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 minorities (29, 71). The long-term implications for micro- and
cardiovascular disease in patients with type 1 (DM1) and type macrovascular disease and quality of life are enormous. In an
2 (DM2) diabetes mellitus (12, 81–83, 91, 119). Microalbu- effort to understand the development of DM2 in youth, high-
minuria refers to the excretion of albumin in the urine at a rate risk populations are being closely monitored with emphasis on
that exceeds normal limits but is less than the detection level early markers of disease. The goal is the development of
for traditional dipstick methods (4). Microalbuminuria has treatment strategies that will prevent or change the natural
been utilized as a screening test for the presence of diabetes- history of diabetes and its complications.
related kidney disease in patients with DM1. Results are The goal of this review is to summarize the evidence
expressed as milligrams per 24-h urine specimen, micrograms supporting an association of microalbuminuria with conditions
per minute in a timed urine specimen, or as micrograms per that may occur before the development of DM2 in high-risk
milligram creatinine in a random spot urine test (4). Detection populations, including obesity, the insulin resistance syn-
of microalbuminuria is important from a clinical standpoint drome, and impaired glucose tolerance. First Nation (Canadian
because, once detected, it is an indication for the initiation of North American Indians) and American Indians in North
anti-angiotensin II therapy with the purpose of preventing or America are highlighted as an example of a high-risk popula-
delaying the advance of progressive diabetic nephropathy (4, tion, but similar data exist for other ethnic groups at high-risk
10, 70, 79, 89, 90). Although the positive predictive value of for DM2, including African Americans and Hispanics (36). It
microalbuminuria for progressive diabetic nephropathy is less is clear that cardiovascular risk and disease begin before the
than once thought, it remains a standard clinical test with diagnosis of DM2 in patients with insulin resistance and can be
important ramifications for patient management (12). accelerated in young adults. The challenge is to learn more
As noted below, the development of diabetes-related kidney about the temporal pattern of disease markers that reflect
disease is similar in patients with DM1 and DM2 (88). How- disease evolution and why they occur, choose appropriate
ever, issues involving the time course of the process are blurred strategies for intervention, and conduct clinical trials that will
by the insidious onset of DM2. In patients with DM2, it has prevent both cardiovascular and renal disease in patients at
become evident that microalbuminuria is also a predictor of risk.
cardiovascular death (81). However, the presence of mi-
NATURAL HISTORY OF MICROALBUMINURIA
croalbuminuria in DM2 may be more reflective of generalized
IN DM1 DIABETES
vascular disease than diabetic glomerulopathy.
The past 10 years have seen a troubling increase in the Microalbuminuria is not usually a presenting finding at the
prevalence of DM2 in youth (29, 34, 71, 102, 114). This onset of DM1. After a 5- to 10-yr duration of diabetes,
epidemic of DM2 in youth has preferentially affected ethnic susceptible patients develop intermittent microalbuminuria be-
fore having persistent microalbuminuria (84). Improved blood
Address for reprint requests and other correspondence: J. T. Lane, Dept. of glucose control (23a, 110, 117a), antihypertensive therapy, and
Medicine, Nebraska Medical Center, Omaha, NE 68198-3020 (E-mail: anti-angiotensin II therapy (10, 27a, 67, 70, 74, 77, 80a, 90,
jtlane1@unmc.edu). 120) have been shown to delay or prevent the progression of
F442 0363-6127/04 $5.00 Copyright © 2004 the American Physiological Society http://www.ajprenal.org
 Invited Review
MICROALBUMINURIA AND CV/RENAL RISK F443
microalbuminuria and the development of nephropathy. In estingly, regression was not associated with angiontensin-
DM1, microalbuminuria is a strong risk factor for the devel- converting enzyme inhibitor use but was associated with gly-
opment of nephropathy. The development of microalbuminuria cosylated hemoglobin levels of ⬍8%, systolic blood pressure
is associated with established extracellular matrix expansion in of ⬍115 mmHg, and low levels of cholesterol and triglycer-
the glomerular and tubulointerstitial compartments of the kid- ides. If regression occurs with this frequency, it brings into
ney (69). The natural history results in progressive glomerulo- question the underlying mechanism(s) and true specificity for
sclerosis, increasing proteinuria, and chronic renal failure. The microalbuminuria as a marker for progressive renal impair-
long period between the onset of microalbuminuria and chronic ment.
renal failure (in years) offers a substantial window for thera-
peutic intervention (117). NATURAL HISTORY OF MICROALBUMINURIA IN DM2
Recent data suggest that microalbuminuria in DM1 may
regress over time. Perkins et al. (94) reported data from the Because of the insidious onset of DM2, the true duration of
Joslin Clinic on 386 patients with DM1 who were followed for the disease is often not known. It has been reported that a
8 yr (Table 1). Regression was defined as a 50% decrease in duration of ⬎6 yr of diabetes may have existed before diag-
albumin excretion from one 2-yr study period to the next 2-yr nosis (46). Because of the variable duration of disease at
study period and occurred in 58% of the patients (94). Inter- 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 hypertension, dyslipidemia, or microalbuminuria) (55). If
nephropathy in DM1 with similar pathology, response to in- present, the insulin resistance syndrome increased the risk for
terventions of glucose control and anti-angiotensin II therapy, coronary artery disease and stroke threefold. However, mi-
and progression to chronic renal failure (12, 99). DM2 with croalbuminuria was the strongest risk for cardiovascular death.
nephropathy involves a similar proportion of patients, com- Of those with normal glucose tolerance, 10% had microalbu-
pared with DM1 (49). At present, there is not a similar minuria, suggesting the potential for microalbuminuria as a
long-term study evaluating regression in DM2 as described marker for the risk of coronary artery disease in nondiabetic
above for DM1. However, data taken from recent intervention individuals. This is such an important association that the
studies using angiotensin II receptor antagonists demonstrate World Health Organization has included microalbuminuria in
some regression. Lewis et al. (70) reported on the use of its definition of the metabolic syndrome (2).
irbesartan in patients with DM2 and nephropathy. A 33%
decrease in proteinuria was seen over 2.6 yr, whereas the MICROALBUMINURIA AS A RISK FACTOR
placebo group decreased 10%. A similar study using losartan IN NONDIABETIC PEOPLE
in DM2 and nephropathy found a reduction of 35%, whereas
the placebo group had a rise in proteinuria (10). Parving et al. A number of studies have demonstrated that microalbumin-
(90) reported on the use of irbesartan in a population of uria occurs in individuals without diabetes. In the Mexico City

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hypertensive patients with DM2 and microalbuminuria and Diabetes Study, nondiabetic people with microalbuminuria
found that microalbuminuria was decreased by 38% over 2 yr were more likely to have a family history of diabetes (42).
with only a change of 2% in the controls. Attempts at preven- Similar findings were reported by in the Botnia study, where
tion of nephropathy in DM2 have focused on the prevention of first-degree relatives of patients with DM2 demonstrated insu-
microalbuminuria, the earliest clinical hallmark of nephropa- lin resistance in association with elevated albumin excretion
thy, or its progression to macroalbuminuria (89, 99). In gen- rates (32). In the Insulin Resistance Atherosclerosis Study,
eral, the evolution of nephropathy in DM2 is similar to what is patients with microalbuminuria were more insulin resistant and
found with DM1. had higher fasting insulin concentrations compared with pa-
tients without microalbuminuria (87). However, the relation-
MICROALBUMINURIA IS ASSOCIATED
ship was also partially dependent on blood pressure and obe-
WITH CARDIOVASCULAR DISEASE
sity. Although the bulk of the data supports microalbuminuria
as being a component of the insulin resistance syndrome, not
Microalbuminuria has been associated with increased car- all results support this contention (56). The Hoorn Study
diovascular mortality in populations of both diabetic and non- evaluated a homogenous Caucasian population and found that
diabetic subjects (43, 57, 81, 125). In fact, microalbuminuria microalbuminuria was associated with hypertension, DM2, and
has been used as a marker of cardiovascular disease, along with waist-hip ratio. It did not, however, associate with other com-
other risk factors found in the insulin resistance syndrome. ponents of the insulin resistance syndrome. This raises the
Data from the Framingham Offspring Study suggest that mi- alternative view that microalbuminuria is associated with hy-
croalbuminuria is more likely to be present with additional pertension but not the insulin resistance syndrome. In Data
cardiovascular risk factors (78). The premise is that microalbu- from an Epidemiological Study on the Insulin Resistance
minuria is a marker of generalized endothelial dysfunction. Syndrome findings, the cardiovascular events were greater in
Microalbuminuria has been linked to increased transcapillary subjects with microalbuminuria (45). However, in contrast to
albumin leakage and increased von Willebrand factor and other men, women did not show the same increased cardiovascular
markers of endothelial dysfunction (59, 106). In survivors of risk with the addition of microalbuminuria. A similar trend was
myocardial infarction, both albuminuria and the transvascular seen in the Inter-Tribal Heart Project, where nondiabetic Na-
escape rate of albumin are increased (58). Albuminuria has tive Americans with microalbuminuria often had the insulin
also been shown to predict the severity of atherosclerosis (86, resistance syndrome (52). Thus hormonal differences may play
116). Others have suggested that the elevated insulin levels that a role in the expression of the increased cardiovascular risk in
occur with insulin resistance increase glomerular hemody- patients with insulin resistance and microalbuminuria. Al-
namic pressures that increase albumin excretion (16, 115). The though this may suggest that estrogen may have some protec-
relative contribution of underlying vascular disease vs. diabetic tive effect, when women are administered estrogen in the pre-
nephropathy toward microalbuminuria is not clear. However, a or postmenopausal setting, it is associated with increases in
large body of evidence suggests that microalbuminuria is an microalbuminuria in a dose- and time-dependent fashion (85).
indicator of both micro- and macrovascular disease. In addition, in women high levels of microalbuminuria, when
Cross-sectional studies have clearly demonstrated the pres- present, are still predictive of cardiovascular disease, as dem-
ence of microalbuminuria with other markers of the insulin onstrated in an epidemiological study from The Netherlands in
resistance syndrome. Using clamp studies, hypertension alone which women with the highest quintile of microalbuminuria
was found to associate with a decrease in glucose disposal by were at increased risk of cardiovascular death (101).
27% (37). However, the combination of microalbuminuria and Such terms as the “ticking clock” or the “common soil”
hypertension was associated with the greatest decrease in hypothesis have been used to suggest that the time course for
glucose disposal. The highest triglycerides and the lowest the development of cardiovascular disease begins before the
HDL-C levels, additional markers of the insulin resistance onset of clinical diabetes (44, 107). The common factors for the
syndrome, were associated with patients having hypertension development of cardiovascular disease may represent genetic
and microalbuminuria. In the Botnia Study, 84% of those with or environmental factors that are present before the clinical
DM2 had elements of the insulin resistance syndrome (obesity, manifestations of disease. Indeed, in the Nurses’ Health Study,
AJP-Renal Physiol • VOL 286 • MARCH 2004 • www.ajprenal.org
 Invited Review
MICROALBUMINURIA AND CV/RENAL RISK F445
the risk for cardiovascular disease was found to be elevated at based studies demonstrate that DM2 occurs in African Amer-
least 15 yr before the diagnosis of diabetes (53). Whether the icans at a rate of 7.2/1,000, in contrast to 4.1/1,000 for all U.S.
common factors for onset of microalbuminuria and diabetes are adolescents aged 12–19 yr (29). Without a plateau in the
preventable is of great interest for future therapy. The Heart increasing prevalence, DM2 will be expected to increase into
Outcomes and Prevention Evaluation study provided powerful the future.
data along these lines (73). The use of the ACE inhibitor
ramipril reduced the progression of albuminuria, whether this MICROALBUMINURIA IN AMERICAN INDIAN CHILDREN
was new albuminuria or the progression of microalbuminuria AND ADULTS
to macroalbuminuria. This study also demonstrated that
The prevalence of microalbuminuria amongst all American
ramipril was effective in decreasing cardiovascular death in
Indian tribes is not known. However, the Strong Heart Study
patients with known heart disease or DM2 patients without
recently revealed the prevalence of microalbuminuria in Ari-
established heart disease. The benefits of ramipril were greatest
zona, Oklahoma, and Dakota Indians to be 28.3, 15.2, and
on preventing cardiovascular events in patients with DM2 and
13.8%, respectively (100). However, these subjects were all
in nondiabetic patients with albuminuria.
adults and may not represent the prevalence of microalbumin-
DM2 IS INCREASING IN YOUTH uria in young American Indians.
Fagot-Campagna et al. (28) reported on the prevalence of

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Over the past 20 years, the prevalence of DM2 has increased cardiovascular risk factors, including microalbuminuria, in
18% in the United States (3). Not only is DM2 more prevalent, Pima children age 5–19 yr. The group included 4,092 10- to
but it often begins at a younger age (71, 102). This has serious 19-yr-old patients with normal glucose tolerance. At baseline,
consequences for long-term health as these patients are also at 6% had microalbuminuria, whereas 8% with impaired glucose
increased risk for cardiovascular disease, end-stage renal dis- tolerance had microalbuminuria. After more than 5 yr, 33% of
ease, blindness, amputation, and the associated personal and the entire cohort had developed microalbuminuria. This is in
economic losses at earlier ages. The younger onset of patients contrast to the rates of microalbuminuria in other healthy
with DM2 suggests that those patients will live with compli- ethnic groups. For African Americans, 7.7% of men and 10.5%
cations for a larger percentage of their lifetime. of women aged 6–19 yr have microalbuminuria (60). Non-
Prevalence rates for diagnosed DM2 in children have been Hispanic whites (5.7/9.7, men/women) and Hispanics (5.4/9.5,
estimated at between 2 and 50/1,000, depending on the popu- men/women) have lower rates of microalbuminuria. After age
lation studied, whereas that for the general adult population is 19, in all ethnic groups the rate of microalbuminuria falls in the
30/1,000 (29). Those children and young adults with the third decade to rates roughly one-half those seen at ages 6–19
highest prevalence rates of DM2 are from racial and ethnic yr. If microalbuminuria serves as a marker of future cardio-
minorities, including African Americans, Hispanics, and Na- vascular and renal disease, efforts to define its prevalence in
tive Americans (29, 71). The increased prevalence of DM2 in high-risk populations are an essential first step to a prevention
children has been attributed to increasing obesity, a sedentary strategy.
lifestyle, and increased intrauterine exposure to a diabetic
environment (8, 29, 34, 71, 114). The degree of obesity is ROLE OF PUBERTY IN DEVELOPMENT
significant, as most published studies have found that affected OF MICROALBUMINURIA
children with DM2 have a mean body mass index (BMI)
Puberty is normally associated with complex changes in
exceeding the 95th percentile for age (29, 71). Because of the
renal hemodynamics, somatic growth, and changes in sex
increased prevalence of DM2, DM1 may no longer represent
hormones that may have important interactions with hypergly-
the most common form of diabetes in youth, as up to 50%
cemia and insulin resistance (68). These changes may, in turn,
of new cases of diabetes in youth are DM2 in some popu-
affect microalbuminuria during puberty. It is rare to develop
lations (71).
microalbuminuria before puberty in DM1. In fact, there has
DM2 IS INCREASED IN NATIVE AMERICANS, been a suggestion that diabetic nephropathy does not occur
INCLUDING YOUTH before puberty (24, 65). Although patients may not have
microalbuminuria, histological changes indicative of diabetic
DM2 is epidemic in American Indian populations (3, 11). nephropathy occur in association with duration of diabetes, not
Data from the Indian Health Service suggest that the preva- pubertal stage (25). However, with DM2, pathological insulin
lence rate is 8.0%, over double the rate for the population as a resistance may interact with developmental changes to accel-
whole (14). There is also a female predominance, with erate the onset of microalbuminuria.
prevalence rates 25% higher in American Indian females Puberty is associated with changes in insulin sensitivity (5,
(13). The prevalence rates for other minorities, including 9, 17, 95). Tanner staging characterizes pubertal development,
African Americans and Hispanics, are similar to those of according to physical findings utilizing examination of pubic
American Indians (3). hair and genitalia in boys and pubic hair, breast size, and
Similar to national trends, American Indian children and menarche in girls (75, 76). Tanner stages range from stages 1
youth are also experiencing an increased prevalence of DM2 (preadolescent) to 5 (fully mature). Several studies have dem-
(20, 21, 29, 47). Numbers for American Indians across the U.S. onstrated that insulin sensitivity decreases early in puberty in
vary from 1.3/1,000 for children 0–14 yr of age to 4.5/1,000 for nondiabetic children as well as patients with diabetes, begin-
youth aged 15–19 yr (29). Recent Indian Health System data ning between Tanner stages 1 and 2 and decreasing throughout
indicate the prevalence rate has risen to 5.4/1,000 for ages puberty. Insulin sensitivity improves to normal after linear
15–19 yr, an increase of 68% over a decade (1, 7). Population- growth is complete in adults. Body fat also increases in early
AJP-Renal Physiol • VOL 286 • MARCH 2004 • www.ajprenal.org
Invited Review
F446 MICROALBUMINURIA AND CV/RENAL RISK

puberty, but BMI does not change with Tanner stage in although this relationship was primarily related to BMI and has
adolescents. been described previously (80, 118). These data raise the point
No clear association between insulin sensitivity and rising that inflammatory processes may negatively impact renal func-
sex steroid concentrations has been found in men (123). How- tion, as well as cardiovascular end points. This may be espe-
ever, polycystic ovary syndrome with its proatherosclerotic cially true in individuals who progress from obesity to predi-
effects (123) often includes increased androgens. It has been abetes to diabetes. No prospective data exist in patients with
recently reported that higher free androgen levels in children diabetes to provide insight into this question.
with DM1 were associated with the development of microalbu- Obesity, especially visceral obesity, has been previously
minuria (6). associated with plasma inflammatory markers, including IL-6,
Several studies have implicated a relationship between in- CRP, and TNF-␣ (18, 50, 62, 121, 126, 127). BMI and
sulin sensitivity and the growth hormone-IGF-1 axis, suggest- hemoglobin A1C have also been associated with inflammatory
ing increased tissue growth hormone effect as the cause (9, 17). markers (105). Acute hyperglycemia has been shown to in-
One study found a significant association among IGF-1, renal crease IL-6, TNF-␣, and IL-18 (27). Low levels of adiponectin
hypertrophy, and microalbuminuria (19). However, others did that occur with obesity are associated with increased IL-6 and
not confirm this relationship (104). To date, studies evaluating CRP plasma levels (26). Visceral obesity is also associated
microalbuminuria during puberty have been cross sectional. with increased free fatty acid release into the portal vein (33).

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Additional prospective studies are needed to more closely This leads to increased hepatic glucose output with resultant
characterize the changes that occur with puberty and the hyperglycemia and decreased hepatic insulin extraction with
development of microalbuminuria. resultant hyperinsulinemia (30, 109). Glowinska et al. (35)
reported that traditional risk factors for cardiovascular disease,
ASSOCIATION OF CARDIOVASCULAR DISEASE WITH such as hypertension and dyslipidemia, are also associated with
MARKERS OF INFLAMMATION nontraditional risk factors, such as decreased fibrinolytic ac-
tivity and homocysteinemia, and lipoprotein (a) levels in obese,
The use of the highly-sensitive C-reactive protein (CRP)
diabetic adolescents.
assay, a sensitive marker of inflammation, has been shown in
a number of studies to predict the risk of cardiovascular disease These findings suggest that prevention of obesity, prevention
events (15, 51, 64, 66, 93, 96–98, 112, 113, 128). An active of hyperglycemia, use of antioxidants, and other anti-inflam-
role for elevated CRP levels in the pathophysiology of vascular matory treatments may be beneficial in addressing the early
disease has been suggested but not definitively proven (23, 92, progressive inflammatory response associated with diabetes
122, 129). Because microalbuminuria, CRP, and other markers and vascular disease. Indeed, glutathione has been shown to
of inflammation have been shown to be associated with car- prevent the rise of cytokine levels (27). The increase in oxi-
diovascular disease, the question arises as to whether the dative stress from obesity was further supported in a commu-
inflammatory process causes the microalbuminuria. nity-based cohort in the Framingham Heart Study (61). Thia-
A large cross-sectional study has demonstrated an associa- zolidinediones increase adiponectin levels (72, 124). Salicy-
tion between microalbuminuria and CRP (31). Festa et al. (31) lates may improve fat-induced insulin resistance (63). Exercise
reported on 1,281 subjects from the Insulin Resistance Athero- is associated with decreased CRP levels (54). These are in
sclerosis Study. The study population contained patients with addition to lifestyle changes to lose weight.
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. Fig. 1. Model for the development of cardiovascular and renal disease in
patients with a variety of disorders surrounding insulin resistance and glucose
CRP was also associated with hyperfiltration (defined by an intolerance. It should be noted that microalbuminuria has been found as a
elevated creatinine clearance and seen before a decrease in marker of these conditions, evident before diabetes, and may serve as a marker
creatinine clearance in patients with diabetic nephropathy), of disease activity.

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 Invited Review
MICROALBUMINURIA AND CV/RENAL RISK F447
CLINICAL USE OF THE MICROALBUMIN ASSAY 5. Amiel S, Sherwin R, Simonson D, Lauritano A, and Tamborlane W.
Impaired insulin action in puberty: a contributing factor to poor glycemic
Although there are clear recommendations for the measure- control in adolescents with diabetes. N Engl J Med 315: 215–219, 1986.
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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