(Hypertension. 1995;26:610-615.)
© 1995 American Heart Association, Inc.
Articles |
Combined Renal Effects of Overweight and Hypertension
From the Department of Medicine, Hôpital Lapeyronie, Montpellier, France.
Correspondence to Jean Ribstein, MD, Department of Medicine, Hôpital Lapeyronie, 34295 Montpellier Cedex 5, France.
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Abstract |
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Abstract The existence of a direct relationship between body mass and arterial pressure is well recognized; however, the effect of obesity on known target organs of hypertension is not clearly understood. We undertook the present studies to assess the influence of obesity on renal function and urinary albumin excretion in 40 normotensive subjects and 80 never-treated hypertensive patients matched for age, sex, arterial pressure level, and known duration of hypertension in whom an oral glucose tolerance test was within normal limits. Glomerular filtration rate and effective renal plasma flow (expressed as absolute values or values normalized for height) were increased in overweight compared with lean subjects whether normotensive or hypertensive. Glomerular filtration rate was positively correlated with protein intake (as assessed from urinary excretion of urea) and fasting serum insulin level. Urinary excretion of albumin but not IgG and ß2 microglobulin was higher in hypertensive patients compared with normotensive subjects. The overweight condition clearly enhanced the influence of arterial pressure on albuminuria; in fact, a steeper regression line between albumin excretion rate and arterial pressure was found in overweight compared with lean subjects. These results indicate that the overweight condition is associated with renal hyperfiltration and hyperperfusion, irrespective of the presence of hypertension, and that obesity magnifies the effect of hypertension on albuminuria, thus raising the possibility of an increased susceptibility of obese hypertensive patients to the development of renal damage.
Key Words: hypertension, essential • albuminuria • obesity • glomerular filtration rate • renal circulation • insulin
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Introduction |
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Epidemiological studies have demonstrated the existence of a direct relationship between obesity and hypertension1 ; however, the interaction between the conditions at the level of known target organs remains poorly understood. Hypertension is associated with increased mortality and morbidity from cardiovascular disease,2 and the magnitude of the risk linked to obesity is a matter of controversy. It was observed that obese hypertensive individuals may be at lower risk than lean patients,3 whereas obesity emerged as an independent risk factor in prospective studies such as the Framingham Heart Study.4
Few studies have focused on renal changes associated with the overweight condition in normotensive or hypertensive individuals; nevertheless, it has been demonstrated that glomerular filtration rate (GFR) is increased in obese subjects only in the presence of non–insulin-dependent diabetes mellitus.5 Some authors have reported on the occurrence of proteinuria in patients presenting with obesity and the obstructive sleep apnea syndrome6 or nephrotic range proteinuria associated with focal glomerulosclerosis in patients with massive obesity.7 To date, no study has addressed the issue of whether in nondiabetic subjects body mass exerts a consistent influence on microalbuminuria, an index of incipient renal disease in diabetes mellitus8 and a potential marker of cardiovascular risk.9
In the present study conducted in normotensive subjects and patients with never-treated essential hypertension and a normal oral glucose tolerance test, renal hemodynamics and function and urinary albumin excretion (UAE) were estimated regarding the respective influence of hypertension and overweight. Since recent studies have emphasized the frequent occurrence of insulin resistance, hyperinsulinemia, or both and their potentially detrimental roles with regard to cardiovascular disease in obese and lean hypertensive patients,10 11 the relationship between insulin sensitivity indexes and renal parameters was also analyzed.
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Methods |
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Study Population
Studies were conducted in 40 normotensive (diastolic arterial pressure <85 mm Hg) volunteers (10 women and 30 men, aged 17 to 59 years) and 80 patients (20 women and 60 men, aged 19 to 59 years) who presented with never-treated, uncomplicated essential hypertension. Obese and lean subjects were matched for age and sex; in addition, hypertensive patients were matched for arterial pressure level and known duration of hypertension. Overweight was defined as a body mass index (weight/height2) higher than 27 kg/m2; such a cutoff value corresponds roughly to a 20% excess weight above the accepted norms for desirable body build.12 All overweight subjects had a body mass index above the 90th percentile, and none of the lean subjects had a value above the 75th percentile of the distribution recently described in the French population.13 No severely obese subject (body mass index >40 kg/m2) was included. The waist-hip ratio, taken as an index of fat distribution,14 was greater than 0.80 and 0.90 in all overweight women and men, respectively.
Patients with secondary and severe hypertension (diastolic arterial pressure >120 mm Hg) or complications such as congestive heart failure, renal insufficiency, or clinical proteinuria (Albustix positive) were excluded from the study. Renal function was normal in all participants (serum creatinine <1.2 mg/dL and creatinine clearance >80 mL/min), and no sign of renal disease such as hematuria or clinical proteinuria was detected. Patients displayed no electrocardiographic or echocardiographic (including Doppler echocardiography) signs of valvular, primary myocardial, or coronary artery disease. To minimize the effect of age on renal function, we did not include subjects older than 60 years in the study. Also excluded were women on oral contraceptive therapy, patients with a known history of alcohol abuse (more than five drinks per day), and patients with diabetes mellitus (defined as fasting blood glucose >6.7 mmol/L and/or 2-hour postglucose concentration >11.1 mmol/L) or impaired glucose tolerance (defined as a 2-hour postglucose value >7.8 and <11.1 mmol/L).15 The protocol was approved by the ethics committee of our institution; all patients gave informed consent.
Blood Pressure Measurements
An average sitting diastolic arterial
pressure level above 90 mm Hg was required for inclusion into the
hypertensive group, with elevated readings obtained in the outpatient
clinic being confirmed on at least two subsequent visits. In addition,
arterial pressure was repeatedly measured with an automatic
device (Dynamap 845 XT, Critikon) before oral glucose administration
and during renal clearance studies. Reported values are the average of
at least 10 measurements obtained with subjects in the supine position
during the baseline period on the day of renal function studies. Large
cuff sizes were used in overweight subjects.
Oral Glucose Tolerance Test
The oral glucose tolerance test was performed at 8
AM, after subjects had fasted for 12 to 14 hours. Following
a 1-hour equilibration period with subjects in the supine position,
blood was drawn for the determination of blood glucose,
cholesterol (total and high-density lipoprotein
cholesterol), triglycerides, and immunoreactive
insulin. A 75-g oral load of glucose was then administered, and blood
samples were obtained 30, 60, 90, and 120 minutes thereafter for the
determination of glucose and insulin levels. Serum insulin
concentration was measured by radioimmunoassay. Integrated responses of
glucose and insulin were calculated as the areas under the curve. The
insulin-to-glucose ratio estimated both in the fasting state
and after glucose stimulation was taken as an index of insulin
resistance.11
Determination of Renal Function and
Hemodynamics
Renal studies were performed between 8 AM and noon.
GFR and effective renal plasma flow (ERPF) were estimated by clearances
of technetium-labeled diethylene triaminopentaacetic acid and
131I-orthoiodohippurate, respectively, with the use of the
constant infusion technique, as previously described.16
Briefly, after induction of water diuresis and a 90-minute
equilibration period, three 20- to 30-minute urine collections were
obtained by spontaneous voiding. At the end of each clearance period
patients drank a water volume equal to the preceding urine volume. At
the midpoint of each clearance period blood was drawn for the
determination of plasma radioactivity and hematocrit. Blood samples
were also obtained before clearance determination for the measurement
of creatinine, electrolytes, and plasma renin activity
(radioimmunoassay using the CEA-Sorin kit). Filtration fraction was
calculated as GFR/ERPF and renal vascular resistance as
MAPx(1- Hematocrit)/ERPF, where MAP is mean
arterial pressure.
Two consecutive 24-hour urine collections taken before renal function studies were obtained for the measurement of sodium (as an estimate of sodium intake), urea (as an estimate of protein intake), creatinine, and proteins (total protein, albumin, ß2 microglobulin, and IgG). Urinary concentrations of albumin and ß2 microglobulin were determined by radioimmunoassay (Pharmacia and Immunotech, respectively), and IgG was estimated by nephelometry (Behring).
Statistical Analysis
Data are expressed as mean±SEM. Since UAE values were not
normally distributed, data were analyzed after logarithmic
transformation. Statistical analysis was carried out with ANOVA
followed by Dunnett's test. Linear nonparametric
correlation coefficients between some variables were calculated. A
value of P=.05 was taken as the minimum level of
significance.
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Results |
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Clinical Parameters
As summarized in Table 1, age and the prevalence of smoking tended to be higher (although not significantly) in hypertensive patients compared with normotensive subjects; in addition, the incidence of a positive family history of hypertension was higher in both hypertensive subgroups. Casual arterial pressure (ie, the average of values measured in the clinic at inclusion) was similar within the normotensive group (122±2/74±1 and 125±3/76±2 mm Hg in lean and obese subjects, respectively) and hypertensive group (158±3/99±1 and 159±3/101±2 mm Hg in lean and obese patients, respectively).
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Renal Hemodynamics and Function
When expressed as absolute values, GFR and ERPF were higher in
overweight compared with lean subjects, and no influence of
hypertension could be detected (Fig 1). A
similar observation was made when values were expressed per meter of
height, whereas no significant effect of the overweight condition on
GFR and ERPF was detected when values were normalized for body
surface area (lean versus overweight: 108±3 versus 105±3
and 500±20 versus 474±19 mL/min per 1.73 m2 in
normotensive subjects and 105±3 versus 107±3 and 484±24 versus
459±14 mL/min per 1.73 m2 in hypertensive patients).
Interestingly, filtration fraction was higher in overweight
hypertensive patients compared with overweight normotensive subjects,
whereas no difference in filtration fraction was observed within the
lean population (Table 2).
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As summarized in Table 2, urinary excretion of urea (considered as an index of protein intake) was higher in overweight compared with lean subjects in both normotensive and hypertensive groups. Hematocrit and serum albumin concentration as well as urinary sodium excretion (considered as an index of sodium intake), urinary potassium excretion, and plasma renin activity were similar in all groups.
When the entire population was considered, GFR expressed as an absolute value or per meter of height was positively correlated with the urinary excretion of urea (r=.30, P<.002 and r=.24, P<.01, respectively). A similar observation was made using absolute values of GFR within normotensive subjects (r=.44, P<.01) and hypertensive patients (r=.26, P<.03).
Urinary Excretion of Albumin and Proteins
As depicted in Table 2 and Fig 2, UAE estimated in
24-hour urine collections was significantly enhanced by the overweight
condition in both normotensive and hypertensive groups. Similar
between-group differences were observed when UAE was expressed with
the use of the ratio of urinary albumin to urinary
creatinine (0.55±0.07 and 0.79±0.15 mg/mmol in lean and
overweight normotensive subjects and 1.43±0.23 and
2.71± 0.52 mg/mmol in lean and overweight hypertensive patients,
respectively). The prevalence of microalbuminuria (UAE
>16 and <200 µg/min) was 25% and 40% (P=NS,
2 test) in lean and overweight hypertensive
patients, respectively. The threshold value of 16 µg/min was defined
as the 90th percentile in a population of 80 normotensive subjects aged
16 to 60 years studied in this laboratory.17 No
between-group difference in the urinary excretion of IgG and
ß2 microglobulin was found.
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UAE (expressed by its logarithmic value) was positively correlated with systolic arterial pressure in both overweight (r=.55, P<.0001) and lean (r=.34, P<.01) subjects. Significant correlations were also obtained when diastolic and mean arterial pressure were considered. Of interest, the slope of the regression line between UAE and systolic arterial pressure was steeper (P<.05) in overweight than lean subjects. When the entire population was considered, UAE was correlated with both GFR expressed per meter of height (r=.20, P<.03) and filtration fraction (r=.19, P<.05).
Metabolic Characteristics
As shown in Table 3, serum levels of total
cholesterol and triglycerides were higher and
high-density lipoprotein cholesterol was lower in
overweight compared with lean subjects. Glucose tolerance was within
normal limits in all subjects included in the present studies;
however, the fasting insulin level was significantly higher in
hypertensive patients than normotensive subjects and in overweight
compared with lean individuals. The fasting insulin-to-glucose
ratio, which can be considered as an index of insulin
sensitivity,11 was higher than 2.2 mU/mmol (the upper
range of normal in our reference population of lean normotensive
subjects) in 7 of 40 lean and 28 of 40 overweight hypertensive patients
(P<.05, 2 test).
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Within the entire population the fasting insulin level was positively correlated with the absolute value of GFR (r=.22, P<.02) as well as GFR expressed per meter of height (r=.24, P<.01). Similar correlations were obtained when only the population of hypertensive patients was considered. Fasting insulin was not correlated with ERPF within the entire population and within the normotensive or hypertensive groups considered separately. Fasting insulin and the area-under-the curve of insulin during the glucose tolerance test was not correlated with UAE. None of the lipid parameters was correlated with GFR or UAE.
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Discussion |
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In the present studies conducted in a predominantly male population it was observed that mild to moderate obesity is associated with an increase in GFR and ERPF in normotensive subjects and patients with never-treated hypertension of rather short duration (mean, 21 months). In addition, the overweight condition enhanced the effect of hypertension on the kidney, as assessed by the estimation of UAE.
Hyperfiltration is a frequent early finding in patients with insulin-dependent8 and non–insulin-dependent5 8 diabetes and is a possible predictor of the subsequent development of microalbuminuria and ultimately proteinuric nephropathy.8 In the documented absence of diabetes mellitus and impaired glucose tolerance, hyperfiltration (GFR >140 mL/min) was actually present in 11 of 40 (27.5%) of our overweight hypertensive population, a prevalence clearly higher than in lean essential hypertensive patients (5 of 40; ie, 12.5%). In a study conducted in supposedly normotensive women, GFR was higher in markedly overweight compared with age-matched lean individuals.18 In another study ERPF was increased to the same extent in overweight normotensive and hypertensive subjects compared with their lean counterparts.19 Of note, reported GFR values in the present and previous20 studies normalize when expressed per standardized body surface area in the same way as renal blood flow and cardiac output in other studies conducted in obese subjects.19 21 In fact, the comparison of lean and obese groups with regard to a number of physiological variables is confounded by the issue of whether size-corrected values are more meaningful than absolute values. It was suggested that when related to body surface area, inappropriately low values of renal plasma flow were calculated for obese patients. Indexing hemodynamic data to body height might be less misleading in overweight subjects.22
In support of a renal hyperfiltration state associated with obesity, it was reported that glomerular volume was higher in the presence of an identical number of nephrons in overweight compared with lean subjects.23 Observations of increased GFR, mainly in superficial nephrons and in association with an expansion of glomerular area and mesangial matrix, were made in Zucker rats with genetic obesity studied at 9 to 13 weeks of age24 ; at a later stage, GFR tended to normalize and subsequently decrease together with the development of progressive albuminuria and glomerulosclerosis.25 26 In dogs with diet-induced obesity, large and proportional increases in GFR and ERPF were observed in association with the development of hypertension.27 Taken together, observations made in these experimental models suggest that hyperfiltration is an early characteristic of obesity and primarily results from renal hyperperfusion rather than elevated glomerular capillary pressure.
Among factors underlying the increase in GFR and augmented prevalence of hyperfiltration associated with obesity, the present results suggest an important role for glomerular hyperperfusion. Previous reports have also demonstrated that renal perfusion rate was increased in overweight subjects, irrespective of the presence of hypertension,19 together with an elevated cardiac output19 28 29 and expanded extracellular fluid volume, intravascular volume, or both.28 30 The findings of a higher filtration fraction in our hypertensive compared with normotensive overweight patients suggest the existence of a predominant decrease in afferent rather than efferent glomerular tone (consistent with an increased glomerular capillary pressure) in patients with obesity-associated hypertension.
The role of protein intake in the genesis of hyperfiltration31 is suggested by the positive correlation between GFR and urinary excretion of urea in the entire population and normotensive and hypertensive groups analyzed separately. Moreover, the present observation of a positive correlation between GFR and fasting serum insulin favors a role for circulating insulin. In studies conducted in healthy humans32 and non–insulin-dependent diabetes mellitus,33 GFR was unaffected during euglycemic hyperinsulinemic clamp. In contrast, long-term insulin infusion associated with normal blood glucose concentration resulted in a consistent increase in GFR and ERPF in dogs.34 Similar results were obtained in rats during short-term insulin infusion.35 A role for other factors with renal vasodilator potency cannot be excluded.
UAE was higher in overweight compared with lean normotensive individuals and overweight compared with lean patients with uncomplicated, never-treated hypertension matched for the level of arterial pressure and known duration of hypertension. This confirms previous observations made in a larger population of lean and overweight subjects.17 Interestingly, the correlation between albumin excretion rate and arterial pressure, the most prominent determinant of albuminuria,17 36 was steeper in overweight compared with lean subjects, indicating that the overweight condition enhances the effect of arterial pressure on albuminuria. In the present studies the excessive albuminuria observed in overweight subjects was probably related to an increase in the filtered load of albumin rather than a decrease in proximal reabsorption as evidenced by the absence of an increase in urinary ß2 microglobulin and the positive correlation with GFR. Moreover, the correlation between albuminuria and filtration fraction found in the entire study population may suggest a role for glomerular capillary pressure in the genesis of excessive albuminuria in overweight hypertensive patients. No relationship between UAE and fasting as well as post-stimulative insulin levels was observed; our results do not confirm the recent report that in essential hypertension microalbuminuria was associated with an enhanced insulin response to glucose.37
The significance of microalbuminuria in essential hypertension is not clearly elucidated; excessive albuminuria may be an indicator of a generalized increase in the capillary permeability to albumin and endothelial dysfunction as well as a renal abnormality. In a recent study we observed that microalbuminuric lean hypertensive patients displayed a blunted renal vasodilator response to short-term angiotensin-converting enzyme blockade compared with normoalbuminuric patients with a similar circulating renin level, thus suggesting that microalbuminuria could be a marker of early intrarenal vascular dysfunction.38
The renal consequence of lipid abnormalities is not well defined. However, several studies have emphasized that excessive albuminuria may be associated with increased total cholesterol in diabetic39 and essential hypertensive37 38 patients. Of interest, it was reported that correction of lipid abnormalities by mevilonin or clofibric acid between 8 and 40 weeks of age prevented the increase in albuminuria and glomerular damage in genetically obese Zucker rats40 ; treatment by enalapril started over the same time period attenuated the development of glomerular injury and lipid abnormalities in these rats.26
Received March 27, 1995; first decision April 17, 1995; accepted June 22, 1995.
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T. E. Lohmeier, T. M. Dwyer, E. D. Irwin, M. A. Rossing, and R. S. Kieval Prolonged Activation of the Baroreflex Abolishes Obesity-Induced Hypertension Hypertension, June 1, 2007; 49(6): 1307 - 1314. [Abstract] [Full Text] [PDF]
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K. Narkiewicz Obesity and hypertension--the issue is more complex than we thought Nephrol. Dial. Transplant., February 1, 2006; 21(2): 264 - 267. [Full Text] [PDF]
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P. Delanaye, R. P. Radermecker, M. Rorive, G. Depas, and J. M. Krzesinski Indexing glomerular filtration rate for body surface area in obese patients is misleading: concept and example Nephrol. Dial. Transplant., October 1, 2005; 20(10): 2024 - 2028. [Full Text] [PDF]
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J. Ribstein, G. Du Cailar, P. Fesler, and A. Mimran Relative Glomerular Hyperfiltration in Primary Aldosteronism J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1320 - 1325. [Abstract] [Full Text] [PDF]
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A. M. Schreihofer, C. D. Hair, and D. W. Stepp Reduced plasma volume and mesenteric vascular reactivity in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R253 - R261. [Abstract] [Full Text] [PDF]
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A. M. Sharma Is There a Rationale for Angiotensin Blockade in the Management of Obesity Hypertension? Hypertension, July 1, 2004; 44(1): 12 - 19. [Abstract] [Full Text] [PDF]
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J.-P. Gutzwiller, S. Tschopp, A. Bock, C. E. Zehnder, A. R. Huber, M. Kreyenbuehl, H. Gutmann, J. Drewe, C. Henzen, B. Goeke, et al. Glucagon-Like Peptide 1 Induces Natriuresis in Healthy Subjects and in Insulin-Resistant Obese Men J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3055 - 3061. [Abstract] [Full Text] [PDF]
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A. Chagnac, T. Weinstein, M. Herman, J. Hirsh, U. Gafter, and Y. Ori The Effects of Weight Loss on Renal Function in Patients with Severe Obesity J. Am. Soc. Nephrol., June 1, 2003; 14(6): 1480 - 1486. [Abstract] [Full Text] [PDF]
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B. O. Ogunnaike, S. B. Jones, D. B. Jones, D. Provost, and C. W. Whitten Anesthetic Considerations for Bariatric Surgery Anesth. Analg., December 1, 2002; 95(6): 1793 - 1805. [Full Text] [PDF]
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