Proteinuria: An Underappreciated Risk Factor in Cardiovascular Disease

Julián Segura, MD, Carlos Campo, MD, and Luis M. Ruilope, MD

AddressUnidad de Hipertensión Arterial, Hospital 12 de Octubre, Avenida Córdoba s/n, 28041 Madrid, Spain.E-mail: jsegurad@senefro.orgCurrent Cardiology Reports 2002, 4:458–462Current Science Inc. ISSN 1523-3782Copyright © 2002 by Current Science Inc.

IntroductionCardiovascular mortality is profoundly affected by thepresence of renal failure. In patients undergoing main-tenance hemodialysis, cardiovascular mortality is approxi-mately three to 20 times that of age-matched nonuremiccontrol subjects [1]. The increased mortality is associatedwith a higher frequency of conditions such as myocardialinfarction (MI), left ventricular hypertrophy (LVH),and congestive heart failure. Hypervolemia, arterial hyper-tension, and dyslipidemia are among the most relevantcauses leading to increased cardiovascular morbidity andmortality in patients presenting with renal failure.

Recent analyses have shown that renal function is a majordeterminant of cardiovascular outcome in patients withessential hypertension [2•,3•,4••] or heart failure [5,6] inthe absence of primary renal disease. A minor increase inserum creatinine above normal values, and converselya slight decrease in creatinine clearance, were powerfulpredictors of future cardiovascular death. We summarizethe available evidence in this field, which is highlyrelevant, because renal data are easy to obtain and providevaluable information.

Diagnosis of Renal Damage in Clinical PracticeThe diagnosis of renal dysfunction in patients withdifferent forms of cardiovascular disease is based ontwo findings: elevated serum creatinine, or a decrease inglomerular filtration rate (GFR) usually measured ascreatinine clearance, or the detection of an elevatedurinary excretion of albumin below (microalbuminuria,30–300 mg/d) or above (macroalbuminuria, > 300 mg/d)the usual laboratory methods to detect proteinuria. Mildrenal insufficiency has recently been defined as serumcreatinine values above 1.5 mg/dL (132 µmol/L) in menand 1.4 mg/dL (123 µmol/L) in women [7,8], or bythe finding of estimated creatinine clearance valuesbelow 60 to 70 mL/min [2•,6]. Although an elevatedserum creatinine concentration points to a reduced rateof glomerular filtration, an increased rate of albumin orprotein excretion points to a derangement in the glomer-ular filtration barrier [9]. Microalbuminuria has beenshown to correlate with the presence of nephrosclerosis[10], whereas the presence of proteinuria generally indi-cates the existence of established renal parenchymatousdamage [9]. On the other hand, the finding of a serumcreatinine value within the normal range can be accom-panied by a diminished GFR value, particularly in elderlypatients [11]. The presence of a diminished renal functionis more prevalent than previously thought in essentialhypertension. This is particularly so if estimated creati-nine clearance is considered routinely in the evaluation ofall hypertensive patients [12•]. An estimate of creatinineclearance in the absence of 24-hour urine collection canbe obtained based on prediction equations corrected forage, sex, and body size [8].

Changes in renal function produced by hypertension appear to be associated with higher cardiovascular morbidity and mortality. Indices of altered renal function (eg, micro-albuminuria, increased serum creatinine concentrations, decrease in estimated creatinine clearance, or overtproteinuria) are independent predictors of cardiovascular morbidity and mortality. The Framingham Heart Studydocumented the relevance of proteinuria for cardiovascular prognosis in the community. The International Nifedipine GITS study: Intervention as a goal in Hypertension Treat-ment (INSIGHT) study assessed the role of proteinuria as a very powerful risk factor. Several studies demonstrated that microalbuminuria is a predictor of cardiovasculardisease. It has been shown that the presence of microalbu-minuria in primary hypertension carries an elevated cardio-vascular risk. Furthermore, recent data indicate that even minor derangements of renal function are associated with an increase in cardiovascular risk factors, and promote pro-gression of atherosclerosis. All these parameters should routinely be evaluated in clinical practice, and in the future must be considered in any stratification of cardiovascular risk in hypertensive patients.

Proteinuria: An Underappreciated Risk Factor in Cardiovascular Disease • Segura et al. 459

Proteinuria and Microalbuminuria As Predictors of Cardiovascular RiskThe relevance of proteinuria for cardiovascular prognosis inthe community was documented by the Framingham HeartStudy [13]. The presence of proteinuria in patients withtreated essential hypertension varies between 4% and 16%in different series of treated hypertensive patients [14]. TheInternational Nifedipine GITS study: Intervention as a goalin Hypertension Treatment (INSIGHT) study [3•] comparedthe capacity of a long-acting dihydropyridine and a diureticto diminish cardiovascular events and death in essentialhypertension. This study assessed the role of proteinuria as arisk factor. The analysis of the different risk factors revealedthat proteinuria conferred a very powerful risk similar tothat accompanying an elevated serum creatinine and theexistence of a previous MI.

Attention has recently been drawn to microalbumin-uria and its relevance as a predictor of cardiovasculardisease [15]. Its prevalence varies between 20% and 30%of untreated patients, and up to 25% in treated patients.Very recently, it has been shown that the presence ofmicroalbuminuria in primary hypertension carries with itan elevated cardiovascular risk [9,16]. The risk is similar tothe one accompanying previous history of coronary arterydisease. According to a persuasive hypothesis, micro-albuminuria constitutes the renal expression of a general-ized disorder characterized by increased endothelialpermeability. This hypothesis provides an explanation forthe link between increased urinary albumin excretion(UAE) and elevated cardiovascular risk [15]. Somepreliminary data indicate that in primary hypertension,microalbuminuria is also a predictor of progressivedeterioration of renal function [17,18]. In the majority ofthe published studies involving hypertensive patients,microalbuminuria was defined as a UAE between 30 and300 mg/d. As used in the Losartan Intervention forEndpoint Reduction in Hypertension (LIFE) Study [19••],a simpler alternative is the measurement of the albuminto creatinine ratio in a single morning first void urinespecimen (> 3.5 mg/albumin/mmol creatinine) for thediagnosis of microalbuminuria. In patients with moder-ately severe hypertension, this recent study showed thatLVH is associated with increased prevalences of micro- andmacroalbuminuria compared with patients without LVH[19••]. Furthermore, in the Heart Outcomes PreventionEvaluation (HOPE) study [20••], the relative risk of theprimary endpoint in the fourth quartile was 1.97 (albuminto creatinine ratio > 1.62 mg/mmol) compared with thelowest quartile of albumin to creatinine ratio. For every 0.4mg/mmol increase in albumin to creatinine ratio level, theadjusted hazard of major cardiovascular events increasesby 5.9% [20••]. As the data accumulate from the ongoingtrials and the normal range for UAE in hypertension isbetter defined, the measurement of UAE rates may servea dual purpose [21•]. Microalbuminuria is a powerfulway of identifying those at risk for multiple cardiovascular

risk factor intervention. Moreover, a failure to regressmicroalbuminuria may indicate the inadequacy of thatintervention [21•].

Renal Function As a Predictor of Cardiovascular Risk in Essential HypertensionThe kidney and high blood pressure are closely related. Adefective capacity to handle the dietary sodium normallyresulting from intrinsic renal abnormalities [22], or aninadequate response of the kidney to an extrarenal mecha-nism triggering the hypertensive process [23] are amongthe most important mechanisms in the initiation andmaintenance of essential hypertension. Furthermore, renalvasoconstriction is found at the initial stages of essentialhypertension, and this is reversed by the administration ofcalcium channel blockers and angiotensin-convertingenzyme (ACE) inhibitors [23]. In more advanced stages ofthe disease, renal vascular resistance is permanentlyelevated as a consequence of structural lesions of the renalvessels (nephrosclerosis). Such structural damage mayunderlie the clinical finding of microalbuminuria [10], orthe development of overt proteinuria, as well as an increasein serum creatinine or a decrease in creatinine clearance.

Before antihypertensive treatment became available,renal involvement was frequent in patients with primaryhypertension. In a series of 500 patients followed untildeath, Perera [24] described that proteinuria was present in42%, and chronic renal failure in 18%. In this series, lifeexpectancy after the onset of renal involvement wasreported to be no more than 5 to 7 years. With the adventof antihypertensive therapy, cardiovascular and renalprognosis of hypertensive patients improved dramatically.There is agreement that renal prognosis is excellent whenhypertension is treated. Today, only a small percentage oftreated hypertensive patients develop chronic renal failuredefined by serum creatinine values [2•]. However, thispercentage has been described to attain 10.7% of patientsincluded in the HOPE study [4••], around 8% of thepopulation included in the Framingham study [8], 7.6% inpatients referred to our unit [12•], and 3% in the generalpopulation in United States according to the data of thethird National Health and Nutrition Examination Surveydata [25•]. The results of this survey also demonstratethat such a high prevalence is not explained by thesimultaneous presence of diabetes, but is related toinadequate treatment of high blood pressure [25•]. Avoid-ing serum creatinine as a parameter of renal functionevaluation, when GFR is determined by estimated creati-nine clearance the percentage of hypertensive patients witha diminished renal function found was at least 13% in theHypertension Optimal Treatment (HOT) study [2•],36% in the HOPE study [4••], and 21.5% in patientsreferred to our unit [12•]. It is necessary to reinforce theneed to estimate creatinine clearance for renal functionevaluation, to avoid the misclassification of hypertensive

460 Hypertension

patients with magnetic resonance imaging as patients withnormal renal function (Fig. 1). Interestingly, this parameteris diminished in more than 50% of the US populationabove 50 years of age [26]. These data help explain theprogressive increase in prevalence of nephrosclerosis as acause of end-stage renal failure in patients entering dialysisprograms; however, is rising steadily both in the UnitedStates and Europe [27,28].

In the Hypertension Detection and Follow-upProgram trial [29], the presence of elevated serum creati-nine values (> 1.7 mg/dL) at baseline was found to be avery potent predictor for 5- and 8-year all-cause mortality.In the Cardiovascular Health Study [30], baseline serumcreatinine values above 1.7 mg/dL were associated with a70% increase in risk for all-cause mortality in elderly menand women followed for 5 years. The risk conferred wassimilar to that associated with the presence of congestiveheart failure at baseline. Data from the HOT Study [2•]have confirmed this finding, demonstrating that serumcreatinine values above the cutoff point for mild renalinsufficiency predict an elevated cardiovascular risk evenwhen blood pressure control is excellent. In fact, in theHOT study serum creatinine values were the most power-ful predictor of mortality, stronger than any of the knownaccompanying risk factors [2•]. The investigators alsoassessed the prognostic value of a diminished creatinineclearance, as estimated by the Cockcroft and Gaultformula [31]. Values below 60 mL/min were associatedwith a significantly higher cardiovascular risk [2•]. Inthe general population, the presence of an elevatedserum creatinine concentration was also associated witha high prevalence of cardiovascular disease [7], asin the case of essential hypertension. This has beenattributed to the fact that elevated serum creatinine con-centrations frequently coexist with several cardiovascularrisk factors [7,17].

Renal Protection and Cardiovascular DiseaseDevelopment of renal damage can be the consequence ofuncontrolled hypertension [24], but it also seems to coexistwith small elevations of blood pressure in a percentage ofthe population characterized by the simultaneous presenceof several other cardiovascular risk factors [17,26,32]. In thiscase, the development of mild renal failure is accompaniedby a significant increase in global cardiovascular risk, mostlyas a consequence of the clustering of cardiovascular riskfactors. Prevention of this disorder would need an earlyidentification of the people at risk to develop renal damagein conjunction with small blood pressure elevations in thepresence of several associated cardiovascular risk factors.This group of patients could constitute one of the intermedi-ate phenotypes deserving genetic investigation [18]. On theother hand, Table 1 summarizes the therapeutic attitudesthat must be considered once renal insufficiency is present.They contemplate the simultaneous performance of cardio-vascular and renal protection. First are lifestyle changes, andamong them are three of particular relevance: diminishingsalt intake, avoidance of obesity, and withdrawal fromsmoking. A high salt intake impedes blood pressure controlas soon as the renal function is slightly deranged [33].Obesity can cause a further fall in renal function; makingit more difficult to control hypertension [34•], and smokinghas been shown to clearly facilitate the progression ofrenal damage [35].

Strict blood pressure control is necessary to avoid renaldamage in primary hypertension. Two issues arise if onetries to achieve maximum improvement in the renalprognosis of hypertensive patients. The first is the bloodpressure goal, which obtains the best renal protection.According to a recent publication [36], strict blood pressurecontrol obtained with different antihypertensive agents didnot seem to further protect renal function. In contrast, strictblood pressure control slows the decay in renal function inpatients with primary renal disease and heavy proteinuria[37]. This has led to the recommendation that in patientswith renal failure and proteinuria in excess of 1 g/d, the

Figure 1. Prevalence of mild renal insufficiency in the population of hypertensive patients followed in our hypertension unit according three different criteria of renal insufficiency diagnosis. Figures represent percentages.

Table 1. Therapeutic attitudes in patients with mild renal insufficiency and hypertension

Lifestyle changesSalt intakeBody weightSmoking

Strict blood pressure control< 130/85 mm Hg: combination therapy required in most cases< 125/75 mm Hg: if proteinuria > 1 g/dBlockade of angiotensin II effects is required

Control of associated risk factorsLipids: statins, fibratesInsulin resistance: insulin sensitizers

(metformin, glitazones?)Platelet aggregation: aspirin, others?

Proteinuria: An Underappreciated Risk Factor in Cardiovascular Disease • Segura et al. 461

blood pressure goal should be 125/75 mm Hg [37]. Theresults of the HOT Study [2•], in which patients wererandomly allocated to one of three different diastolic bloodpressure control goals (< 90, < 85, < 80 mm Hg) haveconfirmed the relevance of strict blood pressure control oncardiovascular protection and on indices of renal damage(ie, serum creatinine concentration).

Another issue is whether all antihypertensive drugs areequally effective on renal outcome. Uniformly better out-comes of renal function were obtained when ACE inhibitorswere compared with placebo both in diabetic [38] and non-diabetic renal disease [39]. In essential hypertension, ACEinhibitors reduced urinary albumin excretion more effectivelyas compared with diuretics, β-blockers, and calcium antago-nists [40]. Furthermore, in hypertensive patients, ACE inhibi-tors facilitate the regression of remodeling of [41] andimprove endothelial function in resistance arterioles [42]. Werecently published study results indicating that the adminis-tration of an ACE inhibitor as antihypertensive therapy signif-icantly improves the long-term renal outcome of patientswith nephrosclerosis in comparison with patients withoutACE inhibitor s [43•]. The presence of mild renal insuffi-ciency (serum creatinine > 1.4 mg/dL) was accompanied inthe HOPE study [4••] by an enhanced protective effect oframipril to prevent cardiovascular death, total death, andheart failure requiring hospitalization. Further studies onrenal and cardiovascular outcome are needed to elucidatewhether renal protection goes hand in hand with cardio-vascular protection and vice versa.

ConclusionsIn summary, recent data indicate that even minor derange-ments of renal function are associated with an increase incardiovascular risk factors, and promote progression ofatherosclerosis. All these parameters should routinely beevaluated in clinical practice, and in the future must beconsidered in any stratification of cardiovascular risk inhypertensive patients. The presence of diminished renalfunction is more prevalent than previously thought inessential hypertension. This is particularly so if estimatedcreatinine clearance is considered routinely in the evalua-tion of all hypertensive patients. This significant increase incardiovascular risk reinforces the need to pay attention toany of the manifestations of renal damage observed in theusual clinical assessment of any hypertensive patient.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

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This paper shows that ACE inhibitors are positive for renal protection even in the absence of proteinuria.