Hypertension In Chronic Renal Failure Research Articles

1037 INHIBITION OF THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM AND ITS IMPACT ON KIDNEY OXIDATIVE STRESS, RENAL FUNCTION AND HYPERTENSION IN POLYCYSTIC KIDNEY DISEASE

Background: The renin angiotensin aldosterone system (RAAS) regulates blood pressure (BP), and is a target for treatment of hypertension in chronic renal failure (CRF). Both angiotensin II (AngII) and aldosterone can have local effects, including production of reactive oxygen species (ROS), which are detrimental to tissue function. We examined if angiotensin converting enzyme or aldosterone receptor inhibition can reduce renal ROS pathway gene expression in the Lewis Polycystic Kidney (LPK) model of CRF. Methods: Rats were treated with perindopril (n = 12, 3 mg/kg/day p.o.) or spironolactone (n = 12, 20 mg/kg/day p.o.) from age 4-12 weeks. BP was measured, and urine & blood assessed for protein, urea and creatinine. Quantitative RT-PCR was used to determine renal expression of markers of oxidative stress hypoxia-inducible factor-1α, vascular-endothelial growth factor, hemeoxygenase-1, p47phox, gp91phox and superoxide dismutase-1. Results: Perindopril treatment caused a significant reduction in SBP in LPK (164 ± 13 mmHg vs. 226 ± 10 mmHg, treated vs. untreated, P < 0.0001). In contrast spironolactone did not have a significant impact on SBP. Serum and urine markers of kidney dysfunction were unchanged after perindopril treatment, however a significant reduction in urinary protein (0.4 ± 0.2 vs. 1.02 ± 0.25 g/L) was seen after spironolactone (P < 0.0001). Intra-renal levels of ROS genes were largely unchanged after both treatments. Conclusions: Spironolactone significantly reduced proteinuria, independent of any impact on BP. In contrast, perindopril was effective in ameliorating hypertension, but had no impact on renal function. Neither treatment had an impact on markers of oxidative stress, suggesting this does not contribute to their mechanism of action.

Association of Hyperuricemia With Carotid Intima-Media Thickness, Albuminuria, Diabetes, Hypertension in Chronic Renal Failure

Background: Carotid artery intima-media thickness (CAIMT) measured by B-mode ultrasonography is widely used as a surrogate marker atherosclerosis. Hyperuricemia is also a well recognized risk factor for cardiovascular diseases. This study was done to find out the role of hyperuricemia on CAIMT and albuminuria, diabetes and hypertension in chronic renal failure (CRF) patients. Methods: 132 CRF patients and 66 age and sex matched healthy controls were included in this study. Out of 132 CRF patients, 35 were hyperuricemic. CAIMT were measured by B-mode ultrasonography. Statistical analyses were done by SPSS (Statistical package for the social Sciences) soft ware (window version 17.0). Results: Hyperuricemia was independently correlated with CAIMT in CRF patients (P = 0.018). CRF patients with hyperuricemia had significantly higher CAIMT compared to CAIMT of CRF patients without hyperuricemia (P value &lt; 0.001) and healthy controls (P &lt; 0.001). In hyperuricemic CRF patients, prevalence of hypertension (P &lt; 0.001) and diabetes (P = 0.007) was significantly higher than non-hyperuricemic CRF patients. Conclusions: Hyperuricemia is independently responsible for increased thickening of Carotid artery intima media thickness and also associated with higher level of albuminuria, and higher prevalence of hypertension and diabetes in CRF patients. doi:10.4021/wjnu14w

Role of the Rostral Ventrolateral Medulla in the Arterial Hypertension in Chronic Renal Failure

Sympathetic activation in chronic renal failure (CRF) is a major mechanism leading to the progression of renal disease and hypertension. In the present study, we tested the hypothesis that in CRF increased reactive oxygen species (ROS) production in the RVLM mediated by enhanced circulating Angiotensin II (Ang II) is an important mechanism leading to hypertension in CRF. In CRF rats we found an increase in the abundance of p47phox and gp91phox mRNA within the RVLM associated with a reduction of Ang II type 1 receptors (AT1) mRNA in the brainstem compared to controls (C). Tempol but not candesartan into the RVLM decreased MAP in CRF but not in C rats. GABA into the RVLM decreased MAP in CRF (63 ± 8 mmHg) more intensely than in C (33 ± 3 mmHg). The results suggest that increased oxidative stress within the RVLM has an important participation to maintain hypertension in CRF rats apparently independently of AT1 Ang II receptors.

Influence of progressive renal dysfunction in chronic heart failure.

Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.

Oxygen species in the microvascular environment: regulation of vascular tone and the development of hypertension.

Derangements of the three endothelium-related vasodilator systems (prostaglandins, endothelium-derived hyperpolarizing factor(s) and nitric oxide) cause the endothelial dysfunction observed in hypertension. Free radical-induced nitric oxide degradation plays a crucial role in hypertension. An increase in superoxide producing enzymes such as NAD(P)H oxidase and xanthine oxidase has been demonstrated. Superoxide dismutase may correct endothelial dysfunction in vitro and superoxide dismutase mimetics can lower blood pressure in experimental animals. Antioxidant agents and xanthine oxidase-inhibiting compounds have been used in humans. In addition, the synthesis of vasoconstrictor peroxides derived from the activity of cyclooxygenase in the endothelium and the vascular smooth muscle is stimulated by the OH. radical. Hydrogen peroxide levels are augmented in hypertension, but its role is unclear because recent investigations have shown that this substance may act as a hyperpolarizing factor. It is thought that the therapeutic benefit of anti-hypertensive drugs, such as calcium antagonists and angiotensin-converting enzyme inhibitors, could be in part due to an inhibition of free radical production. A role of superoxide in the endothelial dysfunction and hypertension of chronic renal failure has also been suggested by recent animal experiments.

Sympathetic overactivity as a cause of hypertension in chronic renal failure.

To review the current literature on sympathetic mediation of hypertension in chronic renal failure. Hypertension is present in the vast majority of patients with chronic renal failure and constitutes a major risk factor for the excessive cardiovascular morbidity and mortality in this patient population. Although, traditionally, this hypertension is thought to be largely volume-dependent, an increasing body of literature suggests that there is an important sympathetic neural component. Microneurographic studies have demonstrated sympathetic overactivity without baroreflex impairment in both hypertensive chronic hemodialysis patients as well as in those with less advanced renal insufficiency. Sympathetic nerve activity was found to be normal in hemodialysis patients with bilateral nephrectomy, leading to the hypothesis that sympathetic overactivity in uremia is caused by a neurogenic signal (carried by renal afferents) arising in the failing kidney. This hypothesis is supported by rat studies showing that renal deafferentation abrogates hypertension in the 5/6 nephrectomy model of chronic renal insufficiency. In addition, in patients with chronic renal insufficiency and renin-dependent hypertension, sympathetic overactivity was normalized by chronic angiotensin converting enzyme inhibition but not by calcium channel blockade, implicating a major central neural action of angiotensin II. Sympathetic overactivity in chronic renal failure is caused by neurohormonal mechanisms arising in the failing kidney. Future clinical studies are needed to determine whether normalization of sympathetic activity should constitute an important therapeutic goal in this high-risk patient population.

Hypertension in chronic renal failure.

Introduction. When compared with essential arterial hypertension, the incidence of secondary arterial hypertension is low (8-10%), but it can be cured by surgery in the case of renovascular hypertension, renin producing tumors, coartaction of the aorta and some types of suprarenal gland diseases. The most frequent form of secondary hypertension is caused by chronic renal parenchymatous injury, which occurs in approximately 5% of all cases of hypertension. Table I presents the most frequent causes of this type of hypertension. As the renal insufficiency progresses, the percentage of patients who suffer arterial hypertension increases; about 85-90% of the patients in end-stage chronic renal failure present elevated blood pressure levels prior to entering in the dialysis program.

Blood pressure and body water distribution in chronic renal failure patients.

Evidence exists of the important role of sodium balance and extracellular fluid volume in the genesis of hypertension in chronic renal failure (CRF). Several studies have shown that patients with advanced CRF have an increased, interstitial and intravascular, extracellular water volume (ECW). The relationship between the increase in ECW and high blood pressure has also been reported. Using electric bioimpedance, body water distribution was studied in 32 patients from our dialysis unit. Twelve of these patients were hypertensive and 20 had normal blood pressure. Hypertensive patients had a significantly greater total body water volume and ECW than the normotensive patients. Given the importance of ECW in controlling blood pressure, one of the main aims of haemodialysis is a suitable extraction of sodium and water during the treatment. Despite technological advances in dialysis therapy, cardiovascular instability during treatment is still a clinical problem. In recent years, new strategies to control ECW, with good haemodynamic tolerance, have been developed. These strategies include haemofiltration, haemodiafiltration and sodium and ultrafiltration profiles.

Hypertension in chronic renal failure and ESRD: prevalence, pathophysiology, and outcomes.

Hypertension and cardiovascular disease were detected to be major problems in end-stage renal disease patients soon after the application of chronic dialysis to treat uremia. Nearly 40 years later, and despite awesome technological and pharmacological advances, cardiovascular diseases remain the number one cause of death in all categories of renal patients, ie, chronic renal insufficiency, end-stage renal disease on dialysis and the renal transplant recipient. This is quite likely related to the massive clinical burden of cardiovascular risk factors: hypertension, cardiac fibrosis and hypertrophy, abnormal lipid profiles, smoking, dietary factors, and enhanced sympathetic activity. For example, left ventricular hypertrophy and abnormal echocardiograms are present in up to 75% to 80% of incident dialysis patients related to the interactions of these cardiovascular risks. It is important to understand how hypertension and the other cardiovascular disease risk factors interact in these patients. Based on the latest national data from the USRDS, the prevalence of underlying cardiac disease is increasing during the period of chronic renal failure. A proper understanding of the pathophysiology and prevalence of hypertension and its consequences in renal patients may lead to more rational therapies and clinical trials. At this time, the nephrologists are dealing with an epidemic of cardiovascular diseases in their patients.

Hypertension in chronic renal failure and end-stage renal disease patients treated with haemodialysis or peritoneal dialysis.

Guidelines should be used for clinical decisions about although it remains debatable whether ‘dry weight’ individual patients. However, most of the available was really achieved in all of these patients [4,5]. guidelines are based on randomized clinical trials which only provide a statistical prediction of the likely effect of an intervention, usually based on the ‘average’ Effect of hypertension on survival outcome, aggregated across all the heterogeneous patients participating in the trial. Heterogeneity due to The well established concept that hypertension is a the stage of the disease, its severity, organ complica- risk factor for death both in the general population tion, comorbid conditions etc., together with exclusion and in dialysis patients has recently been questioned of the patients with major complications from the trial, by independent studies [4–9] showing that low prelimit the information generated by such trials for a dialysis systolic BP is associated with increased precise prediction of outcome for an individual patient. adjusted mortality risk. No association with elevated Although these limitations may be partially circum- mortality risk has been observed for pre-dialysis sysvented by the clinical experience and pathophysiolog- tolic hypertension. A number of explanations may be ical knowledge of clinicians or experts (in the case of offered for this rather unexpected finding: (i) it may a guideline), personal bias is almost inevitable. A be an iatrogenic effect due to overmedication; (ii) all comprehensive approach to the issue of hypertension the studies were carried out in the USA on patients has recently been published [1]. The present review with an overall poor prognosis. The influence of summarizes the most important aspects discussed in expected survival is indeed crucial. The beneficial effect that review and, in particular, addresses some specific of BP reduction may need several years to become topics whcih, in the opinion of the Medical Expert visible, and this may not be detectable if life expectancy Group, are rather relevant. is only 2–3 years; (iii) older malnourished patients have lower BP and shorter survival; and (iv) the presence of overt or not fully developed heart failure Prevalence or disease may lower BP and survival. The Cox proportional hazard used in some of these studies may be The prevalence of hypertension varies according to the inadequate to correct for all these confounding factors. degree and the cause of renal failure in chronic renal insufficiency (CRI ) or according to the type of dialytic treatment, haemodialysis ( HD) or peritoneal dialysis Pathophysiological basis for management (PD). However, the prevalence of hypertension is much greater in the CRI population (60–100%) than in the In these clinical conditions, it is still not known if general population. With the remarkable exception of hypertension is caused by inappropriate secretion of Tassin, France, where >90% of patients achieve norm- renin for the status of body sodium and water, or if otension without anti-hypertensive medication [2], the other renal or extra-renal factors are involved. A control of hypertension in HD patients is rather poor correct answer to this question is crucial not only for despite administration of anti-hypertensive drugs. This the understanding of the pathogenesis of hypertension poor control has also been documented with 24 h but also for a correct therapeutical approach. ambulatory blood pressure (BP) monitoring where a There are close interrelationships among the various feedback loops regulating BP (renal, hormonal, haemo

Tratamiento farmacológico de la hipertensión arterial en pediatría

There are a great number of drugs available in the market for the treatment of arterial hypertension. New drugs whose effectiveness and toxicity are studied only in adults, are introduced, and so their efficacy, safety and effect on growth and development in children are not known. Hypertension in paedriatrics is usually due to renal causes. Choice of treatment will depend on the etiology, degree of hypertension and organ involvement as well as the physician´s experience. This article outlines step by step the usual treatment of hypertension in children and some special cases, such as hypertensive emergencies requiring admission to an ITU as well as newborn hypertension, which is being diagnosed with increasing frequency, and hypertension in chronic renal failure that require careful dose adjustments depending on renal function and in which careful management can prevent or retard further renal deterioration.

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-1beta.

Erythropoietin does not affect nitric oxide system in rats with chronic renal failure.

We investigated to see whether an altered role of nitric oxide (NO) system is involved in erythropoietin (EPO)-induced hypertension in chronic renal failure (CRF). Male Sprague-Dawley rats were five-sixths nephrectomized to induce CRF. Six weeks after the operation, EPO or vehicle was injected for another 6 weeks. Plasma and urine nitrite/nitrate (NOx) levels were determined. Expression of NO synthase (NOS) proteins in the aortae and kidneys were also determined. In addition, the isometric tension of isolated aorta in response to acetylcholine and nitroprusside was examined. Blood pressure progressively rose in CRF groups, the degree of which was augmented by EPO treatment. Plasma NOx levels did not differ among the groups, while urine NOx levels were lower in CRF groups. Endothelial NOS expression was lower in the kidney and aorta in CRF rats, which was not further affected by EPO-treatment. The inducible NOS expression in the kidney and aorta was not different among the groups. Acetylcholine and sodium nitroprusside caused dose-dependent relaxations of aortic rings, the degree of which was not altered by EPO-treatment. Taken together, EPO-treatment aggravates hypertension in CRF, but altered role of NO system may not be involved.

Nitric Oxide and Endothelin-1 in Chronic Renal Failure

Nitric oxide (NO) and endothelin-1 (ET-1) are two substances that take part in the regulation of vascular smooth muscle tone. ET-1 is a vasoconstrictor peptide and NO is a vasodilating molecule. There have been contradictory reports of the plasma levels of these substances in patients with chronic renal failure (CRF). We studied plasma levels of ET-1 and NO in hypertensive and normotensive patients with CRF either on dialysis or on non-dialysis treatment. A total of 41 patients were studied, 23 males and 18 females with mean age of 50.39±14.46 years. The control group consisted of healthy subjects (22 males and 8 females) with a mean age of 46.50±8.21 years. The plasma levels of ET-1 were significantly higher and NO levels were lower in the CRF patients than in controls (p<0.05). The plasma levels of NO were lower in patients hypertensive CRF than in normotensive CRF patients (p<0.05). Plasma ET-1 levels, however, did not show any difference (p<0.05). However, plasma NO levels were lower in patients on haemodialysis than in patients on non-dialysis conservative treatment (p<0.01). Except for the negative correlation between the plasma NO and creatinine levels (p<0.01), there were not any relationship between the plasma NO and ET-1 levels, renal function tests (BUN, creatinine), duration of disease and haemodialysis. We concluded that hypertension in CRF has a multifactorial aetiology and that decrease of NO levels, and disturbance of the balance between NO and ET-1 levels might be more important than the above factors alone.

Hypertension in the ESRD patient: pathophysiology, therapy, outcomes, and future directions.

Cardiovascular disease remains the leading cause of death in the end-stage renal disease (ESRD), chronic renal failure, and transplant patient population. The majority of dialysis patients begin renal replacement therapy with a disproportionate cardiovascular disease risk factor burden, eg, premature atherosclerosis, hypertensive vascular disease, nonhypertensive left ventricular dysfunction, hyperlipidemia, age, and so on. Each of these accelerates the other. This report will review hypertension in the ESRD patient population. The Joint Clinical Practices Committee of the Renal Physicians Association and the American Society of Nephrology was asked to develop an evidence-based clinical practice guideline for the treatment of hypertension in chronic renal failure and the ESRD patient, to be presented to the Health Care Financing Administration (HCFA). The group was also asked to identify areas for future study and prepare an up-to-date bibliography in the field. Based on an in-depth review of the literature, the committee concluded that not enough data were available to submit an evidence-based clinical practice guideline. Thus, a treatment algorithm was not provided to the HCFA. This manuscript, based on the scientific data for the report to the HCFA, is an in-depth review of the literature on hypertension in the ESRD patient. Pathogenesis, relation to outcome, clinical therapeutic guidelines, and areas for future study are discussed. In addition, the separate exhaustive bibliography (obtainable from the National Kidney Foundation) for hypertension, renal disease, and dialysis should be a valuable resource to all nephrologists interested in clinical practice and research.

Intracelluiar Free Magnesium Concentrations in Skeletal Muscle in Chronic Uraemia

Low intracellular free magnesium concentrations ([Mg2+]i) are associated with essential hypertension and may reflect a disordered cellular ionic environment. 31P magnetic resonance spectroscopy was used to study skeletal muscle [Mg2+]i in a group of chronic renal failure (CRF) patients and data were compared with a group of control subjects of similar age. Other data including the patients' blood pressure, medication and plasma biochemistry were collected. There was a significant inverse correlation of [Mg2+]i with systolic (p < 0.001) and diastolic blood pressure (p < 0.05) in the CRF population. In CRF [Mg2+]i was similar (0.52 +/- 0.01 mM, SEM) to controls (0.53 +/- 0.01 mM; p = 0.20), even if just the normotensive patients and controls were compared. There was no correlation of [Mg2+]i with plasma parathyroid hormone, total [Mg2+] or [Ca2+]. Similar to studies in subjects with essential hypertension, these data support a role for [Mg2+]i specifically, and an abnormal intracellular environment more generally, in the pathophysiology of hypertension in CRF.

Time-dependent effect of isradipine on the nocturnal hypertension in chronic renal failure

Nocturnal hypertension is frequently observed in chronic renal failure and contributes to the risk of target organ damages. We assessed whether antihypertensive therapy may restore a nocturnal blood pressure (BP) fall in this condition. A sustained-release oral formulation (SRO) of isradipine was used, and the possible differences in the response to morning nu evening dosing were also investigated. Sixteen hypertensive patients with chronic renal failure due to parenchymal kidney disease were studied after 2 weeks of single-blind placebo runin. According to the double-blind, randomized, cross-over design, they received 5 mg isradipine SRO at 08:00, or at 20:00 for 4 weeks, separated by a single-blind placebo period of 2 weeks. A 24-h BP monitoring at 10-min intervals was carried out at the end of each treatment using a SpaceLabs 90207 instrument. Under placebo, blunt BP profiles were observed, whereas HR showed a mean nocturnal fall of 17.4%, which remained unaltered after isradipine. Both isradipine treatments were equally effective in reducing the mean 24-h BP levels. However, the evening regimen showed a more pronounced effect during the night. The mean nocturnal fall in systolic/diastolic BP represented 4.8/8.7% and 7.5/10.9% of the corresponding daytime mean after morning and evening dosing, respectively. Only the evening administration reset the normal synchronization of the 24-h BP and HR profiles. Our findings demonstrate that antihypertensive treatment may restore a nocturnal BP fall in renal patients. An evening regimen of isradipine SRO seems more apt than a morning regimen to obtain this therapeutic goal.

Twenty-four hour monitoring of blood pressure and heart rate in patients with chronic renal failure or renal transplant recipients: analysis by the cosinor method.

Hypertension is a major problem of patients with chronic renal failure or renal transplant recipients. To clarify the characteristics of blood pressure, heart rate, and circadian rhythms of these patients we used an ambulatory blood pressure monitor (ABPM) for 24 h monitoring and analyzed the data by the cosinor method. In eight chronic renal failure patients without dialysis the midline estimating statistic of rhythm (MESOR) of diastolic blood pressure was higher than in controls, but the MESOR of systolic blood pressure was not. Of 11 patients on dialysis some had hypertension and some had hypotension. In 14 renal transplant recipients, especially those with chronic graft rejection, the MESOR of systolic and diastolic pressures were higher than controls, and the increase of blood pressure MESOR had a significant correlation with the elevation of serum creatinine levels. Circadian rhythms of blood pressure were frequently absent in the patients on dialysis, but circadian rhythms of heart rate were not. The use of an ABPM is a non-invasive method to monitor patients and allowed us to know changes of blood pressure and heart rate in the daytime as well as during the night. For the control of hypertension in chronic renal failure, monitoring with an ABPM seems to provide invaluable information.

Mechanisms of cortisol-induced hypertension in humans

There is emerging evidence that cortisol plays a significantly greater role in human hypertension than previously thought. Apart from the well recognized role of cortisol in the hypertension of Cushing's syndrome, local cortisol excess has been recognized as responsible for rare forms of hypertension such as apparent mineralocorticoid excess and licorice abuse and more recently implicated in the hypertension of chronic renal failure, hypertension related to low birth weight and essential hypertension. Although cortisol-induced hypertension is characterized by sodium retention and volume expansion, studies with synthetic glucocorticoids or sodium restriction suggest that the hypertension is, to a substantial degree, independent of sodium and volume. Increase in cardiac output is not essential for cortisol-induced blood pressure rise but the precise role of increases in total or regional peripheral resistance as a primary mechanism has not been determined. Increased pressor responsiveness, particularly to catechols, is a prominent feature but whether these changes are sufficient to account for the hypertension remains unclear. There is no evidence for increased sympathetic nervous activity as judged by measurements of plasma catcholamines, neuropeptide-Y, or resting noradrenaline spillover rate. Responses to mental stress or maximal hand-grip are unchanged and baroreflex sensitivity is increased. Octreotide profoundly reduced the elevated plasma insulin concentrations seen with cortisol administration but had no effect on the rise in blood pressure.

Tiny Tim, Dickens, renal disease, and rickets.

Sir.—It is fitting that Lewis proposes that Charles Dickens' Tiny Tim was afflicted with renal disease,1since a number of Dickensian characters have autobiographical attributes. Charles Dickens was reported to suffer much of his life from renal colic and may have died of kidney failure.2The fact that he had strokes at a relatively young age suggests he also may have had the attendant hypertension of chronic renal failure. In addition, John Dickens, Charles' father, suffered from a form of kidney disease since his death was related to the removal of a bladder stone.2 Lewis speculates that Tiny Tim could have had distal RTA type 1, citing Dickens' descriptions of Tim's symptoms and considering the potential treatability of such an illness in 19th-century England. Other writers have suggested that poor Tim may have suffered from polio, tuberculosis of the hip, or pseudocoxalgia.3While it is