Department of Internal Medicine, University of Genoa, and Department of Cardio-Nephrology, Azienda Opedaliera Universitaria San Martino, Genoa, Italy
Address correspondence to: Dr. Roberto Pontremoli, Department of Internal Medicine, University of Genoa, and Department of Cardio-Nephrology, Azienda Opedaliera Universitaria San Martino, Genoa Viale Benedetto XV 6, 16132 Genoa, Italy. Phone/Fax: +39-010-353-8932; E-mail: roberto.pontremoli{at}unige.it
Microalbuminuria, i.e., abnormal urinary excretion of albumin,which is detectable by low cost and widely available tests,is a first-line tool for identifying hypertensive patients whoare at higher cardiovascular (CV) risk. Numerous studies haveprovided evidence that microalbuminuria is a concomitant ofcardiac and vascular damage as well as a strong, independentpredictor of CV events. An important, emerging issue is thatthe risk for CV morbidity and mortality is linearly relatedto urinary albumin excretion and persists well below the currentlyused cutoff for defining microalbuminuria. Furthermore, late-breakingevidence suggests that a reduction of albuminuria under antihypertensivetreatment is paralleled by changes in CV risk. The routine searchfor target organ damage by means of microalbuminuria could leadto a significant improvement in the evaluation and treatmentof patients with primary hypertension.
Cardiovascular diseases are the leading cause of death in Westerncountries, accounting for more than one third of all deaths.This is due mainly to the steady increase in the prevalenceof hypertension and diabetes, which affect 30 and 8% of thegeneral population, respectively, and have now reached the proportionof a worldwide epidemic. Unfortunately, the prevalence ratesof these abnormalities are expected to increase in the next2 decades, resulting in a further rise in the number of deathsfrom cardiovascular (CV) complications (1,2). A similar scenariomandates the need for both better implementation of antihypertensivetreatment and early identification of patients who are at increasedCV risk.
The assessment of global risk profile, including the severityof hypertension and the presence of concomitant CV risk factors,represents a prerequisite for devising effective antihypertensivetreatment (3). The National Health and Nutrition ExaminationSurvey Epidemiologic Follow-Up Study showed that reducing agiven BP (by approximately 12 mmHg) over a 10-yr period is muchmore beneficial in patients with a worse global risk profile(4). Recently, international hypertension guidelines acknowledgedthe relevance of minor abnormalities in renal function for stratifyingpatients with arterial hypertension. The Seventh Report of theJoint National Committee, for example, considers the presenceof microalbuminuria or a slight reduction in GFR (<60 ml/min)as major CV risk factors (5). European guidelines go even furtherand list a slight elevation in serum creatinine (>1.3 mg/dlin men and 1.2 mg/dl in women) and/or the presence of microalbuminuriaamong the signs of hypertensive organ damage (3). This briefreview focuses on the role of microalbuminuria as an integratedmarker of subclinical organ damage and its usefulness for globalrisk assessment and effective treatment.
The occurrence of microalbuminuria in patients who do not havediabetes but have primary hypertension was first described byParving et al. (6) in 1974. Although 24-h urine collection isstill considered the reference method for measuring urinaryalbumin excretion, evaluating the albumin to creatinine ratioin a first morning urine sample is easier but no less accurateand has rapidly become the method of choice in clinical practice.Since 1974, several studies have shown that microalbuminuria,whose prevalence ranges from 5 to 40%, is a useful tool whenevaluating CV risk in hypertensive patients. We and others havedemonstrated that microalbuminuria is associated with extrarenalsigns of hypertensive target organ damage, such as left ventricularhypertrophy and carotid atherosclerosis (7). Furthermore, alarge body of data indicate that microalbuminuria is a strong,independent predictor of CV events both in patients with andin patients without diabetes. An important, emerging issue isthat the risk for CV morbidity and mortality is linearly relatedto urinary albumin excretion, without any recognizable thresholdor plateau. In the LIFE study, for example, the rate of theprimary composite end point increased linearly four- to five-foldin patients from the lowest to the highest deciles of the albuminto creatinine ratio (8). On the basis of these findings, itwas suggested recently that the cutoff value for defining microalbuminuriain essential hypertension be lowered to improve diagnostic sensitivity(9).
Late-breaking evidence suggests that a reduction of albuminuriaunder antihypertensive treatment is paralleled by changes inCV risk. In the LIFE study, baseline and in-treatment valuesof albuminuria were classified into four increasing categoriesthat were added as time-varying covariates in Cox regressionmodels. Hazard ratios for in-treatment albuminuria also werecalculated. Therefore, the risk for each albuminuria categorychanged over time and patients shifted among the different classesas their albumin to creatinine ratio levels changed during thestudy period. It is interesting that this analysis providedproof that when albuminuria decreased during treatment, therisk for the primary composite end point also was reduced, suggestingthat changes in albuminuria translate to changes in risk (10).These results led the authors to suggest that reducing albuminuriamight become a therapeutic goal in itself.
The finding that a reduction in albuminuria parallels an improvementin CV prognosis supports, at least in part, the concept thatmicroalbuminuria may be a CV risk factor rather than simplya risk marker. It is noteworthy that the prognostic role ofalbuminuria seems to be even stronger than that of left ventricularmass, at least with regard to the occurrence of CV mortality.In fact, in the LIFE study, albuminuria and left ventricularmass proved to be independent of each other and additive inpredicting CV outcomes (11). However, in Cox regression analysis,adjusting for traditional CV risk factors, albuminuria but notleft ventricular hypertrophy predicted the composite end point.
Usefulness of Microalbuminuria in Clinical Practice
The likelihood of identifying cardiac and vascular subclinicalabnormalities in clinical practice strongly depends on the diagnostictechniques that are used. We and others previously demonstratedthat the percentage of patients who are allocated to high/veryhigh risk classes increases progressively according to the numberof diagnostic tests that are performed on each patient (12).Undoubtedly, the widespread use of sensitive diagnostic testssuch as ultrasound scans of the cardiac and vascular structuresin the search for left ventricular hypertrophy and carotid abnormalitiesis a good option. However, because of the high prevalence ofhypertension, this approach may not always be implemented inclinical practice because of both logistic and financial reasons.
We provided evidence to support the routine search for microalbuminuriain hypertensive patients as a cost-effective approach to thestratification of global risk. First, by means of albuminuriaand an artificial neural network, we demonstrated that hypertensivepatients can be placed into different risk classes with a degreeof accuracy that is almost superimposable to what can be obtainedby assessing target organ damage by ultrasound scan but at asignificantly lower cost (13). Second, by showing that differentsigns of target organ damage only partly cluster and that microalbuminuriais an integrated marker of target organ damage, we showed thatthe routine search for microalbuminuria might lead to optimizationof the diagnostic workup (12). Because the relationship betweenalbuminuria and left ventricular mass is linear over the entirerange, adopting a lower cutoff value for albuminuria might furtherimprove the cost-effectiveness of CV risk stratification. Sucha hypothesis certainly is worth testing in the clinical setting.
The evaluation of urinary albumin excretion represents an importantpart of the management of hypertension, even in younger patients.Microalbuminuria should be assessed before treatment is startedto optimize the diagnostic workup and during antihypertensivetherapy to monitor the effectiveness of treatment even beyondBP control.
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Abstract
Introduction
