REVIEW ARTICLE

Slowing Progression Along the Renal Disease Continuum

Nelson P. Kopyt, DO

Patients in whom nephropathy develops as a result of

hypertension or diabetes mellitus are more likely to die of
cardiovascular disease (CVD) than of kidney disease. An
early sign of impending nephropathy is microalbuminuria,
defined as urinary excretion of albumin at a rate of
28.8 mg/24 h to 288 mg/24 h. Microalbuminuria is a marker
of endothelial dysfunction, vascular injury, and renal disease and CVD, and it is associated with increased risk for
myocardial infarction. Oxidative stress and endothelial
dysfunction are unifying factors mediated by the reninangiotensin system in renal disease and CVD. Clinical
trials show reduced cardiovascular risk and a reversal of
microalbuminuria with the use of agents that affect the
renin-angiotensin system: angiotensin-receptor blockers in
patients with type 2 diabetes mellitus and nephropathy, or
angiotensin-converting enzyme inhibitors in patients with
type 1 diabetes mellitus.

reventing renal impairment is an urgent challenge for

the medical profession. No treatment modality other
than kidney transplantation effectively restores renal function
once end-stage renal disease (ESRD) develops, and cardiovascular disease (CVD) is the leading cause of death among
patients with ESRD.1 Progression along the continuum from
early renal impairment to ESRD involves interactions of risk
factors and deleterious conditions with increasing cardiovascular and renal risk (Figure).
The excessive risk for CVD associated with nephropathy
is due to a greater prevalence of cardiovascular risk factors
older age, hypertension, high blood cholesterol and lipid levels,
diabetes mellitus, and physical inactivityin patients with
renal disease.2 Use of the glomerular filtration rate (GFR) as a
reliable indicator of renal function (Table 1),3 indicates an estimated 8.3 million persons in the United States have chronic
kidney disease (CKD); of these, 5.9 million have stage 1 renal
disease, and 300,000 are in stage 5, or kidney failure.3 Age,
hypertension, and diabetes mellitus are key predictors of CKD

From Temple University, Philadelphia, Pa, and the Department of Nephrology,

Lehigh Valley Hospital, Allentown, Pa.
Address correspondence to Nelson Kopyt, DO, FACP, Nephrology Hypertension Associates of the Lehigh Valley, 50 S 18th St, Easton, PA 18042-3912.
Dr Kopyt serves on the speakers bureau of Novartis; Merck & Co, Inc;
Pfizer Inc; Amgen; Sankyo Pharma Inc; and Scios Inc.
E-mail: DrNPK@aol.com

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(stages 3 through 5), and 11% of individuals in the United

States aged 65 years and older have stage 3 kidney disease
or worse, even without hypertension or diabetes.3
Renal disease clearly increases the risk for premature
CVD. Even after the stratification by age, gender, race, and
presence of diabetes, CVD mortality in patients with ESRD is
10 to 20 times greater than in the general population, and in
patients aged 45 years and younger, more than 100 times
greater.4 Left ventricular hypertrophy (LVH) already is present
in approximately 75% of patients who start dialysis.5 Other cardiovascular diseases that occur in patients with ESRD include
coronary atherosclerosis, heart failure, ischemic heart disease
(angina pectoris, myocardial infarction), and aortic and arterial stiffening.6
Kidney impairment that leads to ESRD usually progresses
through several well-defined stages: microalbuminuria,
macroalbuminuria (dipstick-positive albuminuria), chronic
renal insufficiency, chronic renal failure, and ESRD. This progression to ESRD collectively is called chronic kidney disease
and is classified into five stages as defined in Table 1. Diabetes
mellitus is the most common cause of ESRD.2 Among patients
with type 2 diabetes, the annual transition rate from one stage
of renal disease to the next is between 2% and 3%.7

Microalbuminuria: A Marker
for Cardiovascular Disease
Microalbuminuria (a slight elevation in urinary albumin excretion) is associated with cardiovascular risk factors and is considered an independent risk factor for morbidity.8 In the Third
National Health and Nutrition Examination Survey (NHANES
III), the prevalence of microalbuminuria varied with the
number and type of risk factors: 28.1% in diabetic patients,
12.8% in nondiabetic patients with hypertension, and 4.8% in
persons with neither diabetes nor hypertension.9
Patients with microalbuminuria may progress along the
renal continuum to CKD (indicated by macroalbuminuria or
proteinuria), increased serum creatinine concentration, and
decreased GFR. Serum creatinine levels are used to estimate the
GFR. With progressive CKD, single nephron glomerular pressure increases,3,10 eventually leading to glomerulosclerosis. In
patients with early nephropathy, serum creatinine concentration and creatinine clearance are within normal limits, but
microalbuminuriathe earliest clinical sign of nephropathy
already is present.11 Microalbuminuria is measured through
laboratory assessments of 24-hour urine collection, timed colJAOA Vol 105 No 4 April 2005 207

REVIEW ARTICLE
RAS activity
Angiotensin II
Oxidative Stress/
Vasoconstriction

Hypertension

IGT
DM Risk
CVD Risk

GFR
Serum Creatinine

Glomerular Pressure

Microalbuminuria
UAER

Gomerular Sclerosis

Macroalbuminuria
Proteinuria

Predicts Stroke,
CHD, CVD Risk

Chronic Kidney
Disease

End-Stage
Renal Disease

Figure. The renal disease continuum. Ang II indicates angiotensin II; CHD, coronary heart disease; CVD, cardiovascular disease; DM, diabetes
mellitus; GFR, glomerular filtration rate; IGT, impaired glucose tolerance; RAS, renin-angiotensin system; UAER, urinary albumin excretion rate.

lection, or spot collection11-13; because the creatinine concentration in urine remains relatively constant, the albumin
creatinine ratio also can be used to quantify 24-hour urinary
albumin excretion rates.14 Table 2 shows classifications
of kidney function based on various methods of measuring
urinary albumin excretion.11
Microalbuminuria now is recognized as an important
marker of renal disease and CVD.15 Microalbuminuria, or estimated GFR of less than 60 mL/min, is considered a major
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cardiovascular risk factor in the Seventh Report of the Joint

National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC 7).16 In Finland,
among patients with and without type 2 diabetes, presence of
microalbuminuria (defined as total urinary albumin excretion

150 mg/dL) predicted stroke and serious coronary heart
disease.17 A population-based study of more than 40,000 persons in the Netherlands found that microalbuminuria was
present in 6.6% of nonhypertensive individuals without diaKopyt Review Article

REVIEW ARTICLE

Table 2
Urinary Albumin Excretion: Definitions*

Category

Normal

Microalbuminuria

Clinical Albuminuria
(Overt Proteinuria)

24-Hour Urine
Excretion
(mg/24 h)

Timed
Collection
(g/min)

Spot Collection,
AlbuminCreatinine
Ratio (g/mg)

30
30299

300

20
20199

200

30
30299

300

* Adapted from American Diabetes Association.

Position Statement: Diabetic Nephropathy. Diabetes Care. 2003;26(suppl 1):S94-S98.

atinine clearance 39  18 mL/min/1.73 m2), muscle sympathetic activity was significantly greater than in control subjects (P  .05) and correlated with plasma renin activity.24

Role of the Renin-Angiotensin System

Angiotensin II binds to the angiotensin II type 1 (AT1) receptor
on cell membrane surfaces of a wide variety of tissues,
including vascular smooth muscle, the heart, and the kidneys.
Increased plasma renin activity leads to increased levels of
angiotensin II. Data from a variety of sources now point to
the renin-angiotensin systems central role in the pathophysiology of diabetic and hypertensive nephropathy and the relationship between nephropathy and CVD. The presence of
microalbuminuria, an important marker of renal disease and
CVD, appears to indicate that vascular injuryendothelial
dysfunctionalready has occurred.25 In turn, endothelial dysfunction appears to be a consequence of oxidative stress,26,27 and
evidence from animal studies indicates oxidative stress is
reduced or reversed by the action of either AT1 receptor
blockers (ARBs) or angiotensin-converting enzyme (ACE)
inhibitors.28
The kidney is susceptible to oxidative stress26; oxidative
stress is associated with hyperglycemia and has a role in the
development and progression of diabetic nephropathy.26
Oxidative stress represents discord in the dynamic equilibrium between antioxidants and prooxidants (reactive oxygen
species such as free radicals, increased levels of which lead to
tissue damage) and also in the equilibrium among prooxidants.27
Nitric oxide, a free radical with a short half-life, mediates
normal endothelial function. Nitric oxide deficiency is an
important factor in endothelial dysfunction and atherogen210 JAOA Vol 105 No 4 April 2005

Downloaded From: http://jaoa.org/ on 05/23/2015

esis.29 Nitric oxide deficiency secondary to inactivation by

reactive oxygen species may have a central role in diabetic
nephropathy. A potential source of reactive oxygen species,
p47phox, is enhanced in the kidneys of diabetic rats, indicating oxidative stress.28 In diabetic rats treated with either
the ACE inhibitor quinapril hydrochloride or the ARB candesartan cilexetil, however, expression of p47phox was suppressed significantly (P  .005 vs diabetic animals and P .002
vs diabetic animals, respectively). Another manifestation of
oxidative stress is increased production of nitrotyrosine.
Nitrotyrosine production was significantly suppressed by
treatment with either quinapril (P  .05) or candesartan
(P  .01) versus untreated animals in this same study.28 In
addition, treatment with either drug significantly reduced the
renal excretion of albumin (P  .02 with quinapril and P  .05
with candesartan vs diabetic animals; which had increased
substantially 4 weeks after induction of diabetes.
Data obtained from studies of diabetes in rats indicate
the AT1 receptor plays a critical role in the pathophysiology of
oxidative stress in the diabetic kidney and, probably, in the
hypertensive kidney. Angiotensin II type 1 receptordependent
oxidative stress and the consequent adverse effects on endothelial function appear to be unifying factors in renal disease and
CVD. The central role of the AT1 receptor in oxidative stress
also explains what has been observed in clinical trials: Either
ARB treatment or ACE inhibition not only reverses or retards
the progression of renal disease, but also reduces the risk of
CVD in patients with nephropathy. The concept of AT1-dependent oxidative stress also may explain why the beneficial
effects of renin-angiotensin system antagonism on CVD and
renal disease are independent of a reduction in blood pressure30
or changes in renal hemodynamics.28,31
Kopyt Review Article

REVIEW ARTICLE

Table 2
Urinary Albumin Excretion: Definitions*

Category

Normal

Microalbuminuria

Clinical Albuminuria
(Overt Proteinuria)

24-Hour Urine
Excretion
(mg/24 h)

Timed
Collection
(g/min)

Spot Collection,
AlbuminCreatinine
Ratio (g/mg)

30
30299

300

20
20199

200

30
30299

300

* Adapted from American Diabetes Association.

Position Statement: Diabetic Nephropathy. Diabetes Care. 2003;26(suppl 1):S94-S98.

atinine clearance 39  18 mL/min/1.73 m2), muscle sympathetic activity was significantly greater than in control subjects (P  .05) and correlated with plasma renin activity.24

Role of the Renin-Angiotensin System

Angiotensin II binds to the angiotensin II type 1 (AT1) receptor
on cell membrane surfaces of a wide variety of tissues,
including vascular smooth muscle, the heart, and the kidneys.
Increased plasma renin activity leads to increased levels of
angiotensin II. Data from a variety of sources now point to
the renin-angiotensin systems central role in the pathophysiology of diabetic and hypertensive nephropathy and the relationship between nephropathy and CVD. The presence of
microalbuminuria, an important marker of renal disease and
CVD, appears to indicate that vascular injuryendothelial
dysfunctionalready has occurred.25 In turn, endothelial dysfunction appears to be a consequence of oxidative stress,26,27 and
evidence from animal studies indicates oxidative stress is
reduced or reversed by the action of either AT1 receptor
blockers (ARBs) or angiotensin-converting enzyme (ACE)
inhibitors.28
The kidney is susceptible to oxidative stress26; oxidative
stress is associated with hyperglycemia and has a role in the
development and progression of diabetic nephropathy.26
Oxidative stress represents discord in the dynamic equilibrium between antioxidants and prooxidants (reactive oxygen
species such as free radicals, increased levels of which lead to
tissue damage) and also in the equilibrium among prooxidants.27
Nitric oxide, a free radical with a short half-life, mediates
normal endothelial function. Nitric oxide deficiency is an
important factor in endothelial dysfunction and atherogen210 JAOA Vol 105 No 4 April 2005

Downloaded From: http://jaoa.org/ on 05/23/2015

esis.29 Nitric oxide deficiency secondary to inactivation by

reactive oxygen species may have a central role in diabetic
nephropathy. A potential source of reactive oxygen species,
p47phox, is enhanced in the kidneys of diabetic rats, indicating oxidative stress.28 In diabetic rats treated with either
the ACE inhibitor quinapril hydrochloride or the ARB candesartan cilexetil, however, expression of p47phox was suppressed significantly (P  .005 vs diabetic animals and P .002
vs diabetic animals, respectively). Another manifestation of
oxidative stress is increased production of nitrotyrosine.
Nitrotyrosine production was significantly suppressed by
treatment with either quinapril (P  .05) or candesartan
(P  .01) versus untreated animals in this same study.28 In
addition, treatment with either drug significantly reduced the
renal excretion of albumin (P  .02 with quinapril and P  .05
with candesartan vs diabetic animals; which had increased
substantially 4 weeks after induction of diabetes.
Data obtained from studies of diabetes in rats indicate
the AT1 receptor plays a critical role in the pathophysiology of
oxidative stress in the diabetic kidney and, probably, in the
hypertensive kidney. Angiotensin II type 1 receptordependent
oxidative stress and the consequent adverse effects on endothelial function appear to be unifying factors in renal disease and
CVD. The central role of the AT1 receptor in oxidative stress
also explains what has been observed in clinical trials: Either
ARB treatment or ACE inhibition not only reverses or retards
the progression of renal disease, but also reduces the risk of
CVD in patients with nephropathy. The concept of AT1-dependent oxidative stress also may explain why the beneficial
effects of renin-angiotensin system antagonism on CVD and
renal disease are independent of a reduction in blood pressure30
or changes in renal hemodynamics.28,31
Kopyt Review Article

REVIEW ARTICLE
ACE Inhibitors in Patients With Renal Disease
Since the 1993 publication of the first randomized clinical trial
to demonstrate an antihypertensive-independent renoprotective effect of captopril in patients with type 1 diabetes mellitus
and chronic renal insufficiency (proteinuria
500 mg/24 h;
serum creatinine 2.5 mg/dL),32 other studies33-35 have confirmed the beneficial effects of ACE inhibition on diabetic
nephropathy. Patients with microalbuminuria and normotensive, normoalbuminuric patients with type 2 diabetes
mellitus have benefited from ACE inhibition. The benefits of
this antagonism of the renin-angiotensin system also extend to
patients with nondiabetes-associated renal disease.36
Among 3577 patients with diabetes and a high risk for
CVDwho were enrolled in the Heart Outcomes Prevention
Evaluation (HOPE) trial and received conventional therapy
including -blockers, diuretics, and calcium channel blockers
ramipril significantly decreased primary outcome (myocardial infarction, cardiovascular death, or stroke) (P  .0004),
all-cause mortality (P  .004), and the development of overt
nephropathy (P  .027) compared with either vitamin E or
placebo.37,38 Ramipril also was significantly more effective
than placebo in reducing the risk of death, myocardial infarction, and stroke in high-risk patients with and without diabetes
and without left ventricular systolic dysfunction or heart failure
(P  .001), independent of its antihypertensive effect.38 The
HOPE trial showed that microalbuminuria predicted the onset
of overt nephropathy and macroalbuminuria in patients with
and without diabetes, and that treatment with ramipril reduced
the risk for disease progression.39
A HOPE substudyMicroalbuminuria, Cardiovascular,
and Renal Outcomes in the HOPE Study (MICRO-HOPE)
examined the relationships among microalbuminuria and
other renal and cardiovascular risk factors and between
microalbuminuria and cardiovascular outcomes in patients
at high risk for CVD.40 Microalbuminuria was associated independently with several risk factors for CVD, including
increased age, hypertension, history of a cardiovascular event,
abdominal obesity, and LVH.40 Treatment with ramipril
reduced the relative risk of myocardial infarction, stroke, and
death by 25% and overt nephropathy by 24%, compared with
placebo.37
The Captopril Primary Prevention Project (CAPPP)a
randomized, open-label, blinded endpoint trial of 10,985
patientsdemonstrated that captopril was equivalent to conventional therapy (diuretics and -blockers) in preventing
cardiovascular morbidity and mortality in hypertensive
patients.41 During the 6-year course of the study, captopril
significantly reduced the risk of new-onset diabetes by 14%
(P  .039)41 and significantly decreased cardiovascular risk in
patients with diabetes mellitus with a relative risk of 0.59 (95%
CI, 0.380.91; P  .019), independent of blood pressure.41,42
Hypertension and nephropathy pose a greater risk for
ESRD in African Americans than in Caucasians, and African
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Americans represent 32% of treated patients with ESRD.2 The

African American Study of Kidney Disease and Hypertension (AASK) trial evaluated the efficacy of two levels of blood
pressure control in African American patients with hypertensive renal disease (GFR, 20 mL/min/1.73 m 2 to
65 mL/min/1.73 m2) but without diabetes. Ramipril appeared
more effective in slowing the progression of hypertensive
nephropathy than metoprolol or amlodipine.43-45 A somewhat
surprising finding was that achieving the goal of lower blood
pressure (mean arterial pressure 92 mm Hg) provided no
additional benefit in terms of slowing the progression of
nephropathy than achieving the usual blood pressure goal
(mean arterial pressure, 102107 mm Hg).44

ARBs in Patients With Renal Disease

In patients with type 2 diabetes mellitus, ARBs are especially
effective for decreasing nephropathy progression rate, independent of their blood pressurelowering effect (Table 3). The
randomized, double-blind, active-controlled, parallel-group
MicroAlbuminuria Reduction with VALsartan (MARVAL)
trial investigated the renoprotective effects of valsartan and
amlodipine in patients with diabetes, with or without hypertension.31 During the 24-week course of the MARVAL trial, valsartan was significantly more effective than amlodipine in
reducing the urinary albumin excretion rate in the entire population with diabetes (P  .001), in patients with diabetes and
hypertension at study entry (P  .001), and in normotensive
patients with diabetes at study entry (P  .001) with equivalent effects on blood pressure.31
In the Reduction of Endpoints in NIDDM (noninsulindependent diabetes mellitus) with the Angiotensin II
Antagonist Losartan (RENAAL) study, 1513 patients were
assigned at random to receive losartan or placebo in addition
to conventional antihypertensive therapy (excluding ACE
inhibitors or another ARB).46 Losartan reduced the risk of the
doubling of serum creatinine concentration by 25% (P  .006)
and of ESRD by 28% (P  .002).46 The decreased risks of
ESRD (26%; P  .007) and of ESRD or death (19%; P  .02)46
remained unchanged after adjustment for blood pressure,
indicating renoprotection was independent of blood
pressure reduction.46
The Losartan Intervention For Endpoint reduction in
hypertension study (LIFE) found that losartan was more effective than atenolol in preventing cardiovascular morbidity or
death in hypertensive patients with and without diabetes
(P  .021),47,48 with a 25% lower incidence of new-onset diabetes
and stroke (both P  .001) and a lower adverse event rate
(P  .001).47 Throughout the mean 4.8 years of follow-up,
blood pressure responses (systolic, diastolic, and mean arterial
pressure) were virtually identical in patients randomly assigned
to either drug, indicating the reduced risk for cardiovascular
events with losartan was independent of its blood pressurelowering effect.47,48 In contrast, in a community-based
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REVIEW ARTICLE

Table 3
Trials of Angiotensin-Receptor Blockers in Patients
With Type 2 Diabetes Mellitus and Nephropathy*

Study

Patients (N)

Treatment

Mean
Duration

Endpoints

Results (P)

RENAAL

Type 2
diabetes mellitus,
nephropathy (1513)

Losartan
vs placebo

3.4 y

Composite of
doubling serum
creatinine concentration,
ESRD, death

15% risk reduction of

composite endpoint (.03)

IDNT

Hypertension, type 2
diabetes mellitus,
nephropathy (1715)

Irbesartan vs
amlodipine
vs placebo

2.6 y

Composite of
doubling serum
creatinine concentration,
ESRD, death

24% risk reduction of

composite endpoint vs
amlodipine (.005); 19% risk
reduction of composite
endpoint vs placebo (.03)

IRMA-2

Hypertension, type 2
diabetes mellitus,
microalbuminuria
(590)

Irbesartan
vs placebo

2y

Time to new-onset
diabetic nephropathy

39% risk reduction in

150-mg group (.08); 70% risk
reduction in 300-mg group
(.001)

MARVAL

Type 2 diabetes
mellitus,
microalbuminuria
(332)

Valsartan vs
amlodipine

Percent change in
urinary baseline albumin
excretion rate

44% risk reduction from

baseline with valsartan (.001);
8% risk reduction from
baseline with amlodipine;
treatment effect, valsartan
vs amlodipine (.001)

LIFE

55 years with

hypertension,
left ventricular
hypertrophy
(9193)

Losartan vs
atenolol (with
or without
other medications)

Cardiovascular death,
myocardial infarction,
or stroke (composite);
stroke; diabetes
mellitus

13% risk reduction of endpoint

(.021); 25% risk reduction
of stroke (.001); 25% risk
reduction of diabetes mellitus
(.001)

24 wk

4.8 y

* ESRD indicates end-stage renal disease.

Sources:
RENAAL (Reduction of Endpoints in NIDDM (non-insulindependent diabetes mellitus) with the Angiotensin II Antagonist Losartan): Brenner BM,
Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al, for the RENAAL Study Investigators. Effects of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
IDNT (Irbesartan Diabetic Nephropathy Trial): Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al, for the Collaborative Study
Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J
Med. 2001;345:851-860.
IRMA 2 (IRbesartan in patients with type 2 diabetes and MicroAlbuminuria): Parving HH, Lehnert H, Brchner-Mortensen J, Gomis R, Andersen S,
Arner P, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of
diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-878.
MARVAL (MicroAlbuminuria Reduction with VALsartan): Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with
type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672-678.
LIFE (Losartan Intervention For Endpoint reduction in hypertension study): Dahlf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et
al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study
(LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.
Lindholm LH, Ibsen H, Dahlf B Devereux RB, Beevers G, et al, for the LIFE study group. Cardiovascular morbidity and mortality in patients with
diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet.
2002;359:1004-1010.

Adjusted values.

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study of 12,550 adults, type 2 diabetes mellitus was almost
2.5 times more likely to develop in patients with hypertension, and 28% more likely to develop in patients taking blockers than in those receiving no medication (relative hazard,
1.28; 95% CI, 1.041.57).49 This increased risk was not seen in
patients receiving thiazide diuretics, calcium channel blockers,
or ACE inhibitors. In addition, risk was not influenced by the
presence or absence of hypertension, weight gain, healthrelated behavior, level of education, or a variety of diabetesrelated clinical traits and coexisting conditions.49 Potential
mechanisms for the increased incidence of diabetes with blockers include an attenuation of the -receptormediated
release of insulin from pancreatic beta cells and decreased
blood flow through the microcirculation in skeletal muscle
tissue leading to decreased insulin sensitivity.50
Among patients with echocardiographic evidence of LVH
at entry into the LIFE study, the urinary albumin-creatinine
ratio was significantly higher in those with both eccentric and
concentric LVH than in hypertensive patients with normal
left ventricular geometry.51 The correlation between urinary
albumin-creatinine ratio and LVH was independent of age,
race, systolic blood pressure, and presence of diabetes.51
The Irbesartan Diabetic Nephropathy Trial (IDNT) compared irbesartan with amlodipine and placebo in diabetic
hypertensive patients with macroalbuminuria (urinary protein
excretion
900 mg/24 h).52 Over the mean 2.6 years of followup, irbesartan was associated with a significantly slower
increase in serum creatinine concentration compared with
placebo (P  .008) and with amlodipine (P  .02).52 Although
the degree of blood pressure control in the irbesartan and
amlodipine groups was the same, patients receiving
amlodipine had worse renal outcomes (primary renal endpoint, doubling of baseline serum creatinine concentration).52
This observation supports the concept that renoprotection
provided by angiotensin-receptor blockade in patients
with type 2 diabetes mellitus and nephropathy is a result of
suppression of angiotensin II activity.52
The randomized, double-blind, placebo-controlled trial
IRbesartan in patients with type 2 diabetes and MicroAlbuminuria (IRMA-2) compared the effects of two doses of irbesartan and placebo on development of diabetic nephropathy.25
This trial differed from the IDNT in that microalbuminuria, not
macroalbuminuria, was an enrollment criterion. Overt
nephropathy developed in significantly fewer patients taking
irbesartan during the 24-month study (group treated with
150 mg of irbesartan vs group receiving placebo, P  .05;
group treated with 300 mg of irbesartan vs group receiving
placebo, P  .001).25 Kaplan-Meier curves for the group
receiving placebo and the group treated with 300 mg of irbesartan separated after 3 months of therapy and continued to
diverge over the ensuing 21 months.25 As in other studies
with ARBs, the renoprotective effects of irbesartan were independent of its blood pressure effects.25
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Therapeutic Options
Tight blood pressure control reduces the risk of microvascular and macrovascular complications in patients with type 2
diabetes,53 and intensive blood glucose control delays the
onset and slows the progression of diabetic vascular complications.54 Based on results of clinical trials and basic research
data implicating the renin-angiotensin system in the etiology
of endothelial dysfunction, renal disease, and CVD, the JNC 7
report recommends ARBs or ACE inhibitors as first-line
treatment in patients with diabetic hypertension and in
patients with hypertension and microalbuminuria, often in
combination with another medication, to achieve target
blood pressure.16
American Diabetes Association guidelines emphasize the
necessity of reducing risk factors for CVD and delaying the
onset of nephropathy or slowing progression along the renal
continuum from microalbuminuria to macroalbuminuria.55
An important strategy to reduce CVD risk in patients with
diabetes is blood pressure control, with a target of
130/80 mm Hg or lower.55 In patients with hypertension, diabetes mellitus prompts consideration of an ARB or ACE
inhibitor as first-line therapy because both classes of medication reduce proteinuria and slow progression of diabetic
nephropathy. In addition, ARBs reduce progression to macroalbuminuria,10,16,55 as indicated by the 44% reduction from baseline urinary albumin excretion rate in patients taking valsartan
in the MARVAL trial.31
In patients with type 1 diabetes mellitus, with or without
hypertension and with any degree of albuminuria, ACE inhibition delays the progression to nephropathy; in patients with
type 2 diabetes mellitus, hypertension, and microalbuminuria, ARBs delay progression to macroalbuminuria and
nephropathy; and in patients with type 2 diabetes mellitus,
hypertension, and nephropathy (macroalbuminuria and serum
creatinine 1.5 mg/dL), ARBs slow progression of
nephropathy and are the initial agent of choice.55
The randomized, double-blind, placebo-controlled
Nateglinide And Valsartan in Impaired Glucose Tolerance
Outcomes Research (NAVIGATOR) trial56 is investigating
associations among the renin-angiotensin system, cardiovascular risk, and diabetes progression in a large, high-risk population (N  7500 to 11,000 patients) with impaired glucose tolerance that has been treated with valsartan, the antidiabetic
agent nateglinide, a combination of both, or neither. Results are
expected in 2007.

Comment
Microalbuminuria, an early indication of nephropathy, appears
to indicate widespread endothelial dysfunction. Experimental
evidence shows endothelial dysfunction is a consequence of
AT1-dependent oxidative stress, an early step in the progression along the renal continuum. Microalbuminuria is a risk
factor for both CVD and renal disease progression in patients
JAOA Vol 105 No 4 April 2005 213

REVIEW ARTICLE
with diabetes or hypertension or both, and patients with
reduced renal function have an increased risk of cardiovascular
death. Multiple randomized clinical trials have demonstrated
that medications can: suppress the renin-angiotensin system,
either through ACE inhibition or blocking the AT1 receptor;
improve vascular and renal function as evidenced by reduced
microalbuminuria; slow the progression of nephropathy in
patients with diabetes and in hypertensive patients with and
without diabetes; and reduce the risk for CVD.
Medications that slow the progression along the renal
continuum include ACE inhibitors in type 1 diabetes mellitus
and ARBs in type 2 diabetes mellitus. ARBs are effective antihypertensive agents with a better tolerability profile that may
lead to improved patient care. Their actions independent of
blood pressure effects improve cardiovascular and renal function. ARBs are a reasonable choice as initial therapy for patients
with microalbuminuria, particularly when both hypertension
and microalbuminuria are present.

References
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