Microalbuminuria in Patients With Essential Hypertension: Effects of Several Antihypertensive Drugs STEFANO BIANCHI, M.D., ROBERTO BIGAZZI, M.D., GIORGIO BALDARI, M.D., Livorno,/ta/y, VITO M. CAMPESE, M.D., LosAngele$, California

PURPOSF= Microalbuminuria can be present in 10% to 40% of patients with essential hyperten- sion and is associated with an increased inci- dence of cardiovascular events. The effect of commonly used antihypertensive agents on uri- nary albumin excretion (UAE) hA~ not been well established. The aim of this study was to evalu- ate the effects of a converting enzyme inhibitor, a calcium channel blocker, a/~ blocker, and a di- uretic on UAE and on creatlnlne clearance in patients with mild to moderate hypertension.

PATIENTS AND METHODS: We prospectiv@ly measured UAE prior to and 4 and 8 weeks after treatment with enalapril, nitrendipine, atenolol, or a diuretic in 48 patients with essential hyper- tension and microalbuminuria.

RESULTS: All these agents were equelly effec- tive in reducing arterial pressure. However, ena- lapril but not the other agents significantly de- creased UAE.

CONCLUSION: Eight weeks of therapy with ena- iapril may reduce UAE in patients with mild to moderate essential hypertension, whereas other agents, such as nitrendipine, atenolol, or diuret- ies, had no measurable effect on UAE. The cllni- cad and prognostic significance of these observa- tions remains to be established.

From the U.O. di Nefrologia e Dialisi (SB, RB, GB), Spedali Riuniti, Livorno, Italy, and the Division of Nephrology (VMC), University of South- ern California, Los Angeles, California.

Requests for reprints should be addressed to Roberto Bigazzi, M.D., Nefrologia e Dialisi, Spedali Riuniti, Viale Alfieri, 36, Livorno, Italy.

Manuscript submitted January 29, 1992, and accepted in revised form June 11, 1992.

A pproximately 10% of patients with essential hypertension develop proteinuria [1-6]. Using

more sensitive methods to quantitate urinary albu- min excretion (UAE), several investigators have shown an increase in UAE in a substantial number of patients with essential hypertension [7-10]. We have recently observed an increase in UAE in 40% of 123 patients with essential hypertension [11].

Several investigators have shown that microalbu- minuria may predict the progression of renal dis- ease in patients with diabetic nephropathy [12-14]. In addition, several epidemiologic studies have shown a close relationship between proteinuria or microalbuminuria and cardiovascular morbidity and mortality in patients with essential hyperten- sion [2-4,15].

Whether microalbuminuria may represent a use- ful predictor of progressive renal disease in patients with essential hypertension is still unknown. It re- mains also to be established whether a reduction in UAE after long-term treatment of hypertension may lead to an improvement in cardiovascular com- plications in these patients.

We and others [16,17] have shown that despite similar antihypertensive effects, converting enzyme inhibitors (CEIs) can reduce UAE more effectively than calcium channel blockers (CCBs) in patients with essential hypertension. Insufficient data are available on the effects of/9 blockers and diuretics on UAE in patients with essential hypertension [10,18,19], and most of these studies used combina- tions of antihypertensive drugs, making it difficult to discern the effect of each drug.

The aim of this study was to prospectively evalu- ate the effects of a CEI (enalapril), a CCB (nitrendi- pine), a/9 blocker (atenolol), and a diuretic on UAE and on creatinine clearance in a group of patients with mild to moderate essential hypertension.

PATIENTS AND METHODS Patients were included in the study if their dia-

stolic blood pressure was persistently between 95 and 115 mm Hg during three subsequent visits to the outpatient clinic, if their UAE was greater than 20 ~g/min in two separate measurements, and if their creatinine clearance was greater than 80 mL/min/1.73 m 2. We chose the level of 20 ~g/min to

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TABLE I

Systolic (SBP) and Diastolic (DBP) Blood Pressure, Creatinine Clearance (CrCl), and Urine Sodium Excretion (Urine Na +) Prior to and 4 and 8 Weeks After Treatment With Enalaprii, Nicardipine, Diuretics, or Atenolol

SBP DBP CrCl Urine Na + (mm Hg) (mm Hg) (mL/min) (mEq/d)

Enalapril Baseline 161 _+ 2.1 105 -+ 0.6 99.5 -+ 2.4 147 + 7.1 4weeks 141 ± 3.4* 90 -+ 1.7" 96.3 -+ 1.7 141 ± 4.2 8 weeks 137 ± 2.8* 86 ± 1.3" 95.4 ± 2.2 133 ± 3.0

Nitrendipine Baseline 164 ± 2.9 105 ± 1.3 99.1 ± 2.3 138 ± 2.9 4weeks 143 ± 4.0* 90.2 ± 1.8' 99.9 ± 2.5 152 ± 6.9 8weeks 140_+ 3.2* 85.5-+ 1.2" 102 -+ 3.0 135 ± 3.4

Diuretics Baseline 160 ± 2.4 104 +_ 1.2 98.2 _+ 2.1 142 -* 4.0 4weeks 142 _+ 2.2* 90 ± 1.9" 97.9 ± 2.8 139 ± 6.6 8weeks 142-+ 2.2* 87 ± 1.2" 102.2 ± 4.8 138 ± 3.5

Atenolol Baseline 161 ± 2,5 106 t 1.4 99.8 +_ 2.4 135 + 4.3 4 weeks 148 +_ 3.8* 90 +- 1.5" 96.7 ± 1.9 134 ± 5.1 8 weeks 140 +- 3.9* 86 t 1.5" 95.1 t 2.4 135 ± 3.4

*p <0,01.

define the presence of microalbuminuria, because in a previous study we had shown that all our nor- real subjects had UAE below this value [11]. We enrolled 48 patients, 29 men and 19 women. Their mean age was 53.4 + 1.2 years (range 40 to 69 years). Thirty-one patients had never received antihyper- tensive drugs prior to the study, and in the remain- ing 17 patients antihypertensive medications were withheld at least 4 weeks before the study. Women taking birth control pills were excluded. A diagnosis of secondary hypertension was adequately excluded by the findings of normal serum electrolytes, creati- nine clearance, urinalysis, electrocardiogram, and chest radiographs, and, when clinically indicated, by normal urinary metanephrines, serum aldoste- rone, and renal angiogram. All patients were in- structed to adhere to a dietary intake of 6 g of sodi- um chloride per day, and to continue their usual protein intake.

Patients were randomly divided into 4 groups of 12, matched for age, arterial pressure, creatinine clearance, urine sodium excretion, and UAE. Pa- tients of Group 1 received 20 mg/d of enalapril (Merck Sharp & Dohme, West Point, PA); those of Group 2 received 20 mg/d of nitrendipine (Bayer Pharmaceuticals, Basel, Switzerland); eight pa- tients of Group 3 were treated with 50 mg/d of chlorthalidone (CIBA-Geigy Pharmaceuticals, Summit, NJ), while the remaining four patients were treated with a combination of hydrochlorothi- azide 50 mg/d and amiloride 5 mg/d (Merck Sharp & Dohme); patients of Group 4 were treated with

UAE pg/mln

• l~rml~nt'tl

• nlm-efic~ e0. [ ] . ~ 1 o l

40.

30.

10.

0 • 8

Figure 1. Urinary albumin excretion (UAE) prior to and 4 and 8 weeks after t reatment with enalapril, nitrendipine, diure- tics, or atenolol. *p <0.01.

100 mg/d of atenolol (ICI Pharmaceuticals, Wil- mington, DE). The administration of the drugs was open-labeled. The patients were studied prior to initiation of the study, and 4 and 8 weeks after the administration of each medication.

Antihypertensive drugs were administered at 8 AM, except on the day of the study, when the drugs were given only after blood pressure was measured and blood samples were drawn. Four patients of Group 2 received an additional 20 mg of nitrendi- pine at 8 PM to achieve adequate control of blood pressure. The dose of all the other medications was not titrated.

Twenty-four-hour urine collections were ob- tained twice prior to the initiation of the study and once each after 4 and 8 weeks of treatment to mea- sure the urinary excretion of sodium, creatinine, and albumin.

Blood pressure was measured with a standard mercury sphygmomanometer, after the patients had been sitting for at least 5 minutes. The average of three measurements was recorded. Urine sodium was measured by a flame photometer, serum and urine creatinine levels were determined by auto- analyzer, and UAE was measured by radioimmuno- assay (albumin RIA, Pharmacia, Piscataway, NJ).

The data were evaluated statistically by one-way analysis of variance. The results are shown as means ± SEM.

RESULTS

The results are summarized in Table I and in Figure 1. Baseline systolic and diastolic blood pres- sure, creatinine clearance, urinary sodium excre- tion, and UAE were not different among the four groups of patients studied. After 4 and 8 weeks of therapy, there was a significant reduction in both systolic and diastolic blood pressure in the four

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groups of patients studied, and the decrease in blood pressure was comparable among them (Table I).

Baseline creatinine clearance and urinary sodium excretion were similar among the four groups of patients, and did not change during treatment (Ta- ble I). After 4 and 8 weeks of therapy with nitrendi- pine, diuretics, or atenolol, UAE did not change, despite a significant reduction in blood pressure. On the contrary, UAE decreased significantly (p <0.01) from 51 ~- 4.8 ~g/min to 27.2 ± 3 pg/min after 4 weeks and to 27 ± 5.7 pg/min after 8 weeks of therapy in patients treated with enalapril (Figure 1).

COMMENTS The results of our study clearly demonstrate that

despite similar antihypertensive efficacy, enalapril, but not the other antihypertensive agents tested, reduced UAE in patients with essential hyperten- sion and microalbuminuria.

A large number of experimental and clinical stud- ies have shown that CEIs may reduce UAE in a variety of renal diseases [20-31]. On the other hand, limited information is available on the effect of CEIs on microalbuminuria in patients with essen- tial hypertension.

In a previous crossover study, we have shown that despite similar antihypertensive efficacy, enalapril but not nitrendipine reduced UAE in a group of patients with essential hypertension [16]. In anoth- er study, captopril was shown to significantly re- duce UAE in a small group of patients with essen- tial hypertension, but this beneficial effect appeared to disappear after 1 year of treatment [18].

Valvo et al [32], on the other hand, have shown that benazepril, an angiotensin-converting enzyme inhibitor without a sulfhydryl group, failed to de- crease UAE in 17 patients with essential hyperten- sion and microalbuminuria treated for 6 weeks, de- spite adequate control of blood pressure.

The effects of CCBs on proteinuria are controver- sial and may possibly depend on their chemical structure and on the type of renal disease. Nifedi- pine, a dihydropiridine derivative, was shown to have no beneficial effects on proteinuria or filtra- tion fraction in hypertensive patients with renal insufficiency [33], and to increase proteinuria in a small number of patients with incipient diabetic nephropathy [17]. In contrast, other investigators have shown that nifedipine and perindopril, anoth- er CEI, had similar effects on UAE, both preventing increases in albuminuria in normotensive patients and decreasing albuminuria in hypertensive pa- tients [34]. Similarly, StorneUo et al [35] have shown that both nicardipine, a dihydropiridine de-

rivative, and captopril reduced UAE to a similar extent in 12 hypertensive patients with type II diabetes.

Reams et al [33] have studied the short-term ef- fects of nifedipine on renal function in 26 patients with essential hypertension. Nifedipine caused an increase in glomerular filtration rate and renal blood flow, but no changes in filtration fraction or in albuminuria. These investigators have also shown no significant changes in proteinuria in six patients with advanced renal insufficiency treated with nifedipine for 4 weeks [36].

We have previously studied the effect of nicardi- pine on renal function and proteinuria in 16 hyper- tensive patients with renal insufficiency treated for i year, and we did not detect any significant effect of this drug on proteinuria [20]. As previously men- tioned, nitrendipine had no effect on UAE in pa- tients with essential hypertension and normal renal function [16].

Bakris [37] has recently shown that diltiazem, a benzodiazepine derivative, was as effective as lisin- opril in reducing UAE in eight patients with non- insulin-dependent diabetes. Limited information is available on the effect of

blockers and diuretics on UAE in patients with es- sential hypertension. Pedersen and Mogensen [10] observed a decrease in UAE in 20 patients with moderate to severe essential hypertension treated with a combination of aprenolol and hydralazine. De Venuto et al [18] evaluated the effect of a diuret- ic given in combination with a ~ blocker in 34 pa- tients with mild to moderate essential hypertension and observed no change in UAE. On the other hand, when they substituted the/~ blocker with captopril in 17 of these patients, they observed a significant decrease in UAE.

Pedersen et al [19] studied the effect of exercise on UAE in young patients with mild essential hy- pertension receiving either propranolol or no treat- ment, and observed a reduction in the exercise-in- duced increase in UAE in patients treated with propranolol, compared with patients receiving no treatment.

The mechanisms for the beneficial effect of CEIs on proteinuria have not been well established. The reduction in proteinuria cannot be exclusively at- tributed to a decrease in blood pressure, since agents with similar antihypertensive efficacy had no beneficial effect. CEIs may reduce proteinuria by reducing intrarenal pressure [28-30,38], and/or by decreasing the permselectivity of the glomerular basement membrane [39-41]; these pharmacologic properties may not necessarily apply to other anti- hypertensive agents.

In conclusion, this study has shown that 8 weeks of therapy with enalapril may reduce UAE in pa-

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tients with mild to moderate essential hyperten- sion, whereas other ageqts, such as nitrendipine, atenolol, or diuretics, had no measurable effect on UAE, despite similar a~ltihypertensive efficacy.

The implications of this observation on cardio- vascular morbidity and mortality and on future progression of renal disease in patients with essen- tial hypertension remain to be established.

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