Albert Mimran

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.

Prevention of the Cardiovascular and Renal Effects of Angiotensin II by Endothelin Blockade

Angiotensin II (Ang II) stimulates the release and gene expression of endothelin-1 in isolated vascular smooth muscle cells. In 47 Sprague-Dawley rats, we assessed the influence of concomitant treatment by the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan (30 mg/kg per day, gavage) on the effect of a 10-day infusion of Ang II (200 ng/kg per minute, SC, osmotic pump) on arterial pressure, renal hemodynamics (microsphere method), albuminuria, cardiac weight, and carotid structure. Ang II increased systolic arterial pressure (SAP) by 49+/-7 mm Hg. Although bosentan alone did not affect SAP, the development of Ang II-induced hypertension was entirely prevented by the endothelin antagonist. In addition, the reduction in renal blood flow induced by Ang II (4.9+/-0.3 versus 7.4+/-0.2 mL x min-1 x g-1 in control rats) was prevented by concomitant administration of bosentan (8.8+/-0.8 mL x min-1 x g-1). The marked increase in albuminuria observed in rats infused with Ang II (2524+/-961 versus 91+/-6 microg/24 h in control rats) was prevented by bosentan. Similarly, bosentan abolished the increase in heart weight index (from 2.96+/-0.03 to 3.41+/-0.08 mg/g body weight) and carotid media thickness (from 73+/-14 to 108+/-6 microm) induced by Ang II infusion. Of interest, the dipsogenic action of Ang II was not influenced by bosentan. In conclusion, endogenous endothelin contributes to the cardiovascular and renal effects of Ang II.

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.

Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

Diabetic nephropathy has developed into a worldwide epidemic and is responsible for the majority of end-stage renal disease in most countries. Antihypertensive treatment slows the progression of the disease. In addition, blockade of the renin–angiotensin system reduces the degree of albuminuria and angiotensin II receptor blockers (ARBs) have been shown to delay the progression from microalbuminuria to overt proteinuria in patients with diabetes. However, few studies have examined whether the initial stage of diabetic nephropathy (i.e. the development of microalbuminuria) in patients with type 2 diabetes can be slowed or prevented by ARB treatment. The Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study is a placebo-controlled, multicentre, double-blind, parallel group study investigating the effect of the ARB, olmesartan medoxomil, on the incidence of microalbuminuria. A total of 4400 type 2 diabetes patients with normoalbuminuria will be randomized to treatment with 40 mg of olmesartan medoxomil once daily or placebo. Goal blood pressure will be 130/80 mmHg. The primary endpoint of the study is the occurrence of microalbuminuria. In ROADMAP, we will also assess as secondary endpoints the effects of olmesartan on fatal and non-fatal cardiovascular events in patients with diabetes. In addition, within subgroups of the ROADMAP patients, the effects of olmesartan on retinopathy and other microvascular circulations will be analysed. The study is expected to last a median of 5 years. The ROADMAP study will answer the question whether an ARB can prevent or delay the onset of microalbuminuria and whether this translates into protection against cardiovascular events and renal disease.

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.

Microalbuminuria in Type 2 Diabetes and Hypertension : A marker, treatment target, or innocent bystander?

Albuminuria is a well-known predictor of poor renal outcomes in patients with type 2 diabetes and in essential hypertension (1–4). Albuminuria has also been shown more recently to be a predictor of cardiovascular outcomes in these populations (5–8). There is emerging data that reduction of albuminuria leads to reduced risk of adverse renal and cardiovascular events (9–12). It has become increasingly clear that albuminuria should not only be measured in all patients with type 2 diabetes and hypertension, but also steps should be taken to suppress albuminuria to prevent future renal and cardiovascular adverse events. This review discusses the measurement of albuminuria and summarizes the current literature on the association between albuminuria and adverse cardiovascular and renal outcomes in type 2 diabetes and hypertension. It also summarizes the evidence that reduction of albuminuria leads to improvement in the risk profiles of these patients. Microalbuminuria is defined as levels of albumin ranging from 30 to 300 mg in a 24-h urine collection (13). Overt albuminuria, macroalbuminuria, or proteinuria is defined as a urinary albumin excretion of ≥300 mg/24 h. Urinary albuminuria comprises 20–70% or urinary total protein excretion. Measuring urinary albumin excretion by dipstick without simultaneously measuring creatinine is subject to false-negative and false-positive results due to variations in urine concentration caused by hydration level (13). Although urinary dipsticks are acceptable for quick screening, other more precise measurements should be done to quantify urinary albumin excretion rates (AERs). Albuminuria can be measured in several ways (Table 1): 1 ) measurement of albumin-to-creatinine ratio (ACR) in a random or first morning spot collection, 2 ) 24-h urine collection with measurement of creatinine to verify adequacy of the collection, and 3 ) timed (4-h or overnight) urine collections (13). Although the 24-h urine collection would overcome issues of diurnal variation …

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.