Microalbuminuria as a Target to Improve Cardiovascular and Renal Outcomes

AJKD

VOL 47, NO 6, JUNE 2006

American Journal of Kidney Diseases

REVIEWS

Microalbuminuria as a Target to Improve Cardiovascular and Renal Outcomes Seema Basi, MD, MSCI, and Julia B. Lewis, MD ● Albuminuria is a cardiovascular and renal risk factor in patients with diabetes, patients with hypertension, and the general population. Risk has been shown to increase continuously with increasing urinary albumin levels, starting at levels that once were considered normal. This association is maintained even after adjusting for numerous other factors. Studies also established that a decrease in albuminuria leads to improvement in both cardiovascular and renal outcomes. These data suggest that urinary albumin should be measured routinely and treated to afford cardiovascular and renoprotection. Am J Kidney Dis 47:927-946. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Microalbuminuria; kidney disease; cardiovascular disease; angiotensin-converting enzyme inhibitor; angiotensin II receptor antagonist.

A

LBUMINURIA HAS been known to be a predictor of poor renal outcomes for patients with diabetes mellitus for many years.1-3 It also was shown that albuminuria is a risk factor for cardiovascular and kidney disease in patients with hypertension, as well as in the general population.4-6 In addition, data are emerging that treatment of albuminuria leads to improvement in risk profiles of patients.7-9 Therefore, it is imperative not only that nephrologists measure and treat albuminuria, but also that cardiologists and internists are cognizant of this important risk marker. Prevalence studies in the United States, such as the Third National Health and Nutrition Examination Survey, report a prevalence of albuminuria of 29% in patients with diabetes.10 In Asia, the Microalbuminuria Prevalence Study11 screened 5,549 adult patients with hypertension and type 2 diabetes without previously known macroalbuminuria and found a 40% prevalence of microalbuminuria and 19% prevalence of macroalbuminuria. Similarly, the Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes Study, a cross-sectional study of 24,151 patients in 33 countries, showed overall global prevalences of

39% for microalbuminuria and 10% for macroalbuminuria.12 Clearly, this is a highly prevalent condition. This review summarizes the current literature on the association between microalbuminuria

From the Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN. Received October 21, 2005; accepted in revised form February 22, 2006. Originally published online as doi:10.1053/j.ajkd.2006.02.182 on May 4, 2006. Support: Research support, None; Editorial support, the authors acknowledge the provision of editorial support by a medical writer, Sally Fairbrother, in the preparation of this manuscript. Potential conflicts of interest: J.B.L. is investigator in Bristol Myer Squibb Irbesartan in Diabetic Nephropathy Study, investigator in Sulodexide in Diabetic Nephropathy Study, and on advisory board for Nemikiren in Diabetic Nephropathy Study. S.B. is co-investigator in Sulodexide in Diabetic Nephropathy Study. Address reprint requests to Julia B. Lewis, MD, Vanderbilt University Medical Center, 1161 21st Ave S & Garland, Division of Nephrology, S-3223 MCN, Nashville, TN 372322372. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4706-0001$32.00/0 doi:10.1053/j.ajkd.2006.02.182

American Journal of Kidney Diseases, Vol 47, No 6 (June), 2006: pp 927-946

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BASI AND LEWIS Table 1. Definition and Measurement of Albuminuria Measurement Method

Definition

Dipstick for Protein

24-Hour Protein (mg)

24-Hour Albumin (mg)

Timed Collection (␮g/min)

Spot Collection

Normal Microalbuminuria Macroalbuminuria

⫺ ⫺ ⫹

⬍150 ⬍500 ⱖ500

⬍30 30-300 ⬎300

⬍20 20-200 ⬎200

⬍30 ␮g albumin/mg creatinine 30-300 ␮g albumin/mg creatinine ⬎300 ␮g albumin/mg creatinine

and adverse cardiovascular and renal outcomes. It also summarizes the evidence that a decrease in albuminuria is associated with decreased risk for cardiovascular and renal events in key patient groups. Finally, it speculates on the pathophysiological process of albuminuria and how clinicians should approach and manage this important risk marker. DEFINITION AND MEASUREMENT OF ALBUMINURIA

Microalbuminuria has been defined as 30 to 300 mg of albumin in a 24-hour urine collection, whereas clinical albuminuria or macroalbuminuria is defined arbitrarily as albumin excretion of 300 mg/24 h or greater (Table 1).13 Because albuminuria represents an average of approximately 40% of total urinary protein excretion, patients classified as having albuminuria or macroalbuminuria also will have overt proteinuria. Measurement of albuminuria may be performed in several ways: (1) measurement of albumin-creatinine ratio (ACR) in a random or first-morning spot collection, (2) 24-hour urine collection with measurement of creatinine to verify adequacy of the collection, and (3) timed (4-hour or overnight) urine collection.13 According to the Kidney Disease Outcomes Quality Initiative guidelines, under most circumstances, ACR measurement in a first-morning spot urine collection is adequate and timed urine collection is not necessary.14 Measurement of a spot urine for albumin only by using a dipstick test specific for albumin without simultaneously measuring urine creatinine is susceptible to false-negative and false-positive determinations as a result of variations in urine concentrations caused by hydration level.13 Because women excrete less creatinine than men, it is likely that definitions of microalbuminuria based on ratios ultimately will be different for men and women.15

MECHANISM OF PATHOLOGICAL PROCESS OF ALBUMINURIA

Albuminuria is an independent risk marker for both cardiovascular and renal disease. Although the pathogenic mechanisms that lead to albuminuria remain unclear, several hypotheses have been put forward. It was hypothesized that albuminuria reflects endothelial cell dysfunction, which, in the kidney, is manifested as albuminuria, and in blood vessels, as atherosclerosis.16 Ritz17 proposed that the increased cardiovascular risk seen with microalbuminuria may be caused by endothelial dysfunction acting through various mechanisms, including increased levels of biomarkers of inflammation (C-reactive protein, fibrinogen, interleukin 6, and intercellular adhesion molecule), as well as increased indicators of a procoagulatory state (factor VIII, D-dimers). Another possibility is that urinary albumin leakage causes vascular inflammation. Russo et al18 speculated that upregulation of specific growth factors and cytokines may have a role in tissue damage and fibrosis in the vasculature of the kidney because levels of transforming growth factor ␤ correlate with increased levels of urinary albumin. They postulated that transforming growth factor ␤ may affect albumin uptake and lysosomal breakdown of filtered albumin by proximal tubular cells before excretion. In patients with cardiovascular disease and diabetic kidney disease, albuminuria may reflect alterations in the degradation pathway of filtered albumin, rather than or in addition to being a primary effect of glomerular permeability. Another possibility is that a change in glomerular permeability and charge is responsible for albuminuria. Patients with diabetes and proteinuria have large pores within the glomerular membrane that permit unrestricted passage of large plasma proteins into urine.19 There also is a loss of anionic charge in the glomerular basement

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

membrane.20 This is caused by a decrease in heparan sulfate proteoglycans in the glomerular basement membrane in patients with advanced diabetic nephropathy.21 An inverse correlation was shown between heparan sulfate staining in the glomerular basement membrane and proteinuria.22 Albuminuria also may reflect abnormalities in the renin-angiotensin-aldosterone system (RAAS). The Steno hypothesis16 suggests that microalbuminuria represents a marker of endothelial cell dysfunction, and it is well established that activation of the RAAS, working through the actions of angiotensin II on the angiotensin II type 1 receptor has a major role in the development of endothelial dysfunction and atherosclerosis.23 Stimulation of the angiotensin II type 1 receptor activates multiple pathways that may lead to endothelial damage, including induction of the

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synthesis and release of the inflammatory cytokine interleukin 6,24 increased generation of reactive oxygen species,25 induction of receptors for oxidized low-density lipoprotein,26 and induction of such adhesion molecules as intercellular adhesion molecule 1.27 The possible mechanisms by which activation of the RAAS may lead to endothelial dysfunction (leading to albuminuria in the kidneys and atherosclerosis in the vasculature) and the points at which RAAS inhibitors act on the pathway are shown in Fig 1.16,23 Patients with diabetes have abnormalities in their RAAS. Miller28 studied 10 patients with type 1 diabetes with no evidence of microalbuminuria and normal creatinine clearance. When these patients were hyperglycemic, renal vascular resistance and filtration fraction increased. Administration of the angiotensin receptor blocker (ARB) losartan abolished this effect of hypergly-

Vasculature

Kidney

Renin Inhibitor

Renin Inhibitor

Angiotensinogen

Angiotensinogen Ang I

Ang I

Renin

ACE

Renin

ACE

ACEIs Compensatory feedback

ACEIs

Ang II

Compensatory feedback

ARBs

AT1 receptor

Ang II ARBs

AT1 receptor

Aldosterone

Aldosterone

Aldosterone inhibitor

Aldosterone inhibitor

Reactive oxygen species Inflammatory mediators (e.g. IL-6) Adhesion molecules (e.g. ICAM-1) Cellular growth and apoptosis

Reactive oxygen species Inflammatory mediators (e.g. IL-6) Adhesion molecules (e.g. ICAM-1) Cellular growth and apoptosis

Endothelial dysfunction

Endothelial dysfunction

ATHEROSCLEROSIS

ALBUMINURIA

Fig 1. Mechanisms by which activation of the RAAS may lead to the development of albuminuria. According to the Steno hypothesis,16 albuminuria reflects endothelial cell dysfunction, which, in the kidney, is manifested as albuminuria (after other processes, such as glomerular basement membrane thickening and podocyte apoptosis/ detachment), and in blood vessels, as atherosclerosis (after plaque formation caused by subendothelial lipoprotein accumulation). RAAS activation was implicated in the development of endothelial dysfunction through increased levels of reactive oxygen species, inflammatory mediators (eg, interleukin 6 [IL-6]) and cell adhesion molecules (intercellular adhesion molecule 1 [ICAM-1]).23 Abbreviations: Ang, Angiotensin; AT1, angiotensin II type 1; ACEI, ACE inhibitor.

930

BASI AND LEWIS

cemia. A study of intrarenal vascular resistance in 40 patients with type 2 diabetes and 15 age- and sex-matched healthy controls was performed by using duplex Doppler sonography.29 Blockade of RAAS activation by the angiotensin-converting enzyme (ACE) inhibitor captopril decreased intrarenal vascular resistance in patients with diabetes, but not healthy controls. Further evidence that the RAAS is important in the pathogenesis of albuminuria is evidence that inhibitors of the RAAS decrease albuminuria. A study of 9 patients with type 1 diabetes showed that treatment with the ARB losartan decreased glomerular filtration fraction, and these changes paralleled changes in urine albumin excretion (UAE).30 The Microalbuminuria Reduction With Valsartan (MARVAL) Study examined 332 patients with type 2 diabetes and microalbuminuria, with or without hypertension.31 Patients were randomly assigned to administration of the ARB valsartan (80 mg/d) or the calcium channel blocker amlodipine (5 mg/d) for 6 months. Target blood pressure (135/85 mm Hg) was achieved by adding bendrofluazide and doxazosin. Valsartan decreased the UAE rate by 44%, whereas amlodipine decreased the UAE rate by only 8%, although there was no significant difference in blood pressure values between the 2 groups. The Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA-2) Study examined the effect of the ARB irbesartan (150 and 300 mg/d) on progression of albuminuria in 590 hypertensive patients with type 2 diabetes and microalbuminuria.9 In IRMA-2, irbesartan decreased UAE and slowed the onset of overt proteinuria and progressive nephropathy, independent of blood pressure control. Although studies cited in this review clearly show that albuminuria is associated with worse renal and cardiovascular outcomes, much research is needed to further understand the pathophysiological process of albuminuria. ASSOCIATION OF ALBUMINURIA WITH RENAL OUTCOMES

Studies of the General Population Renal impairment usually progresses through several stages: microalbuminuria, macroalbuminuria, chronic renal insufficiency, and end-stage renal disease (ESRD).32 It was shown in numerous studies that increasing levels of urinary albu-

min are associated with increased risk for progressive loss of renal function (Table 2).5,6,33-39 In a 17-year follow-up of a community-based mass screening of 106,177 patients in Japan, Iseki et al36 showed that a positive dipstick result for urinary albumin (ie, proteinuria) was an independent predictor of ESRD. A small increase in proteinuria (dipstick 1⫹) was associated with an adjusted relative risk (RR) for developing ESRD of 1.93 in men (95% confidence interval [CI], 1.53 to 2.41; P ⬍ 0.001) and 2.42 in women (95% CI, 1.91 to 3.06; P ⬍ 0.001). Although these studies highlight the strong association between macroalbuminuria or proteinuria and progression of renal disease, the relationship between microalbuminuria and renal outcomes is less well defined, and there have been fewer prospective studies in individuals with microalbuminuria in the general population with follow up after the development of proteinuria to ESRD. Studies of Patients With Type 1 Diabetes Microalbuminuria is a strong predictor of developing clinical proteinuria in patients with diabetes. For example, early studies of patients with type 1 diabetes showed an association between microalbuminuria and the development of overt diabetic nephropathy.3,40 Mogensen and Christensen1 examined patients with type 1 diabetes who were studied between 1969 and 1976 and reevaluated in 1983 and found that although 86% of patients who initially had albumin excretion rates of 15 ␮g/min or greater progressed to overt proteinuria, none of those who initially had an albumin excretion rate less than 15 ␮g/min had progressed to overt proteinuria. It was estimated that approximately 80% of patients with type 1 diabetes and microalbuminuria progress to overt proteinuria during 10 years of follow-up.41 When patients progress to proteinuria, they are at a high risk for progression to ESRD. Studies of Patients With Type 2 Diabetes With or Without Hypertension Similarly, in patients with type 2 diabetes, the presence of microalbuminuria predicted which patients would have decreasing glomerular filtration rates (GFRs).42 Decreases in GFRs in patients with microalbuminuria also were seen in a study of 108 patients with type 2 diabetes.43 During a mean of 4 years, patients with mi-

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

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Table 2. Studies Evaluating Treatment Effects: Impact on Long-Term Renal Outcomes

Trial

No. of Patients

Study and Population

Mean Follow-Up (y)

AIPRD33

1,860

Nondiabetic renal disease

2

IDNT34

1,715

3

NICS35

456

ODS36

106,177

Type 2 diabetes with hypertension and proteinuria Chronic renal failure with diabetes and/ or hypertension General population

3

17

Measure and Format of Albuminuria in Risk Analyses

Risk Reference

Albuminuria as a Risk for Decreased Renal Function Risk*† (95% CI)

Albuminuria‡: ● 0.5-g/d increments ⬍ 2.0 g/d ● g/d increments from 2.0-5.9 g/d ● ⱖ6 g/d Proteinuria#: ● Log transformed: continuous Proteinuria#: ● Proteinuria: continuous

B

1.67 (1.09-2.54)§储¶

A

2.04 (1.87-2.22)§

C

1.50 (1.26-1.79)§

B

2.71 (2.51-2.92)**

Proteinuria (dipstick): Normal: (⫺) or (⫹) ● Proteinuria: 1⫹ to 4⫹ Microalbuminuria5#: ● Normal ● Microalbuminuria (0.03-0.3 g/d) Microalbuminuria6#: ● Log transformed: continuous Proteinuria39#: ● ⱖ1.0 g/d ● ⬍1.0 g/d Albuminuria38‡: ● Log transformed: continuous Albuminuria37‡: ● ⬍2 g/g ● ⱖ2 g/g ●

PREVEND5,6

8,592

RENAAL37-39

1,513 Type 2 diabetes with 252‡‡ nephropathy

General population

4

3

B,5 C6

1.07 (0.65-1.77)5†† 1.30 (1.11-1.52)6††

B,39 C,38 B,37

1.42 (1.3-1.55)39 1.41 (1.36-1.47)38§§ 6.2 (4.4-8.7)37§

Abbreviations: A, doubling of baseline albuminuria; B, normoalbuminuria or lowest level of albuminuria; C, albuminuria as a continuous variable; AIPRD, Angiotensin-Converting Enzyme (ACE) Inhibition in Progressive Renal Disease; DsCr, doubling of serum creatinine level; NICS, National Italian Cooperative Study; ODS, Okinawa Dialysis Study. *Risk evaluated based on 1 of the following: RR or odds ratio. †Risk for developing renal outcome based on multivariate analysis. ‡Proteinuria measured as urinary protein excretion rate per 24 hours. §Renal outcomes defined as DsCr level or ESRD (typically defined as need for dialysis or renal transplantation). 储Results presented for urine protein excretion (UPE) of 2.0 to 2.9 g/d (risk is higher for higher UPE categories). ¶Meta-analysis based on 11 studies. #Proteinuria measured as urinary ACR. **Renal outcomes defined as ESRD. ††Renal outcomes defined as GFR less than 60 mL/min/1.73 m2 (⬍1.00 mL/s/1.73 m2) or GFR decline. ‡‡Asian subsample. §§Renal outcomes defined as DsCr, ESRD, or death.

croalbuminuria had a median decrease in GFR of ⫺0.4% per year compared with ⫺1.8% in patients with proteinuria. During this study, 11 of 74 patients with microalbuminuria (15%) progressed to macroalbuminuria and 1 patient developed ESRD. Of patients who already had mac-

roalbuminuria, 6 of 34 patients (35%) progressed to ESRD. Patients with microalbuminuria therefore appear to have a substantial risk for progressing to macroalbuminuria during a relatively short interval, and when such progression has occurred, they are at a high risk for developing

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ESRD. This finding was supported by results of a study by Mogensen2 that showed microalbuminuria not only predicted progression to overt proteinuria, but also was associated with increased mortality. This increase in mortality in patients with type 2 diabetes results from death largely from cardiovascular disease, often before patients reach ESRD. However, if they survive, patients with type 2 diabetes appear to progress from microalbuminuria to macroalbuminuria to ESRD very similarly to patients with type 1 diabetes. Several large-scale trials showed the link between proteinuria and renal outcomes in patients with type 2 diabetes. For example, the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) Study followed up 1,513 patients with type 2 diabetes and nephropathy (defined as urinary ACR ⱖ 300 mg/g with a serum creatinine level of 1.3 to 3.0 mg/dL [115 to 265 ␮mol/L]).7 Albuminuria was shown to be the most important risk factor for doubling of serum creatinine level or ESRD; the presence of albuminuria was associated with an adjusted hazard ratio (HR) of 6.2 (95% CI, 4.4 to 8.7; P ⬍ 0.0001).37 Similarly, the Irbesartan Diabetic Nephropathy Trial (IDNT) compared effects of irbesartan, amlodipine, and placebo in 1,715 patients.34 In this trial, risk for kidney failure doubled for each doubling of proteinuria level (HR, 2.04; 95% CI, 1.87 to 2.22). Similarly, for each halving of proteinuria level between baseline and 12 months of treatment, risk for kidney failure decreased by more than half. Studies of Patients With Hypertension and Nondiabetic Renal Disease The association between proteinuria and renal outcomes also is maintained in patients with hypertension. The African American Study of Kidney Disease and Hypertension (AASK) was a randomized study of 1,094 African Americans with hypertensive renal disease (GFR, 20 to 65 mL/min/1.73 m2 [0.33 to 1.08 mL/s/1.73 m2]).44 Baseline proteinuria predicted renal outcomes in AASK; patients with urinary protein excretion of 300 mg/24 h or greater showed a 3-fold increased risk for occurrence of the composite outcome of a 50% decrease in GFR, ESRD, or death compared with those with baseline urinary

BASI AND LEWIS

protein less than 300 mg/24 h. In AASK, albuminuria represented a strong continuous risk factor for progressive renal disease, even in the microalbuminuric range. The association between proteinuria and progression of kidney disease was shown in a meta-analysis of 11 randomized controlled trials of antihypertensive therapy for patients with nondiabetic kidney disease.33 RR for kidney disease progression increased from 1.67 in patients with urinary protein excretion of 2.0 to 2.9 g/d to 4.77 in those with urinary protein excretion of 6.0 g/d or greater compared with patients with values less than 0.50 g/d. There clearly is an increased risk for renal outcomes in patients with proteinuria. Although many studies do not follow up patients long enough to show that patients with only microalbuminuria progress to ESRD, there is clear evidence that there is progression from microalbuminuria to macroalbuminuria and subsequent renal failure. Hypertension is associated with a greatly increased risk for renal impairment, and it was suggested that microalbuminuria in patients with hypertension may provide an early indicator of an elevated long-term risk for developing ESRD.45 A retrospective study of 141 patients with hypertension showed that creatinine clearance decreased by 12.1 mL/min (0.20 mL/s) in patients with microalbuminuria compared with 7.1 mL/min (0.12 mL/s) in individuals with normal albumin levels, indicating that renal function was deteriorating more rapidly in patients with microalbuminuria.46 Decreases in creatinine clearance also were reported in hypertensive patients with high-normal albuminuria (albumin, 9.4 to 15 ␮g/min) compared with patients with lower levels of albuminuria.47 Data from a cohort of 787 untreated patients with hypertension showed that microalbuminuria was associated with a cluster of abnormalities (including high body mass index, older age, and elevated cholesterol level) and could reflect diffuse atherosclerotic vascular changes that also involved the renal vasculature.48 It also was shown that RR for progression of kidney disease is associated with both blood pressure and urine protein excretion.49 Patients with greater levels of proteinuria (protein ⱖ 1 g/d) had a large increase in risk for kidney disease progression at higher systolic blood pressures, whereas patients

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

with lower levels of proteinuria had little increase in risk at higher blood pressures. In patients with such nondiabetic renal disease as focal segmental glomerulosclerosis, proteinuria is predictive of renal outcomes. In a study of rats with Adriamycin-induced glomerulosclerosis (Pharmacia Inc, Kalamazoo, MI), De Boer et al50 found a direct correlation between proteinuria and sclerosis score. Another study of patients with nondiabetic renal disease, the Ramipril Efficacy in Nephropathy (REIN) Trial, found that percentage of decrease in proteinuria correlated inversely with decrease in GFR.51 Overall, these data indicate that microalbuminuria provides an early indicator of renal impairment in patients with hypertension and other nondiabetic renal disease. Progression of microalbuminuria to proteinuria is associated with a substantial risk for severe renal impairment. As seen from these data from multiple studies of patients with diabetic and nondiabetic nephropathy, there is a strong and consistent association between degree of albuminuria and adverse renal outcomes. EFFECT OF TREATMENT OF ALBUMINURIA ON RENAL OUTCOMES

Not only is degree of albuminuria associated with loss of renal function, but there also is evidence that decreasing albuminuria is associated with improving renal outcomes. Studies of Patients With Type 1 Diabetes A 5-year study of 73 patients with type 1 diabetes and microalbuminuria showed that the ACE inhibitor enalapril reduced or delayed progression of structural glomerular damage.49 However, it is unclear whether this apparent renoprotection was caused by renoprotective properties of enalapril or the decrease in blood pressure. In a study of 22 patients with type 1 diabetes and microalbuminuria, low doses of enalapril effectively decreased UAE in both normotensive and hypertensive patients. The effect of ACE inhibition on albuminuria appeared to be independent of blood pressure changes.52 In the ACE Inhibitor in Diabetic Nephropathy Study, 409 patients with type 1 diabetes and diabetic nephropathy were randomly assigned to administration of captopril or placebo. Patients randomly assigned to captopril administration not only had risk

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reduction in progression to ESRD or death, but also had a decrease in microalbuminuria independent of effects on systemic blood pressure.53 Studies of Patients With Type 2 Diabetes Several studies found a strong predictive value for interventions that decrease albuminuria (Tables 3 and 4).4,7-9,31,34,38,39,44,51,53,54 The decrease in albuminuria by inhibition of the RAAS has predicted preserved renal function. In the RENAAL Study, losartan, 50 to 100 mg/d, decreased the incidence of doubling of serum creatinine level by 25% (P ⫽ 0.006) and that of ESRD by 28% (P ⫽ 0.002).7 Each 50% decrease in albuminuria in the first 6 months was associated with a 45% decrease in risk for ESRD.38 Decrease in albuminuria was the single most important predictor of preserved renal function. The IDNT trial,8 which examined 1,715 patients with diabetic nephropathy, showed that patients administered the ARB irbesartan (300 mg/d) had a decreased risk for doubling of serum creatinine level compared with placebo, with an adjusted RR of 0.71 (95% CI, 0.54 to 0.92; P ⫽ 0.009). This effect was independent of blood pressure. Albuminuria reduction in the first 12 months of irbesartan therapy was associated with 36% of the total renoprotective effect observed.34 Although RAAS blockade clearly is beneficial in decreasing microalbuminuria and improving renal outcomes, the optimal dose of ACE inhibitor or ARB remains to be established. In the IRMA-2 study,9 a 300-mg/d dosage of irbesartan decreased microalbuminuria significantly more effectively than irbesartan, 150 mg/d, despite no difference in blood pressure control between the 2 groups. Moreover, the HR for the development of diabetic nephropathy, adjusted for baseline microalbuminuria and blood pressure level achieved during the study, was 0.56 in the irbesartan 150-mg/d group (95% CI, 0.31 to 0.99; P ⫽ 0.05) and 0.32 in the irbesartan 300-mg/d group (95% CI, 0.15 to 0.65; P ⬍ 0.001), indicating that the greater dose of ARB also was associated with improved renal outcomes independent of changes in blood pressure. Ongoing clinical studies are investigating the possibility that use of high doses of ARBs, beyond current recommended dosage levels, may provide increased RAAS blockade and thus

Table 3. Studies Evaluating Treatment Effects: Impact on Albuminuria, Including Both Cardiovascular and Renal Studies

AASK44

ACE Inhibitor in Diabetic Nephropathy53

No. of Patients

1,094

Study and Population

African Americans with hypertension and renal disease

Mean Follow-Up (y)

3

934

Trial

Treatments (mg/d)

Treatment Effect for Change in Proteinuria

Ramipril, 2.5-10 Amlodipine, 5-10 Metoprolol, 50-200

Decrease in proteinuria*: 58% ramipril v 20% amlodipine in first 6 mo (P ⬍ 0.001)†

Captopril, 75 Placebo

Significantly less proteinuria in the captopril group during 4 y (P ⫽ 0.001 v placebo)

Type 1 diabetes and diabetic nephropathy

HOPE54

3,654

History of cardiovascular disease or type 2 diabetes plus 1 other cardiovascular risk factor

5

Ramipril, 10 Placebo

Lower levels of proteinuria* for ramipril v placebo at 1 y (P ⫽ 0.001) and end of study (P ⫽ 0.02)

IDNT8,34

1,715

Type 2 diabetes with hypertension and proteinuria

3

Irbesartan, 300 Amlodipine, 10 Placebo

Decrease in proteinuria‡: 41% irbesartan, 11% amlodipine, 16% placebo urine protein excretion rate in first 12 mo (both P ⬍ 0.001 v irbesartan)34 Decrease in proteinuria‡: 33% irbesartan, 6% amlodipine, 10% placebo (P not provided)8†

IRMA-29

590

Type 2 diabetes and hypertension with microalbuminuria

2

Irbesartan, 300 Irbesartan, 150 Placebo

Decrease in proteinuria‡: 38% irbesartan, 300 mg/d; 24% irbesartan, 150 mg/d; 2% placebo throughout the study (P ⬍ 0.001 placebo v combined irbesartan) Frequency of restoration to normoalbuminuria by the last visit‡: 34% irbesartan, 300 mg/d; 24% irbesartan, 150 mg/d; 21% placebo (P ⬍ 0.006 placebo v irbesartan, 300 mg)

MARVAL31

232

Type 2 diabetes and microalbuminuria with or without hypertension

1

Valsartan, 80 Amlodipine, 5

Decrease in proteinuria‡: 44% valsartan v 8% amlodipine (P ⬍ 0.001)§ Frequency of restoration to normoalbuminuria by the last visit‡: 30% valsartan v 15% amlodipine (P ⬍ 0.001)

REIN4,51

35251 1864

Hypertension or normal blood pressure with nephropathy and proteinuria

151 34

Ramipril, 2.5-10 Placebo

Change in proteinuria‡: 13% decrease ramipril v 15% increase placebo (P ⬍ 0.003)4

Type 2 diabetes with nephropathy

3

Losartan 50-100 Placebo

Decrease in proteinuria*: 35% losartan v increase (% not specified) placebo (P ⬍ 0.001)7 Decrease in proteinuria*: 47% losartan v decrease (% not specified) placebo (P ⬍ 0.001)39

RENAAL7,38,39

1,513 25239

*Proteinuria measured as urinary ACR. †Decreases or differences maintained throughout the follow-up period. ‡Proteinuria measured as urinary protein excretion rate. §Decreases similar in normotensive and hypertensive subgroups (P ⬍ 0.001 for both subgroups).

BASI AND LEWIS

409

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

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Table 4. Studies Evaluating Risk Ratios for Baseline Albuminuria to Long-Term Renal Outcomes

Trial

No. of Patients

HOPE54

3,654

IDNT8

1,715

Study and Population

Mean Follow-Up (y)

Treatments (mg/d)

History of cardiovascular disease or type 2 diabetes plus 1 other cardiovascular risk factor Type 2 diabetes with hypertension and proteinuria

5

Ramipril 10 Placebo

24% overt nephropathy for ramipril v placebo (P ⫽ 0.03)*

3

Irbesartan, 300 Amlodipine, 10 Placebo

19% primary composite (DsCr, ESRD, or death) for irbesartan v placebo (P ⫽ 0.03)† 24% primary composite for irbesartan v amlodipine (P ⫽ 0.005)† 44% diabetic nephropathy for irbesartan, 150 mg/d, v placebo (P ⫽ 0.05)† 68% diabetic nephropathy for irbesartan, 300 mg/d, v placebo (P ⬍ 0.001)† 56% ESRD for ramipril v placebo (P ⬍ 0.01)† 49% ESRD for ramipril v placebo in patients with GFR ⱕ45 mL/min (P ⫽ 0.04)† 16% primary composite (DsCr, ESRD, or death), 25% DsCr, 28% ESRD, 20% ESRD or death for losartan v placebo (all P ⬍ 0.02)7* 35% primary composite (DsCr, ESRD, or death), 36% ESRD or death for losartan v placebo (both P ⬍ 0.05)39*

IRMA-29

590

Type 2 diabetes and hypertension with microalbuminuria

2

Irbesartan, 300 Irbesartan, 150 Placebo

REIN4

186

Hypertension or normal blood pressure with nephropathy and proteinuria

3

Ramipril, 2.5-10 Placebo

Type 2 diabetes with nephropathy

3

Losartan, 50-100 Placebo

RENAAL7,39

1,513 252‡

Treatment Effect for Change in Renal Outcomes (decrease in risk for renal outcomes based on adjusted risk ratios)

Abbreviations: DsCr, doubling of serum creatinine level. *Proteinuria measured as urinary ACR. †Proteinuria measured as urinary protein excretion rate. ‡Asian subsample.

greater renal benefits in patients with renal disease. Although trials assessing renal outcomes remain to be completed, initial evidence suggests that greater doses of ARBs may provide greater decreases in microalbuminuria, even when effects on blood pressure have reached a plateau. Rossing et al55 investigated the effects of irbesartan, 600 or 900 mg/d, compared with the current recommended maximal daily dosage of 300 mg/d in 52 hypertensive patients with type 2 diabetes. Irbesartan, 900 mg/d, caused an additional 15% decrease in microalbuminuria compared with irbesartan, 300 mg/d (P ⫽ 0.02),

despite causing no additional change in blood pressure.55 It is important to note that although such trials as RENAAL and IDNT showed that RAAS blockade can delay the development of nephropathy in patients with diabetes, a significant decrease in renal function still occurs. The mean rate of decrease in GFR of 4.4 mL/min/1.73 m2 (0.07 mL/s/ 1.73 m2) per year despite losartan treatment in RENAAL7 and the rate of 5.5 mL/min/1.73 m2 (0.09 mL/s/1.73 m2) per year with irbesartan treatment in IDNT8 remain much greater than the acceptable decrease of 1 mL/min/1.73 m2

936

(0.02 mL/s/1.73 m2) caused by ageing that is specified in National Kidney Foundation guidelines. These findings indicate the need to explore new approaches to treatment to improve renal outcomes. Studies of Patients With Hypertension Several studies of antihypertensive therapy showed that treatment can decrease microalbuminuria. However, it is difficult to determine whether decreases in microalbuminuria are related directly to the renoprotective capacity of particular classes of agents or simply caused by blood pressure–lowering effects. In general, it appears that effects of antihypertensive therapy on microalbuminuria are proportional to decreases in blood pressure.56 However, studies of ACE inhibitors and ARBs showed an additional beneficial effect on UAE that is independent of blood pressure lowering. For example, a study of 40 patients with hypertension and microalbuminuria showed that although the ACE inhibitor enalapril and the calcium channel blocker nicardipine had similar effects on blood pressure, the decrease in UAE was greater with enalapril.57 Similar findings were reported in a number of other studies.58-61 Several studies showed that ACE inhibitors have renoprotective properties in patients with proteinuria. For example, the REIN Study examined the effect of the ACE inhibitor ramipril (1.25 to 5 mg/d) in 352 patients with proteinuria with protein greater than 1 g/24 h.51 The interim analysis showed that in patients with proteinuria with protein greater than 3 g/24 h, ramipril halved the GFR decline; progression to ESRD was significantly more common in the placebo group, with an RR of 2.72 (95% CI, 1.22 to 6.08).4 An early decrease in urinary protein excretion within the first 3 months of treatment correlated inversely with long-term (⬎6 months) rate of GFR decrease.51 This issue also was examined in AfricanAmerican patients with hypertensive renal disease. The AASK Trial found that a change in proteinuria in the first 6 months of the study was a predictor of subsequent disease progression, with this relationship extending to participants with baseline proteinuria levels with protein less than 300 mg/d.62

BASI AND LEWIS

Therefore, it was shown in the general population and patients with diabetes or hypertension that the presence of albuminuria is associated with worse renal outcomes, and decrease in albuminuria decreases the risk for renal events. Figure 2 illustrates this point by comparing treatment-induced decreases in albuminuria with associated changes in renal outcomes across 7 randomized controlled trials: AASK44; the Angiotensin Converting Enzyme Inhibition in Progressive Renal Insufficiency Study63; Diabetes, Hypertension, Cardiovascular Events and Ramipril64; IDNT8; IRMA-29; REIN51; and RENAAL.7,39 This figure shows that RAAS inhibition with ACE-inhibitor or ARB therapy was effective at decreasing both albuminuria and risk for renal outcomes, and greater decreases in albuminuria generally were associated with lower risk for renal outcomes. Conversely, the use of other classes of antihypertensive treatments that do not inhibit the RAAS (for example, the calcium channel blocker amlodipine) may not be associated with such benefits on proteinuria or renal outcomes. The finding that irbesartan, 300 mg/d, provided greater decreases in albuminuria and improvements in renal outcomes compared with irbesartan, 150 mg/d, in IRMA-2 indicates that there is scope for increased RAAS suppression to provide further renoprotective benefits. However, the long-term tolerability of treatment with very high doses of ARBs remains to be established. A more appropriate means of providing increased RAAS suppression, and thus improved renoprotection, therefore may be to combine ARB treatment with an ACE inhibitor or renin inhibitor. It should be noted that the numerically large percentage of decrease in renal outcomes obtained with irbesartan treatment in IRMA-2 (44% with the 150-mg/d dose and 68% with the 300-mg/d dose) reflects the use of the weaker renal end point of time to development of overt nephropathy (defined as UAE rate ⬎ 200 ␮g/min and at least 30% greater than baseline) in that study. This contrasts with the more robust end point of a doubling of serum creatinine level used in other studies, such as IDNT and RENAAL.

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

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Fig 2. Change in risk for renal outcomes associated with treatment-induced decreases in albuminuria. Treatmentinduced decreases in albuminuria (%) and associated changes in renal outcomes observed in clinical trials in patients with renal disease are shown. Open rectangles, ARB; filled triangles, ACE inhibitors; filled circles, treatment with other classes of antihypertensive drugs. Study acronyms are presented with the respective active treatment and dose in milligrams per day. Changes in renal outcomes were assessed relative to placebo in all studies, except for*, in which change in renal outcomes was relative to amlodipine. Renal outcomes are defined as a doubling in serum creatinine level in all studies with the following exceptions: †doubling in serum creatinine level or ESRD; ‡development of overt nephropathy, and * decrease in GFR (by 50% or 25 mL/min/1.73 m2 from baseline) or ESRD. Dotted line, best-fit correlation line determined by linear regression. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension44; AIPRI, Angiotensin Converting Enzyme Inhibition in Progressive Renal Insufficiency63; DIABHYCAR, Diabetes, Hypertension, Cardiovascular Events and Ramipril64; IDNT, Irbesartan Diabetic Nephropathy Trial8; IRMA-2, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria-29; REIN, Ramipril Efficacy in Nephropathy51; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (Asian Subgroup).7,39

ASSOCIATION OF ALBUMINURIA WITH CARDIOVASCULAR OUTCOMES

Studies of the General Population Albuminuria was associated with cardiovascular outcomes in multiple studies and analyses of large databases (Table 5).65-78 Damsgaard et al79 examined 216 elderly patients without diabetes and found an association between albumin excretion rate and mortality, most of which was cardiovascular in cause. Yudkin et al80 examined 187 subjects older than 40 years attending a diabetic screening project and found that albumin excretion rate was associated with coronary heart

disease (odds ratio, 6.38; 95% CI, 1.91 to 21.4) and mortality (odds ratio, 24.33; 95% CI, 5.40 to 109.7).80 Culleton et al69 measured proteinuria by means of dipstick in 2,586 participants from the Framingham Heart Study and subsequently followed them up for 17 years. They found that in women, trace proteinuria was associated with cardiovascular disease–related death (HR, 1.6; 95% CI, 1.1 to 2.4). Miettinen et al75 studied subjects without diabetes and those with type 2 diabetes in Finland and measured their urinary protein concentration during 7 years. They found that cardiovascular disease mortality was greater

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BASI AND LEWIS Table 5. Studies Evaluating Treatment Effects: Impact on Long-Term Cardiovascular Outcomes

Trial DIABHYCAR65

No. of Patients

Study and Population

Mean Follow-Up (y)

Measure and Format of Albuminuria in Risk Analyses

Risk Reference

Albuminuria as Risk for Cardiovascular Outcomes*† (95% CI)

Type 2 diabetes

5

Proteinuria‡: ● Continuous

C

2.3 (1.71-3.09)§ 1.08 (1.03-1.14)67§

23,630

General population

7.2

Microalbuminuria66‡: ● Normal ● Microalbuminuria (0.25-25 mg/mmoL) Microalbuminuria67,68‡: ● Log transformed: continuous

B66 C67,68

1.23 (1.16-1.31)68储 1.49 (1.13-2.14)66¶

FHS69

2,586

General population

Albuminuria (dipstick): ● No, trace, and greater-than-trace proteinuria

B

HOPE70,71

9,043

History of cardiovascular disease or diabetes plus at least 1 other cardiovascular risk factor

4.5

Microalbuminuria‡: ● Normal ● Microalbuminuria (⬎2 mg/mmoL)

B

1.83 (1.64-2.05)70,71# 3.23 (2.54-4.10)70,71§

IDNT72

1,715

Diabetes with nephropathy and hypertension

3

Proteinuria‡: Log transformed: continuous

C

1.29 (1.13-1.48)

EPIC-Norfolk66-68

4,912

17

1.4 (1.0-2.0)储

●

LIFE73,74

96074 8,20673

Hypertension

5

Proteinuria‡: ● Log transformed: continuous

C

1.35 (1.05-1.74)74# 2.3 (NA)73#

Miettinen et al,75 1996

2,431

With or without type 2 diabetes

7

Proteinuria (spot urine specimen) ● No proteinuria (⬍150 mg/L) ● Borderline proteinuria (150-299 mg/L) ● Clinical proteinuria (ⱖ300 mg/L)

B

1.36 (0.82-2.25)¶**†† 2.81 (1.73-4.58)¶**‡‡

Microalbuminuria‡: Normal ● Microalbuminuria (⬎1.07 mg/mmoL)

B

3.5 (1.0-12.1)#

8

Microalbuminuria§§: ● Normal ● Microalbuminuria (30-300 mg/24 h)

B

1.10 (1.00-1.20)#

NA

Microalbuminuria§§: ● Normal ● Microalbuminuria (30-300 mg/24 h)

B

1.6 (1.17-2.18)§

Albuminuria§§: ● ⬍10 mg/24 h ● 10.1-20 mg/24 h ● 20.1-30 mg/24 h

B

1.9 (0.8-2.5)#†† 9.8 (6.7-12.3)#‡‡

MONICA76

Nakamura et al,77 2003 PREVEND5

Rachmani et al,78 2000

204

599

6,669

599

Hypertension

Hypertension

General population

Type 2 diabetes

1,978 person-years

8

●

Abbreviations: DIABHYCAR, Diabetes, Hypertension, Cardiovascular Events and Ramipril; EPIC-Norfolk, European Prospective Investigation into Cancer and Nutrition; FHS, Framingham Heart Study; MONICA, Multinational Monitoring of Trends and Determinants of Cardiovascular Disease; A, doubling of baseline albuminuria; B, normoalbuminuria or lowest level of albuminuria; C, albuminuria as a continuous variable; NA, not available. ⴱRisk evaluated based on 1 of the following: RR or odds ratio. †Risk for developing cardiovascular outcome based on multivariate analysis. ‡Proteinuria measured as urinary ACR. §Cardiovascular outcomes defined as fatal and nonfatal chronic heart failure or coronary heart disease. 储Cardiovascular outcomes defined as cardiovascular mortality. ¶Cardiovascular outcomes defined as stroke. #Cardiovascular outcomes may include MI, stroke, angina, or cardiovascular death. ⴱⴱType 2 diabetes only. ††Middle group versus lowest level of proteinuria. ‡‡Highest versus lowest level of proteinuria. §§Proteinuria measured as urinary protein excretion rate per 24 hours.

in subjects without diabetes and those with type 2 diabetes with proteinuria than in those without proteinuria. In the Prevention of Renal and Vascular EndStage Disease (PREVEND) study, which examined 40,856 subjects, microalbuminuria was present in 7% of subjects and was associated

independently with previous myocardial infarction (MI) and stroke.5,6 They found that UAE was a predictor of all-cause mortality in the general population. The excess risk was attributable mostly to death from cardiovascular causes and was independent of effects of other cardiovascular risk factors.81 Data from the Framingham

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

study showed that in 1,568 nonhypertensive participants without diabetes, UAE less than the microalbuminuria threshold predicted the development of cardiovascular disease.82 The Framingham investigators also were able to show that UAE predicts blood pressure progression in nondiabetic nonhypertensive individuals and may be a useful biomarker for identifying individuals most likely to develop hypertension.83 Klausen et al84 performed a substudy of the Third Copenhagen City Heart Study, which included 2,762 participants with no history of coronary heart disease. They found that microalbuminuria was a strong and independent determinant of coronary heart disease and death. Finally, the European Prospective Investigation into Cancer in Norfolk Study, which was a prospective cohort study of 20,911 subjects, found that all-cause and cardiovascular mortality increased with increasing albuminuria.66 The multivariate HR for cardiovascular mortality was 2.03 (95% CI, 1.55 to 2.67). In the general population, albuminuria has been associated strongly and repeatedly with increased risk for cardiovascular events. Studies of Patients With Diabetes The Heart Outcomes Prevention Evaluation (HOPE) Study, a randomized trial examining the effects of ramipril and vitamin E on 9,541 individuals (ⱖ55 years of age) with a history of cardiovascular disease or diabetes and at least 1 cardiovascular risk factor, found that microalbuminuria increased the risk for major cardiovascular events (RR, 1.83; 95% CI, 1.64 to 2.05).70,85 For every 0.4-mg/mmoL increase in urinary ACR, the adjusted risk for major cardiovascular events increased by 6% (95% CI, 4.9 to 7.0). The IDNT study, described previously, showed that albuminuria was an independent risk factor for cardiovascular events (the study composite end point consisted of cardiovascular death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization).72 For every 1-unit increase in the natural logarithm of urinary ACR, there was an adjusted RR of 1.29 for a cardiovascular event (95% CI, 1.13 to 1.48; P ⫽ 0.0002). Finally, the RENAAL Study found that patients with greater baseline albuminuria (albumin ⱖ 3 g/g creatinine) had an increased risk for

939

cardiovascular end points (RR, 1.92; 95% CI, 1.54 to 2.38) and heart failure (RR, 2.7; 95% CI, 1.94 to 3.75) compared with patients with low albuminuria (albumin ⬍ 1.5 g/g creatinine).38 Risk for cardiovascular events and heart failure decreased by 18% and 27% for every 50% decrease in albuminuria, respectively. Studies of Patients With Hypertension The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study found that for hypertensive patients without diabetes with left ventricular hypertrophy (LVH), risk for the composite cardiovascular end point (cardiovascular death, fatal or nonfatal stroke, fatal or nonfatal MI) increased continuously as albuminuria increased (P ⬍ 0.001 for trend).73 Most importantly, there was no threshold for increased risk. Microalbuminuria has been hypothesized to be as important a risk factor for cardiovascular disease as other traditional risk factors, such as cholesterol level. Jensen et al76 prospectively studied 204 hypertensive subjects without ischemic heart disease or diabetes at baseline.76 They followed up subjects for 20 years and found that microalbuminuria at baseline conferred an RR of 4.2 (95% CI, 1.5 to 11.9; P ⫽ 0.006) for an ischemic cardiac disease event. When adjusted for age, sex, blood pressure, lipoprotein level, body mass index, and smoking, RR was 3.5 (95% CI, 1.0 to 12.1; P ⫽ 0.05). Studies of Patients Post-MI An analysis of a subset of 583 post-MI patients with left ventricular dysfunction enrolled in the Survival and Ventricular Enlargement (SAVE) trial showed that proteinuria (assessed by means of dipstick urinalysis at baseline) was present in 20.9% of patients. Patients with proteinuria were older, more hypertensive, and had decreased ejection fraction and lower GFR compared with patients without proteinuria.86 Under multivariate analysis, patients with proteinuria showed an increased risk for total mortality (HR, 1.73; 95% CI, 1.15 to 2.59) and cardiovascular mortality (HR, 1.81; 95% CI, 1.16 to 2.81). Notably, the absolute benefit of treatment with the ACE inhibitor captopril in SAVE was greater in patients with compared with those without proteinuria (P ⫽ 0.02). The investigators concluded that proteinuria may identify a group of

940

patients who receive greater benefit from ACEinhibitor therapy post-MI. As for renal disease, multiple lines of evidence showed that the presence of albuminuria is associated with increased cardiovascular risk in the general population. Effect of Treatment of Albuminuria on Cardiovascular Outcomes In terms of the effect of treatment of albuminuria on cardiovascular outcomes, the HOPE Study found that the rate of developing heart failure was significantly increased with microalbuminuria (RR, 1.82; 95% CI, 1.58 to 2.10).87 Although the ACE inhibitor ramipril significantly decreased the risk for developing heart failure in HOPE, it is important to note that the study did not assess whether this was the direct consequence of a treatment-induced decrease in microalbuminuria. More convincing evidence for the cardiovascular outcome benefits of decreasing albuminuria was provided by the LIFE Study, which included 8,206 men and women with LVH and hypertension who were randomly assigned to atenolol or losartan therapy.88 In LIFE, patients who had a urinary ACR greater than the median value at baseline (1.21 mg/mmoL), but who were able to decrease their ACR to less than the median value at 1 year (0.67 mg/mmoL), had a reduced risk for cardiovascular mortality, stroke, and MI compared with patients who were not able to decrease their ACR (P ⬍ 0.001); this effect was independent of on-treatment blood pressure levels.88 The PREVEND study also showed that treatment with the ACE inhibitor fosinopril resulted in a significant decrease in UAE and a trend toward a decrease in cardiovascular events in patients with microalbuminuria.89 UAE decreased by 26%, and the incidence of cardiovascular mortality and hospitalization decreased by 40%. Although confirmation is required by clinical trials in which decreases in albuminuria represent the target measure for treatment, these findings nevertheless indicate that treatment-induced decreases in albuminuria may translate into decreases in cardiovascular risk. There is compelling evidence of an association of albuminuria with cardiovascular outcomes. Decrease in albuminuria is associated with decreased risk. Therefore, decrease in albuminuria is a potential target for therapy for patients with hypertension and

BASI AND LEWIS

LVH, preexisting cardiovascular disease, or diabetes. DECREASE IN ALBUMINURIA WITH COMBINED THERAPY

The first mainstay of treatment for decrease in albuminuria is the use of an ACE inhibitor and/or an ARB. As is evident from the studies described, the use of both ACE inhibitors and ARBs is associated with decreased albuminuria. In addition, there has been an additive effect noted when both drugs are used simultaneously. Jacobsen et al90 studied 20 white patients with type 1 diabetes and found that dual blockade with benazepril and valsartan induced an additional decrease in albuminuria of 43% compared with either monotherapy.90 Jacobsen et al91 also performed a randomized double-blind crossover study of 24 patients with type 1 diabetes with irbesartan versus placebo added on top of enalapril. They found that dual blockade of the RAAS induced an additional decrease in albuminuria. Dual blockade not only decreased albuminuria further than monotherapy, but also improved renal outcomes. The Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting–Enzyme Inhibitor in Nondiabetic Renal Disease Trial examined 336 patients with nondiabetic disease who were randomly assigned to administration of losartan, trandolapril, or both.92 They found that 23% of those on monotherapy reached the combined primary end point of time to doubling of serum creatinine concentration or ESRD, whereas 11% of those on dual blockade reached the primary end point. Although the evidence for combined therapy is less compelling than for the individual drugs, it certainly supports the hypothesis that blocking the RAAS system at multiple sites will further protect patients. DECREASE IN ALBUMINURIA WITH BLOOD PRESSURE DECREASE

The IDNT Study randomly assigned patients to irbesartan, amlodipine, and control and showed that decrease in proteinuria was associated significantly with both systolic and diastolic blood pressure decrease in the first 12 months.34 The MARVAL Study, which randomized patients to valsartan versus amlodipine, showed a decrease in proteinuria of 8% with blood pressure reduc-

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

tion in the amlodipine groups simply with blood pressure control.31 Therefore, if blood pressure is not optimized with an ACE inhibitor and/or ARB, one should strive to reach blood pressure targets with additional antihypertensive medications. TREATMENT RECOMMENDATIONS

The first mainstay of treatment for decrease in albuminuria is the use of an ACE inhibitor and/or ARB. As is evident from the studies described, the use of both ACE inhibitors and ARBs is associated with decreased albuminuria. In addition, there has been an additive effect noted when both drugs are used simultaneously. The second mainstay of treatment is adequate blood pressure control. Once treated with an ACE inhibitor and/or ARB, further prevention of progression of nephropathy may be achieved by blood pressure control with additional antihypertensives to a goal of less than 130/80 mm Hg. Finally, the use of statins has been considered. Statins may improve renal outcomes by decreasing circulating levels of low-density lipoproteins, improving endothelial function, or decreasing patterns of low-density lipoprotein oxidation.43 In addition, there is some evidence that statins may directly decrease albuminuria.93 Potential Treatment Options for the Future Other therapies that may provide additional benefit in the future include sulodexide, thromboxane antagonists, and additional inhibitors of the RAAS, such as aldosterone antagonists and renin inhibitors.94-96 Sulodexide, composed of 4 naturally occurring glycosaminoglycan polysaccharide components, was studied in a multicenter, placebo-controlled, double-blinded pilot study of 149 patients with type 2 diabetes already administered a maximum dose of an ACE inhibitor or ARB.97 Interim results in 120 patients who completed 6 months of therapy showed that 24% of patients on sulodexide treatment achieved normoalbuminuria (albumin excretion rate ⬍ 20 mg/g creatinine plus a decrease ⬎ 25%) or a 50% decrease in initial albumin excretion rate versus 13% of patients administered placebo. Other potential therapeutic agents are thromboxane antagonists. Picotamide, a thromboxane antagonist, was shown to decrease albuminuria after 6 months of treatment.96 Additional RAAS

941

inhibitors are of particular promise because the initial described studies using very high doses of ARBs showed that increased RAAS inhibition is associated with greater decreases in albuminuria.55 New RAAS inhibitors may be required because the ability of existing drugs to suppress the RAAS is limited; both ACE inhibitors and ARBs disrupt the feedback loop by which angiotensin II normally inhibits renin release and thus stimulate the release of renin from the kidney (Fig 1).98 Drugs that inhibit renin activity, administered in combination with ACE inhibitors or ARBs, therefore would be expected to increase RAAS inhibition and improve albuminuria. Although evidence is scant at present, an early study of 14 patients with hypertension showed that the renin inhibitor remikiren caused a significant decrease in albuminuria.99 Preclinical studies of the novel orally effective renin inhibitor aliskiren in a transgenic rat model of RAASinduced end-organ damage showed that renin inhibition prevented the development of albuminuria,100 and results of ongoing clinical trials of this drug are awaited. There was some suggestion that aldosterone has a pathogenic role in renal injury. Studies by Epstein101 showed that aldosterone antagonists, such as eplerenone, are antiproteinuric in patients with type 2 diabetes. DISCUSSION

It is evident that albuminuria is an important and powerful predictor of both cardiovascular and renal risk in patients with such comorbid conditions as diabetes and hypertension, as well as in the general population. Studies examined in this review had differing designs and measured albuminuria in different ways, but reached the same consistent conclusions. The pathophysiological process of albuminuria is not definitively known, but may be related to endothelial dysfunction, inflammation, and/or abnormalities in the RAAS. It is notable that studies investigating other markers of end-organ damage confirmed that albuminuria is a strong predictor of cardiovascular disease progression. Thus, in patients with hypertension, microalbuminuria correlates with increases in left ventricular mass (indicative of LVH), serum creatinine levels, and the presence of retinal vascular changes (indicative of hypertensive retinopathy).48,102 The presence of microalbuminuria also is associated with mark-

942

ers of vascular dysfunction, such as increased carotid intima-media thickness103 and aortic stiffness.104 These results emphasize the role of microalbuminuria as a marker of early cardiac, renal, vascular, and retinal structural and functional changes. Albuminuria therefore is an important modifiable risk factor for cardiovascular and renal disease and should be measured regularly in patients at risk. Currently, the American Diabetic Association recommends that patients with type 2 diabetes be tested for albuminuria at the time of initial diabetes diagnosis and yearly thereafter.13 It also is advisable to measure urine albumin in patients with hypertension or diabetes to help with risk stratification and to consider initiation of ACEinhibitor or ARB therapy if the patient is not already on it, or increase the dose if they are already administered one of these medications. Furthermore, microalbuminuria was shown to be as important a risk factor as cholesterol level for future cardiovascular events in some populations, and its measurement therefore should form part of cardiovascular risk assessment in the general population.76 The next consideration is the level of proteinuria that should be considered abnormal. As stated earlier, microalbuminuria has been defined as 30 to 300 mg of albumin in a 24-hour urine collection, whereas clinical albuminuria or macroalbuminuria is albumin of 300 mg/24 h or greater.105 If using a spot urine collection, greater than 30 mg albumin/g creatinine is considered abnormal,94 although these ratios may need to be adjusted for sex difference in creatinine excretion. Normal UAE rate is approximately 7 mg/d, but the risk for renal and cardiovascular disease increases even in the normal range. Arguably, a goal of therapy should be to maximally decrease albuminuria. As shown in the studies mentioned, ACE inhibitors and ARBs decrease albuminuria. Doses should be titrated upward to maximize effects on albuminuria, although tolerability issues may limit the dose used. Level of albuminuria should be treated as an end point for therapy and should be followed up during treatment. In addition, the combination of ACE inhibitors and ARBs may provide additional benefit over ACE inhibitors or ARBs alone.90

BASI AND LEWIS

The second mainstay of treatment should be adequate blood pressure control. If blood pressure is still elevated after maximal ACE-inhibitor and/or ARB therapy, further attempts should be made to maintain blood pressure at less than 130/80 mm Hg with additional agents. Finally, statins and such new therapies as renin inhibitors may offer additional albuminuria reduction and additional renal outcome benefits. In summary, decreasing albuminuria by means of ACE-inhibitor or ARB therapy, blood pressure lowering, or, in the future, renin inhibitors leads to improved cardiovascular and renal outcomes. Decreasing albuminuria therefore should be a goal of therapy. Physicians should measure UAE routinely as a screening test, similar to measuring blood pressure, cholesterol, and blood glucose. REFERENCES 1. Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311:89-93, 1984 2. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356-360, 1984 3. Parving HH, Oxenboll B, Svendsen PA, Christiansen JS, Andersen AR: Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion. Acta Endocrinol (Copenh) 100: 550-555, 1982 4. Ruggenenti P, Perna A, Gherardi G, et al: Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354:359-364, 1999 5. Stuveling EM, Hillege HL, Bakker SJ, et al: CReactive protein and microalbuminuria differ in their associations with various domains of vascular disease. Atherosclerosis 172:107-114, 2004 6. Verhave JC, Gansevoort SJ, de Zeeuw D, de Jong PE: An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population. Kidney Int Suppl 92:S18-S21, 2004 7. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861869, 2001 8. Lewis EJ, Hunsicker LG, Clarke WR, et al: 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 9. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, 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 10. Jones CA, Francis ME, Eberhardt MS, et al: Microalbuminuria in the US population: Third National Health

MICROALBUMINURIA AND CARDIOVASCULAR/RENAL OUTCOMES

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