Abstract

Background:

Mild renal dysfunction (MRD) is an often overlooked but relatively common condition in patients with primary hypertension (PH), and is associated with high cardiovascular morbidity and mortality. Whether MRD is also associated with abnormalities in renal vascular resistance is currently unknown.

Methods:

Two hundred ninety-one untreated patients with PH were studied. The MRD was defined as a creatinine clearance ≥60 mL/min but <90 mL/min (Cockcroft-Gault formula) or the presence of microalbuminuria. Albuminuria was measured as the albumin-to-creatinine ratio in first morning urine samples. Renal resistive index (RI) was evaluated by ultrasound Doppler of the interlobar arteries.

Results:

The prevalence of MRD in our cohort was 63%. Patients with MRD were older, had higher mean blood pressure (BP), pulse pressure, and total cholesterol, longer history of hypertension, and were more likely to be men. Renal RI was positively related to female gender, age, systolic BP, pulse pressure, total cholesterol, albuminuria, and to carotid wall thickness and cross-sectional area, whereas it was inversely related to diastolic BP and creatinine clearance. Patients with the highest renal resistance (upper quartile, ≥0.63) showed a greater prevalence of renal dysfunction (P = .0005). After adjusting for age, pulse pressure, and LDL-cholesterol, we found that the risk of MRD increased twofold (P = .04) when renal RI was ≥0.63.

Conclusions:

A reduction in creatinine clearance and the presence of microalbuminuria are associated with increased renal vascular impedence, as well as with signs of extrarenal arterial stiffness. Am J Hypertens 2005;18:966–971 © 2005 American Journal of Hypertension, Ltd.

Mild renal dysfunction is an often overlooked but relatively common condition in patients with primary hypertension. Although a slight elevation of serum creatinine is present in 3% to 10% of hypertensive patients, up to 30% of them show a mild or moderate reduction in renal function when glomerular filtration rate is estimated by more sensitive tests such as creatinine clearance.1,2 It has recently been emphasized that the presence of renal dysfunction entails a cluster of unfavorable hemodynamic and metabolic changes that may accelerate the process of atherosclerosis and concur to aggravate the global burden of cardiovascular risk.3–5

The evaluation of renal vasculature and blood flow by Doppler ultrasonography is performed in hypertensive patients with increasing frequency.6 The resistive index (RI), measured at the level of the interlobar arteries, is thought to reflect downstream vascular impedence and therefore, has been suggested as a measure of renal arterial stiffness.7 Increased RI has been shown to correlate with the severity of renal damage in primary renal diseases7–9 and to predict the rate of progression to end-stage renal disease.10,11

Nonetheless, to date it is unclear whether abnormalities of renal function (ie, reduction of glomerular filtration rate and albuminuria) are associated with increased renal vascular resistance in hypertensive patients.

To this aim we evaluated ultrasound Doppler renal RI in a large group of middle-aged, untreated, hypertensive patients with primary hypertension and normal serum creatinine.

Methods

Study Population

Between January 2001 and January 2003, 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 Ethical Committee of our Department. Details of the study have already been published.3 Exclusion criteria were the presence of neoplastic, hepatic or renal disease (serum creatinine >1.4 mg/dL for women and >1.5 mg/dL for men, or proteinuria >300 mg/24 h, chronic heart failure (New York Heart Association class III and IV), positive history or clinical signs of ischemic heart disease, diabetes mellitus, severe obesity (defined as body weight >150% of ideal body weight), or disabling diseases such as dementia or inability to cooperate. Diagnosis of essential hypertension was made by the attending physician after complete medical history, physical examination, and routine biochemical analyses of blood and urine (including urine sediment evaluation) were carried out for each patient. Further investigation was performed only when abnormalities were found in these analyses, or when other symptoms or signs suggesting secondary hypertension were present. Hypertension was defined as an average blood pressure (BP) ≥140/90 mm Hg on at least two different occasions. None of the patients were on medication at the time of the study. Altogether, 338 hypertensive patients were seen at our clinic within the above mentioned time range, and among them 318 (94%) were eligible for the study on the basis of available clinical and laboratory data. Twelve of these patients did not meet study criteria based on the results of additional tests prescribed for clinical reasons during their first visit to our clinic. Among the remaining 306 patients (all white Europeans), 15 declined and 291 form the basis of the present report. Of the participating patients, 256 (88%) had never been treated for hypertension, and 35 (12%) 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 the following procedures: 1) clinic BP measurement; 2) blood and urine sampling; 3) thorough evaluation of target organ damage, including urinary albumin excretion, electrocardiogram, echocardiogram, and carotid ultrasonography; and 4) renal ultrasound and Doppler studies. On the study day, after an overnight fast, height and weight were measured and venous blood was drawn to carry out routine blood tests. Blood pressure was measured by a trained nurse, with the patient in the sitting position after a 5-min rest, with a mercury sphygmomanometer (cuff size 12.5 by 40 cm). The systolic and diastolic BPs were read to the nearest 2 mm Hg. Disappearance of Korotkoff's sounds (phase V) was the criterion for diastolic BP. The lowest of three consecutive readings were recorded. Body mass index (BMI) was calculated by the formula: weight (in kilograms)/height (in meters squared). Creatinine, blood urea nitrogen, electrolytes, uric acid, triglycerides, total and HDL-cholesterol, and other standard blood chemistry evaluations were performed on the serum, according to routine methods. Low-density lipoprotein-cholesterol was calculated using Friedewald's formula.12 Family history and lifestyle habits were assessed by means of a standard questionnaire. Twenty-four-hour urine collection was obtained to evaluate urinary sodium excretion.

Renal Function

The presence of microalbuminuria was evaluated in each patient by measuring the albumin-to-creatinine ratio (ACR) on three nonconsecutive first morning samples as described in Pontremoli et al.2 Urine albumin concentration was measured by a commercially available radioimmunoassay kit (Immunotech, Pantec, Torino, Italy). To account for differences in basal creatinine excretion rates and BMI, different values were used to define microalbuminuria in men (ACR ≥2.5 mg/mmol) and women (ACR ≥3.5 mg/mmol). Creatinine clearance was estimated by the Cockcroft-Gault formula.13 Ideal body weight was used in the formula. Estimated creatinine clearance ≥60mL/min but <90 mL/min, or microalbuminuria, was used to indicate the presence of mild renal dysfunction. Estimated creatinine clearance ≥30 mL/min but <60 mL/min was used to indicate the presence of moderate renal dysfunction.

Renal Ultrasound and Doppler Studies

Renal ultrasonography was performed as reported in Pontremoli et al.14 Doppler signals were obtained from the interlobar arteries by placing the sample volume at the edge of the medullary pyramids. Mean RI [(Peak systolic velocity − End-diastolic velocity)/Peak systolic velocity] was calculated by using six measurements (three from each of the two kidneys) taken for each patient. The ultrasound examination of the kidneys and pulsed Doppler of the intrarenal arteries were performed using a Hitachi AU 450 machine (Tokyo, Japan) with a 3.5-MHz transducer working at 2.5 MHz for Doppler analysis.

Extrarenal Hypertensive Target Organ Damage

All echocardiographic studies were performed using an Acuson Sequoia C-256 ultrasound machine (Mountain View, CA). The overall, monodimensional left ventricular measurements and the bidimensional (apical four and two chamber) views were obtained according to the recommendations of the American Society of Echocardiography15 as described in Pontremoli et al.16 All tracings were obtained and read by a single observer blinded to the clinical characteristics of the patients under observation. The presence of left ventricular hypertrophy (LVH) was defined as left ventricular mass index (LVMI) ≥51 g/m2.7.17

The intima-media thickness (IMT) of both carotid arteries was evaluated by high-resolution ultrasound scan, as described in Pontremoli et al.16 Carotid arteries were investigated in the longitudinal and the transverse projections by high-resolution, real-time ultrasonography using a 10-MHz in-line duplex Diasonic Spectra System (Milpitas, CA). The IMT was always measured on the common carotid artery outside the plaque, if any was present. Each measurement was calculated by taking the average of three readings. The cross-sectional area of the carotid artery (CSA) was calculated using the following formula: 3.14 × [(Lumen diameter/2 + IMT)2 − (Lumen diameter/2)2].

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. Relationships among variables were assessed using linear regression analysis and Pearson's correlation coefficient. One-way analysis of variance (ANOVA) with Bonferroni or Tukey multiple comparison post-test (as appropriate) was used to analyze data from patients with or without end-organ damage. Comparison of proportion among groups was performed using the χ2 test. A forward stepwise multiple regression analysis was performed to investigate the association between RI and its potential predictors (age, BMI, creatinine clearance, urinary albumin excretion, pulse pressure, and LDL-cholesterol). Relative risk and 95% confidence intervals were calculated by exponentiation of logistic regression coefficients. All statistical analyses were performed using Statview for Windows, SAS Institute Inc. (version 5.0.1, Cary, NC). P < .05 was considered statistically significant.

Results

The main clinical characteristics of our study patients are reported in Table 1. The average creatinine clearance was 87 ± 20 mL/min, and the prevalence of microalbuminuria and renal dysfunction was 14% and 67%, respectively. Among patients with renal dysfunction, 6% (n = 12) had moderate renal dysfunction and 94% had mild renal dysfunction. Patients with mild renal dysfunction were older, had higher systolic BP, pulse pressure, total and LDL-cholesterol, and were more likely to be men. Furthermore, after adjusting for several confounding variables (ie, age, BP, and serum cholesterol) they showed larger left ventricular mass (P = .001), higher prevalence of LVH (48% v 30%, P = .004), increased carotid intima-media thickness (P = .0039), as well as higher renal RI (P = .0016) (Fig. 1). Renal RI was positively related to female gender, age, systolic BP, pulse pressure, total cholesterol, urinary albumin excretion, and to carotid intima-media thickness and cross-sectional area, whereas it was inversely related to diastolic BP and creatinine clearance (Table 2). Age (standard coefficient 0.198) and pulse pressure (standard coefficient 0.301) were independently associated with RI in a stepwise forward regression analysis performed with age, BMI, pulse pressure, creatinine clearance, urinary albumin excretion, and total cholesterol as independent variables. Patients with microalbuminuria, reduced creatinine clearance (ie, <90 mL/min) or mild renal dysfunction showed a greater prevalence of increased renal vascular resistance (upper quartile, RI ≥0.63) (P = .0004, P = .02, and P = .0009, respectively) (Fig. 2). After adjusting for pulse pressure, LDL-cholesterol, and age, we found that a RI above 0.63 was associated with a 2.83 higher risk (P = .04) of having mild renal dysfunction (Table 3).

Table 1

Clinical characteristics of the study patients (n = 279)

 All Normal Renal Function Mild Renal Dysfunction P 
Count 279 96 183  
Age (y) 47.5 ± 9.0 41.9 ± 8.5 50.4 ± 7.7 <.0001 
Gender (% males) 63 77 56 .0006 
Body mass index (kg/m226.1 ± 3.2 26.2 ± 3.1 26.1 ± 3.2 NS 
Systolic blood pressure (mm Hg) 157 ± 14 155 ± 14 159 ± 14 .02 
Diastolic blood pressure (mm Hg) 101 ± 8 101 ± 8 101 ± 8 NS 
Mean blood pressure (mm Hg) 120 ± 8 119 ± 8 121 ± 9 NS 
Pulse pressure (mm Hg) 56 ± 13 54 ± 14 57 ± 12 .02 
Duration of hypertension (mo) 51 (3–360) 49 (3–240) 53 (3–360) NS 
Family history of hypertension (%) 79 73 82 NS 
Family history of CV diseases (%) 52 44 56 NS 
Smokers (%) 23 21 25 NS 
Serum creatinine (mg/dL) 0.9 ± 0.2 0.8 ± 0.2 0.9 ± 0.2 <.0001 
Estimated creatinine clearance (mL/min) 88 ± 19 108 ± 16 78 ± 12 <.0001 
Serum glucose (mg/dL) 90 ± 12 90 ± 11 90 ± 12 NS 
Serum uric acid (mg/dL) 5.1 ± 1.4 5.2 ± 1.3 5.0 ± 1.4 NS 
Total serum cholesterol (mg/dL) 211 ± 44 203 ± 47 215 ± 42 .03 
Triglycerides (mg/dL) 122 (26–400) 117 (26–400) 124 (30–400) NS 
HDL-cholesterol (mg/dL) 54 ± 15 53 ± 15 54 ± 15 NS 
LDL-cholesterol (mg/dL) 135 ± 42 128 ± 48 139 ± 38 .04 
ACR (mg/mmol) 1.9 ± 4.8 0.6 ± 0.5 2.5 ± 5.8 .0017 
Left ventricular mass index (g/m2.749.0 ± 11.6 45.8 ± 10.2 50.8 ± 11.9 .001 
Prevalence of LVH, ECHO (%) 41 30 48 .005 
Common carotid IMT (mm) 0.68 ± 0.2 0.63 ± 0.19 0.70 ± 0.20 .003 
 All Normal Renal Function Mild Renal Dysfunction P 
Count 279 96 183  
Age (y) 47.5 ± 9.0 41.9 ± 8.5 50.4 ± 7.7 <.0001 
Gender (% males) 63 77 56 .0006 
Body mass index (kg/m226.1 ± 3.2 26.2 ± 3.1 26.1 ± 3.2 NS 
Systolic blood pressure (mm Hg) 157 ± 14 155 ± 14 159 ± 14 .02 
Diastolic blood pressure (mm Hg) 101 ± 8 101 ± 8 101 ± 8 NS 
Mean blood pressure (mm Hg) 120 ± 8 119 ± 8 121 ± 9 NS 
Pulse pressure (mm Hg) 56 ± 13 54 ± 14 57 ± 12 .02 
Duration of hypertension (mo) 51 (3–360) 49 (3–240) 53 (3–360) NS 
Family history of hypertension (%) 79 73 82 NS 
Family history of CV diseases (%) 52 44 56 NS 
Smokers (%) 23 21 25 NS 
Serum creatinine (mg/dL) 0.9 ± 0.2 0.8 ± 0.2 0.9 ± 0.2 <.0001 
Estimated creatinine clearance (mL/min) 88 ± 19 108 ± 16 78 ± 12 <.0001 
Serum glucose (mg/dL) 90 ± 12 90 ± 11 90 ± 12 NS 
Serum uric acid (mg/dL) 5.1 ± 1.4 5.2 ± 1.3 5.0 ± 1.4 NS 
Total serum cholesterol (mg/dL) 211 ± 44 203 ± 47 215 ± 42 .03 
Triglycerides (mg/dL) 122 (26–400) 117 (26–400) 124 (30–400) NS 
HDL-cholesterol (mg/dL) 54 ± 15 53 ± 15 54 ± 15 NS 
LDL-cholesterol (mg/dL) 135 ± 42 128 ± 48 139 ± 38 .04 
ACR (mg/mmol) 1.9 ± 4.8 0.6 ± 0.5 2.5 ± 5.8 .0017 
Left ventricular mass index (g/m2.749.0 ± 11.6 45.8 ± 10.2 50.8 ± 11.9 .001 
Prevalence of LVH, ECHO (%) 41 30 48 .005 
Common carotid IMT (mm) 0.68 ± 0.2 0.63 ± 0.19 0.70 ± 0.20 .003 

ACR = urinary albumin-to-creatinine ratio; CV = cardiovascular; LVH = left ventricular hypertrophy; ECHO = echocardiography, IMT = intima-media thickness.

Values are mean ± SD, except for reported duration of hypertension, and triglycerides expressed as median (range).

Table 3

Multiple logistic regression analysis: relationship of selected variables to the presence of mild renal dysfunction

Variable Relative Risk 95% Confidence Interval P 
Renal resistive index >0.63 2.83 1.03–7.74 .04 
Age (per 5-y increase) 1.81 1.46–2.25 <.0001 
Variable Relative Risk 95% Confidence Interval P 
Renal resistive index >0.63 2.83 1.03–7.74 .04 
Age (per 5-y increase) 1.81 1.46–2.25 <.0001 

Also included in the model: pulse pressure and LDL-cholesterol not significantly related to the presence of mild renal dysfunction.

Renal resistive index in hypertensive patients on the basis of the presence of mild renal dysfunction.

Table 2

Univariate correlation between renal resistance and selected clinical variables

Variable r P 
Female gender 0.223 .0002 
Age 0.283 <.0001 
Systolic blood pressure 0.238 <.0001 
Diastolic blood pressure −0.202 .0007 
Pulse pressure 0.377 <.0001 
Estimated creatinine clearance −0.139 .02 
ACR 0.128 .03 
Total cholesterol 0.131 .03 
Carotid cross-sectional area 0.157 .01 
Carotid IMT 0.225 .0003 
Variable r P 
Female gender 0.223 .0002 
Age 0.283 <.0001 
Systolic blood pressure 0.238 <.0001 
Diastolic blood pressure −0.202 .0007 
Pulse pressure 0.377 <.0001 
Estimated creatinine clearance −0.139 .02 
ACR 0.128 .03 
Total cholesterol 0.131 .03 
Carotid cross-sectional area 0.157 .01 
Carotid IMT 0.225 .0003 

Abbreviations as in Table 1.

Prevalence of increased renal resistive index (RI ≥0.63) in patients with primary hypertension on the basis of urinary albumin excretion, creatinine (Cr.) clearance, and the presence/absence of mild renal dysfunction.

Discussion

The present study demonstrates that even a slight increase in renal vascular impedence, as measured by ultrasound Doppler at the interlobar arteries, is associated with subclinical abnormalities of renal function in a large group of untreated, middle-aged patients with primary hypertension and normal serum creatinine levels (Fig. 1). In fact, patients with the highest renal RI (upper quartile) showed a greater prevalence of mild renal dysfunction, creatinine clearance lower than 90 mL/min, as well as microalbuminuria (Fig. 2). Furthermore, the association between renal damage and increased renal RI was independent of several potential confounders, such as BP levels, age, and lipid abnormalities (see Results section and Table 3). These findings suggest that an increase in intrarenal vascular stiffness may occur together with the impairment of renal function.

A reduction in creatinine clearance or the presence of albuminuria >30 mg/d is relatively common in patients with long-standing primary hypertension, ranging from 10% to 40% in several studies.1,2 The 67% prevalence we observed in our study patients fits well with what was reported in the Heart Outcome Prevention Evaluation (HOPE) and International Nifedipine Gits Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) studies, where a lower cutoff value for creatinine clearance (ie, 60 mL/min) was applied to a relatively high risk population.1 Mild renal dysfunction has recently been shown to entail a significant increase in cardiovascular risk, and both JNC VII and ESH-ESC guidelines suggest that creatinine clearance should be part of the diagnostic workup in hypertensive patients.18,19 Nonetheless, to date, renal hemodynamics in patients with primary hypertension has been poorly investigated.

Increased RI has been shown to be a concomitant factor of reduced effective renal plasma flow, increased renal vascular resistance and filtration fraction,20 and a marker of the severity of arteriolar and glomerular sclerosis in patients with chronic nephropathy.7 Furthermore, Petersen et al11 demonstrated that RI correlates to the progression of renal damage, measured as the rate of decline in the reciprocal of serum creatinine in a group of patients with chronic renal failure under antihypertensive therapy. More recently, Radermacher et al21 demonstrated that an RI ≥0.80 is an even greater independent predictor of renal disease progression than clinical proteinuria and glomerular filtration rate reduction.

Whether an increased intrarenal RI is a feature of mild renal impairment and a predictor of subsequent progressive renal disease in primary hypertension is presently unclear. Thus, our findings that even mild reductions in glomerular filtration rate or microalbuminuria are associated with increased renal vascular impedence provide interesting pathophysiologic insight into this condition (Fig. 1). Previous studies have shown that intraparenchymal RIs are higher in patients with long-standing primary hypertension as compared to normotensive patients, and correlate with the severity and duration of the disease.11,22,23 On the other hand, a reduction in glomerular filtration rate and the presence of microalbuminuria are also known to be risk factors for widespread atherosclerotic damage.24 In keeping with this hypothesis, the results of logistic regression analysis show that both increased RI and age significantly contribute to the presence of mild renal dysfunction (Table 3).

Furthermore, recent clinical studies have demonstrated a significant relationship between arterial stiffness, as evaluated by aortic pulse wave velocity, and renal function in subjects with mild-to-moderate renal insufficiency and normal or high BP levels.25–27 Interestingly, we found a positive correlation between increased intrarenal RI and factors known to either influence vascular stiffness or to be the consequence of it, such as age, dyslipidemia, increased pulse pressure, carotid wall thickness, and cross-sectional area (Table 2). Moreover, in a stepwise regression analysis, RI was independently associated with age and pulse pressure. Thus, our findings confirm and integrate those reported by Okura et al28 suggesting that renal vascular resistance is related to carotid stiffness. They further support the possibility that atherosclerosis may play a role in the functional and structural changes that lead to increases in renal vascular resistance and mild renal dysfunction.

Whether the increased renal RI in our study patients indicates irreversible renal sclerotic lesions, and whether further loss of renal function can be prevented by optimal BP control or specific agents is currently unclear. It has been suggested that increased renal impedence may initially represent a functional, reversible change that is caused by renal vasoconstriction. This phenomenon occurs before the onset of structural abnormalities, which, in turn, lead to ischemic and atherosclerotic lesions both at the glomerular and arterial levels.29 In agreement with this hypothesis, Veglio et al22 reported that renal vasculature becomes unresponsive to pharmacologic challenge with captopril in patients with long-standing, severe hypertension, unlike what is observed in normotensive subjects or those with mild hypertension. Unfortunately, due to the cross-sectional design of our study we cannot speculate on the mechanisms that are responsible for these associations. Nonetheless, our data suggest that the link between increased renal resistance and mild dysfunction may be due to arteriosclerosis. These results might have practical, clinical implications, especially with regard to the effects that antihypertensive drugs may have on the kidney. In fact, we previously reported that in a relatively small group of patients, who were followed-up for 2 years, RI were not affected by calcium-channel blockers, although they were significantly reduced by angiotensin-converting enzyme inhibitors.30 Whether antihypertensive agents that reduce intrarenal resistance actually provide better renal outcome in the long term awaits further confirmation by longer prospective trials.

In conclusion, the data presented here indicate that a reduction in creatinine clearance, as well as the presence of microalbuminuria in patients with primary hypertension are associated with increased renal vascular impedence and with markers and signs of extrarenal atherosclerosis. Therefore, they might be the result of nephroangiosclerosis. Furthermore, longitudinal studies are needed to assess the predictive role of increased RI in patients with mild renal dysfunction.

We thank Massimo Del Sette, MD, and Gian Paolo Bezante, MD, for performing cardiovascular ultrasound scans.

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