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Experimental evidence suggests that aldosterone contributes to progressive kidney disease. Angiotensin-converting enzyme inhibitors and angiotensin type 1 receptor antagonists suppress the renin-angiotensin system but they do not effectively reduce plasma aldosterone. Hence, administration of aldosterone receptor antagonists may provide additional renal protection. In the present prospective randomized open-label study, we evaluated the effects of spironolactone (25 mg/day for 1 year) on proteinuria and estimated glomerular filtration rate in 83 patients with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists. Eighty-two patients were treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists alone and served as controls. After 1 year of therapy, proteinuria decreased from 2.1+/-0.08 to 0.89+/-0.06 g/g creatinine (P0.001) in patients treated with spironolactone, but it did not change in control patients. Baseline aldosterone levels were significantly correlated with proteinuria (r=0.76, P0.0001), and predicted the degree of reduction in proteinuria with spironolactone (r=0.42, P0.0002). Baseline estimated glomerular filtration rate was similar in patients treated with spironolactone and controls (62.4+/-2.4 and 62.2+/-2.1 ml/min/1.73 m(2), respectively). After 1 month of therapy with spironolactone, estimated glomerular filtration rate decreased more in patients treated with spironolactone than in controls. However, by the end of 1 year the monthly rate of decrease in estimated glomerular filtration rate from baseline was lower in patients treated with spironolactone than in controls (0.323+/-0.044 vs 0.474+/-0.037 ml/min/1.73 m(2), P0.01). Spironolactone caused a significant rise in serum potassium levels (from 4.2+/-0.04 at baseline to 5.0+/-0.05 mEq/l after 12 months of treatment, P0.001). In conclusion, this study has shown that spironolactone may reduce proteinuria and retard renal progression in chronic kidney disease patients.

The association between hypertension and chronic renal disease is well known. The pathogenesis of hypertension in patients with chronic kidney disease (CKD) is complex and multifactorial, which may explain why it is resistant to treatment. The traditional paradigm is that hypertension in CKD is due either to an excess of intravascular volume (volume dependent) or to excessive activation of the renin-angiotensin system in relation to the state of sodium/volume balance (renin-dependent hypertension). This review focuses on the importance of less established mechanisms, such as increased activity of the sympathetic nervous system, increased endothelin production, decreased availability of endothelium-derived vasodilators and structural changes of the arteries, renal ischemia, and sleep apnea.

During the last two decades, numerous studies have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) diminish the risk of cardiovascular morbidity and mortality. Although these studies have focused primarily on the ability of statins to lower circulating levels of low-density lipoprotein cholesterol, more recent research has shown that statins may protect the vasculature via pleiotropic effects not directly related to lipid lowering. These include adjustments in cell-signaling pathways that play a role in atherogenesis and that affect the expression of inflammatory elements, curtail oxidative stress, and enhance endothelial function. More recently, researchers have begun to explore whether these agents exert similar beneficial effects in renal parenchymal and renovascular disease. This review examines the available evidence that dyslipidemia may augment the inflammatory reaction of cytokines in patients with renal disease and that statins may improve renal dysfunction by altering the response of the kidney to dyslipidemia, even in persons with end-stage renal disease on dialysis or with renal transplantation. In this context, some data suggest that statin-mediated alterations in inflammatory responses and endothelial function may reduce proteinuria and the rate of progression of kidney disease.

Evidence for a role of PTH in the reduced pressor response to norepinephrine in chronic renal failure. Reduced pressor response to norepinephrine (NE) is present in patients with chronic renal failure (CRF) and is responsible partly for some of the manifestations of autonomic nervous system dysfunction in these patients. PTH blunts the pressor response to NE in normal rats, suggesting that excess PTH in CRF may be responsible for this abnormality. However, the relative roles of uremia and of excess PTH in the uremic state in the genesis of this abnormality are not defined. The present study examines this question. Rats with chronic renal failure display reduced pressor response to NE administration, but this derangement can be prevented by prior parathyroidectomy and abolished by administration of indo-methacin. The role of PTH in the genesis of this abnormality can also be demonstrated in the hind limb preparation obtained from rats with CRF.Our data show that excess PTH and not other consequences of CRF plays a paramount pathogenetic role in the reduced pressor response to NE and that this effect of PTH is due to a direct action on the blood vessels. Further, this hormone action is most likely mediated through increased production of vasodilating prostaglandins. These observations are constant with the idea that PTH would contribute to the pathogenesis of some of the manifestations of autonomic nervous system dysfunction in CRF.

Neurogenic factors and hypertension in renal disease. Hypertension in chronic renal failure (CRF) is very common and contributes to morbidity and mortality and to the progression of renal disease. The pathogenesis of hypertension in CRF has been attributed mostly to sodium retention and to activation of the renin-angiotensin-aldosterone system. More recently an abundance of evidence has accumulated to support a role for increased sympathetic nervous system (SNS) activity in the genesis of hypertension associated with CRF. Evidence from our laboratory has also demonstrated that the rise in central SNS activity is mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NO) production, and that the upregulation of NO production in the brain is mediated by IL-1β.

Association between hyperlipidemia and microalbuminuria in essential hypertension.BackgroundSome patients with essential hypertension manifest greater than normal urinary albumin excretion (UAE). A few retrospective studies have suggested that there is an association between microalbuminuria and cardiovascular risk. The reasons for this association are not well established, and they are the object of this review.MethodsWe found that hypertensive patients with microal-buminuria manifest greater levels of blood pressure, particularly at night. Serum levels of cholesterol, triglycerides, and uric acid in patients with microalbuminuria were higher than levels in those with normal UAE, whereas levels of high-density lipoprotein cholesterol in patients with microalbuminuria were lower than levels in patients with normal UAE. Patients with microalbuminuria manifest a greater incidence of insulin resistance, and thicker carotid arteries. After a follow-up of seven years we observed that 12 cardiovascular events occurred among 54 (21.3%) patients with microalbuminuria, and only two such events among 87 patients with normal UAE (P < 0.0002). Stepwise logistical regression analysis showed that UAE, cholesterol level and diastolic blood pressure were independent predictors of the cardiovascular outcome. The rate of clearance of creatinine from patients with microalbuminuria decreased more than did that from those with normal urinary albumin excretion.ConclusionsThese studies suggest that hypertensive individuals with microalbuminuria manifest a variety of biochemical and hormonal derangements with pathogenic potential, which result in greater incidence of cardiovascular events and a greater decline in renal function than do patients with normal UAE.

Abnormal norepinephrine uptake and release in brain synaptosomes in chronic renal failure. Abnormalities in the function of the central nervous system exist in chronic renal failure (CRF) and some of these derangements may be related to excess parathyroid hormone (PTH) which causes a rise in brain calcium. The latter may affect metabolism of neurotransmitters such as norepinephrine (NE) in brain synaptosomes. We measured NE content, uptake and release in brain synaptosomes of CRF rats and studied whether excess PTH affects these parameters. Synaptosomes from rats with 21 days of CRF compared to those from normal animals have higher calcium content (11.4 ± 0.92 vs. 7.1 ± 0.50 nmol/mg protein, P < 0.01) and lower Na-K ATPase activity (6.5 ± 0.81 vs. 11.4 ± 0.76 µmol Pi/mg protein/hr, P < 0.01). NE content (11.0 ± 0.60 vs. 13.6 ± 0.55 pmol/mg protein/hr, P < 0.01), uptake (46 ± 4.5 vs. 110 ± 5.9 pmol/mg protein times 50 min, P < 0.01) and release (2.0 ± 0.2 vs. 5.1 ± 0.47 pmol/mg protein times 10 min, P < 0.01). Parathyroidectomy (PTX) in CRF rats kept normocalcemic reversed these abnormalities in brain synaptosomes; indeed calcium content, Na-K ATPase activity and NE content, uptake and release in synaptosomes from PTX-CRF rats were not different from those seen in normal rats. Administration of 1-84 PTH for 21 days produced abnormalities in brain synaptosomes similar to those seen in CRF rats; the synaptosomes from PTH-treated animals had significantly (P < 0.01) higher calcium content (10.0 ± 0.80 nmol/mg protein) and lower Na-K ATPase activity (8.3 ± 0.58 µmol Pi/mg protein/hr), and NE content (8.8 ± 0.51 pmol/mg protein), uptake (87 ± 4.0 pmol/mg protein times 50 min) and release (2.3 ± 0.27 pmol/mg protein times 10 min). However, in PTH-treated animals the initial rate of NE uptake was not different from normal but the steady state rate was reduced. In contrast, both the initial and steady state NE uptake were significantly reduced in CRF control rats. Despite this greater effect of CRF on NE uptake, the decrease in NE content in the synaptosomes of CRF control rats was significantly less than that in PTH-treated animals. The data show that abnormalities in the function of synaptosomes occur in CRF and they are most likely due in large part to excess PTH. The latter may act directly and/or mediate its effect through accumulation of calcium in the synaptosomes. Other factors associated with CRF or administration of PTH may also contribute to some of these abnormalities in synaptosomes function.

Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. To examine the mechanisms underlying the sensitivity to sodium intake in a subset of patients with essential hypertension, we studied the effects of different sodium intake (10, 100, 200 mEq/day) on blood pressure, the function of the renin-angiotensin-aldosterone system, and on blood levels of catecholamines in 20 patients with essential hypertension and 10 normal subjects. Mean blood pressure (MBP) was not different in hypertensive and normal subjects during low sodium diet. But, with high sodium intake, MBP increased by at least 10% in 12 patients (salt-sensitive), whereas in the remaining 8 patients (salt-resistant) and in normal subjects, MBP did not change significantly. This phenomenon cannot be attributed to differences in sodium retention because the percent change in body weight and the urinary sodium excretion in the salt-sensitive patients was not different than it was in salt-resistant patients or in normal subjects. The observed difference in blood pressure response to high sodium intake in salt-sensitive patients is also not dependent on an impaired suppressibility of the renin-angiotensin-aldosterone system because there were no significant differences in the basal levels of PRA and aldosterone between the groups, and because the orthostatic increments in PRA were significantly lower in salt sensitive than they were in the salt-resistant patients and in normal subjects. Plasma norepinephrine (NE) levels were not significantly different between normal subjects or hypertensive patients while on low sodium intake. But during high sodium intake, they decreased significantly (P < 0.05) in normal subjects (from 22 ± 3.4 to 12 ± 2.3 ng/dl) and in salt-resistant patients (from 17 ± 4.5 to 13 ± 2.4 ng/dl) but not in salt-sensitive patients (from 20 ± 1.9 to 22 ± 3.2 ng/dl). Furthermore, the majority of salt-sensitive patients displayed inappropriately high plasma NE in relation to their urine excretion of sodium during high sodium intake. Finally, the increments in plasma NE after 5min of standing were significantly greater in salt-sensitive patients than they were in salt-resistant patients and normal subjects during both low or high sodium intake. These data indicate that a subset of patients with essential hypertension may have impaired suppressibility of plasma NE during high sodium intake, which suggests hyperactivity of the sympathetic nervous system in these patients. These aberrations may be responsible for the increase in MBP in the salt-sensitive patients during high sodium intake.Relation anormale entre l'ingestion de sodium et l'activité du système nerveux sympathique chez les malades atteints d'hypertension essentielle sensibles au sel. Afin d'étudier les mécanismes qui sous-tendent la sensibilité à l'apport de sodium dans un sous-groupe de malades atteints d'hypertension essentielle, les effets de différents apports de sodium (10, 100, 200 mEq/jour) sur la pression artérielle, la fonction du système rénine-angiotensine-aldostérone, et les concentrations sanguines de catécholamines ont été évaluées chez 20 malades atteints d'hypertension essentielle et chez 10 sujets normaux. La pression artérielle moyenne (MBP) n'était pas différente chez les malades hypertendu et les sujets normaux recevant une alimentation pauvre en sodium. Mais, avec le régime riche en sodium, MBP a augmenté d'au moins 10% chez 12 malades (sensibles au sel) alors que chez les autres 8 malades (résistants au sel) et chez les sujets normaux MBP n'a pas changé de façon significative. Ce phénomène ne peut pas être attribué à des différences de rétention de sodium parce que le pourcentage de modifications du poids corporel et l'excrétion urinaire de sodium chez les malades sensibles au sel ne sont pas différents de ceux observés chez les malades résistants au sel ou chez les sujets normaux. La différence de pression artérielle observée chez les malades sensibles au sel au cours de l'alimentation riche en sodium n'est pas non plus dépendante d'une altération du freinage du système rénine-angiotensine-aldostérone parce qu'il n'a pas été observé de différences significatives dans les concentrations basales de PRA et d'aldostérone entre les groupes, et parce que l'augmentation orthostatique de PRA était significativement plus faible chez les malades sensibles au sel que chez les malades résistants au sel et les sujets normaux. Les concentrations plasmatiques de la norépinéphrine (NE) n'étaient pas significativement différentes entre les sujets normaux et les malades hypertendus soumis à un régime pauvre en sel. Mais, au cours du régime riche en sel ils ont diminué significativement (P < 0,05) chez les sujets normaux (de 22 ± 3,4 à 12 ± 2,3 ng/dl) et chez les malades résistants au sel (de 17 ± 4,5 à 13 ± 2,4 ng/dl) mais non chez les malades sensibles au sel (de 20 ± 1,9 à 22 ± 3,2 ng/dl). De plus, la majorité des malades sensibles au sel ont eu une concentration plasmatique de NE élevée de façon inappropriée par rapport à leur excrétion urinaire de sodium au cours du régime riche en sel. Enfin, les augmentations de NE plasmatique après 5min de position debout ont été significativement plus grandes chez les malades sensibles au sel que chez les malades résistants au sel et les sujets normaux aussi bien au cours du régime riche que du régime pauvre en sodium. Ces résultats indiquent qu'un sous-groupe de malades atteints d'hypertension essentielle peut avoir une altération du freinage de la NE plasmatique au cours de l'ingestion d'un régime riche en sodium ce qui suggère une hyperactivité du système nerveux sympathique chez ces malades. Ces désordres peuvent être responsables de l'augmentation de MBP chez les malades sensibles au sel au cours de l'ingestion d'une régime riche en sodium.

Alpha1 adrenergic receptors in mesenteric arteries of rats with chronic renal failure. In previous studies we have shown that patients or rats with chronic renal failure display reduced blood pressure response to norepinephrine (NE). This abnormality is related to the high levels of parathyroid hormone (PTH) which stimulates vasodilator prostaglandin production. To determine whether chronic renal failure (CRF) also affects pressor response to NE through changes in the properties of alpha1 adrenoceptors, we have measured plasma NE and the number of binding sited (Bmax) and the KD of these receptors in isolated mesenteric arteries of normal CRF rats and of CRF rats previously parathyroidectomized (PTX). Plasma NE was greater (P < 0.01) in CRF than in control (67 ± 14 vs. 32 ± 3.1 ng/dl), but it was not different from CRF-PTX rats. The Bmax of alpha1 adrenoceptors was lower (P < 0.05) in CRF than control (80 ± 10 vs. 173 ± 29 fmol/mg protein), but it was similar in CRF and CRF-PTX rats. The KD was not significantly different among the three groups of rats studied. The data show that the number of alpha1 adrenoceptors is reduced in CRF and this is not related to excess PTH. This abnormality may contribute to the reduced pressor response to NE in CRF. The effect of PTH, on the vascular response to NE is not related to changes in plasma levels of NE or in binding sites for NE.

Role of sympathetic nerve inhibition and body sodium-volume state in the antihypertensive action of clonidine in essential hypertension. A simultaneous analysis of the interrelationships between mean blood pressure (MBP), plasma catecholamines, plasma renin activity (PRA) and aldosterone, exchangeable body sodium, and blood volume was carried out before and after acute and chronic administration of clonidine in 15 patients with essential hypertension, in order to further elucidate the mechanism(s) of action of this drug. After a single oral dose of 200 µg, clonidine produced a significant fall in MBP, heart rate, plasma norepinephrine (NE), PRA, and aldosterone. There were significant correlations (P < 0.01) between NE and MBP, but not between PRA or aldosterone and MBP both before and after the ingestion of clonidine. Furthermore, there was a significant correlation (P < 0.05) between the magnitude of the fall of plasma NE and change in MBP. After 6 weeks of treatment, clonidine at a dose of 960 ± 80 µg/day produced a significant decrement in MBP and NE, but not in PRA and aldosterone; with upright posture, the magnitude of the fall in MBP was significantly greater (P < 0.01), and the rise in plasma NE was significantly smaller (P < 0.01) after chronic clonidine treatment. There was also a significant fall (P < 0.01) in exchangeable sodium and plasma volume. The data provide evidence that inhibition of the sympathetic nervous system by clonidine plays a major role and that the decrease in exchangeable body sodium and blood volume after chronic treatment may contribute to the antihypertensive action of the drug.Rôles de l'inhibition sympathique du bilan de sodium et du volume circulant dans l'action antihypertensive de la clonidine au cours de l'hypertension essentielle. Une analyse simultanée des relations entre la pression artérielle moyenne (MBP), les catécholamines (NE), l'activité rénine (PRA), l'aldostérone plasmatiques, le sodium échangeable et le volume sanguin a été conduite avant et après l'administration aiguë et chronique de clonidine à 15 malades atteints d'hypertension essentielle afin de mieux élucider le mécanisme d'action de cette drogue. Après une dose moyenne de 200 µg par voie orale, la clonidine produit une chute significative de MBP, du rythme cardiaque, de NE, PRA et aldostérone plasmatiques. Il existe une corrélation significative (P < 0,01) entre NE et MBP mais pas entre PRA ou aldostérone et MBP aussi bien avant qu'après l'ingestion de clonidine. De plus il existe une corrélation significative (P < 0,05) entre l'importance de la chute de NE plasmatique et la modification de MBP. Après six semaines de traitement à la dose de 960 ± 80 µg/jour, la clonidine produit une chute significative de MBP et NE mais non de PRA et aldostérone. En orthostatisme la chute de MBP est significativement plus grande (P < 0,01) et l'augmentation de NE du plasma significativement plus faible (P < 0,01) après un traitement prolongé. Il est observé aussi une baisse significative (P < 0,01) du sodium échangeable et du volume plasmatique. Ces résultats apportent la preuve de ce que l'inhibition sympathique joue un rôle majeur et de ce que la diminution du sodium échangeable et du volume sanguin peut contribuer, au cours d'un traitement chronique, à l'action antihypertensive de cette drogue.