endothelin-1 and Kidney-Failure--Chronic

The concept of reversing chronic kidney disease (CKD) has been intensively researched over the past decade. Indeed, as the prevalence of end-stage renal disease is constantly on the rise, the lack of established antifibrotic therapies is a considerable unmet need in clinical practice. Now, the possibility of effective antifibrotic treatment has been established in experimental models of CKD and multiple antifibrotic compounds-in kidney disease, as well as in fibrotic diseases of the skin, liver and lung-are being assessed in clinical trials. These strategies target various components of the fibrotic pathway, from signalling molecules that include transforming growth factor-β, phosphatidylinositide 3-kinase and chemokines to microRNAs. Here, we discuss therapeutic concepts to inhibit or even reverse chronic kidney injury and review the leading candidate antifibrotic drugs to be introduced to clinical use.

Topics: Anti-Inflammatory Agents; Bone Morphogenetic Protein 7; Connective Tissue Growth Factor; Disease Progression; Endothelin-1; Epigenesis, Genetic; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Microcirculation; Phosphodiesterase Inhibitors; Pyridones; Transforming Growth Factor beta

Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment. However the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade. Infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.

Topics: Animals; Clinical Trials as Topic; Diabetic Nephropathies; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Isoxazoles; Kidney Failure, Chronic; Pyridines; Pyrimidines; Renal Dialysis; Renal Insufficiency, Chronic; Thiophenes; Treatment Outcome

Treatment of chronic kidney disease (CKD) can slow its progression to end-stage renal disease (ESRD). However, the therapies remain limited. Blood pressure control using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) has the greatest weight of evidence. Glycemic control in diabetes seems likely to retard progression. Several metabolic disturbances of CKD may prove to be useful therapeutic targets but have been insufficiently tested. These include acidosis, hyperphosphatemia, and vitamin D deficiency. Drugs aimed at other potentially damaging systems and processes, including endothelin, fibrosis, oxidation, and advanced glycation end products, are at various stages of development. In addition to the paucity of proven effective therapies, the incomplete application of existing treatments, the education of patients about their disease, and the transition to ESRD care remain major practical barriers to better outcomes.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Diabetes Mellitus, Type 2; Disease Progression; Endothelin-1; Humans; Hypertension; Kidney Failure, Chronic; Oleanolic Acid; Pyridones; Renal Insufficiency, Chronic; Renin-Angiotensin System

Chronic kidney diseases are increasing worldwide at an alarming rate, and they are emerging as a major public health problem. Treatments that slow the progression of chronic kidney disease are needed. Endothelin-1 (ET-1) is a potent vasoconstrictor with proinflammatory, mitogenic and profibrotic effects that is closely involved in both normal renal physiology and pathology. Increasing evidence suggests that ET-1 and its cognate receptors are involved in a variety of progressive renal disorders to the extent that renal ET-1 expression correlates with disease severity and renal function impairment. Endothelin receptor antagonists have been used in renoprotection studies owing to their capacity of improving renal hemodynamics and reducing proteinuria. Whether selective ET(A) or non-selective ET(A)/ET(B) receptor antagonists are preferable is still a matter of debate. As angiotensin II blockers are not invariably effective in retarding disease progression when treatment is started late in the course of the disease, it is foreseeable that an ET-1 antagonist in addition to angiotensin-converting enzyme inhibitors could represent a combined treatment for progressive nephropathies. The focus of this review is to examine the role endothelin-1 plays in kidney diseases and to determine the ideal setting for antagonizing its biological activity in chronic nephropathies.

Topics: Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Humans; Kidney Failure, Chronic; Rats; Receptors, Endothelin; Renin-Angiotensin System

Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ET(A) and ET(B). In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ET(A) receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ET(A) receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ET(B) receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.

Topics: Animals; Antihypertensive Agents; Diabetic Nephropathies; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Evidence-Based Medicine; Humans; Kidney Failure, Chronic; Receptors, Endothelin

Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.

Topics: Anemia; Animals; Blood Platelets; Blood Pressure; Causality; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Drug Overdose; Endothelin-1; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Morbidity; Nitric Oxide; Oxidative Stress

End-stage renal disease patients receiving chronic haemodialysis via arteriovenous access often develop various cardiovascular complications, including vascular calcification, cardiac-vascular calcification and atherosclerotic coronary disease. This review describes recently published studies that demonstrate a high incidence of pulmonary hypertension among patients with end-stage renal disease receiving long-term haemodialysis via a surgical arteriovenous fistula. Both end-stage renal disease and long-term haemodialysis via arteriovenous fistula may be involved in the pathogenesis of pulmonary hypertension by affecting pulmonary vascular resistance and cardiac output.. Morbidity and mortality from cardiovascular disease are greatly increased in patients on maintenance haemodialysis therapy. Using Doppler echocardiography, we found a significant increase in cardiac output in 40% of chronic haemodialysis patients, probably related to the large arteriovenous access or altered vascular resistance as a result of the local vascular tone and function expressed by the imbalance between vasodilators such as nitric oxide, and vasoconstrictors such as endothelin-1.. We propose different potential mechanisms as explanations for the development of pulmonary hypertension. Hormonal and metabolic derangement associated with end-stage renal disease might lead to pulmonary arterial vasoconstriction and an increase in pulmonary vascular resistance. Pulmonary arterial pressure may be further increased by high cardiac output resulting from the arteriole-venous access itself, worsened by commonly occurring anaemia and fluid overload.

Topics: Adult; Aged; Blood Pressure; Calcinosis; Cardiac Output; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Pulmonary Artery; Renal Dialysis; Time Factors; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

The global epidemic of diabetes mellitus has led to a continuous increase in the prevalence of diabetic nephropathy over the past years. Thus, diabetic nephropathy is currently the number one cause of end-stage renal disease in the Western world. It represents a major public health problem for which more effective prevention and treatment strategies are needed. Thiazolidinediones (TZDs) are a class of agents that lower blood glucose through reduction of insulin resistance in patients with type 2 diabetes. Growing evidence support the concept that TZDs have several beneficial effects on the cardiovascular system beyond their effects on glycemic control. These benefits include: blood pressure lowering, triglyceride reduction, high-density lipoprotein-cholesterol elevation, and reduction in subclinical vascular inflammation. Moreover, data from several animal and human studies support the notion that TZDs reduce urine albumin excretion and may prevent development of renal injury. The relative lack of evidence, however, demonstrating the effects of TZDs on hard renal outcomes mandates the need for well-designed trials with this particular objective. This paper summarizes all the data from clinical and experimental studies relevant to a possible renoprotective effect of TZDs and discusses actions of these compounds that may contribute toward this effect.

Topics: Albuminuria; Animals; Blood Pressure; Chromans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Humans; Hypoglycemic Agents; Kidney; Kidney Failure, Chronic; Pioglitazone; PPAR gamma; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Factors; Rosiglitazone; Thiazolidinediones; Time Factors; Troglitazone

Endothelin (ET)-1 is a potent vasoconstrictor with profibrotic and proinflammatory effects. Increasing evidence suggests that ET-1 and its cognate receptors are involved in a variety of progressive renal disorders, including diabetes, hypertension and glomerulonephritis. Several laboratory studies have demonstrated elevated expression of ET-1, which colocalizes with glomerular and tubulointerstitial injury, in addition to enhanced urinary excretion. Moreover, ET-1 expression correlates with disease severity and renal function. With the availability of ET receptor antagonists, a pathogenetic role has been further corroborated in animal models, demonstrating both structural and functional improvement. Thus, antagonizing the ET system may be useful in major renal pathologies associated with glomerular and tubulointerstitial damage.

Topics: Endothelin-1; Fibrosis; Humans; Kidney Failure, Chronic; Receptors, Endothelin

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension; Kidney Failure, Chronic; Receptors, Endothelin

Chronic renal failure (CRF) is associated with hypertension, endothelial dysfunction, and a strong propensity for arteriosclerotic cardiovascular disease. Nitric oxide (NO) is an endogenous modulator with diverse biological functions. Chronic inhibition of NO synthases (NOS) has been shown to cause hypertension and vasculopathy. In light of these considerations, numerous studies have explored the effect of CRF on NO metabolism with the assumption that NO deficiency may be involved in the pathogenesis of cardiovascular and other consequences of uremia. The purpose of this review is to provide a brief overview of the effect of CRF on (1) the bioavailability of NO substrate, L-arginine; (2) the expression of NOS isoforms in the relevant organs; (3) the interaction of NO with reactive oxygen species that are known to be increased in CRF, and (4) the accumulation of uremic inhibitors of NOS.

Topics: Animals; Arginine; Arteries; Biological Availability; Brain; Down-Regulation; Endothelin-1; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Protein Isoforms; Reactive Oxygen Species; Up-Regulation

Topics: Animals; Diabetic Nephropathies; Endothelin-1; Humans; Kidney Failure, Chronic; Reactive Oxygen Species

Chronic renal failure is a self-perpetuating, progressive disease leading to end-stage renal failure, even if primary insult to the kidneys was removed. Progressive course of disease is caused by chronic interstitial inflammation leading to fibrosis, tubular atrophy, and glomerular sclerosis. Main predictive risk factors of the disease progression include: proteinuria, systemic and glomerular hypertension. It is presumed that in most cases progressive course of the disease is related to genetic predisposition to greater activity of renin-angiotensin system. Among attempts to slow progressive course of the disease effective are interventions acting on renin-angiotensin system, endothelin 1 and on profibrotic cytokines. Role of dietary factors and potential treatment modalities are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Humans; Kidney; Kidney Failure, Chronic

Topics: Acute Kidney Injury; Angiotensin II; Animals; Endothelin-1; Endothelins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Nitric Oxide

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Hemodynamics; Humans; Kidney Failure, Chronic; Metalloendopeptidases; Renin-Angiotensin System

Hemodialysis (HD) patients have altered pulmonary function and this is associated with impaired endothelial function and cardiovascular events. Respiratory muscle training (RMT) has the potential to improve cardiovascular outcomes in patients undergoing maintenance HD. Here, we evaluated the effects of RMT on endothelium/glycocalyx, oxidative stress biomarkers and pulmonary function test in HD patients.. This is a randomized controlled clinical trial including 41 patients undergoing thrice-weekly maintenance HD. Patients were randomly assigned at a 2:1 ratio to receive or not RMT during HD sessions for 8 weeks. Main outcomes were changes in levels of the biomarkers related to endothelium activation (vascular cell adhesion molecule 1, VCAM-1, and intercellular adhesion molecule 1, ICAM-1), glycocalyx derangement (syndecan-1), aberrant angiogenesis (angiopoietin-2) and oxidative stress (malondialdehyde) compared to baseline. Also, maximal inspiratory/expiratory pressure (MIP, MEP), Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were evaluated. Other outcomes included changes in functional capacity and pulmonary function test. We also performed a post-hoc analysis of plasma endothelin-1 levels.. Of 56 randomly assigned patients, 41 were included in the primary final analyses. RMT increased all pulmonary function parameters evaluated and significantly reduced plasma syndecan-1 levels at 8 weeks compared to placebo (between-group difference: -84.5; 95% CI, -148.1 to -20.9). Also, there was a reduction in plasma levels of angiopoietin-2 (between-group difference: -0.48; 95% CI, -1.03 to -0.097). Moreover, there was a significant reduction in mean blood pressure at rest (between-group difference: -12.2; 95%CI, -17.8 to -6.6) associated with a reduction in endothelin-1 levels (between-group difference: -0.164; 95% CI, -0.293 to -0.034). There was no difference regarding biomarkers of endothelial activation or oxidative stress.. A short-term RMT program ameliorate FVC, FEV1 and reduces syndecan-1 and angiopoietin-2 biomarker levels. Finally, better blood pressure control was attained during training and it was associated with a reduction in endothelin-1 levels.

Topics: Adult; Biomarkers; Blood Pressure; Breathing Exercises; Endothelin-1; Endothelium; Female; Forced Expiratory Volume; Glycocalyx; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Renal Dialysis; Respiratory Function Tests; Respiratory Mechanics; Respiratory Muscles; Treatment Outcome; Vital Capacity

Blocking the renin-angiotensin system (RAS) with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors protects against renal injury in patients with chronic kidney disease (CKD). The aim of this study was to compare the chronic effects of telmisartan and enalapril on proteinuria, urinary liver-type fatty acid-binding protein (L-FABP) and endothelin (ET)-1 levels in patients with mild CKD.. Thirty CKD patients with mild to moderate renal insufficiency (20 men and 10 women; mean age, 37 years; estimated glomerular filtration rate (eGFR) > 60 mL min(-1) and blood pressure > 130/85 mmHg) were included in the study. Patients were randomly assigned to receive telmisartan at 80 mg day(-1) (n = 15) or enalapril at 10 mg day(-1) (n = 15). We measured blood pressure, serum creatinine, eGFR, urinary protein, L-FABP and ET-1 before the start of treatment and 6 and 12 months after the start of treatment.. The blood pressure reduction rate was similar between the two groups. Urinary protein, L-FABP and ET-1 levels were significantly reduced in both groups 6 and 12 months (P < 0.001) after treatment, but the reduction rates were more pronounced in patients receiving telmisartan than in those receiving enalapril (P < 0.001). Estimated glomerular filtration rate was increased similarly in both groups at 12 months.. The study results suggest that telmisartan results in a greater reduction of urinary markers than does enalapril and that this effect occurs by a mechanism independent of blood pressure reduction. It would be needed to investigate whether the differences may be distinct or not the same when other dosages are used.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Creatinine; Enalapril; Endothelin-1; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Proteinuria; Telmisartan

Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: -7+/-1%; P<0.001 versus placebo) and increased renal blood flow (17+/-4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (-26+/-4%; P<0.01 versus placebo) and pulse wave velocity (-5+/-1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (-38+/-3% versus 26+/-11%; P<0.001) and pulse wave velocity (-9+/-1% versus -3+/-1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

Topics: Adult; Aged; Antihypertensive Agents; Arteries; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Kidney Failure, Chronic; Middle Aged; Nifedipine; Peptides, Cyclic; Proteinuria; Renal Circulation; Sodium; Treatment Outcome

Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy.. Randomized, double-blind, placebo-controlled trial.. Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months.. In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group.. Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.

Topics: Ankle; Branchial Region; Carnitine; Double-Blind Method; Endothelin-1; Homocysteine; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Peripheral Vascular Diseases; Placebos; Renal Dialysis

Steal syndrome is a well-known complication of arteriovenous shunt placement. Increased frequency of Raynaud's phenomenon (RP) especially concerning shunt limb is reported among hemodialysis (HD) patients. The aim of the study was to assess the relation of impairment of peripheral circulation diagnosed with cold stress test (CST) and thermography to the AV shunt location and markers of endothelial dysfunction in HD patients.. The study group comprised 21 patients (6 male, 15 female, mean age 32.6 +/- 15.0 years) treated with HD for a mean of 69 +/- 54 months. 10 healthy individuals (4 male, 6 female, mean age 38.6 +/- 14.7 years) served as controls. The diagnosis of RP was made upon the results of thermographic measurements during CST. Von Willebrand factor activity and antigen, endothelin-1 and plasma total homocysteine (tHcy) were measured in all subjects.. RP was found significantly more often in HD patients than in controls: 11/21 vs. 1/10 (p = 0.04). RP occurred in both hands in 7/11 (64%) patients. tHcy was higher in HD patients than in the controls (31.7 +/- 13.9 vs. 10.9 +/- 3.2 microg/l, p < 0.0001). tHcy and von Willebrand factor antigen were significantly higher in the RP-positive than RP-negative patients or controls.. Small vessel dysfunction diagnosed as positive RP is a frequent finding in HD patients. It seems that endothelial injury rather than AV shunt steal syndrome is responsible for development of RP in HD patients.

Topics: Adolescent; Adult; Endothelin-1; Endothelium, Vascular; Female; Hand; Homocysteine; Humans; Kidney Failure, Chronic; Male; Middle Aged; Raynaud Disease; Renal Dialysis; von Willebrand Factor

Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.. We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4+/-2%, CRF -13+/-2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8+/-23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5+/-11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.. ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

Topics: Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Proteinuria; Renal Circulation; Sodium

Recombinant human erythropoietin (rHuEPO) has been reported to induce hypertension. We investigated the effect of a single injection of rHuEPO on blood pressure in patients receiving hemodialysis (HD) and in patients with predialysis chronic renal failure (CRF). Forty-one patients receiving HD and 36 patients with predialysis CRF received an intravenous injection of rHuEPO, and blood pressure and plasma endothelin-1 were measured before and 30 min after the injection. Mean blood pressure was increased significantly in HD patients, but not in CRF patients (HD: 103+/-5 to 105+/-6 mmHg, p<0.05; CRF: 103+/-4 to 103+/-6, NS). The percentage of patients with increased mean blood pressure of more than 10 mmHg after rHuEPO injection was significantly larger in the HD than in the CRF group (27.0% vs. 5.5%, p<0.01). A positive correlation was found between changes in endothelin-1 level and mean blood pressure in the HD (r=0.43, p<0.01) but not in predialysis chronic renal failure. In conclusion, a single injection of rHuEPO increased blood pressure with a positive correlation with endothelin-1 release in hemodialysis patients, but not in predialysis chronic renal failure patients.

Topics: Adult; Aged; Anemia; Blood Pressure; Endothelin-1; Erythropoietin; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

The hemodynamic significance of elevated endothelin-1 (ET) plasma levels in hemodialysis (HD) patients is unknown. Therefore, we studied the role of ET in the regulation of vascular tone in normotensive HD patients and matched healthy controls (C).. The forearm blood flow (FBF) responses to adenosine, norepinephrine, the ET-A receptor antagonist BQ-123 (40 nmol/min), the ET-B receptor antagonist BQ-788 (1 and 50 nmol/min), and ET (5 pmol/min) were measured. Results are percent of baseline change +/- SEM (baseline = 100%).. Responses to adenosine and norepinephrine were both unchanged in HD. In HD, BQ-123 increased FBF less than in C (133 +/- 9 vs. 178 +/- 27%; P = 0.02). BQ-788 failed to change FBF in C but decreased FBF to 83 +/- 4% in HD. Compared to BQ-123 alone, BQ-123 plus BQ-788 (50 nmol/min) caused an additional increase of FBF (234 +/- 32%, P < 0.001) in C, but not in HD (139 +/- 14%). This additional increase was absent when BQ-788 was co-infused at 1 nmol/min. ET reduced FBF comparably in both groups.. Resistance vessels of HD patients have unremarkable contractile properties, as shown by responses to adenosine and norepinephrine. In HD, the basal vascular ET-mediated tone is reduced. The main action of the ET-B receptor in C is vasoconstrictive, which also is blunted in HD. The intact response to exogenous ET indicates the normal function of ET receptors in HD. Our results could be explained by a reduced generation or reduced metabolic clearance rate of ET in normotensive HD patients. Controversy remains concerning the role of the ET-B receptor when comparing the present data with previously published literature.

Topics: Adenosine; Adult; Antihypertensive Agents; Blood Pressure; Brachial Artery; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Renal Dialysis; Vasoconstrictor Agents; Vasodilator Agents

Elevated plasma endothelin-1 (ET-1) was found in end-stage renal failure (ESRF). However, there are discordant reports on the influence of hypertension on plasma ET-1 in ESRF and on the effect of hemodialysis on ET-1 concentrations.. To compare the time course of plasma ET-1 during hemodialysis in hypertensive (HT) and normotensive (NT) ESRF patients.. Plasma ET-1 and mean blood pressure (MP) were measured in 12 HT patients and 11 matched NT patients on maintenance hemodialysis at baseline (B), after a 2.5-3.5 h hemodialysis with ultrafiltration (P1) and after a subsequent 1 h isovolumic dialysis (P2).. In HT patients, plasma ET-1 increased at P1 with no further change after P2 (B vs. P1 and P2, p < 0.05). In NT patients, ET-1 levels were similar at B, P1 and P2. In HT, but not in NT subjects, volume loss correlated with change of ET-1 at P1. In HT patients, MP fell during P1 and tended to return towards baseline at P2. In NT patients, MP dropped after P1 and remained lower also at P2.. Hypertensive ESRF subjects exhibit potentiated ET-1 release on hemodialysis, possibly stimulated by volume depletion with sympathetic activation, which may attenuate hypotensive hemodialysis effects thus contributing to hypertension in ESRF.

Topics: Adult; Blood Pressure; Endothelin-1; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Ultrafiltration

Endothelin-1 generated by the vascular endothelium contributes to basal vascular tone and blood pressure in healthy humans. Plasma concentrations of endothelin-1, which are elevated in chronic renal failure (CRF), may contribute to increased vascular tone.. We investigated the contribution of endogenous and exogenous endothelin-1 to the maintenance of vascular tone in patients with CRF (creatinine > or = 200 mumol/liter) and in age- and sex-matched healthy subjects. In a series of experiments, we measured forearm vascular responses to intra-arterial norepinephrine (30 to 240 pmol/min), endothelin-1 (5 pmol/min), the selective endothelin A (ETA) receptor antagonist BQ-123 (3 mg/hr), the mixed endothelin-converting enzyme and neutral endopeptidase inhibitor phosphoramidon (30 nmol/min), and the selective neutral endopeptidase inhibitor thiorphan (30 nmol/min).. The maximum reduction in forearm blood flow (FBF) to norepinephrine in CRF (33 +/- 7%) was similar to that in controls (43 +/- 7%, P = 0.53). Endothelin-1 also produced a similar reduction in FBF in CRF (35 +/- 6%) and controls (36 +/- 5%, P = 0.81). BQ-123 increased FBF in CRF (11 +/- 4%) but significantly less than in controls (44 +/- 10%, P = 0.02). Phosphoramidon increased FBF in CRF (68 +/- 20%), again significantly less than in controls (181 +/- 41%, P = 0.001). Thiorphan reduced FBF similarly in CRF (22 +/- 6%) and controls (14 +/- 6%, P = 0.39). Responses to phosphoramidon were substantially greater than to BQ-123.. These studies show that endogenous generation of endothelin-1 contributes to the maintenance of resting vascular tone in patients with CRF, as well as in healthy subjects. Although the contribution of endogenous endothelin-1 to resting vascular tone appears to be reduced in CRF, ETA receptor antagonism, and particularly endothelin-converting enzyme inhibition, should be explored as means by which to reduce vascular tone and blood pressure in patients with CRF.

Topics: Adult; Endothelin Receptor Antagonists; Endothelin-1; Female; Forearm; Glycopeptides; Humans; Injections, Intra-Arterial; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Peptides, Cyclic; Protease Inhibitors; Receptor, Endothelin A; Regional Blood Flow; Thiorphan; Vasomotor System

Indexes of myocardial ischemia and vasoconstrictive hormonal release were evaluated in order to investigate the difference between essential hypertension and hypertension during chronic renal failure.. Arterial hypertension induces several cardiovascular alterations that reflect themselves either on the heart and/or on the coronary blood flow enhancing the cardiovascular risk. Since chronic renal failure can influence the neuroendocrine response, various mechanisms involved in hypertension during chronic renal failure are still unclear. High endothelin 1 (ET-1) levels have been found both in arterial hypertension and during chronic renal failure. Interestingly, either ET-1 or catecholamines seem also to be implied in the pathogenesis of myocardial ischemia.. 20 hypertensive uremic and 20 essentially hypertensive patients underwent echocardiographic wall motion and wall thickening analysis performed at baseline and immediately after the end of exercise. Simultaneously, myocardial perfusion was evaluated by 99mTc-MIBI-SPECT. In addition, plasma norepinephrine and ET-1 concentrations were measured at baseline and at peak exercise.. The segmental radionuclide analysis showed a greater ischemic degree in hypertensive uremic patients. Yet, we were able to identify one or more regions of the left ventricle in which both systolic thickening measurements and wall motion after exercise were impaired. After exercise, wall thickening impairment was correlated with both wall motion abnormalities (r = 0.72, p < 0.01) and MIBI ischemic grade (r = 0.82, p < 0.001). Basal and after-exercise plasmatic norepinephrine and endothelin levels were higher in hypertensive uremic than in essentially hypertensive patients. Moreover, there was a significant correlation between increments in norepinephrine concentration and MIBI perfusion defects, and between the increment in ET-1 concentration and both MIBI perfusion defects, or kinetic alterations assessed by wall motion as well as by wall thickening.. This is the first cross-sectional study in which a higher degree of myocardial ischemia has been observed in hypertensive uremic patients combined with an enhanced plasma release of both norepinephrine and ET-1. This phenomenon may contribute to enhance the cardiovascular risk of these patients.

Topics: Aged; Cross-Sectional Studies; Echocardiography; Endothelin-1; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Image Interpretation, Computer-Assisted; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Tomography, Emission-Computed, Single-Photon

Topics: Adolescent; Child; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Renal Dialysis

This study was carried out to investigate the impact of duration of different renal replacement therapies such as hemodialysis and continuous ambulatory peritoneal dialysis on potential overproduction of endothelin-1 (ET-1) and pulmonary function tests in these patients.. The study included 26 patients (14 males, mean age 54.9±16.2 years) with end stage renal diseases (ESRD) receiving regular hemodialysis (HD) and 23 patients (10 males, mean age 55.8±15.8 years) with ESRD treated with continuous ambulatory peritoneal dialysis (CAPD). The spirometry values were recorded before the onset of HD and prior to emptying the peritoneal cavity in CAPD patients and ET-1 was measured using the enzyme immunoassay (EIA) methodology. Two groups of patients (groups 1 and 2) were further divided into subgroups (group A and group B). Groups A (1-A and 2-A) included patients treated with any type of renal replacement therapy (RRT) (HD or CAPD) less than 5 years, and groups B (1-B and 2-B) included patients treated with any type of RRT (HD or CAPD) longer than 5 years.. Patients treated with HD or CAPD for more than five years were found to have significantly higher serum levels of ET-1 (HD = 41.49±21.28 vs. 185.13±73.67, p<0.01; PD = 51.24±32.11 vs. 139.53±42.42, p<0.01, respectively). Values of most pulmonary function parameters differed significantly between groups treated longer or shorter than 5 years: FVC (HD = 108.4±13.34 vs. 80.82±11.26, p<0.01; CAPD = 97.20±18.99 vs. 73.25±10.73, p<0.01, respectively), FEV1 (HD = 108.33±15.8 vs. 76.73±4.9, p<0.01; CAPD = 100.67±18.31 vs. 66.75±6.25, p<0.01, respectively).. Prolonged duration of any type of renal replacement therapy is associated with higher serum levels of ET-1 and with lower pulmonary function tests in ESRD patients.

Topics: Adult; Aged; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Renal Replacement Therapy; Spirometry

Intradialytic hypertension (IDH) is a major problem of hemodialysis and it is a multifactorial disorder and need early identification and management.. Evaluate the serum concentration of endothelin-1 in patients with IDH and healthy control and the impact of pre-pro-endothelin gene polymorphism on level of endothelin-1 and susceptibility to IDH in Egyptian population.. The patient groups divided into group I, End stage renal disease (ESRD) on chronic hemodialysis with IDH (112); group II, ESRD on chronic hemodialysis without IDH (112); group III, healthy control (112). All undergone to full history, clinical examination, routine laboratory investigations, echocardiography, serum ET-1 level by ELISA and A(8002)G polymorphism detection in pre-pro-endothelin gene by PCR-RFLP.. Our results showed significantly higher concentration of Endothelin-1 (ET-1) in both patient groups than healthy control and in group with IDH than cases without IDH (p < 0.001). GG, GA and mutated G allele carry the risk of IDH (OR = 15.94, 13.5, 5.51 respectively p < 0.001). There was association between GG and GA genotypes and higher ET-1 level in both patient groups (p < 0.001) and association between GG and GA genotype and higher mean arterial pressure (MAP), delta MAP (DMAP) and increased left ventricular mass index (LVMI) in both patient groups (p = 0.001, 0.028).. Pre-pro-endothelin gene polymorphism A(8002)G is an independent risk factor for IDH through changing the level of ET-1 concentration in Egyptian population undergoing chronic hemodialysis.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Egypt; Endothelin-1; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Polymorphism, Single Nucleotide; Renal Dialysis; Risk Factors; Young Adult

Hypertension is common in hemodialysis (HD) patients. Increased blood pressure (BP) variability, particularly higher and lower extremes, is associated with adverse outcomes. We explored the association of endothelin-1 (ET-1), a potent vasoconstrictor, with different BP parameters (pre-HD, intra-HD, and post-HD) during HD in a contemporary patient cohort.. This study uses the DaVita Biorepository, a longitudinal prospective cohort study with quarterly collection of clinical data and biospecimens. Unadjusted and adjusted linear mixed effects regression models were fit to determine association of pre-HD ET-1 (log-transformed and quartiles) with HD-related systolic BP (SBP) parameters (pre-HD, nadir intra-HD, and post-HD). As ET-1 was measured at baseline, analyses were restricted to 1 year of follow-up.. Among 769 participants, mean age was 52 years, 42% were females, and 41% were Black. Mean pre-HD SBP was 152 (±28) mm Hg and mean ET-1 concentration was 2.3 (±1.2) ng/ml. In fully adjusted models, each unit increase in SD of log-transformed ET-1 was associated with a 2.7 (95% confidence interval [CI] 1.5, 4.0) mm Hg higher pre-SBP; 1.6 (95% CI 0.9, 2.3) mm Hg higher nadir SBP; and 2.0 (95% CI 1.1, 2.9) mm Hg higher post-SBP. Each SD increase in log-transformed ET-1 was associated with 21% higher odds of experiencing intradialytic hypertension (odds ratio 1.21; 95% CI 1.10-1.34).. Higher baseline ET-1 levels are independently associated with higher SBP and higher odds of intradialytic hypertension. These results highlight a potential role for ET-1 in BP control in HD patients and raise the possibility of ET-1 antagonism as a therapeutic target.

Topics: Blood Pressure; Endothelin-1; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Vasoconstrictor Agents

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.

Topics: Acid-Base Equilibrium; Acidosis; Adaptation, Physiological; Aldosterone; Angiotensin II; Biomarkers; Disease Progression; Endothelin-1; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Prospective Studies; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide implicated in the pathogenesis of hypertension, congestive heart failure, and inflammation, all of which are critical pathophysiologic features of CKD.. To test the hypothesis that plasma endothelin-1 levels are associated with increased risks of mortality and hospitalization in patients with chronic kidney failure, we measured plasma endothelin-1 levels in a prospective cohort of 794 individuals receiving maintenance hemodialysis. The primary outcomes were time to death and time to hospitalization.. The median plasma endothelin-1 level was 2.02 (interquartile range, 1.57-2.71) pg/ml. During a median follow-up period of 28 (interquartile range, 21-29) months, 253 individuals (32%) died and 643 individuals (81%) were hospitalized at least once. In multivariable models adjusted for demographic, clinical, and laboratory variables, individuals in the highest quartile of plasma endothelin-1 had a 2.44-fold higher risk of death (hazard ratio, 2.44; 95% confidence interval, 1.61 to 3.70) and a 1.54-fold higher risk of hospitalization (hazard ratio, 1.54; 95% confidence interval, 1.19 to 1.99) compared with individuals in the lowest quartile. The Harrell. Higher plasma endothelin-1 is associated with adverse clinical events in patients receiving hemodialysis independent of previously described risk factors.. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_05_15_CJN11130919.mp3.

Topics: Aged; Endothelin-1; Female; Follow-Up Studies; Hospitalization; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Risk Factors; Time Factors

Left ventricular hypertrophy (LVH) is a common abnormality in hemodialysis (HD) patients. Mitochondrial dysfunction contributes to the progression of LVH. As an inner mitochondrial membrane structural protein, mitofilin plays a key role in maintaining mitochondrial structure and function. The aim of this study was to investigate the relationship between mitofilin and LVH in HD patients. A total of 98 HD patients and 32 healthy controls were included in the study. Serum N-terminal proBNP (NT-proBNP), endothelin-1 (ET-1), and atrial natriuretic peptide (ANP) were examined. The protein level of mitofilin and the mitochondrial DNA (mtDNA) copy number were estimated in peripheral blood mononuclear cells (PBMCs). The left ventricle mass index (LVMI) was evaluated in all participants, and the interaction between these variables and the LVMI was assessed. The LVMI was positively correlated with the NT-proBNP, ET-1, and ANP levels, and it was negatively correlated with mtDNA copy number and mitofilin levels. Multiple regression analysis showed that the NT-proBNP, ET-1, and ANP levels as well as mitofilin levels and mtDNA copy number were associated with the LVMI. Although further research of these associations is needed, this result suggests that LVH may affect the levels of mitofilin in HD patients.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Cross-Sectional Studies; DNA, Mitochondrial; Echocardiography; Endothelin-1; Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Mitochondrial Proteins; Muscle Proteins; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis; Risk Factors

Evidence points to activation of pro-inflammatory and pro-thrombotic stimuli during the haemodialysis process in end-stage renal disease (ESRD) with potential to predispose to cardiovascular events. Diabetes is associated with a higher incidence of cardiovascular disease in haemodialysis patients. We tested the hypothesis that a range of mediators and markers that modulate cardiovascular risk are elevated in haemodialysis patients with diabetes compared to those without.. Men and women with diabetes (n = 6) and without diabetes (n = 6) aged 18-90 years receiving haemodialysis were recruited. Blood samples were collected and analysed pre- and post-haemodialysis sessions for (platelet-monocyte conjugates (PMC), oxidised LDL (Ox-LDL), endothelin 1 (ET-1) and vascular endothelial growth factor (VEGF-A).. PMC levels significantly increased after haemodialysis in both groups (diabetes p = 0.047; non-diabetes p = 0.005). Baseline VEGF-A was significantly higher in people with diabetes (p = 0.009) and post-dialysis levels were significantly reduced in both groups (P = 0.002). Ox-LDL and CRP concentrations were not significantly different between groups nor affected in either group post-dialysis. Similarly, ET-1 concentrations were comparable in all patients at baseline, with no change post-dialysis in either group.. In this pilot study, we have confirmed that circulating PMCs are increased following dialysis irrespective of diabetes status. This is likely to be a mechanistic process and offers a potential explanation for high rates of vascular events associated with haemodialysis. The higher VEGF-A concentrations between patients with and without diabetes is a previously unreported finding in diabetic ESRD. Further research is merited to establish whether VEGF-A is a marker or mediator (or both) of cardiovascular risk in haemodialysis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Complications; Endothelin-1; Female; Humans; Hypoxia; Kidney Failure, Chronic; Male; Middle Aged; Pilot Projects; Renal Dialysis; Risk; Vascular Endothelial Growth Factor A; Young Adult

Cardiovascular (CV) complications are the main cause of death in end-stage renal disease (ESRD) patients. The high CV risks are attributable to the additive effects of multiple factors. Endothelin (EDN) is a potent vasoconstrictor and plays a role in regulating vascular homeostasis. However, whether variants of the EDN gene are associated with risks of CV events is not known. We conducted a study to investigate associations of variants of the EDN gene with CV events in ESRD patients.. A cohort of 190 ESRD patients was recruited, and 19 tagged single-nucleotide polymorphisms within the EDN gene family were selected for genotyping through a TaqMan assay. Data on clinical characteristics and hospitalizations for CV events were collected. Associations of genetic variants of the EDN gene with CV events were analyzed.. In this cohort, 62% (n = 118) of patients were hospitalized for a CV event. The EDN1 rs4714384 (CC/TC vs. TT) polymorphism was associated with an increased risk of a CV event after multiple testing (p < 0.001). Further functional exploration showed that it was a quantitative trait locus which may significantly alter gene expression in the tibial artery.. EDN1 rs4714384 is very likely an important biomarker of CV events in ESRD patients.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Endothelin-1; Female; Genetic Association Studies; Genetic Variation; Humans; Kidney Failure, Chronic; Male; Middle Aged

Angiopoietin-like-2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelial dysfunction, atherosclerosis, and cardiovascular disease (CVD). Circulating ANGPTL2 is increased in chronic kidney disease (CKD), where the risk of CVD is amplified. The objectives of the present study were to (i) examine whether kidney transplantation (KTx) reduces ANGPTL2 levels, (ii) identify the determinants of ANGPTL2 after KTx, (iii) study the association of ANGPTL2 with aortic stiffness, and (iv) assess the impact of ANGPTL2 on mortality after KTx.. In 75 patients, serum ANGPTL2 levels were measured at baseline and 3 months after KTx. Aortic stiffness was determined by carotid-femoral pulse wave velocity, glomerular filtration rate was estimated by CKD-EPI formula, and serum cytokines and endothlin-1 levels were determined 3 months after KTx. Survival analysis was performed using Kaplan-Meier and Cox regression after a median follow-up of 90 months.. After 3 months of KTx, ANGPTL2 levels decreased from 71 ng/ml (53-95) to 11 ng/ml (9-15) (P < 0.001). In multivariate analysis, age, lower renal function, and endothelin-1 were independently associated with higher post-KTx ANGPTL2 levels. ANGPTL2 was positively associated with aortic stiffness after KTx, even when adjusted for mean blood pressure (standardized β = 0.314; P = 0.008). During follow-up, 13 deaths occurred. The group of patients with higher post-KTx ANGPTL2 levels had a hazard ratio for mortality of 3.9 (95% confidence interval: 1.07-14.4; P = 0.039).. KTx significantly reduced serum ANGPTL2 levels. The positive association between post-KTx ANGPTL2, aortic stiffness and mortality, suggests that ANGPTL2 may play a biological role in CKD-related CVD.

Topics: Adult; Angiopoietin-Like Protein 2; Angiopoietin-like Proteins; Endothelin-1; Female; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Logistic Models; Male; Middle Aged; Mortality; Multivariate Analysis; Prognosis; Proportional Hazards Models; Pulse Wave Analysis; Survival Rate; Vascular Stiffness

Cardiac valve calcification (CVC) and left ventricular (LV) alterations are frequent complication in end-stage renal disease (ESRD). We determined the prevalence of CVC and LV hypertrophy (LVH) in ESRD patients before renal replacement therapy and 12 months after peritoneal dialysis (PD).. A prospective longitudinal of 50 incident PD patients was studied. Demographic and clinical data were recorded and blood assayed at baseline and after 1-year of follow-up. CVC and LVH were evaluated by M-mode two-dimensional echocardiography.. CVC of the mitral and aortic valves and of both valves were noted in 30, 18 and 10% of patients, respectively. After 12 months of PD regimen, 20% patients had aortic, 24% mitral and 8% had calcification of both valves. After one year of PD, LVH was 62 and 36% in patients with and without CVC, respectively (p < 0.05). Endothelin-1 is an independent predictor of CVC at the baseline, while nitric oxide is inversely an independent predictor at the end of follow-up.. CVC is associated with LVH in PD patients. These findings identified a potential role for monitored markers to be incorporated into therapeutic strategies aimed at detection and treatment of cardiovascular complications and prevention strategies.

Topics: Adult; Aged; Aorta; Biomarkers; Calcinosis; Echocardiography; Endothelin-1; Female; Heart Valve Diseases; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Mitral Valve; Peritoneal Dialysis; Prospective Studies; Young Adult

Left ventricular hypertrophy is the most common structural cardiac alteration in chronic dialysis patients. The aim of this study was to determine the possible association of endotelin-1 (ET-1) and nitric oxide (NO) with parameters of echocardiography in order to assess their participation in left ventricular (LV) remodeling in patients on peritoneal dialysis (PD).. This prospective longitudinal study included 40 PD patients. Serum levels of ET-1 and NO baseline and after 12 months of PD treatment were measured and compared with echocardiography parameters done at the same time of PD treatment. Linear regression analysis was used to detect independent correlations of variables.. Mean ET-1 serum concentration decreased significantly after 12 months of PD treatment compared to baseline values (p < 0.01). NO serum concentration increased significantly 12 months after treatment compared to baseline values (p < 0.01). Left ventricular hypertrophy (LVH) was observed in 72.5% of patients at baseline with significant reduction in LV mass index after 12 months of PD treatment (p < 0.001). On linear regression analysis serum concentration of ET-1 was independent predictors of LV mass index, as well as NO at the end of observed period.. According to our data ET-1 and NO are independently related to the process of left ventricular remodeling in PD patients.

Topics: Adult; Aged; Biomarkers; Endothelin-1; Endothelium, Vascular; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Peritoneal Dialysis; Prospective Studies; Regression Analysis; Ultrasonography; Ventricular Remodeling

End-stage renal disease (ESRD) and its treatment modules affect almost all organs and organ systems including vascular endothelium. It is well known that disturbance of vasoactive substances (nitric oxide - NO and endothelin-1 - ET-1) production appears in these patients. There is a small number of studies which investigated serum levels of NO and ET-1 in ESRD patients treated with continuous ambulatory peritoneal dialysis (CAPD). Therefore our study aimed to measure serum levels of NO and ET-1 in this population. This study included 23 ESRD patients (10 males and 13 females) treated with CAPD, mean age 55.8 ± 15.8 years. Mean duration of CAPD treatment in this group of patients was 3.4 ± 14.7 years. Besides this group of patients (CAPD), we included a second group which consisted of 30 healthy controls [14 males, 16 females, mean age 51.8 (±15.6) years]. Our results show significantly higher serum levels of NO in CAPD patients  x ± SD = 19.09 ± 6.9) in comparison to the control group (x ± SD = 9.5 ± 1.9) (p < 0.05). There was no significant difference in serum levels of ET-1 between CAPD patients x ± SD = 7.3 ± 5.6) and the control group (x ± SD = 6.6 ± 4.2), (p > 0.05). From our results, we concluded that imbalance in production of vasoactive substances is present in CAPD patients. This imbalance can lead to disturbance in local blood flow control. These pathophysiological mechanisms can cause significant hemodynamic disturbance (hypertension) and atherosclerosis.

Topics: Adult; Aged; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Peritoneal Dialysis, Continuous Ambulatory; Prospective Studies

The purpose of this study was to determine endothelin (ET)-1 and nitric oxide (NO) serum concentration levels at baseline and after 1 year of peritoneal dialysis (PD) treatment. A further aim was to evaluate the association between ET-1 and NO with parameters of echocardiography and the common carotid artery (CCA) ultrasound, and to assess their impact on cardiovascular remodeling. We also aimed to evaluate the influence of dialysis adequacy and residual renal function (RRF) on cardiovascular remodeling.. This study included 40 PD patients in whom we measured serum ET-1 and NO concentrations, echocardiography and CCA ultrasound parameters.. ET-1 decreased and NO serum concentration levels increased (p < 0.01) after 12 months of PD treatment compared to baseline values. Left ventricular (LV) hypertrophy was observed in 77.5% of patients at baseline with significant reduction in LV mass index (LVMI), CCA intima media thickness (IMT) and plaque score after 12 months of PD treatment (p < 0.001). The dialysis adequacy and RRF were significantly associated with LVMI and CCA IMT after 12 months on PD.. In our study, ET-1 significantly decreased while NO increased during PD treatment and both were independently related to the cardiovascular remodeling parameters in PD patients.

Topics: Adult; Aged; Biomarkers; Carotid Artery Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Female; Follow-Up Studies; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Peritoneal Dialysis; Prospective Studies; Ultrasonography; Ventricular Remodeling

Progressive fibrosis accompanies all chronic renal disease, connective tissue growth factor (CTGF,) and platelet-derived growth factor-B, (PDGF-B,) play important roles in extra-cellular matrix abnormal accumulation, while endothelin-1 (ET-1) nitric oxide (NO,) are related to endothelial dysfunction, which mediates the progression of renal fibrosis. Shenqi Detoxification Granule (SDG), a traditional Chinese herbal formula, has been used for treatment of chronic renal failure in clinic for many years.. In order to evaluate the efficacy, and explore the mechanism of SDG to inhibit the progression of renal fibrosis, study was carried out using the adenine-induced Wister rats as the CRF model, and losartan as postive control drug. Levels of serum creatinine [Scr], and blood urea nitrogen (BUN), albumin (ALB), 24hrs, urine protein (24hUP), triacylglycerol (TG), and cholesterol (CHO), together with ET-1, and NO were detected. Pathological changes of renal tissues were observed by HE, staining. In addition, CTGF and PDGF-B expression were analyzed by immuno-histo-chemistry.. The results indicated that SDG can effectively reduce Scr, BUN, 24hUP, TG, and CHO levels, increase ALB levels, inhibit renal tissue damage in CRF rats, and the mechanism maybe reduce PDGF-B, CTGF expression and ET-1/NO.. Shenqi Detoxification Granule is a beneficial treatment for chronic renal failure.

Topics: Adenine; Albumins; Animals; Blood Urea Nitrogen; Cholesterol; Connective Tissue Growth Factor; Creatinine; Disease Models, Animal; Drugs, Chinese Herbal; Endothelin-1; Fibrosis; Kidney; Kidney Failure, Chronic; Magnoliopsida; Male; Nitric Oxide; Phytotherapy; Proto-Oncogene Proteins c-sis; Rats; Rats, Wistar; Triglycerides

End-stage renal disease (ESRD) is a complex illness that involves different organs including the lungs. We studied the pulmonary function tests, arterial blood gases (ABG) and plasma endothelin-1 (ET-1) levels to check whether there is any change in their levels after hemodialysis (HD) in patients with ESRD. In this cross-sectional study (from July 2009 to April 2010), 20 patients with ESRD were evaluated. ABG, spirometric parameters and plasma ET-1 were measured before and after HD in these patients. Student's t-test was performed to clarify the differences and Pearson's test was used for correlations. P <0.05 was considered statistically significant. Significant reduction was seen in oxygen saturation (O₂sat), partial pressure of carbon-dioxide (PaCO₂) and oxygen (PaO₂) after a HD session (P <0.001). Also, improvement was seen in all spirometric parameters except forced expiratory volume (FEV1)/forced vital capacity (FVC) after HD. Plasma ET-1 levels decreased significantly after HD. Mean ET-1 before HD was 6.88 + 5.81 pg/mL while it was 3.91 + 2.76 pg/mL after HD (P = 0.009). Based on the plasma levels of ET-1, the patients were divided into two groups. The mean level of ET-1 was higher in the first group. Significant increase was seen in spirometric parameters in the second group. Our study suggests that, in patients with ESRD, plasma ET-1 level is higher than in the normal population, and this is closely related to deterioration of pulmonary function tests. Significant reduction of plasma ET-1 may be an important factor in the improvement of spiro-metry parameters after HD.

Topics: Adult; Biomarkers; Blood Gas Analysis; Cross-Sectional Studies; Endothelin-1; Female; Forced Expiratory Volume; Humans; Kidney Failure, Chronic; Lung; Lung Diseases; Male; Middle Aged; Recovery of Function; Renal Dialysis; Respiratory Function Tests; Treatment Outcome; Vital Capacity; Young Adult

This study assessed whether endothelin-1 (ET-1) helps mediate postischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24 h or 2 weeks following 30 min of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II (Pol II) binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just postischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can have a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results.

Topics: Animals; Atrasentan; Disease Models, Animal; Disease Progression; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Kidney Failure, Chronic; Male; Mice; Mice, Inbred Strains; Oligopeptides; Piperidines; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Renal Insufficiency, Chronic; Reperfusion Injury; RNA, Messenger

To investigate the effect of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (t-PA), and endothelin-1 (ET-1) on the atherosclerosis progress in the maintenance hemodialysis patients.. We enrolled 19 patients with maintenance hemodialysis (MHD) and 11 healthy people as control. Patients were divided into 2 groups according to their age above or below 40 years old (11 and 8 in each, respectively), whereas the subjects in control group were below 40 years old. All the clinical information of the research subjects was collected: including age, gender, time of hemodialysis, blood pressure, blood urea nitrogen (BUN), and serum creatinine (SCr). Immunohistochemistry and pathological image analysis were used to investigate the pathological changes, calcification and the expression of PAI-1, t-PA, and ET-1 on the blood vessel.. Compared with the age-matched healthy control group, there were higher blood vascular media thickness, blood vascular media thickness/diagmeter ratio, blood vascular media thickness area/vascular inter-wall area ratio (P<0.05) and more calcification (P<0.05) in the the internal iliac artery in the chronic renal failure MHD patients. All the results were similar when compared the above 40 years old group with the below 40 years old one in the chronic renal failure MHD patients. There were positive correlation of blood vascular media thickness with age and blood pressure (P<0.05). Expression of PAI-1, ET-1, t-PA on the internal iliac artery vessel was elevated in the chronic renal failure MHD patients compared with the health control (P<0.05). The level of PAI-1 or ET-1 was much higher in the above 40 years old group than the below 40 years old one in the chronic renal failure MHD patients, whereas there was no significant difference in the t-PA expression between the 2 groups (P<0.05). There were positive correlation of PAI-1 or ET-1 expression with age and blood pressure (P<0.05). There were positive correlation of PAI-1 or ET-1 expression with blood vascular media thickness and calcification (P<0.05 or P<0.01). There was no correlation of hemodialysis time with blood vascular media thickness, calcification, PAI-1, t-PA, or ET-1 expressions.. MHD patients accompany with atherosclerosis which is severer in the patients above 40 years old than the patients below 40 years old. The higher of the blood pressure, the severer of the atherosclerosis. Abnormal expression of PAI-1 plays an important role in the progress of the atherosclerosis in the chronic renal failure MHD patients, whereas t-PA has no function in this process. The level of PAI-1 and ET-1 would be helpful to evaluating the degree of atherosclerosis in the chronic renal failure MHD patients. Hemodialysis time may not be a potential accelerator for atherosclerosis progression.

Topics: Adult; Atherosclerosis; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Renal Dialysis

The incidence of acute kidney injury (AKI) is increasing. It is now widely accepted that patients surviving an episode of AKI have a significant risk of progression to chronic kidney disease (CKD) and even end-stage renal failure. Zager and colleagues describe the role of endothelin-1 (ET-1) in the progression of AKI to CKD and provide a basis for the potential use of ET receptor antagonists as a therapeutic strategy in AKI.

Topics: Animals; Disease Progression; Endothelin-1; Kidney Failure, Chronic; Male; Renal Insufficiency, Chronic; Reperfusion Injury

Several studies demonstrated a six-fold increase in plasma concentration of endothelin-1 (ET-1) in diaysis patients (hemodialysis and peritoneal dialysis) compared to healthy control subjects. However, the effects of ET-1 on respiratory function in these patients are less known. The aim of this study was to determine the potential differences in spirometric values in relation to ET-1 levels.. The study included 28 patients (15 male, 13 female, mean age 55.9 +/- 16. 2 years) with end stage renal diseases (ESRD) receiving regular hemodialysis (HD), 23 patients (10 males, 13 females, mean age 55.8 +/- 15.8 years) with ESRD treated with continuous ambulatory peritoneal dialysis (CAPD) without any cardiovascular or respiratory diseases, and 30 healthy volunteers (14 male, 16 female, mean age 51.8 +/- 15.6 years) in control group. In each of the three groups the participants were divided into two additional sub-groups according to the serum levels of ET-1. The spirometry values were recorded before the onset of hemodialysis and prior to emptying the peritoneal cavity in CAPD patients. The results were analyzed using standard statistical methods (Student's t-test).. Patients who were treated with HD or CAPD were found to have significant difference in values of most pulmonary function parameters between subjects with ET-1 levels lower than 6.6 pg/ml and subjects with ET-1 levels higher than 6.6 pg/ml. In the control group there was no difference in pulmonary function parameters in correlation with ET-1 levels. ET-1 values in patients of both dialysis groups were significantly higher compared to healthy subjects.. Higher levels of ET-1 in dialysis patients over healthy subjects is associated with lower parameters of lung function tests. A possible pathophysiological mechanism for deterioration of pulmonary function might be explained by progression of inflammation, pulmonary oedema also known as "uraemic lung" or/and the progression of pulmonary hypertension.

Topics: Biomarkers; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Lung; Male; Middle Aged; Prognosis; Renal Dialysis; Severity of Illness Index; Spirometry

Big endothelins (pro-endothelin; inactive-precursor) are converted to biologically active endothelins (ETs). Mammals and humans produce three ET family members: ET-1, ET-2 and ET-3, from three different genes. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3, which is produced by neuronal cells and organs such as the thyroid, salivary gland and the kidney. In patients with end-stage renal disease, abnormal vascular endothelial cell function and elevated plasma ET-1 and big ET-1 levels have been reported. It is unknown whether big ET-2 and big ET-3 plasma levels are altered in these patients. The purpose of the present study was to determine whether endogenous ET-1, ET-2, and ET-3 systems including big ETs are altered in patients with end-stage renal disease.. We measured plasma levels of ET-1, ET-3 and big ET-1, big ET-2, and big ET-3 in patients on chronic hemodialysis (n=23) and age-matched healthy subjects (n=17).. In patients on hemodialysis, plasma levels (measured just before hemodialysis) of both ET-1 and ET-3 and big ET-1, big ET-2, and big ET-3 were markedly elevated, and the increase was higher for big ETs (Big ET-1, 4-fold; big ET-2, 6-fold; big ET-3: 5-fold) than for ETs (ET-1, 1.7-fold; ET-3, 2-fold).. In hemodialysis patients, plasma levels of the inactive precursors big ET-1, big ET-2, and big ET-3 levels are markedly increased, yet there is only a moderate increase in plasma levels of the active products, ET-1 and ET-3. This suggests that the activity of endothelin converting enzyme contributing to circulating levels of ET-1 and ET-3 may be decreased in patients on chronic hemodialysis.

Topics: Adult; Case-Control Studies; Endothelin-1; Endothelin-2; Endothelin-3; Humans; Kidney Failure, Chronic; Male; Middle Aged; Protein Precursors; Renal Dialysis

To evaluate endothelin-1 (ET-1) levels and to characterize reflex vasomotor reactions of skin vessels in distant exposure to cold in patients with chronic kidney disease (CKD) of stage I and II.. Glomerular filtration rate (GFR) was calculated by MDRD formula for 40 healthy subjects (mean age 39.2 +/- 2.0 years) and 147 CKD patients (mean age 41.4 +/- 1.8 years). All the patients were also exposed to the cold test (a modified variant).. Patients with CKD stage I demonstrated a 35.1% fall in blood flow rate (Qas) in response to cold stimulus, patients of stage II--a 42.2% fall, healthy patients--a 19.3%. CKD patients of stage I and II retained a Qas fall for 3 min after exposure to cold, while healthy subjects resumed skin blood circulation immediately after exposure to cold. Blood plasma ET-1 concentration in healthy subjects was 0.239 +/- 0.055 fmol/ml, in stage I CKD patients--0.334 +/- 0.066 fmol/l, in stage II CKD patients--0.422 +/- 0.041 fmol/l. Relationships were found between ET-1 level and GFR (Rs = 0.242; p < 0.05), 24 h proteinuria (Rs = 0.375; p < 0.003) and Qas% in the cold test (Rs = -0.389; p < 0.003) as well as time of recovery of the background Qas (Rs = -0.311; p < 0.003).. Dysfunction of autonomic nervous system at early stages of CKD may arise by means of activation of ET-1 synthesis in response to enhancement of sympathetic impacts.

Topics: Adolescent; Adult; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Microvessels; Middle Aged; Skin; Vasomotor System; Young Adult

The relationship between renal disease progression and genetic polymorphism of enzymes influencing endothelial function remains incompletely understood. We genotyped three cohorts of elderly Hungarian patients: 245 patients with end-stage renal disease (ESRD) on chronic hemodialysis (HD), 88 patients with mild chronic kidney disease (CKD), and 200 healthy controls. The underlying diagnoses of renal diseases were primary glomerulonephritis, interstitial nephritis, hypertension, diabetic nephropathy, and hereditary diseases. We examined genetic polymorphisms of eight candidate genes associated with endothelial function: endothelial constitutive nitric oxide synthase (ecNOS) T-786C, endothelin-1 G5727T, methylenetetrahydrofolate reductase (MTHFR) C677T, paraoxonase-1 Q192R and M55L, angiotensinogen M235T, angiotensin-converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C gene. Six gene polymorphisms were detected by real-time polymerase chain reaction with melting-point analysis, and two via allele-specific amplification and gel electrophoresis. Control group patients were in Hardy-Weinberg equilibrium for all tested genotypes. In ESRD patients attributed to hypertension, the endothelin gene G5727T GG genotype occurred significantly less but GT genotype more frequently (P < 0.01 for both). In ESRD patients attributed to primary glomerulonephritis, more ACE DD and less ID genotypes were found (P < 0.02 for both) than in the controls. The underlying diagnosis may modify the association of genetic polymorphism and dialysis-dependent ESRD.

Topics: Adult; Aryldialkylphosphatase; Endothelin-1; Female; Humans; Hungary; Kidney Failure, Chronic; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renal Dialysis; Risk Factors

Erythropoietin (EPO) administration in uremic rats leads to an increase in blood pressure (BP). Because chronic renal failure has been associated with oxidative stress, we hypothesize that EPO treatment could accentuate this condition and contribute to hypertension. The present study was designed to investigate the role of reactive oxygen species in EPO-induced hypertension and the effect of tempol, a superoxide dismutase-mimetic.. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 3-week stabilization period. Uremic rats were divided into four groups and received for 4 weeks: vehicle; EPO (100 U/kg, subcutaneously, three times per week); vehicle + tempol (1 mmol/l in drinking water); and EPO + tempol. Systolic BP and biochemical parameters were assessed before and at the end of the treatment. Renal histology, creatinine clearance rate, endothelin-1 (ET-1) concentrations and superoxide anion production were assessed at the end of the study.. The uremic rats developed anemia and hypertension. ET-1 concentrations and superoxide anion production were increased. EPO administration corrected anemia, but accentuated hypertension and renal injuries such as glomerulosclerosis, interstitial fibrosis, and inflammation. EPO therapy further increased tissue levels of ET-1 and superoxide anion production. Tempol treatment improved hypertension and renal injury, and reduced ET-1 concentrations and superoxide anion production.. Oxidative stress contributes to the development of hypertension and to the progression of renal injuries in uremic rats. EPO administration further increases oxidative stress, which might partly account for the accentuation of hypertension and renal injury.

Topics: Anemia; Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hypertension; Kidney Failure, Chronic; Male; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins; Uremia

Diabetes and arterial hypertension continue to be the main causes of chronic renal failure in 2010, with a rising prevalence in part due to the worldwide obesity epidemic. Proteinuria is a main feature of chronic renal disease and mediated by defects in the glomerular filtration barrier and is as a good predictor of cardiovascular events. Indeed, chronic renal disease due to glomerulosclerosis is one of the important risk factors for the development of coronary artery disease and stroke. Glomerulosclerosis develops in response to inflammatory activation and increased growth factor production. Preclinical and first preliminary clinical studies provide strong evidence that endogenous endothelin-1 (ET-1), a 21-amino-acid peptide with strong growth-promoting and vasoconstricting properties, plays a central role in the pathogenesis of proteinuria and glomerulosclerosis via activation of its ET(A) subtype receptor involving podocyte injury. These studies have not only shown that endothelin participates in the disease processes of hypertension and glomerulosclerosis but also that features of chronic renal disease such as proteinuria and glomerulosclerosis are reversible processes. Remarkably, the protective effects of endothelin receptors antagonists (ERAs) are present even on top of concomitant treatments with inhibitors of the renin-angiotensin system. This review discusses current evidence for a role of endothelin for proteinuric renal disease and podocyte injury in diabetes and arterial hypertension and reviews the current status of endothelin receptor antagonists as a potential new treatment option in renal medicine.

Topics: Endothelin A Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension; Kidney Failure, Chronic; Podocytes; Proteinuria; Receptor, Endothelin A

to refine a role of free radical oxidation (FRO), anemia, and endothelial dysfunction in the development of cardiovascular events in patients with chronic renal failure (CRF) at diferent stages of the disease.. Eighty-six patients, including 46 (53%) women and 40 (47%) men with Stages II-IV CRF, were examined. The patients' mean age was 43.6 +/- 14 years. Echocardiography, measurements of the blood levels of hemoglobin, albumin, cholesterol, and uric acid, and determination of blood electrolytic composition were made. Blood creatinine concentrations in the group averaged 0.3 mmol/l. Glomerular filtration rate (GFR) calculated from the Cockroft-Goult formula averaged 33.96 +/- 13 ml/min; the duration of CRF was 9.3 +/- 1.6 years. Anemia was detected in 46 (53%) patients. Iron metabolism was estimated from serum ferritin levels. Special studies involved determination of FRO--malondialdehyde (MDA) and the activities of catalase and superoxide dismutase (SOD) in plasma and serum. The plasma concentrations of endohelin-1 (ET-1), thromboxane A2, and prostacyclin were measured by radioimmunoassay. Results. The higher concentrations of MDA and the decreased activities of catalase and SOD, i.e., FRO, correlated with the progression of renal failure. There were also increases in the levels of ET-1 and thromboxane A, and a reduction in the concentration of prostacyclin as blood creatinine levels elevated. Left ventricular hypertrophy was found in 43 (50%) of the 86 patients. Its severity depended on the decrease of creatine phosphokinase and the severity of anemia and arterial hypertension. There was a stable correlation between the changes in left ventricular myocardial mass, MDA levels, and catalase and SOD activities.. The higher level of MDA and the lower activities of catalase and SOD in patients with CRF, which correlate with diminished renal function, confirm that the disease is closely associated with FRO, that, by aggravating anemia and endothelial dysfunction, affects the magnitude of morphological and functional changes in the cardiovascular system in patients with CRF patients.

Topics: Adult; Cardiovascular Diseases; Catalase; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Free Radical Scavengers; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Oxidative Stress; Prognosis; Superoxide Dismutase; Thromboxane A2

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A (ET(A)) and B (ET(B)), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function.

Topics: Animals; Down-Regulation; Endothelin-1; Gene Expression Regulation, Developmental; Homeodomain Proteins; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Microscopy, Electron; Nephrons; Receptors, Endothelin; Sodium-Potassium-Exchanging ATPase; Transcription Factors

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.

Topics: Adult; Aged; Biomarkers; Endothelin-1; Female; Humans; Inflammation; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Young Adult

Instruction. We investigated the correlation between atherosclerosis and tissue and serum levels of endothelin-1 in patients with chronic kidney disease (CKD). MATERIALS AND METHODS. Arterial samples were obtained from 35 patients with CKD during arteriovenous fistula placement. Thirty-one patients with cardiovascular disease who underwent coronary artery bypass graft (CABG) were selected as the atherosclerotic group, and a piece of their aorta punched during CABG was obtained. Also, a small piece of the renal artery was dissected during donation in 24 kidney donors (control group). Tissue endothelin-1 level was measured and atherosclerosis grading was determined by pathologic examination. Serum levels of endothelin-1 were also measured in the three groups. Results. The mean tissue endothelin-1 levels were 10.73+/-7.57 pg/mL, 12.16 +/- 3.95 pg/mL, and 0.93 +/- 1.06 pg/mL in the patients with CKD, those with CABG, and donors, respectively (P < .001). The mean serum endothelin-1 level was 25.23 +/- 15.15 pg/mL in the patients with CKD, 21.13 +/- 17.22 pg/mL in the patients with CABG, and 2.66 +/- 1.51 pg/mL in the donors (P < .001). Atherosclerosis grades correlated with tissue endothelin-1 level (r = 0.823, P < .001) and serum endothelin-1 level (r = 0.608, P < .001) in the patients with CKD. Multiple regression analysis showed tissue endothelin-1 level as the main predicting factor of atherosclerosis (P < .001). CONCLUSIONS. Tissue endothelin-1 concentration is more important than serum endothelin-1 or lipids levels in prediction of atherosclerosis. Thus, blockade of tissue endothelin-1 receptors with its antagonists may prevent atherosclerosis progression.

Topics: Adult; Arteriovenous Shunt, Surgical; Atherosclerosis; Case-Control Studies; Cohort Studies; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Risk Factors

The complex pathogenesis of chronic renal disease (CRD) depends on endothelin (ET) axis (ETs and ET receptors) and nitric oxide (NO) because of their vasoactive effects and their role in general modulation of vascular homeostasis. Various renal cells synthesize ETs and NO that play a significant role in renal hemodynamics as well as in water and salt excretion via urine. ET-1 is a strong vasoconstrictor. Besides its vasoactive effects, ET-1 modulates mitosis and apoptosis in a cell type-dependent manner, and may play an important role in CRD pathogenesis. The aims of this study were to emphasize the role and interactions of ET-1, Big ET-1, and NO in CRD. Concentrations of these vasoactive molecules were measured in plasma/serum and/or urine of 57 patients with diabetic nephropathy (subgroup 1), arterial hypertension (subgroup 2) or CRD with chronic renal insufficiency (subgroup 3), and in healthy control subjects (n=18). In comparison with control group, urine concentration of Big ET-1 was significantly increased (13.13 pmol/L vs. 11.34 pmol/L; P<0.001) in CRD patients, whereas plasma and urine concentrations of ET-1 did not differ significantly. NO concentrations were also significantly increased in CRD patients (serum, 72.55 micromol/L; P<0.001, and urine 141.74 micromol/L; P<0.05) as compared to control group. Study results indicated that Big ET-1 and NO could be useful diagnostic parameters in CRD for their diagnostic sensitivity and diagnostic specificity (Big ET-1 in urine: 56.1 and 88.9%, and NO in serum: 66.7 and 83.3%, respectively). In addition, Big ET-1 may prove useful in the differential diagnosis of diabetic nephropathy (78.6% diagnostic sensitivity and 88.9% diagnostic specificity).

Topics: Adult; Endothelin-1; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Regression Analysis; ROC Curve; Young Adult

Parathyroid hormone secretion is mainly influenced by hypocalcaemia, hyperphosphataemia and vitamin D deficiency. However, previous in vitro and in vivo studies showed that endothelin-1 can influence parathyroid hormone secretion. This study was aimed at evaluating this relationship in vivo in uraemic patients.. Parathyroid hormone and endothelin-1 plasma concentrations were measured in 67 haemodialysed patients. Patients with history of cardiovascular diseases and those with parathyroid adenoma were excluded.. Plasma levels of endothelin-1 were found to be inversely related to those of parathyroid hormone (P < 0.04) The multiple regression analysis, carried out considering parathyroid hormone as a dependent variable, and including age, sex, blood pressure, calcium x phosphorus product, and endothelin-1, demonstrated that the independent correlates of parathyroid hormone were endothelin-1 (beta = -0.276; P = 0.015), and calcium x phosphorus product (beta = 0.417; P < 0.0001).. For the first time in vivo, we demonstrated an inverse independent relationship between endothelin-1 and parathyroid hormone in haemodialysed patients. Because both endothelin-1 and parathyroid hormone are endowed with well-known harmful actions on cardiovascular apparatus, whether such inverse relation may really influence the natural history of cardiovascular damage due to secondary hyperparathyroidism remains to be elucidated.

Topics: Adult; Aged; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Regression Analysis; Renal Dialysis

The etiology of hemodialysis (HD)-induced hypotension and hypertension remains speculative. There is mounting evidence that endothelin-1 (ET-1) may play a vital role in these hemodynamic changes. We examined the possible role of intradialytic changes of ET-1 in the pathogenesis of hypotension and rebound hypertension during HD.. The present study included 45 patients with end-stage renal disease (ESRD) on regular HD. They were divided according to their hemodynamic status during HD into three groups (group I had stable intradialytic hemodynamics, group II had dialysis-induced hypotension, and group III had rebound hypertension during HD). In addition, 15 healthy volunteers were included as a control group. Pulse and blood pressure were monitored before, during (every half hour), and after HD session. ET-1 level was measured at the beginning, middle, and end of HD. ET-1 was measured in the control group for comparison.. Pre-dialysis levels of ET-1 were significantly higher in dialysis patients compared to the controls (P < 0.001); however, they were comparable in the three HD groups. The post-dialysis ET-1 level was not changed significantly in group I compared with predialysis values (14.49 +/- 2.04 vs. 14.33 +/- 2.23 pg/ml; P = NS), while the ET-1 concentration decreased significantly in group II and increased in group III in comparison to predialysis values (8.56 +/- 1.44 vs. 11.75 +/- 2.51; 16.39 +/- 3.12 vs. 11.93 +/- 2.11 pg/ml, respectively; P < 0.001).. Altered ET-1 levels may be involved in the pathogenesis of rebound hypertension and hypotension during HD.

Topics: Adult; Blood Pressure; Case-Control Studies; Egypt; Endothelin-1; Female; Heart Rate; Humans; Hypertension; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension.. Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight).. Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P < 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P < 0.001) and irbesartan (P < 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P < 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure.. Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.

Topics: Angiotensin II; Animals; Animals, Genetically Modified; Calcium Channels, L-Type; Disease Models, Animal; Endothelin-1; Fibrosis; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Male; Rats

We have followed 99 patients with end stage renal failure, treated by regular haemodialysis. Chronic renal failure is frequently accompanied by chronic heart failure (over 50%), especially by heart failure with preserved ejection fraction. Patients treated by regular haemodialysis had a tendency to cardiomegaly (51%), mild systolic dysfunction of the left ventricle (mean LVEF 53%) and diastolic dysfunction (88%) of the hypertrophic left ventricle. They had also activated endothelin and neurohumoral system. Only 3% of the patients had normal values of Nt-proBNP and big endothelin. The plasma level of Nt-proBNP in haemodialysed patients correlated with cardiothoracic ratio and with ejection fraction. The plasma level of big endothelin correlated only with cardiothoracic ratio.

Topics: Biomarkers; Endothelin-1; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis

To study the effects of high-protein diet (HPD) and high-grade proteinuria in aggravating the progression of chronic renal failure (CRF) in rats.. CRF with high-grade proteinuria was induced by supplying HPD in five sixth nephrectomy rats, and the changes of serum creatinine (Scr), blood urea nitrogen (BUN), endothelin-1 (ET-1), thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(l alpha) (6-Keto-PGF(l alpha)) were observed. At the same time, the content of malondialdehyde (MDA), and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase(SOD)were measured in blood and renal tissue of the rats.. HPD and high-grade proteinuria could accelerate the damage of kidney through increasing the levels of ET-1 and TXB(2), reducing the level of 6-Keto-PGF(l alpha), and attenuating the activities of SOD and GSH-Px.. HPD can accelerate the damage of kidney through inducing the high-grade proteinuria in five sixth nephrectomy rats, influencing the expression of kidney vasoactive substance, and reducing the anti-oxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Dietary Proteins; Disease Progression; Endothelin-1; Glutathione Peroxidase; Kidney Failure, Chronic; Liver; Male; Malondialdehyde; Nephrectomy; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Inter-dialysis variability in levels of big endothelin and NT-proBNP in plasma were studied in 22 patients with established systolic and/or diastolic dysfunction of the left cardiac ventricle assigned to a chronic haemodialysis programme. The plasmatic level of NT-proBNP in all patients was practically unchanged. There was a falling trended between haemodialysis treatments but this was not statistically significant and in absolute values clinically insignificant. Fluctuations were found between individuals but on average all values were stable and high in the pathological range. No significant changes in the plasmatic level of big endothelin were found either. The average levels were again stable and insignificant and the indicated trend did not achieve clinical or statistical significance. The values were once again high in the pathological range. Plasmatic levels of NT-proBNP and big endothelin do not vary according to the phase of the dialysis cycle and mainly reflect the long-term condition of endothelium failure and long-term stress in the left ventricle. Concentrations are not affected by changes in volume or uraemia between dialysis treatments and the suggested trend towards a fall in NT-proBNP and a rise in big endothelin does not have a clear explanation. In any case, this trend remained within the pathological range and is probably not clinically significant.

Topics: Aged; Endothelin-1; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis

The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure.

Topics: Animals; Blood Pressure; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Endothelin-1; Hypertension; Kidney; Kidney Failure, Chronic; Myocardium; Rats; Rats, Mutant Strains; Receptor, Endothelin A; Receptor, Endothelin B

We have demonstrated that ischemic acute renal failure (ARF) is attenuated by pre-ischemic treatment with a spontaneous nitric oxide (NO) donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409). In the present study, we evaluated the effect of post-ischemic treatment with FK409 on ARF, compared with the pre-ischemic treatment effect. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated ARF rats markedly decreased. In addition, increases in renal contents of endothelin-1 (ET-1), a deleterious mediator in the pathogenesis of ischemic ARF, were evident in untreated ARF rats at 24 h after reperfusion. Pre-ischemic treatment with FK409 (1 or 3 mg/kg, i.v.) at 5 min before ischemia attenuated ischemia/reperfusion-induced renal dysfunction and increased ET-1 contents after reperfusion. In contrast, post-ischemic treatment with FK409 (3 or 10 mg/kg, i.v.) at 6 h after reperfusion aggravated the renal injury, but did not affect the increased ET-1 content after reperfusion. These results suggest that pre-ischemic treatment with FK409 exerts renoprotective effects on ischemic ARF, probably through the suppression of renal ET-1 overproduction, whereas post-ischemic treatment with the NO donor worsens the ischemia/reperfusion-induced renal injury, through mechanisms unrelated to the ET-1 production after reperfusion.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Endothelin-1; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Function Tests; Male; Nitric Oxide Donors; Nitro Compounds; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Intradialysis hypertension is a frustrating complication among hemodialysis (HD) patients. This study was conducted to investigate the physiological changes during intradialytic hypertension. The beat-to-beat continuous heart rate, hematocrit (Hct) changes during HD, serum levels of nitric oxide, plasma levels of catecholamine, renin, endothelin (ET-1), cardiac output (CO), and peripheral vascular resistance (PVR) were measured before and after HD in patients prone to develop intradialysis hypertension (n = 30) and from age, sex-matched control HD subjects (n = 30). It was found that the baseline values of Hct, serum levels of nitric oxide, plasma levels of catecholamine, renin, and ET-1, CO, PVR, and power index (low frequency/high frequency ratios) of heart rate variability were not significantly different between the patients and control subjects. In the hypertension-prone group, the plasma levels of catecholamine, renin, and the serial measurements of power index, did not show significant changes. However, the patients showed a significant elevation of systemic vascular resistance (56.8 +/- 9.2% vs 17.7 +/- 9.5; P < 0.05), ET-1 (510.9 +/- 43.3 vs 276.7 +/- 30.1 pg/ml; P < 0.05) and a significant decrease of nitric oxide (NO)/ET-1 balance (0.018 +/- 0.003 vs 0.034 +/- 0.005; P < 0.05) at the end of HD compared with the control patients. It was found that the physiological changes in intradialysis hypertension patients were characterized by inappropriately increased PVR through mechanisms that did not involve sympathetic stimulation or renin activation but might be related with altered NO/ET-1 balance.

Topics: Autonomic Nervous System; Blood Urea Nitrogen; Cardiac Output; Case-Control Studies; Catecholamines; Endothelin-1; Female; Heart Rate; Hematocrit; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Renal Dialysis; Renin; Vascular Resistance

Renal failure causes sympathetic overactivity and inadequate capillary growth in response to cardiomyocyte hypertrophy in experimental renal failure, as well as in uremic patients. In nonuremic animals, sympathetic overactivity was shown to suppress capillary growth. The purpose of this study was to examine whether blockade with alpha- and beta-adrenoblockers ameliorates the capillary deficit that was documented in the hearts of rats with moderate renal failure. Male Sprague-Dawley rats, 3 days after surgical ablation [subtotal nephrectomy (SNX)] or sham operation (sham), were treated with phenoxybenzamine, metoprolol, or a combination of both: After 12 weeks, the hearts were investigated using morphometric and stereologic techniques. The length density of myocardial capillaries was lower (p<0.05) in untreated SNX than in sham (2,786+/-372 vs 3,397+/-602 mm/mm3); the decrease was abrogated by metoprolol (3,305+/-624 mm/mm3), but not by phenoxybenzamin (2,628+/-480 mm/mm3). The intercapillary distance increased (p<0.05) in SNX (20.5+/-1.5 microm) and tended to be lower after metoprolol treatment (19.0+/-1.9 microm). The media area of intramyocardial arterioles was significantly higher in untreated SNX (1,158+/-1,343 vs 686+/-771 microm2 in sham). Metoprolol in nonhypotensive doses prevents the capillary deficit in the hearts of rats with moderate renal failure and presents an argument for an important role of sympathetic overactivity in the genesis of the capillary deficit in moderate chronic renal insufficiency.

Topics: Adrenergic beta-Antagonists; Animals; Arterioles; Blood Pressure; Capillaries; Coronary Vessels; Endothelin-1; Kidney Failure, Chronic; Male; Metoprolol; Phenoxybenzamine; Rats; Rats, Sprague-Dawley

Endothelin (ET)-1 is involved in the pathophysiology of various renal disorders, promoting renal cellular proliferation and extracellular matrix protein accumulation, and, thus, diminishing fundamental renal function, including filtration. To determine whether ET-1 and ET-2 play a role in feline chronic renal failure, we analyzed the messenger RNA (mRNA) expression of the prepro-ET (PPET )-1 and PPET-2 genes in affected cat kidney after molecular cloning of full-length PPET-2 complementary DNA (cDNA). Conceptual analysis of the primary structure of cat PPET-2 based on the cloned sequence demonstrated that the putative regions corresponding to a mature peptide and peptidase processing sites are present in cat PPET-2. Homology analysis showed that the similarity of the cat PPET-2 amino acid sequence with those from human, mouse, rat, rabbit, dog, ferret, cow, and horse was 73.0%, 68.6%, 69.1%, 76.4%, 81.2%, 83.1%, 76.3%, and 79.2%, respectively. Analysis of PPET-1 and PPET-2 mRNA in cat by reverse transcription polymerase chain reaction showed upregulated expression of both genes in kidneys affected by renal failure.

Topics: Amino Acid Sequence; Animals; Cat Diseases; Cats; Conserved Sequence; DNA, Complementary; Endothelin-1; Endothelins; Kidney Failure, Chronic; Molecular Sequence Data; Protein Precursors; RNA, Messenger; Sequence Homology, Amino Acid

Endothelial dysfunction was observed in patients with chronic renal failure (CRF). Endothelial cells produce a lot of factors among them endothelin and nitric oxide. The aim of this study was to evaluate the plasma/serum and urine levels of edothelin 1 (ET 1) and nitric oxide (NO) in children with CRF treated conservatively. 52 children (23 girls and 29 boys) aged 2-20 years (mean 13.19 years) were enrolled into the study. Patients were divided into 2 groups according to the creatinine level: group I--children with CRF and creatinine level below 265.2 micromol/l, group II CRF children with creatinine level above 265.2 micromol/l. We evaluated serum and urine metabolites of NO (nitrates + nitrites).. in children with chronic renal failure elevated level of ET1 and enhanced excretion of ET1 were observed. Decreased plasma and urine NOx levels were found in CRF children. The disorders are connected with progression of renal failure.

Topics: Adolescent; Adult; Child; Child, Preschool; Endothelin-1; Endothelium, Vascular; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Nitric Oxide; Renal Dialysis

A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. Endothelin-1 (ET-1) has been suggested to be a major promoting factor in renal diseases. The role of the ET-1 gene locus (EDN1) in the renal function in the general nondiabetic population was evaluated. We examined the influence of three single-nucleotide polymorphisms of the ET-1 gene (EDN1)--K198N, 3A/4A, and T-1370G--on the progression of ADPKD towards end-stage renal disease (ESRD).. Two hundred and five ADPKD patients (113 males and 92 females) who had reached ESRD were analyzed. The patients were divided into three groups: (1) 48 patients (23 males and 25 females) with ESRD later than 63 years of age (slow progressors), (2) 74 patients (41 males and 33 females) with ESRD before 45 years of age (rapid progressors), and (3) 83 patients (49 males and 34 females) with ESRD between 45 and 63 years old. DNA samples from collected blood were genotyped for three single-nucleotide polymorphisms of EDN1: K198N, 3A/4A, and T-1370G. Haplotype analysis was also done in 200 healthy individuals. We compared the frequencies of the different genotypes between the groups of slow and rapid progressors and the ages at the time of ESRD regarding the EDN1 genotypes.. The EDN1 genotype distribution showed no differences among the groups of slow progressors, rapid progressors, the ADPKD group with ESRD between 45 and 63 years old, and the control group. Comparing the ages of ESRD of all patients, we did not find significant differences with regard to the different genotypes. Furthermore, we compared the combinations of the different haplotypes and the ages at the time of ESRD. We found no differences in ages at the time of ESRD in patients with different haplotypes in the endothelin promoter (T-1370G) in combination with 3A/4A or K198N polymorphisms. Comparing the ages at the time of ESRD in patients with different 3A/4A and K198N haplotypes, we found a significantly lower age at the time of ESRD (47.1 +/- 8.7 years) in the carriers of the 4A allele in combination with the 198N allele (4A/4A, 3A/4A + 198KN,NN) than in the carriers of the 4A allele homozygous for the K198 allele (52.9 +/- 10.9 years; 4A/4A, 3A/4A + 198KK; t test: p < 0.01) and in the carriers of the 198N allele homozygous for the 3A allele (53 +/- 11.2 years; 3A/3A + 198KN,NN; t test: p < 0.05).. We excluded an effect of K198N, 3A/4A, and T-1370G polymorphisms of EDN1 on the progression of ADPKD. However, a deleterious effect of the combination of 4A and 198N alleles of EDN1 was observed in APKDK individuals.

Topics: Aged; Chi-Square Distribution; Disease Progression; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Point Mutation; Polycystic Kidney, Autosomal Dominant; Polymorphism, Single Nucleotide

Advanced glycation end-products (AGEs), which accumulate in the blood and tissues of patients with chronic renal failure (CRF) undergoing chronic hemodialysis, play an important role in the pathogenesis of uremic complications. Endothelin 1 (ET1), a 21-amino acid peptide with vasoconstricting and mitogenic properties, is an important factor in the endothelial dysfunction occurring in uremia. The circulating levels of both AGEs and ET1 have been reported to be increased in chronic renal failure. In the present study we evaluated the possible relationship between pentosidine and ET1 plasma levels in CRF patients undergoing chronic hemodialysis treatment. The plasma concentrations of "free" and bound pentosidine (HPLC methods) and endothelin-1 (RIA method) were measured before the hemodialysis session in 40 nondiabetic CRF patients (22 males and 18 females; 54+/-3 years) on chronic hemodialysis for at least 1 year. Forty age- and sex-matched normal subjects served as a control group. In hemodialyzed patients, the overall pentosidine residues and pentosidine-free adduct plus pentosidine-free adduct bound reversibly to protein levels (24.9+/-2.04 pmol/mg protein and 110.5+/-5.9 pmol/ml, respectively) were significantly higher than those recorded in normal subjects (2.0+/-0.2 pmol/mg protein and 0.7+/-0.2 pmol/ml, respectively ). Endothelin-1 was also significantly (p<0.01) increased in CRF patients (10.6+/-0.4 pmol/ml in CRF patients and 2.7+/-0.3 pmol/ml in normal subjects). A significant positive correlation (p<0.01) was seen between "total" pentosidine (pentosidine residues and pentosidine-free adduct plus pentosidine-free adduct bound reversibly to protein) levels and endothelin-1 plasma values. The correlation between pentosidine and endothelin-1 provides further evidence that some AGEs exert a detrimental effect on the vascular endothelium, thereby contributing to the hypertension and other cardiovascular damage seen in CRF patients.

Topics: Arginine; Case-Control Studies; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Lysine; Male; Middle Aged; Renal Dialysis

Endothelial cell (EC) dysfunction markers are increased in end-stage renal disease (ESRD). The present study focused on the relationship between EC markers, conduit artery wall mechanics and hemodynamics in ESRD.. In 29 ESRD patients and 16 controls, brachial artery diameter, distension, and wall thickness was measured and circumferential wall stress (CWS) calculated. Shear stress was determined with a shear rate-estimating system. Furthermore, von Willebrand factor antigen (vWF) and endothelin-1 (ET-1) levels were measured.. vWF (p = 0.002) and ET-1 (p < 0.001) were higher in ESRD patients and vWF was related to ET-1 (r = 0.70, p = 0.005). Peak (p = 0.001) and mean shear stress (p = 0.003) were significantly lower in ESRD patients, and ET-1 showed an inverse log linear relation with both (peak: r = -0.59, p = 0.016; mean: r = -0.64, p = 0.007). Also, ET-1 was log linearly related to CWS (r = 0.58, p = 0.014).. These results indicate that, in ESRD, conduit artery shear stress is lower, which might be secondary to an increased peripheral vascular resistance caused by higher ET-1 levels.

Topics: Aged; Biomarkers; Brachial Artery; Endothelial Cells; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Stress, Mechanical; Vascular Resistance; von Willebrand Factor

We recently have shown a high incidence of unexplained pulmonary hypertension (PHT) in end-stage renal disease (ESRD) patients on chronic haemodialysis (HD) therapy via arterio-venous (A-V) access. This study evaluated the possibility that PHT in these patients is triggered or aggravated by chronic HD via surgical A-V access, and the role of endothelin-1 (ET-1) and nitric oxide (NO) in this syndrome.. Forty-two HD patients underwent clinical evaluation. Pulmonary artery pressure (PAP) was evaluated using Doppler echocardiography. Levels of ET-1 and NO metabolites in plasma were determined before and after the HD procedure and were compared between subgroups of patients with and without PHT.. Out of 42 HD patients studied, 20 patients (48%) had PHT (PAP = 46+/-2; range 36-82 mmHg) while the rest had a normal PAP (29+/-1 mmHg) (P<0.0001). HD patients with PHT had higher cardiac output compared with those with normal PAP (6.0+/-1.2 vs 5.2+/-0.9 l/min, P<0.034). HD patients, with or without PHT, had elevated plasma ET-1 levels compared with controls (1.6+/-0.7 and 2.4+/-0.8 fmol/ml vs 1.0+/-0.2, P<0.05) that remained unchanged after the HD procedure. HD patients without PHT and control subjects showed similar basal plasma levels of NO2 + NO3 (24.2+/-5.2 vs 19.7+/-3.1 microM, P>0.05) that was significantly higher compared with HD patients with PHT (14.3+/-2.3 microM, P<0.05). HD therapy caused a significant increase in plasma NO metabolites that was greater in patients without PHT (from 24.2+/-5.2 to 77.1+/-9.6 microM, P<0.0001, and from 14.3+/-2.3 to 39.9+/-11.4 microM, P<0.0074, respectively). Significant declines in PAP (from 49.8+/-2.8 to 38.6+/-2.2 mmHg, P<0.004) and cardiac output (CO) (from 7.6+/-0.6 to 6.1+/-0.3 l/min, P<0.03) were found in 11 HD patients with PHT that underwent successful transplantation. Similarly, temporary closure of the A-V access by a sphygmomanometer in eight patients with PHT resulted in a transient decrease in CO (from 6.4+/-0.6 to 5.3+/- 0.5 l/min, P = 0.18) and systolic PAP (from 47.2+/-3.8 to 34.6+/-2.8 mmHg, P<0.028).. This study demonstrates a high prevalence of PHT among patients with ESRD on chronic HD via a surgical A-V fistula. In view of the vasodilatory and antimitogenic properties of NO, it is possible that the attenuated basal and HD-induced NO production in patients with PHT contributes to the increased pulmonary vascular tone. Furthermore, the partial restoration of normal PAP and CO in HD patients that underwent either temporal A-V shunt closure or successful transplantation indicates that excessive pulmonary blood flow is involved in the pathogenesis of the disease.

Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Shunt, Surgical; Cardiac Output; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nitric Oxide; Pulmonary Artery; Pulmonary Wedge Pressure; Renal Dialysis

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Nitric Oxide; Peroxynitrous Acid

In patients on chronic hemodialysis the prevalence of atherosclerosis is increased and is by far the leading cause of morbidity and mortality. Endothelin-1, an endothelium-derived peptide with vasoconstrictive and mitogenic effects on vascular smooth muscles, is involved in the pathogenesis of atherosclerosis. The aim of the present study was to investigate the time course of plasma endothelin-1 levels during a hemodialysis session and to explore the influence of preexisting type 2 diabetes mellitus. Forty-five clinically stable hemodialysis patients (21 females, 24 males; mean age 62 +/- 12 years) were evaluated. Patients with type 2 diabetes (n= 11) were compared with the group of patients without diabetes (n=34). Relative blood volume (BV) changes (hemoglobinometry) and blood pressure (BP) was measured. Samples were taken before, every hour during, and after hemodialysis. Plasma endothelin-1 levels were measured by enzyme-linked immunoassay (ELISA) and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration of 2215 +/- 952 mL was performed. Total BV at the end of hemodialysis was 89.3% +/- 8.3% of the pretreatment volume. Plasma endothelin-1 was enhanced in hemodialysis patients compared to normal subjects and increased from 1.28 +/- 0.47 before to 1.44 +/- 0.54 pg/mL (ref. 0.3-0.9) at the end of hemodialysis (p<0.05). The BV change (r=0.41) and the BP (mean BP: r=0.34) correlated with plasma endothelin-1 at the end of hemodialysis (p<0.05). The levels of endothelin-1 were significantly higher in the group of dialysis patients with type 2 diabetes compared to nondiabetics in all measurements (p<0.05). These findings suggest a potential role of endothelin-1 in the pathogenesis of vascular dysfunction in diabetes mellitus. The dialysis procedure per se, through vasoconstriction due to BV decrease, local endothelial injury (a.v. fistula), or bioincompatibility reactions (foreign surface contact) may additionally alter endothelial cell functions.

Topics: Aged; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Probability; Reference Values; Renal Dialysis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome

The role of HO-1 inducer, hemin, in chronic renal failure (CRF) rats and its possible mechanism of action was studied. 5/6 subtotal nephrectomy was performed to establish chronic renal failure model. Rats were randomly assigned to 4 groups: sham-operated group, CRF group, ferrous gluconate group and hemin group. At the 10th week after operation, serum creatinine, BUN, RBC, HGB and HCT were measured. Renal pathologic changes were observed. RT-PCR and immunohistochemistry were used to detect the expression and distribution of HO-1. RT-PCR and radioimmunoassay was used to determine the expression of ET-1 in the kidney and plasma. The results showed that as compared with CRF group, serum creatinine and BUN in hemin group were reduced significantly and nephrogenic anemia was improved markedly. Glomerular mesangial proliferation and interstitial lesion were also ameliorated significantly. Hemin not only increased the expression of HO-1 but also reduced the expression of ET-1 in the kidney. The level of ET-1 protein in the plasma was also reduced after hemin treatment. Most of these indexes were not obviously changed in ferrous gluconate group. It was suggested that through inducing the expression of HO-1 and reducing the level of ET-1 in the kidney and plasma, hemin plays an important protective role in 5/6 subtotal nephrectomized rats.

Topics: Animals; Endothelin-1; Heme Oxygenase-1; Hemin; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Random Allocation; Rats; Rats, Sprague-Dawley

In patients on chronic hemodialysis hypotensive episodes are frequently encountered during the course of treatment and the prevalence of atherosclerosis is increased. Endothelin-1 (ET-1), an endothelium-derived peptide with vasoconstrictive and mitogenic effects on smooth muscles, is involved in vascular tone regulation and in the pathogenesis of atherosclerosis. The aim of the present study was to investigate plasma ET-1 during hemodialysis treatment and to explore the probable influence of pre-existing hypertension. Forty-seven hemodialysis patients (21 females, mean age 62 +/- 12 years) were evaluated and hypertensive patients (n = 33) were compared to normotensive patients (n = 14). Relative blood volume changes (hemoglobinometry) and blood pressure were measured. Samples were taken before, every hour during and after hemodialysis. Plasma ET-1 was measured by enzyme-linked immunosorbent assay and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration rate of 2224 +/- 933 mL was performed. Total blood volume at the end of hemodialysis was 89.4 +/- 8.2% of the pretreatment volume. The fall in blood pressure (137/74 +/- 22/11 mmHg vs 127/73 +/- 30/14 mmHg) correlated with the decrease in blood volume (mean blood pressure: r = 0.33). Plasma ET-1 increased from 1.29 +/- 0.47 pg/mL before to 1.46 +/- 0.56 pg/mL (reference range 0.3-0.9) at the end of hemodialysis (P < 0.05). This rise was more pronounced in patients with hypertension than in normotensive individuals (P < 0.05). The change in blood volume (r = 0.41) and blood pressure (mean blood pressure: r = 0.34) correlated with plasma ET-1 at the end of hemodialysis (P < 0.05). Plasma ET-1 was enhanced in hemodialysis patients compared to normal subjects. During the hemodialysis session an increase in ET-1 was encountered, which was more pronounced in hypertensive than in normotensive patients and paralleled the hemodynamic changes. Apart from pre-existing hypertension, further factors potentially influencing ET-1 include local endothelial injury (arteriovenous fistula) and generalized bioincompatibility reactions (e.g. foreign surface contact) occurring during hemodialysis.

Topics: Aged; Blood Pressure; Blood Volume; Endothelin-1; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors

The role of endothelin-B (ETB) receptor in partial ablation-induced chronic renal failure was evaluated using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ETB receptor gene. After 5/6 nephrectomy in ETB-deficient homozygous and wild-type (+/+) rats, we measured the systolic blood pressure and renal functional parameters for 12 weeks. At the end of the experimental period, we collected an arterial blood sample and excised the remnant kidney, heart and aorta for biochemical measurements and histopathological studies. The ETBdeficient homozygous rats exhibited earlier and higher increases in systolic blood pressure, urinary protein excretion, blood urea nitrogen and plasma creatinine concentration, compared with cases in wild-type rats. Histopathologic examination of the kidney revealed glomerular and tubular lesions, alterations of which were more severe in homozygous than in wild-type rats. There was a significant increase in the renal endothelin-1 content in homozygous rats, but not in the wild-type rats. However, the aortic endothelin-1 contents were increased similarly in both groups. These results suggest that enhanced endothelin-1 production is at least partly responsible for the increased susceptibility to partial ablationinduced chronic renal failure in ETB receptor-deficient rats and that ETB receptor-mediated actions are protective against vascular and renal injuries in this disease.

Topics: Animals; Animals, Genetically Modified; Aorta; Blood Pressure; Blood Urea Nitrogen; Creatinine; Endothelin-1; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Nephrectomy; Rats; Receptor, Endothelin B; Time Factors; Up-Regulation

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB2), prostacyclin (6-keto-PGF1alpha), and cyclic guanosine 3',5'-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB2, and 6-keto-PGF1alpha were measured by radioimmunoassay. Plasma NOx was measured by high-performance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB2, 6-keto-PGF1alpha, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Biomarkers; Blood Pressure; Cyclic GMP; Endothelin-1; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Thromboxane B2; Time Factors; Treatment Outcome

A decreased GFR in the range of mild renal insufficiency and an increased urinary albumin excretion (UAE) rate in the range of microalbuminuria are important cardiovascular risk factors. Endothelin-1 (ET-1) has been suggested to be a major disease promoting factor in renal disease. The role of the ET-1 gene locus (EDN1) for renal function in the general nondiabetic population was evaluated. To explore the overall relevance of EDN1, two suitable single-nucleotide polymorphisms, EDN1 K198N and EDN1 T-1370G, were selected, and haplotype analysis was performed. Determined were genotypes in 7291 nondiabetic subjects from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Genetic analysis was related to UAE and GFR as continuous variables and to microalbuminuria and diminished filtration as dichotomous traits. In a logistic regression analysis, no significant higher risk for increased UAE, microalbuminuria, decreased GFR, or diminished filtration could be observed for either single-nucleotide polymorphism separately. Haplotype analysis revealed that individuals with the homozygous G-N haplotype (compound EDN1 -1370GG/198NN genotype) have a lower GFR than the remaining subjects (P < 0.05) and exhibit a significant higher risk for the presence of a diminished filtration (relative risk, 2.4; 95% confidence interval, 1.07 to 5.33; P < 0.05). Further analysis demonstrated no association between this haplotype and UAE or plasma ET-1 levels. Although a functional relevance of the EDN1 G-N haplotype itself remains unclear, the data demonstrate that genetic variation at the EDN1 locus has a significant effect on glomerular filtration but not on UAE in the general nondiabetic population.

Topics: Adult; Aged; Albuminuria; Case-Control Studies; Cohort Studies; Endothelin-1; Female; Glomerular Filtration Rate; Haplotypes; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Elevated serum concentration of cardiac troponin I (cTnl) is a highly sensitive and specific marker of myocardial damage. Patients with chronic renal failure (crf) treated by hemodialysis often have increased serum cTnl level without evidence of acute myocardial ischemia. In chronic HD patients, elevated serum concentration of endothelin-1 (ET-1) and angiotensin II have been reported which may be associated with ischemic heart disease. The aim of the present study was to investigate possible association between cTnl serum level, ET-I, angiotensin II, other cardiac markers and the structural changes of myocardium assessed by echocardiographic (ECHO) method. Fifty nine patients with crf treated by HD were studied. ECHO and ECG examinations were performed in all patients and serum levels of cTnl, endothelin-1 (ET-1), angiotensin II were evaluated. In all patients left ventricular mass (LVM) was increased, and in 78% of patients was found concentric hypertrophy of the heart while in 22% excentric hypertrophy was found. In 54 patients there was no ECG changes and ST segment depression in V4-V6 leads, less than 1 mm was found in 5 patients. Arterial hypertension was found in 44 patients (75%), systolic and diastolic pressure was significantly higher (p<0.05) than in a control group. Increased serum level of cTnl was found in 12.0% of HD patients, increased serum level of endothelin-1 and angiotensin II were found in all patients. LVM in HD patients with elevated cTnl levels was significantly higher than in patients with normal cTnl concentration. There was a positive correlation between LVM and cTnl levels, and between angiotensin II serum concentration and cTnl levels and between ET-1 serum level and RWT.. our findings suggest that elevated cTnl serum level reflect left ventricular hypertrophy and/or myocardial ischemia in HD patients, and indicate that ET-1 and angiotensin II might be associated with these conditions.

Topics: Electrocardiography; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardium; Renal Dialysis; Troponin I

Plasma endothelin (ET)-1 concentrations have been shown to be elevated in patients receiving calcineurin-inhibitors (CI). We investigated urinary and plasma ET-1 (uET-1, pET-1), BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble endothelin-converting enzyme (ECE) concentrations in 381 adult caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. Blood and urine probes were always drawn immediately before morning dosage of immunosuppressants. Mean of urinary protein excretion (meanProt) and mean of serum creatinine (meanCrea) were calculated from all available measurements in the most recent year. uET-1 and uBigET-1 were adjusted for urinary protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Patients (n=310) were on a cyclosporine A or FK506 (CI-group) based immunosuppression protocol, and 71 patients were immunosuppressed without use of CI (nonCI group). Time since transplantation was similar in both groups (mean+/-S.D.; CI-group: 7.55+/-2.50; nonCI-group: 7.74+/-3.06 years, P=0.240) as well as meanCrea (mean+/-S.D.; CI-group: 1.97+/-1.34; nonCI-group: 1.77+/-1.29 mg/dl, P=0.326). pET-1 was significantly higher in the CI-group, compared with nonCI (mean+/-S.D.; 0.87+/-1.4 versus 0.56+/-0.76 fmol/ml, P=0.011). pBigET-1 was similar (mean+/-S.D.; 0.85+/-1.41 versus 0.70+/-1.21 fmol/ml, P=0.33). ECE concentrations were higher in the CI group (mean+/-S.D.; 14.30+/-18.02 versus 9.23+/-7.42 ng/ml, P=0.001). uET-1/meanProt and uBigET-1/meanProt concentration were similar in the CI-group compared with the nonCI-group (mean+/-S.D.; uET-1/meanProt: 15+/-24 versus 21+/-40 pmol/g, P=0.139; uBigET-1/meanProt: 34+/-55 versus 19+/-23pmol/g, P=0.248). pET-1 elevation in patients receiving CI might be more likely to be due to elevated conversion of pBig-ET-1 by more ECE, and not to higher concentrations of pBigET-1.

Topics: Adult; Aspartic Acid Endopeptidases; Calcineurin Inhibitors; Cyclosporine; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Inhibitors; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Metalloendopeptidases; Protein Precursors; Tacrolimus; Transplantation, Homologous

Etiology of dialysis induced hypotension and hypertension remains speculative. There is mounting evidence that nitric oxide (NO) and endothelin (ET-1) may play a vital role in these hemodynamic changes. We examined the intradialytic dynamic changes in NO and ET-1 levels and their role in the pathogenesis of hypotension and rebound hypertension during hemodialysis (HD).. The serum nitrate + nitrite (NT), fractional exhaled NO concentration (FENO), L-arginine (L-Arg), NGNG-dimethyl-L-arginine (ADMA) and endothelin (ET-1) profiles were studied in 27 end-stage renal disease (ESRD) patients on HD and 6 matched controls. The ESRD patients were grouped according to their hemodynamic profile; Group I patients had stable BP throughout HD, Group II had dialysis-induced hypotension, and Group III had intradialytic rebound hypertension.. Pre-dialysis FENO was significantly lower in the dialysis patients compared to controls (19.3 +/- 6.3 vs. 28.6 +/- 3.4 ppb, P < 0.002). Between the experimental groups, pre-dialysis FENO was significantly higher in Group II (24.1 +/- 6.7 ppb) compared to Group I (17.8 +/- 5.6 ppb) and Group III (16.1 +/- 4.2 ppb; P < 0.05). Post-dialysis, FENO increased significantly from the pre-dialysis values (19.3 +/- 6.3 vs. 22.6 +/- 7.9 ppb; P=0.001). Pre-dialysis NT (34.4 +/- 28.2 micromol/L/L) level was not significantly different from that of controls (30.2 +/- 12.3 micromol/L/L). Serum NT decreased from 34.4 +/- 28.2 micromol/L/L at initiation of dialysis to 10.0 +/- 7.4 micormol/L/L at end of dialysis (P < 0.001). NT concentration was comparable in all the three groups at all time points. Pre-dialysis L-Arg (105.3 +/- 25.2 vs. 93.7 +/- 6.0 micromol/L/L; P < 0.05) and ADMA levels were significantly higher in ESRD patients (4.0 +/- 1.8 vs. 0.9 +/- 0.2 micromol/L/L; P < 0.001) compared to controls. Dialysis resulted in significant reduction in L-Arg (105.3 +/- 25.2 vs. 86.8 +/- 19.8 micromol/L/L; P < 0.005) and ADMA (4.0 +/- 1.8 vs. 1.6 +/- 0.7 micromol/L/L; P < 0.001) concentrations. Pre-dialysis ET-1 levels were significantly higher in ESRD patients compared to the controls (8.0 +/- 1.9 vs. 12.7 +/- 4.1 pg/mL; P < 0.002), but were comparable in the three study groups. Post-dialysis ET-1 levels did not change significantly in Group I compared to pre-dialysis values (14.3 +/- 4.3 vs.15.0 +/- 2.4 pg/mL, P=NS). However, while the ET-1 concentration decreased significantly in Group II (12.0 +/- 4.0 vs. 8.7 +/- 1.8 pg/mL, P < 0.05), it increased in Group III from pre-dialysis levels (12.8 +/- 3.8 vs. 16.7 +/- 4.5 pg/mL, P=0.06).. Pre-dialysis FENO is elevated in patients with dialysis-induced hypotension and may be a more reliable than NT as a marker for endogenous NO activity in dialysis patients. Altered NO/ET-1 balance may be involved in the pathogenesis of rebound hypertension and hypotension during dialysis.

Topics: Adult; Aged; Arginine; Endothelin-1; Female; Humans; Hypertension, Renal; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Renal Dialysis

Endothelin-1 (ET-1), acting mainly through the ET(A) receptor, is a potent endothelium-derived vasoconstrictor peptide. Circulating concentrations of ET-1 are increased in chronic renal failure (CRF) and may influence vascular tone.. We investigated dorsal hand vein responsiveness to local infusion of ET-1 and noradrenaline in 12 hypertensive and 12 normotensive CRF patients and in 12 age and sex matched control subjects. We also investigated dorsal hand vein responses to the ET(A) receptor antagonist, BQ-123, and the endothelium-independent vasodilator glyceryl trinitrate (GTN), in six patients with CRF.. The dose of noradrenaline causing a 50% of maximal vasoconstriction was similar in the hypertensive (32+/-11 pmol/min) and normotensive (26+/-7 pmol/min) CRF patients and control subjects (21+/-6 pmol/min). Vasoconstriction to ET-1 (5 pmol/min) was similar in CRF patients as a whole (AUC 35+/-5%) and controls (32+/-4%; P=0.70). However, venoconstriction was significantly less in hypertensive (23+/-6%) than in normotensive CRF patients (48+/-8%; P=0.01). Overall, venoconstriction to ET-1 correlated inversely with mean arterial blood pressure in the CRF patients (R=-0.43, P=0.04). In addition, basal vein size was smaller, and plasma endothelin concentrations greater, in the hypertensive CRF group. However, infusion of BQ-123 or GTN did not cause venodilatation in these subjects.. These studies are consistent with the hypothesis that elevated plasma ET-1 contributes to vascular tone, and elevated blood pressure, in hypertensive CRF patients, and is associated with vascular receptor downregulation consequent on the increased exposure to ET-1. The reduced vein size in CRF patients appears to be structural rather than functional in nature. Further long-term studies with endothelin antagonists are required to determine the pathophysiological role of ET-1 in the altered structure and function of blood vessels in patients with CRF.

Topics: Dose-Response Relationship, Drug; Endothelin-1; Female; Hand; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Vasoconstriction; Vasoconstrictor Agents; Veins

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Enalapril; Endothelin-1; Interleukin-1; Kidney Cortex; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

The pathological role of oxidative stress in patients treated by hemodialysis has gained increasing recognition in recent years. Because complications related to vascular access are a major source of morbidity, immunohistochemical evidence of oxidative stress and activation of growth factors were examined in native arteriovenous (AV) fistulae (n = 11) and expanded polytetrafluoroethylene (ePTFE) grafts (n = 15) recovered from hemodialysis patients at the time of surgical revision or resection. To show the presence of oxidative stress in tissues, three markers were chosen: N(epsilon)(carboxymethyl)lysine, a structurally identified advanced glycation end product; 4-hydroxy-2,3-nonenol, a lipid peroxidation product; and redox-active transition metals bound to proteins, a source of Fenton chemistry-generated free radicals. Markers of cell growth and proliferation were endothelin-1 (ET-1), a potent mitogenic peptide implicated in the formation of intimal hyperplasia; transforming growth factor-beta (TGF-beta), a stimulus to vascular cell growth and matrix production; and platelet-derived growth factor (PDGF), a mediator of intimal hyperplasia. All specimens studied showed significant intimal hyperplasia. In general, the neointima close to the vascular lumen of the AV fistula and the pseudointima close to the lumen of the ePTFE graft were positive for oxidative stress markers. At sites of injury, especially in the presence of histological evidence of inflammation and healing, expression of oxidative markers was particularly intense. Prominent staining of PDGF was shown at sites of anastomotic hyperplasia and in neovasculature. TGF-beta was associated with proliferation or repair in both AV fistulae and ePTFE grafts. ET-1 staining was most intense in the neointima and pseudointima. This study showed histochemical colocalization of markers of oxidative stress with growth factors known to contribute to intimal hyperplasia.

Topics: Adult; Aged; Arteriovenous Anastomosis; Arteriovenous Fistula; Arteriovenous Shunt, Surgical; Biomarkers; Constriction, Pathologic; Endothelin-1; Female; Growth Substances; Humans; Hyperplasia; Iron; Kidney Failure, Chronic; Lipid Peroxidation; Lysine; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Platelet-Derived Growth Factor; Polytetrafluoroethylene; Renal Dialysis; Transforming Growth Factor beta; Tunica Intima; Vascular Patency

To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Creatinine; Cyclic GMP; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Thromboxane B2; Vasomotor System

Children with end-stage renal disease (ESRD) often remain hypertensive despite bilateral nephrectomy and aggressive fluid removal on hemodialysis. We speculated that an extrarenal source of renin might contribute to the release of "tissular" angiotensin-II (AT-II) generating hypertension in anephric patients. At the same time, experimental evidence supports that peripheral AT-II vasoconstrictive effect is likely mediated by endothelin-1 (ET-1). Thus, it is conceivable that hypertension in ESRD patients may be due, in part, to a cascade involving vascular production and secretion of AT-II and ET-1. In order to establish the relationship between AT-II, ET-1, and blood pressure we performed a pilot study to measure predialysis systolic and diastolic blood pressures (SBP and DBP, respectively) and serum AT-II and ET-1 levels in 12 anephric children receiving hemodialysis. Predialysis AT-II and ET-1 levels were similar in all patients, and neither value correlated with their mean SBP or DBP. In patients with postdialysis hypertension, there was no correlation between predialysis AT-II and ET-1 plasma levels. We therefore find no evidence to suggest that vascular-mediated AT-II and/or ET-1 contributes significantly to hypertension in anephric patients.

Topics: Adolescent; Angiotensin II; Blood Pressure; Child; Diastole; Endothelin-1; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Nephrectomy; Postoperative Period; Renal Dialysis; Systole

The correction of anemia with human recombinant erythropoietin (rHuEPO) in end stage renal disease is associated with hypertension in about one third of hemodialysis patients. The pathogenesis of the rHuEPO-induced hypertension is still uncertain, though evidence of the involvement of endothelial cells has emerged. The aim of this study was to determine plasma endothelin-1 during hemodialysis and to compare the endothelin-1 levels in hemodialysis patients with and without rHuEPO substitution. Nineteen stable patients (13 male and 6 female, mean age 62 +/- 11 years) with end stage renal disease were studied. Cuprophan dialysers (GFS 12, Gambro, Lund, Sweden) were used for hemodialysis in all cases. rHuEPO (40 U/kg s.c.) was administered to 10 patients. Blood pressure (BP; RR mmHg) and blood volume changes (deltaBV; hemoglobinometry %) were serially measured. Samples were taken before and every hour during hemodialysis. Plasma endothelin-1 was measured by ELISA (R&D Systems, Minneapolis, USA) and corrected for hemoconcentration. Endothelin-1 concentration was elevated before commencement of hemodialysis (1.16 +/- 0.36 pg/ml) when compared to healthy controls (ref. 0.3-0.9) and increased to 1.47 +/- 0.51 pg/ml by the end of the session (p<0.05). In patients under rHuEPO-substitution plasma endothelin-1 was higher when compared to patients without substitution before (1.25 +/- 0.3 vs. 1.05 +/- 0.3 pg/ml) and at the end of HD (1.62 +/- 0.5 vs. 1.28 +/- 0.3 pg/ml, p<0.05). There was no difference in BP and deltaBV between the two groups during treatment. Plasma endothelin-1 was higher in hemodialysis patients and there was a continuous rise in plasma endothelin-1 during a session. Comparison of two groups of hemodialysis patients with and without s.c. rHuEPO-replacement treatment revealed a significantly higher plasma endothelin-1 concentration in patients with s.c. rHuEPO treatment. However, the elevated endothelin-1 levels were not accompanied by arterial hypertension.

Topics: Anemia; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric

Patients with chronic renal failure (CRF) face a markedly increased risk of cardiovascular death. CRF is frequently complicated by hypertension and changes in both the heart (left ventricular hypertrophy) and the vasculature (endothelial dysfunction and accelerated atherosclerosis). The mechanisms underlying changes in vascular function and specifically endothelial dysfunction are unclear. This present study therefore examined subcutaneous resistance artery function in vitro, comparing adult uremic patients and controls using wire myography.. Subcutaneous fat biopsies were obtained from 12 patients with CRF (median serum creatinine 735 micromol/L) at the time of renal transplantation or peritoneal dialysis catheter insertion, and from eight controls without renal disease at the time of abdominal surgery. Resistance arteries were mounted on a wire myograph. Their contractile ability was tested with high potassium depolarization, and endothelial integrity was tested by relaxation to acetylcholine. Cumulative concentration-response curves were then constructed for norepinephrine, endothelin-1, acetylcholine, and sodium nitroprusside (SNP).. Following preconstriction with norepinephrine, vessels from uremic patients vasodilated less well to acetylcholine compared with vessels from controls [maximum % relaxation 77% (range 41, 97) vs. 98% (78, 100), P < 0.001]. The vasodilation to SNP was similar [95% (63, 100) vs. 94% (71, 100), P = 0.751]. There was a trend toward increased maximum pressure (kPa) achieved with both norepinephrine and endothelin-1 in vessels from uremic patients, and the contractions to both of these agents were more prolonged in the uremic vessels.. The pattern of normal vasodilation to SNP but reduced vasodilation to acetylcholine is consistent with endothelial dysfunction due to impaired nitric oxide (NO) production in uremic vessels. Similar results have been demonstrated in vivo in uremia, one suggested mechanism being accumulation of endogenous inhibitors of NO synthase such as asymmetric dimethylarginine (ADMA). This in vitro study suggests that a short-lived circulating factor is not entirely responsible and that there may be an inherent abnormality in endothelial function in uremia, although the exact pathophysiology remains unclear. Endothelial dysfunction may predispose the patient to accelerated atherosclerosis and may be involved in the pathogenesis of hypertension in end-stage renal failure.

Topics: Acetylcholine; Adult; Aged; Arteries; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Humans; In Vitro Techniques; Kidney Failure, Chronic; Middle Aged; Myography; Nitroprusside; Norepinephrine; Uremia; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Topics: Acid-Base Equilibrium; Endothelin-1; Humans; Hydrogen-Ion Concentration; Kidney Failure, Chronic; Kidney Tubules

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 +/- 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 +/- 1.1 ng/l; n = 10), normals (1.2 +/- 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 +/- 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 +/- 0.6 vs. 0.89 +/- 0.05 mg/dl, P < 0.05), creatinine clearance (107 +/- 9 ml/min vs. 44.6 +/- 5.5 ml/ min, P < 0.001), and bilirubin (11.4 +/- 3.8 vs. 3.7 +/- 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS.

Topics: Acute Kidney Injury; Analysis of Variance; Bilirubin; Biomarkers; Creatinine; Endothelin-1; Hepatorenal Syndrome; Humans; Kidney Failure, Chronic; Liver Failure; Liver Transplantation; Postoperative Complications; Reference Values; Time Factors

Genetic factors have been implicated in the development of the common aetiologies of end-stage renal disease (ESRD), including renal failure attributed to hypertension, diabetes mellitus, systemic lupus erythematosus and human immunodeficiency virus infection. Nitric oxide (NO) and endothelin are powerful vasoactive mediators involved in inflammation and regulation of vascular tone and blood pressure. We evaluated the role of the neuronal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide synthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans.. The study population for the linkage and association analyses in ESRD consisted of 361 individuals from 168 multiplex African-American families. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample. In addition, a mutation, Glu298Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) marker in intron 4 of NOS3 were evaluated in the sibling pairs and in an additional 92 unrelated African-Americans with type 2 diabetes mellitus-associated ESRD (singletons). Association analyses utilized the relative predispositional effect method. Model independent linkage analyses were performed using GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software.. Significant evidence for association with ESRD was detected for alleles 7 and 9 of the NOS1 gene (11.9 and 34.2%, respectively, in unrelated probands of ESRD families versus 6.5 and 27.5%, respectively, in race-matched controls, both P:<0.01). These associations were maintained when the unrelated first sibling from each family was used in a case-control comparison and was most pronounced in the non-diabetic ESRD cases. The NOS3 and EDN-1 markers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel endothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Significant evidence for linkage was not detected between the NOS genes or the EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were stratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies).. Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted.

Topics: Adult; Amino Acid Substitution; Base Sequence; Black or African American; Black People; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Exons; Genetic Markers; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Microsatellite Repeats; Minisatellite Repeats; Molecular Sequence Data; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; North Carolina; Nuclear Family

Recently, it was reported that blood vessel immunoreactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET(A) and nonselective ET(A)/ET(B) receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk. In protocol A, half of the rats in each group were simultaneously treated with the ET(A)/ET(B) receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET(A) receptor antagonist LU 135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study. rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160+/-7 mmHg versus 187+/-9 mmHg, P < 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172+/-10 mmHg versus 168+/-9 mmHg, NS). In summary, selective ET(A) but not ET(A)/ET(B) receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ET(A) and ET(B) receptors.

Topics: Animals; Blood Pressure; Bosentan; Creatinine; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Recombinant Proteins; Sulfonamides

Elevated plasma and urine endothelin-1 (ET-1) levels have been reported in renal failure and may be involved in renal disease progression. We investigated whether these changes are related to increased vascular and renal ET-1 production in the pole resection remnant kidney model of chronic renal failure in the rat.. Uraemic Wistar rats were prepared by surgical renal mass 5/6 ablation and compared with sham-operated controls (protocol 1). Immunoreactive-ET-1 (ir-ET-1) concentration was measured by radioimmunoassay after sample extraction and purification. To investigate the functional role of ET-1 during the progression of chronic renal failure, uraemic rats (protocol 2) were treated with either the vehicle or the ET-1 type A (ET(A)) receptor antagonist LU135252 (LU).. Systolic blood pressure and serum creatinine, as well as urinary volume and proteinuria, were significantly higher, whereas creatinine clearance was reduced in uraemic rats compared with sham-operated controls. As expected, plasma and urine ir-ET-1 concentrations were increased in uraemic rats (P<0.01) and were related to the increased ir-ET-1 levels in blood vessels and glomeruli (P<0.001). Positive correlation was found between plasma, thoracic aorta and mesenteric arterial bed ir-ET-1 levels and systolic blood pressure, as well as blood vessel hypertrophy. In addition, increased urinary ir-ET-1 excretion correlated with the rise in serum creatinine and proteinuria. In protocol 2, a 3-week treatment period with LU was initiated once uraemia and hypertension were established. In untreated uraemic rats, systolic blood pressure increased further (P<0.05), but this was not the case in LU-treated uraemic rats. At the end of treatment, serum creatinine and proteinuria were significantly lower (P<0.05) and creatinine clearance was higher (P<0.01) in LU-treated rats compared with uraemic-untreated animals. While plasma ir-ET-1 concentration was similar in the two groups, ir-ET-1 concentration in thoracic aorta, mesenteric arterial bed, renal cortex and urine was significantly lower in LU-treated animals (P<0.01). In addition, heart, thoracic aorta and mesenteric arterial wet weight to body weight ratios were also significantly reduced in LU-treated uraemic rats (P<0.05).. Elevated plasma ET-1 concentration and urinary ET-1 excretion in rats with renal mass ablation are related to enhanced ET-1 production in vascular and renal tissues, thus suggesting an important role for ET-1 in the aggravation of hypertension and vascular hypertrophy as well as in the progression of renal insufficiency. These pathophysiological effects are prevented by treatment with selective ET(A) receptor blockade.

Topics: Animals; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Kidney; Kidney Failure, Chronic; Male; Osmolar Concentration; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Uremia

The present study suggests that ET-1 is involved in the pathogenesis of uraemic cardiac hypertrophy and in the progression of renal failure in rats with subtotal nephrectomy examined after an intermediate period of 12 weeks of renal failure. Furthermore, proteinuria is reduced by the selective ETA receptor antagonist more than by the unselective ETAB receptor antagonist, without reducing the blood pressure. ET receptor blockade might preserve renal function by reduction of protein excretion. In addition, ET receptor antagonists influence the aldosterone system. In our animal studies, the medication was well tolerated. Our study results provide a possible therapeutic approach using ET receptor antagonists for cardiac hypertrophy and renal protein excretion by blockade of endogenous ET-1. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life expectancy of patients suffering from chronic renal failure, of patients on dialysis or after kidney transplantation.

Topics: Animals; Blood Pressure; Cardiomegaly; Endothelin Receptor Antagonists; Endothelin-1; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysis > or = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressure < or = 19 mm Hg and > or = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P < 0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

Topics: Acute Disease; Anions; Blood Pressure; Cyclic GMP; Endothelin-1; Female; Heart Rate; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Renal Dialysis; Sympathetic Nervous System

The present study was performed to compare circulating levels of tumour necrosis factor-alpha (TNFalpha) and plasma endothelin 1 (ET-1), of hypertensive patients with or without renal failure and with those of normotensive healthy subjects. The study population consisted of 21 healthy normotensive subjects and 22 hypertensive patients, 11 with essential hypertension, and 11 with hypertension and chronic renal failure (CRF). Plasma ET-1 levels, serum TNFalpha and creatinine, creatinine clearance, 24-h urinary albumin excretion (UAE) were assayed, and 24-h blood pressure monitoring was obtained in all subjects. Office blood pressure was similar between hypertensive patients with and without CRF. However, 24-h blood pressure was greater in patients with CRF than in those with essential hypertension and normal renal function. Patients with hypertension manifested greater ET-1 levels than normotensive subjects (P < 0.01). Serum TNFalpha and ET-1 levels were higher in hypertensive patients with CRF than in patients with essential hypertension and normotensive subjects. In the 22 hypertensive patients, TNFalpha levels were negatively correlated with serum creatinine (r=0.60; P < 0.01), and ET-1 levels were positively correlated with UAE (r=0.47, P < 0.05). The present study has shown that hypertensive patients, and particularly those with renal insufficiency, manifest abnormal blood levels of ET-1 and TNFalpha. These factors could contribute to both cardiovascular and renal damage.

Topics: Adult; Albuminuria; Blood Pressure Monitoring, Ambulatory; Creatinine; Endothelin-1; Female; Humans; Hypertension; Hypertension, Renovascular; Kidney Failure, Chronic; Male; Middle Aged; Tumor Necrosis Factor-alpha

Recently, we have reported that endothelin-1 (ET-1) production is increased in blood vessels and glomeruli of rats with chronic renal failure. This study was design to investigate the role of angiotensin II (Ang II) in endogenous ET-1 production in rats with reduced renal mass. One week after subtotal (5/6) nephrectomy, uremic rats were divided into three groups, and received either no treatment, the Ang II subtype 1 receptor (AT1) antagonist losartan (10 mg/kg/day), or the angiotensin-converting enzyme inhibitor (ACE-I) captopril (30 mg/kg/day) for 6 weeks. Sham-operated rats were used as controls and received no treatment. The levels of immunoreactive ET-1 (ir-ET-1) in plasma and urine, as well as in vascular and renal tissues, were determined by radioimmunoassay (RIA) after extraction. In uremic rats, losartan and captopril completely prevented the increase in systolic blood pressure. At week 6, plasma ir-ET-1 was similar in the different groups of uremic rats and in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed, the thoracic aorta, preglomerular arteries, and glomeruli, as well as urinary ir-ET-1 excretion were significantly greater in uremic-untreated rats compared to controls (P < .01). Treatment of uremic rats with losartan or captopril reduced irET-1 concentration in the thoracic aorta and preglomerular arteries (P < .05), but ir-ET-1 concentration in the mesenteric arterial bed was unchanged. Although both drugs completely prevented the increase in proteinuria, losartan but not captopril significantly reduced ir-ET-1 concentration in glomeruli (P < .05) and normalized urinary ir-ET-1 excretion. This indicates that increased ET-1 production in blood vessels and glomeruli of uremic rats is modulated, at least in part, by Ang II through the AT1 receptor. The beneficial effects of the AT1 antagonist losartan could be attributable to the attenuation of Ang II-induced ET-1 production in this rat remnant kidney model of chronic renal failure, whereas those of the ACE-I captopril are not related to changes in ET-1 production in glomeruli.

Topics: Angiotensin II; Animals; Blood Pressure; Blood Vessels; Captopril; Endothelin-1; Kidney Failure, Chronic; Kidney Glomerulus; Losartan; Male; Nephrectomy; Rats; Rats, Sprague-Dawley

Treatment with recombinant human erythropoietin (rHuEPO) has solved the problem of anemia in patients on dialysis. However, its application to predialysis patients has raised some doubts about its effects on the progression of renal disease and on blood pressure (BP) and hemodynamic regulation. We have prospectively studied over at least 6 months a group of 11 predialysis patients receiving rHuEPO treatment (initial dose, 1,000 U subcutaneously three times a week). Clinical assessment and biochemical and hematologic measurements were made once every 2 weeks. Twenty-four-hour ambulatory BP monitoring, echocardiography, and determination of neurohumoral mediators of hemodynamics were performed once every 3 months. An adequate hematologic response was found (hemoglobin, 11.7 +/- 0.4 g/dL v 9 +/- 0.3 g/dL) without changes in the progression of renal disease. A decrease in cardiac output and an increase in total peripheral resistance was seen as anemia improved. A trend toward decreased left ventricular (LV) thickness and a significant decrease in LV mass index (from 178.2 +/- 20.6 g/m2 to 147.3 +/- 20.6 g/m2) were observed. Blood pressure control did not improve; moreover, in some patients an increase in systolic values was detected by ambulatory BP. Casual BP remained seemingly stable. Sequential determinations of neurohumoral mediators of hemodynamic substances (endothelin, renin, norepinephrine, epinephrine, dopamine) failed to explain these results. Ambulatory BP reveals a worse control in some patients who were previously hypertensive and confirms the utility of this technique in the assessment of patients under erythropoietin treatment. The trend toward LV hypertrophy regression without improved BP control confirms the role of anemia among the multiple factors leading to LV hypertrophy in end-stage renal disease (ESRD), and opens therapeutic possibilities. Better control of BP may avoid a potential offsetting of beneficial effects that correcting anemia would have on the cardiovascular system.

Topics: Adult; Aged; Anemia; Blood Pressure; Catecholamines; Echocardiography; Endothelin-1; Erythropoietin; Female; Hemodynamics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renin; Ventricular Function, Left

The purpose of this study was to determine the effect of chronic ETA receptor blockade, using the orally active antagonist A-127722 in rats with reduced renal mass. The initial series of experiments was designed to characterize the effects of the ETA-selective antagonist A-127722 on arterial pressure and renal function when administered via drinking water over a 4-wk period. Male Sprague-Dawley rats were acclimated to metabolism cages, and baseline 24-h urine collections were obtained. A-127722 was placed in the drinking water at concentrations that delivered doses of 1 to 10 mg/kg per d. The compound had no effect on any of the variables measured, including arterial pressure, food and water intake, urine volume, and sodium and potassium excretion. In a separate group of rats, ETA receptor blockade was verified after 3 d of drinking water containing A-127722. Rats were anesthetized, a jugular vein catheter was inserted for infusions, and a femoral artery catheter was used for monitoring arterial pressure. The pressor response to intravenous injection of Big endothelin-1 (1 nmol/kg, intravenously) was inhibited by > 50% in rats given A-127722 at 10 mg/kg per d, which confirms the efficacy of A-127722 in blocking ETA-mediated responses when placed in drinking water. In an additional series of experiments, rats were anesthetized, the right kidney was removed, and two of three major branches of the left renal artery were ligated. After recovery, rats were returned to their cages and given A-127722 in the drinking water to deliver 1 or 10 mg/kg per d. Control rats underwent the same surgical procedures but were given tap water to drink. After 4 wk, rats that were treated with A-127722 developed similar increases in arterial pressure and urinary protein excretion as rats that received tap water. Therefore, although the ETA receptor antagonist A-127722 can inhibit ETA-mediated hypertension, it has no effect on hypertension produced by a reduction in renal mass. It is concluded that ETA receptor activation does not play a significant role in the functional derangements associated with renal mass reduction in the rat.

Topics: Administration, Oral; Animals; Atrasentan; Blood Pressure; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Protein Precursors; Proteinuria; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

Patients undergoing hemodialysis, present platelets (PLTs) with physiological dysfunction. Aggregated PLTs stimulate endothelin-1 (ET-1) secretion from endothelial cells. In turn, ET-1 abolishes PLT aggregation. The aim of this study was to determine any presence of ET-1 in the PLTs of hemodialysed patients and to compare its levels with normal subjects. Platelets, isolated from hemodialysed patients, revealed lower aggregation (76 +/- 13%) compared with healthy subjects (96 +/- 2%). Plasma ET-1 was increased in hemodialysed patients 23.5 +/- 3.2 fmol/ml, vs. 10.9 +/- 1.6 fmol/ml in normal subjects. Immunoreactive endothelin-1 was detected in the platelets of both groups. The intraplatelet ET-1 of hemodialysed patients was 13.8 +/- 3.1 fmol/mg protein, vs. 7.9 +/- 1.3 fmol/mg protein in normal individuals. Total RNA was isolated from platelets and reverse transcriptase-mediated polymerase chain reaction (RT-PCR) revealed no presence of the preproET-1 mRNA in either normal or hemodialysed platelets. This suggests that ET-1 is internalized from the plasma. In summary, platelets contain but do not express ET-1. The increased levels of ET-1 in the platelets of the hemodialysed patients may be partly responsible for their lower aggregation.

Topics: Adult; Blood Platelets; Blood Protein Electrophoresis; Case-Control Studies; Electrophoresis, Polyacrylamide Gel; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Platelet Aggregation; Polymerase Chain Reaction; Renal Dialysis

Surgical ablation of renal mass leads to a reduction in kidney function and commonly to the development of hypertension and chronic renal failure (CRF) in rats. The objective of this study was to determine whether endothelin (ET)-1 is involved in the maintenance of the hypertension that accompanies loss of renal mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a selective, orally active ET(A) receptor antagonist, in a group of rats made hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[-1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4 micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6 reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days resulted in a sustained reduction in BP. Sham-operated rats also showed a slight hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma creatinine, urinary protein excretion, and creatinine clearance were not altered by PD 155080 administration in RRM or sham rats. In a third experiment, we investigated the contribution of the renin-angiotensin system to BP control in RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment days, and this antihypertensive effect was not altered by coadministration of the angiotensin-converting enzyme inhibitor enalapril in the drinking water (508 micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in established RRM hypertension through activation of the ET(A) receptor subtype, (2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism is not opposed by the renin-angiotensin system.

Topics: Animals; Blood Pressure; Dioxoles; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypertension, Renal; Infusions, Intravenous; Kidney Failure, Chronic; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renin-Angiotensin System

Elevated plasma and urinary endothelin-1 (ET-1) levels have been reported in patients with renal failure as well as in remnant kidney models of chronic renal failure. We investigated whether these changes are related to increased ET-1 production in cardiovascular and renal tissues of rats with reduced renal mass. In uremic rats, systolic blood pressure rose in parallel with the progression of renal insufficiency. At week 6, changes in systolic blood pressure were positively correlated with serum creatinine levels (r = 0.728, p < 0.01). Plasma immunoreactive ET-1 (ir-ET-1) concentration was similar in uremic rats and sham-operated controls. In contrast, urinary ir-ET-1 excretion was significantly greater in uremic rats and was correlated with the elevation of serum creatinine and proteinuria (r = 0.795, and 0.922, p < 0.01, respectively). Compared to the controls, ir-ET-1 concentration in the thoracic aorta, preglomerular arteries and glomeruli were 1.4-, 3.5- and 6.7-fold higher, respectively, in uremic rats (p < 0.01) than in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed and the left ventricle remained similar in the 2 groups, whereas it was significantly lower in the renal papilla of uremic rats (p < 0.01). Thus, ET-1 production is unchanged or slightly increased in extrarenal cardiovascular tissues of rats with reduced renal mass. In contrast, ET-1 production is significantly augmented in preglomerular arteries and glomeruli, but reduced in the papilla, suggesting that increased urinary ir-ET-1 excretion in uremic rats reflects ET-1 overproduction in the former renal tissues. Elevated ET-1 production in blood vessels and glomeruli may thus play a key role in the aggravation of hypertension and the progression of renal insufficiency in this rat remnant kidney model of chronic renal failure.

Topics: Animals; Biomarkers; Blood Vessels; Disease Models, Animal; Disease Progression; Endothelin-1; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Uremia

Plasma endothelin-1 (ET-1) and calcitonin gene related peptides (cGRP) were studied by immunoradiological method in 60 hemodialysis (HD) patients. The results showed that: (1) Plasma level of ET-1 and cGRP were increased in the HD patients. (2) Plasma level of ET-1 and cGRP varied in different times of HD. (3) A significantly positive relation between plasma ET-1 and blood pressure (BP) existed in the HD patients, while a significantly negative relation between plasma cGRP and BP existed in the HD patients. The results suggest that ET-1 and cGRP are major factors which lead to BP changes in HD patients.

Topics: Adult; Blood Pressure; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

In order to investigate endothelial cell dysfunction in patients with impaired renal function, we measured circulating endothelin (ET-1) and thrombomodulin (Tm) concentrations used as markers for endothelial cell injury in patients with renal failure. 1) ET-1 and Tm were significantly higher in patients with renal failure and pre-dialysis patients than in normal subjects. Tm in CRF patients was significantly greater than that in ARF patients. In contrast, ET-1 was significantly greater in ARF than in CRF. 2) A positive correlation was found between serum creatinine concentration (Cr) and Tm in pre-dialysis patients. However, no correlation was found between Cr and ET-1. 3) A positive correlation was found between Tm and the duration of dialysis in HD patients, but not in CAPD patients. 4) With the improvement of renal function after regular HD treatment, a substantial reduction was found in ARF patients in both Tm and ET-1, but not in CRF patients. The present study suggests the presence of endothelial cell dysfunction in patients with impaired renal function. The progression of endothelial cell damage may differ between patients on HD and those on CAPD. In addition, it is suggested that endothelial cell dysfunction reverses in ARF patients with improved renal function.

Topics: Acute Kidney Injury; Creatinine; Endothelin-1; Endothelium; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Renal Insufficiency; Thrombomodulin

Patients with chronic renal failure show almost equal levels of sodium excreted in the urine as healthy subjects through an increase of the fractional excretion sodium (FE(Na)). The mechanisms of this adaptation, however, are unknown. Recently, urinary arginine vasopressin (AVP) has been shown to inhibit the antidiuretic action of plasma AVP in the collecting ducts of rabbits and rats. In this article, the roles of plasma and urinary AVP are examined with other hormones in the sodium excretion of 57 patients with chronic renal disease. The fractional excretion of AVP, plasma atrial natriuretic peptide (ANP) and endothelin-1 (ET-1), urinary ET-1, and FE(ET-1) correlated with the decrease of creatinine clearance (Ccr). Multiple and stepwise regression analyses showed that FE(AVP) is the major dependent determinant for FE(Na) (adjusted r2 = 0.78). These results suggest that the increase of AVP excretion per remaining nephron could be a cause of the increase of FE(Na) in patients with renal failure. Although plasma AVP works as an antidiuretic hormone, urinary AVP serves as an intrinsic diuretic, especially in patients with chronic renal failure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arginine Vasopressin; Atrial Natriuretic Factor; Child; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Regression Analysis; Sodium

We analysed the effect of hemodialysis (HD) on endothelin (ET) plasma level in children with terminal renal failure. Twenty-five patients (pts) and 27 healthy children as controls were included in the study. There was no difference in ET plasma levels in pts before HD (1.97 +/- 1.45) and controls (2.08 +/- 1.47), but ET increased in plasma of pts after HD (4.10 +/- 3.66). To estimate the relationship of volume depletion or depuration on ET plasma level changes in pts during HD, ET was measured at three time points of HD (before ultrafiltration-UF, after UF, and after HD without fluid removal) in 10 pts. ET level was not significantly changed after UF (1.93 +/- 2.25 vs 1.71 +/- 1.50; ns), but was significantly increased after depuration (4.46 +/- 3.56; p < 0.05). There was no correlation between ET and blood pressure in controls and pts in either period of testing, neither with plasma renin activity, left ventricular mass index, and body weight changes during HD.

Topics: Adolescent; Child; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Uremia

Several studies have indicated that endothelin-1 (ET-1) and endothelin-3 (ET-3) are produced by different cells. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3. In the present study, we measured plasma concentrations of both ET-1 and ET-3 by sandwich-enzyme immunoassays which we developed recently in patients on chronic hemodialysis, age-matched normal subjects, patients with acute myocardial infarction, patients undergoing surgery, and healthy subjects before and after strenuous endurance exercise. Plasma levels of ET-1 and ET-3 were demonstrated to be altered differently in the above conditions in humans. Although the exact origin of circulating endothelins has yet to be elucidated, the different alterations of plasma levels suggest that both ET-1 and ET-3 may play different roles in physiological and/or pathophysiological responses to various conditions in humans.

Topics: Adult; Aged; Endothelin-1; Endothelins; Exercise; Female; Humans; Immunoenzyme Techniques; Intraoperative Period; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Protein Precursors; Renal Dialysis