Koenig W,
Waltenberger J, Fitzsimmons C, and Hombach V. C-reactive protein
frequently colocalizes with the terminal complement complex in the
intima of early atherosclerotic lesions of human coronary arteries. Arte-
rioscler Thromb Vasc Biol 18: 1386–1392, 1998.
113. Tracy R, Lemaitre R, Psaty B, Ives D, Evans R, Cushman M,
Meilahn E, and Kuller L. Relationship of C-reactive protein to risk of
cardiovascular disease in the elderly: results from the Cardiovascular
Health Study and the Rural Health Promotion Project. Arterioscler
Thromb Vasc Biol 17: 1121–1127, 1997.
www.ajprenal.org
Invited Review
F450 MICROALBUMINURIA AND CV/RENAL RISK
114. Troiano R and Flegal K. Overweight children and adolescents: descrip-
tion, epidemiology, and demographics. Pediatrics 101: 497–504, 1998.
115. Tucker B, Anderson C, Thies R, Collins R, and Blantz R. Glomerular
hemodynamic alterations during acute hyperinsulinemia in normal and
diabetic rats. Kidney Int 42: 1160–1168, 1992.
116. Tuttle K, Puhlman M, Cooney S, and Short R. Urinary albumin and
insulin as predictors of coronary artery disease: an angiographic study.
Am J Kidney Dis 34: 918–925, 1999.
117. Tuttle K, Stein J, and DeFronzo R. The natural history of diabetic
nephropathy. Semin Nephrol 10: 184–193, 1990.
117a.United Kingdom Prospective Diabetes Study Group. An intensive
blood glucose control policy with sulphonylureas or insulin reduces the
risk of diabetic complications in patients with type 2 diabetes. Lancet
352: 837–853, 1998.
118. Valensi P, Assayag M, Busby M, and Attali JR. Microalbuminuria in
obese patients with or without hypertension. Int J Obes Relat Metab
Disord 20: 574–579, 1996.
119. Viberti G, Hill R, Jarrett R, Argyropoulos A, Mahmud U, and Keen
H. Microalbuminuria as a predictor of clinical nephropathy in insulin-
dependent diabetes mellitus. Lancet 1: 1430–1432, 1982.
120. Viberti G, Mogensen C, Groop L, Pauls J, and Group TEMCS. Effect of
captopril on progression to clinical proteinuria in patients with insulin-dependent
diabetes mellitus and microalbuminuria. JAMA 271: 275–279, 1994.
121. Winkler G, Lakatos P, Salamon F, Nagy Z, Speer G, Kovacs M,
Harmos G, Dworak O, and Cseh K. Elevated serum TNF-␣ level as a
link between endothelial dysfunction and insulin resistance in normoten-
sive obese patients. Diabet Med 16: 207–211, 1999.
AJP-Renal Physiol • VOL
122. Wolbink G, Brouwer M, Buysmann S, Berge IT, and Hack C. CRP
mediated activation of complement in vivo: assessment by measuring
circulating complement-C-reactive protein complexes. J Immunol 157:
473–479, 1996.
123. Wu F and Eckardstein AV. Androgens and coronary artery disease.
Endocr Rev 24: 183–217, 2003.
124. Yang W, Jeng C, Wu T, Tanaka S, Funahashi T, Matsuzawa Y,
Chen JWC, Tai T, and Chuang L. Synthetic peroxisome prolifera-
tor-activated receptor-␥ agonist, rosiglitazone, increases plasma lev-
els of adiponectin in type 2 diabetic patients. Diabetes Care 25:
376–380, 2002.
125. Yudkin J, Forrest R, and Jackson C. Microalbuminuria as predictor of
vascular disease in non-diabetic subjects. Lancet 2: 530–533, 1988.
126. Yudkin J, Kumari M, Humphries S, and Mohamed-Ali V. Inflam-
mation, obesity, stress, and coronary heart disease: is interleukin-6 the
link? Atherosclerosis 148: 209–214, 2000.
127. Yudkin J, Stehouwer C, Emeis J, and Coppack S. C-reactive protein
in healthy subjects: associations with obesity, insulin resistance, and
endothelial dysfunction: a potential role for cytokines originating from
Downloaded from http://ajprenal.physiology.org/ by guest on June 14, 2013
adipose tissue? Arterioscler Thromb Vasc Biol 19: 972–978, 1999.
128. Zimmermann J, Herrlinger S, Pruy A, Metzger T, and Wanner C.
Inflammation enhances cardiovascular risk and mortality in hemodialysis
patients. Kidney Int 55: 648–658, 1999.
129. Zwaka T, Hombach V, and Torzewski J. C-reactive protein-mediated
low density lipoprotein uptake by macrophages: implications for athero-
sclerosis. Circulation 103: 1194–1197, 2001.
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Am J Physiol Renal Physiol 286: F1239, 2004;
10.1152/ajprenal.00067.2004. Corrigendum

Volume 286, March 2004

Volume 55, March 2004

Pages F426 –F442: Lane, JT. “Microalbuminuria as a marker of cardiovascular and renal risk in type 2
diabetes mellitus: a temporal perspective.” On p. F443, the references in Table 1 were printed incorrectly. A
corrected version of Table 1 appears below.

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http://www.ajprenal.org 0363-6127/04 $5.00 Copyright © 2004 the American Physiological Society F1239