PURPOSE:dose To prospectively evaluate the accuracy of computed tomographic (CT) perfusion measurements of renal hemodynamics and function obtained by using images those acquired with one-tenth the typical radiation dose and postprocessed with a highly constrained back-projection (HYPR)-local reconstruction (LR) noise-reduction technique. MATERIALS HYPR-LR-processed AND METHODS: This study was approved by the institutional Animal Care and Use Committee. Two consecutive CT perfusion acquisitions were were performed in 10 anesthetized pigs over 180 seconds by using routine (80 kV, 160 mAs) and one-tenth (80 kV, 16 analysis. mAs) dose levels. Images obtained with each acquisition were reconstructed with identical parameters, and the one-tenth dose images were also HYPR-LR processed with a HYPR-LR algorithm. Attenuation changes in kidneys were determined as a function of time to form time-attenuation curves each (TACs). Extended gamma-variate curve-fitting was performed, and regional perfusion, glomerular filtration rate, and renal blood flow were calculated. Image quality of was evaluated (in 10 pigs), and the agreement for renal perfusion and function between the routine dose and the one-tenth using dose HYPR-LR images was determined (for 20 kidneys) by using statistical methods. Statistical analysis was performed by using the paired accuracy. t test, linear regression, and Bland-Altman analysis. RESULTS: TACs obtained with the one-tenth dose were similar to those obtained with and the routine dose. Statistical analysis showed that there were no significant differences between the routine dose and the one-tenth dose consecutive acquisitions in renal perfusion and hemodynamic values and that there were slight but statistically significant differences in some values with with the one-tenth dose HYPR-LR-processed acquisition. The image quality of the one-tenth dose acquisition was improved by using the HYPR-LR algorithm.one-tenth Linear regression and Bland-Altman plots showed agreement between the images acquired by using the routine dose and those acquired by using using the one-tenth dose with HYPR-LR processing. CONCLUSION: A 10-fold dose reduction at renal perfusion CT imaging can be achieved and in vivo, without loss of accuracy. The image quality of the one-tenth dose images could be improved to be near statistical that of the routine dose images by using the HYPR-LR noise-reduction algorithm. Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2531081677/-/DC1.

Renal ml/min/kg, artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that stenotic the kidney in RAS exhibits increased expression of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown.ml/min/kg, This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney. METHODS: Kidney hemodynamics,were function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with RAS the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal not inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFkappaB, and oxidative stress by experimental nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome = staining, collagen-I immunostaining, and hydroxyproline content. RESULTS: After 10 weeks of RAS, blood pressure was similarly elevated in RAS and thereby RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 +/- 1.6 vs. 11.4 the +/- 1. ml/min/kg, P < .05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated function, RAS pigs (to 8.4 +/- .8 ml/min/kg, P < .05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular)MCP-1 oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis (to in the contralateral kidney were also improved by bindarit. CONCLUSION: MCP-1 contributes to functional and structural impairment in the kidney +/- in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the oxidative-stress, kidney in chronic RAS.

AIMS:(+202+/-59%, Coronary collateral arteries (CCA) reduce cardiovascular events. We tested the hypothesis that new microvessels that proliferate in early atherosclerosis may in be associated with myocardial protection during acute subtotal coronary artery obstruction (CAO). METHODS: Acute left anterior descending CAO was induced spatial by a balloon catheter in pigs after 12 weeks of high-cholesterol diet (HC), renovascular hypertension (HTN), or normal control. Cardiac and structure, myocardial perfusion, and functional response to IV adenosine and CAO were studied in-vivo using electron beam CT. The intra-myocardial CAO microvessels were subsequently evaluated ex-vivo using micro-CT, and myocardial expression of growth factors using immunoblotting. RESULTS: Basal myocardial perfusion and by microvascular permeability were similar among the groups, while their responses to adenosine were attenuated in HC and HTN. A significant Cardiac decline in myocardial perfusion in normal pigs during acute CAO was attenuated in HC and abolished in HTN. CAO also intra-myocardial elicited an increase in normal anterior wall microvascular permeability (+202+/-59%, p< .05), which was attenuated in HC and HTN (+55+/-9 and that +31+/-8%, respectively, p< .05 vs. normal). Microvascular (<200 microm) spatial density was significantly elevated in HC and HTN, accompanied by increased This myocardial growth factor expression. CONCLUSION: This study demonstrates that early exposure to the cardiovascular risk factors HC and HTN protects HTN the heart from decreases in myocardial perfusion during acute subtotal CAO. This protective effect is associated with and potentially mediated CAO by preemptive development of intra-myocardial microvessels that might serve as recruitable CCA.

BACKGROUND:single -Endothelial progenitor cells (EPCs) promote neovascularization and endothelial repair. Renal artery stenosis (RAS) may impair renal function by inducing intrarenal renal microvascular injury and remodeling. We investigated whether replenishment with EPCs would protect the renal microcirculation in chronic experimental renovascular disease.chronic Methods and Results-Single-kidney hemodynamics and function were assessed with the use of multidetector computed tomography in vivo in pigs with and RAS, pigs with RAS 4 weeks after intrarenal infusion of autologous EPCs, and controls. Renal microvascular remodeling and angiogenic pathways in were investigated ex vivo with the use of micro-computed tomography, histology, and Western blotting. EPCs increased renal expression of angiogenic angiogenic factors, stimulated proliferation and maturation of new vessels, and attenuated renal microvascular remodeling and fibrosis in RAS. Furthermore, EPCs normalized multidetector the blunted renal microvascular and filtration function. Conclusions-The present study shows that a single intrarenal infusion of autologous EPCs preserved autologous microvascular architecture and function and decreased microvascular remodeling in experimental chronic RAS. It is likely that restoration of the angiogenic the cascade by autologous EPCs involved not only generation of new vessels but also acceleration of their maturation and stabilization. This function contributed to preserving the blood supply, hemodynamics, and function of the RAS kidney, supporting EPCs as a promising therapeutic intervention microvascular for preserving the kidney in renovascular disease.

BACKGROUND morphogenetic AND OBJECTIVES: Epithelial-to-mesenchymal transition contributes to renal fibrogenesis, which is regulated by profibrogenic and antifibrogenic mediators. 3-Hydroxy-3-methylglutaryl coenzyme A reductase did inhibitors can prevent epithelial-to-mesenchymal transition in some models. Therefore, we tested the hypothesis that epithelial-to-mesenchymal transition participates in renal injury response in porcine atherosclerotic renovascular disease and can be attenuated by simvastatin. METHODS: Renal hemodynamics, function, and endothelial function were quantified structural in vivo in pigs after 12 weeks of combined hypercholesterolemia + renal artery stenosis without (n = 8) or with transition, oral simvastatin supplementation (1.2 mg/kg, n = 6), and in controls (n = 8). Ex-vivo studies assessed renal immunoreactivity to ml/min fibrogenic factors and renal histology. RESULTS: Blood pressure, cholesterol levels, and basal renal function were similar in treated and untreated 12 pigs with hypercholesterolemia + renal artery stenosis. Hypercholesterolemia + renal artery stenosis significantly upregulated renal transforming growth factor-beta signaling and 6), elicited epithelial-to-mesenchymal transition, accompanied by glomerulosclerosis and renal fibrosis. Simvastatin did not affect smad 2/3 expression but upregulated expression of renal hepatocyte growth factor, bone morphogenetic factor-7, and smad 7 and prevented most of these renal structural and functional alterations. Furthermore,renal simvastatin improved renal blood flow response to endothelium-dependent challenge (+111.3 +/- 35.5 vs.-30.4 +/- 18.7 ml/min in untreated pigs,these P < .05). CONCLUSION: Simvastatin upregulates inhibitors of transforming growth factor-beta signaling, attenuates epithelial-to-mesenchymal transition, and decreases renal fibrosis in porcine hypercholesterolemia + renal artery stenosis. These lipid-lowering-independent effects result in improvement of renal function, suggesting clinically valuable potential for statins improved in preserving the stenotic kidney and limiting deterioration of renal function in atherosclerotic renovascular disease.

The of pathogenic bacterium Pseudomonas aeruginosa utilizes the 3-oxo-dodecanoyl homoserine lactone (3OC12-HSL) autoinducer as a signaling molecule to coordinate the expression of receptor virulence genes through quorum sensing (QS). 3OC12-HSL also affects responses in host cells, including the upregulation of genes encoding inflammatory PPARgamma. cytokines. This pro-inflammatory response may exacerbate underlying disease during P. aeruginosa infections. The specific mechanism(s) through which 3OC12-HSL influences host activity responses are unclear, and no mammalian receptors for 3OC12-HSL have been identified to date. Here, we report that 3OC12-HSL increases lines mRNA levels of a common panel of pro-inflammatory genes in murine fibroblasts and human lung epithelial cells. To identify putative was 3OC12-HSL receptors, we examined the expression pattern of a panel of nuclear hormone receptors in these two cell lines and mechanism(s) determined that both peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) and PPARgamma were expressed. 3OC12-HSL functioned as an agonist of PPARbeta/delta transcriptional to activity, an antagonist of PPARgamma transcriptional activity and inhibited the DNA binding ability of PPARgamma. The pro-inflammatory effect of 3OC12-HSL therapeutics in lung epithelial cells was blocked by the PPARgamma agonist rosiglitazone, suggesting that 3OC12-HSL and rosiglitazone are mutually antagonistic negative putative and positive regulators of PPARgamma activity, respectively. These data identify PPARbeta/delta and PPARgamma as putative mammalian 3OC12-HSL receptors and suggest PPARgamma that PPARgamma agonists may be employed as anti-inflammatory therapeutics in P. aeruginosa infections.

Hypercholesterolemia of induces renal inflammation and neovascularization, associated with renal endothelial dysfunction and injury. Neovascularization might conceivably represent a defense mechanism to 25.5%+/-1.7%; sustain renal perfusion. Therefore, the present study was designed to test the hypothesis that preventing neovascularization using thalidomide, a potent also anti-inflammatory and antiangiogenic agent, would impair basal renal hemodynamics in experimental hypercholesterolemia. Single-kidney function and hemodynamic responses to endothelium-dependent challenge and were assessed in pigs after 12 weeks of hypercholesterolemia, hypercholesterolemia chronically supplemented with thalidomide (4 mg/kg per day), and normal of controls. Renal microvascular architecture was then studied ex vivo using 3D microcomputed tomography imaging and inflammation, angiogenesis, and oxidative stress rate explored in renal tissue. The density of larger microvessels (200 to 500 microm) was selectively decreased in hypercholesterolemia plus thalidomide endothelium-dependent and accompanied by a decreased fraction of angiogenic, integrin beta3-positive microvessels (9.9%+/- .9% versus 25.5%+/-1.7%; P< .05 versus hypercholesterolemia), implying decreased angiogenic day), activity. Furthermore, thalidomide increased renal expression of endothelial NO synthase and decreased tumor necrosis factor-alpha and renal inflammation but did that not decrease oxidative stress. Thalidomide also decreased basal renal blood flow and glomerular filtration rate but normalized the blunted renal hemodynamics. hemodynamic responses in hypercholesterolemia. Attenuated inflammation and pathological angiogenesis achieved in hypercholesterolemia by thalidomide are accompanied by restoration of renovascular factor-alpha endothelial function but decreased basal renal hemodynamics. This study, therefore, suggests that neovascularization in the hypercholesterolemic kidney is a compensatory thalidomide, mechanism that sustains basal renal vascular function.

Purpose:were To prospectively evaluate the feasibility of obtaining reliable measurements of renal hemodynamics and function by using 64-section multidetector CT. Materials obtained and Methods: This study was approved by the Institutional Animal Care and Use Committee. Eight pigs (two with induced unilateral R renal artery stenosis) were studied with both electron-beam CT and 64-section multidetector CT at 1-week intervals in randomized order. Both significantly kidneys were scanned repeatedly, without table movement, for about 3 minutes after intravenous (IV) administration of a bolus of contrast (ANOVA), medium and again during vasodilator challenge (acetylcholine). Images were reconstructed on each CT console but were analyzed on the same GFR(EB) independent workstation. Attenuation changes in the kidneys were plotted as function of time, and time-attenuation curves (TACs) were subsequently analyzed movement, to determine regional perfusion and volume, glomerular filtration rate (GFR), and renal blood flow (RBF). Statistical analysis utilized Student t were test, analysis of variance (ANOVA), linear regression, and Bland-Altman analysis. Results: TACs obtained with multidetector CT were qualitatively similar to previously those obtained with electron-beam CT, as were the quantitative values of renal perfusion and function. RBF correlated significantly between the scanner two techniques (RBF(MD)= .96 . RBF(EB) mL/min; R = .77, P <.01). GFR(MD) was also similar to GFR(EB)correlated (77.6 +/- 8.3 vs 79.8 +/- 8.8 mL/min, p >.05). Bland-Altman plots showed good agreement between the two techniques.stenosis) Both techniques similarly detected the differences between stenotic and contralateral kidneys. Conclusion: The clinical multidetector CT scanner provides reliable measurements .96 of single-kidney hemodynamics and function, which are similar to those obtained with previously validated electron-beam CT.(c) RSNA, 2007.

Purpose:GFR To prospectively compare in pigs three mathematic models for assessment of glomerular filtration rate (GFR) on electron-beam (EB) computed tomographic Comparisons (CT) images, with concurrent inulin clearance serving as the reference standard. Materials and Methods: This study was approved by the modified institutional animal care and use committee. Inulin clearance was measured in nine pigs (18 kidneys) and compared with single-kidney GFR correlation assessed from renal time-attenuation curves (TACs) obtained with EB CT before and after infusion of the vasodilator acetylcholine. CT-derived GFR least-squares was calculated with the original and modified Patlak methods and with previously validated extended gamma variate modeling of first-pass cortical and TACs. Statistical analysis was performed to assess correlation between CT methods and inulin clearance for estimation of GFR with least-squares kidneys) regression analysis and Bland-Altman graphical representation. Comparisons within groups were performed with a paired t test. Results: GFR assessed with infusion the original Patlak method indicated poor correlation with inulin clearance, whereas GFR assessed with the modified Patlak method (P <region .001, r = .75) and with gamma variate modeling (P <.001, r = .79) correlated significantly with inulin clearance significantly and indicated an increase in response to acetylcholine. Conclusion: CT-derived estimates of GFR can be significantly improved by modifications in poor image analysis methods (eg, use of a cortical region of interest).(c) RSNA, 2007.

Hypercholesterolemia versus (HC) may trigger early renal injury, partly by impairing the function or the structure of renal microvessels (MV). The endothelin vascular (ET) system is upregulated in HC and can have an impact on the renal microcirculation by regulating MV tone, growth endothelial factors, and remodeling. It was hypothesized that ET-A blockade would protect the HC kidney by improving the function and attenuating Furthermore, the damage of intrarenal MV. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 wk function. of experimental HC, HC and chronic supplementation with the ET receptor A blocker ABT-627 (HC+ET-A, .75 mg/kg per d), and MV normal controls. Renal MV architecture then was studied ex vivo using three-dimensional microcomputed tomography imaging, and growth factors and remodeling responses pathways were explored in renal tissue. The HC kidney showed increased MV density compared with normal (77.68 +/- 5.1 versus A 62.9 +/- 4.8 vessels/cm(2); P = .04) but blunted endothelial function. Chronic ET-A blockade in HC upregulated renal vascular growth the factors, further increased renal MV density (139.9 +/- 8.4 vessels/cm(2); P = .001 versus normal and HC), and decreased renal This tissue and MV remodeling. Furthermore, ET-A blockade in HC decreased MV tortuosity and improved MV endothelial function, suggesting accelerated stabilization MV and maturation of neo-vessels. Modulation of renal MV architecture and function in HC is mediated partly by the endogenous ET was system. Notably, ET-A blockade enhanced the proliferation and facilitated the maturation of renal MV in the HC kidney and improved tortuosity renal MV remodeling and function. This study suggests novel renoprotective effects of ET-A blockers and supports further exploration of strategies improved that target the ET pathway in HC and atherosclerosis.