Jean Ribstein

Combined Renal Effects of Overweight and Hypertension

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 nevertreated 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 beta 2 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.

Dietary sodium and target organ damage in essential hypertension

In addition to its widely contested influence on arterial pressure, dietary sodium may exert some nonpressure-related effects on left ventricular mass in humans. In the present study, we hypothesized that sodium intake (estimated by two consecutive measurements of 24-h urinary sodium excretion) may amplify the effect of arterial pressure on target organ damage (ie, left ventricular mass and microalbuminuria) in a large group of normotensive subjects and patients with never-treated uncomplicated essential hypertension. Left ventricular mass (M-mode echocardiography) and urinary albumin excretion were assessed in 839 subjects (471 men and 368 women) aged 15 to 70 years, with elevated (60%) or normal arterial pressure. In the entire population, multivariate analysis indicated that the relationship between urinary sodium excretion and left ventricular mass index (beta = 0.02, P < .01) as well as urinary albumin excretion (beta = 0.001, P < .0001) was independent from sex, age, body mass index, and systolic arterial pressure. When subjects were divided into quintiles according to urinary sodium excretion, left ventricular mass index and urinary albumin excretion increased significantly from the lowest to the highest quintile in both genders, despite similar values of systolic arterial pressure. The slope of the regression line linking systolic arterial pressure to left ventricular mass index (in men) and urinary albumin excretion (in the entire population) obtained within each quintile of urinary sodium excretion, progressively and linearly increased from the lowest to the highest quintile. These results suggest that sodium intake may amplify the effect of arterial pressure on both the left ventricle and the kidney, and thus suggest that dietary sodium may be an independent factor of cardiovascular risk.

Relative Glomerular Hyperfiltration in Primary Aldosteronism

Experimental and clinical data suggest that primary aldosteronism (PA) may be associated with cardiovascular hypertrophy and fibrosis, in part independent of the BP level. Whether PA may also result in specific deleterious effects on the kidneys was less studied. In 25 patients with tumoral PA, renal studies (urinary excretion of proteins, GFR, and effective renal plasma flow [ERPF], as clearances of technetium-labeled diethylene triaminopentaacetic acid and 131I-ortho iodohippurate, respectively) were performed both before and 6 mo after surgical cure. A control group consisting of patients with essential hypertension (EH) was studied before and after 6 mo of antihypertensive therapy. At baseline, PA and EH patients were similar with respect to demographic data, duration and level of hypertension, and GFR and ERPF. Urinary excretion of albumin and beta2 microglobulin were higher in PA than EH (88 +/- 26 versus 39 +/- 12 and 0.91 +/- 0.23 versus 0.26 +/- 0.19 mg/24 h, respectively; both P < 0.05). Adrenalectomy was followed by a decrease in arterial BP (by 28 +/- 3/13 +/- 2 mmHg), urinary excretion of albumin and beta2 microglobulin (by 48 +/- 19 and 0.53 +/- 0.21 mg/24 h, respectively), and GFR and ERPF (by 15 +/- 3 and 54 +/- 15 ml/min per 1.73 m(2), respectively). In EH, a similar decrease in pressure was associated with a decrease in albuminuria but no change in GFR or ERPF. In 17 of the 25 PA patients who received a 6-mo treatment of spironolactone, both GFR and ERPF decreased in parallel with BP, similar to what was observed after surgery. These data suggest that PA was associated with relative hyperfiltration, unmasked after suppression of aldosterone excess.

Elevated Pulse Pressure Is Associated With Low Renal Function in Elderly Patients With Isolated Systolic Hypertension

In the past decade, pulse pressure has emerged as a strong predictor of cardiovascular morbidity and mortality. During aging, elevation of pulse pressure is a consequence of stiffening of the arterial wall. The relationship between pulse pressure and the renal aging process was studied in a cohort of 212 patients with never-treated isolated systolic hypertension. Glomerular filtration rate and effective renal plasma flow were measured using constant infusion of technetium 99m (99mTc)-DTPA and 131I-ortho-iodohippurate, respectively, and timed urine collections. The relationship between pulse pressure and renal function was studied using a linear regression model in the total population and in 40 to 49, 50 to 59, and 60 years and older age categories. In the whole population, there was an inverse relationship between pulse pressure and glomerular filtration rate; however, this relation did not persist after adjustment for age. In fact, the inverse relationship between pulse pressure and glomerular filtration rate was only present in patients 60 years of age or older. This relationship in elderly patients remained after adjustment for age, gender, MAP, and cardiovascular risk factors (P=0.006). It is suggested that pulse pressure, a marker of arterial stiffening, may have a detrimental influence on the age-related decline in glomerular filtration rate, after 60 years of age in patients with never-treated isolated systolic hypertension.

Albuminuria in normals and essential hypertension

The prevalence and determinants of urinary albumin excretion rate (AER) were assessed in lean and overweight normotensive subjects (NT) and patients with essential hypertension (EH). In NT and EH, the presence of overweight was associated with a significant exacerbation of AER. In the normotensive population, AER was higher in subjects with a positive family history of hypertension. An important role for smoking was observed in the hypertensive population; in fact, the prevalence of microalbuminuria (MA) was almost twofold in lean hypertensive smokers when compared to nonsmokers. Among other determinants of AER, a major influence of systolic arterial pressure, urinary excretion of urea (an estimate of protein intake), and high-density lipoprotein (HDL) cholesterol (inversely correlated with AER) was observed mainly in lean EH patients. The significance of microalbuminuria is unclear. Is it a marker of cardiovascular risk and/or a predictor of the future development of renal disease in EH?

LONG-TERM IMPROVEMENT IN RENAL FUNCTION AFTER CYCLOSPORINE REDUCTION IN RENAL TRANSPLANT RECIPIENTS WITH HISTOLOGICALLY PROVEN CHRONIC CYCLOSPORINE NEPHROPATHY

BACKGROUND Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.

Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy.

Microalbuminuria is a reliable predictor of the eventual development of overt diabetic nephropathy and blood pressure is known to accelerate the course of this nephropathy. In the present studies, the effect of a 6-week treatment by placebo (n = 7), nifedipine (n = 7) and captopril (n = 8) on renal function and urinary excretion of albumin (UAE) was investigated in normotensive, insulin-dependent, diabetic patients with incipient nephropathy (UAE greater than 15 micrograms/min). No change in arterial pressure, renal function or UAE was observed in the placebo group. In response to captopril and nifedipine, mean arterial pressure decreased slightly and similarly in both groups. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased to a similar extent in the nifedipine group, thus resulting in no change in filtration fraction (FF). In response to captopril, GFR was unchanged whilst ERPF increased; as a consequence FF decreased. Opposite changes in UAE were observed in response to the two treatments; UAE decreased by 40% in the captopril group and by 40% in nifedipine-treated patients. These results indicate that intrarenal changes may be crucial with respect to the effect of therapy on UAE. It is suggested that only agents which reduce FF and probably intraglomerular capillary pressure, such as converting enzyme inhibitors, alter UAE and may possibly interfere with the course of incipient diabetic nephropathy in normotensive patients.

Comparative Effect of Captopril and Nifedipine in Normotensive Patients With Incipient Diabetic Nephropathy

In these studies, the effect of a 6-wk treatment by placebo, the calcium-channel blocker nifedipine, or the converting-enzyme inhibitor captopril was assessed in normotensive patients with insulin-dependent diabetes and incipient nephropathy. In response to captopril and nifedipine, arterial pressure decreased slightly and to a similar extent. These drugs resulted in opposite effects on urinary excretion of albumin [i.e., increase in urinary albumin excretion (UAE) by 40% during nifedipine treatment and decrease by 40% during captopril treatment]. No change in UAE was observed in the p acebo group. This observation of opposite changes in U E i the presence of a similar fall in arterial pressur suggests that the effects of captopril and nifedipine o UAE result from some difference in their intrarenal a ction. The data do not present recommendations for the use or disuse of captopril or nifedipine in such a group of patients and do not allow extrapolation to hypertensive diabetic subjects well controlled by other conventional antihypertensive agents.

Is microalbuminuria a marker of early intrarenal vascular dysfunction in essential hypertension

The relation between basal intrarenal hemodynamics and the renal response to acute inhibition of angiotensin-converting enzyme by captopril and albuminuria was assessed in 106 lean patients with essential hypertension without detectable proteinuria. It was observed that the microalbuminuric group (24.5% of the total population) was characterized by a higher systemic arterial pressure, a lower level of high-density lipoprotein cholesterol, and similar mean values of age, duration of hypertension, glomerular filtration rate, renal plasma flow, filtration fraction, and plasma renin activity when compared with normoalbuminuric subjects. In response to captopril, a significant renal vasodilatation without a change in glomerular filtration rate or a fall in filtration fraction was observed in normoalbuminuric patients only. In contrast, the renal vasodilator response was abolished in microalbuminuric subjects, together with blunting of the rise in plasma renin activity associated with captopril. This occurred despite similar indexes of activity of the endogenous renin-angiotensin system. It is suggested that microalbuminuria may be a marker of early functional or fixed intrarenal vascular dysfunction in never-treated lean patients with essential hypertension.

Pulse pressure is an independent determinant of renal function decline during treatment of essential hypertension.

Background In large epidemiological studies and using serum creatinine or estimates of glomerular filtration rate (GFR), blood pressure has emerged as a predominant determinant of the age-associated decline in renal function. Methods The present longitudinal study (median follow-up period of 5.8 years) was conducted in 132 never-treated patients with essential hypertension at baseline. The effect of treatment on the GFR and effective renal plasma flow, estimated by urinary clearances of isotopic markers, was assessed. Results Satisfactory control of hypertension (<140/90 mmHg) was achieved in 57% of the population. During follow-up, the yearly change in the GFR was −1.72 ± 0.21 ml/min per year (mean ± SEM). In univariate regression analysis, the change in the GFR was correlated with baseline pulse pressure (r = −0.27, P = 0.002), whereas no influence of systolic, diastolic or mean blood pressures, as well as baseline albuminuria or left ventricular mass index, was found. Multivariate logistic regression analysis showed that only baseline pulse pressure conveyed a significant odds ratio of accelerated decline of GFR (> median of 1.5 ml/min per year), independently of age, baseline GFR, mean blood pressure and other known cardiovascular risk factors. No influence of the type of antihypertensive treatment (64% of the population had received angiotensin-converting enzyme inhibitor) was detected. Conclusion Pulse pressure (a marker of arterial stiffening) is suggested as an independent determinant of the treatment-associated decline in renal function in essential hypertension. No influence of target organ damage (albuminuria of left ventricular hypertrophy) was detected.