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Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine.

ABSTRACT: The impact of coronary artery stenosis (CAS) on renal injury is unknown. Here we tested whether the existence of CAS, regardless of concurrent atherosclerosis, would induce kidney injury and magnify its susceptibility to damage from coexisting hypertension (HT). Pigs (seven each) were assigned to sham, left-circumflex CAS, renovascular HT, and CAS plus HT groups. Cardiac and nonstenotic kidney functions, circulating and renal inflammatory and oxidative markers, and renal and microvascular remodeling were assessed 10 weeks later. Myocardial perfusion declined distal to CAS. Systemic levels of PGF2-? isoprostane, a marker of oxidative stress, increased in CAS and CAS plus HT, whereas single-kidney blood flow responses to acetylcholine were significantly blunted only in CAS plus HT compared with sham, HT, and CAS, indicating renovascular endothelial dysfunction. Tissue expression of inflammatory and oxidative markers were elevated in the CAS pig kidney, and further magnified in CAS plus HT, whereas angiogenic factor expression was decreased. Bendavia, a mitochondria-targeted peptide, decreased oxidative stress and improved renal function and structure in CAS. Furthermore, CAS and HT synergistically amplified glomerulosclerosis and renal fibrosis. Thus, mild myocardial ischemia, independent of systemic atherosclerosis, induced renal injury, possibly mediated by increased oxidative stress. Superimposed HT aggravates renal inflammation and endothelial dysfunction caused by CAS, and synergistically promotes kidney fibrosis, providing impetus to preserve cardiac integrity in order to protect the kidney.

SUBMITTER: Sun D

PROVIDER: S-EPMC4382395 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine.

Sun Dong D Eirin Alfonso A Zhu Xiang-Yang XY Zhang Xin X Crane John A JA Woollard John R JR Lerman Amir A Lerman Lilach O LO

Kidney international 20141022 4

The impact of coronary artery stenosis (CAS) on renal injury is unknown. Here we tested whether the existence of CAS, regardless of concurrent atherosclerosis, would induce kidney injury and magnify its susceptibility to damage from coexisting hypertension (HT). Pigs (seven each) were assigned to sham, left-circumflex CAS, renovascular HT, and CAS plus HT groups. Cardiac and nonstenotic kidney functions, circulating and renal inflammatory and oxidative markers, and renal and microvascular remode ...[more]

PMID: 25337776

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Project description:Rationale & objectiveThe presence of calcified plaques in the coronary arteries is associated with cardiovascular mortality and is a hallmark of chronic kidney failure, but it is unclear whether this is associated with the same degree of coronary artery stenosis as in patients without kidney disease. We compared the relationship of coronary artery calcification (CAC) and stenosis between dialysis patients and patients without chronic kidney disease (CKD).Study designObservational cohort study.Setting & participants127 dialysis patients and 447 patients without CKD with cardiovascular risk factors underwent cardiac computed tomography (CT), consisting of non-contrast-enhanced CT and CT angiography. CAC score and degree of coronary artery stenosis were assessed by independent readers.PredictorDialysis treatment.OutcomeAssociation between calcification and stenosis.Analytical approachLogistic regression to determine the association between CAC score and the presence of stenosis in a matched cohort and, in the full cohort, testing for the interaction of dialysis status with this relationship.Results112 patients were matched from each cohort, totaling 224 patients, using propensity scores for dialysis, balancing numerous cardiovascular risk factors. Median CAC score was 210 (IQR, 19-859) in dialysis patients and 58 (IQR, 0-254) in patients without CKD; 35% of dialysis patients and 36% of patients without CKD had coronary artery stenosis ≥ 50%. Per each 100-unit higher CAC score, the matched dialysis cohort had significantly lower ORs for stenosis than the non-CKD cohort, 0.67 (95% CI, 0.52-0.83) for stenosis ≥ 50% and 0.75 (95% CI, 0.62-0.90) for stenosis ≥ 70%.LimitationsNo comparison with the gold standard fractional flow reserve.ConclusionsDialysis patients have higher risk for coronary artery stenosis with higher CAC scores, but this risk is comparatively lower than in patients without CKD with similar CAC scores. In dialysis patients, a high CAC score can easily be found without significant stenosis. Our data enable "translation" of degree of calcification to the probability of coronary stenosis in dialysis patients.

Project description:Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified "preconditioning" approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.

Project description:PurposeThis report describes the change in atherosclerotic renovascular disease (AS-RVD) among hypertensive adults referred for renal duplex sonography (RDS) scan.MethodsFrom Oct 1993 through July 2008, 20,994 patients had RDS at our center. A total of 434 hypertensive patients with two or more RDS exams without intervention comprised the study cohort. Patient demographics (blood pressures, medications, serum creatinine levels, and data from RDS) were collected. Analyses of longitudinal changes in Doppler scan parameters, blood pressures, and renal function were performed by fitting linear growth-curve models. After confirming the linearity of change in Doppler scan parameters among patients with variable number of studies, estimates of mean slopes were calculated using maximum likelihood techniques. For changes in renal function, quadratic growth curves were required to describe longitudinal change.ResultsA total of 434 subjects (212 men [49%] and 222 women [51%]; mean age, 64.6 +/- 12.2 years) provided 1351 studies (mean, 3.2 +/- 2.4; range, 2 to 18) for 863 kidneys over a mean follow-up of 34.4 +/- 25.1 months. At baseline, 20.6% of kidneys demonstrated hemodynamically significant stenosis. On follow-up, 72 kidneys (9.1%) demonstrated anatomic progression of disease. A total of 54 kidneys (6.9%) progressed to significant stenosis and 18 (2.3%) progressed to occlusion. Controlling for progression of disease, baseline renal artery status demonstrated a strong association with baseline kidney length (P = .0006). Significant annualized change in renal length was observed (cm change/year +/- standard error of the mean [SEM]: 0.042 +/- 0.011; P = .0002) among both kidneys with and without critical disease at baseline, however, decline in length was significantly greater among kidneys exhibiting progression of renovascular disease (-0.152 +/- 0.028 cm/year; comparison of slopes between groups P = .0005). In the absence of progression, the presence or absence of critical renal artery stenosis at baseline did not affect the rate of decline in renal length. Fitted models for the natural log transform of serum creatinine demonstrated a significant increase during follow-up (P < .0001). No association was observed between change in serum creatinine and baseline renovascular disease status, or its progression.ConclusionA total of 32% of hypertensive adults referred for RDS demonstrated hemodynamically significant renal artery stenosis. Regardless of the presence or absence of baseline disease, a small percentage of patients demonstrated anatomic progression of AS-RVD. A total of 9.1% demonstrated anatomic progression and 2.3% progressed to occlusion. Although anatomic progression of AS-RVD was associated with an increased rate of decline in renal length, progression did not predict a decline in excretory renal function. Intervention for AS-RVD should be selective and reserved for strict indications.

Project description:BackgroundCoronary artery stenosis induces heart diseases including acute coronary syndrome (ACS). Some studies reported the ceramide species are associated with the ACS and major adverse cardia and cerebrovascular events (MACE). However, few studies investigated the association between plasma ceramide levels and the severity of stenosis, together with the onset of diseases. This aim of the present study was to investigate the association betweencertain ceramide species, coronary artery stenosis and acute coronary syndrome.MethodsFive hundred fifty-three patients with definite or suspected CAD were recruited and received angiography. Subjects were assigned into 4 groups according to the severity of coronary artery stenosis. The measurements of 4 plasma ceramide species, namely, Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/24:1), Cer (d18:1/24:0) were carried out by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the ratio of Cer (d18:1/16:0), Cer (d18:1/18:0) and Cer (d18:1/24:1) to Cer (18:1/24:0), respectively, were calculated as index to evaluate the association between plasma ceramides levels and coronary artery stenosis. Multiple logistic regression analysis was used to establish the prognostic model for the prediction of ACS risk.ResultsAfter the adjustment by multiple clinical risk factors including age, gender, pre-existing myocardial/cerebral infarction, hemoglobin A1c% (HbA1c%), smoking and the diagnosis during index hospitalization, multiple logistic regression analysis showed that the high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c%, unstable angina (UAP) and acute myocardial infarction (AMI) diagnosis (compared with atherosclerosis) during index hospitalization were associated with more severe coronary artery stenosis. Furthermore, the prognostic model was established after adjustment of risk factors and the area under curve (AUC) of receiver operating characteristics (ROC) for the prognostic model was 0.732 and 95% CI was 0.642-0.822.ConclusionThe severity of coronary artery stenosis is associated with high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c% and AMI. Although the reported prognostic model showed a good discrimination, further investigation on long term MACE is needed to evaluate the role of ceramide for the prediction of MACE risk.

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Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine.

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Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine.

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