These findings suggest that abnormal HDL capacity to mediate cholesterol efflux is a key driver of excess CVD in patients on chronic hemodialysis and may explain why statins have limited effect to decrease CV events. The findings also suggest cellular cholesterol transporters as potential therapeutic targets to decrease CV risk in this population.

The development of new modes of diagnosis and targeted therapy for lung cancer is dependent on the identification of unique cell surface features on cancer cells and isolation of reagents that bind with high affinity and specificity to these biomarkers. We recently isolated a 20-mer peptide which binds to the lung adenocarcinoma cell line, H2009, from a phage-displayed peptide library. We show here that the cellular receptor for this peptide, TP H2009

The hypoxia-inducible transcription factors HIF-1 and HIF-2 mediate key cellular adaptions to hypoxia and contribute to renal homeostasis and pathophysiology; however, little is known about the cell type-specific functions of HIF-1 and HIF-2 in response to ischemic kidney injury. Here, we used a genetic approach to specifically dissect the roles of endothelial HIF-1 and HIF-2 in murine models of hypoxic kidney injury induced by ischemia reperfusion or ureteral obstruction. In both models, inactivation of endothelial HIF increased injury-associated renal inflammation and fibrosis. Specifically, inactivation of endothelial HIF-2α, but not endothelial HIF-1α, resulted in increased expression of renal injury markers and inflammatory cell infiltration in the postischemic kidney, which was reversed by blockade of vascular cell adhesion molecule-1 (VCAM1) and very late antigen-4 (VLA4) using monoclonal antibodies. In contrast, pharmacologic or genetic activation of HIF via HIF prolyl-hydroxylase inhibition protected wild-type animals from ischemic kidney injury and inflammation; however, these same protective effects were not observed in HIF prolyl-hydroxylase inhibitortreated animals lacking endothelial HIF-2. Taken together, our data indicate that endothelial HIF-2 protects from hypoxia-induced renal damage and represents a potential therapeutic target for renoprotection and prevention of fibrosis following acute ischemic injury.

Background and objectives Electronic health record (EHR) patient portals allow individuals to access their medical information with the intent of patient empowerment. However, little is known about portal use in nephrology patients. We addressed this gap by characterizing adoption of an EHR portal, assessing secular trends, and examining the association of portal adoption and BP control (,140/90 mmHg).Design, setting, participants, & measurements Patients seen between January 1, 2010, and December 31, 2012, at any of four university-affiliated nephrology offices who had at least one additional nephrology follow-up visit before June 30, 2013, were included. Sociodemographic characteristics, comorbidities, clinical measurements, and office visits were abstracted from the EHR. Neighborhood median household income was obtained from the American Community Survey 2012.Results Of 2803 patients, 1098 (39%) accessed the portal. Over 87% of users reviewed laboratory results, 85% reviewed their medical information (e.g., medical history), 85% reviewed or altered appointments, 77% reviewed medications, 65% requested medication refills, and 31% requested medical advice from their renal provider. ConclusionWhile portal adoption appears to be increasing, greater attention is needed to understand why vulnerable populations do not access it. Future research should examine barriers to the use of e-health technologies in underserved patients with CKD, interventions to address them, and their potential to improve outcomes.

Objective Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized. Methods We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients who had been dosed to steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked, de-identified electronic medical record data. Genotyping included Affymetrix DMET Plus (1936 polymorphisms), custom Sequenom MassARRAY iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration-to-dose ratio. Results In analyses that adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration-to-dose ratio with CYP3A5 rs776746 (p = 7.15 × 10−29), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1/2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement, and 46% was explained by the model containing clinical covariates. Conclusion This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F-isoprostane concentrations, and peak oxygen uptake (VO). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

Fibroblast growth factor 23 (FGF23) is elevated in chronic kidney disease and associated with increased mortality, but data on FGF23 in humans with acute kidney injury (AKI) are limited. Here we tested whether FGF23 levels rise early in the course of AKI following cardiac surgery, and if higher postoperative FGF23 levels are independently associated with severe AKI and adverse outcomes. Plasma C-terminal FGF23 (cFGF23) levels were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3 in 250 patients undergoing cardiac surgery. We also measured intact FGF23 (iFGF23), parathyroid hormone, phosphate, and vitamin D metabolites in a subgroup of 18 patients with severe AKI and 18 matched non-AKI controls. Beginning at the end of cardiopulmonary bypass, cFGF23 levels were significantly and consistently higher in patients who developed AKI compared to those who did not. The early increase in cFGF23 predated changes in other mineral metabolites. The levels of iFGF23 also increased in patients who developed severe AKI, but the magnitude was lower than cFGF23. In analyses adjusted for age, preoperative eGFR, and cardiopulmonary bypass time, higher cFGF23 levels at the end of cardiopulmonary bypass were significantly associated with greater risk of severe AKI and the need for renal replacement therapy or death. Thus, cFGF23 levels rise early in AKI following cardiac surgery, and are independently associated with adverse postoperative outcomes.

No abstract