SECTION II

Microalbuminuria in Type 2 and A marker, treatment target, or innocent bystander?

1 2 SEEMA BASI, MD, MSCI ALBERT MIMRAN, MD are different in men and women when us- 2 3 PIERRE FESLER, MD JULIA B. LEWIS, MD ing ACRs (15). was first defined by Mogensen (1) and others as 30–300 lbuminuria is a well-known predic- as a urinary albumin excretion of Ն300 mg urinary albumin excretion per 24 h. tor of poor renal outcomes in pa- mg/24 h. Urinary comprises However, at the time, there was not wide- A tients with and in 20–70% or urinary total protein excre- spread use of inhibitors of the renin an- essential hypertension (1–4). Albumin- tion. Measuring urinary albumin excre- giotensin system. As noted below, uria has also been shown more recently to tion by dipstick without simultaneously inhibition of the renin angiotensin system be a predictor of cardiovascular outcomes measuring is subject to false- decreases urinary albumin excretion, and in these populations (5–8). There is negative and false-positive results due to drugs to inhibit the renin angiotensin sys- emerging data that reduction of albumin- variations in concentration caused tem are currently in wide use. A patient uria leads to reduced risk of adverse renal by hydration level (13). Although urinary being treated with drugs that inhibit the and cardiovascular events (9–12). It has dipsticks are acceptable for quick screen- renin angiotensin system, with urinary al- become increasingly clear that albumin- ing, other more precise measurements bumin excretion of 30–300 mg per 24 h, uria should not only be measured in all should be done to quantify urinary albu- would have likely had much higher levels patients with type 2 diabetes and hyper- min excretion rates (AERs). Albuminuria of AER without such drugs when Mo- tension, but also steps should be taken to can be measured in several ways (Table gensen first defined microalbuminuria. suppress albuminuria to prevent future 1): 1) measurement of albumin-to- Hence, most patients who have urinary renal and cardiovascular adverse events. creatinine ratio (ACR) in a random or first albumin excretion in the microalbumin- This review discusses the measurement of morning spot collection, 2) 24-h urine uria range currently have more advanced albuminuria and summarizes the current collection with measurement of creati- disease than patients in the past. In addi- literature on the association between al- nine to verify adequacy of the collection, tion, microalbuminuria and albuminuria buminuria and adverse cardiovascular and 3) timed (4-h or overnight) urine col- or are part of a clinical contin- and renal outcomes in type 2 diabetes and lections (13). Although the 24-h urine uum of risk and prognosis. hypertension. It also summarizes the evi- collection would overcome issues of diur- dence that reduction of albuminuria leads nal variation in albumin excretion, it is to improvement in the risk profiles of subject to collection errors. The PREVALENCE OF these patients. Disease Outcomes Quality Initiative MICROALBUMINURIA IN guidelines state that ACR measurement in ESSENTIAL HYPERTENSION — DEFINITION AND a first-morning spot urine collection is ad- Reported figures concerning the preva- MEASUREMENT OF equate and a timed urine collection is not lence of albuminuria in essential hyper- ALBUMINURIA — Microalbumin- necessary (14). However, because women tension have yielded variable results due uria is defined as levels of albumin rang- excrete less creatinine than men and mi- to the chosen cutoff value, patient selec- ing from 30 to 300 mg in a 24-h urine croalbuminuria is based on a fixed tion, and more importantly the duration collection (13). Overt albuminuria, mac- amount of urinary albumin excretion per of hypertension and of prior treatment. roalbuminuria, or proteinuria is defined day, the definitions of microalbuminuria In a cohort of 787 patients aged 18–72 years, studied after discontinua- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tion of antihypertensive treatment for at From the 1University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New least 4 weeks, a prevalence of microalbu- Brunswick, New Jersey; the 2Department of Internal Medicine, Hoˆpital Lapeyronie, Montpellier, France; and minuria (AER Ն30 mg/24 h) of 8% was 3 Vanderbilt University Medical Center, Nashville, Tennessee. observed (16). A prevalence of mi- Address correspondence and reprint requests to Julia B. Lewis, MD, Vanderbilt University Medical Center, 1161 21st Ave. South and Garland, Division of , S-3223 MCN, Nashville, TN 37232-2372. croalbuminuria of 6% was found in a co- E-mail: [email protected]. hort of 1,041 younger patients (aged J.B.L. has been a paid consultant for Astra Zeneca and Novartis. 18–45 years) with untreated mild hyper- This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and tension (140–159/90–99 mmHg) (17). Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted Analysis of the population of the Losartan educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson. Intervention for Endpoint Reduction in Hy- Abbreviations: ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; ARB, angiotensin recep- pertension (LIFE) study of 8,029 subjects tor blocker; GFR, glomerular filtration rate; IDNT, Irbesartan Trial; LIFE, Losartan (aged 55–80 years) with stage II–III essen- Intervention for Endpoint Reduction in Hypertension; LVH, left ventricular hypertrophy; PREVEND, Pre- tial hypertension (sitting office blood pres- vention of Renal and Vascular End-Stage Disease; RENAAL, Reduction of Endpoints in Non-Insulin Depen- dent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; SAP, systolic arterial pressure. sure of 160–200/95–115 mmHg) and DOI: 10.2337/dc08-s249 electrocardiographic left ventricular hyper- © 2008 by the American Diabetes Association. trophy (LVH) and using a single cutoff value

S194 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Basi and Associates

Table 1—Measurement of albuminuria

Normal Microalbuminuria Macroalbuminuria Advantages Disadvantages Dipstick for Protein ϪϪ ϩConvenience Dependent on level of hydration 24-h protein (mg) Ͻ150 Ͻ500 Ն500 Overcomes problem of diurnal Subject to collection variation in excretion errors 24-hour albumin (mg) Ͻ30 30–300 Ͼ300 Overcomes problem of diurnal Subject to collection variation in excretion errors Timed collection (␮g/min) Ͻ20 20–200 Ͼ200 Overcomes problem of diurnal Subject to collection variation in excretion errors Spot collection (␮g Ͻ30 30–300 Ͼ300 Convenience Ratios vary based on albumin/mg creatinine) Not dependent on hydration level sex Most reproducible for AER in men and women (Ն3.5 mg/ of patients and 57% were free of target FACTORS INFLUENCING mmol creatinine corresponding to 30 organ damage. Overall, the presence of THE RELATIONSHIP mg/24 h) revealed a prevalence of mi- microalbuminuria was found in 16%, BETWEEN ARTERIAL croalbuminuria of 26%. Before inclusion, whereas LVH was found in 37% of the PRESSURE AND treatment was discontinued for 2–4 weeks; population. In addition, 21% of patients ALBUMINURIA — It is generally ac- this may have increased the prevalence of with LVH were classified as microalbu- cepted that arterial pressure, mainly sys- microalbuminuria (18). Of interest, it was minuric, whereas 59% of patients with tolic arterial pressure (SAP) and to a lesser recently shown that 70% of patients with microalbuminuria had LVH, thus sug- extent pulse pressure, is a major determi- electrocardiographic LVH included in the gesting that microalbuminuria is a good nant of albuminuria. The slope of the re- LIFE study have echocardiographic LVH predictor of the presence of LVH. Of in- lationship between albuminuria and SAP (left ventricular mass index Ն104 in terest, male patients were more frequently is steeper in men than in women. In fact, women and Ն116 g/m2 in men) (19). affected by the combination of LVH and albuminuria remains almost unaltered In a subgroup of 376 never-treated microalbuminuria than women (15 vs. with SAP within the normotensive range individuals aged Ն40 years from our per- 4% in the population aged Ն40 years). (Ͻ140 mmHg). In contrast, the response sonal cohort of essential hypertensive pa- The group of patients with both LVH and of the left ventricle to SAP is linear within tients, analysis of the prevalence of target microalbuminuria had the highest arterial the whole range of SAP (20). Some factors organ damage (LVH defined as left ven- pressure level, a larger proportion of were shown to influence this relationship tricular mass index Ն110 in women and smokers, and a longer duration of hyper- such as oral contraception in nonmeno- Ն125 g/m2 in men and microalbumin- tension than patients with only one iso- pausal women (21) and impaired uria defined as AER Ն30 mg/24 h) lated target organ damage. Importantly, tolerance or diabetes. In 2002, du Cailar showed that 27% had LVH alone and 6% urinary sodium excretion taken as an in- et al. (22) assessed the influence of so- had microalbuminuria alone, whereas dex of dietary sodium intake was mark- dium intake (estimated by two consecu- both abnormalities were present in 10% edly higher than in the other groups. tive determinations of 24-h natriuresis) on the relationship between SAP and tar- get organs (i.e., left ventricular mass index and AER) in a large cohort of 839 normo- tensive and never-treated hypertensive subjects aged 15–70 years. It was ob- served that increasing dietary sodium was associated with an increasingly steeper slope of the relationship of SAP versus AER or left ventricular mass index. As shown in Fig. 1, the prevalence of LVH or microalbuminuria was higher in hyper- tensive patients aged Ն40 years with a natriuresis above a median of 147 mmol/24 h than in patients with natriure- sis below the median. This was the first evidence in favor of a modulating influ- ence of dietary sodium on blood pressu- re–associated target organ lesions. In addition to SAP, obesity as well as Figure 1—Prevalence of microalbuminuria (MA) (f)(Ն20 ␮g/min) or LVH ()(Ն125 in men insulin resistance and smoking were and 110 g/m2 in women) in a cohort of 376 patients with never-treated essential hypertension aged shown to be associated with a level of AER Ն40 years. inappropriately high for the SAP status

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S195 Microalbuminuria and renal and cardiovascular outcomes

(23). The influence of obesity and insulin administration for 4.8 years of losartan ciency (creatinine clearance Ͻ60 ml/min resistance suggests that albuminuria may (an angiotensin II receptor antagonist)- or per 1.73 m2) of 4.2% was observed. Al- be linked to the presence of the metabolic atenolol (a ␤-blocker)-based treatment to though age as well as serum cholesterol syndrome. It was reported that in patients a target blood pressure of 140/90 mmHg and glucose were higher, whereas base- with the defined ac- was associated with a more marked de- line renal function was lower in this group cording to the Adult Treatment Panel III crease in AER with losartan (Ϫ33 vs. of the population, multivariate analysis report, the prevalence of LVH and mi- Ϫ25% at the 1-year follow-up) (12). As in showed that baseline AER was a good pre- croalbuminuria was higher in patients most studies on the long-term effect of dictor of the risk of developing impaired with the metabolic syndrome than in pa- treatment on target organ damage, the renal function (32). In a group of 486 ab- tients without (30 vs. 24% for LVH and numbers as well as the characteristics of origines (10.5% with type 2 diabetes at 11 vs. 8% for microalbuminuria) (24). A patients in whom no improvement in inclusion), Hoy et al. (33) reported on a similar prevalence of target organ damage LVH or AER occurred were not disclosed. close correlation between baseline albu- was found in a larger population; in fact, Efforts should be devoted to the issue of minuria (range ACR Ͻ1.1 in 30% to the prevalence of microalbuminuria in- resistance of target organ damage despite Ͼ100 mg/mmol in 6.2% of the popula- creased with the number of components adequate control of blood pressure. In a tion) and the decline in GFR estimated by of the metabolic syndrome (from 3% in study conducted in 187 normoalbumin- the Cockroft and Gault equation within a subjects without any abnormality to 9.8% uric patients aged Ͻ50 years, with previ- follow-up period of 1–6 years. In fact, the in subjects with three abnormalities and ously untreated hypertension and annual decrease in GFR was almost neg- 22.1% in subjects with five abnormali- followed up for 2.7 years on various anti- ligible in normoalbuminuric people, but Ϫ ties) (25). hypertensive regimens including ACE in- increased to 2.2 and 11.6 ml min 1 Ϫ C-reactive protein is a sensitive hibitors, Redon et al. (30) observed year 1 in micro- and macroalbuminuric marker of subclinical inflammation that progression from normo- to microalbu- subjects, respectively. was shown to be a good predictor of car- minuria (AER Ն30 mg/24 h) in 11% of In patients with essential hyperten- diovascular outcomes. In a cross- patients and less frequently in subjects sion, no difference in GFR was detected sectional study conducted in the large treated with ACE inhibitors. Moreover, a between normo- and microalbuminuric Groningen cohort, Stuveling et al. (26) tendency to a higher BMI, less reduction individuals, and no alteration in intra- observed that increasing C-reactive pro- in blood pressure, and an increase in renal hemodynamics, including an in- tein values from 0.2 to 10 mg/l resulted in blood glucose and uric acid was found in crease in the filtration fraction that would a remarkable steepening of the slope of “albuminuria progressors.” Analysis of be suggestive of elevated intra-glomerular the relationship of albuminuria versus the influence of obesity, insulin resis- pressure, was detected. Of interest, the mean arterial pressure, with a potentiat- tance, or the metabolic syndrome and renal vasodilatory response to acute ad- ing effect of C-reactive protein that be- more importantly sodium intake could be ministration of the ACE inhibitor capto- came significant for mean arterial of great value in the search for causes of pril was significantly blunted in pressures Ͼ90 mmHg. resistance of target organ damage despite microalbuminuric subjects, despite a sim- With regard to plasma homocysteine satisfactory control of blood pressure. ilar level of circulating renin. This sug- as a predictor of clinical vascular disease, gested that microalbuminuria may be a it was shown that this parameter was cor- ALBUMINURIA AND RENAL marker of early intra-renal vascular dys- related with arterial stiffness assessed by OUTCOMES IN ESSENTIAL function (34). In a minority of patients, the pulse wave velocity in hypertensive HYPERTENSION — In population hyperfiltration relative to a theoretical subjects with a mean age of 58 years (27). studies, no correlation between albumin- age-related value may be observed and as- Nevertheless, the highest level of homo- uria and glomerular filtration rate (GFR) sociated with a slightly higher level of al- cysteine was associated with the lowest has been detected. In the Prevention of buminuria (35). Whether micro- level of glomerular filtration rate. Taking Renal and Vascular End-Stage Disease albuminuria or hyperfiltration is a precur- into account the fact that plasma homo- (PREVEND) study conducted in nondia- sor of further renal alterations, as already cysteine concentration is closely related to betic residents of the city of Groningen reported in , remains to be renal function (28), the significance of (the Netherlands), it was observed that documented. plasma homocysteine should be consid- GFR estimated by 24-h creatinine clear- In cross-sectional studies, age is ered with great caution. ance tended to be elevated in subjects strongly inversely correlated with GFR, with high-normal AER (15–30 mg/day), and glomerular filtration progressively ALBUMINURIA AND whereas macroalbuminuria was indepen- decreases during aging at a rate of ϳ0.5 to Ϫ Ϫ TREATMENT OF dently associated with a reduction in cre- 1ml min 1 year 1. Several factors were HYPERTENSION — In the Treat- atinine clearance below values expected identified as accelerators of the age- ment of Mild Hypertension Study for age and sex (4). In the Gubbio study related decline in GFR. In a recent study (TOMS) conducted in patients with mild conducted in a sample of an Italian com- conducted in 195 normotensive subjects hypertension (diastolic blood pressure munity of 1,632 subjects aged 45–64 and 645 patients with never-treated hy- 85–99 mmHg), it was reported that the years, no relationship between increasing pertension, it was observed that the exis- use of enalapril over 12 months afforded a AER and the prevalence of “low” creati- tence of hypertension and more precisely larger decrease in albuminuria despite a nine clearance (Ͻ60 ml/min) was found concentric LVH was associated with a similar achieved blood pressure decrease (31). marked acceleration of the age-related de- when compared with acebutolol, amlo- In the PREVEND cohort and within a cline in GFR (36). Other cross-sectional dipine, chlortalidone, and doxazosin follow-up period of 4 years, an incidence studies have shown that the slope of the (29). In the population of the LIFE study, of de novo development of renal insuffi- relationship age versus GFR is steeper in

S196 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Basi and Associates

Table 2—Morbidity mortality studies and albuminuria in nondiabetic patients

Follow-up Age range duration (years) Population characteristics (years) Outcome Cutoff value of albuminuria Copenhagen (43) 30–70 HT in 10–15% 5 CHD Ͼ4.8 ␮g/min (0.64 mg/mmol) Monica (42) 30–70 Blood pressure Ͻ150/90 mmHg 10 CHD Ͼ0.65 mg/mmol (5.1 ␮g/min) Hunt (44) Ͼ20 Nondiabetic subjects 4.4 All-cause death Ͼ0.76 mg/mmol (6 ␮g/min) Life (41) 55–80 Electrocardiogram LVH 4.8 Cardiovascular death, first Ͼ1.28 mg/mmol (10 ␮g/min) myocardial infarction, stroke Hunt (45) Ͼ20 Treated HT 4.3 All-cause death Ͼ1.7 mg/mmol (13.3 ␮g/min) Hoorn (46) 50–75 Peripheral arterial disease 5 Cardiovascular death Ͼ2 mg/mmol (16 ␮g/min) Utrecht (47) 52–67 Postmenopausal 20 Cardiovascular death Ͼ2.4 mg/mmol (18 ␮g/min) CHD, coronary heart disease; HT, hypertension.

patients with impaired glucose tolerance of some of these important prospective tients with type 2 diabetes and albumin or diabetes discovered during an oral glu- studies are shown in Table 2. It clearly concentrations of 30–140 ␮g/ml at base- cose tolerance test (37). appears that threshold values of mi- line were more likely to develop clinically Although a recent longitudinal study croalbuminuria that increase risk are con- detectable proteinuria (Ͼ400 ␮g/ml) af- confirmed that the decline in GFR found sistently lower than the usually accepted ter 9 years of average follow-up than pa- in hypertensive subjects left untreated for cutoff points for microalbuminuria crite- tients with baseline urinary albumin 6 years is accentuated compared with a ria. In studies performed in people aged concentrations Ͻ30 ␮g/ml. These find- normotensive group (Ϫ1.22 vs. 0.12 ml/ Ͼ40 years, the risk of increased cardio- ings were supported by Berrut et al. (2), min using 99m-Tc-DTPA urinary clear- vascular mortality was significant above who examined patients with type 2 diabe- ance) (38), only a few studies have ACR values of 1.28 (8) to 2 mg/mmol tes and hypertension. The GFR of patients assessed the evolution of renal function (45), which corresponds to AER of 10–16 with microalbuminuria declined more ␮ during long-term antihypertensive treat- g/min in timed urine collections. In con- than the GFR of patients with normoalbu- ment in individuals with normal renal trast, in two studies conducted in popu- minuria over the average 22 months of function. In a retrospective study con- lations aged 30–70 years (41,42) with follow-up (P Ͻ 0.01). ducted in 141 patients (38% with mi- ischemic heart disease as the primary end There have also been several larger croalbuminuria defined as 30–300 mg/ point, the threshold of ACR was 0.65 mg/ trials that have shown the association be- day), it was shown that within the 7 years mmol creatinine, roughly corresponding ␮ tween albuminuria and renal outcomes in of follow-up, the decrease in 24-h creati- to AER of 5–6 g/min. The hypothesis patients with type 2 diabetes (Table 3). nine clearance amounted to 12.1 in mi- that microalbuminuria may reflect gener- The Irbesartan Diabetic Nephropathy croalbuminuria vs. 7.7 ml/min in alized atherosclerosis was tested in the Trial (IDNT) examined 1,715 patients normoalbuminuric patients, and no influ- 5-year follow-up period of the Hoorn with hypertension, type 2 diabetes, and ence of the type of antihypertensive regi- study (45) conducted in 50- to 75-year- proteinuria. Patients enrolled in IDNT men (containing or not containing an old subjects. It was observed that both had urinary protein excretion of at least ACE inhibitor) was detected (39). Within microalbuminuria (ACR Ͼ2 mg/mmol) a follow-up period of 14 years, a decrease and peripheral arterial disease (assessed 900 mg/24 h and serum creatinine con- in GFR, estimated by inulin clearance, of by the ankle-brachial index) were associ- centration between 1.0 and 3.0 mg/dl in ϳ19 ml/min was found in a small group ated with a fourfold increase in cardiovas- women and 1.2 and 3.0 mg/dl in men at of 23 hypertensive subjects adequately cular mortality, which was more marked baseline (10). The risk for the develop- controlled by antihypertensive therapy in hypertensive subjects than in normo- ment of end-stage renal disease or dou- (40). No relationship between baseline al- tensive subjects; however, it was con- bling of serum creatinine during the buminuria and the yearly decline in GFR cluded that microalbuminuria affected average 4 years of follow-up doubled for was reported in most studies (38,40). Of mortality through a mechanism different each doubling of baseline proteinuria interest, the most important determinant from extensive atherosclerosis. level (hazard ratio [HR] 2.04, 95% CI of the GFR progression was the baseline 1.87–2.22) (47). Similarly, the Reduction level of blood pressure. ALBUMINURIA AND RENAL of Endpoints in Non-Insulin Dependent OUTCOMES IN TYPE 2 Diabetes Mellitus with the Angiotensin II ALBUMINURIA AND DIABETES — There have been several Antagonist Losartan (RENAAL) study fol- CARDIOVASCULAR studies examining the relationship be- lowed 1,513 patients with type 2 diabetes OUTCOMES IN ESSENTIAL tween microalbuminuria and renal out- and nephropathy (9). Nephropathy was HYPERTENSION — In the last few comes in type 2 diabetes. Mogensen (1) defined as a urinary ACR Ն300 mg/g with years, several studies have pointed out the studied the predictive value of microalbu- a serum creatinine level of 1.3–3.0 mg/dl. role of microalbuminuria as a predictor of minuria in patients with type 2 diabetes. The presence of albuminuria was associ- cardiovascular morbidity (8,41,42) and It was predictive of the development of ated with an adjusted HR of 6.2 (95% CI mortality (8,43–46). The characteristics overt proteinuria as well as mortality. Pa- 4.4–8.7; P Ͻ 0.001) for the outcome of

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S197 Microalbuminuria and renal and cardiovascular outcomes

Table 3—Albuminuria and renal outcomes in type 2 diabetes

Number of Study patients population Mean follow-up Intervention Renal risk with albuminuria IDNT (5,10,47) 1,715 Type 2 diabetes, 4 years Irbesartan, amlodipine, or • HR 2.04; 95% CI 1.87–2.22 hypertension placebo • Each 50% decrease in proteinuria in the first 12 months: reduction in renal risk (HR 0.44; 95% CI 0.40–0.49 RENAAL (3,7,9,48) 1,513 Type 2 diabetes 3.4 years Losartan (50 mg or 100 mg) • HR 6.2; 95% CI 4.4–8.7 vs. placebo • Each 50% decrease in albuminuria in the first 6 months: reduction in risk for end-stage renal disease of 45% MARVAL (49) 332 Type 2 diabetes 6 months vs. amlodipine • Urinary AER at 24 weeks was 56% (95% CI 49.6–63.0) of baseline with valsartan and 92% (95% CI 81.7–103.7) of baseline with amlodipine IRMA-2 (11) 590 Type 2 diabetes, 2 years Irbesartan (150 mg or 300 mg) • HR for progression to overt hypertension vs. placebo nephropathy: in the 150 mg group: HR 0.56, 95% CI 0.31– 0.99; in the 300 mg group: 0.32, 95% CI 0.15–0.65) doubling of serum creatinine or end-stage with a reduction in risk for end-stage re- Blood pressure reductions were similar renal disease (3). nal disease of 45% (48). The decrease in between the two treatments. Multiple datasets have demonstrated albuminuria associated with losartan The use of angiotensin receptor that microalbuminuria is a potent risk fac- therapy was an important predictor of blockers (ARBs) is clearly beneficial in re- tor for the development of progressive preservation of renal function. ducing proteinuria, and this is associated . It portends the future de- Similarly, the IDNT trial compared with improving renal outcomes. In addi- velopment of overt proteinuria, doubling the effects of irbesartan, amlodipine, and tion, increasing the dose of ARB has been of serum creatinine, end-stage renal dis- placebo in 1,715 hypertensive patients found to have greater renoprotection, in- ease, and mortality. Because of this rela- with type 2 diabetes and nephropathy dependent of blood pressure control. The tionship, the association between (10). The risk of doubling the serum cre- Irbestartan in Patients with Type 2 Diabe- reduction of albuminuria and renal out- atinine concentration was 33% lower in tes and Microalbuminuria (IRMA-2) comes was examined. the irbesartan group than in the placebo study, which compared 150 and 300 mg group (P ϭ 0.003) and 37% lower in the irbesartan daily to placebo in 590 hyper- TREATMENT OF irbesartan group than in the amlodipine tensive patients with type 2 diabetes and ALBUMINURIA AND RENAL group (P Ͻ 0.001). Treatment with irbe- microalbuminuria found the hazard ratio OUTCOMES IN TYPE 2 for progressing to overt nephropathy (uri- sartan was associated with a relative risk DIABETES — Several studies have nary albumin excretion rate in an over- of end-stage renal disease that was 23% shown that reduction of albuminuria by night specimen Ͼ200 ␮g/min and at least lower than that in both other groups. For inhibition of the renin-angiotensin- 30% higher than the baseline rate on at aldosterone system is associated with the each halving of proteinuria level between least two consecutive visits) was 0.56 in preservation of renal function. RENAAL baseline and 12 months, with treatment, the 150 mg group (95% CI 0.31–0.99) was a randomized double-masked study the risk for doubling of baseline serum and 0.32 in the 300 mg group (95% CI of patients with type 2 diabetes and ne- creatinine level or the development of 0.15–0.65) (11). This was after adjust- phropathy comparing losartan (50–100 end-stage renal disease was reduced by ment for the baseline level of microalbu- mg once daily) with placebo, both taken more than half (HR 0.44, 95% CI 0.40– minuria and the blood pressure achieved in addition to conventional antihyperten- 0.49) (47). during the study. Given the improvement sive treatment (9). In patients random- The Microalbuminuria Reduction in outcomes with higher doses of ARBs, ized to losartan, proteinuria declined by with Valsartan (MARVAL) trial adminis- there is now interest in whether doses be- 35% compared with placebo. Losartan re- tered 80 mg/day valsartan or 5 mg/day yond the current recommended dosage duced the incidence of a doubling of the amlodipine to 332 patients with type 2 levels may provide increased RAAS block- serum creatinine concentration (risk re- diabetes and microalbuminuria (49). The ade and therefore greater renoprotection. duction 25%; P ϭ 0.006) and end-stage urinary albumin excretion rate at 24 Irbesartan, 600 or 900 mg/day, compared renal disease (risk reduction 28%; P ϭ weeks was 56% (95% CI 49.6–63.0) of to the current maximal daily dosage of 0.002). Each 50% decrease in albumin- baseline with valsartan and 92% (95% CI 300 mg/day was given to 52 hypertensive uria in the first 6 months was associated 81.7–103.7) of baseline with amlodipine. type 2 diabetic patients with microalbu-

S198 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Basi and Associates minuria also treated with other antihyper- had baseline cardiovascular disease or mi- in the same light as other risk factors tensive medications (50). Irbesartan, 900 croalbuminuria. Patients with no baseline such as blood pressure, cholesterol, and mg/day, caused an additional 15% de- cardiovascular disease, but microalbu- blood glucose. crease in microalbuminuria compared minuria, had an increased RR for incident with 300 mg/day irbesartan (P ϭ 0.02). In cardiovascular disease (RR 2.8, 95% CI TREATMENT OF addition to increasing the dose of ACE 1.7–4.6) compared with patients with no ALBUMINURIA AND inhibitors or ARBs, other potential ways baseline cardiovascular disease and nor- CARDIOVASCULAR to increase the inhibition of the rennin moalbuminuria. In addition, patients OUTCOMES — In the PREVEND In- angiotensin system include combining with no baseline cardiovascular disease tervention Trial (PREVEND IT), patients ACE inhibitors and ARBs, adding an al- and microalbuminuria had the same risk with albuminuria treated with fosinopril dosterone inhibitor, or adding a renin for a subsequent cardiovascular event as experienced a significant decrease in uri- inhibitor. patients who had a previous cardiovascu- nary albumin excretion (26%) and a trend lar event documented at baseline. Mi- toward a decrease in cardiovascular ALBUMINURIA AND croalbuminuria was as potent a risk factor events (40%) (56). In the LIFE study, pa- CARDIOVASCULAR for cardiovascular events as a previous tients with a urinary ACR greater than the OUTCOMES IN TYPE 2 history of actual cardiovascular disease. median value at baseline (1.21 mg/ DIABETES — A strong association has Microalbuminuria may also be a risk mmol), but who were able to decrease been reported between microalbuminuria factor for more severe or advanced cardio- their ACR to less than the median value at and cardiovascular outcomes in patients vascular disease as well. The 330 patients 1 year (0.67 mg/mmol), had a reduced with type 2 diabetes. An analysis of 3,498 who underwent coronary angiography risk for cardiovascular mortality, stroke, patients with diabetes and 5,545 patients were divided into groups based on the and myocardial infarction compared with without diabetes in the Heart Outcomes presence or absence of diabetes and the patients who were not able to decrease Prevention Evaluation (HOPE) study presence or absence of microalbuminuria their ACR (12). This suggests that there found that microalbuminuria increased (52). Diabetic patients with microalbu- may be a cardiovascular benefit to reduc- the adjusted relative risk (RR) of major minuria had a higher prevalence of three- ing albuminuria in patients with essential cardiovascular events (RR 1.83, 95% CI vessel coronary artery disease compared hypertension but also in type 2 diabetes. 1.64–2.05) (6). Participants with diabe- with those without microalbuminuria (75 Future trials are needed in patients with tes had a RR of 1.97 (95% CI 1.68–2.31) vs. 42%). This relationship was also seen type 2 diabetes to explore the relationship and those without diabetes had an RR of in those patients studied without diabetes between reduction in albuminuria and 1.61 (95% CI 1.36–1.90). and with or without microalbuminuria improvement in cardiovascular events. The IDNT study, described above, (39 vs. 20%). also reported that albuminuria was an in- Multiple lines of evidence demon- CONCLUSIONS — The presence of dependent risk factor for cardiovascular strate a strong association between the albuminuria is a powerful predictor of re- events (5). The study defined a cardiovas- presence of microalbuminuria and the nal and cardiovascular risk in patients cular composite end point consisting of risk of adverse cardiovascular events. Ev- with type 2 diabetes and hypertension. In cardiovascular death, nonfatal myocar- idence suggests that as the amount of uri- addition, multiple studies have shown dial infarction, hospitalization for heart nary albumin excretion increases along that decreasing the level of albuminuria failure, stroke, amputation, and coronary the continuum from microalbuminuria to reduces the risk of adverse renal and car- and peripheral revascularization. The albuminuria and proteinuria, the risk of diovascular outcomes. The pathophysiol- ACR was associated with an increased risk adverse cardiovascular events increases. ogy is not definitively known, but is of this cardiovascular composite end Although this has been primarily studied hypothesized to be related to endothelial point (RR 1.29 per natural log unit, 95% in the diabetic population, evidence sup- dysfunction, inflammation, or possibly CI 1.13–1.48). Data from the RENAAL ports the presence of albuminuria as a po- abnormalities in the renin-angiotensin- study also demonstrated that the presence tent risk factor for adverse cardiovascular aldosterone system. of albuminuria was associated with in- events in the nondiabetic population as Albuminuria is therefore an impor- creased cardiovascular events (7). Cardio- well. Data from the Framingham study tant risk factor to measure in patients at vascular events were defined as a showed that in 1,568 nonhypertensive risk. The American Diabetes Association composite of myocardial infarction, participants without diabetes, urinary al- recommends that patients with type 2 di- stroke, first hospitalization for heart fail- bumin excretion less than the microalbu- abetes be tested for albuminuria at the ure or unstable , coronary or minuria threshold predicted the time of initial diabetes diagnosis and peripheral revascularization, or cardio- development of cardiovascular disease yearly thereafter (13). Initiation of ACE vascular death. It was found that patients (53). In the PREVEND study, urinary inhibitor or ARB therapy should be con- with a high baseline ACR (Ն3 g/g) had a albumin was measured in 6,669 nondi- sidered in patients with microalbumin- 1.92-fold higher risk (95% CI 1.54–2.38) abetic participants, and microalbumin- uria or overt proteinuria. The level of for the cardiovascular end point and a uria was associated with cardiovascular albuminuria should be followed up dur- 2.70-fold higher risk (95% CI 1.94–3.75) disease (54). Indeed some studies have ing treatment, and doses of the ACE in- for heart failure compared with patients suggested that the presence of mi- hibitor or ARB should be titrated upward with low baseline levels of ACR (Ͻ1.5 croalbuminuria increases the relative to maximize the beneficial effect on albu- g/g). risk of an adverse cardiovascular event minuria. It is possible that the combina- Furthermore, Gimeno-Orna et al. similarly to the presence of hypercho- tion of ACE inhibitors and ARBs may (51) classified 436 type 2 diabetic patients lesterolemia (55). The presence of mi- provide additional benefit over ACE in- into one of four groups based on if they croalbuminuria may need to be viewed hibitors or ARBs alone (57). In addition to

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S199 Microalbuminuria and renal and cardiovascular outcomes

ACE inhibitors and ARBs, adequate blood 421–426, 2001 Complications. Hypertension 30:1135– pressure control is an important mainstay 7. de Zeeuw D, Remuzzi G, Parving HH, 1143,1997 of treatment. If blood pressure is still ele- Keane WF, Zhang Z, Shahinfar S, Snapinn 17. Palatini P, Mormino P, Mos L, Mazzer A, vated after maximal ACE inhibitor and/or S, Cooper ME, Mitch WE, Brenner BM: Dorigatti F, Zanata G, Longo D, Garbe- ARB therapy, additional anti-hyperten- Albuminuria, a therapeutic target for car- lotto R, De Toni R, Graniero G, Pessina diovascular protection in type 2 diabetic AC: Microalbuminuria, renal function sion medications should be added to Ͻ patients with nephropathy. Circulation and development of sustained hyperten- maintain the blood pressure at 125/75 110:921–927, 2004 sion: a longitudinal study in the early mmHg. Finally, additional agents such as 8. Ibsen H, Wachtell K, Olsen MH, Borch- stage of hypertension. J Hypertens statins, renin inhibitors, and glycosami- Johnsen K, Lindholm LH, Mogensen CE, 23:175–182, 2005 noglycans may provide additional albu- Dahlof B, Devereux RB, de Faire U, Fyhr- 18. Wachtell K, Olsen MH, Dahlof B, De- minuria reduction and are actively being quist F, Julius S, Kjeldsen SE, Lederballe- vereux RB, Kjeldsen SE, Nieminen MS, studied (58). Pedersen O, Nieminen MS, Omvik P, Okin PM, Papademetriou V, Mogensen In summary, albuminuria is associated Oparil S, Wan Y: Does albuminuria pre- CE, Borch-Johnsen K, Ibsen H: Mi- with adverse renal and cardiovascular out- dict cardiovascular outcome on treatment croalbuminuria in hypertensive patients comes, and decreasing albuminuria with with losartan versus atenolol in hyperten- with electrocardiographic left ventricular sion with left ventricular hypertrophy? A hypertrophy: the LIFE study. J Hypertens ACE inhibitor or ARB therapy, blood pres- LIFE substudy. J Hypertens 22:1805– 20:405–412, 2002 sure lowering, and/or other agents can lead 1811, 2004 19. Devereux RB, Wachtell K, Gerdts E, Bo- to improved outcomes. Physicians should 9. Brenner BM, Cooper ME, de Zeeuw D, man K, Nieminen MS, Papademetriou V, measure urinary albumin excretion in pa- Keane WF, Mitch WE, Parving HH, Re- Rokkedal J, Harris K, Aurup P, Dahlof B: tients with type 2 diabetes and hypertension muzzi G, Snapinn SM, Zhang Z, Shahinfar Prognostic significance of left ventricular routinely and be as aggressive in treating S: Effects of losartan on renal and cardio- mass change during treatment of hyper- this modifiable risk factor as they do blood vascular outcomes in patients with type 2 tension. JAMA 292:2350–2356, 2004 pressure, cholesterol, or blood glucose. diabetes and nephropathy. N Engl J Med 20. Fesler P, du Cailar G, Ribstein J, Mimran 345:861–869, 2001 A: Heterogeneity of cardiorenal character- 10. Lewis EJ, Hunsicker LG, Clarke WR, Berl istics in normotensive subjects. Hyperten- References T, Pohl MA, Lewis JB, Ritz E, Atkins RC, sion 43:219–223, 2004 1. Mogensen CE: Microalbuminuria pre- Rohde R, Raz I: Renoprotective effect of 21. Ribstein J, Halimi JM, du Cailar G, Mim- dicts clinical proteinuria and early mortal- the angiotensin-receptor antagonist irbe- ran A: Renal characteristics and effect of ity in maturity-onset diabetes. N Engl sartan in patients with nephropathy due angiotensin suppression in oral contra- J Med 310:356–360, 1984 to type 2 diabetes. N Engl J Med 345:851– ceptive users. Hypertension 33:90–95, 2. Berrut G, Bouhanick B, Fabbri P, Guillo- 860, 2001 1999 teau G, Bled F, Le Jeune JJ, Fressinaud P, 11. Parving HH, Lehnert H, Brochner- 22. du Cailar G, Ribstein J, Mimran A: Dietary Marre M: Microalbuminuria as a predictor Mortensen J, Gomis R, Andersen S, Arner sodium and target organ damage in essen- of a drop in glomerular filtration rate in P: The effect of irbesartan on the develop- tial hypertension. Am J Hypertens 15:222– subjects with non-insulin-dependent dia- ment of diabetic nephropathy in patients 229, 2002 betes mellitus and hypertension. Clin with type 2 diabetes. N Engl J Med 345: 23. Mimran A, Ribstein J, DuCailar G, Halimi Nephrol 48:92–97, 1997 870–878, 2001 JM: Albuminuria in normals and essential 3. Keane WF, Brenner BM, de Zeeuw D, 12. Ibsen H, Olsen MH, Wachtell K, Borch- hypertension. J Diabetes Complications Grunfeld JP, McGill J, Mitch WE, Ribeiro Johnsen K, Lindholm LH, Mogensen CE, 8:150–156, 1994 AB, Shahinfar S, Simpson RL, Snapinn Dahlof B, Devereux RB, de Faire U, Fyhr- 24. Cuspidi C, Meani S, Fusi V, Severgnini B, SM, Toto R: The risk of developing end- quist F, Julius S, Kjeldsen SE, Lederballe- Valerio C, Catini E, Leonetti G, Magrini F, stage renal disease in patients with type 2 Pedersen O, Nieminen MS, Omvik P, Zanchetti A: Metabolic syndrome and tar- diabetes and nephropathy: the RENAAL Oparil S, Wan Y: Reduction in albumin- get organ damage in untreated essential study. Kidney Int 63:1499–1507, 2003 uria translates to reduction in cardiovas- hypertensives. J Hypertens 22:1991– 4. Pinto-Sietsma SJ, Janssen WM, Hillege cular events in hypertensive patients: 1998, 2004 HL, Navis G, De Zeeuw D, De Jong PE: losartan intervention for endpoint reduc- 25. Chen J, Muntner P, Hamm LL, Jones DW, Urinary albumin excretion is associated tion in hypertension study. Hypertension Batuman V, Fonseca V, Whelton PK, He J: with renal functional abnormalities in a 45:198–202, 2005 The metabolic syndrome and chronic kid- nondiabetic population. J Am Soc Nephrol 13. American Diabetes Association: Stan- ney disease in U.S. adults. Ann Intern Med 11:1882–1888, 2000 dards of medical care in diabetes. Diabetes 140:167–174, 2004 5. Anavekar NS, Gans DJ, Berl T, Rohde RD, Care 28 (Suppl. 1):S4–S36, 2005 26. Stuveling EM, Bakker SJ, Hillege HL, Cooper W, Bhaumik A, Hunsicker LG, 14. K/DOQI clinical practice guidelines for Burgerhof JG, de Jong PE, Gans RO, de Rouleau JL, Lewis JB, Rosendorff C, : evaluation, classi- Zeeuw D: C-reactive protein modifies the Porush JG, Drury PL, Esmatjes E, Raz I, fication, and stratification. Am J Kidney Dis relationship between blood pressure and Vanhille P, Locatelli F, Goldhaber S, 39:S1–S266, 2002 microalbuminuria. Hypertension 43:791– Lewis EJ, Pfeffer MA: Predictors of cardio- 15. Connell SJ, Hollis S, Tieszen KL, McMur- 796, 2004 vascular events in patients with type 2 di- ray JR, Dornan TL: Gender and the clini- 27. Bortolotto LA, Safar ME, Billaud E, Lac- abetic nephropathy and hypertension: a cal usefulness of the albumin: creatinine roix C, Asmar R, London GM, Blacher J: case for albuminuria. Kidney Int Suppl ratio. Diabet Med 11:32–36, 1994 Plasma homocysteine, aortic stiffness, S50–S55, 2004 16. Pontremoli R, Sofia A, Ravera M, Nicolella and renal function in hypertensive pa- 6. Gerstein HC, Mann JF, Yi Q, Zinman B, C, Viazzi F, Tirotta A, Ruello N, Tomolillo tients. Hypertension 34:837–842, 1999 Dinneen SF, Hoogwerf B, Halle JP, Young C, Castello C, Grillo G, Sacchi G, Defer- 28. Bostom AG, Culleton BF: Hyperhomocys- J, Rashkow A, Joyce C, Nawaz S, Yusuf S: rari G: Prevalence and clinical correlates teinemia in chronic renal disease. JAmSoc Albuminuria and risk of cardiovascular of microalbuminuria in essential hyper- Nephrol 10:891–900, 1999 events, death, and heart failure in diabetic tension: the MAGIC Study: Microalbu- 29. Abraham PA, Mascioli SR, Launer CA, and nondiabetic individuals. JAMA 286: minuria: A Genoa Investigation on Flack JM, Liebson PR, Svendsen KH,

S200 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Basi and Associates

Grandits GA, Opsahl JA, Schoenberger and urinary albumin excretion in primary 2309–2320, 2004 JA, Grimm RH Jr: Urinary albumin and hypertension. Am J Hypertens 9:841–849, 49. Viberti G, Wheeldon NM: Microalbumin- N-acetyl-beta-D-glucosaminidase excre- 1996 uria reduction with valsartan in patients tions in mild hypertension. Am J Hyper- 41. Borch-Johnsen K, Feldt-Rasmussen B, with type 2 diabetes mellitus: a blood tens 7:965–974, 1994 Strandgaard S, Schroll M, Jensen JS: Uri- pressure-independent effect. Circulation 30. Redon J, Rovira E, Miralles A, Julve R, Pas- nary albumin excretion: an independent 106:672–678, 2002 cual JM: Factors related to the occurrence predictor of ischemic heart disease. Arte- 50. Rossing K, Schjoedt KJ, Jensen BR, of microalbuminuria during antihyper- rioscler Thromb Vasc Biol 19:1992–1997, Boomsma F, Parving HH: Enhanced reno- tensive treatment in essential hyperten- 1999 protective effects of ultrahigh doses of sion. Hypertension 39:794–798, 2002 42. Klausen K, Borch-Johnsen K, Feldt-Ras- irbesartan in patients with type 2 diabetes 31. Cirillo M, Laurenzi M, Panarelli P, Man- mussen B, Jensen G, Clausen P, Scharling and microalbuminuria. Kidney Int 68: cini M, Zanchetti A, De Santo NG: Rela- H, Appleyard M, Jensen JS: Very low lev- 1190–1198, 2005 tion of urinary albumin excretion to els of microalbuminuria are associated 51. Gimeno-Orna JA, Molinero-Herguedas E, coronary heart disease and low renal with increased risk of coronary heart dis- Sanchez-Vano R, Lou-Arnal LM, Boned- function: role of blood pressure. Kidney ease and death independently of renal Juliani B, Castro-Alonso FJ: Microalbu- Int 65:2290–2297, 2004 function, hypertension, and diabetes. Cir- minuria presents the same vascular risk as 32. Verhave JC, Gansevoort RT, Hillege HL, culation 110:32–35, 2004 overt CVD in type 2 diabetes. Diabetes Res Bakker SJ, De Zeeuw D, de Jong PE: An 43. Romundstad S, Holmen J, Kvenild K, Hal- Clin Pract 74:103–109, 2006 elevated urinary albumin excretion pre- lan H, Ellekjaer H: Microalbuminuria and 52. Sukhija R, Aronow WS, Kakar P, Garza L, dicts de novo development of renal func- all-cause mortality in 2,089 apparently Sachdeva R, Sinha A, Mehta JL: Relation tion impairment in the general healthy individuals: a 4.4-year follow-up of microalbuminuria and coronary artery population. Kidney Int Suppl S18–S21, study: The Nord-Trondelag Health Study disease in patients with and without dia- 2004 (HUNT), Norway. Am J Kidney Dis 42: betes mellitus. Am J Cardiol 98:279–281, 33. Hoy WE, Wang Z, VanBuynder P, Baker 466–473, 2003 2006 PR, Mathews JD: The natural history of 44. Romundstad S, Holmen J, Hallan H, Kve- 53. Arnlov J, Evans JC, Meigs JB, Wang TJ, renal disease in Australian Aborigines. nild K, Ellekjaer H: Microalbuminuria Fox CS, Levy D, Benjamin EJ, D’Agostino Part 1. Changes in albuminuria and glo- and all-cause mortality in treated hyper- RB, Vasan RS: Low-grade albuminuria merular filtration rate over time. Kidney tensive individuals: does sex matter? The and incidence of cardiovascular disease Int 60:243–248, 2001 Nord-Trondelag Health Study (HUNT), events in nonhypertensive and nondia- 34. Mimran A, Ribstein J, DuCailar G: Is mi- Norway. Circulation 108:2783–2789, betic individuals: the Framingham Heart croalbuminuria a marker of early intrare- 2003 Study. Circulation 112:969–975, 2005 nal vascular dysfunction in essential 45. Jager A, Kostense PJ, Ruhe HG, Heine RJ, 54. Stuveling EM, Hillege HL, Bakker SJ, As- hypertension? Hypertension 23:1018– Nijpels G, Dekker JM, Bouter LM, Stehou- selbergs FW, de Jong PE, Gans RO, de 1021, 1994 wer CD: Microalbuminuria and periph- Zeeuw D: C-reactive protein and mi- 35. Mimran A, Ribstein J, Du Cailar G: Mi- eral arterial disease are independent croalbuminuria differ in their associations croalbuminuria in essential hypertension. predictors of cardiovascular and all-cause with various domains of vascular disease. Curr Opin Nephrol Hypertens 8:359–363, mortality, especially among hypertensive Atherosclerosis 172:107–114, 2004 1999 subjects: five-year follow-up of the Hoorn 55. Jensen JS, Feldt-Rasmussen B, Strandgaard 36. Fesler P, Du Cailar G, Ribstein J, Mimran Study. Arterioscler Thromb Vasc Biol 19: S, Schroll M, Borch-Johnsen K: Arterial hy- A: Left ventricular remodeling and renal 617–624, 1999 pertension, microalbuminuria, and risk of function in never-treated essential hyper- 46. Roest M, Banga JD, Janssen WM, Grobbee ischemic heart disease. Hypertension 35: tension. J Am Soc Nephrol 14:881–887, DE, Sixma JJ, de Jong PE, de Zeeuw D, van 898–903, 2000 2003 Der Schouw YT: Excessive urinary albumin 56. Asselbergs FW, Diercks GF, Hillege HL, 37. Ribstein J, Du Cailar G, Mimran A: Glu- levels are associated with future cardiovas- van Boven AJ, Janssen WM, Voors AA, de cose tolerance and age-associated decline cular mortality in postmenopausal women. Zeeuw D, de Jong PE, van Veldhuisen DJ, in renal function of hypertensive patients. Circulation 103:3057–3061, 2001 van Gilst WH: Effects of fosinopril and J Hypertens 19:2257–2264, 2001 47. Atkins RC, Briganti EM, Lewis JB, Hun- pravastatin on cardiovascular events in 38. Fesler P, Ribstein J, du Cailar G, Mimran sicker LG, Braden G, Champion de Cre- subjects with microalbuminuria. Circula- A: Determinants of cardiorenal damage spigny PJ, DeFerrari G, Drury P, Locatelli tion 110:2809–2816, 2004 progression in normotensive and never- F, Wiegmann TB, Lewis EJ: Proteinuria 57. Jacobsen P, Andersen S, Jensen BR, Parv- treated hypertensive subjects. Kidney Int reduction and progression to renal failure ing HH: Additive effect of ACE inhibition 67:1974–1979, 2005 in patients with type 2 diabetes mellitus and angiotensin II receptor blockade in 39. Bigazzi R, Bianchi S, Baldari D, Campese and overt nephropathy. Am J Kidney Dis type I diabetic patients with diabetic ne- VM: Microalbuminuria predicts cardio- 45:281–287, 2005 phropathy. J Am Soc Nephrol 14:992–999, vascular events and renal insufficiency in 48. de Zeeuw D, Remuzzi G, Parving HH, 2003 patients with essential hypertension. J Hy- Keane WF, Zhang Z, Shahinfar S, Snapinn 58. Epstein M: Adding spironolactone to con- pertens 16:1325–1333, 1998 S, Cooper ME, Mitch WE, Brenner BM: ventional antihypertensives reduces albu- 40. Siewert-Delle A, Ljungman S, Hartford M, Proteinuria, a target for renoprotection in minuria in patients with diabetic nep- Wikstrand J: Effect of 14 years of antihy- patients with type 2 diabetic nephropa- hropathy. Nat Clin Pract Nephrol 2:310–311, pertensive treatment on renal function thy: lessons from RENAAL. Kidney Int 65: 2006

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S201