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Highlights • Fabry is an X-linked lysosomal storage disease with deficiency in α-galactosidase. • This deficiency results in the accumulation of glycosphinogolipids. • Diagnosis is often made by analysis of globotriaosylceramide in fluids and tissues. • Fabry is often misdiagnosed in female patients due to residual enzyme activity. • Lipidomics by LC-HRMS enables identification of new biomarkers in Fabry., Introduction Lipidomics analysis or lipid profiling is a system-based analysis of all lipids in a sample to provide a comprehensive understanding of lipids within a biological system. In the last few years, lipidomics has made it possible to better understand the metabolic processes associated with several rare disorders and proved to be a powerful tool for their clinical investigation. Fabry disease is a rare X-linked lysosomal storage disorder (LSD) caused by a deficiency in α-galactosidase A (α-GAL A). This deficiency results in the progressive accumulation of glycosphingolipids, mostly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), as well as galabiosylceramide (Ga2) and their isoforms/analogs in the vascular endothelium, nerves, cardiomyocytes, renal glomerular podocytes, and biological fluids. Objectives The primary objective of this study was to evaluate lipidomic signatures in renal biopsies to help understand variations in Fabry disease markers that could be used in future diagnostic tests. Methods Lipidomic analysis was performed by ultra-high pressure liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) on kidney biopsies that were left over after clinical pathology analysis to diagnose Fabry disease. Results We employed UHPLC-HRMS lipidomics analysis on the renal biopsy of a patient suspicious for Fabry disease. Our result confirmed α-GAL A enzyme activity declined in this patient since a Ga2-related lipid biomarker was substantially higher in the patient's renal tissue biopsy compared with two controls. This suggests this patient has a type of LSD that could be non-classical Fabry disease. Conclusion This study shows that lipidomics analysis is a valuable tool for rare disorder diagnosis, which can be conducted on leftover tissue samples without disrupting normal patient care.

Nonatherosclerotic vascular diseases are manifested by endothelial dysfunction, hypertension, vascular calcification, coronary microvascular dysfunction, and calciphylaxis. Unfortunately, there are no definitive treatments for many of these disorders other than hypertension. In addition, although hypertension is more difficult to treat in the chronic kidney disease population, it is necessary to try and target a blood pressure of less than 130/80 mm Hg through the use of aggressive angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, diuretics, and other antihypertensive medications. New therapies are being actively investigated in an attempt to treat nonatherosclerotic vascular diseases in the chronic kidney disease population.

BACKGROUND Early initiation of maintenance hemodialysis has been associated with excess mortality in some studies, but the effects on cardiovascular (CV) mortality has not been studied. Moreover, whether the increased mortality is due to co-morbidities or early initiation of dialysis is unclear. We used a propensity score weighted analysis of the United States Renal Data System (USRDS) to examine how the estimated glomerular filtration rate (eGFR) at initiation of dialysis affects total and CV mortality. METHODS Association between tertiles of eGFR at initiation of hemodialysis and all-cause and CV mortality were assessed in 676,196 adult patients who initiated hemodialysis between 2006 and 2014, using inverse probability of treatment weighting (IPTW) weighted multivariable regression models. RESULTS The intermediate (eGFR 8.7 to

Circulating endothelial cells (CEC) are thought to be markers of endothelial injury. We hypothesized that the numbers of CEC may provide a novel means for predicting long-term survival and cardiovascular events in hemodialysis patients. 54 hemodialysis patients underwent enumeration of their CEC number. We retrospectively analyzed their survival and incidence of adverse cardiovascular events. 22 deaths (41%) were noted over the median follow up period of 3.56 years (IQR 1.43-12) and 6 were attributed to cardiovascular deaths (11%) of which 1 (4%) was in the low CEC (CEC20 cells/ml) and 5 (19%) in the high CEC (CEC≥20 cells/ml) group. High CEC was associated with worse cardiovascular survival (p = 0.05) and adverse cardiac events (p = 0.01). In multivariate analysis, CEC20 cells/ml was associated with a 4-fold increased risk of adverse cardiac events (OR, 4.16 [95% CI,1.38-12.54],p = 0.01) while all-cause mortality and cardiovascular mortality were not statistically different. In this hemodialysis population, a single measurement of CEC was a strong predictor of long term future adverse cardiovascular events. We propose that CEC may be a novel biomarker for assessing cardiovascular risk in dialysis patients.

Background: Kidney Disease Education (KDE) has been shown to improve informed dialysis selection and home dialysis use, two long-held but underachieved goals of US nephrology community. In 2010, the Center for Medicare and Medicaid Services launched a policy of KDE reimbursements for all Medicare beneficiaries with advanced chronic kidney disease. However, the incorporation of KDE service in real-world practice and its association with the home dialysis utilization has not been examined. Methods: Using the 2016 US Renal Data System linked to end-stage renal disease (ESRD) and pre-ESRD Medicare claim data, we identified all adult incident ESRD patients with active Medicare benefits at their first-ever dialysis during the study period (1 January 2010 to 31 December 2014). From these, we identified those who had at least one KDE service code before their dialysis initiation (KDE cohort) and compared them to a parsimoniously matched non-KDE control cohort in 1:4 proportions for age, gender, ESRD network, and the year of dialysis initiation. The primary outcome was home dialysis use at dialysis initiation, and secondary outcomes were home dialysis use at day 90 and anytime through the course of ESRD. Results: Of the 369,968 qualifying incident ESRD Medicare beneficiaries with their first-ever dialysis during the study period, 3469 (0.9%) received KDE services before dialysis initiation. African American race, Hispanic ethnicity, and the presence of congestive heart failure and hypoalbuminemia were associated with significantly lower odds of receiving KDE services. Multivariate analyses showed that KDE recipients had twice the odds of initiating dialysis with home modalities (15.0% vs. 6.9%; adjusted odds ratio (aOR):95% confidence interval (CI) 2.0:1.7–2.4) and had significantly higher odds using home dialysis throughout the course of ESRD (home dialysis use at day 90 (17.6% vs. 9.9%, aOR:CI 1.7:1.4–1.9) and cumulatively (24.7% vs. 15.1%, aOR:CI 1.7:1.5–1.9)). Conclusions: Utilization of pre-ESRD KDE services is associated with significantly greater home dialysis utilization in the incident ESRD Medicare beneficiaries. The very low rates of utilization of these services suggest the need for focused systemic evaluations to identify and address the barriers and facilitators of this important patient-centered endeavor.

In women who conceived with or without assisted reproduction, we evaluated endothelial function by EndoPAT [reactive hyperemia index (RHI)], circulating numbers of endothelial cells (CEC) and endothelial progenitor cells (EPC), and their function before during and after pregnancy. In vitro fertilization (IVF) pregnancies were stratified by method of conception and corpus luteum (CL) number—controlled ovarian stimulation (>1 CL) or programmed (0 CL) cycles and spontaneous singleton pregnancies (1 CL). We observed 1) comparable gestational decline of RHI in the three participant groups secondary to gestational rise of baseline preocclusion pulse-wave amplitude (PWA) incorporated into the RHI calculation by EndoPAT software; 2) progressive rise in “normalized” RHI throughout pregnancy (calculated by substituting prepregnancy baseline preocclusion PWA into the RHI equation), greater in spontaneous conception vs. IVF cohorts; 3) similar gestational increase of maximum PWA and time to maximum PWA after the ischemia stimulus among the three participant groups; 4) modest gestational increase of ischemia response (reactive hyperemia) in the spontaneous conception group and no change or significant decline, respectively, in women who conceived using programmed or controlled ovarian stimulation cycles; 5) enhanced basal nitric oxide production by early (primitive) outgrowth EPC during pregnancy in women who conceived spontaneously, but not through IVF; and 6) gestational increase in CEC in all three participant cohorts, more pronounced in women who conceived by IVF using programmed cycles. On balance, the evidence supported enhanced endothelial function during pregnancy in spontaneous conceptions but less so in IVF pregnancies using either controlled ovarian stimulation or programmed cycles.

Isolation of cancer cells, bacteria, and viruses from peripheral blood has important applications in cancer diagnosis, therapy monitoring, and drug development. Magnetic particles functionalized with antibodies that target receptors of cancer cells have been shown to isolate such entities using magnetic field gradients. Here, we report enhancement in capture efficiency and specificity by engineering magnetic nanoparticles and integrating them with microfluidics for the enumeration of tumor cells. Nanoparticles were made from iron oxide, coated with poly(ethylene glycol), and conjugated through avidin-biotin chemistry with antibody specifically against epithelial cell adhesion molecule (EpCAM). On exposure of targeted nanoparticles to tumor cells, specific uptake by EpCAM-expressing tumor cells (e.g., BxPC3, a pancreatic cancer cell) was observed, whereas there was negligible uptake by cells with low EpCAM expression (e.g., CCRF-CEM, a leukemia cell). Using an arrangement of magnets called a Halbach array, capture efficiency and specificity towards BxPC3 cells tagged with magnetic nanoparticles were enhanced, compared to conditions without the magnetic field gradient and/or without magnetic nanoparticles, either in buffer or in whole blood. These results illustrate that engineered magnetic nanoparticles and their integration with microfluidics have great potential for tumor cell enumeration and cancer prognosis.

BACKGROUND: Pre-ESKD Kidney Disease Education (KDE) has been shown to improve multiple CKD outcomes, but its effect on vascular access outcomes is not well studied. In 2010, Medicare launched KDE reimbursements policy for patients with advanced CKD. METHODS: In this retrospective USRDS analysis, we identified all adult patients on incident hemodialysis with ≥6 months of pre-ESKD Medicare coverage during the first 5 years of CMS-KDE policy and divided them into CMS-KDE services recipients (KDE cohort) and nonrecipients (non-KDE cohort). The primary outcome was incident arteriovenous fistula (AVF) and the composite of incident AVF or arteriovenous graft (AVG) utilization. Secondary outcomes were central venous catheter (CVC) with maturing AVF/AVG and pure CVC utilizations. Step-wise multivariate analyses were performed in four progressive models (model 1, KDE alone; model 2, multivariate model encompassing model 1 with sociodemographics; model 3, model 2 with comorbidity and functional status; and model 4, model 3 with pre-ESKD nephrology care). RESULTS: Of the 211,990 qualifying patients on incident hemodialysis during the study period, 2887 (1%) received KDE services before dialysis initiation. The rates of incident AVF and composite AVF/AVG were more than double (30% and 35%, respectively, compared with 14% and 17%), and pure catheter use about a third lower (40% compared with 65%) in the KDE cohort compared with the non-KDE cohort. The maximally adjusted odds ratios in model 4 for study outcomes were incident AVF use, 1.78, 99% confidence interval, 1.55 to 2.05; incident AVF/AVG use, 1.78, 99% confidence interval, 1.56 to 2.03; incident CVC with maturing AVF/AVG, 1.69, 99% confidence interval, 1.44 to 1.97; and pure CVC without any AVF/AVG, 0.51, 99% confidence interval, 0.45 to 0.58. The benefits of the KDE service were maintained even after accounting for the presence, duration, and facility of ESKD care. CONCLUSION: The occurrence of pre-ESRD KDE service is associated with significantly improved incident vascular access outcomes. Targeted studies are needed to examine the effect of KDE on patient engagement and self-efficacy as a cause for improvement in vascular access outcomes.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

BackgroundSepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host immunologic response to sepsis is the increase in circulating myeloid-derived suppressor cells (MDSCs), which have been demonstrated to be present and independently associated with poor long-term clinical outcomes. MDSCs are plastic cells and potentially modifiable, particularly through epigenetic interventions. The objective of this study was to determine how the suppressive phenotype of MDSCs evolves after sepsis in surgical ICU patients, as well as to identify epigenetic differences in MDSCs that may explain these changes.MethodsCirculating MDSCs from 267 survivors of surgical sepsis were phenotyped at various intervals over 6 weeks, and highly enriched MDSCs from 23 of these samples were co-cultured with CD3/CD28-stimulated autologous T cells. microRNA expression from enriched MDSCs was also identified.ResultsWe observed that MDSC numbers remain significantly elevated in hospitalized sepsis survivors for at least 6 weeks after their infection. However, only MDSCs obtained at and beyond 14 days post-sepsis significantly suppressed T lymphocyte proliferation and IL-2 production. These same MDSCs displayed unique epigenetic (miRNA) expression patterns compared to earlier time points.ConclusionsWe conclude that in sepsis survivors, immature myeloid cell numbers are increased but the immune suppressive function specific to MDSCs develops over time, and this is associated with a specific epigenome. These findings may explain the chronic and persistent immune suppression seen in these subjects.

Commonly used in vitro fertilization protocols produce pregnancies without a corpus luteum (CL), a major source of reproductive hormones. In vitro fertilization pregnancies without a CL showed deficient gestational increases of central (aortic) arterial compliance during the first trimester and were at increased risk for developing preeclampsia. Here, we investigated whether there was generalized impairment of cardiovascular adaptation in in vitro fertilization pregnancies without a CL compared with pregnancies conceived spontaneously or through ovarian stimulation, which lead to 1 and >1 CL, respectively (n=19–26 participants per cohort). Prototypical maternal cardiovascular adaptations of gestation were serially evaluated noninvasively, initially during the follicular phase before conception, 6× in pregnancy, and then, on average, 1.6 years post-partum. The expected increases of cardiac output, left atrial dimension, peak left ventricular filling velocity in early diastole (E wave velocity), peripheral/central arterial pulse pressure ratio, and global AC, as well as decrease in augmentation index were significantly attenuated or absent during the first trimester in women who conceived without a CL, when compared with the 1 and >1 CL cohorts, which were comparable. Thereafter, these cardiovascular measures showed recovery in the 0 CL group except for E wave velocity, which remained depressed. These results provided strong support for a critical role of CL factor(s) in the transformation of the maternal cardiovascular system in early gestation. Regimens that lead to the development of a CL or replacement of missing CL factor(s) may be indicated to improve cardiovascular function and reduce preeclampsia risk in in vitro fertilization pregnancies.

In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P =0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P =0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14–6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94–25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P =0.02) and preeclampsia with severe features (9.6% versus 0.8%; P =0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.

We evaluated maternal pregnancy adaptations and their relationships with circulating hormones in women who conceived with or without in vitro fertilization (IVF). Pregnancies were grouped by corpus luteum (CL) number: 1 CL with physiological plasma relaxin concentration (PRLN; spontaneous pregnancies); 0 CL without circulating RLN (programmed cycles); >1 CL with elevated PRLN (ovarian stimulation). Major findings were that declines in plasma osmolality (Posm) and plasma sodium concentration ([Formula: see text]) were comparable in the 1 CL and 0 CL cohorts, correlated with plasma estradiol and progesterone concentrations but not PRLN; gestational declines in plasma uric acid (UA) concentration (PUA) were attenuated after IVF, especially programmed cycles, partly because of subdued increases of renal UA clearance; and PRLN and cardiac output (CO) were inversely correlated when plasma estradiol concentration was below ∼2.5 ng/mL but positively correlated above ∼2.5 ng/mL. Unexpectedly, PRLN and plasma sFLT1 (PsFLT1) were directly correlated. Although PsFLT1 and CO were not significantly associated, CO was positively correlated with plasma placental growth factor (PLGF) concentration after the first trimester, particularly in women who conceived with 0 CL. Major conclusions are that 1) circulating RLN was unnecessary for gestational falls in Posm and [Formula: see text]; 2) PRLN and CO were inversely correlated during early gestation, suggesting that PRLN in the lower range may have contributed to systemic vasodilation, whereas at higher PRLN RLN influence became self-limiting; 3) evidence for cooperativity between RLN and estradiol on gestational changes in CO was observed; and 4) after the first trimester in women who conceived without a CL, plasma PLGF concentration was associated with recovery of CO, which was impaired during the first trimester in this cohort.

Physicians routinely order blood pressure (BP) medications on an as needed basis or pro re nata to control BPs in hospitalized patients. We hypothesized that treatment of inpatients, who do not have a hypertensive emergency, with the use of antihypertensive medication on an as needed basis could lead to adverse outcomes. Four thousand two hundred nineteen patients who received BP medications on an as needed basis in addition to scheduled antihypertensive medications were matched 1:1 using propensity matching to those who received only scheduled BP medications. Compared with the propensity-matched cohort, patients who received antihypertensive medications on an as needed basis were more likely to experience abrupt lowering of systolic BPs (odds ratio, 2.05 [95% CI, 1.56–2.71],PP=0.002), and ischemic stroke (odds ratio, 8.5 [95% CI, 1.96–36.79];PP=0.001) and an increase in the median length of stay (4.7 versus 2.9 days;P

Introduction and Hypothesis: Acute kidney injury (AKI), even if renal function returns to normal, is associated with an increased risk of cardiovascular disease. We have developed a novel, mouse model that allows investigation into the mechanism of this clinical scenario. We hypothesized that AKI, particular at a severe level, may result in a permanent change to the vasculature that would promote atherosclerotic lesions. Methods and Results: AKI was induced by clamping the bilateral renal vessels of male, C57/BL mice for 28-30 minutes. The creatinine (Cr) was measured two days later to determine the severity of the AKI. An increase in the Cr of at least three-fold, was defined as severe damage, corresponding to Kidney Disease Improving Global Outcomes (KDIGO) AKI Stage 3. If the Cr increased less than three times, this was defined as mild/moderate AKI. Ten weeks after AKI, the Cr was measured to determine if renal function returned to baseline and the femoral artery was injured by repeated introduction of a guidewire. After four weeks, the animals were sacrificed and the neointima lesions were analyzed. Immunohistochemistry for smooth muscle myosin heavy chain revealed that the neointima was mostly composed of smooth muscle cells. The re-endothelialization was almost complete, as determined by anti-CD31 staining. More interestingly, the narrowing rate of the injured artery in animals who suffered severe AKI was higher than in the mild/moderate AKI animals (53.2% vs 27.2%; P= 0.04). There is no difference between the sham-AKI animals and the mild/moderate AKI animals (34.9 % vs 27.2%, see picture). Conclusions: Severe AKI induces a permanent change to the vasculature and/or the immune cells that hastens the development of neointima even after renal function recovers. This work has implications for the development of human atherosclerosis in the clinical setting after AKI. Potential mechanisms for this increased propensity will be discussed.

Introduction: Atherosclerosis, inflammation, and vascular stiffness are prominent interrelated risk factors contributing to the high incidence of cardiovascular disease (CVD) in patients with CKD. Conventional CVD management strategies in CKD largely target atherosclerotic CVD and have had a limited impact on the cardiovascular mortality in this population. Multiple in vivo and in vitro studies and epidemiological evidence from the rheumatologic cohorts have shown that low-dose hydroxychloroquine has beneficial effects on inflammation, endothelial function, insulin sensitivity, and metabolic syndrome. Our recent proof-of-concept animal study showed that hydroxychloroquine has marked protection against atherosclerosis and vascular stiffness. We hypothesize that hydroxychloroquine has the potential to provide significant cardiovascular benefits in patients with CKD. Methods: The Management of Cardiovascular disease in Kidney disease study (NCT 03636152) is a phase 2B, randomized, double-blind, placebo-controlled trial evaluating the effects of low-dose hydroxychloroquine therapy on the parameters of atherosclerosis, inflammation, and vascular stiffness in patients with CKD. The study plans to enroll 100 CKD patients estimated to be at high cardiovascular risk by a combination of low estimated glomerular filtration rate and albuminuria and treat them for 18 months with hydroxychloroquine or placebo in 1:1 allocation. Results: The study will assess the change in the total carotid plaque volume as measured by serial noncontrast carotid MRI as the primary outcome and the serial changes in plasma inflammation markers, vascular stiffness, renal function, and the composition characteristics of the carotid plaque as secondary outcome measures. Discussion/Conclusion: The results of this trial will provide the proof-of-applicability for hydroxychloroquine in the CVD in CKD. If positive, this trial should lead to phase-3 trials with clinical end points for this potentially transformative, novel, and inexpensive therapy for CVD in CKD.

Supplemental Digital Content is available in the text., Objectives: Identify alterations in gene expression unique to systemic and kidney-specific pathophysiologic processes using whole-genome analyses of RNA isolated from the urinary cells of sepsis patients. Design: Prospective cohort study. Setting: Quaternary care academic hospital. Patients: A total of 266 sepsis and 82 control patients enrolled between January 2015 and February 2018. Interventions: Whole-genome transcriptomic analysis of messenger RNA isolated from the urinary cells of sepsis patients within 12 hours of sepsis onset and from control subjects. Measurements and Main Results: The differentially expressed probes that map to known genes were subjected to feature selection using multiple machine learning techniques to find the best subset of probes that differentiates sepsis from control subjects. Using differential expression augmented with machine learning ensembles, we identified a set of 239 genes in urine, which show excellent effectiveness in classifying septic patients from those with chronic systemic disease in both internal and independent external validation cohorts. Functional analysis indexes disrupted biological pathways in early sepsis and reveal key molecular networks driving its pathogenesis. Conclusions: We identified unique urinary gene expression profile in early sepsis. Future studies need to confirm whether this approach can complement blood transcriptomic approaches for sepsis diagnosis and prognostication.

New treatments, new understanding, and new approaches to translational research are transforming the outlook for patients with kidney diseases. A number of new initiatives dedicated to advancing the field of nephrology-from value-based care to prize competitions-will further improve outcomes of patients with kidney disease. Because of individual nephrologists and kidney organizations in the United States, such as the American Society of Nephrology, the National Kidney Foundation, and the Renal Physicians Association, and international nephrologists and organizations, such as the International Society of Nephrology and the European Renal Association-European Dialysis and Transplant Association, we are beginning to gain traction to invigorate nephrology to meet the pandemic of global kidney diseases. Recognizing the timeliness of this opportunity, the American Society of Nephrology convened a Division Chief Retreat in Dallas, Texas, in June 2019 to address five key issues: (1) asserting the value of nephrology to the health system; (2) productivity and compensation; (3) financial support of faculty's and divisions' educational efforts; (4) faculty recruitment, retention, diversity, and inclusion; and (5) ensuring that fellowship programs prepare trainees to provide high-value nephrology care and enhance attraction of trainees to nephrology. Herein, we highlight the outcomes of these discussions and recommendations to the American Society of Nephrology.

Background: Kidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD. Methods: We measured baseline urine concentrations of uromodulin, β2-microglobulin (β2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR 2. We used linear mixed models to evaluate biomarker associations with annualized relative change in eGFR, stratified by randomization arm. Results: At baseline, the mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. In the standard blood pressure treatment arm, each 2-fold higher urinary uromodulin was associated with slower % annual eGFR decline (0.34 [95% CI: 0.08, 0.60]), whereas higher urinary β2m was associated with faster % annual eGFR decline (−0.10 [95% CI: −0.18, −0.02]) in multivariable-adjusted models including baseline eGFR and albuminuria. Associations were weaker and did not reach statistical significance in the intensive blood pressure treatment arm for either uromodulin (0.11 [−0.13, 0.35], p value for interaction by treatment arm = 0.045) or β2m (−0.01 [−0.08, 0.08], p value for interaction = 0.001). Urinary α1m was not independently associated with eGFR decline in the standard (0.01 [−0.22, 0.23]) or intensive (0.03 [−0.20, 0.25]) arm. Conclusions: Among trial participants with hypertension and CKD, baseline measures of tubular function were associated with subsequent declines in kidney function, although these associations were diminished by intensive blood pressure control.

We used electronic health records (EHRs) data from 5658 ambulatory chronic kidney disease (CKD) patients with hypertension and prescribed antihypertensive therapy to examine antihypertensive drug prescribing patterns, blood pressure (BP) control, and risk factors for resistant hypertension (RHTN) in a real-world setting. Two-thirds of CKD patients and three-fourths of those with proteinuria were prescribed guideline-recommended renoprotective agents including an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB); however, one-third were not prescribed an ACEI or ARB. CKD patients, particularly those with stages 1-2 CKD, who were prescribed regimens including beta-blocker (BB) + diuretic or ACEI/ARB + BB + diuretic were more likely to have controlled BP (

Cardiac dysrhythmia and sudden death account for a large proportion of cardiac mortality in dialysis patients. Risk factors for sudden death that are specific to dialysis patients include fluid and electrolyte imbalances during hemodialysis, particularly those of potassium. The risk of arrhythmia may be related to changes in serum K+ concentration during dialysis, and thus close attention should be paid to the dialysate K+ concentration and the serum–dialysate concentration gradient. Potassium profiling is a technique where the dialysate K+ concentration is gradually reduced to keep the gradient between blood and dialysate at a non-fluctuating low level. We provide a review of studies that compare constant potassium concentration in dialysate to gradual reduction in dialysate potassium concentration. These studies illustrate that adequate and more gradual potassium removal can be achieved with potassium profiling techniques, while having lower cardiac irritability.

As early as the 1990s, chronic critical illness, a distinct syndrome of persistent high-acuity illness requiring management in the ICU, was reported under a variety of descriptive terms including the "neuropathy of critical illness," "myopathy of critical illness," "ICU-acquired weakness," and most recently "post-intensive care unit syndrome." The widespread implementation of targeted shock resuscitation, improved organ support modalities, and evidence-based protocolized ICU care has resulted in significantly decreased in-hospital mortality within surgical ICUs, specifically by reducing early multiple organ failure deaths. However, a new phenotype of multiple organ failure has now emerged with persistent but manageable organ dysfunction, high resource utilization, and discharge to prolonged care facilities. This new multiple organ failure phenotype is now clinically associated with the rapidly increasing incidence of chronic critical illness in critically ill surgery patients. Although the underlying pathophysiology driving chronic critical illness remains incompletely described, the persistent inflammation, immunosuppression, and catabolism syndrome has been proposed as a mechanistic framework in which to explain the increased incidence of chronic critical illness in surgical ICUs. The purpose of this review is to provide a historic perspective of the epidemiologic evolution of multiple organ failure into persistent inflammation, immunosuppression, and catabolism syndrome; describe the mechanism that drives and sustains chronic critical illness, and review the long-term outcomes of surgical patients who develop chronic critical illness.

In short-term animal models of ischemia, erythropoietin (EPO) signaling through the heterodimeric EPO receptor (EPOR)/β-common receptor (βCR) is believed to elicit tissue protective effects. However, large, randomized, controlled trials demonstrate that targeting a higher hemoglobin level by administering higher doses of EPO, which are more likely to activate the heterodimeric EPOR/βCR, is associated with an increase in adverse cardiovascular events. Thus, inhibition of long-term activation of the βCR may have therapeutic implications. This study aimed to design and evaluate the efficacy of novel computationally designed βCR inhibitory peptides (βIP). These novel βIPs were designed based on a truncated portion of Helix-A from EPO, specifically residues 11–26 (VLERYLLEAKEAEKIT). Seven novel peptides (P1 to P7) were designed. Peptide 7 (P7), VLERYLHEAKHAEKIT, demonstrated the most robust inhibitory activity. We also report here the ability of P7 to inhibit βCR-induced nitric oxide (NO) production and angiogenesis in human umbilical vein endothelial cells (HUVECs). Specifically, we found that P7 βIP completely abolished EPO-induced NO production. The inhibitory effect could be overcome with super physiological doses of EPO, suggesting a competitive inhibition. βCR-induced angiogenesis in HUVEC’s was also abolished with treatment of P7 βIP, but P7 βIP did not inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis. In addition, we demonstrate that the novel P7 βIP does not inhibit EPO-induced erythropoiesis with use of peripheral blood mononuclear cells (PBMCs). These results, for the first time, describe a novel, potent βCR peptide inhibitor that inhibit the actions of the βCR without affecting erythropoiesis.

To determine if the effects of intensive lowering of systolic blood pressure (goal of less than 120 mmHg) versus standard lowering (goal of less than 140 mmHg) upon cardiovascular, renal, and safety outcomes differed by gender.Nine thousand three hundred and sixty-one men and women aged 50 years or older with systolic blood pressure of 130 mmHg or greater, taking 0-4 antihypertensive medications, and with increased risk of cardiovascular disease, but free of diabetes, were randomly assigned to either a systolic blood pressure target of less than 120 mmHg (intensive treatment) or a target of less than 140 mmHg (standard treatment). The primary composite outcome encompassed incident myocardial infarction, heart failure, other acute coronary syndromes, stroke, or cardiovascular-related death. All-cause mortality, renal outcomes, and serious adverse events were also assessed.Compared with the standard treatment group, the primary composite outcome in the intensive treatment group was reduced by 16% [hazard ratio 0.84 (0.61-1.13)] in women, and by 27% in men [hazard ratio 0.73 (0.59-0.89), P value for interaction between treatment and gender is 0.45]. Similarly, the effect of the intensive treatment on individual components of the primary composite outcome, renal outcomes, and overall serious adverse events was not significantly different according to gender.In adults with hypertension but not with diabetes, treatment to a systolic blood pressure goal of less than 120 mmHg, compared with a goal of less than 140 mmHg, resulted in no heterogeneity of effect between men and women on cardiovascular or renal outcomes, or on rates of serious adverse events.ClinicalTrials.gov number, NCT01206062.

BackgroundMonitoring of mycophenolic acid (MPA) levels may be useful for effective mycophenolate mofetil (MMF) dosing. However, whether commonly obtained trough levels are an acceptable method of surveillance remains debatable. We hypothesized that trough levels of MPA would be a poor predictor of area under the curve (AUC) for MPA.MethodsA total of 51 patients with lupus nephritis who were on MMF 1500 mg twice a day and had a 4-h AUC done were included in this study. MPA levels were measured prior to (C0) and at 1 (C1), 2 (C2) and 4 (C4) h, followed by 1500 mg of MMF. The MPA AUC values were calculated using the linear trapezoidal rule. Regression analysis was used to examine the relationship between the MPA trough and AUC. Differences in the MPA trough and AUC between different clinical and demographic categories were compared using t-tests.ResultsWhen grouped by tertiles there was significant overlap in MPA, AUC 0-4 and MPA trough in all tertiles. Although there was a statistically significant correlation between MPA trough levels and AUC, this association was weak and accounted for only 30% of the variability in MPA trough levels. This relationship might be even more unreliable in men than women. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with increased MPA trough levels and AUC at 0-4 h (AUC0–4).ConclusionTrough levels of MPA do not show a strong correlation with AUC. In clinical situations where MPA levels are essential to guide therapy, an AUC0–4 would be a better indicator of the adequacy of treatment.

A growing number of patients survive sepsis but remain chronically critically ill. We sought to define clinical outcomes and incidence of chronic critical illness (CCI) after sepsis and to determine whether selected biomarkers of inflammation, immunosuppression, and catabolism differ between these patients and those that rapidly recover (RAP).This 3-year prospective observational cohort study (NCT02276417) evaluated 145 surgical intensive care unit patients with sepsis for the development of CCI (≥14 days of intensive care unit resource utilization with persistent organ dysfunction). Patient clinical demographics, outcomes, and serial serum/urine samples were collected for plasma protein and urinary metabolite analyses.Of 145 sepsis patients enrolled, 19 (13%) died during their hospitalization and 71 (49%) developed CCI. The CCI patients were significantly older (mean, 63 ± 15 vs. 58 ± 13 years, p = 0.006) and more likely to be discharged to long-term acute care facilities (32% vs. 3%, p0.0001), whereas those with RAP were more often discharged to home or a rehabilitation facility. Six-month mortality was significantly higher in CCI as compared with RAP cohort (37% vs. 2%; p0.01). Multivariate logistic regression modeling revealed delayed onset sepsis (48 hours after admission; odds ratio [OR], 10.93; 95% confidence interval [CI], 4.15-28.82]), interfacility transfer (OR, 3.58; 95% CI, 1.43-8.96), vasopressor-dependent septic shock (OR, 3.75; 95% CI, 1.47-9.54), and Sequential Organ Failure Assessment score of 5 or greater at 72 hours (OR, 5.03; 95% CI, 2.00-12.62) as independent risk factors for the development of CCI. The CCI patients also demonstrated greater elevations in inflammatory cytokines (IL-6, IL-8, IL-10), and biomarker profiles are consistent with persistent immunosuppression (absolute lymphocyte count and soluble programmed death ligand 1) and catabolism (plasma insulin-like growth factor binding protein 3 and urinary 3-methylhistidine excretion).The development of CCI has become the predominant clinical trajectory in critically ill surgical patients with sepsis. These patients exhibit biomarker profiles consistent with an immunocatabolic phenotype of persistent inflammation, immunosuppression, and catabolism.Prognostic, level II.

The brain and muscle aryl hydrocarbon receptor nuclear translocator–like protein (BMAL)-1 constitutes a major transcriptional regulator of the circadian clock. Here, we explored the impact of conditional deletion of Bmal1 in endothelium and hematopoietic cells in murine models of microvascular and macrovascular injury. We used two models of Bmal1 fx/fx ; Tek-Cre mice, a retinal ischemia/reperfusion model and a neointimal hyperplasia model of the femoral artery. Eyes were enumerated for acellular capillaries and were stained for oxidative damage markers using nitrotyrosine immunohistochemistry. LSK (lineage-negative, stem cell antigen-1–positive, c- Kit –positive) cells were quantified and proliferation assessed. Hematopoiesis is influenced by innervation to the bone marrow, which we assessed using IHC analysis. The number of acellular capillaries increased threefold, and nitrotyrosine staining increased 1.5-fold, in the retinas of Bmal1 fx/fx ; Tek-Cre mice. The number of LSK cells from the Bmal1 fx/fx ; Tek-Cre mice decreased by 1.5-fold and was accompanied by a profound decrease in proliferative potential. Bmal1 fx/fx ; Tek-Cre mice also exhibited evidence of bone marrow denervation, demonstrating a loss of neurofilament-200 staining. Injured femoral arteries showed a 20% increase in neointimal hyperplasia compared with similarly injured wild-type controls. Our study highlights the importance of the circadian clock in maintaining vascular homeostasis and demonstrates that specific deletion of BMAL1 in endothelial and hematopoietic cells results in phenotypic features similar to those of diabetes.

Cardiovascular function is impaired and preeclampsia risk elevated in women conceiving by in vitro fertilization (IVF) in the absence of a corpus luteum (CL). Here, we report the serial evaluation of hormones and other circulating factors in women who conceived with (or without) IVF. After a prepregnancy baseline, the study participants ( n = 19–24/cohort) were evaluated six times during pregnancy and once postpartum (~1.6 yr). IVF pregnancies were stratified by protocol and CL number, i.e., ovarian stimulation (>1 CL) or hypothalamic-pituitary suppression (0 CL) versus spontaneous conceptions (1 CL). Results include the following: 1) relaxin was undetectable throughout pregnancy (including late gestation) in the 0 CL cohort, but markedly elevated in ~50% of women in the >1 CL cohort; 2) progesterone, plasma renin activity, and aldosterone transiently surged at 5–6 gestational weeks in the >1 CL group; 3) soluble vascular endothelial growth factor-1 (sFLT-1) abruptly increased between 5–6 and 7–9 gestational weeks in all three participant cohorts, producing a marked elevation in sFLT-1/PLGF (placental growth factor) ratio exceeding any other time point during pregnancy; 4) sFLT-1 was higher throughout most of gestation in both IVF cohorts with or without abnormal obstetrical outcomes; 5) during pregnancy, C-reactive protein (CRP) increased in 0 and 1 CL, but not >1 CL cohorts; and 6) plasma protein, but not hemoglobin, was lower in the >1 CL group throughout gestation. The findings highlight that, compared with spontaneously conceived pregnancy, the maternal milieu of IVF pregnancy is not physiologic, and the specific perturbations vary according to IVF protocol and CL status.

The aim of the study was to determine the long-term cardiovascular-specific mortality in patients with acute kidney injury (AKI) or chronic kidney disease (CKD) after major surgery.In surgical patients, pre-existing CKD and postoperative AKI are associated with increases in all-cause mortality.In a single-center cohort of 51,457 adult surgical patients undergoing major inpatient surgery, long-term cardiovascular-specific mortality was modeled using a multivariable subdistributional hazards model while treating any other cause of death as a competing risk and accounting for the progression to end-stage renal disease (ESRD) after discharge. Pre-existing CKD and ESRD, and postoperative AKI were the main independent predictors.Before the admission, 4% and 8% of the cohort had pre-existing ESRD and CKD not requiring renal replacement therapy, respectively. During hospitalization, 39% developed AKI. At 10-year follow-up, adjusted cardiovascular-specific mortality estimates were 6%, 11%, 12%, 19%, and 27% for patients with no kidney disease, AKI with no CKD, CKD with no AKI, AKI with CKD, and ESRD, respectively (P0.001). This association remained after excluding 916 patients who progressed to ESRD after discharge, although it was significantly amplified among them. Compared with patients having no kidney disease, adjusted hazard ratios for cardiovascular mortality were significantly higher among patients with kidney disease, ranging from 1.95 (95% confidence interval, 1.80-2.11) for patients with de novo AKI to 5.70 (95% confidence interval, 5.00-6.49) for patients with pre-existing ESRD.Both AKI and CKD were associated with higher long-term cardiovascular-specific mortality compared with patients having no kidney disease.

Objective In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fcγ receptor–mediated uptake of nucleic acid–containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo. Methods Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects. Results Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (μMT), C3−/−, and CD18−/− mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in μMT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of “natural” IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature. Conclusion These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.

Background. Opioid use is common in end-stage renal disease (ESRD) patients. However, safety of individual opioids and concomitant benzodiazepine use has not been studied. Objective. To study the epidemiology of opioid and concomitant benzodiazepine use in ESRD population. To study the clinical safety profile of individual opioids in patients on hemodialysis. Design. Retrospective analysis of the U.S. Renal Data System. A comprehensive review of the current literature was performed to update currently used opioid safety classification. Participants. ESRD patients ≥18 years on hemodialysis who were enrolled in Medicare A and B and Part D between 2006 and 2012, excluding those with malignancy. Main Measures. Hospital admission with diagnosis of prescription opioid overdose within 30, 60, and 90 days of prescription; death due to opioid overdose. Results. Annually, the percentage of patients prescribed any opioid was 52.2%. Overall trend has been increasing except for a small dip in 2011, despite which the admissions due to opioid overdose have been rising. 30% of those who got a prescription for opioids also got a benzodiazepine prescription. 56.5% of these patients received both prescriptions within a week of each other. Benzodiazepine use increased the odds of being on opioids by 3.27 (CI 3.21–3.32) and increased the odds of hospitalization by 50%. Opioids considered safe such as fentanyl and methadone were associated with 3 and 6 folds higher odds of hospitalization within 30 days of prescription. Hydrocodone had the lowest odds ratio (1.9, CI 1.8–2.0). Conclusions. Concurrent benzodiazepine use is common and associated with higher risk of hospitalization due to opioid overdose. Possible opioid-associated hospital admission rate is 4-5 times bigger in ESRD population than general population. Current safety classification of opioids in these patients is misleading, and even drugs considered safe based on pharmacokinetic data are associated with moderate to very high risk of hospitalization. We propose a risk-stratified classification of opioids and suggest starting to use them in all ESRD patients.

Objective— Patients with systemic lupus erythematosis are at risk for premature atherosclerosis and half of the patients with systemic lupus erythematosis have elevated type I interferon (IFN-I) levels. We hypothesized that IFN-I would induce premature atherosclerosis by increasing the number of smooth muscle progenitor cells (SMPC) in the bloodstream and promoting atherosclerotic lesions within the vasculature. Approach and Results— SMPC isolated from wild-type and IFN receptor knockout animals were cultured in medium±IFN-I. In vivo, we used electroporation to generate stable IFN-I expression for as long as 4 months. The number of SMPC was determined in mice that expressed IFN-I and in control mice and sections from the bifurcation of the abdominal aorta were analyzed 3 months after electroporation of an IFN-I expression plasmid or a control plasmid. Adding IFN-I to the media increased the number of cultured wild-type SMPC and increased mRNA for SM22, but had no effect on SMPC isolated from IFN receptor knockout mice. Our in vivo results demonstrated a positive relationship between the preatherosclerotic-like lesions and endothelial damage. Although, there were no significant differences in smooth muscle cell density or thickness of the medial layer between groups, the IFN-I–expressing mice had a significant increase in preatherosclerotic-like lesions and immature smooth muscle cells, cells that expressed CD34 and smooth muscle α-actin; but lacked smooth muscle myosin heavy chain. Conclusions— IFN-I seems to enhance SMPC number in vitro. In vivo IFN-I expression may maintain SMPC in an immature state. These immature smooth muscle cells could give rise to macrophages and eventually foam cells.

Half of all deaths in patients with chronic kidney disease (CKD) arise from cardiovascular causes. Congestive heart failure (CHF) is specifically more frequent with CKD. Cardiovascular therapies with proven benefit are often withheld from patients with renal disease for fear of adverse events. The renin-angiotensin-aldosterone system (RAAS) has been implicated as an important maladaptive neurohormonal pathway in heart failure. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to suppress it ineffectively. Current guidelines support the use of spironolactone for more comprehensive suppression of the RAAS in heart failure patients. Most supporting trials have however excluded patients with renal dysfunction resulting in a dearth of data to support use of spironolactone in CKD patients with CHF. Several small studies that prospectively interrogated the benefits of augmented RAAS blockade with spironolactone in CKD patients have shown improvement in predictors of cardiovascular mortality. More recently, improved mortality outcomes were demonstrated with the use of spironolactone in hemodialysis patients. Although reduction in glomerular filtration rate and hyperkalemia are potential adverse effects with its use, the available evidence suggests that it is uncommon and serious consequences can be avoided with close monitoring. Studies investigating the optimal spironolactone dosage in such a setting recommend starting with a low dose and careful uptitration. This review attempts to provide a comprehensive insight into the issues associated with the use of spironolactone in the setting of concomitant CHF and CKD.

Objective To determine the incremental hospital cost and mortality associated with the development of postoperative acute kidney injury (AKI) and with other associated postoperative complications. Background Each year 1.5 million patients develop a major complication after surgery. Postoperative AKI is one of the most common postoperative complications and is associated with an increase in hospital mortality and decreased survival for up to 15 years after surgery. Methods In a single-center cohort of 50,314 adult surgical patients undergoing major inpatient surgery, we applied risk-adjusted regression models for cost and mortality using postoperative AKI and other complications as the main independent predictors. We defined AKI using consensus Risk, Injury, Failure, Loss and End-Stage Renal Disease criteria. Results The prevalence of AKI was 39% among 50,314 patients with available serum creatinine. Patients with AKI were more likely to have postoperative complications and had longer lengths of stay in the intensive care unit and the hospital. The risk-adjusted average cost of care for patients undergoing surgery was $42,600 for patients with any AKI compared with $26,700 for patients without AKI. The risk-adjusted 90-day mortality was 6.5% for patients with any AKI compared with 4.4% for patients without AKI. Serious postoperative complications resulted in increased cost of care and mortality for all patients, but the increase was much larger for those patients with any degree of AKI. Conclusions Hospital costs and mortality are strongly associated with postoperative AKI, are correlated with the severity of AKI, and are much higher for patients with other postoperative complications in addition to AKI.

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia.We categorized 876 women from the Women's Ischemia Syndrome Evaluation cohort according to estimated glomerular filtration rate (eGFR) (eGFR ≥90 mL/min per 1.73 m(2) [normal], 60-89 mL/min per 1.73 m(2) [mild CKD], ≤59 mL/min per 1.73 m(2) [severe CKD]). Time to death from all-cause and cardiovascular causes and major adverse outcomes were assessed by multivariate regression adjusted for baseline covariates.Obstructive coronary artery disease (CAD) was present only in few patients (39%). Even after adjusting for CAD severity, renal function remained a strong independent predictor of all-cause and cardiac mortality (P.001). Every 10-unit decrease in eGFR was associated with a 14% increased risk of all-cause mortality (adjusted hazard ratio [AHR] 1.14 [1.08-1.20], P.0001), 16% increased risk of cardiovascular mortality (AHR 1.16 [1.09-1.23], P.0001), and 9% increased risk of adverse cardiovascular events (AHR 1.09 [1.03-1.15], P = .002).Even mild CKD is a strong independent predictor of all-cause and cardiac mortality in women with symptoms/signs of ischemia, regardless of underlying obstructive CAD severity, underscoring the need to better understand the interactions between ischemic heart disease and CKD.

Clinically, erythropoietin (EPO) is known to increase systemic vascular resistance and arterial blood pressure. However, EPO stimulates the production of the potent vasodilator, nitric oxide (NO), in culture endothelial cells. The mechanism by which EPO causes vasoconstriction despite stimulating NO production may be dependent on its ability to activate two receptor complexes, the homodimeric EPO (EPOR 2) and the heterodimeric EPOR/β‐common receptor (β CR). The purpose of this study was to investigate the contribution of each receptor to the vasoactive properties of EPO. First‐order, mesenteric arteries were isolated from 16‐week‐old male C57BL/6 mice, and arterial function was studied in pressure arteriographs. To determine the contribution of each receptor complex, EPO‐stimulating peptide (ESP), which binds and activates the heterodimeric EPOR/β CR complex, and EPO, which activates both receptors, were added to the arteriograph chamber 20 min prior to evaluation of endothelium‐dependent (acetylcholine, bradykinin, A23187) and endothelium‐independent (sodium nitroprusside) vasodilator responses. Only ACh‐induced vasodilation was impaired in arteries pretreated with EPO or ESP. EPO and ESP pretreatment abolished ACh‐induced vasodilation by 100% and 60%, respectively. EPO and ESP did not affect endothelium‐independent vasodilation by SNP. Additionally, a novel β CR inhibitory peptide (β IP), which was computationally developed, prevented the impairment of acetylcholine‐induced vasodilation by EPO and ESP, further implicating the EPOR/β CR complex. Last, pretreatment with either EPO or ESP did not affect vasoconstriction by phenylephrine and KCl. Taken together, these findings suggest that acute activation of the heterodimeric EPOR/β CR in endothelial cells leads to a selective impairment of ACh‐mediated vasodilator response in mouse mesenteric resistance arteries.

Background Kidney stone (KS) disease has high, increasing prevalence in the United States and poses a massive economic burden. Diagnostics algorithms of KS only use a few variables with a limited sensitivity and specificity. In this study, we tested a big data approach to infer and validate a ‘multi-domain’ personalized diagnostic acute care algorithm for KS (DACA-KS), merging demographic, vital signs, clinical, and laboratory information. Methods We utilized a large, single-center database of patients admitted to acute care units in a large tertiary care hospital. Patients diagnosed with KS were compared to groups of patients with acute abdominal/flank/groin pain, genitourinary diseases, and other conditions. We analyzed multiple information domains (several thousands of variables) using a collection of statistical and machine learning models with feature selectors. We compared sensitivity, specificity and area under the receiver operating characteristic (AUROC) of our approach with the STONE score, using cross-validation. Results Thirty eight thousand five hundred and ninety-seven distinct adult patients were admitted to critical care between 2001 and 2012, of which 217 were diagnosed with KS, and 7446 with acute pain (non-KS). The multi-domain approach using logistic regression yielded an AUROC of 0.86 and a sensitivity/specificity of 0.81/0.82 in cross-validation. Increase in performance was obtained by fitting a super-learner, at the price of lower interpretability. We discussed in detail comorbidity and lab marker variables independently associated with KS (e.g. blood chloride, candidiasis, sleep disorders). Conclusions Although external validation is warranted, DACA-KS could be integrated into electronic health systems; the algorithm has the potential used as an effective tool to help nurses and healthcare personnel during triage or clinicians making a diagnosis, streamlining patients’ management in acute care.

Various non‐invasive methods are available to measure cardiac output (CO) during pregnancy. We compared serial measures of CO using various methods to determine which provided the least variability. Ten patients with spontaneous pregnancy had estimation of CO at baseline prior to becoming pregnant and at the end of the first and third trimesters. Echocardiographic data were used to estimate CO using the Teichholz method, Simpson's biplane method, and the Doppler determined velocity time integral (VTI) method. In addition, a Bioz Dx device was used to estimate CO by impedance cardiography. CO estimated with the VTI method had the lowest beat‐to‐beat variability. CO estimated with the VTI method was higher than CO estimated with the 2D‐Teichholz method and Simpson's method. The percent change in CO during pregnancy was similar for all echo methods (VTI, Teichholz, and Simpson's biplane). Baseline CO determined with impedance cardiography was higher than CO determined with the VTI method. However, change in CO during pregnancy was significantly lower when measured with impedance cardiography. There was marked heterogeneity in the degree of rise in CO during the first trimester (−3 to 55%). The wide variation in the gestational rise in CO was unexpected, and at least in part secondary to variable increase in heart rate. We recommend the use of the Doppler determined VTI method for the estimation of CO in pregnancy.

Uric acid affects endothelial and adipose cell function and has been linked to diseases such as hypertension, metabolic syndrome, and cardiovascular disease. Interestingly uric acid has been shown to increase endothelial progenitor cell (EPC) mobilization, a potential mechanism to repair endothelial injury. Since EPC mobilization is dependent on activity of the enzyme CD26/dipeptidyl peptidase (DPP)IV, we examined the effect uric acid will have on CD26/DPPIV activity. Uric acid inhibited the CD26/DPPIV associated with human umbilical vein endothelial cells but not human recombinant (hr) CD26/DPPIV. However, triuret, a product of uric acid and peroxynitrite, could inhibit cell associated and hrCD26/DPPIV. Increasing or decreasing intracellular peroxynitrite levels enhanced or decreased the ability of uric acid to inhibit cell associated CD26/DPPIV, respectively. Finally, protein modeling demonstrates how triuret can act as a small molecule inhibitor of CD26/DPPIV activity. This is the first time that uric acid or a uric acid reaction product has been shown to affect enzymatic activity and suggests a novel avenue of research in the role of uric acid in the development of clinically important diseases.

Key Clinical Message Hydroxocobalamin causes reddish discoloration of the urine, mimicking hematuria. Clinicians should be aware of this common side effect of the rarely used drug to prevent unnecessary consultations and work‐up. Additional benign causes of red urine include foods such as beets, rhubarb, and medications such as rifampin, phenazopyridine.

Objective Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.

In carefully selected individuals, receiving expanded criteria donor (ECD) kidneys confer a survival advantage over remaining on dialysis. However, wait lists for ECD kidneys often include a significant proportion of young patients, who have no predictable survival benefit from ECD kidneys. This study hypothesized that educational and socioeconomic factors might influence a younger patient's decision to accept an ECD kidney.This study was a retrospective analysis of all first single-kidney transplants in the Scientific Registry of Transplant Recipients database from 2000 to 2009 in patients aged 18-40 years and waitlisted3 years. The primary outcome measured was the odds of receiving an ECD kidney compared with an standard criteria donor kidney in different demographic subgroups. Race, income, and education were analyzed in main-effect and two-way interaction models, corrected for candidate panel reactive antibodies and sex.Of 13,615 ECD transplants, 591 kidneys (4.3%) went to recipients aged between 18 and 40 years who were waitlisted3 years. African Americans (odds ratio, 1.71; 95% confidence interval, 1.26 to 2.33) or those with low education (odds ratio, 2.32; 95% confidence interval, 1.38 to 3.89) were more likely to receive an ECD kidney than Caucasians or those with a college degree, respectively. However, African Americans with higher education levels did not have significantly higher odds of receiving an ECD kidney than Caucasians with a college degree.In patients aged40 years and waitlisted3 years, African Americans and those with lower educational status and low income are more likely to receive an ECD kidney than Caucasians or those with higher education. It is important that health care providers and patients understand such disparities to facilitate a more rational use of ECD kidneys.

The directed migration of mammalian cells is a foundation of development and growth. A variety of processes such as tissue development, wound healing, pathogen recognition/destruction as well as cancer metastasis are the result of regulated or dysregulated cell migration. While the ability to measure a cell's propensity to migrate has clinical relevance in several settings, no universal protocol has been established to measure cell migration. A variety of techniques are currently used to measure migration including manual counting, flow cytometry or Coulter counting, microfluidic devices, computerized spectroscopic methods, or the use of various tracking dyes interfaced with fluorescent or non-fluorescent plate readers. In order to expedite the measurement of migration, we compared several common cytoplasmic and lipophilic cell tracking dyes to determine the best dye for determining migration of rare population of cells. CellVue® Burgundy was found to be superior over calcein AM, Cell Tracker Green CMFDA (chloromethyl fluorescein diacetate), Vybrant CFDA (carboxy fluorescein diacetate succinimidyl ester) in its retention within cells, superior to CellVue® NIR 815, PKH67, and CM DiI with regard to signal to noise ratio, and superior to PKH26 with regard to instrument versatility.