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(Hypertension. 2003;42:14.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Mild Renal Dysfunction and Subclinical Cardiovascular Damage in Primary Hypertension

Giovanna Leoncini; Francesca Viazzi; Denise Parodi; Simone Vettoretti; Elena Ratto; Maura Ravera; Cinzia Tomolillo; Massimo Del Sette; Gian Paolo Bezante; Giacomo Deferrari; Roberto Pontremoli

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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The presence of mild renal dysfunction is associated with high cardiovascular morbidity and mortality rates in patients with primary hypertension. The pathophysiological mechanisms underlying this association are currently unknown. We investigated the relation between mild renal dysfunction and subclinical cardiovascular organ damage in 358 never previously treated patients with primary hypertension. Mild renal dysfunction was defined as a creatinine clearance <60 mL/min and/or the presence of microalbuminuria. Left ventricular mass index and carotid intima-media thickness were assessed by ultrasound scan. The prevalence of mild renal dysfunction, left ventricular hypertrophy, and carotid plaque was 18%, 48%, and 28%, respectively. Mild renal dysfunction was related to the presence of several risk factors, such as older age, higher blood pressure levels and lipid status, and smoking habits. Patients with the highest left ventricular mass and carotid intima-media thickness (upper quartiles) showed a higher prevalence of mild renal dysfunction (P<0.0001). After adjusting for duration of hypertension, mean blood pressure, smoking habits, and age, we found that the risk of left ventricular hypertrophy and/or carotid atherosclerosis increased by 43% with each SD reduction in creatinine clearance, and by 89% with each SD increase in albuminuria. Mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help explain the high cardiovascular mortality rates reported in patients with low glomerular filtration rate or with increased albuminuria. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying subjects at higher cardiovascular risk.

Key Words: albuminuria • carotid arteries • echocardiography • glomerular filtration rate • hypertension, arterial • ultrasonography

	Introduction

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The kidney plays a dual role in primary hypertension.¹ On the one hand, it is thought to be the cause of blood pressure elevation; on the other, it may suffer from the long-term, negative consequences of the hypertensive state. Furthermore, renal function may serve as a sensor of cardiovascular risk, since it is inversely related to the occurrence of cardiovascular events. The incidence of cardiovascular disease progressively increases as glomerular filtration rate deteriorates, reaching dramatically high levels in patients on renal replacement therapy.²

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.^3–5 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.^7–10

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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Patients
Between January 1998 and January 2001, all untreated patients with primary hypertension attending the outpatient clinic of our institution were asked to participate in this study, which was part of a larger trial (MAGIC, Microalbuminuria: A Genoa Investigation on Complications) approved by the ethics committee of our department.⁵ Hypertension was defined as an average blood pressure 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 Korotkoff’s 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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The main clinical characteristics of the study patients are reported in Table 1. The average creatinine clearance was 86±21 mL/min and the prevalence of microalbuminuria and mild renal dysfunction was 9% and 18%, respectively. The prevalence of LVH and carotid plaque was 48% and 28%, respectively. Patients with renal dysfunction were older, had higher SBP and uric acid, longer history of hypertension, and were more likely to be smokers. Furthermore, they showed bigger left ventricular mass (P=0.02), higher prevalence of LVH (71% versus 42%, P<0.0001), and concentric geometry (76% versus 57%, P=0.02), as well as increased carotid IMT (P=0.004) after adjusting for age, SBP, reported duration of disease, and serum uric acid. Creatinine clearance was inversely related to several variables for example, family history of hypertension, SBP, total and LDL cholesterol, urinary sodium excretion, and ECG-detected LVH (Table 2). Urinary albumin excretion was positively related to age, body mass index, smoking, blood pressure components, and triglycerides and was inversely related to HDL cholesterol (Table 2). There was no correlation between creatinine clearance and urinary albumin excretion. Moreover, there was a significant linear trend for the relation between the prevalence of mild renal dysfunction and left ventricular mass and carotid IMT (P=0.002 and P<0.0001, respectively) (Figure). Adjusting for the duration of hypertension, mean blood pressure, smoking habits, and age showed that the risk for the presence of target organ damage, that is, LVH and/or carotid atherosclerosis, increased by 43% with each SD decrease in creatinine clearance and by 89% with each SD increase in log ACR (Table 3). Patients with mild renal dysfunction had a significantly higher chance of having either LVH and/or carotid atherosclerosis (OR, 2.75; IC, 1.33 to 5.67; P<0.01).

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics of Study Patients

View this table: [in this window] [in a new window]   TABLE 2. Univariate correlation Between Estimated Creatinine Clearance and Urinary Albumin Excretion (Log ACR) and Selected Clinical Variables

View larger version (37K): [in this window] [in a new window]   Percentage prevalence of mild renal dysfunction according to left ventricular mass index (a) and carotid IMT (b) quartiles. Left ventricular mass (a) and IMT (b) range for each quartile is indicated in parentheses. P refers to intergroup comparison.

View this table: [in this window] [in a new window]   TABLE 3. Multiple Logistic Regression Analysis*

	Discussion

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This study demonstrates that mild renal dysfunction is associated with subclinical end-organ damage, namely, LVH and carotid atherosclerosis, in a population of untreated patients with primary hypertension and normal serum creatinine levels. In fact, patients with creatinine clearance <60 mL/min and/or microalbuminuria showed significantly higher left ventricular mass index and carotid IMT as compared with those with normal glomerular filtration rate and urinary albumin excretion, even after adjusting for potential confounders such as blood pressure levels, history of hypertension, smoking habits, age, and serum uric acid. The association between renal function and organ damage appears to be rather graded and linear, since patients with more severe organ involvement (top quartiles of left ventricular mass and IMT) are characterized by a higher prevalence of mild renal damage (Figure). Furthermore, the presence of mild renal damage entails an almost 3-times-higher risk of having LVH and/or carotid atherosclerosis.

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,^22–25 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.

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This Article Abstract Full Text (PDF) Data Supplement All Versions of this Article: 42/1/14    most recent 01.HYP.0000075789.58883.73v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leoncini, G. Articles by Pontremoli, R. Search for Related Content PubMed PubMed Citation Articles by Leoncini, G. Articles by Pontremoli, R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Kidney Diseases Related Collections Clinical Studies Echocardiography Risk Factors