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AbstractAcute kidney injury (AKI) may develop in patients with coronavirus disease 2019 (COVID‐19) and is associated with in‐hospital death. We investigated the incidence of AKI in 223 hospitalized COVID‐19 patients and analyzed the influence factors of AKI. The incidence of cytokine storm syndrome and its correlation with other clinicopathologic variables were also investigated. We retrospectively enrolled adult patients with virologically confirmed COVID‐19 who were hospitalized at three hospitals in Wuhan and Guizhou, China between February 13, 2020, and April 8, 2020. We included 124 patients with moderate COVID‐19 and 99 with severe COVID‐19. AKI was present in 35 (15.7%) patients. The incidence of AKI was 30.3% for severe COVID‐19 and 4.0% for moderate COVID‐19 (p < 0.001). Furthermore, cytokine storm was found in 30 (13.5%) patients and only found in the severe group. Kidney injury at admission (odds ratio [OR]: 3.132, 95% confidence interval [CI]: 1.150–8.527; p = 0.025), cytokine storm (OR: 4.234, 95% CI: 1.361–13.171; p = 0.013), and acute respiratory distress syndrome (ARDS) (OR: 7.684, 95% CI: 2.622–22.523; p < 0.001) were influence factors of AKI. Seventeen (48.6%) patients who received invasive mechanical ventilation developed AKI, of whom 64.7% (11/17) died. Up to 86.7% of AKI patients with cytokine storms may develop a secondary bacterial infection. The leukocyte counts were significantly higher in AKI patients with cytokine storm than in those without (13.0 × 10⁹/L, interquartile range [IQR] 11.3 vs. 8.3 × 10⁹/L, IQR 7.5, p = 0.005). Approximately 1/6 patients with COVID‐19 eventually develop AKI. Kidney injury at admission, cytokine storm and ARDS are influence factors of AKI. Cytokine storm and secondary bacterial infections may be responsible for AKI development in COVID‐19 patients.

Introduction: Morbidity and mortality attributable to hypertension are higher in African American (AAEH) compared to Caucasian essential hypertensive (EH) patients, possibly related to a differential effect on vascular injury and repair. While circulating endothelial progenitor cells (EPC) preserve endothelial integrity IEC detach from sites of injury and represent markers of vascular damage. We hypothesized that plasma levels of IEC and inflammatory markers would be higher in AAEH compared to EH patients. METHODS: Inferior vena cava levels of CD34+/KDR+ (EPC) and VAP-1+ (IEC) cells were measured by FACS in EH and AAEH under fixed sodium intake (150 mEq/d) and blockade of the renin-angiotensin-system, and compared to systemic levels in normotensive control subjects (n=19 each). Systemic levels of inflammatory cytokines and EPC homing factors were measured by Luminex. Results: Blood pressure, serum creatinine, lipids, antihypertensive medications, and EPC levels did not differ between EH and AAEH patients. Circulating IEC were higher in AAEH, and inversely correlated with EPC levels (Figure). Systemic levels of inflammatory cytokines and EPC homing factors were higher in AAEH compared to EH patients (Table), and correlated directly with IEC. Conclusion: Despite preserved kidney function and controlled BP, circulating inflammatory markers were elevated in AAEH and correlated with increased IEC and decreased EPC levels. Increased release of cytokines and IEC in AAEH may impair EPC reparative capacity and predispose to hypertensive vascular injury. This process may aggravate vascular damage and accelerate hypertension-related morbidity/mortality rates in AAEH.

Objective: Excessive autophagy (degradation of intracellular structures) characterizes cardiomyocyte injury in hypertensive heart disease. The effect of Angiotensin II receptor blocker Valsartan on RVH-induced myocardial autophagy remains unexplored. Method: Twenty-one domestic pigs (50-60 Kg) were randomized into 3 groups: RVH, RVH+Valsartan, and Control (n=7 each), and observed for 10 wks. Valsartan (320mg/d PO) was administered for 4 wks starting at 6 wks of RVH. After 10 wks, myocardial fibrosis was examined by trichrome staining, and inflammation by M1 macrophage (M1 Ø, CD163+/iNOS+) staining and TNF-α expression (immunoblotting). Autophagy was examined for Atg 12-Atg 5, Beclin-1 and its inhibitor mTOR. Result: At 6 wks, MAP was higher in both RVH and RVH+Valsartan compared to Control (147.6 ±14.0 and 139.1±11.2 vs. 105.9±11.4 mmHg, respectively, P<0.05). At 10 wks, Valsartan did not decrease MAP compared to RVH (P=0.31), Both Beclin-1 and Atg 12-Atg 15 expressions that were elevated in RVH (P<0.05 vs. Control), indicating increased autophagy, were restored by Valsartan (Figure). Valsartan restored a compensatory increase in mTOR expression in RVH, and ameliorated myocardial fibrosis, M1 Ø, and TNF-α expression (Figure). Conclusion: Valsartan decreased myocardial autophagy, fibrosis and inflammation in pigs with RVH, independent of effective blood pressure control. Valsartan has novel pleiotropic effects on turnover of cellular structures in RVH-induced myocardial damage.

Background : Renovascular disease (RVD) and impaired renal function are important risk factors for cardiac disease, but it remained unclear whether selective recovery of renal function can reverse cardiac dysfunction. Aims: This study tested the hypothesis that improvement in renal function using selective intra-renal administration of endothelial progenitor cells (EPC) in swine renovascular hypertension would improve myocardial microvascular (MV) integrity. Methods: The functions of the myocardial MV (response to IV adenosine) and the stenotic kidney of 7 pigs were assessed in-vivo using multi-detector CT after 6 weeks of RVD and hypertension. Autologous EPC expanded in culture were then infused (10x10 6 cells) intra-renally, and in vivo studies repeated 4 wks later. Six normal pigs served as controls. Results : Glomerular filtration rate was lower in RVD compared to normal (47.9±10.1 vs. 70.8±4.3 mL/min, p<0.05) and improved after EPC (to 62.7±1.5 mL/min, p=NS vs. normal), as did renal blood flow. Mean arterial pressure remained elevated after EPC (120.7±11 and 129.4±6 vs. 99.9±4.7 mmHg in normal, p<0.05), and plasma renin activity was unchanged. Myocardial MV permeability-surface area increased in RVD in response to adenosine (0.009±0.001 to 0.011±0.002 AU, p=0.01), while MV volume fraction decreased (4.3±0.8 to 2.7±0.6%, p=0.01), indicating impaired MV barrier function and integrity. Contrarily, both remained unchanged in response to adenosine 4 wks after EPC (0.01±0.002 to 0.01±0.002 AU, p=0.24, and 3.5±0.8 to 3.4±0.5%, p=0.46, respectively), as did normal MV. Conclusion : A single intra-renal infusion of EPC that improved renal function in experimental RVD also preserved remote myocardial MV function, despite sustained systemic hypertension. These findings underscore the cross talk between renal and cardiac function, and the potential of selective renal EPC intervention to preserve both the kidney and heart in RVD. Renal and myocardial microvascular function change in normal and RVD before and after EPC treatment

Introduction: Cardiovascular disease (CVD) is the leading cause of morbidity/mortality in the US. Despite being a class 1A evidence-based recommendation, secondary prevention efforts in the period following cardiac rehabilitation (CR) lack a proven and successful intervention. A previously validated digital health intervention (DHI) delivered Mayo Clinic’s CR, including educational material, tracking CVD indices, and diet/exercise adherence, for 3 months after usual CR. Hypothesis: We hypothesized DHI use would improve CVD risk factors and rehospitalizations/ emergency department (ED) visits. Methods: Patients undergoing usual Mayo Clinic CR were recruited to use the application following usual CR (n=17) and compared to a similar cohort undergoing standard post-CR care, but not assigned to the application (n=11). DHI patients performed daily informational tasks, entered their own risk factor information (weight, blood pressure (BP), glucose, lipids, physical activity, and diet) at baseline and for three months post-CR. Changes in risk factors, re-hospitalizations/ED visits were assessed after three months. Results: There were no differences in baseline demographics between the two groups. There was no difference in weight change between the two groups during the three months of usual CR, yet in the three months following usual CR the DHI group had significant reductions in weight (-2.5±3.8 kg, p=0.04) and systolic BP (-12.6±12.4 mmHg, p=0.001) compared to the control group. The DHI group also showed significantly lower rate of rehospitalizations/ED visits (-28%, p=0.04, Figure). Conclusions: A DHI post-CR program can enhance secondary prevention strategies compared to standard post-CR care by augmenting weight and BP reduction and reducing the healthcare burden of repeat CVD events. This study thus supports development and implementation of DHI programs.

Introduction: Venous thromboembolism (VTE) is a cause of significant morbidity and mortality. The vascular endothelium may be involved in the pathogenesis of both VTE and arterial thrombosis, as endothelial injury and dysfunction may disrupt normal anticoagulation mechanisms. We aimed to test the hypothesis that coronary endothelial dysfunction (CED) is associated with development of VTE in prospective follow-up. Methods: Coronary vascular reactivity was evaluated in 502 patients with non-obstructive coronary artery disease by administration of intracoronary acetylcholine during diagnostic angiography. Microvascular CED was defined as ≤50% increase in coronary blood flow (CBF) from baseline in response to maximal dose of acetylcholine. After median follow-up of 6.3 years (IQR 3.5, 10.7), patients were assessed by standardized questionnaire, phone-call and review of medical records for development of VTE. Results: Median age of the population was 53 years (IQR 45, 62); 68% were females. Hypertension was prevalent in 40.8%, diabetes in 8.4%, and hyperlipidemia in 58.3% of patients. Of 502 patients, 279 had CED. There were no significant differences in baseline characteristics including cardiovascular and VTE risk factors between patients with and without CED (p>0.05). Eighty-nine percents of patients who developed VTE had CED. Patients who developed spontaneous or provoked VTE both had significantly lower % change in CBF than patients who did not develop VTE (p<0.05) (Figure 1). In univariate analysis, microvascular dysfunction was associated with increased risk of VTE (OR 6.55 (95% confidence interval (0.81, 52.79); p=0.04). Conclusion: We found a seven-fold increased risk of VTE with CED, suggesting a link between the two. Endothelial injury disrupting vascular homeostasis may predispose patients to VTE.

Mesenchymal stem/stromal cells (MSCs) are the most utilized cell type for cellular therapy, partly due to their important proliferative potential and ability to differentiate into various cell types. MSCs produce large amounts of extracellular vesicles (EVs), which carry genetic and protein cargo to mediate MSC paracrine function. Recently, MSC-derived EVs have been successfully used in several preclinical models of chronic kidney disease. However, uncertainty remains regarding EV fate, safety, and long-term effects, which might impose important limitations on their path to clinical translation. This review discusses the therapeutic application of MSC-derived EV therapy for renal disease, with particular emphasis on potential mechanisms of kidney repair and major translational barriers. Emerging evidence indicates that the cargo of MSC-derived EVs is capable of modulating several pathways responsible for renal injury, including inflammation, oxidative stress, apoptosis, fibrosis, and microvascular remodeling. EV-induced modulation of these pathways has been associated with important renoprotective effects in experimental studies. However, scarce clinical data are available, and several challenges need to be addressed as we move toward clinical translation, including standardization of methods for EV isolation and characterization, EV fate, duration of EV effects, and effects of cardiovascular risk factors. MSC-derived EVs have the potential to preserve renal structure and function, but further experimental and clinical evidence is needed to confirm their protective effects in patients with chronic kidney disease.

Polycystic kidney disease (PKD) is the most common monogenic kidney disorder and an important cause of end stage renal disease. Vascular abnormalities are the most important non‐cystic complication and contribute to renal disease progression. Homocysteine (Hcy)‐mediated endothelial dysfunction (ED) and oxidative stress are evident early on, but the underlying mechanisms remain unknown. We hypothesized that abnormalities in Hcy metabolism are responsible for the increased levels, leading to Hcy‐induced ED from early stages of PKD. Methods We investigated the Hcy metabolic pathway (transulfuration/remethylation fig. 1) and downstream effects ‐main sources of renal tubular (RT) and endothelial cell (EC) reactive oxygen species (ROS), NADPH oxidase 4, (NOX4) and mitochondria‐ in 4‐week‐old PCK and Sprague‐Dawley (SD) control rats (n=12 each). Kidneys were harvested, frozen in liquid nitrogen, or preserved in formalin for metabolomics and ex‐vivo studies. Twenty‐four‐hour urine and terminal blood samples were collected for metabolite analysis and chemistries. Plasma folic acid, vitamin B12, and Hcy were determined by ELISA. Hcy pathway metabolites (betaine, dimethylglycine) were determined by 1 HNMR. Endothelial NO (eNOS) and oxidative stress were assessed by double immunofluorescence staining for CD31/eNOS and CD31/NOX4, respectively. RT and EC mitochondrial structure was assessed by electron microscopy. Results Serum creatinine and BUN remained unchanged, yet kidney weight/body weight ratio were increased in PCK. eNOS immunoreactivity was lower in PCK vs SD. Plasma Hcy and urine excretion of methyl donor betaine were elevated in PCK, and Hcy positively correlated with urine betaine. Plasma betaine was similar between the groups, but its tissue concentration was lower in PCK, which may lead to betaine insufficiency, impaired betaine dependent remethylation, and hyperhomocysteinemia. Contrarily, tissue glutathione concentration was higher in PCK vs SD, and plasma folate and vitamin B12 were similar, arguing against a defect in the transsulfuration or folate‐dependent remethylation pathways. RT NOX4 expression and immunoreactivity were increased in PCK compared to SD, in association with renal oxidative stress. PCK had increased number of CD31/NOX4 positive cells in peritubular capillaries, indicating increased EC ROS production. Collecting duct and EC mitochondria were swollen and showed cristae remodeling. Conclusion In PKD, early elevation in Hcy is likely related to betaine insufficiency and impaired betaine‐dependent remethylation may be responsible for the early elevation of Hcy. NOX4 and mitochondria abnormalities may be important contributors to oxidative stress and disease severity. Our data suggests these may not only be early vascular disease markers, but also play an important pathogenic role in vascular complications associated with PKD, and contribute to renal disease progression. Support or Funding Information R25‐DK101405, NIDDK P30 DK090728, NIDDK P30 DK 106912 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .