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(Hypertension. 2003;42:14.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
From the Department of Internal Medicine (G.L., F.V., D.P., S.V., E.R., M.R., C.T., G.P.B., G.D., R.P.) and the Department of Neurology (M.D.S.), University of Genoa, Genoa, Italy.
Correspondence to Roberto Pontremoli, MD, PhD, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6-16132 Genoa, Italy. E-mail rpontrem{at}libero.it
| Abstract |
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Key Words: albuminuria carotid arteries echocardiography glomerular filtration rate hypertension, arterial ultrasonography
| Introduction |
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Mild renal dysfunction, defined as a glomerular filtration rate <60 mL/min and/or the presence of albuminuria >30 mg/d, is relatively common in patients with long-standing primary hypertension, varying from 10% to 40% in various studies.35 Although this condition does not necessarily imply progression toward end-stage renal disease, it contributes heavily to the burden of cardiovascular risk.6,7 In fact, it has recently been reported that its presence entails a 3-times-higher incidence of fatal events, regardless of other common risk factors.3 The pathophysiological mechanisms underlying this association, however, have not yet been fully clarified. It has been suggested that a decrease in glomerular filtration rate and the presence of microalbuminuria are associated with a number of proatherogenic factors, such as insulin resistance, lipid abnormalities, hyperhomocysteinemia, endothelial dysfunction, and chronic inflammation, which, together with hemodynamic abnormalities, lead to a worse cardiovascular prognosis.710
The occurrence of major events is usually the result of long-term exposure to risk factors and, in most hypertensive patients, is preceded by the development of asymptomatic structural and functional abnormalities at the vascular and cardiac level.11 This so-called target organ damage phase is potentially reversible and, in turn, represents a strong independent predictor of unfavorable outcome. An association between mild renal dysfunction and cardiac and vascular hypertrophy might therefore help explain the pathophysiological processes underlying the occurrence of cardiovascular complications in patients with high blood pressure and renal damage.
This study was therefore initiated to investigate the relation between renal function, and left ventricular hypertrophy (LVH), and carotid atherosclerosis in a large group of never previously treated hypertensive patients.
| Methods |
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140/90 mm Hg on at least 2 different occasions. Altogether, among a total of 422 hypertensive patients seen at our clinic within the above-mentioned time range, 358 patients (all Caucasian Europeans) fulfilled inclusion criteria. Of the participating patients, 311 (87%) had never been treated for hypertension, whereas 47 (13%) had received antihypertensive treatment in the past, albeit intermittently and not during the 6 months before the study. After written informed consent had been obtained, all patients underwent to the following procedures: (1) clinic blood pressure measurement; (2) blood and urine sampling; (3) standard 12-lead ECG; (4) echocardiogram, and (5) carotid ultrasonography (US). Blood pressure was measured by a trained nurse, with the patient in the sitting position after a 5-minute rest, with a mercury sphygmomanometer (cuff size, 12.5x40 cm). The systolic (SBP) and diastolic blood pressures (DBP) were read to the nearest 2 mm Hg. Disappearance of Korotkoffs sounds (phase V) was the criterion for diastolic blood pressure. The lowest of 3 consecutive readings were recorded.
Creatinine Clearance
Creatinine clearance was estimated by the Cockcroft-Gault formula.12 Ideal body weight was used in the formula.
Albuminuria
The presence of microalbuminuria was evaluated in each patient by measuring the albumin-to-creatinine ratio (ACR) on 3 nonconsecutive first-morning samples, as described in Reference 5.5 Estimated creatinine clearance <60 mL/min and/or microalbuminuria was used to indicate the presence of mild renal dysfunction.
Echocardiography
All echocardiographic studies were performed with an Acuson Sequoia C-256 ultrasound machine. The overall monodimensional left ventricular measurements and the bidimensional (apical 4- and 2-chamber) views were obtained according to the recommendations of the American Society of Echocardiography,13 as described in References 14 and 15.14,15
Common Carotid US Scan
The intima-media thickness (IMT) of both carotid arteries was evaluated by high-resolution US scan (Diasonic Spectra System), as described by Pontremoli et al.14 Carotid plaque was defined as IMT>1.1 mm.
Statistical Analysis
All data are expressed as mean±SD. Variables found to deviate from normality were log-transformed (log) before statistical analysis was carried out. One-way ANOVA with Bonferroni or Tukey multiple comparison posttest (as appropriate) was used to analyze data from patients with or without end-organ damage. Relations among variables were assessed by using linear regression analysis and the Pearson correlation coefficient. Comparison of proportion among groups was performed by using the
2 test. Relative risk and 95% confidence intervals were calculated by exponentiation of logistic regression coefficients. All statistical analyses were performed with the use of Statview for Windows (SAS Institute Inc, version 5.0.1). A value of P<0.05 was considered statistically significant.
| Results |
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| Discussion |
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Cardiovascular disease is the main cause of morbidity and mortality in patients with end-stage renal disease.16 Previous studies indicate that among patients entering renal replacement therapy, up to 75% show LVH, and
40% have angina or coronary or peripheral vascular disease.17 More recently, a high prevalence of cardiovascular disease has also been described in patients with less severe renal impairment. In the Framingham Study, patients with mild renal dysfunction showed an almost 2-times-higher prevalence of coronary heart disease, congestive heart failure, ischemic stroke, and LVH as compared with control subjects.7 It has long been known that overt proteinuria is a strong independent risk factor for cardiovascular disease both in diabetic and nondiabetic populations.18,19 Over the last several years, the association between urinary protein excretion and cardiovascular events has been extended to low-grade albuminuria (ie, microalbuminuria).20,21 It has been pointed out that the development of subclinical cardiovascular damage, such as carotid atherosclerosis and/or LVH,2225 often precedes and predicts the acute onset of major events and has proven to be a powerful independent predictor of cardiovascular prognosis.11 Thus, our results indicating a strong relation between microalbuminuria, mild reduction in creatinine clearance, and the presence of cardiac and vascular hypertrophy could explain, at least in part, the excess morbidity and mortality rates observed in patients with renal dysfunction and could further support the role of the kidney as an integrated sensor of cardiovascular risk.
The novelty of our findings resides in the fact that only patients with normal serum creatinine were included in the study. Serum creatinine, however, is a less accurate indicator of renal function as compared with creatinine clearance, since the latter takes into account age, gender, and body weight, variables that are known to influence glomerular filtration rate.26 Furthermore, calculated creatinine clearance is easily obtained and obviates the inaccuracy and practical obstacles related to 24-hour urine collection.27 Thus for the first time, it was possible to extend the findings that had been previously described in advanced chronic renal failure to patients with primary hypertension, by means of sensitive assessment of renal function. These results may also help, albeit indirectly, shed light on the pathophysiology of cardiovascular damage in hypertension.
In fact, the mechanisms linking a reduction in glomerular filtration rate to the development of hypertensive end-organ damage have not yet been completely clarified. Earlier studies have shown that renal dysfunction entails the presence of several metabolic and hemodynamic abnormalities, which may have a negative impact on long-term cardiovascular prognosis.28 In our study, patients with abnormal renal function showed a cluster of unfavorable abnormalities, for example, they were more likely to be older and smokers, with a longer history of hypertension and higher blood pressure and serum uric acid levels (Table 1). These results support the role that multiple factors play in the pathogenesis of hypertensive organ damage. On the other hand, our data also indicate that the relation between renal dysfunction and hypertensive organ damage remains significant even after adjusting for common risk factors, such as duration of hypertension, mean blood pressure, and smoking habits (Table 3). This would suggest that its impact on cardiovascular prognosis is also due, at least in part, to factors that are unknown or not accounted for in the present study. Our study was conducted on a relatively selected population, more representative of a referral center than primary care. However, we believe that our results might also be applicable to the population of hypertensives at large, including older patients.
Perspectives
The present data might have practical, useful implications. In fact, global cardiovascular risk assessment is a key component in the evaluation of patients with high blood pressure and should serve as a guide in devising effective therapeutic strategies.29,30 Although extensive diagnostic workup can lead to the identification of a larger number of patients at risk, routine US evaluation of target organ damage may be too expensive and impractical to be applied on a large scale.31 The development of new, integrated, and low-cost tools to identify patients at higher risk may therefore prove to be very helpful in clinical practice. The combined evaluation of urinary albumin excretion and creatinine clearance allowed us to predict the presence of cardiac and vascular hypertrophy and provided a more accurate estimate of overall risk. A wider application of these tests could significantly improve the cost-effectiveness of the diagnostic approach in patients with hypertension.
Received March 12, 2003; first decision March 28, 2003; accepted April 25, 2003.
| References |
|---|
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|
|---|
2. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998; 32 (suppl 3): S112S119.[Medline] [Order article via Infotrieve]
3. Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I, Wedel H, Zanchetti A. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol. 2001; 12: 218225.
4. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134: 629636.
5. Pontremoli R, Sofia A, Ravera M, Nicolella C, Viazzi F, Tirotta A, Ruello N, Tomolillo C, Castello C, Grillo G, Sacchi G, Deferrari G. Prevalence and clinical correlates of microalbuminuria in essential hypertension. The MAGIC study. Hypertension. 1997; 30: 11351143.
6. Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: results from the hypertension detection and follow-up program: the Hypertension Detection and Follow-up Program Cooperative Group. Hypertension. 1989; 13: 180193.
7. Culleton BF, Larson MG, Wilson PW, Evans JC, Parfrey PS, Levy D. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int. 1999; 56: 22142219.[CrossRef][Medline] [Order article via Infotrieve]
8. Kronenberg F, Kuen E, Ritz E, Junker R, Konig P, Kraatz G, Lhotta K, Mann JF, Muller GA, Neyer U, Riegel W, Reigler P, Schwenger V, Von Eckardstein A. Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol. 2000; 11: 105115.
9. Fliser D, Pacini G, Engelleiter R, Kautzky-Willer A, Prager R, Franek E, Ritz E. Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int. 1998; 53: 13431347.[CrossRef][Medline] [Order article via Infotrieve]
10. Jungers P, Joly D, Massy Z, Chauveau P, Nguyen AT, Aupetit J, Chadefaux B. Sustained reduction of hyperhomocysteinaemia with folic acid supplementation in predialysis patients. Nephrol Dial Transplant. 1999; 14: 29032906.
11. Devereux RB, Alderman MH. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation. 1993; 88: 14441455.
12. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 3141.[Medline] [Order article via Infotrieve]
13. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantitation of the left ventricle by two dimensional echocardiography: American Society of Echocardiography Committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr. 1989; 2: 358367.[Medline] [Order article via Infotrieve]
14. Pontremoli R, Ravera M, Bezante GP, Viazzi F, Nicolella C, Berruti V, Leoncini G, Del Sette M, Brunelli C, Tomolillo C, Deferrari G. Left ventricular geometry and function in patients with essential hypertension and microalbuminuria. J Hypertens. 1999; 17: 9931000.[CrossRef][Medline] [Order article via Infotrieve]
15. De Simone G, Devereux RB, Daniels SR Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol. 1995; 25: 10561062.[Abstract]
16. United States Renal Data System 1998 Annual Data Report V. Patient mortality and survival. Am J Kidney Dis. 1998; 32: S69S80.[Medline] [Order article via Infotrieve]
17. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, Barre PE. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int. 1995; 47: 186192.[Medline] [Order article via Infotrieve]
18. Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham study. Am Heart J. 1984; 108: 13471352.[CrossRef][Medline] [Order article via Infotrieve]
19. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996; 27: 20332039.
20. Jager A, Kostense PJ, Ruhe HG, Heine RJ, Nijpels G, Dekker JM, Bouter LM, Stehouwer CD. Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study. Arterioscler Thromb Vasc Biol. 1999; 19: 617624.
21. Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K. Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension. 2000; 35: 898903.
22. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, Clegg LX. Association of CAD incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) study, 19871993. Am J Epidemiol. 1997; 146: 483494.
23. OLeary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999; 340: 1422.
24. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991; 114: 345352.
25. Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lombardo M, Solinas P, Gorini M, Maggioni AP, MAVI (MAssa Ventricolare sinistra nellIpertensione) Study Group. Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol. 2001; 38: 18291835.
26. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insight into old concepts. Clin Chem. 1992; 38: 19331953.[Abstract]
27. Walser M. Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis. 1998; 32: 2331.[Medline] [Order article via Infotrieve]
28. Rostand SG, Brunzell JD, Cannon RO, Victor RG. Cardiovascular complications in renal failure. J Am Soc Nephrol. 1991; 2: 10531058.[Abstract]
29. The sixth report of Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med. 1997; 157: 24132446.
30. Guidelines Subcommittee. World Health OrganizationInternational Society of Hypertension Guidelines for the management of hypertension. J Hypertens. 1999; 17: 151183.[Medline] [Order article via Infotrieve]
31. Leoncini G, Sacchi G, Viazzi F, Ravera M, Parodi D, Ratto E, Vettoretti S, Tomolillo C, Deferrari G, Pontremoli R. Microalbuminuria identifies overall cardiovascular risk in essential hypertension: an artificial neural network-based approach. J Hypertens. 2002; 20: 13151321.[CrossRef][Medline] [Order article via Infotrieve]
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