Insulin resistance and glomerular hemodynamics in essential hypertension

Kidney International, Vol. 62 (2002), pp. 1005–1009

Insulin resistance and glomerular hemodynamics in essential hypertension GIUSEPPE ANDRONICO, ROSELLA FERRARO-MORTELLARO, MARIA T. MANGANO, MARIA ROME´, FRANCESCO RASPANTI, ANTONIO PINTO, GIUSEPPE LICATA, GIOVANNA SEDDIO, GIUSEPPE MULE´, and GIOVANNI CERASOLA Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche and Istituto di Clinica Medica, Universita` degli Studi di Palermo, Palermo, Italy

Insulin resistance and glomerular hemodynamics in essential hypertension. Background. Arterial hypertension is an important cause of end-stage renal failure. Insulin has been shown to modify glomerular hemodynamics in hypertensive subjects. The aim of this work, therefore, was to observe the relationships between renal hemodynamics and insulin resistance in arterial hypertension. Methods. Sixty-two non-diabetic hypertensive patients and 25 healthy normal subjects were studied. Renal plasma flow and the glomerular filtration fraction were determined by renoscintigraphy and the insulin sensitivity by an oral glucose test. Results. Renal plasma flow in hypertensive subjects was lower than expected and was related to pressure values, whereas the mean glomerular filtration rates were not different in the two groups. In most patients the filtration fraction was higher than expected. A lower glomerular filtration rate and lower filtration fraction were found in patients with higher insulin resistance. Conclusions. The progressive decrease of glomerular function in subjects with hypertension is linked with insulin-resistance.

Patients with essential hypertension usually show insulin resistance [1]. This metabolic pattern is a regular finding in about 90% of obese hypertensive humans [2], but at least one-third of the lean hypertensive subjects can be affected by an insulin resistance state as well [3]. Hyperinsulinemia, which is a typical feature of the insulin-resistance condition, is thought to have a role in hypertension by promoting tubular sodium reabsorption [4] with a consequent fluid overload. On the other hand, essential hypertension is an important cause of progressive glomerulosclerosis and is second to diabetes mellitus as a cause of chronic uremia [5, 6]. Key words: glomerular filtration rate, renal plasma flow, insulin-resistance, filtration fraction, arterial hypertension. Received for publication June 21, 2001 and in revised form April 17, 2002 Accepted for publication April 22, 2002

 2002 by the International Society of Nephrology

Therefore, less severe hypertension is a strong independent risk factor for end-stage renal disease (ESRD) [7]. Arterial hypertension, moreover, frequently arises from kidney failure [8], which is the most frequent cause of secondary hypertensive disease [9]. We therefore undertook this study in patients with mild-to-moderate essential hypertension, to analyze the relationships between blood pressure values, insulin sensitivity and glomerular hemodynamics. METHODS Sixty-two patients who were consecutively seen at our outpatient clinic because of mild-to-moderate essential hypertension, and 25 healthy subjects from the laboratory and ward staff who matched the patients with respect to age, gender and body mass index (BMI) were included in the study (Table 1). The patients had been aware of their hypertensive condition for a mean of five years and were free from diabetes mellitus or other major pathological conditions except hypertensive disease. Twenty-eight of the hypertensive patients never had been treated for hypertension; 16 were on calcium channel blockers as a monotherapy for not more than one year; ten were taking clonidine, eight were on an angiotensin-converting enzyme inhibitor (ACEi; 6 of them in association with a diuretic agent) for not more than one year. None of the subjects in this study took any other kind of drug the month before the study. No subject had serum creatinine levels above normal values (ⱕ1.1 mg/dL), and secondary hypertension was excluded by clinical and laboratory assessment with the determination of plasma renin activity and aldosterone urinary excretion, plasma and urinary electrolytes, urinalysis, urinary metanephrines, plasma and urinary cathecolamines, and renal echography. All participants gave voluntary informed consent. All were prescribed a washout from drugs and a balanced

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Table 1. Characteristics of the hypertensive and normal subjects

N male, female Age years BMI kg/m2 24-hour SBP 24-hour DBP

Normal

Hypertensive

P

15, 10 46.5 ⫾ 2.0 29.0 ⫾ 0.9 115.4 ⫾ 1.5 70.9 ⫾ 1.2

36, 26 47.2 ⫾ 1.3 28.8 ⫾ 0.5 133.5 ⫾ 2.0 83.7 ⫾ 1.4

NS NS NS ⬍0.0001 ⬍0.0001

Abbreviations are: BMI, body mass index; 24-hour SBP, mean 24-hour systolic blood pressure; 24-hour DBP, mean 24-hour diastolic blood pressure.

isoenergetic diet with a controlled sodium intake (about 1800 Kcal with 150 mEq of Na⫹/day). After three weeks they underwent 24-hour ambulatory blood pressure measurement by means of a Spacelab 90207 device. The day after at 8.30 am they underwent standard oral glucose (75 g) tolerance test where blood was drawn one minute before and 30, 60, 90 and 120 minutes after the load to determine glucose and insulin levels. Glucose was measured by glucose-oxidase method and insulin by radioimmunoassay (Incstar Co., Stillwater, MN, USA). In our laboratory this method has ⱕ6.0% of coefficient of variation between-assay and it has sensitivity below 4 ␮U/mL at 95% confidence limits. The percentage of cross-reactivity of the used antiserum is less than 0.01% with human C peptide and 28.0% with porcine pro-insulin. Data obtained by the oral glucose tolerance test were used to calculate the Composite Insulin Sensitivity Index (C-ISI) according to Matzuda and De Fronzo. This index considers insulin sensitivity in the steady state and after the ingestion of glucose. It represents a composite of hepatic and peripheral tissue sensitivity and correlates strongly with the direct measure of insulin sensitivity derived from the euglycemic insulin clamp [9]. Two days later, to obtain renal plasma flow (RPF) and the glomerular filtration rate (GFR) measurements, we performed 131Iodine-labeled hippuran and 99mtechnetiumlabeled DTPA renoscintigraphy using the method of Schlegel, Halikiopoulos and Prima [10] and Gates [11]. This technique is a simple way to measure renal function, and the values obtained are not significantly different from those obtained by inulin and para-aminohippuric acid clearance methods [12]. Expected values for RPF and GFR were calculated for each patient taking into account sex and body surface according to Smith [13]. Data are expressed as means ⫾ SEM. Values of the composite sensitivity index were log transformed to obtain normal distribution of data. Statistical analysis was carried out using the ANOVA test, partial correlation coefficient and multiple regression analysis where appropriate. A P value less than 0.05 was considered significant.

RESULTS In normotensive subjects the observed renal plasma flow was not significantly different from expected, whereas in hypertensive subjects it was lower (Table 2). The glomerular filtration rate was not different from the expected value in both normal and hypertensive subjects. Consequently, the mean filtration fraction was higher in hypertensive than in normotensive subjects and in the former group it was 25% above the expected mean value (Table 2). Fifty-one patients (82%) had increased filtration fraction and the others had normal values or values only slightly decreased. For each patient the following parameters were calculated: the percent of differences between the measured and expected renal plasma flow (%DRPF), the measured and expected glomerular filtration rate (%DGFR), and the measured and expected filtration fraction (%DFF). Both 24-hour systolic and diastolic blood pressures correlated with the %DRPF; the relationship between %DRPF and systolic pressure, however, disappeared when it was corrected for age, whereas the correlation with 24-hour diastolic blood pressure was independent of age (r ⫽ 0.293, P ⫽ 0.03; Fig. 1). No relationship was observed between blood pressure and %DGFR. The composite insulin sensitivity was calculated because the composite insulin sensitivity index was significantly higher in the normotensive than in the hypertensive subjects. In the group of hypertensive patients, the composite insulin sensitivity index was positively related with GFR (r ⫽ 0.37, P ⫽ 0.003; Fig. 2), negatively related with the %DGFR (r ⫽ ⫺0.349, P ⫽ 0.005; Fig. 3), and positively related with the filtration fraction (r ⫽ 0.416, P ⫽ 0.001; Fig. 4). No correlation is found between the C-ISI and renal plasma flow. In our hypertensive patients, no relationship was found between BMI and the studied renal parameters. In normal subjects there was a weak inverse relationship between BMI and C-ISI (r ⫽ 0.46, P ⫽ 0.02), whereas in the hypertensive group the correlation between C-ISI and BMI was not significant. The differences between normotensive and hypertensive subjects and the relationships between the studied parameters are not significantly different when male subjects or female subjects were considered alone and, therefore, gender-related confounding factors can be excluded. DISCUSSION High blood pressure is an important risk factor for renal disease and hypertensive nephrosclerosis is the second more important cause of ESRD in Western countries [14]. The reduction of renal plasma flow with increased peripheral resistance has been described in the early stage

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Andronico et al: Renal hemodynamics in hypertension Table 2. Insulin sensitivity and glomerular function Normal subjects

RPF mL/min (range) %DRPF (range) GFR mL/min (range) %DGFR (range) FF % (range) %DFF (range) C-ISI log (range) Total insulin mU/L (range)

Hypertensive patients

Expected

Observed

Expected

Observed

N vs. H

709.1 ⫾ 18.0 (529.0/870.5)

689.4 ⫾ 18.5 (550.0/870.0) 2.7 ⫾ 1.0 (⫺4.4/14.8) 128.2 ⫾ 2.6 (98.0/149.0) 3.2 ⫾ 1.9 (⫺19.4/21.0) 18.0 ⫾ 0.3 (14.4/21.1) 0.3 ⫾ 1.9 (⫺19.0/21.4) 0.673 ⫾ 0.040 (0.291/1.047) 225.4 ⫾ 12.8 (118/391)

708.4 ⫾ 13.1 (520.7/898.9)

488.6 ⫾ 79.8 (285.0/668.0) 29.9 ⫾ 1.8 (⫺0.170/58.107) 122.7 ⫾ 3.6 (64.0/199.0) 1.0 ⫾ 4.0 (⫺103.0/55.3) 25.0 ⫾ 0.6a (15.8/38.3) ⫺24.2 ⫾ 3.0 (⫺92.7/20.9) 0.462 ⫾ 0.045 (⫺0.243/1.429) 304.9 ⫾ 17.3 (121/722)

⬍0.0001

128.4 ⫾ 3.5 (93.8/159.4) 18.1 ⫾ 0.1 (17.7/18.6)

128.2 ⫾ 2.6 (92.3/164.6) 20.0 ⫾ 0.1 (19.0/20.0)

a

⬍0.0001 NS NS ⬍0.0001 ⬍0.0001 ⫽0.0065 ⫽0.01

A negative value in percent difference indicates an increase of observed parameter. Abbreviations are: C-ISI, composite index of insulin sensitivity (log tranformation); RPF, renal plasma flow; %DRPF, percent difference between expected and observed RPF; GFR, glomerular filtration rate; %DGFR, percent difference between expected and observed GFR; FF, filtration fraction; %DFF, percent difference between expected and observed FF; Total insulin, sum of insulin values during the oral glucose tolerance test; NS, not significant; N vs. H, P value on comparison (ANOVA) of observed values between normal and hypertensive subjects. a P ⬍ 0.0001 expected vs. observed

Fig. 1. Relationship between the mean 24-hour diastolic blood pressure (24-hour DBP) and the percent of difference between expected and measured renal plasma flow (%DRPF) in the hypertensive patients in this study. A positive difference indicates a reduction of the considered parameter. Symbols are: (䊉) values from hypertensive subjects (r ⫽ 0.293; P ⫽ 0.03); (䉭) values from normotensive subjects.

of arterial hypertension [15–17]; however, this finding is controversial, since other studies failed to demonstrate differences in renal plasma flow between normotensive and hypertensive subjects [18–20]. Our results show that the mean plasma renal flow was significantly reduced in hypertensive patients when compared with the expected value calculated according to sex and the body surface area. A reduction of RPF usually develops with aging [21]; however, the relationship between the reduction of renal plasma flow and 24-hour mean diastolic blood pressure values observed in our patients was independent of age. Therefore, our results confirm that a reduction of renal

Fig. 2. Relationship between the Composite Insulin Sensitivity Index (C-ISI) and measured glomerular filtration rate (GFR) in the hypertensive patients. Symbols are: (䊉) values from hypertensive subjects (r ⫽ 0.37; P ⫽ 0.003); (䉭) values from normotensive subjects.

plasma flow is a typical glomerular hemodynamic state in hypertensive subjects. Our patients, on the other hand, had mean glomerular filtration rates that were not different in comparison with the mean expected values, so that the filtration fraction was increased. The differences between the expected and the measured glomerular filtration rates differ greatly among our hypertensive patients, ranging from ⫺103 to ⫹55%. These differences appear to result from insulin resistance as the patients with higher insulin sensitivity showed a lower reduction or an increase of the glomerular filtration rate (Fig. 3) and a higher filtration fraction (Fig. 4). Insulin resistance is usually characterized by hyperin-

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Fig. 3. Relationship between the C-ISI and the percent of difference between expected and measured GFR (%DGFR) in hypertensive patients. A positive difference indicates a reduction of the considered parameter. Symbols are: (䊉) values from hypertensive subjects (r ⫽ ⫺0.35; P ⫽ 0.005); (䉭) values from normotensive subjects.

sulinemia, but it is not simple to explain why our insulin resistant patients also have a reduced GFR, since other studies have shown that insulin infusion is able to increase GFR [22, 23]. ter Maaten and colleagues reported a higher increase of GFR during insulin infusion in more insulin sensitive subjects, pointing out that insulin sensitivity predisposes these patients to an increased glomerular filtration rate [22]. Our patients did not receive an insulin load and the glomerular hemodynamic status we measured was a consequence of hypertension and chronic resistance or sensitivity to insulin only. Dengel and colleagues suggested that insulin resistance is linked with an increase of glomerular filtration rate and glomerular filtration fraction [24]. Their study was conduced on a small number of obese, older sedentary patients with mild renal insufficiency who cannot be representative of other populations. Moreover, the relationships they found between insulin resistance and glomerular filtration rate and filtration fraction were attenuated by changes in the dietary salt intake. In another study, Fliser et al demonstrated that insulin resistance is present in renal disease even in patients who still have a GFR value in the normal range [25]. They suggest that the normal glomerular filtration rate could be explained by adaptive changes in renal dynamics related to the abnormalities in glucose metabolism. The same mechanism may explain our findings, as our patients likely had a very early renal impairment due to hypertension. In agreement with our results, Kubo and colleagues conducted the Hisayama study in a general Japanese population and found that the reciprocal of plasma cre-

Fig. 4. Relationship between the C-ISI and the filtration fraction (FF) in the hypertensive patients. Symbols are: (䊉) values from hypertensive subjects (r ⫽ 0.416; P ⫽ 0.001); (䉭) values from normotensive subjects.

atinine value is related to the sum of fasting and twohour post-loading insulin levels. This fact suggests that a relatively reduced renal function in normal people also can be related to hyperinsulinemia and insulin-resistance [26]. In conclusion, our results confirm that in non-diabetic hypertensive patients there is a blood pressure-related reduction of plasma renal flow, and that the progressive decrease of glomerular function is more prominent and earlier in insulin-resistant hypertensive subjects and likely linked with and worsened by insulin resistance. Efforts to reduce insulin resistance in hypertension could delay the evolution toward hypertensive glomerulosclerosis. ACKNOWLEDGMENTS This work was partially funded by Italian MURST (Ministero per l’Universita` e la Ricerca Scientifica e Tecnologica) with ‘60% quotas.’ Reprint requests to Giuseppe Andronico, M.D., Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, via Lenin Mancuso 15, 90129 Palermo, Italy. E-mail: [email protected]

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