endothelin-1 and Renal-Insufficiency--Chronic

Metabolic acidosis affects about 15% of patients with chronic kidney disease. As kidney function declines, the kidneys progressively fail to eliminate acid, primarily reflected by a decrease in ammonium and titratable acid excretion. Several studies have shown that the net acid load remains unchanged in patients with reduced kidney function; the ensuing acid accumulation can precede overt metabolic acidosis, and thus, indicators of urinary acid or potential base excretion, such as ammonium and citrate, may serve as early signals of impending metabolic acidosis. Acid retention, with or without overt metabolic acidosis, initiates compensatory responses that can promote tubulointerstitial fibrosis via intrarenal complement activation and upregulation of endothelin-1, angiotensin II, and aldosterone pathways. The net effect is a cycle between acid accumulation and kidney injury. Results from small- to medium-sized interventional trials suggest that interrupting this cycle through base administration can prevent further kidney injury. While these findings inform current clinical practice guidelines, large-scale clinical trials are still necessary to prove that base therapy can limit chronic kidney disease progression or associated adverse events.

Topics: Acidosis; Aldosterone; Ammonium Compounds; Angiotensin II; Citrates; Endothelin-1; Humans; Kidney; Renal Insufficiency, Chronic

Hyperlipidemia and oxidative stress are indispensable features of chronic kidney disease (CKD) that favor the development of atherogenic plaques and cardiovascular disease (CVD). A number of vasoactive mediators including proprotein convertase subtilisin-kexin type 9 (PCSK9), endothelin-1, nitric oxide, and angiotensin II have fundamental roles in the pathophysiology of atherosclerotic events; moreover, their levels are affected by dyslipidemia and oxidative stress due to renal dysfunction. Therefore, therapeutic measures aimed at correcting dyslipidemia and alleviating oxidative stress could potentially protect against CVD in CKD patients. In this review, we discuss the relation between dyslipidemia, oxidative stress, and vasoactive mediators as well as the available treatment options against these disturbances in CKD patients.

Topics: Angiotensin II; Dyslipidemias; Endothelin-1; Humans; Nitric Oxide; Oxidative Stress; Proprotein Convertase 9; Renal Insufficiency, Chronic

: Kidney damage is a common consequence of arterial hypertension, but is also a cause of atherogenesis. Dysfunction and/or harm of the endothelium in glomeruli and tubular interstitium damage the function of these structures and translates into dynamic changes of filtration fraction, with progressive reduction in glomerular filtration rate, expansion of extracellular fluid volume, abnormal ion balance, and hypoxia, ultimately leading to chronic kidney disease. Considering the key role played by endothelial dysfunction in chronic kidney disease, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension have critically reviewed available knowledge on the mechanisms underlying endothelial cell injury. This resulted into two articles: in the first, we herein examine the mechanisms by which endothelial factors induce vascular remodeling and the role of different players, including endothelin-1, the renin-angiotensin-aldosterone system and their interactions, and of oxidative stress; in the second, we discuss the role of endothelial dysfunction in the major disease conditions that affect the kidney.

Topics: Aldosterone; Animals; Arterial Pressure; Consensus; Endothelin-1; Endothelium, Vascular; Fibrosis; Glomerular Filtration Rate; Glycocalyx; Humans; Hypertension; Kidney; Nitric Oxide; Oxidative Stress; Renal Insufficiency, Chronic; Renin-Angiotensin System; Vascular Remodeling; Vasoconstriction; Vasodilation

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

Topics: Angiogenesis Inhibitors; Animals; Consensus; Diabetic Nephropathies; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Humans; Hyperhomocysteinemia; Hypertension; Kidney; Kidney Transplantation; Pre-Eclampsia; Pregnancy; Renal Insufficiency, Chronic; Vitamin D

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.

Topics: Animals; Antihypertensive Agents; Diuretics; Endothelin A Receptor Antagonists; Endothelin-1; Humans; Hypertension; Receptor, Endothelin A; Renal Insufficiency, Chronic; Renin-Angiotensin System

Endothelin-1 (ET-1) is the most potent vasoconstrictor, and is involved in the renal regulation of salt and water homeostasis. When produced in excess in the kidney, ET-1 promotes proteinuria and tubulointerstitial injury. There is great interest in the clinical use of endothelin receptor antagonists (ERAs) in chronic kidney disease (CKD), mainly in diabetic nephropathy (DN). Areas covered: Physiopathological actions of ET-1 on the kidney. Both dual ETAR/ET

Topics: Animals; Atrasentan; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Humans; Proteinuria; Pyrrolidines; Renal Insufficiency, Chronic

Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in treatment of chronic kidney diseases (CKD). However, reversal of the course of CKD or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. New treatments are needed to enhance protective actions of RAAS inhibitors (RAASis), such as angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and improve prognosis in CKD patients. Inhibition of endothelin (ET) system in combination with established RAASis may represent such an approach. There are complex interactions between both systems and similarities in their renal physiological and pathophysiological actions that provide theoretical rationale for combined inhibition. This view is supported by some experimental studies in models of both diabetic and nondiabetic CKD showing that a combination of RAASis with ET receptor antagonists (ERAs) ameliorate proteinuria, renal structural changes, and molecular markers of glomerulosclerosis, renal fibrosis, or inflammation more effectively than RAASis or ERAs alone. Practically all clinical studies exploring the effects of RAASis and ERAs combination in nephroprotection have thus far applied add-on designs, in which an ERA is added to baseline treatment with ACEIs or ARBs. These studies, conducted mostly in patients with diabetic nephropathy, have shown that ERAs effectively reduce residual proteinuria in patients with baseline RAASis treatment. Long-term studies are currently being conducted to determine whether promising antiproteinuric effects of the dual blockade will be translated in long-term nephroprotection with acceptable safety profile.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Endothelin Receptor Antagonists; Endothelin-1; Humans; Renal Insufficiency, Chronic; Renin-Angiotensin System

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.

Topics: Adaptive Immunity; Animals; Carbon Monoxide; Carrier Proteins; Endothelin-1; Endothelium, Vascular; Epigenesis, Genetic; Female; Heme Oxygenase (Decyclizing); Humans; Immunity, Innate; Neovascularization, Physiologic; Nitric Oxide; Placenta; Placentation; Podocytes; Pre-Eclampsia; Pregnancy; Receptors, Notch; Renal Insufficiency, Chronic; Signal Transduction

There is an increasing number of clinical studies suggesting that acute kidney injury (AKI) can be complicated by the onset of progressive renal disease. Indeed, given the frequency of AKI in hospitalized patients, it could potentially be a leading cause of, or contributor to, end-stage renal disease. Insights into the natural history of AKI and potential mechanisms for disease progression can be gleaned from experimental studies. Although such studies underscore the principle that AKI can 'heal with defects', whether ongoing renal disease develops remains a subject of debate. Indeed, in the aftermath of AKI, a variety of secondary renal protective pathways are activated, which may retard or prevent severe chronic kidney disease. Furthermore, the onset of acute uremia per se may exert surprisingly potent renal protective effects. The purpose of this brief report is to review some of the clinical and experimental data that deal with these complex issues.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Blood Urea Nitrogen; Disease Models, Animal; Disease Progression; Endothelin-1; Glucocorticoids; Humans; Kidney; Nephritis, Interstitial; Renal Insufficiency, Chronic; Renal Replacement Therapy; Reperfusion Injury; Uremia

There is a well-documented association between erythropoiesis-stimulating agents (ESAs) and hypertension in chronic kidney disease. Studies suggest that the mechanism for this is multifactorial. First, some chronic kidney disease patients may have a limited ability to accommodate a rapid increase in red cell volume because of a decreased glomerular filtration rate, left ventricular hypertrophy, and decreased arterial compliance. Second, there is likely a direct vasoconstrictor effect of ESAs. Although no large randomized controlled trials of ESAs have been designed with blood pressure as an a priori outcome, several meta-analyses have explored this relationship and generally support the existence of ESA-induced hypertension. There are as of yet no data directly linking ESA-induced hypertension with increased cardiovascular morbidity and mortality. Despite this, clinicians should be vigilant for ESA-induced hypertension, use caution when using ESAs in patients with resistant hypertension, and be attentive to the rate of hemoglobin increase in patients with poorly controlled blood pressure.

Topics: Anemia; Blood Pressure; Drug Resistance; Endothelin-1; Erythropoietin; Hematinics; Humans; Hypertension; Nitric Oxide; Recombinant Proteins; Renal Insufficiency, Chronic; Renin-Angiotensin System

Hypertension contributes greatly to global disease burden and in many patients current treatments do not adequately control blood pressure (BP). Endothelin-1 (ET-1) is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, including the hypertension that is often associated with chronic kidney disease (CKD) and the metabolic syndrome. ET receptor antagonists, currently licensed for the treatment of pulmonary arterial hypertension and scleroderma-related digital ulcers, are being investigated for the treatment of hypertension. Clinical trials have addressed the use of ET receptor antagonists as monotherapy in primary hypertension, as an add-on therapy in resistant hypertension and in CKD. This review will evaluate the current evidence regarding the therapeutic potential of ET receptor antagonists in hypertension, as well as highlighting important issues that still need to be addressed.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension; Renal Insufficiency, Chronic

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

Topics: Adult; Animals; Diuresis; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Kidney Tubules; Male; Natriuresis; Receptors, Endothelin; Renal Insufficiency, Chronic; Sodium; Treatment Outcome; Water-Electrolyte Balance

Endothelin 1 (ET-1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET-1 peptides, endothelin-like domain peptide (ELDP) and C-terminal pro-ET-1 (CT-proET-1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists.. We assessed plasma and urine ELDP and plasma CT-proET-1 in CKD patients with minimal comorbidity. Next, in a randomized double-blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT-proET-1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT-proET-1. Sitaxentan increased both plasma ELDP and CT-proET-1 (baseline versus week 6±SEM: ELDP, 11.8±0.5 versus 13.4±0.6 fmol/mL; CT-proET-1, 20.5±1.2 versus 23.3±1.5 fmol/mL; both P<0.0001). Plasma ET-1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT-proET-1 correlated negatively with 24-hour urinary sodium excretion.. ELDP and CT-proET-1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents.. URL: www.clinicalTrials.gov Unique identifier: NCT00810732.

Topics: Adult; Biomarkers; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Isoxazoles; Male; Middle Aged; Nifedipine; Protein Precursors; Proteinuria; Receptor, Endothelin A; Renal Insufficiency, Chronic; Scotland; Thiophenes; Time Factors; Treatment Outcome; Up-Regulation; Vascular Stiffness

Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.

Topics: Adult; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cross-Over Studies; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Isoxazoles; Male; Middle Aged; Nifedipine; Proteinuria; Pulse Wave Analysis; Renal Insufficiency, Chronic; Thiophenes; Vascular Stiffness; Vasodilator Agents

Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

Topics: Acetylglucosaminidase; Acidosis; Biomarkers; Buffers; Citrates; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Sodium Citrate

Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient's prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ET. CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation.. The final survival in untreated group was 15%. The treatment with ET. Our results show that treatment with ET

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Endothelin A Receptor Antagonists; Endothelin-1; Fistula; Heart Failure; Kidney; Rats; Rats, Transgenic; Receptor, Endothelin A; Renal Insufficiency, Chronic; Renin-Angiotensin System

Endothelial cell function is mediated by different mechanisms in different vascular beds. Moreover, in humans, endothelial cell dysfunction triggers and accelerates the progression of cardiovascular and chronic kidney diseases. Progression of such diseases can be in part mitigated by the control of cardiovascular risk factors and drugs targeting different systems, including endothelin receptor antagonists (ERAs), renin-angiotensin aldosterone antagonists and agents affecting glucose metabolism, all of which were shown to improve endothelial cell function. In recent years, the microRNAs, which are endogenous regulators of gene expression, have been identified as transmitters of information from endothelial cells to vascular smooth muscle cells, suggesting that they can entail tools to assess the endothelial cell dysfunction in arterial hypertension and target for pharmacologic intervention. This article critically reviews current challenges and limitations of available techniques for the invasive and noninvasive assessment of endothelial cell function, and also discusses therapeutic aspects as well as directions for future research in the areas of endothelial cell biology and pathophysiology in humans.

Topics: Endothelial Cells; Endothelin-1; Endothelins; Endothelium, Vascular; Humans; Hypertension; Renal Insufficiency, Chronic

The vasoconstricting peptide endothelin-1 (ET-1) is associated with endothelial dysfunction. The aim of this paper was to investigate whether circulating ET-1 levels predicts chronic kidney disease (CKD) in a prospective population study.. In 2002-2005, 2816 participants (30-74 years) were randomly selected from two municipalities in South-Western Sweden and followed up in a representative sample of 1327 individuals after 10 years. Endothelin-1 levels were assessed at baseline. Outcome was defined as CKD stage 3 or above based on eGFR < 60 mL/min/1.73m. At follow-up, 51 (8%) men and 47 (7,8%) women had CKD stage 3 and above. Based on levels of ET-1 the population was divided into quintiles showing that women in the highest quintile (n = 132) had a significantly increased risk of developing CKD during the follow up period (OR = 2.54, 95% CI:1.19-5.45, p = 0.02) compared with the other quintiles (1-4). The association was borderline significant after adjusted for age, current smoking, alcohol consumption, hypertension, diabetes, BMI, high- sensitive CRP and LDL-cholesterol (OR = 2.25, 95% CI:0.97-5.24, p = 0.06). No significant differences were observed between quintiles of ET-1 and development of CKD in men (NS).. High levels of ET-1 are associated with development of CKD in women.

Topics: Adult; Aged; Cohort Studies; Endothelin-1; Female; Humans; Longitudinal Studies; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renal Insufficiency, Chronic; Sex Distribution; Sweden

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

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

The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival.. In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis.. Endothelin levels and height-adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1-4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension.. Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Disease Progression; Endothelin-1; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prognosis; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Up-Regulation

Introduction: The study increase in the incidence of non-alcoholic steatohepatitis (NASH) on the background of obesity and chronic kidney disease (CKD) in people of working age in Ukraine and in the world necessitates the research into mechanisms of mutual burden and the search for new factors in the pathogenesis of this comorbidity progression . The aim: To establish the role of endothelial dysfunction in the mechanisms of mutual burden and progression of non-alcoholic steatohepatitis and chronic kidney disease in patients with obesity.. Materials and methods: 135 patients were examined: of which 52 patients with non-alcoholic steatohepatitis with obesity I degree (1 group), 53 patients with nonalcoholic steatohepatitis with comorbid obesity of the I degree and chronic kidney disease of the І-ІІ stage (group 2). The control group consisted of 30 practically healthy persons of the corresponding age and sex. The average age of patients was (45.8 ± 3.81) years.. Results: The results of the study showed that in patients with NASH, a significant increase in the content of NO in the blood was detected in comparison with the index in PHP (p <0,05) in group 1 - in 2,1 times, in the 2nd group - in 2,6 times (p <0,05). The role of nitrosative stress in the pathogenesis of NASH was proved, the confirmation of which is the increase in the concentration of nitrosothiols, peroxynitrite and other metabolites NO in the blood. Increased peroxynitrite formation due to the generation of NO by leukocytes is an important aspect of the damaging effect and inflammation process in NASH. Pathological hyperproduction of NO by endothelial cells and leukocytes from inflammatory infiltrates in the liver contributes to the development of nitrosative stress in NASH. The established hypernitrate in blood may also be considered compensatory in response to hyperproduction of ET-1 in all observational groups.. Conclusions: Confirmation of the presence of endothelial dysfunction (ED) in patients with NASH with CKD resulted in a probable growth of the number of desquamated endothelial cells (DEC) in the 2nd group of patients in 1.9 times (p2 <0.05). Generation by neutrophils during the exacerbation of NASH of a significant number of active forms of oxygen and nitrogen and hyperproduction of endothelial cells and endometrial lymphocytes with progressive damage to the endothelium (growth of DEC) leads to significant ED, accompanied by mosaic angiospasm of the arteries due to hyperproduction of ET-1 and parectic vasodilatation of the veins of the portal vein system because of the hyperproduction of NO.

Topics: Adult; Case-Control Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Humans; Middle Aged; Nitric Oxide; Non-alcoholic Fatty Liver Disease; Obesity; Renal Insufficiency, Chronic; Ukraine

In chronic kidney disease (CKD), endothelin-1 (ET-1) always increases and there are changes in cardiac ultrasonography. In the present study, we aimed at investigating the role of serum ET-1 in predicting cardiac complications in patients with CKD.. The level of serum ET-1 was measured by enzyme-linked immunosorbent assay (ELISA) and cardiac ultrasonography was performed in enrolled patients. Indexes of heart failure, such as left ventricular mass index, interventricular septum thickness and left ventricular end diastolic diameter, were measured in patients with CKD.. In the present study, we found that the level of serum ET-1 was significantly correlated with left ventricular mass index, interventricular septum thickness and left ventricular end diastolic diameter (p < .001) in non-dialysis patients with CKD.. The results of the present study indicated that the level of serum ET-1 is closely related to the cardiac complications of CKD and is a useful predictor of cardiac complication.

Topics: Adult; Echocardiography; Endothelin-1; Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Insufficiency, Chronic; Ventricular Dysfunction, Left; Ventricular Remodeling; Ventricular Septum

Endothelin-1 (ET-1) is associated with endothelial dysfunction and vasoconstriction. Increased circulating ET-1 levels are associated with long-term cardiovascular mortality. Renalase, released from kidney, metabolizes catecholamines and regulates blood pressure. An increase in circulating renalase levels has been reported in patients with chronic kidney disease (CKD) and is associated with coronary artery disease (CAD). We hypothesized the existence of a synergistic effect of serum renalase levels and CKD on ET-1 levels in patients with CAD. We evaluated 342 non-diabetic patients with established CAD. ET-1 and renalase levels were measured in all patients after an overnight fast. Patients with CKD had higher ET-1 (1.95 ± 0.77 vs. 1.62 ± 0.76 pg/ml, P < 0.001) and renalase levels (46.8 ± 17.1 vs. 33.9 ± 9.9 ng/ml, P < 0.001) than patients without CKD. Patients with both CKD and high renalase levels (>the median of 36.2 ng/ml) exhibited the highest serum ET-1 (P value for the trend <0.001). According to multivariate linear regression analysis, the combination of high serum renalase levels with CKD was a significant risk factor for increased serum ET-1 levels (regression coefficient = 0.297, 95% confidence interval = 0.063‒0.531, P = 0.013). In conclusion, our data suggest a synergistic effect of high serum renalase levels and CKD on increases in ET-1 levels in patients with established CAD.

Topics: Aged; Catecholamines; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Humans; Kidney; Male; Middle Aged; Monoamine Oxidase; Renal Insufficiency, Chronic

Topics: Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Humans; Receptor, Endothelin A; Receptor, Endothelin B; Renal Insufficiency, Chronic

Atherosclerosis is an important predictor of mortality in patients with chronic kidney disease (CKD) and is associated with a wide inflammatory response. The aim of this study is to evaluate in vitro how different membranes can remove mediators associated with this pathology in a closed loop dialysis model. We performed experimental hemofiltration in vitro using three different membrane materials. Human plasma was preliminarily incubated with various inflammatory mediators and filtered in a closed loop circulation model for 240 min. Respective concentrations of 17 different mediators were measured over time to study the removal mechanisms of each membrane, including associated removal time course. The experiment was repeated three times for the assay of tumor necrosis factor (TNF)-α to document the model variability. Means were compared using Mann-Whitney test. Most of the investigated mediators were effectively removed with the different dialysis membranes. Adsorption mechanism was mainly at the origin of the decrease in mediators circulating concentrations and was maximized in the region 10 000-20 000 Da. Especially, the HeprAN membrane showed fast removal capacities of mediators with elevated isoelectric point including complement factors and chemokines or having basic groups located in the protein periphery, plasminogen activator inhibitor (PAI-1), and TNF-α-like. The latter was further significantly removed with HeprAN and polymethylmethacrylate (PMMA) compared to polyethersulfone (PES) material (P < 0.01). We concluded that dialysis using ionic adsorptive membrane could have a beneficial impact for CKD patients with atherosclerosis and would deserve further clinical investigations.

Topics: Adsorption; Atherosclerosis; Chemokine CCL2; Endothelin-1; Equipment Design; Hemofiltration; Humans; Inflammation; Inflammation Mediators; Membranes, Artificial; Pilot Projects; Plasminogen Activator Inhibitor 1; Polymers; Polymethyl Methacrylate; Renal Insufficiency, Chronic; Sulfones; Tumor Necrosis Factor-alpha

Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD.. CKD was induced in Wistar rats by renal mass ablation. To induce medial vascular calcification, mineral imbalance was established with a identified as calcium-rich/phosphate-rich diet and vitamin D supplementation (Ca/P/VitD). One group of CKD + Ca/P/VitD rats was given the ETA receptor antagonist atrasentan (10 mg/kg/day) for 6 weeks. Hemodynamic parameters including SBP, pulse pressure (PP) and pulse wave velocity (PWV) were determined. Vascular calcification, smooth muscle cells osteoblastic differentiation and expression of inflammatory markers such as inflammatory cytokines and calgranulins S100A8 and S100A9 were assessed in the thoracic aorta.. As compared with CKD control rats, CKD + Ca/P/VitD rats developed medal vascular calcification that was associated with increased SBP, PP and PWV. These changes were also associated with increased macrophage infiltration and expression of IL-6, calgranulins and osteoblastic markers. Treatment of CKD + Ca/P/VitD rats with atrasentan reduced vascular calcification, SBP, PP and PWV, macrophage infiltration and expression of IL-1β, IL-6, tumor necrosis factor, calgranulins and osteoblastic markers.. This study shows that ETA receptor blockade reduced vascular inflammation, smooth muscle cells differentiation, calcification and stiffness indicating a pivotal role for ET-1 in medial vascular calcification in this rat remnant kidney model of CKD with mineral imbalance. Therefore, the endothelin system may be a potential therapeutic target for improving cardiovascular morbidity in patients with CKD.

Topics: Animals; Aorta, Thoracic; Atrasentan; Biomarkers; Blood Pressure; Calcium; Calgranulin A; Calgranulin B; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Interleukin-1beta; Interleukin-6; Macrophages; Male; Phosphorus, Dietary; Pulse Wave Analysis; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha; Vascular Calcification; Vascular Stiffness; Vitamin D

Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-β and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin-angiotensin system regenerated kidney vasculature and normalized Tgf-β and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency.

Topics: Actins; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Capillaries; Cell Proliferation; Endothelial Cells; Endothelin-1; Gene Expression; Kidney Glomerulus; Microscopy, Electron, Scanning; Neovascularization, Physiologic; NF-E2-Related Factor 2; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Renin-Angiotensin System; Transforming Growth Factor beta; X-Ray Microtomography

We aimed to study the relationship of peripheral arteries' atherosclerosis with serum and tissue endothelin-1 in chronic kidney disease patients.. Ninety patients were enrolled, including 35 patients with chronic kidney disease (case group), 31 patients with coronary artery diseases who were candidates for coronary artery bypass grafting (positive control group), and 24 living kidney donors (negative control group). Intima-media thickness of the common carotid and femoral arteries was determined by ultrasonography. Serum and tissue endothelin-1 were measured by ELISA method.. The mean serum and tissue endothelin-1 levels in the donor group were significantly lower than other groups (p < 0.001 for both). The coronary artery bypass grafting group had higher carotid and femoral intima-media thickness than other groups (p < 0.001), and the chronic kidney disease group had higher carotid and femoral intima-media thickness than the donor group (p < 0.001). Regression analysis in all groups did not reveal any correlation between the carotid intima-media thickness/femoral intima-media thickness and the serum/tissue endothelin-1. There was a direct linear correlation between the carotid and femoral intima-media thickness (p < 0.001) in all groups.. Endothelin-1 level and intima-media thickness were higher in the chronic kidney disease patients and coronary artery bypass grafting candidates, without any correlation between endothelin-1 and peripheral arteries' intima-media thickness of both groups. Perhaps endothelin-1 rises and remains high upon endothelial damage and initiation of atherosclerosis.

Topics: Adult; Aged; Biomarkers; Carotid Artery, Common; Carotid Intima-Media Thickness; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Femoral Artery; Humans; Iran; Male; Middle Aged; Peripheral Arterial Disease; Predictive Value of Tests; Prognosis; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Ultrasonography, Doppler; Up-Regulation; Young Adult

Cardiovascular disease is frequent in chronic kidney disease and has been related to angiotensin II, endothelin-1 (ET-1), thromboxane A2, and reactive oxygen species (ROS). Because activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS, which can generate ET-1, we tested the hypothesis that chronic kidney disease induces cyclooxygenase-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6 or TP-R+/+ and TP-R-/- mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin; increased plasma ET-1; and increased microvascular expression of p22(phox), cyclooxygenase-2, TP-Rs, preproendothelin and endothelin-A receptors, and increased arteriolar remodeling. They had increased contractions to U-46,619 (118 ± 3 versus 87 ± 6, P<0.05) and ET-1 (108 ± 5 versus 89 ± 4, P<0.05), which were dependent on cellular and mitochondrial ROS, cyclooxygenase-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P<0.05). TP-R-/- mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by cyclooxygenase-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling, and contractility and may thereby coordinate vascular dysfunction in chronic kidney disease.

Topics: Animals; Arterioles; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Kidney; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Thromboxane; Renal Circulation; Renal Insufficiency, Chronic; RNA; Vascular Remodeling; Vasoconstriction

Hypertensive chronic kidney disease is one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. However, early events initiating the progression to hypertensive chronic kidney disease are poorly understood. We hypothesized that elevated endothelial hypoxia-inducible factor-1α (HIF-1α) is a common early insult triggering initial glomerular injury leading to hypertensive chronic kidney disease. To test our hypothesis, we used an angiotensin II infusion model of hypertensive chronic kidney disease to determine the specific cell type and mechanisms responsible for elevation of HIF-1α and its role in the progression of hypertensive chronic kidney disease. Genetic studies coupled with reverse transcription polymerase chain reaction profiling revealed that elevated endothelial HIF-1α is essential to initiate glomerular injury and progression to renal fibrosis by the transcriptional activation of genes encoding multiple vasoactive proteins. Mechanistically, we found that endothelial HIF-1α gene expression was induced by angiotensin II in a nuclear factor-κB-dependent manner. Finally, we discovered reciprocal positive transcriptional regulation of endothelial Hif-1α and Nf-κb genes is a key driving force for their persistent activation and disease progression. Overall, our findings revealed that the stimulation of HIF-1α gene expression in endothelial cells is detrimental to induce kidney injury, hypertension, and disease progression. Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertensive chronic kidney disease.

Topics: Angiotensin II; Animals; Antigens, CD; Cadherins; Cells, Cultured; Disease Progression; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Feedback, Physiological; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Glomerulus; Mice; Mice, Transgenic; NF-kappa B; Organ Culture Techniques; Renal Insufficiency, Chronic; RNA, Small Interfering; Up-Regulation

Topics: Animals; Cardiovascular Diseases; Cholesterol, HDL; Diabetic Nephropathies; Endothelin-1; Female; Humans; Male; Podocytes; Renal Insufficiency, Chronic

Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, −3.2±4.8%, P<0.05; diastolic BP, −6.4±6.2%, P=0.001; pulse wave velocity, −5.8±5.2%, P<0.01) but not in 15 patients with CKD. In CKD, plasma ET-1 increased by 1.2±1.4 pg/mL from midday to midnight compared with healthy volunteers (P<0.05). Urinary ET-1 did not change. In a randomized, double-blind, 3-way crossover study in 27 patients with CKD, 6-week treatment with placebo and nifedipine did not affect nocturnal dips in systolic BP or diastolic BP between baseline and week 6, whereas dipping was increased after 6-week sitaxentan treatment (baseline versus week 6, systolic BP: −7.0±6.2 versus −11.0±7.8 mm Hg, P<0.05; diastolic BP: −6.0±3.6 versus −8.3±5.1 mm Hg, P<0.05). There was no nocturnal dip in pulse pressure at baseline in the 3 phases of the study, whereas sitaxentan was linked to the development of a nocturnal dip in pulse pressure. In CKD, activation of the ET system seems to contribute not only to raised BP but also the loss of BP dipping. The clinical significance of these findings should be explored in future clinical trials.

Topics: Adult; Blood Pressure; Case-Control Studies; Circadian Rhythm; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Isoxazoles; Male; Middle Aged; Renal Insufficiency, Chronic; Thiophenes; Vascular Stiffness

To investigate the role of endothelial dysfunction on left ventricular remodeling in patients with chronic kidney disease and to evaluate the correlation between endothelial dysfunction and left ventricular remodeling.. Seventy-three patients with chronic kidney disease as study-group and thirty healthy volunteers as control-group were enrolled in the present study. All patients in both groups had echocardiography examination. The concentration of endothelin-1, nitric oxide, and inducible nitric oxide synthase of serum of all patients and healthy volunteers was measured. The incidence of cardiac structural abnormalities in patients with chronic kidney disease, and the relationship between endothelial dysfunction and cardiac structural abnormalities were analyzed.. The incidence of left ventricular hypertrophy, left ventricular concentric remodeling, and left ventricular systolic dysfunction was 65%, 8.33%, and 16.67%, respectively. The level of endothelin-1 and nitric oxide increased in study-group, and the concentration of inducible nitric oxide synthase decreased. There was significant positively relationship between plasma endothelin-1 and left ventricular mass index, interventricular septal thickness, left ventricular diastolic diameter. There was negatively relationship between the level of serum nitric oxide and the maximum flow velocity at the mitral in left ventricular diastolic stage. There was not any correlation between inducible nitric oxide synthase with left ventricular remodeling.. The results showed that there was a higher incidence of left ventricular hypertrophy in patients with chronic kidney disease. Endothelin-1 and nitric oxide played an important role on the development of left ventricular hypertrophy.

Topics: Adult; Biomarkers; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Nitric Oxide Synthase Type II; Renal Insufficiency, Chronic; Ventricular Remodeling

Recent studies have raised concern about the safety of erythropoiesis-stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m(2)) aged 63±13 years.. Arteries were mounted on a pressurized myograph. EPO impaired endothelium-dependent relaxation in a concentration-dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P<0.001). EPO-induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine-induced vasoconstriction or sodium nitroprusside-induced relaxation. ABT-627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO (P<0.01). Increased expression of endothelin-1 was found in the vessel wall after incubation with EPO.. EPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO-induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials.

Topics: Acetylcholine; Aged; Anemia; Arteries; Buttocks; Carotid Arteries; Carotid Intima-Media Thickness; Endothelin-1; Endothelium, Vascular; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Pulse Wave Analysis; Recombinant Proteins; Renal Insufficiency, Chronic; Vasodilator Agents

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

An increase in serum uric acid (UA) occurs during the early and middle stages of chronic kidney disease (CKD) and aggravates the deterioration of kidney function. This study aims to explore the relation between UA and endothelial dysfunction in early CKD and its mechanisms in a murine model.. The experimental animals were randomly divided into three groups (n = 10): sham-operation group (control group), right nephrectomy only group (CKD group) and right nephrectomy with oxonic potassium group (CKD with hyperuricemia group). Furthermore, we analyzed the relation between UA and endothelial dysfunction indices in early CKD as well as its mechanisms.. Linear regression analysis showed that the level of serum UA had a significant positive correlation with serum endothelin-1 and the percentage of collagen I positive area, but a negative correlation with serum nitric oxide (NO) and NO/endothelin-1 ratio. In addition, the level of serum UA had significant positive correlations with serum malonaldehyde, serum C-reactive protein, serum oxidatively-modified low-density lipoprotein and serum low-density lipoprotein, but a negative correlation with serum superoxide dismutase.. Endothelial dysfunction in the CKD group was significant and had a positive correlation with the level of serum UA. Endothelial dysfunction in early CKD with hyperuricemia is perhaps related to oxidative stress, micro-inflammation and lipid oxidation.

Topics: Animals; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hyperuricemia; Lipoproteins, LDL; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Superoxide Dismutase; Uric Acid

This study was aimed at determining the serum concentration of homocysteine (Hcy) and big endothelin-1 (big ET-1, the precursor of endothelin) in dogs with chronic kidney disease (CKD) with and without hypertension, proteinuria and inflammation, in order to explore their role as biomarkers of hypertension associated with CKD. Hcy and big ET-1 were measured using an enzyme-linked immunosorbent assay and an enzymatic cyclic reaction, respectively, in dogs with CKD staged, as proposed by the International Renal Interest Society (IRIS), using serum creatinine, urinary protein to creatinine (UPC) ratio and systolic blood pressure, and classified as affected or not by inflammation based on the serum concentration of C-reactive protein (CRP). Serum Hcy was significantly higher in dogs of IRIS stages II, III and IV compared with controls and in proteinuric compared with non-proteinuric dogs. No differences relating to the degree of hypertension or to the CRP concentration were found. Serum big ET-1 significantly increased in dogs of IRIS stage IV compared with controls, in proteinuric compared with non-proteinuric dogs, in dogs with severe hypertension compared with those without hypertension, and in dogs with increased CRP compared to those with normal CRP concentrations. Hcy only correlated with serum creatinine but big ET-1 significantly correlated with serum creatinine, UPC ratio, systolic blood pressure, and increased CRP. In conclusion, both Hcy and big ET-1 increase in dogs with CKD. Although further research is needed, big ET-1, but not Hcy, may also be considered as a biomarker of hypertension.

Topics: Animals; Biomarkers; Blood Pressure; Creatinine; Dog Diseases; Dogs; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Homocysteine; Hypertension; Inflammation; Male; Proteinuria; Renal Insufficiency, Chronic

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

Chronic kidney disease (CKD) is a prevalent life-threatening disease frequently associated with hypertension, progression to renal fibrosis, and eventual renal failure. Although the pathogenesis of CKD remains largely unknown, an increased inflammatory response is known to be associated with the disease and has long been speculated to contribute to disease development. However, the causative factors, the exact role of the increased inflammatory cascade in CKD, and the underlying mechanisms for its progression remain unidentified. Here we report that interleukin 6 (IL-6) expression levels were significantly increased in the kidneys collected from CKD patients and further elevated in CKD patients characterized with hypertension. Functionally, we determined that angiotensin II is a causative factor responsible for IL-6 induction in the mouse kidney and that genetic deletion of IL-6 significantly reduced hypertension and key features of CKD, including renal injury and progression to renal fibrosis in angiotensin II-infused mice. Mechanistically, we provide both human and mouse evidence that IL-6 is a key cytokine functioning downstream of angiotensin II signaling to directly induce fibrotic gene expression and preproendothelin 1 mRNA expression in the kidney. Overall, both the mouse and human studies reported here provide evidence that angiotensin II induces IL-6 production in the kidney, and that, in addition to its role in hypertension, increased IL-6 may play an important pathogenic role in CKD by inducing fibrotic gene expression and ET-1 gene expression. These findings immediately suggest that the IL-6 signaling is a novel therapeutic target to manage this devastating disorder affecting millions worldwide.

Topics: Adult; Angiotensin II; Animals; Biopsy; Blood Pressure; Disease Progression; Endothelin-1; Female; Fibrosis; Humans; Hypertension, Renal; Interleukin-6; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Organ Culture Techniques; Proteinuria; Renal Insufficiency, Chronic; Signal Transduction; Vasoconstrictor Agents

Increased production of tumor necrosis factor-α (TNF-α) in chronic kidney disease may be involved in the progression of renal failure and injury, and cardiovascular disease. We investigated the effect of TNF-α neutralization on renal failure, inflammation and fibrosis, and blood pressure in rats with renal failure.. Renal failure was induced by renal mass reduction and the animals were treated with PEG-sTNFR1, a pegylated form of soluble TNF type 1 receptor that neutralizes TNF-α, for 6 weeks. Systolic, diastolic and mean arterial pressures were higher in renal failure rats that were associated with increased serum creatinine, albuminuria and renal injury comprised of blood vessel media hypertrophy, focal and segmental glomerulosclerosis, tubular atrophy and interstitial inflammation and fibrosis. These changes were associated with greater levels of TNF-α, transforming growth factor (TGF)-β1, nuclear transcription factor NF-ĸB and cytosolic phospho-IĸB-α, and inflammatory markers expression (ICAM-1, VCAM-1 and MCP-1). Moreover, endothelin (ET)-1 production was also increased, whereas nitric oxide (NO) release was decreased. TNF-α neutralization reduced hypertension, albuminuria and renal inflammation and fibrosis, which were coupled to a reduction in renal NF-ĸB activation, inflammatory markers expression, TGF-β1 and ET-1 production, and an increase in NO release.. Neutralization of TNF-α in rats with renal failure decreases NF-ĸB activity that is associated with a reduction in renal TGF-β1 and ET-1 production, and an improvement of NO release. These effects likely reduce renal inflammation and fibrosis, and blood pressure indicating a pivotal role for TNF-α, at least, in the progression of renal injury.

Topics: Animals; Blood Pressure; Body Weight; Chemokine CCL2; Disease Progression; Endothelin-1; Fibrosis; Heart Rate; Humans; Hypertension, Renal; Intercellular Adhesion Molecule-1; Male; NF-kappa B; Nitric Oxide Synthase Type III; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor, Type I; Renal Insufficiency, Chronic; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

To study changes in apoptosis and endothelial function in patients with chronic kidney disease (CKD) stage I-IIIb (CKDsI-IIIb).. A complex of biochemical, enzyme immunoassay and device investigations was used to examine 128 patients with CKDsI-IIIb.. In CKD stage I reduction of endothelium-dependent vasodilation (EDV) was detected in 34% patients, in stage II -- in 52 %, in stage IIIa -- y 52 %, in stage IIIb - in 70%. An EDV decrease was associated with glomerular filtration rate (GFR), a homocysteine level and hemodynamic factors. Elevation of endothelin-1 (ET-1) level was seen in CKDsI in 41 %, in CKDsII - in 54 %, in CKDsIIIa - in 70 %, in stage IIIb - in 83% patients. A negative correlation was observed between the level of ET-1 and GFR and positive - with diurnal proteinuria. A significant rise of annexin A5 concentration versus normal was detected as early as in CKDsI (1,14 +/- 0,68 ng/ml). In CKDsII annexin A5 was 2,61 +/- 0,75 ng/ml, in CKDsIIIa - 3,75 +/- 0,93 ng/ml and in CKDsIIIb - 5,16 +/- 1.01 ng/ml. Negative correlations were found between annexin A5 level and GFR, a maximal growth of volumetric blood flow rate in skin vessels in the acetylcholine test, positive correlations with systolic blood pressure, body mass index.. The levels of ET-1 and annexin A5 are factors having an independent impact on EDV in patients with CKDsI-II.

Topics: Adult; Annexin A5; Apoptosis; Blood Flow Velocity; Blood Pressure; Cardio-Renal Syndrome; Case-Control Studies; Data Interpretation, Statistical; Endothelin-1; Endothelium, Vascular; Glomerular Filtration Rate; Homocysteine; Humans; Microcirculation; Renal Insufficiency, Chronic; Severity of Illness Index; Skin; Vasodilation

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is accumulated in plasma during chronic kidney disease (CKD). It is considered an independent mortality and cardiovascular risk factor in CKD patients. To test the involvement of ADMA in CKD progression, we investigated the effects of chronic ADMA administration on renal structure and compared these effects with NG-nitro-L-arginine methyl ester (L-NAME) treatment, a widely used exogenous inhibitor of NOS that induces CKD. Three groups of uninephrectomized mice were studied: ADMA (60 mg/kg per day), L-NAME (60 mg/kg per day), and isotonic saline (control) were infused through osmotic mini-pumps for 8 weeks. ADMA and L-NAME induced hypertension (PAS 167 ± 16 and 168 ± 10 versus 100 ± 4 mmHg, p < 0.01, respectively). High level of ADMA was associated with increased renal oxidative stress. ADMA treatment induced glomerular and vascular fibrosis as evidenced by the elevated deposits of collagen I, III, and fibronectin (p < 0.01). A similar profile was observed in the L-NAME group. Mice treated with ADMA had reduced peritubular capillaries versus controls (p < 0.01). Collagen I mRNA expression and renal TGF-β1 concentrations were higher in the ADMA and L-NAME groups. Increased level of TGF-β1 was associated with a significant rise of HIF-1α and endothelin-1 expression. These results demonstrate for the first time that elevated concentrations of ADMA are associated with the development of renal fibrosis. These data suggest that in pathophysiological conditions of endothelial dysfunction, the exaggerated endogenous synthesis of ADMA could contribute to CKD progression by favouring hypertension, extracellular matrix synthesis, and rarefaction of peritubular capillaries.

Topics: Animals; Arginine; Collagen; Endothelin-1; Enzyme Inhibitors; Fibrosis; Gene Expression Regulation; Hypertension; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxidative Stress; Renal Insufficiency, Chronic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta1

Metabolic acidosis often complicates chronic kidney disease (CKD) and adversely affects bone, nutrition, and metabolism. Phisitkul et al. demonstrate that sodium citrate may ameliorate kidney injury in CKD patients not on dialysis. Further, they provide evidence in humans that treatment lowers urinary endothelin levels, and hence increased endothelin may be part of the mechanism whereby acidosis hastens CKD progression.

Topics: Acidosis; Buffers; Citrates; Endothelin-1; Humans; Renal Insufficiency, Chronic; Sodium Citrate

Hypertension and additional non-traditional risk factors can damage the kidney directly and by promoting atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate a large part of the effects of risk factors on the kidney. We hypothesized that in hypertensive patients (HT), oxidative stress, measured as 8-ISO-prostaglandin F2alpha (8-ISO-PGF2alpha), should raise paralleling decreasing renal function and should correlate with estimated glomerular filtration rate (eGFR).. In 626 HT with renal function ranging from stages 1 to 5 and 100 healthy controls, plasma levels of 8-ISO-PGF2alpha, high-sensitivity C-reactive protein (CRP), transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) were measured. GFR was estimated by the Modification of Diet in Renal Disease study equation.. When HT were stratified according to renal function stages, 8-ISO-PGF2alpha, CRP, TGF-beta and ET-1 increased progressively and significantly with decreasing eGFR. The multiple regression analysis, considering eGFR as a dependent variable, showed that 8-ISO-PGF2alpha (beta = -0.361, P < 0.000001), ET-1 (beta = -0.197, P < 0.0001) and TGF-beta (beta = -0.170, P < 0.0004) correlated independently with eGFR. All biomarkers were good predictors of eGFR <60 ml/min/1.73 m(2) [receiver-operator-curve (ROC) areas]. ET-1 was shown to be the best predictor with a ROC area = 0.938; with a threshold of 4 pg/ml, 91% sensitivity and 85% specificity were observed, whereas 8-ISO had a ROC area = 0.931, and for a threshold of 329 pg/ml, sensitivity and specificity were 89%, respectively. In contrast, CRP showed the lower predictive value with a ROC area = 0.917; with a threshold of 2.52 mg/l, an 87% sensitivity and an 83% specificity were obtained.. Our findings are a clear-cut demonstration of a strong and negative correlation of both oxidative stress and ET-1 with renal function stages in HT. ET-1 and 8-isoprostane are predictive of eGFR.

Topics: Adult; Aged; Atherosclerosis; C-Reactive Protein; Case-Control Studies; Dinoprost; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors; Transforming Growth Factor beta