Development of an assessment technique for basic science retention using the NBME subject exam data.

INTRODUCTION: One of the challenges in medical education is effectively assessing basic science knowledge retention. National Board of Medical Examiners (NBME) clerkship subject exam performance is reflective of the basic science knowledge accrued during preclinical education. The aim of this study was to determine if students' retention of basic science knowledge during the clerkship years can be analyzed using a cognitive diagnostic assessment (CDA) of the NBME subject exam data. METHODS: We acquired a customized NBME item analysis report of our institution's pediatric clerkship subject exams for the period of 2017-2020 and developed a question-by-content Q-matrix by identifying skills necessary to master content. As a pilot study, students' content mastery in 12 major basic science content areas was analyzed using a CDA model called DINA (deterministic input, noisy "and" gate). RESULTS: The results allowed us to identify strong and weak basic science content areas for students in the pediatric clerkship. For example: "Reproductive systems" and "Skin and subcutaneous tissue" showed a student mastery of 83.8 ± 2.2% and 60.7 ± 3.2%, respectively. CONCLUSIONS: Our pilot study demonstrates how this new technique can be applicable in quantitatively measuring students' basic science knowledge retention during any clerkship. Combined data from all the clerkships will allow comparisons of specific content areas and identification of individual variations between different clerkships. In addition, the same technique can be used to analyze internal assessments thereby creating an opportunity for the longitudinal tracking of student performances. Detailed analyses like this can guide specific curricular changes and drive continuous quality improvement in the undergraduate medical school curriculum.

Predictors of reduced cardiac index in patients with acute submassive pulmonary embolism.

OBJECTIVES: Determine the baseline clinical, laboratory, and echocardiographic values that predict reduced cardiac index (CI) among subjects with acute submassive pulmonary embolism (PE). BACKGROUND: Submassive PE represents a large portion of acute PE population and there is controversy regarding optimal treatment strategies for these patients. There is significant heterogeneity within the submassive PE population and further refinement of risk stratification may aid clinical decision-making. METHODS: We identified subjects with normotensive acute PE who underwent echocardiogram and right heart catheterization (RHC) prior to catheter-directed thrombolysis (CDT). We sought to determine the predictors of reduced CI, defined as CI < 2.2 L min-1 m-2 . RESULTS: Thirty-two subjects met the inclusion criteria and 41% had reduced CI. Baseline variables did not distinguish subjects with reduced versus normal CI. Brain natriuretic peptide (BNP) was significantly different between the reduced versus normal CI groups (BNP 440 vs. 160 pg/ml, p = .004, respectively). Univariate logistic regression identified BNP, right ventricular (RV):left ventricular (LV) diameter ratio, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic pressure as predictors of reduced CI. In a multivariate logistic regression model, only TAPSE was an independent predictor of reduced CI. ROC curve analysis identified the following optimal cut points for prediction of reduced CI: BNP > 216 pg/ml, RV:LV ratio > 1.41, or TAPSE <1.6 cm. CONCLUSIONS: Almost half of subjects with acute submassive PE have reduced CI, despite normal systemic blood pressure. Optimal cut points for BNP, RV:LV ratio, and TAPSE were identified to predict reduced CI among patients with acute PE. These findings may aid in clinical decision-making and risk stratification of patients with acute submassive PE.

Long-term mortality after massive, submassive, and low-risk pulmonary embolism.

Guidelines for management of normotensive patients with acute pulmonary embolism (PE) emphasize further risk stratification on the basis of right ventricular (RV) size and biomarkers of RV injury or strain; however, the prognostic importance of these factors on long-term mortality is not known. We performed a retrospective cohort study of subjects diagnosed with acute PE from 2010 to 2015 at a tertiary care academic medical center. The severity of initial PE presentation was categorized into three groups: massive, submassive, and low-risk PE. The primary endpoint of all-cause mortality was ascertained using the Centers for Disease Control National Death Index (CDC NDI). A total of 183 subjects were studied and their median follow-up was 4.1 years. The median age was 65 years. The 30-day mortality rate was 7.7% and the overall mortality rate through the end of follow-up was 40.4%. The overall mortality rates for massive, submassive, and low-risk PE were 71.4%, 44.5%, and 28.1%, respectively (p < 0.001). Landmark analysis using a 30-day cutpoint demonstrated that subjects presenting with submassive PE compared with low-risk PE had increased mortality during both the short- and the long-term periods. The most frequent causes of death were malignancy, cardiac disease, respiratory disease, and PE. Independent predictors of all-cause mortality were cancer at baseline, age, white blood cell count, diabetes mellitus, liver disease, female sex, and initial presentation with massive PE. In conclusion, the diagnosis of acute PE was associated with substantial long-term mortality. The severity of initial PE presentation was associated with both short- and long-term mortality.

An alternative empirical likelihood method in missing response problems and causal inference.

Missing responses are common problems in medical, social, and economic studies. When responses are missing at random, a complete case data analysis may result in biases. A popular debias method is inverse probability weighting proposed by Horvitz and Thompson. To improve efficiency, Robins et al. proposed an augmented inverse probability weighting method. The augmented inverse probability weighting estimator has a double-robustness property and achieves the semiparametric efficiency lower bound when the regression model and propensity score model are both correctly specified. In this paper, we introduce an empirical likelihood-based estimator as an alternative to Qin and Zhang (2007). Our proposed estimator is also doubly robust and locally efficient. Simulation results show that the proposed estimator has better performance when the propensity score is correctly modeled. Moreover, the proposed method can be applied in the estimation of average treatment effect in observational causal inferences. Finally, we apply our method to an observational study of smoking, using data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions clinical trial. Copyright © 2016 John Wiley & Sons, Ltd.

Endovascular versus medical therapy for atherosclerotic renovascular disease.

The diagnosis of renal artery stenosis (RAS) has become increasingly common in part due to greater awareness of ischemic renal disease and increased use of diagnostic techniques. Over 90 % of RAS cases are caused by atherosclerotic renovascular disease (ARVD). Patients with ARVD are at high risk for fatal and nonfatal cardiovascular and renal events. The mortality rate in patients with ARVD is high, especially with other cardiovascular or renal comorbidities. Recent clinical studies have provided substantial evidence concerning medical therapy and endovascular interventional therapeutic approaches for ARVD. Despite previous randomized clinical trials, the optimal therapy for ARVD remained uncertain until the results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial were released recently. CORAL demonstrated that optimal medical therapy was equally effective to endovascular therapy in the treatment of ARVD. Clinicians can now practice with more evidence-based medicine to treat ARVD and potentially decrease mortality in patients with ARVD using optimal medical therapy.

Fit for Health? Levels of Physical Activity Among Preclinical and Clinical Medical Students.

Physical, mental, and emotional wellness are just some avenues to maintain a person's overall well-being. These components of wellness influence each other; mental wellness is known to be affected by physical wellness. Physical wellness in the form of regular exercise stands as a method to mitigate the high rates of depression and burnout among medical students. This study examines the levels of physical activity among preclinical and clinical medical students. This is an observational, non-randomized study with data collection over one month. Fifty-nine percent of students surveyed met the CDC recommendation for exercise. The major reason to exercise was to improve mental health, with 37% of respondents citing this as a motivator. For those who did not meet the physical activity recommendation, lack of time was cited in 75% of respondents. Greater knowledge of prevention methods, risk factors, and outcomes of chronic health conditions may contribute to higher physical activity levels among medical students compared to the general population. Emphasizing exercise and physical wellness campaigns may be a solution for medical schools to improve the overall wellness of their students.

Impact of renal artery stenosis on acute kidney injury and outcomes after heart failure hospitalization.

BACKGROUND: Renal artery stenosis (RAS) is known to co-exist with heart failure (HF), however the impact of RAS on rates of acute kidney injury during an acute HF hospitalization, and adverse events after acute HF hospitalizations has not been well studied. METHODS: We performed a retrospective cohort study of subjects hospitalized for acute HF at a tertiary academic care center. We identified subjects who had a renal artery duplex ultrasound or other diagnostic study for RAS to categorize heart failure subjects as RAS+ or RAS-. AKI was defined as a rise from admission to peak creatinine of >0.3 mg/dL or >1.5 fold. In-hospital outcomes including rates of AKI were ascertained. Adverse outcomes over a two-year follow up period were also ascertained. RESULTS: A total of 93 subjects with acute HF hospitalization met the inclusion criteria and were enrolled in this study; 27 (29%) were identified as RAS+. At admission, subjects with RAS had higher rates of diabetes and prior PCI. During the HF hospitalization, subjects with RAS were more likely to develop AKI. No significant differences were identified in baseline or hospital medication use among subjects with versus without RAS. Importantly, the rate of ACE-I/ARB use was low in both groups and no significant difference in ACE-I/ARB use was demonstrated. Subjects with RAS had higher rates of recurrent HF hospitalization during the follow-up period. CONCLUSIONS: RAS is prevalent among subjects with acute HF, associated with higher rates of AKI during HF hospitalization, and associated with higher rates of recurrent HF hospitalization during follow-up.

Impact of Baseline Heart Failure on Acute Pulmonary Embolism Risk Stratification and Clinical Outcomes.

Among patients with acute pulmonary embolism (PE), abnormal cardiac biomarkers and elevated right ventricular to left ventricular (RV/LV) diameter ratio are associated with increased morbidity and mortality. However, subjects with baseline heart failure (HF) have abnormalities in cardiac chamber dimensions and biomarkers. We sought to describe risk stratification variables in a cohort with acute PE and categorized HF status as no HF, HF with reduced ejection fraction (HFrEF), or HF with preserved ejection fraction (HFpEF). In total, 182 subjects were identified for this study, of whom 142 were categorized as having no HF, 16 as having HFrEF, and 24 as having HFpEF. The median age was 65 years [interquartile range 51 to 75 years], and 43% were male. Subjects with HFrEF had significantly greater LV diameters and significantly lower RV/LV diameter ratio (no HF 0.94, HFrEF 0.65, HFpEF 0.89, p = 0.002). Subjects with HFrEF also had significantly higher B-type natriuretic peptide levels (no HF 112 pg/mL, HFrEF 835 pg/mL, HFpEF 241 pg/mL, p <0.001) and higher 90-day mortality rates. Among subjects with acute PE, those with baseline HFrEF had significantly greater LV diameter and lower RV/LV diameter ratio than those of patients with HFpEF or no HF. In addition, subjects with HFrEF had significantly higher B-type natriuretic peptide levels and worse survival at 90 days. In conclusion, these results indicate that PE risk stratification using current guidelines, especially reliance on RV/LV ratio, is inaccurate among subjects with baseline HFrEF.

Determinants of renal function in patients with renal artery stenosis.

Renal artery stenosis (RAS) is an important cause of renal failure; however, the factors associated with loss of kidney function in patients with RAS are poorly described, as are the predictors of an improvement in kidney function after stenting. One hundred patients at seven centers undergoing renal stenting were randomly assigned to an embolic protection device or double-blind use of a platelet glycoprotein IIb/IIIa inhibitor. The glomerular filtration rate (GFR) was measured using the creatinine-derived modified Modification of Diet in Renal Disease (MDRD) equation, cystatin C, and iohexol clearance. In univariate and multivariate models, baseline MDRD and cystatin C GFR were associated with congestive heart failure (CHF) (p = 0.01), lesion length (p = 0.01), and percent stenosis (-0.27, p = 0.01). In multivariate models, MDRD-estimated GFR 1 month after stenting was associated with bilateral stenosis (p < 0.05) and lesion length (p < 0.05), whereas with cystatin C the multivariate model included angiotensin receptor blocker (ARB) (p < 0.05) and minimal luminal diameter (MLD) (p < 0.05). The improvement in GFR from baseline to 1 month, measured as percent change, was related to baseline MDRD (p = 0.009) and cystatin C (p = 0.03) GFR. For MDRD GFR combined treatment with abciximab and Angioguard(®) embolic protection (p = 0.02) remained significant in multivariate analysis as did CHF, which was also significant with cystatin C (p = 0.05). In conclusion, CHF and lesion characteristics (MLD, percent stenosis and lesion length) are determinants of renal function in patients with RAS. In contrast, the acute improvement in renal function after revascularization is most strongly influenced by baseline GFR, and to a lesser degree CHF and combined procedural treatment with abciximab and embolic protection but not lesion characteristics. Clinical Trial Registration - URL:http://www.clinicaltrials.gov. Unique identifier: NCT00234585.

Rationale and Design of Assessing the Effectiveness of Short-Term Low-Dose Lithium Therapy in Averting Cardiac Surgery-Associated Acute Kidney Injury: A Randomized, Double Blinded, Placebo Controlled Pilot Trial.

Background: Burgeoning pre-clinical evidence suggests that therapeutic targeting of glycogen synthase kinase 3ß (GSK3ß), a convergence point of multiple cellular protective signaling pathways, confers a beneficial effect on acute kidney injury (AKI) in experimental models. However, it remains unknown if GSK3ß inhibition likewise mitigates AKI in humans. Cardiac surgery associated acute kidney injury (CSA-AKI) poses a significant challenge for clinicians and currently the only treatment available is general supportive measures. Lithium, an FDA approved mood stabilizer, is the best-known GSK3ß inhibitor and has been safely used for over half a century as the first line regimen to treat bipolar affective disorders. This study attempts to examine the effectiveness of short term low dose lithium on CSA-AKI in human patients. Methods/Design: This is a single center, prospective, randomized, double blinded, placebo controlled pilot study on patients undergoing cardiac surgery with cardiopulmonary bypass. Patients will be randomized to receive a small dose of lithium or placebo treatment for three consecutive days. Renal function will be measured via creatinine as well as novel AKI biomarkers. The primary outcome is incidence of AKI according to Acute Kidney Injury Network (AKIN) criteria, and secondary outcomes include receipt of new dialysis, days on dialysis, days on mechanical ventilation, infections within 1 month of surgery, and death within 90 days of surgery. Discussion: As a standard selective inhibitor of GSK3ß, lithium has been shown to exert a beneficial effect on tissue repair and regeneration upon acute injury in multiple organ systems, including the central nervous system and hematopoietic system. In experimental AKI, lithium at small doses is able to ameliorate AKI and promote kidney repair. Successful completion of this study will help to assess the effectiveness of lithium in CSA-AKI and could potentially pave the way for large-scale randomized trials to thoroughly evaluate the efficacy of this novel regimen for preventing AKI after cardiac surgery. Trial Registration: This study was registered prospectively on the 17th February 2017 at ClinicalTrials.gov (NCT03056248, https://clinicaltrials.gov/ct2/show/NCT03056248?term=NCT03056248&draw=2&rank=1).

Prognostic Value of Computed Tomography Versus Echocardiography Derived Right to Left Ventricular Diameter Ratio in Acute Pulmonary Embolism.

BACKGROUND: Computed Tomography (CT) Pulmonary Angiography is the most commonly used diagnostic study for acute pulmonary embolism (PE). Echocardiogram (ECHO) is also used for risk stratification in acute PE, however the diagnostic performance of CT versus ECHO for risk stratification remains unclear. METHODS: CT and ECHO right ventricle (RV) and left ventricle (LV) diameters were measured in a retrospective cohort of patients with acute PE. RV:LV diameter ratios were calculated and correlation between CT and ECHO RV:LV ratio was assessed. Sensitivity and specificity for the composite adverse events endpoint of mortality, respiratory failure requiring intubation, cardiac arrest, or shock requiring vasopressors within 30 days of admission were assessed for CT or ECHO derived RV:LV ratio alone and in combination with biomarkers (troponin or B-type natriuretic peptide). RESULTS: A total of 74 subjects met the inclusion criteria and had a mean age of 62±18 years. The proportion of patients with RV:LV >1 was similar when comparing CT (37.8%) versus ECHO (33.8%) (P = 0.61). A statistically significant correlation was found between CT derived and ECHO derived RV:LV diameter ratio (r = 0.832, P < 0.001). The sensitivity and specificity to predict 30-day composite adverse events for CT versus ECHO derived RV:LV diameter ratio >1 together with positive biomarker status was similar with sensitivity and specificity of 87% and 41% versus 87% and 42%, respectively. CONCLUSIONS: In patients with acute PE, CT and ECHO RV:LV diameter ratio correlate well and identify similar proportion of PE patients at risk for early adverse events. These findings may streamline risk stratification of patients with acute PE.

Predictors of embolization during protected renal artery angioplasty and stenting: Role of antiplatelet therapy.

OBJECTIVE: The objective of this study was to identify the predictors of distal embolization (DE) during protected renal artery angioplasty and stenting. BACKGROUND: DE may contribute to worsening renal function after renal artery stenting. The factors associated with DE, rates of platelet-rich emboli, and treatments that may prevent DE during renal stenting have not been evaluated. METHODS: The current study evaluated patients randomized to receive an embolic protection device (EPD) in the RESIST trial. Forty-two patients were identified for inclusion in this study. These patients were further randomized to abciximab (N = 22) or placebo (N = 20). Modification in Diet in Renal Disease glomerular filtration rate (GFR) was used as the primary measure of renal function. Creatinine was measured by a modified Jaffe reaction using the IDMS-traceable assay. The primary endpoint was capture of platelet rich emboli in the angioguard basket. RESULTS: DE occurred in 15/42 (35%) of the patients and platelet rich DE in 10 (24%) of the patients who received an EPD. Of the angiographic characteristics only lesion length was significantly higher in patients with DE (16 +/- 7 mm vs. 10 +/- 5 mm, P = 0.04). Preprocedural abciximab reduced DE from 42 to 8% (P = 0.02). The rate of platelet rich emboli was 50% with neither abciximab nor a thienopyridine, 36% with thienopyridine only, 15% abciximab only, and 0% in patients who received both a thienopyridine and abciximab. Only Abciximab use was associated with improved renal function at 1-month, thienopyridine was not. Angiographic characteristics including percent stenosis, minimal luminal diameter (MLD), reference diameter, change in MLD, contrast volume, and procedure time were not predictors of DE during renal stenting. CONCLUSION: Capture of DE and specifically platelet DE are common during protected renal stenting using a filter-type EPD. Abciximab use, and potentially combined thienopyridine and abciximab use, decreased the rate of platelet rich DE; however, only abciximab improved renal function at 1-month.

Embolic protection and platelet inhibition during renal artery stenting.

BACKGROUND: Preservation of renal function is an important objective of renal artery stent procedures. Although atheroembolization can cause renal dysfunction during renal stent procedures, whether adjunctive use of embolic protection devices or glycoprotein IIb/IIIa inhibitors improves renal function is unknown. METHODS AND RESULTS: One hundred patients undergoing renal artery stenting at 7 centers were randomly assigned to an open-label embolic protection device, Angioguard, or double-blind use of a platelet glycoprotein IIb/IIIa inhibitor, abciximab, in a 2x2 factorial design. The main effects of treatments and their interaction were assessed on percentage change in Modification in Diet in Renal Disease-derived glomerular filtration rate from baseline to 1 month using centrally analyzed creatinine. Filter devices were analyzed for the presence of platelet-rich thrombus. With stenting alone, stenting and embolic protection, and stenting with abciximab alone, glomerular filtration rate declined (P<0.05), but with combination therapy, it did not decline and was superior to the other allocations in the 2x2 design (P<0.01). The main effects of treatment demonstrated no overall improvement in glomerular filtration rate; although abciximab was superior to placebo (0+/-27% versus -10+/-20%; P<0.05), embolic protection was not (-1+/-28% versus -10+/-20%; P=0.08). An interaction was observed between abciximab and embolic protection (P<0.05), favoring combination treatment. Abciximab reduced the occurrence of platelet-rich emboli in the filters from 42% to 7% (P<0.01). CONCLUSIONS: Renal artery stenting alone, stenting with embolic protection, and stenting with abciximab were associated with a decline in glomerular filtration rate. An unanticipated interaction between Angioguard and abciximab was seen, with combination therapy better than no treatment or either treatment alone.

Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease.

The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.

Early Rapid Decline in Kidney Function in Medically Managed Patients With Atherosclerotic Renal Artery Stenosis.

Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood. Methods and Results Patients enrolled in the medical therapy-only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy-only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 [1.11-2.85]; P=0.02), age (odds ratio, 1.04 [1.00-1.07]; P<0.05), and Chronic Kidney Disease Epidemiology Collaboration creatinine eGFR (odds ratio, 1.86 [1.15-3.0]; P=0.01) were associated with an early RD. Despite continued medical therapy only, the RD group had an improvement in eGFR at 1 year (6.9%; P=0.04). The RD and nondecline groups were not significantly different for clinical events and all-cause mortality (P=0.78 and P=0.76, respectively). Similarly, renal replacement therapy occurred in 1 of 66 (1.5%) of the RD patients and in 6 of 294 (2%) of the nondecline patients. The regression to the mean of improvement in eGFR at 1 year in the RD group was estimated at 5.8±7.1%. Conclusions Early rapid declines in kidney function may occur in patients with renal artery stenosis when medical therapy is initiated, and their clinical outcomes are comparable to those without such a decline, when medical therapy only is continued.

Prediction of cardiovascular outcomes with machine learning techniques: application to the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study.

BACKGROUND: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. METHODS: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. RESULTS: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. CONCLUSION: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00081731.

Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease.

Soluble CD40 ligand (sCD40L) has been implicated in the development of renal injury. The CD40 receptor exists in a soluble form, sCD40R, and has been shown to function as a competitive antagonist against CD40 activation. We analyzed whether plasma levels of sCD40L and sCD40R predict changes in renal function in an all-cause chronic kidney disease (CKD) cohort. Stratification of subjects based on sCD40L and sCD40R individually, as well as in combination, demonstrated that sCD40L was directly associated with declines in estimated glomerular filtration rate (eGFR). sCD40R was negatively associated with declines in eGFR. Baseline characteristics following stratification, including systolic blood pressure, history of diabetes mellitus or peripheral vascular disease, primary renal disease classification, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker usage were not significantly different. High sCD40L and low sCD40R were both found to be independent predictors of a decline in eGFR at 1-year follow-up (-7.57%, p = 0.014; -6.39%, p = 0.044). Our data suggest that circulating levels of sCD40L and sCD40R are associated with changes in renal function in patients with CKD. The CD40 decoy receptor, sCD40R, may serve as a potential therapeutic target to attenuate renal function decline.

MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes.

Liquid biopsies have advanced rapidly in recent years for use in diagnostic and prognostic applications. One important aspect of this advancement is the growth in our understanding of microRNA (miRNA) biology. The measurement of miRNAs packaged within exosomes, which are constantly released into the blood stream, may reflect pathological changes within the body. The current study performed miRNA profiling using plasma and plasma-derived exosome samples from two animal models of kidney disease, the 5/6th partial nephrectomy (PNx) and two-kidney-one-clip (2K1C) models. The RT-qPCR-based profiling results revealed that the overall miRNA expression level was much higher in plasma than in plasma-derived exosomes. With 200µl of either plasma or exosomes derived from the same volume of plasma, 629 out of 665 total miRNAs analyzed were detectable in plasma samples from sham-operated rats, while only 403 were detectable in exosomes with a cutoff value set at 35cycles. Moreover, the average miRNA expression level in plasma was about 16-fold higher than that in exosomes. We also found a select subset of miRNAs that were enriched within exosomes. The number of detectable miRNAs from plasma-derived exosomes was increased in rats subjected to PNx or 2K1C surgery compared to sham-operated animals. Importantly, we found that the changes of individual miRNAs measured in plasma had very poor concordance with that measured in plasma-derived exosomes in both animal models, suggesting that miRNAs in plasma and plasma-derived exosomes are differentially regulated in these disease conditions. Interestingly, PNx and 2K1C surgeries induced similar changes in miRNA expression, implying that common pathways were activated in these two disease models. Pathway analyses using DIANA-miRPath v3.0 showed that significantly changed exosomal miRNAs were associated with extracellular matrix (ECM) receptor interaction and mucin type-O-glycan synthesis pathways, which are related with tissue fibrosis and kidney injury, respectively. In conclusion, our results demonstrated that due to the differential changes in miRNAs, the measurement of exosomal miRNAs cannot be replaced by the measurement of miRNAs in plasma, or vice versa. We also showed that a set of miRNAs related with kidney injury and organ fibrosis were dysregulated in plasma-derived exosomes from animal models of kidney disease.

Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis.

Cigarette smoking causes cardiovascular disease and is associated with poor kidney function in individuals with diabetes mellitus and primary kidney diseases. However, the association of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The current study utilized data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial to evaluate the effects of smoking on the risk of cardio-renal events and kidney function in this population. Baseline data showed that smokers (n = 277 out of 931) were significantly younger at enrollment than non-smokers (63.3±9.1 years vs 72.4±7.8 years; p<0.001). In addition, patients who smoke were also more likely to have bilateral renal artery stenoses and peripheral vascular disease (PVD). Longitudinal analysis showed that smokers experienced composite endpoint events (defined as first occurrence of: stroke; cardiovascular or renal death; myocardial infarction; hospitalization for congestive heart failure; permanent renal replacement; and progressive renal insufficiency defined as 30% reduction of GFR from baseline sustained for ≥ 60 days) at a substantially younger age compared to non-smokers (67.1±9.0 versus 76.1±7.9, p<0.001). Using linear regression and generalized linear modeling analysis controlled by age, sex, and ethnicity, smokers had significantly higher cystatin C levels (1.3±0.7 vs 1.2±0.9, p<0.01) whereas creatinine and estimated glomerular filtration rate (eGFR) were not different from non-smokers. From these data we conclude that smoking has a significant association with deleterious cardio-renal outcomes in patients with renovascular hypertension.

Regional and physician specialty-associated variations in the medical management of atherosclerotic renal-artery stenosis.

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis.