Vito M. Campese

Renal Afferent Denervation Prevents Hypertension in Rats With Chronic Renal Failure

Increased activity of the sympathetic nervous system has been described in chronic renal failure, but its role in the genesis and maintenance of hypertension associated with this condition has not been established. The kidney has an intense network of chemoreceptors and baroreceptors that send impulses to the brain. To what extent activation of these receptors by the scarred kidney or the uremic milieu may contribute to this model of hypertension is unknown. In the present study, we evaluated the effect of bilateral dorsal rhizotomy on the development of hypertension and neuroadrenergic activity in the anterior, lateral, and posterior hypothalamic nuclei, in the locus ceruleus, and in the nucleus tractus solitarius of Sprague-Dawley rats that underwent 5/6 nephrectomy or were sham operated. Neuroadrenergic activity was determined by calculating norepinephrine turnover rate after inhibition of norepinephrine synthesis with alpha-methyl-DL-p-tyrosine methyl ester hydrochloride. The endogenous norepinephrine concentration was significantly greater in the posterior and lateral hypothalamic nuclei and the locus ceruleus, but not in the nucleus tractus solitarius, and the anterior hypothalamic nuclei of uremic rats compared with control rats. In rats with chronic renal failure and sham rhizotomy, the turnover rate of norepinephrine in the posterior (15.3 +/- 1.61 nmol.g-1.h-1) and lateral hypothalamic nuclei (11.7 +/- 2.12 nmol.g-1.h-1) and in the locus ceruleus (26.6 +/- 2.42 nmol.g-1.h-1) was significantly faster (P < .01) than in rats with renal failure and dorsal rhizotomy (4.1 +/- 0.51, 4.7 +/- 0.77, and 5.1 +/- 1.13 nmol.g-1.h-1, respectively) or control animals with or without rhizotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension

Background Some patients with essential hypertension manifest greater than normal urinary excretion of albumin (UAE). Authors of a few retrospective studies have suggested that there is an association between microalbuminuria and cardiovascular risk. Objective To evaluate whether microalbuminuria is associated with a greater than normal risk of cardiovascular and renal events. Methods We performed a retrospective cohort analysis of 141 hypertensive individuals followed up for approximately 7 years. Hypertensive patients were defined as having microalbuminuria if the baseline average UAE of three urine collections was in the range 30–300 mg/24 h. Results Fifty-four patients had microalbuminuria and 87 had normal UAE. At baseline, the two groups were similar for age, weight, blood pressure, and rate of clearance of creatinine. 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 patient with normal UAE. During follow-up, 12 cardiovascular events occurred among the 54 (21.3%) patients with microalbuminuria and only two such events among the 87 patients with normal UAE (P < 0.0002). Stepwise logistic regression analysis showed that UAE (P = 0.003), cholesterol level (P = 0.047) and diastolic blood pressure (P = 0.03) were independent predictors of the cardiovascular outcome. Rate of clearance of creatinine from patients with microalbuminuria decreased more than did that from those with normal UAE (decrease of 12.1 ± 2.77 versus 7.1 ± 0.88 ml/min, P < 0.03). Conclusions This study suggests that hypertensive individuals with microalbuminuria manifest a greater incidence of cardiovascular events and a greater decline in renal function than do patients with normal UAE.

Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat

Rats with 5/6 nephrectomy develop hypertension and progressive deterioration in renal function. Several mechanisms may contribute to hypertension and to progressive renal disease in these rats. We have shown that increased activity of the sympathetic nervous system may contribute to hypertension in rats we chronic renal failure. However, the role of the sympathetic nervous system activity in the progression of renal disease has not been investigated. We have evaluated whether neurogenic factors contribute to the progression of renal disease in the renal ablation model of chronic renal failure in the rat. Sprague-Dawley rats underwent 5/6 nephrectomy and dorsal rhizotomy or sham rhizotomy (CRF). Age-matched normal rats were used as controls. Six weeks after surgery, rats with chronic renal failure and dorsal rhizotomy had lower blood pressure and serum creatinine than rats with sham rhizotomy. In addition, kidneys from rats with 5/6 nephrectomy and rhizotomy manifested less severe glomerulosclerosis than kidneys from rats without dorsal rhizotomy. These studies have demonstrated in rats with renal ablation. Although normalization of blood pressure may definitely play a role, the data raise the possibility that neurogenic impulses to the kidneys may contribute to the progression of renal disease.

Abnormal renal hemodynamics in black salt-sensitive patients with hypertension.

African-Americans with essential hypertension are more prone to the development of renal failure and are frequently salt-sensitive as well. Because alterations of intrarenal hemodynamics are important in the progression of renal disease and because salt-sensitive animal models with hypertension manifest a greater propensity to develop glomerulosclerosis in association with a rise in glomerular capillary pressure, we tested whether the renal hemodynamic adaptation to high dietary Na+ intake differs in salt-sensitive and salt-resistant hypertensive patients. We studied 17 black and nine white patients with essential hypertension who were placed on a low Na+ diet (20 meq/day) for 9 days, followed by a high Na+ diet (200 meq/day) for 14 days. During the last 4 days of each diet regimen, they received 30 mg/day of slow-release nifedipine. Eleven blacks were salt-sensitive, and all whites were salt-resistant. During the low Na+ diet period, salt-sensitive and salt-resistant patients had similar mean arterial pressure, glomerular filtration rate, effective renal plasma flow, and filtration fraction. During the high Na+ intake period, glomerular filtration rate did not change in either group; effective renal blood flow increased in salt-resistant patients (from 455±25 to 524±27.7 ml/min, p<0.01), but it decreased in salt-sensitive patients (from 538±20 to 426±15.8 ml/min, p<0.01); filtration fraction decreased (from 21±1.8 to 19±1.5%) in salt-resistant patients, but it increased (from 19±0.9 to 23±1.5%, p<0.01) in salt-sensitive patients; glomerular pressure decreased (from 58±2.0 to 52±1.5 mm Hg, p<0.01) in salt-resistant patients, but it increased (from 48±1.6 to 58±1.5 mm Hg, p<0.01) in salt-sensitive patients. During the period of high Na+ intake, nifedipine decreased arterial pressure, renal vascular resistance, and filtration fraction and increased renal blood flow in salt-sensitive but not in salt-resistant patients. These studies show that an abnormal renal hemodynamic adaptation occurs in salt-sensitive patients during high Na+ intake. The rise in filtration fraction and in intraglomerular pressure during high Na+ suggests that these renal hemodynamic derangements might be partially responsible for the greater propensity to renal failure in hypertensive African-Americans.

Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity.

Intrarenal injection of phenol in rats causes a persistent elevation in blood pressure (BP) and in norepinephrine (NE) secretion from the posterior hypothalamus (PH), and downregulation of neuronal nitric oxide synthase (nNOS) and interleukin-1beta (IL-1beta) in the PH. These studies suggest that afferent impulses from the kidney to the brain may be responsible for hypertension associated with renal injury. Downregulation of nNOS and IL-1beta, two modulators of sympathetic nervous system (SNS) activity may mediate this activation. In this study we measured the effects of intrarenal phenol injection on peripheral SNS activity by direct renal nerve recording, plasma NE, nNOS, and IL-1beta abundance in the brain. We also determined whether renal denervation or administration of clonidine prevented these effects of phenol. Acutely, the phenol injection increased both afferent and efferent renal sympathetic nerve activity, decreased urinary sodium excretion, and increased plasma NE. Three weeks after the phenol injection, BP and plasma NE remained elevated. Renal denervation and pretreatment with clonidine prevented the increase in BP and plasma NE caused by phenol. Chronic renal injury caused by phenol was associated with decreased abundance of IL-1beta and nNOS in the PH. These studies have shown that a renal injury caused by phenol injection increases BP and central as well as peripheral SNS activity, which persist long after the injury. Renal denervation and antiadrenergic drugs abolish the effects of phenol on BP and plasma NE. Because NO and IL-1beta modulate SNS activity, the stimulatory action of phenol on the SNS could be mediated by downregulation of nNOS and IL-1beta in the brain.

A Limited Renal Injury May Cause a Permanent Form of Neurogenic Hypertension

Previously, we have shown that an acute injury to the kidney produced by an intrarenal injection of phenol causes an immediate increase in blood pressure and in norepinephrine (NE) secretion from the posterior hypothalamus. The studies suggest that in this model afferent impulses from the kidney to central integrative structures in the brain may be responsible for the increase in blood pressure. To further evaluate whether a renal injury caused by the intrarenal injection of phenol leads to a permanent elevation of blood pressure and whether this is mediated by increased sympathetic nervous system activity, we examined the chronic effects (4 weeks) of an intrarenal injection of 50 microL of 10% phenol on blood pressure and NE secretion from the posterior hypothalamus. Systolic blood pressure increased from 128 +/- 2.1 to 176 +/- 1.5 mm Hg (P < .01) 4 weeks after receiving the intrarenal injection of phenol, but it did not change in rats that received the vehicle (128 +/- 2.4 and 135 +/- 1.7 mm Hg) and in rats that were subjected to renal denervation (127 +/- 3.4 and 124 +/- 1.0 mm Hg). The secretion of NE from the posterior hypothalamic nuclei was greater (P < .01) in rats that received phenol (253 +/- 9.6 pg/mL) than in controls (158 +/- 8.6 pg/mL) and denervated rats (170 +/- 2.1 pg/mL). These studies have shown that a limited injury to one kidney may cause a permanent elevation of blood pressure and this is associated with increased sympathetic nervous system activity.

Prevalence of Microalbuminuria in a Large Population of Patients with Mild to Moderate Essential Hypertension

To determine the prevalence of increased urinary albumin excretion (UAE) in essential hypertension and to establish whether this abnormality is associated with deranged renal function, we have measured UAE in a group of 123 patients with essential hypertension and in 110 normal subjects. Mean arterial pressure (MAP) was 96 +/- 0.6 mm Hg in normal subjects and 121 +/- 0.3 mm Hg in patients with essential hypertension (p less than 0.01). Mean UAE was 8.6 +/- 0.5 in normal subjects and 32.9 +/- 3.3 mg/24 h in patients with essential hypertension (p less than 0.01). Forty percent of patients with essential hypertension manifested a UAE exceeding 30 mg/24 h and had an average UAE of 72.0 +/- 4.7 mg/24 h. MAP in patients with increased UAE was similar to that in subjects with normal UAE (121 +/- 0.5 vs. 121 +/- 0.4 mm Hg). Creatinine clearance was also not different between these two groups (91 +/- 1.8 vs. 94 +/- 1.5 ml/min). No correlation was found between UAE and MAP or creatinine clearance. Long-term prospective studies are needed to extablish whether an increase in UAE may predict future nephrosclerosis in essential hypertension.

International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

Oxidative Stress Mediates Angiotensin II–Dependent Stimulation of Sympathetic Nerve Activity

Evidence indicates that angiotensin II (Ang II) enhances sympathetic nervous system (SNS) activity centrally and peripherally, but the exact mechanisms of this activation are not well established. We have previously shown that infusion of Ang II in the lateral cerebral ventricle raises blood pressure (BP), renal sympathetic nervous system activity (RSNA), and norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH), and reduces the abundance of interleukin-1β (IL-1β) and neuronal NO synthase (nNOS) mRNA in the PH. Pretreatment with an Ang II type 1 (AT1) receptor antagonist abolished these effects of Ang II. The data support the hypothesis that Ang II stimulates SNS through activation of AT1 receptors and downregulation of nNOS. In the current studies, we tested the hypothesis that the effects of Ang II on central SNS are mediated by reactive oxygen species. To this end, we evaluated the effects of Ang II alone or in combination with 2 superoxide dismutase (SOD) mimetics, tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl) and polyethylene glycol–SOD (PEG-SOD) on BP, NE secretion from the PH, RSNA, and abundance of IL-1β and nNOS mRNA in the PH Ang II raised BP, NE secretion from the PH, and RSNA and reduced the abundance of IL-1β and nNOS mRNA in the PH. Tempol and PEG-SOD completely abolished these actions of Ang II. In conclusion, these studies support the hypothesis that the effects of centrally administered Ang II on the SNS are mediated by increased oxidative stress in brain regions involved in the noradrenergic control of BP.

Salt Intake and Plasma Atrial Natriuretic Peptide and Nitric Oxide in Hypertension

In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO2+NO3 in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (P < .01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO2+NO3 levels were higher (P < .05) in salt-sensitive (189 +/- 7.9 mumol/L) and salt-resistant (195 +/- 13.5 mumol/L) black patients than in control subjects (108 +/- 9.7 mumol/L). During high salt intake, plasma NO2+NO3 decreased significantly (P < .01) in both salt-sensitive (150 +/- 7.0 mumol/L) and salt-resistant (142 +/- 9.0 mumol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.