Medical Optimization of Patients with Symptomatic Peripheral Arterial Disease.

Peripheral artery disease (PAD) is a progressive disease associated with the occurrence of major adverse cardiovascular and limb events and elevated mortality rates. Symptoms of PAD, including claudication and chronic limb-threatening ischemia, impair functional capacity and lead to lower quality of life. The focus of current therapies is to minimize symptoms, improve quality of life, and reduce adverse cardiovascular and limb events. Among the medical therapies are antiplatelets, anticoagulants, antihypertensives, lipid lowering therapies, cilostazol and pentoxifylline, and novel blood sugar-lowering therapies, plus exercise therapy and smoking cessation. In this review, we discuss these evidence-based medical therapies that are available for patients with symptomatic PAD.

Trends and outcomes of lytic-based therapies for high-risk pulmonary embolism: A nationwide analysis.

BACKGROUND: Systemic thrombolysis (ST) is the guideline-recommended treatment for high-risk pulmonary embolism (PE), although catheter-directed thrombolysis (CDT) may provide a treatment alternative associated with lower rates of bleeding. Furthermore, the treatment trends and outcomes among those with high-risk PE according to treatment assignments of no lytic therapy (NLT), ST, and CDT are underreported. METHODS: Patients hospitalized for high-risk PE between 2016 and 2019 were identified by administrative claims codes from the National Readmission Database. Therapy assignment was similarly defined by administrative codes, then stratified into NLT, ST, and CDT cohorts to report patient characteristics, care settings, and clinical outcomes. The primary outcome was in-hospital mortality with rates adjusted for patient and hospital characteristics using multivariable logistic regression. Secondary outcomes included intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), and 90-day readmission. Over the years of interest, trends in lytic treatment along with concomitant use of mechanical or surgical thrombectomy were reported. RESULTS: Among 74,516 patients with high-risk PE, 61,569 (82.6%) received NLT, 8445 (11.3%) received ST, and 4502 (6.04%) received CDT. The NLT subgroup, relative to ST and CDT, tended to be older (66.1 ± 15.4, 62.8 ± 15.3, and 63.4 ± 14.4; p < 0.001) and more frequently women (56.0%, 54.4%, and 51.3%; p < 0.001), respectively. The unadjusted in-hospital mortality rate was highest for ST (18.8%, 34.1%, and 18.3% for NLT, ST, and CDT, respectively; p < 0.001) and persisted after multivariable adjustment (adjusted odds ratio (aOR) 0.43; 95% CI 0.38-0.49; p < 0.0001) of in-hospital mortality for CDT relative to ST. The unadjusted rate of ICH or GIB was lowest for NLT (1.0%, 2.0%, and 0.6% for NLT, ST, and CDT, respectively; p < 0.001). CDT, relative to ST, was associated with reduced odds of ICH (aOR 0.32; 95% CI 0.18-0.55; p < 0.0001) and GIB (aOR 0.78; 95% CI 0.62-0.98; p < 0.0001). Readmissions were highest for NLT (21.7%, 9.6%, and 12.1% for NLT, ST, and CDT, respectively; p < 0.001). CDT was associated with a higher incidence of 90-day readmission relative to ST (aOR 1.32; 95% CI 1.10-1.57; p < 0.001). From 2016 to 2019, individual treatment trends were not significantly different, although NLT tended to be offered among smaller and rural hospitals. Rates of concomitant thrombectomy were low in all three treatment groups. CONCLUSIONS: Among a large, contemporary, US cohort with high-risk PE, over 80% of patients did not receive any form of thrombolysis. High-risk PE that did receive systemic thrombolysis was associated with the highest rates of in-hospital mortality, suggesting opportunities to study the implementation of lytic and nonlytic-based treatments to improve outcomes for those presenting with high-risk PE.

Perioperative outcomes of hypertrophic cardiomyopathy: An insight from the National Readmission Database.

BACKGROUND: Data regarding hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing noncardiac surgery is lacking. We sought to examine the perioperative outcomes of HOCM patients undergoing noncardiac surgery using a national database. METHODS: We used the National readmission database from 2016 to 2019. We identified HOCM, heart undergoing noncardiac surgery using ICD 10 codes. We examined hospital outcomes as well as 90 days readmission outcomes. RESULTS: We identified 16,098 HOCM patients and 21,895,699 non-HOCM patients undergoing noncardiac surgery. The HOCM group had more comorbidities at baseline. After adjustment for major clinical predictors, the HOCM group experienced more in-hospital death, odds ratio (OR) 1.33 (1.216-1.47), P < 0.001, acute myocardial infarction (AMI), OR 1.18 (1.077-1.292), P < 0.001, acute heart failure odds ratio OR 1.3 to (1.220-1.431), P < 0.001, 90 days readmission OR 1.237 (1.069-1.432), P < 0.01, cardiogenic shock OR 2.094 (1.855-2.363), P < 0.001. Cardiac arrhythmia was the most common cause of readmission, out of the arrhythmias atrial fibrillation was the most prevalent. Acute heart failure was the most common complication of readmission. There was no difference in major adverse cardiovascular events (MACE), and AMI between both groups and readmission. CONCLUSION: HOCM patients undergoing noncardiac surgery may be at increased risk of in-hospital and readmission events. Acute heart failure was the most common complication during index admission, while cardiac arrhythmias were the most common complication during readmission. More research is needed to address this patient population further.

Safety and outcomes of hip and knee replacement surgery in liver transplant recipients.

BACKGROUND: Liver transplant (LT) is becoming increasingly common with improved life expectancy. Joint replacement is usually a safe procedure; however, its safety in LT recipients remains understudied. AIM: To evaluate the mortality, outcome, and 90-d readmission rate in LT patients undergoing hip and knee replacement surgery. METHODS: Patients with history of LT who underwent hip and knee replacement surgery between 2016 and 2019 were identified using the National Readmission Database. RESULTS: A total of 5046119 hip and knee replacement surgeries were identified. 3219 patients had prior LT. Mean age of patients with no history of LT was 67.51 [95% confidence interval (CI): 67.44-67.58], while it was 64.05 (95%CI: 63.55-64.54) in patients with LT. Patients with history of LT were more likely to have prolonged length of hospital stay (17.1% vs 8.4%, P < 0.001). The mortality rate for patients with no history of LT was 0.22%, while it was 0.24% for patients with LT (P = 0.792). Patients with history of LT were more likely to have re-admissions within 90 d of initial hospitalization: 11.4% as compared to 6.2% in patients without history of LT (P < 0.001). The mortality rate between both groups during readmission was not statistically different (1.9% vs 2%, P = 0.871) respectively. CONCLUSION: Hip and knee replacements in patients with history of LT are not associated with increased mortality; increased re-admissions were more frequent in this cohort of patients. Chronic kidney disease and congestive heart failure appear to predict higher risk of readmission.

Site Variability in Cerebral Embolic Protection for Transcatheter Aortic Valve Implantation and Association With Outcomes.

Background: The effectiveness of cerebral embolic protection devices (CEPD) in mitigating stroke after transcatheter aortic valve implantation (TAVI) remains uncertain, and therefore CEPD may be utilized differently across US hospitals. This study aims to characterize the hospital-level pattern of CEPD use during TAVI in the US and its association with outcomes. Methods: Patients treated with nontransapical TAVI in the 2019 Nationwide Readmissions Database were included. Hospitals were categorized as CEPD non-users and CEPD users. The following outcomes were compared: the composite of in-hospital stroke or transient ischemic attack (TIA), in-hospital ischemic stroke, death, and cost of hospitalization. Logistic regression models were used for risk adjustment of clinical outcomes. Results: Of 41,822 TAVI encounters, CEPD was used in 10.6% (n = 4422). Out of 392 hospitals, 65.8% were CEPD non-user hospitals and 34.2% were CEPD users. No difference was observed between CEPD non-users and CEPD users in the risk of in-hospital stroke or TIA (adjusted odds ratio (OR) = 0.99 [0.86-1.15]), ischemic stroke (adjusted OR = 1.00 [0.85-1.18]), or in-hospital death (adjusted OR = 0.86 [0.71-1.03]). The cost of hospitalization was lower in CEPD non-users. Conclusions: Two-thirds of hospitals in the US do not use CEPD for TAVI, and no significant difference was observed in neurologic outcomes among patients treated at CEPD non-user and CEPD user hospitals.

Temporal trends in the utilization of advanced therapies among patients with acute pulmonary embolism: insights from a national database.

There is a paucity of data regarding the contemporary temporal trends in the adoption of advanced pulmonary embolism (PE) therapies in the United States as well as the parallel trends in outcomes of patients with acute PE. Therefore, we queried the Nationwide Readmissions Database (years 2016-2020) to report the temporal trends in utilization of advanced PE therapies. Our final analysis included 920 770 hospitalizations with acute PE. We demonstrated an increase in the proportion of patients diagnosed with high-risk PE during the study years. Overall, there was an increase in the use of advanced PE therapies, which was mainly due to the increase in the utilization of systemic thrombolytics, and catheter-directed therapies. Also, extracorporeal membrane oxygenation cannulation showed an incremental increase over the study years. The use of inferior vena cava filter has declined, while the use of surgical embolectomy did not change during the study years. The use of advanced therapies has increased among urban teaching, but not among urban non-teaching hospitals. During the study years, there was no change in unadjusted or adjusted in-hospital mortality rates among patients with acute PE, while the 90-day unplanned readmission rate has declined.

Outcomes of Transcatheter Aortic Valve Implant Among Patients With A Previous Coronary Artery Bypass Graft: A Nationwide Analysis.

There is a paucity of data regarding the temporal trends and outcomes of transcatheter aortic valve implant (TAVI) among patients with a previous coronary artery bypass graft (CABG) surgery. We queried the Nationwide Readmissions Database (2016 to 2019) for hospitalized patients who underwent TAVI using the appropriate International Classification of Diseases, Tenth Revision procedural codes. A multivariable regression analysis was used to adjust for the patients' and hospitals' characteristics in comparing the study groups. The primary outcome was in-hospital mortality. The final analysis included 237,829 patients who underwent TAVI, of whom 42,671 (17.9%) had a previous CABG. During the study period, there was a decrease in the proportion of patients with previous CABG who underwent TAVI (21.0% in 2016 vs 15.5% in 2019, ptrend = 0.01), although there was no change in their in-hospital mortality rate (1.08% in 2016 vs 1.25% in 2019, ptrend = 0.43). Patients with a previous CABG were younger and less likely to be women than those without a previous CABG. TAVI among those with a previous CABG was associated with lower in-hospital mortality (adjusted odds ratio [aOR] 0.79, 95% confidence interval [CI] 0.69 to 0.91), similar rate of ischemic stroke (aOR 0.81, 95% CI 0.71 to 0.93) and permanent pacemaker implant (aOR 1.00, 95% CI 0.93 to 1.05). Patients with a previous CABG had a lower all-cause 90-day readmission (odds ratio 0.95, 95% CI 0.94 to 1.06) but higher readmission for transient ischemic attack. Among those with a previous CABG, female gender and chronic kidney disease stage ≥3 were independently associated with a higher in-hospital mortality, whereas obesity was associated with a lower in-hospital mortality. In conclusion, there was a decrease in the proportion of patients with a previous CABG among those who underwent TAVI. TAVI among those with a previous CABG was not associated with increased in-hospital adverse events or 90-day all-cause readmissions.

A modern day perspective on smoking in peripheral artery disease.

Peripheral artery disease (PAD) is associated with increased risk of cardiovascular morbidity and mortality, poor functional status, and lower quality of life. Cigarette smoking is a major preventable risk factor for PAD and is strongly associated with a higher risk of disease progression, worse post-procedural outcomes, and increased healthcare utilization. The arterial narrowing due to atherosclerotic lesions in PAD leads to decreased perfusion to the limbs and can ultimately cause arterial obstruction and limb ischemia. Endothelial cell dysfunction, oxidative stress, inflammation, and arterial stiffness are among the key events during the development of atherogenesis. In this review, we discuss the benefits of smoking cessation among patients with PAD and the use of smoking cessation methods including pharmacological treatment. Given that smoking cessation interventions remain underutilized, we highlight the importance of incorporating smoking cessation treatments as part of the medical management of patients with PAD. Regulatory approaches to reduce the uptake of tobacco product use and support smoking cessation have the potential to reduce the burden of PAD.

Hybrid convergent ablation versus endocardial catheter ablation for atrial fibrillation: A systematic review and meta-analysis.

INTRODUCTION: Endocardial catheter ablation (ECA) for atrial fibrillation (AF) has limited efficacy. Hybrid convergent procedure (HCP) with both epicardial and endocardial ablation is a novel strategy for AF treatment. In this meta-analysis, we aimed to evaluate the efficacy and safety of HCP in AF ablation. METHOD: We performed a comprehensive literature search for studies that evaluated the efficacy and safety of HCP compared with ECA for AF. The primary outcome was freedom of atrial arrhythmia (AA). The secondary outcome was the periprocedural complication rate. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: A total of eight studies, including 797 AF patients (mean age: 60.7 ± 9.8 years, 366 patients with HCP vs. 431 patients with ECA alone), were included. HCP showed a higher rate of freedom of AA compared with ECA (RR: 1.48, 95% CI: 1.13-1.94, p = .004). However, HCP was associated with higher rates of periprocedural complications (RR: 3.64, 95% CI: 2.06-6.43; p = .00001). Moreover, the HCP had a longer procedure time and postprocedural hospital stay. CONCLUSIONS: Although hybrid ablation was associated with a higher success rate, this should be judged for increased periprocedural adverse events and extended hospital stay. Prospective large-scale randomized trials are needed to validate these results.

Adjunctive Vein of Marshall Ethanol Infusion During Atrial Fibrillation Ablation: A Systematic Review and Meta-Analysis.

INTRODUCTION: Catheter ablation (CA) for atrial fibrillation (AF) can be associated with limited efficacy. Due to its autonomic innervation, the vein of Marshall (VOM) is an attractive target during AF ablation. In this meta-analysis, we aimed to evaluate the efficacy and safety of adjunctive ethanol infusion of VOM (VOM-EI) in AF ablation. METHODS: We performed a comprehensive literature search for studies that evaluated the efficacy and safety of VOM-EI in AF ablation compared to AF catheter ablation alone. The primary outcome of interest was late (≥3 months) AF or atrial tachycardia (AT) recurrence. The secondary outcomes included acute mitral isthmus bidirectional block (MIBB) and procedural complications (pericardial effusion, stroke, or atrio-esophageal fistula). Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. RESULTS: A total of four studies, including 804 AF patients (68.2% with persistent AF, the mean age of 63.5±9.9 years, 401 patients underwent VOM-EI plus CA vs. 403 patients who had CA alone), were included in the final analysis. VOM-EI group was associated with a lower risk of late AF/AT recurrence (RR:0.63; 95% CI:0.46-0.87; P = 0.005), and increased probability to achieve acute MIBB (RR:1.39; 95% CI:1.08-1.79; P = 0.009) without an increase in procedural complications (RR:1.05; 95% CI:0.57-1.94; P = 0.87). CONCLUSIONS: Our meta-analysis demonstrated that adjunctive VOM-EI strategy is more effective than conventional catheter ablation with similar safety profiles.

Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is a risk factor for ischemic and hypertensive kidney disease (HKD) for which autologous mesenchymal stem cell (MSC) appears to be a promising therapy. However, MSCs from ARAS patients exhibit impaired function, senescence, and DNA damage, possibly due to epigenetic mechanisms. Hypoxia preconditioning (HPC) exerts beneficial effects on cellular proliferation, differentiation, and gene and protein expression. We hypothesized that HPC could influence MSC function and senescence in ARAS by epigenetic mechanisms and modulating gene expression of chromatin-modifying enzymes. METHODS: Adipose-derived MSC harvested from healthy control (N = 8) and ARAS (N = 8) pigs were cultured under normoxia (20%O2) or hypoxia (1%O2) conditions. MSC function was assessed by migration, proliferation, and cytokine release in conditioned media. MSC senescence was evaluated by SA-ß-gal activity. Specific pro-angiogenic and senescence genes were assessed by reverse transcription polymerase chain reaction (RT-PCR). Dot blotting was used to measure global genome 5-hydroxymethylcytosine (5hmC) levels on DNA and Western blotting of modified histone 3 (H3) proteins to quantify tri-methylated lysine-4 (H3K4me3), lysine-9 (H3K9me3), and lysine-27 (H3K27me3) residues. RESULTS: Specific pro-angiogenic genes in ARAS assessed by RT-PCR were lower at baseline but increased under HPC, while pro-senescence genes were higher in ARAS at baseline as compared healthy MSCs. ARAS MSCs under basal conditions, displayed higher H3K4me3, H3K27me3, and 5hmC levels compared to healthy MSCs. During HPC, global 5hmC levels were decreased while no appreciable changes occurred in histone H3 tri-methylation. ARAS MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased vascular endothelial growth factor and epidermal growth factor expression compared to normoxia, and SA-ß-gal activity decreased in both animal groups. CONCLUSIONS: These data demonstrate that swine ARAS MSCs have decreased angiogenesis and increased senescence compared to healthy MSCs and that HPC mitigates MSC dysfunction, senescence, and DNA hydroxymethylation in ARAS MSC. Thus, HPC for MSCs may be considered for their optimization to improve autologous cell therapy in patients with nephropathies.

Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue-derived MSCs 2 weeks earlier, or sham. STK senescence-associated ß-galactosidase (SA-ß-Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence-associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue-derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA-ß-Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA-ß-Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.

Renal fibrosis detected by diffusion-weighted magnetic resonance imaging remains unchanged despite treatment in subjects with renovascular disease.

Tissue fibrosis is an important index of renal disease progression. Diffusion-weighted magnetic resonance imaging's (DWI-MRI) apparent diffusion coefficient (ADC) reveals water diffusion is unobstructed by microstructural alterations like fibrosis. We hypothesized that ADC may indicate renal injury and response to therapy in patients with renovascular disease (RVD). RVD patients were treated with medical therapy (MT) and percutaneous transluminal renal angioplasty (MT + PTRA) (n = 11, 3 bilaterally, n = 14 kidneys) or MT (n = 9). ADC and renal hypoxia (R2*) by blood-oxygen-level-dependent MRI were studied before (n = 27) and 3 months after (n = 20) treatment. Twelve patients underwent renal biopsies. Baseline ADC values were correlated with changes in eGFR, serum creatinine (SCr), systolic blood pressure (SBP), renal hypoxia, and renal vein levels of pro-inflammatory marker tumor necrosis-factor (TNF)-α. Renal oxygenation, eGFR, and SCr improved after MT + PTRA. ADC inversely correlated with the histological degree of renal fibrosis, but remained unchanged after MT or MT + PTRA. Basal ADC values correlated modestly with change in SBP, but not in renal hypoxia, TNF-α levels, or renal function. Lower ADC potentially reflects renal injury in RVD patients, but does not change in response to medical or interventional therapy over 3 months. Future studies need to pinpoint indices of kidney recovery potential.

In a Phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure.

Atherosclerotic renovascular disease (ARVD) reduces tissue perfusion and eventually leads to loss of kidney function with limited therapeutic options. Here we describe results of Phase 1a escalating dose clinical trial of autologous mesenchymal stem cell infusion for ARVD. Thirty-nine patients with ARVD were studied on two occasions separated by three months. Autologous adipose-derived mesenchymal stem cells were infused through the renal artery in 21 patients at three different dose levels (1, 2.5 and 5.0 × 105 cells/kg) in seven patients each. We measured renal blood flow, glomerular filtration rate (GFR) (iothalamate and estimated GFR), renal vein cytokine levels, blood pressure, and tissue oxygenation before and three months after stem cell delivery. These indices were compared to those of 18 patients with ARVD matched for age, kidney function and blood pressure receiving medical therapy alone that underwent an identical study protocol. Cultured mesenchymal stem cells were also studied in vitro. For the entire stem cell treated-cohort, mean renal blood flow in the treated stenotic kidney significantly increased after stem cell infusion from (164 to 190 ml/min). Hypoxia, renal vein inflammatory cytokines, and angiogenic biomarkers significantly decreased following stem cell infusion. Mean systolic blood pressure significantly fell (144 to 136 mmHg) and the mean two-kidney GFR (Iothalamate) modestly but significantly increased from (53 to 56 ml/min). Changes in GFR and blood pressure were largest in the high dose stem cell treated individuals. No such changes were observed in the cohort receiving medical treatment alone. Thus, our data demonstrate the potential for autologous mesenchymal stem cell to increase blood flow, GFR and attenuate inflammatory injury in post-stenotic kidneys. The observation that some effects are dose-dependent and related to in-vitro properties of mesenchymal stem cell may direct efforts to maximize potential therapeutic efficacy.

Senescent Kidney Cells in Hypertensive Patients Release Urinary Extracellular Vesicles.

Background Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles (EVs), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that EVs released by senescent nephron cells can be identified in urine of patients with hypertension. Methods and Results We recruited patients with essential hypertension (EH) or renovascular hypertension and healthy volunteers (n=14 each). Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine-level measurements. EVs isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle's loop), and prominin-2 (distal tubules). Overall percentage of urinary p16+ EVs was elevated in EH and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16+/urate transporter 1+ were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16+/prominin-2+ levels were elevated only in EH versus healthy volunteers and p16+/uromodulin+ in renovascular hypertension versus EH. Conclusions Levels of p16+ EVs are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In EH, EVs originate also from distal tubules and in renovascular hypertension from Henle's loop. Hence, urinary EVs levels may be useful to identify intrarenal sites of cellular senescence.

A modified two-compartment model for measurement of renal function using dynamic contrast-enhanced computed tomography.

OBJECTIVES: To validate and adapt a modified two-compartment model, originally developed for magnetic resonance imaging, for measuring human single-kidney glomerular filtration rate (GFR) and perfusion using dynamic contrast-enhanced computed tomography (DCE-CT). METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. Thirty-eight patients with essential hypertension (EH, n = 13) or atherosclerotic renal artery stenosis (ARAS, n = 25) underwent renal DCE-CT for GFR and perfusion measurement using a modified two-compartment model. Iothalamate clearance was used to measure reference total GFR, which was apportioned into single-kidney GFR by renal blood flow. Renal perfusion was also calculated using a conventional deconvolution algorithm. Validation of GFR and perfusion and inter-observer reproducibility, were conducted by using the Pearson correlation and Bland-Altman analysis. RESULTS: Both the two-compartment model and iothalamate clearance detected in ARAS patients lower GFR in the stenotic compared to the contralateral and EH kidneys. GFRs measured by DCE-CT and iothalamate clearance showed a close match (r = 0.94, P<0.001, and mean difference 2.5±12.2mL/min). Inter-observer bias and variation in model-derived GFR (r = 0.97, P<0.001; mean difference, 0.3±7.7mL/min) were minimal. Renal perfusion by deconvolution agreed well with that by the compartment model when the blood transit delay from abdominal aorta to kidney was negligible. CONCLUSION: The proposed two-compartment model faithfully depicts contrast dynamics using DCE-CT and may provide a reliable tool for measuring human single-kidney GFR and perfusion.

Tissue hypoxia, inflammation, and loss of glomerular filtration rate in human atherosclerotic renovascular disease.

The relationships between renal blood flow (RBF), tissue oxygenation, and inflammatory injury in atherosclerotic renovascular disease (ARVD) are poorly understood. We sought to correlate RBF and tissue hypoxia with glomerular filtration rate (GFR) in 48 kidneys from patients with ARVD stratified by single kidney iothalamate GFR (sGFR). Oxygenation was assessed by blood oxygenation level dependent magnetic resonance imaging (BOLD MRI), which provides an index for the levels of deoxyhemoglobin within a defined volume of tissue (R2*). sGFR correlated with RBF and with the severity of vascular stenosis as estimated by duplex velocities. Higher cortical R2* and fractional hypoxia and higher levels of renal vein neutrophil-gelatinase-associated-lipocalin (NGAL) and monocyte-chemoattractant protein-1 (MCP-1) were observed at lower GFR, with an abrupt inflection below 20 ml/min. Renal vein MCP-1 levels correlated with cortical R2* and with fractional hypoxia. Correlations between cortical R2* and RBF in the highest sGFR stratum (mean sGFR 51 ± 12 ml/min; R = -0.8) were degraded in the lowest sGFR stratum (mean sGFR 8 ± 3 ml/min; R = -0.1). Changes in fractional hypoxia after furosemide were also absent in the lowest sGFR stratum. These data demonstrate relative stability of renal oxygenation with moderate reductions in RBF and GFR but identify a transition to overt hypoxia and inflammatory cytokine release with severely reduced GFR. Tissue oxygenation and RBF were less correlated in the setting of reduced sGFR, consistent with variable oxygen consumption or a shift to alternative mechanisms of tissue injury. Identifying transitions in tissue oxygenation may facilitate targeted therapy in ARVD.

Renal Adiposity Does not Preclude Quantitative Assessment of Renal Function Using Dual-Energy Multidetector CT in Mildly Obese Human Subjects.

RATIONALE AND OBJECTIVES: Multidetector computed tomography (MDCT) is useful for measuring in the research setting single-kidney perfusion and function using iodinated contrast time-attenuation curves. Obesity promotes deposition of intrarenal fat, which might decrease tissue attenuation and thereby interfere with quantification of renal function using MDCT. The purpose of this study was to test the hypothesis that background subtraction adequately accounts for intrarenal fat deposition in mildly obese human subjects during renal contrast enhanced dynamic CT. MATERIALS AND METHODS: We prospectively recruited seventeen human subjects stratified as lean or mildly obese based on body mass index below or over 30 kg/m2, respectively. Renal perfusion was quantified from CT-derived indicator-dilution curves after background subtraction. Dual-energy MDCT images were postprocessed to generate iodine and virtual-noncontrast datasets, and the ratios between kidney/aorta CT numbers and iodine values calculated as surrogates of renal function. RESULTS: Subcutaneous adipose tissue was increased in obese subjects. Virtual-noncontrast maps revealed in obese patients a decrease in basal cortical and medullary attenuation. Overall, basal attenuation inversely correlated with body mass index, in line with renal fat deposition. Contrarily, the kidney/aorta CT attenuation (after background subtraction) and kidney/aorta iodine ratios were similar between lean and obese subjects and correlated directly. These observations show that following background subtraction, the CT number reliably reflects basal tissue attenuation. CONCLUSION: Therefore, our findings support our hypothesis that background subtraction enables reliable assessment of kidney function in mildly obese subjects using MDCT, despite decreased basal attenuation due to renal adiposity.

Loss of Renal Peritubular Capillaries in Hypertensive Patients Is Detectable by Urinary Endothelial Microparticle Levels.

Hypertension, an important cause of chronic kidney disease, is characterized by peritubular capillary (PTC) loss. Circulating levels of endothelial microparticles (EMPs) reflect systemic endothelial injury. We hypothesized that systemic and urinary PTC-EMPs levels would reflect renal microvascular injury in hypertensive patients. We prospectively measured by flow cytometry renal vein, inferior vena cava, and urinary levels of EMPs in essential (n=14) and renovascular (RVH; n=24) hypertensive patients and compared them with peripheral blood and urinary levels in healthy volunteers (n=14). PTC-EMPs were identified as urinary exosomes positive for the PTC marker plasmalemmal-vesicle-associated protein. In 7 RVH patients, PTC and fibrosis were also quantified in renal biopsy, and in 18 RVH patients, PTC-EMPs were measured again 3 months after continued medical therapy with or without stenting (n=9 each). Renal vein and systemic PTC-EMPs levels were not different among the groups, whereas their urinary levels were elevated in both RVH and essential hypertension versus healthy volunteers (56.8%±12.7% and 62.8%±10.7% versus 34.0%±17.8%; both P≤0.001). Urinary PTC-EMPs levels correlated directly with blood pressure and inversely with estimated glomerular filtration rate. Furthermore, in RVH, urinary PTC-EMPs levels correlated directly with stenotic kidney hypoxia, histological PTC count, and fibrosis and inversely with cortical perfusion. Three months after treatment, the change in urinary PTC-EMPs levels correlated inversely with a change in renal function ( r=-0.582; P=0.011). Therefore, urinary PTC-EMPs levels are increased in hypertensive patients and may reflect renal microcirculation injury, whereas systemic PTC-EMPs levels are unchanged. Urinary PTC-EMPs may be useful as novel biomarkers of intrarenal capillary loss.

Intrarenal fat deposition does not interfere with the measurement of single-kidney perfusion in obese swine using multi-detector computed tomography.

BACKGROUND: Altered vascular structure or function in several diseases may impair renal perfusion. Multi-detector computed tomography (MDCT) is a non-invasive tool to assess single-kidney perfusion and function based on dynamic changes in tissue attenuation during contrast media transit. However, changes in basal tissue attenuation might hamper these assessments, despite background subtraction. Evaluation of iodine concentration using the dual-energy (DECT) MDCT mode allows excluding effects of basal values on dynamic changes in tissue attenuation. We tested whether decreased basal kidney attenuation secondary to intrarenal fat deposition in swine obesity interferes with assessment of renal perfusion using MDCT. METHODS: Domestic pigs were fed a standard (lean) or a high-cholesterol/carbohydrate (obese) diet (n = 5 each) for 16 weeks, and both kidneys were then imaged using MDCT/DECT after iodinated contrast injection. DECT images were post-processed to generate iodine and virtual-non-contrast (VNC) datasets, and the MDCT kidney/aorta CT number (following background subtraction) and DECT iodine ratios calculated during the peak vascular phase as surrogates of renal perfusion. Intrarenal fat was subsequently assessed with Oil-Red-O staining. RESULTS: VNC maps in obese pigs revealed decreased basal cortical attenuation, and histology confirmed increased renal tissue fat deposition. Nevertheless, the kidney/aorta attenuation and iodine ratios remained similar, and unchanged compared to lean pigs. CONCLUSIONS: Despite decreased basal attenuation secondary to renal adiposity, background subtraction allows adequate assessment of kidney perfusion in obese pigs using MDCT. These observations support the feasibility of renal perfusion assessment in obese subjects using MDCT.