Diabetes is not only the single most common

R e v i e w P a p e r : C M E Microalbuminuria in Type 2 Diabetics: An Important, Overlooked Cardiovascular Risk Factor Matthew R. Weir, MD The presence of microalbumin in the urine of persons with type 2 diabetes is perhaps the most important early signal heralding the onset of systemic vasculopathy and associated target organ damage to the brain, the heart, and the kidneys. It is easily measured and, unfortunately, frequently overlooked as a screening tool in clinical medicine. If present, it identifies patients at risk for early cardiovascular death and progressive renal disease. Microalbuminuria also identifies patients who need more rigorous cardiovascular risk management, especially more intensive blood pressure control, preferably below 130/80 mm Hg, and strict attention to glycemic control and lipid levels. Therapeutic strategies to facilitate better blood pressure control and reduce microalbuminuria likely will prove to be the most effective way to retard not only the progression of renal disease but also cardiovascular disease. Consequently, the identification and normalization of urine microalbumin excretion should be an important consideration in patients with diabetes. (J Clin Hypertens. 2004;6:134 143) 2004 Le Jacq Communications, Inc. From the Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD Address for correspondence: Matthew R. Weir, MD, Division of Nephrology, University of Maryland Hospital, 22 South Greene Street, N3 W143, Baltimore, MD 21201-1595 E-mail: mweir@medicine.umaryland.edu Manuscript received June 19, 2003; revised October 17, 2003; accepted October 22, 2003 www.lejacq.com ID: 2524 Diabetes is not only the single most common cause of end-stage renal disease (ESRD) in the Western world, but it is also a major risk factor for cardiovascular disease that often coexists in patients with high blood pressure. 1,2 Third National Health and Nutrition Examination Survey (NHANES III) data indicate that diabetes affects 7.8% of adults over age 20 years in the United States and that the risk of developing type 2 diabetes is more than two times greater in patients with high blood pressure than in their normotensive counterparts. 3 Moreover, 28.2% of patients with type 2 diabetes have microalbuminuria, and 7.6% have clinical proteinuria. 3 Without specific intervention, 20% 40% of patients with type 2 diabetes and microalbuminuria will progress to overt nephropathy and ultimately ESRD. 2,3 Consequently, earlier screening techniques that identify patients at risk for progression of both renal disease and cardiovascular target organ damage are required. Screening for microalbuminuria may be one of the most important, simple clinical tools in practice. MICROALBUMINURIA: A MARKER FOR CARDIOVASCULAR DISEASE In type 2 diabetics, microalbuminuria is the earliest clinical sign indicating vascular damage in the glomerulus, which is reflective of vascular disease throughout the body. 4 Although only 20% 40% of type 2 diabetics with microalbuminuria progress to overt nephropathy and ESRD, 2,3 this figure would likely be much higher if these patients did not die from myocardial infarctions or strokes first. In other words, these patients do not live long enough to develop renal failure. Epidemiologic evidence indicates that the presence of albuminuria is predictive of increased 134 THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. III MARCH 2004

Figure 1. The relationship between cardiovascular events (%) and urine albumin to creatinine ratio in patients from the Heart Outcomes Prevention Evaluation (HOPE) study. Note the continuous relationship, even below the microalbuminuria threshold (30 mg/g creatine) 8 ; deciles 1 and 2 are combined because of very low incidence rates in these two deciles Adapted with permission from JAMA. 2001;2865:421 426. 8 cardiovascular morbidity and mortality independent of other cardiovascular risk factors. 4 There is a near linear relationship between increasing urinary protein excretion and both myocardial infarction and stroke in patients with type 2 diabetes. 5 8 These observations are also valid in patients without type 2 diabetes. 9,10 Thus, screening for albumin, or protein in the urine, (even with lower levels below 150 mg/d) can have important predictive value for identifying patients who are more likely to experience a cardiovascular event. Gerstein and colleagues 8 analyzed information from the Heart Outcomes Prevention Evaluation (HOPE) study and noted that microalbuminuria was a powerful predictor for major cardiovascular events (myocardial infarction, stroke, or cardiovascular death) and all-cause mortality in patients with and without diabetes. Of the more than 9000 highrisk patients who were screened for this study, an abnormal baseline urine albumin to creatinine ratio measurement was detected in 33% of patients with diabetes and in 15% of patients without diabetes. A linear graded relationship was observed between the urine albumin to creatinine ratio and cardiovascular morbidity and mortality. The large number of study participants allowed the investigators to note that the graded relationship between albumin to creatinine ratio and cardiovascular mortality was evident well below the standard microalbuminuria threshold (30 mg/g creatinine), indicating that screening should occur early so preemptive cardiovascular risk reduction therapy can be planned (Figure 1). Microalbuminuria is also commonly associated with cardiovascular risk clustering phenomena. 11 This has been most commonly called the metabolic cardiovascular syndrome and indicates the association between high blood pressure, left ventricular hypertrophy, central obesity, microalbuminuria, dyslipidemia, glucose intolerance, and loss of nocturnal dip of blood pressure. 11 Consequently, the interplay of these risk factors leading to blood vessel damage may be best determined by the early appearance of microalbumin in the urine. Hence, a simple, clinical measurement of urine albumin is useful for not only identifying cardiovascular risk clustering phenomena, but also for identifying increased risk for cardiovascular events. MICROALBUMINURIA: A MARKER OF RENAL INJURY The presence of microalbumin in the urine heralds the onset of kidney disease in diabetics. 4,12 14 It is not known whether it indicates greater risk for kidney disease in patients without diabetes. The presence of albumin indicates early damage to the glomerular blood vessels; however, in diabetics it also could indicate failure of renal autoregulation. Although there is no direct clinical evidence to support this theory, microalbuminuria is evidence of generalized impairment of vascular function, 15 and one of the critical responsibilities of the afferent glomerular arteriole is to assist in the regulation of glomerular hemodynamics. 16 This may be an important concern in patients with diabetes. Consequently, improved control of glomerular capillary pressure with better systemic blood pressure control with drugs that block the renin-angiotensin system have increasing importance to avoid progressive renal injury. Renal autoregulation is the physiologic mechanism whereby glomerular capillary pressure is exquisitely controlled within about 5 mm Hg despite a wide range of renal perfusion pressures. 17,18 The afferent and efferent glomerular arterioles serve as the resistors of blood flow passing through glomerulus. Alterations in vascular tone of the afferent and efferent arteriole regulates intraglomerular pressures. Increasing systemic blood pressure should elicit a myogenic response at the afferent glomerular arteriole to initiate reflex contraction that reduces renal blood flow to a level that is appropriate for filtration (mean arterial pressure 70 80 mm Hg). 17,18 During situations of diminished effective arterial blood volume, the efferent glomerular arteriole vasoconstricts to restore necessary filtration pressure within the glomerulus to maintain ultrafiltration. 19 An additional mechanism that facilitates preglomerular vasoconstriction is the increased delivery of sodium chloride to the distal nephron, which stimulates VOL. VI NO. III MARCH 2004 THE JOURNAL OF CLINICAL HYPERTENSION 135

a tubular glomerular feedback mechanism. 20 In healthy persons, these autoregulatory systems operate quite effectively despite a wide range of perfusion pressures 17 19 ; however, in patients who have diabetes, there is early development of vascular disease. When this occurs at the afferent arteriole, renal autoregulation of blood flow is impaired. Consequently, systemic pressures are more easily transmitted to the glomerular capillary, which can lead to injury. For example, even if the patient has a normal systemic blood pressure of 130 mm Hg, if inadequate afferent glomerular vasoconstriction occurs, this systemic pressure could be only partially dampened as it enters the glomerulus and could lead to progressive mechanical injury. The relationship between albuminuria and progressive renal injury is not completely understood. On one hand, the albuminuria could be indicative of elevated glomerular capillary pressures that over time could lead to mechanical stretch and strain and resultant vascular injury of the filtering apparatus. 21 On the other hand, there is experimental evidence to indicate that renal epithelial cell uptake of filtered proteins may lead to an abnormal accumulation of proteins in the endolysosomes and endoplasmic reticulum that could stimulate nuclear signals for vasoactive and inflammatory genes. 22 The subsequent release of these vasoactive and inflammatory substances within the renal interstitium could lead to myofibroblast proliferation, fibrogenesis, and subsequent scarring. 22 The presence of glomerular capillary hypertension, albuminuria, and renal tubular epithelial cell reabsorption of filtered proteins may be the necessary combination of events to serve as a final common pathway for progressive renal injury. These observations also raise questions about optimal strategies to protect kidney function and whether specific antimicroalbuminuric or antiproteinuric regimens are as important as, or more important than, other cardiovascular risk reduction strategies, such as lowering blood pressure or lipids, in preventing progression of renal disease. SCREENING FOR MICROALBUMINURIA Microalbuminuria can be defined by different measurements as shown in Table I. There are three methods for screening for microalbuminuria: measurement of spot urinary albumin to creatinine ratio, 24- hour urine collection with albumin and creatinine, and a timed 8-hour or overnight urine collection to measure the albumin to creatinine ratio. The spot determination is the easiest to use in an office setting and often provides accurate information. It has been demonstrated to be at least 90% sensitive Table I. Diagnostic Criteria for Albuminuria SPOT SPECIMEN (NOT TIMED) SPOT SPECIMEN (NOT TIMED) Normo albuminuria Micro 30 299 20 200 albuminuria mg/g cr mg/dl Micro >300 mg/g cr >200 albuminuria mg/ml cr=creatinine 24-HOUR SPECIMEN (TIMED) >300 mg/g cr <20 mg/ml <30 mg/g cr 20 299 mg 300 mg Table II. Benefits of Renin-Angiotensin-Aldosterone System Blockade for Renal Protection Hemodynamic effects Reduction in systemic blood pressure Reduction in glomerular capillary pressure Possible reduction in proteinuria Nonhemodynamic effects Possible stimulation of extracellular matrix degradation Possible inhibition of macrophage/monocyte infiltration Possible reduction of oxidative stress for determining microalbuminuria compared with a 24-hour urine collection, even after adjusting for age and gender. 23 26 It is best performed with first morning void urine because of the known diurnal variation in albumin excretion. 27 One can rely on the uniformity of timing with repetitive specimens. If urine collections are used, the ratio of the albumin (in milligrams) to creatinine (in grams) should be measured, as the timed collection of urine specimens is often difficult to perform accurately. Because urine creatinine production is constant on a daily basis (it reflects the muscle mass and its breakdown products) the only variability is the urine albumin excretion. This obviates the need for a timed specimen and encourages the use of spot specimens for screening. The spot specimen can also serve as a means for determining response to antimicroalbuminuric therapy. The simplicity of the measurement allows for its use for monitoring purposes. Because of the variability in urinary albumin excretion, two or three specimens collected within a 3- to 6-month period should be abnormal before considering the patient to have crossed one of the diagnostic thresholds of albuminuria. 2 As discussed previously, there is a continuum of risk based on increasing albumin in the urine even below the traditionally reported thresholds, as outlined in Table I. Note that normal is defined as <30 mg/g creatinine. Microalbuminuria is 30 299 mg/g creatinine, and overt nephropathy or clinical albuminuria is 136 THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. III MARCH 2004

300 mg/g creatinine. 2 One can also use 24-hour collections in milligrams per 24 hours or timed collections in micrograms per minute. However, for simplicity, spot collections evaluating milligrams of albumin per grams of creatinine should be used as the standard. Also, please note that some of the variability in urinary albumin excretion can be based on exercise, infection, or fever within the previous 24 hours. In addition, poor glycemic control, marked hypertension, congestive heart failure, urinary tract infection, protein and salt intake, and even hematuria may elevate urinary albumin excretion over baseline. 2 Screening should always be performed by measuring microalbuminuria, not by measuring protein. Protein measurements in the urine are not sensitive at lower determination levels and are consequently unreliable. 28 Screenings with reagent tablets or dipsticks may also be used since they show acceptable sensitivity and specificity when carried out by trained personnel. However, the reagent strips only indicate concentration and do not correct for creatinine as the spot urine albumin to creatinine ratio does. Thus, there is greater potential for errors in quantification of albumin in the urine based on variations in urine concentration. Any positive test by a reagent strip or tablet should be confirmed by a more specific spot urine albumin to creatinine ratio for quantitation purposes. RATIONALE FOR REDUCING MICROALBUMINURIA OR PROTEINURIA The rationale for reducing microalbuminuria or proteinuria is based on the clinical evidence linking proteinuria to not only cardiovascular events but also to progressive loss of renal function. 12 14,29 35 The severity of albuminuria or proteinuria parallels renal disease progression. This has been demonstrated in patients both with and without diabetes. 30,36 Consequently, antihypertensive and antiproteinuric renal protective strategies are of great interest. The key clinical questions are: How low should we reduce blood pressure in the proteinuric patient? and, specifically, What drugs should we use? If glomerular autoregulation is impaired, mean systemic blood pressure should be reduced to near ideal glomerular capillary pressure levels of 70 80 mm Hg; however, this is often a blood pressure that may induce presyncope and is not necessarily clinically practical. There is likely a continuum of benefit associated with lower systolic pressures (below the currently recommended 130 mm Hg systolic) and reduction of risk of progression of renal disease that can be measured as a graded reduction in albumin or protein excretion. This may be analogous to the relationship between urine albumin excretion and cardiovascular events observed in the HOPE study. 8 Antihypertensive agents that target the reninangiotensin system, such as the angiotensin-converting enzyme (ACE) inhibitor or the angiotensin II receptor blocker, have been demonstrated to have more potent antiproteinuric effects with similar degrees of blood pressure reduction compared with other antihypertensive drug classes. 30,37 44 The majority of these clinical trials demonstrate that opportunity for reducing proteinuria reduces the rate of progression of renal disease. 30,37 44 Is this an effect of the drug on reducing blood pressure, reducing proteinuria, both, or on other factors not yet fully understood (Table II)? The answer is probably all of these. The simultaneous reduction of both systemic blood pressure and glomerular capillary blood pressure is likely the most important and may explain some of the decrease in proteinuria and lessened glomerular injury through a reduction in mechanical stretch and strain. 22,39 However, drugs that block the renin-angiotensin system also disrupt other profibrogenic and scarring pathways that may be important in protecting against glomerular scarring as well as tubulointerstitial injury. 22,45 The benefits of renin-angiotensin blockade were first noted with the ACE inhibitors in experimental models. 21 Subsequently, clinical studies in type 1 and type 2 diabetics 41,43,44 demonstrated an important advantage for these drugs in preventing doubling of serum creatinine and ESRD. Viberti et al. 37 studied 92 patients with type 1 and type 2 diabetes and persistent microalbuminuria who had a mean blood pressure of 124/77 mm Hg and normal renal function. Patients were randomized to receive either the ACE inhibitor captopril or a placebo. After 2 years of treatment, the mean blood pressure in the captopril group was 122/74 mm Hg compared with 126/76 mm Hg in the placebo group. This 4/2 mm Hg difference was statistically different and could explain why the captopril group had a 50% reduction in progression from microalbuminuria to clinical proteinuria. Ravid et al. 38 studied enalapril 10 mg vs. placebo therapy in 156 patients with type 2 diabetes who had a mean blood pressure of 130/80 mm Hg and urine albumin excretion rate of about 30 mg/24 hours. After 5 years of follow-up, ACE inhibitor therapy effectively suppressed an increase in microalbuminuria, whereas those on placebo progressed to develop more clinical proteinuria. Mean arterial pressures increased from 96.1 to 102 mm Hg in VOL. VI NO. III MARCH 2004 THE JOURNAL OF CLINICAL HYPERTENSION 137

the patients receiving placebo, whereas they only increased slightly, from 98.2 to 100 mm Hg, in patients receiving the ACE inhibitor. Thus, these two studies demonstrate the importance of using ACE inhibitor therapy early in microalbuminuric patients who do not manifest the traditional definition of high blood pressure or renal insufficiency. However, these studies cannot answer the question of whether this was a unique effect of the drug or a blood pressure effect. The Collaborative Study Group 41 answered this question in type 1 diabetics when they reported their data on 409 patients with type 1 diabetes who had urinary protein excretion rates over 500 mg/d and serum creatinine levels of >2.5 mg/dl who were randomized to receive either an ACE inhibitor or placebo plus other medicines to control blood pressure below 140/90 mm Hg. After more than 4 years on study therapy, patients in the ACE inhibitor arm had a slower decline in renal function and displayed a 50% reduction in the risk of death, dialysis, and transplantation 41 despite no substantial differences in the net blood pressure achieved in the two groups. These results cemented the ACE inhibitor as an important therapeutic strategy in type 1 diabetic hypertensives. Despite the important observations of this landmark study, there was little convincing evidence about strategies for reducing microalbuminuria and proteinuria with regard to clinical outcome in type 2 diabetics until three important studies were simultaneously published in the New England Journal of Medicine in September 2001. 42 44 These three studies provided important new understandings about the relationship of pharmacotherapy (all three studies used an angiotensin II receptor blocker), level of blood pressure control, and change in albuminuria or proteinuria with renal outcomes. The Irbesartan Microalbuminuria in Type 2 Diabetics (IRMA-2) trial 42 evaluated the impact of three different antihypertensive regimens on the rate of progression of microalbuminuria to clinical proteinuria in patients with hypertension, type 2 diabetes, and normal renal function. Patients could be randomized to receive placebo, irbesartan 150 mg, or irbesartan 300 mg plus additional conventional antihypertensive drugs to lower blood pressure below 140/90 mm Hg. They were followed for 2 years. Despite nearly identical reductions in blood pressure in all three groups, approximately 153/90 mm Hg to 140/83 mm Hg, there was a substantial reduction in risk for patients developing overt proteinuria if their antihypertensive regimen contained irbesartan 150 mm Hg (relative risk reduction, Figure 2. The effect of placebo or irbesartan 150 mg or irbesartan 300 mg plus conventional antihypertensive therapy for 2 years on the risk for developing clinical proteinuria (>300 mg/d) in 590 patients with hypertension, type 2 diabetes, and microalbuminuria Adapted from N Engl J Med. 2001;345:870 878. 42 39%; p=0.08) or irbesartan 300 mg (relative risk reduction, 70%; p 0.001) (Figure 2). The results of this study indicate that including a higher dose of an angiotensin II receptor blocker, independent of changes in blood pressure, helped reduce the risk for progression of microalbuminuria to clinical proteinuria. What was sobering in this study was that nearly 15% of patients progressed from microalbuminuria to clinical proteinuria in 2 years without an angiotensin II receptor blocker as part of the antihypertensive regimen despite reducing blood pressure to 140/90 mm Hg. With irbesartan 300 mg, this risk was reduced to about 5%. The Reduction in Renal Endpoints in Type 2 Diabetes with Angiotensin II Antagonist Losartan (RENAAL) 43 and Irbesartan Diabetic Nephropathy Trials (IDNT) 44 trials were performed in type 2 diabetics with hypertension, early renal insufficiency, and clinical proteinuria. Angiotensin II receptor blockade with either losartan 100 mg or irbesartan 300 mg, respectively, was a more effective strategy in preventing the composite end point of doubling of serum creatinine, reaching ESRD, or death compared with a traditional diuretic/β blocker or calcium channel blocker-based approach (p=0.02). In both of these studies, having an angiotensin II receptor blocker as part of a multidrug antihypertensive regimen consistently provided a more effective antiproteinuric effect compared with a traditional or calcium channel blocker-based approach. In the RENAAL trial, the level of achieved proteinuria reduction was predictive of renal and cardiovascular events (unpublished observations). In the IDNT 138 THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. III MARCH 2004

trial, not only did baseline 24-hour urine protein predict outcome with a doubling of risk for every doubling of protein, the study also demonstrated 50% reduction of proteinuria at 12 months was associated with a 50% reduction in the risk for doubling of serum creatinine or reaching ESRD. 36 The results of these two studies demonstrate that it is not how much proteinuria you start with, it is how much you finish with that is predictive of your risk for developing renal insufficiency. These studies provide important insight into the use of renin-angiotensin system blockers in type 2 diabetics for not only reducing blood pressure but also reducing proteinuria and slowing the risk for progression of microalbuminuria to clinical proteinuria, as well clinical proteinuria to doubling of serum creatinine or ESRD. However, no studies have been designed to correlate the antiproteinuric effect with the renoprotective effect. Other antihypertensive medications are capable of reducing microalbuminuria/proteinuria beyond what would be expected by their antihypertensive effects. Perhaps the most useful are the nondihydropyridine calcium antagonists. 46 48 These drugs, either alone or in combination with other drugs like ACE inhibitors, help lower both blood pressure and microalbuminuria/proteinuria. 49 Most of the clinical trials were performed in patients with clinical proteinuria. There has been some concern that dihydropyridine calcium antagonists may increase or not change proteinuria in patients when used without a renin-angiotensin-systemblocking drug. 46 48 However, when used with ACE inhibitors or angiotensin II receptor blockers, this is not a concern. 50,51 IMPLICATIONS FOR CLINICAL PRACTICE Earlier identification and management of patients with microalbuminuria or clinical proteinuria is imperative. Microalbuminuria is a much more easily treatable clinical problem than proteinuria in that the blood pressure tends to be lower, renal function is usually less impaired, and less medication to reduce albuminuria is required. ACE inhibitors and angiotensin II receptor blockers have been convincingly demonstrated to have renoprotective benefits. 30,41 44 The majority of the data with the ACE inhibitor is in type 1 diabetics and in patients with nondiabetic renal disease. 30,41 The more recent data with angiotensin II receptor blockers is confined to patients with type 2 diabetes 42 44 ; however, more often than not these patients will require multiple drugs to achieve the lower levels of blood pressure, which may be important in correcting glomerular capillary hypertension and optimally reducing proteinuria. Newer strategies to use combinations of drugs will likely prove to be important. Early studies indicate that using an ACE inhibitor and an angiotensin II receptor blocker together may be better than using either one alone in the approved dosing range to reduce microalbuminuria or proteinuria. 52,53 The addition of a thiazide diuretic or a nondihydropyridine calcium antagonist may also amplify the antiproteinuric effects of drugs that block the renin-angiotensin system. 49,54 Moreover, most of the renal outcome trials with ACE inhibitors or angiotensin II receptor blockers included diuretic support and/or calcium antagonists to achieve better blood pressure control. More studies are also needed to evaluate higher doses of ACE inhibitors and angiotensin II receptor blockers beyond those which have been shown to be useful for high blood pressure, to see whether better antiproteinuric effects and enhanced renal protection can be achieved. Additionally, clinicians need to be aware that modification of dietary salt consumption is crucial to optimize the antiproteinuric effects of both ACE inhibitors and angiotensin II receptor blockers 55 because increasing dietary sodium will offset both the antihypertensive and antiproteinuric effects of these drugs. CONCLUSIONS Screening for microalbuminuria should be performed on a yearly basis in every patient with type 2 diabetes, as recommended by the American Diabetes Association. 2 The presence of microalbuminuria indicates that a patient is at greater cardiovascular risk and consequently will require lower blood pressure goals (less than 130/80 mm Hg) and more specific attention to lipids, glucose, diet, and platelets, as well as antimicroalbuminuric therapies. REFERENCES 1 2002 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association; 2001. 2 American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26(suppl 1):S33 S50. 3 Harris ML, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults: the Third National Health and Nutrition Examination Survey, 1988 1994. Diabetes Care. 1998;21:518 524. 4 Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis. 1999;33:1004 1010. 5 Miettinen H, Haffner SM, Lehto S, et al. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non insulin-dependent diabetic subjects. Stroke. 1996;27:2033 2039. VOL. VI NO. III MARCH 2004 THE JOURNAL OF CLINICAL HYPERTENSION 139

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risks or benefits of calcium channel blockers? Kidney Int. 1998;53:1559 1573. 48 Bakris GL, Barnhill BW, Sadler R. Treatment of arterial hypertension in diabetic humans: importance of therapeutic selection. Kidney Int. 1992;41:912 919. 49 Bakris GL, Weir MR, DeQuattro V, et al. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int. 1998;54:1283 1289. 50 Bakris GL, Weir MR, Shanifar S, et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med. 2003;163:1555 1565. 51 Fogari R, Preti P, Zoppi A, et al. Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Am J Hypertens. 2002;15:1042 1049. 52 Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321:1440 1444. 53 Ferrari P, Marti HP, Pfister M, et al. Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade. J Hypertens. 2002;20:125 130. 54 Hemmelder MH, de Zeeuw D, Buter H, et al. Hydrochlorothiazide (HCTZ) potentiates the antiproteinuric efficacy of ACE inhibition (ACEI) comparable to dietary salt restriction. J Am Soc Nephrol. 1995;6:420. 55 Heeg JE, de Jong PE, van der Hem GK, et al. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int. 1989;36:272 279. VOL. VI NO. III MARCH 2004 THE JOURNAL OF CLINICAL HYPERTENSION 141

CME Questions Todd C. Kerwin, MD, Section Editor, Winthrop-University Hospital, Division of Cardiology, Winthrop Cardiology Associates, Mineola, NY INSTRUCTIONS FOR COMPLETING THIS FORM: Read the selected paper and answer all the questions that follow. After each question there is a series of possibly correct answers. Please select the one best answer for each and place your selection on the answer grid. YOU MUST ALSO COMPLETE THE CME EVALUATION SECTION and return the form within 6 months of the paper s publication to receive credit. Letters of credit will be mailed to participants biannually. ACCREDITATION STATEMENT: Winthrop-University Hospital (WUH) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. WUH designates this Continuing Medical Education activity for a maximum of (1) credit hour in Category 1 credit towards the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent on the educational activity. WUH relies upon faculty participants in its CME programs to provide educational information that is objective and as free of bias as possible. In this spirit, and in accordance with the guidelines of the program sponsor, faculty participants are expected to indicate any commercial relationship that might be perceived as a real or apparent conflict of interest. OBJECTIVE AND TARGET AUDIENCE: All primary care physicians and cardiologists are eligible to receive credit. At the conclusion of this activity, participants should be able to: 1) summarize the important points discussed in the paper reviewed; 2) identify patients to whom the paper is relevant; 3) modify management practices as new information is learned; and 4) identify deficiencies in their knowledge base. Please Select the One Best Answer for Each and Place Your Selection on the Answer Grid. 1. Microalbumin in the urine of a patient with type 2 diabetes mellitus is: A Screened for routinely B An indication that blood pressure in well controlled C An indication of good glucose control D A heralding sign of systemic vasculopathy 2. The percentage of patients with type 2 diabetes mellitus with microalbuminuria who will develop nephropathies is: A 20% 40% B 10% 20% C 10% 15% D 5% 10% 3. The statistic referred to in Question 2 would be higher if these patients: A Were routinely screened for microalbumin B Had other risk factors for renal failure C Did not succumb to myocardial infarctions or strokes first D Were normotensive 4. The Heart Outcomes and Prevention Evaluation (HOPE) study results support the idea that: A Microalbuminuria is not a powerful predictor of cardiovascular risk B Screening for microalbumin should occur early to preempt cardiovascular risk C Persons without diabetes need to follow the same screening process D Increased microalbumin level is not associated with increased mortality 5. Cardiovascular risk clustering phenomena include all of the following except: A Obesity B Hypertension C Glucose intolerance D Right ventricular hypertrophy CME Answers are available from The Journal of Clinical Hypertension page at www.lejacq.com 142 THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. III MARCH 2004

CME Answer Grid Answer the questions from the previous page by selecting the best choice of A, B, C, or D Questions: 1. 2. 3. 4. 5. CME Evaluation Agree Disagree 1. My knowledge was enhanced by this activity. 1. 2. 3. 4. 5. 2. The activity helped to clarify issues specific to hypertensive patients. 1. 2. 3. 4. 5. 3. The information obtained from this exercise will have an impact on my care of patients. 1. 2. 3. 4. 5. 4. The format of the exercise was useful. 1. 2. 3. 4. 5. 5. Suggestions for future topics: Where to Send the Completed CME Form Please print all information. Please submit a $5.00 administrative fee in the form of a check made out to the Office of Academic Affairs-WUH. SEND TO: Office of Academic Affairs Winthrop-University Hospital 259 First Street Mineola, NY 11501 Re: Weir MR. Microalbuminuria in type 2 diabetics: an important, overlooked cardiovascular risk factor. J Clin Hypertens (Greenwich). 2004;6:134 143. Name: Address: Social Security Number: VOL. VI NO. III MARCH 2004 THE JOURNAL OF CLINICAL HYPERTENSION 143

E r r a t u m J Clin Hypertens (Greenwich). 2004;6:146. Should Hypertensive Patients Take Aspirin? A Report From the Food and Drug Administration Thomas G. Pickering, MD, DPhil In the heading, the section editor was incorrectly reported. It should have appeared as follows: Reflections in Hypertension Thomas G. Pickering, MD, DPhil, Associate Editor in Chief VOL. VI NO. V MAY 2004 THE JOURNAL OF CLINICAL HYPERTENSION 241