Patterns of Daily Physical Movement, Chronic Inflammation, and Frailty Incidence.

INTRODUCTION: Low physical activity is a criterion of phenotypic frailty defined as an increased state of vulnerability to adverse health outcomes. Whether disengagement from daily all-purpose physical activity is prospectively associated with frailty and possibly modified by chronic inflammation-a pathway often underlying frailty-remains unexplored. METHODS: Using the Study to Understand Fall Reduction and Vitamin D in You data from 477 robust/prefrail adults (mean age = 76 ± 5 yr; 42% women), we examined whether accelerometer patterns (activity counts per day, active minutes per day, and activity fragmentation [broken accumulation]) were associated with incident frailty using Cox proportional hazard regression. Baseline interactions between each accelerometer metric and markers of inflammation that include interleukin-6, C-reactive protein, and tumor necrosis factor-alpha receptor 1 were also examined. RESULTS: Over an average of 1.3 yr, 42 participants (9%) developed frailty. In Cox regression models adjusted for demographics, medical conditions, and device wear days, every 30 min·d -1 higher baseline active time, 100,000 more activity counts per day, and 1% lower activity fragmentation was associated with a 16% ( P = 0.003), 13% ( P = 0.001), and 8% ( P < 0.001) lower risk of frailty, respectively. No interactions between accelerometer metrics and baseline interleukin-6, C-reactive protein, or tumor necrosis factor-alpha receptor 1 were detected (interaction P > 0.06 for all). CONCLUSIONS: Among older adults who are either robust or prefrail, constricted patterns of daily physical activity (i.e., lower total activity minutes and counts, and higher activity fragmentation) were prospectively associated with higher risk of frailty but not modified by frailty-related chronic inflammation. Additional studies, particularly trials, are needed to understand if this association is causal.

Distribution of High-Sensitivity Cardiac Troponin and N-Terminal Pro-Brain Natriuretic Peptide in Healthy Transgender People.

Importance: Sex-specific differences in the commonly used cardiac biomarkers high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are apparent. There is an absence of medical literature delineating the concentration differences for these biomarkers in transgender individuals without cardiac disease. Objective: To determine the distribution of hs-cTn and NT-proBNP in healthy transgender people. Design, Setting, and Participants: In this cross-sectional prospective study, healthy transgender individuals prescribed testosterone or estradiol for 12 months or more were recruited from internal medicine and primary care clinics that specialize in transgender medical care between November 1, 2017, and July 1, 2018. Exposures: Testosterone or estradiol for 12 months. Main Outcomes and Measures: Concentrations for hs-cTnI (troponin I), hs-cTnT (troponin T), and NT-proBNP were measured. Results: Transgender people prescribed testosterone (n = 79; mean [SD] age, 28.8 [7.8] years) or estrogen (n = 93; mean [SD] age, 35.1 [11.7] years) were recruited. The concentration of hs-cTn was significantly higher in transgender men relative to transgender women. For Abbott hs-cTnI levels, the median (IQR) concentration observed in transgender men and women was 0.9 (0.6-1.7) ng/L and 0.6 (0.3-1.0) ng/L, respectively. Results were similar across 2 additional hs-cTn assays. In contrast, NT-proBNP level was higher in transgender women. The median (IQR) NT-proBNP concentration was significantly higher in transgender women ( 49 [32-86] ng/L) than in transgender men (17 [13-27] ng/L). Conclusions and Relevance: Findings of this cross-sectional study suggest that the differences in concentration for hs-cTn and NT-proBNP between transgender men and women were similar to what is observed between cisgender men and women. Sex hormones, rather than sex assigned at birth, may be a stronger driver of the observed concentration differences between healthy men and women for biomarkers of cardiac disease.

Stress-Delta B-Type Natriuretic Peptide Does Not Exclude ACS in the ED.

BACKGROUND: There are many detectable changes in circulating biomarkers in the setting of myocardial ischemia. We hypothesize that there are associated changes in circulating B-type natriuretic peptide (BNP) level after stress-induced myocardial ischemia, which can be used for emergency department (ED) acute coronary syndrome (ACS) risk stratification. METHODS: In a prospective study, we enrolled 340 patients over the age of 30 receiving an exercise echocardiography stress test in an ED observational unit for suspected ACS. We collected blood samples at baseline and at 2 and 4 h post-stress test, measuring the relative and absolute changes (stress-delta) in plasma BNP concentrations. In addition, patients were contacted at 90 days and at 1 year posttest for a follow-up. We calculated the diagnostic test characteristics of stress-delta BNP for a composite outcome of ischemic imaging on stress echocardiogram, nonelective percutaneous coronary intervention, coronary artery bypass graft surgery, subsequent acute myocardial infarction, or cardiac death at 1 year via a logistic regression. We analyzed the 2-h BNP concentrations using an ANOVA model to adjust for the baseline BNP level. RESULTS: Baseline and 2-h post-stress BNP were both higher in the positive outcome group, but the stress-delta BNP was not. Stress-delta BNP had a sensitivity and specificity, respectively, of 53% and 76% at 2 h and 67% and 68% at 4 h. It was noted that patients with the composite outcome had a higher baseline BNP level. CONCLUSIONS: BNP stress-deltas are poor diagnostic means for ACS risk stratification, but resting BNP remains a promising prognostic tool for ED patients with suspected ACS.

Incidence and Durability of SARS-CoV-2 Antibodies in Patients with Cancer and Health Care Workers following the First Wave of the Pandemic.

BACKGROUND: Patients with cancer and health care workers (HCW) are at higher risk for SARS-CoV-2 infection. There are limited data regarding the rate of symptomatic versus asymptomatic infection and subsequent seropositivity in both populations. METHODS: We performed a prospective study of patients and HCW across two institutions during the first wave of the pandemic to analyze the prevalence of SARS-CoV-2 antibodies, the extent of associated symptoms, and durability of serologic response. RESULTS: In 1,953 persons (733 patients and 1,220 HCW), overall seropositivity rates for 3.1% patients (95% CI 2.0-4.7) and 3.7% HCW (95% CI 2.7-4.9, p=0.520), were similar. Each institutions' seropositivity rates were numerically higher in HCW than patients. Non-Hispanic Whites and Asians had lower antibody rates (2.8%, 95% CI 2.0-3.8 and 3.3%, 95% CI 1.2-7.0) compared to Hispanics (6.9%, 95% CI 3.4-12.4) and non-Hispanic Blacks (5.9%, 95% CI 3.3-9.7), p < 0.001. Among persons with a positive SARS-CoV-2 antibody, 87% of patients and 56% of HCW did not recall having had a fever. Among HCW, administrative and technical personnel were most likely to be seropositive. The rate of persistent seropositivity at 3 months was similar between patients and HCW and was not influenced by the reporting of fever, cancer type, or therapy. CONCLUSION: These data suggest that patients are not at higher risk for febrile SARS-CoV-2 infections or more transient immunity than HCWs. Furthermore, racial differences and lack of association with the extent of HCW contact with COVID-19 patients suggest that community rather than hospital virus exposure was a source of many infections.

Lower diagnostic accuracy of hs-cTnI in patients with prior coronary artery bypass grafting.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) and the ESC 0/1h-hs-cTnT-algorithm have worse performance in the early diagnosis of myocardial infarction (MI) in patients with prior coronary artery bypass grafting (CABG). It is unknown, whether this concern applies also to hs-cTnI, the most widely used analyte worldwide. METHODS: In an international multicenter diagnostic study, two cardiologists centrally adjudicated the final diagnosis in patients presenting to the emergency department with symptoms suggestive of MI according to the Third Universal Definition of MI. The objective was to compare the diagnostic accuracy of hs-cTnI assays and their performance within the ESC hs-cTnI 0/1h-algorithms in patients with versus without prior CABG. Findings were externally validated in an U.S. multicenter diagnostic study. RESULTS: A total of 392/5'200 patients (8%) had prior coronary artery bypass grafting (CABG). Diagnostic accuracy of hs-cTnI as quantified by the area under the receiver-operating characteristics-curve (AUC) in these patients was high, but lower versus patients without prior CABG (e.g. hs-cTnI-Architect 0.91 versus 0.95; p = 0.016). Sensitivity/specificity of rule-out/in by the European Society of Cardiology (ESC) 0/1h-hs-cTnI-algorithms remained very high [e.g. hs-cTnI-Architect 100% and 93.5%], but efficacy was lower (52% versus 74%, p < 0.01). External validation (n = 2113) confirmed these findings in 192 patients with prior CABG using hs-cTnI-Atellica, with 52% versus 36% (p < 0.001) remaining in the observe zone. CONCLUSIONS: Diagnostic accuracy of hs-cTnI and efficacy of the ESC 0/1h-hs-cTnI-algorithms are lower in patients with prior CABG, but sensitivity/specificity remain very high. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587.

Glycated Albumin in Pristine and Non-Pristine Stored Samples in the National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND: Glycated albumin is cleared by the Food and Drug Administration (FDA) for clinical use in diabetes care. To understand its performance in the general US population, we conducted measurements in >19 000 samples from the National Health and Nutrition Examination Survey (NHANES). Of these samples, 5.7% had previously undergone at least 2 freeze-thaw cycles and were considered "non-pristine." METHODS: We measured glycated albumin and albumin using the Lucica GA-L (Asahi Kasei) assay in stored serum samples from NHANES 1999-2004. Serum albumin (Roche/Beckman) was previously measured. We examined the correlations of percent glycated albumin with hemoglobin A1C (HbA1c)and fasting glucose in the pristine and non-pristine samples. We also measured cystatin C (Siemens) and compared these to cystatin C (Dade Behring) previously obtained in a subsample. RESULTS: Glycated albumin (%) was significantly lower in pristine vs non-pristine samples (13.8% vs 23.4%, P < 0.0001). The results from the Asahi Kasei albumin assay (g/dL) were highly correlated with albumin originally measured in NHANES (Pearson's correlation coefficient, r = 0.76) but values were systematically higher (+0.25 g/dL, P < 0.0001). Cystatin C (Siemens) was similar to previous cystatin C measurements (r = 0.98) and did not differ by pristine status (P = 0.119). Glycated albumin (%) was highly correlated with HbA1c and fasting glucose in pristine samples (r = 0.78 and r = 0.71, respectively) but not in non-pristine samples (r = 0.11 and r = 0.12, respectively). CONCLUSIONS: The performance of the glycated albumin assay in the pristine samples was excellent. Performance in non-pristine samples was highly problematic. Analyses of glycated albumin in NHANES 1999-2004 should be limited to pristine samples only. These results have major implications for the use of these public data.

Assessing Phlebotomy Device Preference and Specimen Quality in an Oncology Outpatient Clinic.

BACKGROUND: Oncology patients have frequent venipunctures, which causes scarring, making subsequent draws difficult and painful. Novel blood collection systems may decrease discomfort in patients experiencing repeat blood draws. METHODS: Oncology outpatients (n = 101; criteria excluded 12) were recruited to determine their preference for either of two blood collection systems, the 23-gauge standard BD Vacutainer Push Button Blood Collection Set (Standard Push Button system) or the 25-gauge BD Vacutainer UltraTouch Push Button Blood Collection Set (UltraTouch Push Button system). Subjects received two blinded, randomized blood draws, one with each device and just one device for each arm. Subjects subsequently rated their blinded preference for blood collection system. Specimen quality was assessed for each device with measurements for plasma hemoglobin (Shimadzu UV-1800 spectrophotometer, Shimadzu), lactate dehydrogenase, and potassium (Vitros 4600/5600 analyzer, Ortho Diagnostics). RESULTS: Preference for the 25-gauge UltraTouch Push Button system over the 23-gauge Standard Push Button system was significant (UltraTouch, n = 51; Standard n = 30; no preference, n = 8; P = 0.0196). Regarding sample quality, the 25-gauge UltraTouch Push Button system had significantly lower plasma hemoglobin (average 5.34 mg/dL) vs the 23-gauge Standard Push Button system (9.37 mg/dL; P < 0.0001); serum lactate dehydrogenase and potassium differences were not statistically significant. CONCLUSION: Subjects in an oncology clinic preferred phlebotomy with the 25-gauge UltraTouch Push Button system, and samples using this device had less hemolysis as assessed by plasma hemoglobin.

Ideal high sensitivity troponin baseline cutoff for patients with renal dysfunction.

OBJECTIVE: High-sensitivity cardiac troponin assays (hs-cTn) aid in diagnosis of myocardial infarction (MI). These assays have lower specificity for non-ST Elevation MI (NSTEMI) in patients with renal disease. Our objective was to determine an optimized cutoff for patients with renal disease. METHODS: We conducted an a priori secondary analysis of a prospective FDA study in adults with suspected MI presenting to 29 academic urban EDs between 4/2015 and 4/2016. Blood was drawn 0, 1, 2-3, and 6-9 h after ED arrival. We recorded cTn and estimated glomerular filtrate rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation. The primary endpoint was NSTEMI (Third Universal Definition of MI), adjudicated by physicians blinded to hs-cTn results. We generated an adjusted hscTn rule-in cutoff to increase specificity. RESULTS: 2505 subjects were enrolled; 234 were excluded. Patients were mostly male (55.7%) and white (57.2%), median age was 56 years 472 patients [20.8%] had an eGFR <60 mL/min/1.73 m2. In patients with eGFR <15 mL/min/1.73 m2, a baseline rule-in cutoff of 120 ng/L led to a specificity of 85.0% and Positive Predictive Value (PPV) of 62.5% with 774 patients requiring further observation. Increasing the cutoff to 600 ng/L increased specificity and PPV overall and in every eGFR subgroup (specificity and PPV 93.3% and 78.9%, respectively for eGFR <15 mL/min/1.73m2), while increasing the number (79) of patients requiring observation. CONCLUSIONS: An eGFR-adjusted baseline rule-in threshold for the Siemens Atellica hs-cTnI improves specificity with identical sensitivity. Further study in a prospective cohort with higher rates of renal disease is warranted.

Association of Cardiac Biomarkers With the Kansas City Cardiomyopathy Questionnaire in Patients With Chronic Kidney Disease Without Heart Failure.

Background The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a measure of heart failure (HF) health status. Worse KCCQ scores are common in patients with chronic kidney disease (CKD), even without diagnosed heart failure (HF). Elevations in the cardiac biomarkers GDF-15 (growth differentiation factor-15), galectin-3, sST2 (soluble suppression of tumorigenesis-2), hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) likely reflect subclinical HF in CKD. Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score <75 at year 1 and (2) incident decline in KCCQ score to <75. We used multivariable logistic regression and Cox regression models to evaluate the associations between baseline cardiac biomarkers and cross-sectional and longitudinal KCCQ scores. Among 2873 participants, GDF-15 (adjusted odds ratio 1.42 per SD; 99% CI, 1.19-1.68) and galectin-3 (1.28; 1.12-1.48) were significantly associated with KCCQ scores <75, whereas sST2, hsTnT, and NT-proBNP were not significantly associated with KCCQ scores <75 after multivariable adjustment. Of the 2132 participants with KCCQ ≥75 at year 1, GDF-15 (adjusted hazard ratio, 1.36 per SD; 99% CI, 1.12-1.65), hsTnT (1.20; 1.01-1.44), and NT-proBNP (1.30; 1.08-1.56) were associated with incident decline in KCCQ to <75 after multivariable adjustment, whereas galectin-3 and sST2 did not have significant associations with KCCQ decline. Conclusions Among participants with CKD without clinical HF, GDF-15, galectin-3, NT-proBNP, and hsTnT were associated with low KCCQ either at baseline or during follow-up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.

Donor-Derived Cell-Free DNA Testing in Solid Organ Transplantation: A Value Proposition.

BACKGROUND: There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. More efficient biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and to prevent immune activation is also important. Donor-derived cell-free DNA (dd-cfDNA) has become available for comprehensive monitoring of allograft integrity. A value proposition concept was applied to assess the potential benefits of dd-cfDNA to stakeholders (patient, transplant physician, laboratory medicine specialist, hospital management, insurance companies) involved in solid organ transplantation care. CONTENT: There is robust clinical evidence from more than 48 published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. The value proposition framework was used to evaluate published key evidence regarding clinical validity, economic implications, and limitations of this approach. It has been shown that dd-cfDNA testing is essential for guiding earlier transplant injury intervention with potential for improved long-term outcome. SUMMARY: Monitoring dd-cfDNA offers a rapid and reproducible method to detect graft injuries at an early actionable stage without protocol biopsies and allows for more effective personalized immunosuppression. The appropriate use of dd-cfDNA testing can provide both clinical and economic benefits to all transplantation stakeholders.

Plasma EGFR mutation testing in non-small cell lung cancer: A value proposition.

Genomics-driven precision medicine using targeted therapies requires advanced molecular diagnostic tests. Decisions about the use and reimbursement for such tests are increasingly being made on the basis of more outcome-based and value-based approaches. The value proposition concept is a tool to assess the benefits of laboratory testing to each stakeholder of the care pathway with respect to outcomes. This concept was applied to the use of noninvasive plasma epidermal growth factor receptor (EGFR) mutation testing in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to guide treatment with EGFR tyrosine kinase inhibitors (TKIs). Using the value proposition framework, we evaluated published key evidence regarding clinical validity, economic implications, and limitations of this approach. It has been shown that plasma EGFR mutation testing is essential for guiding clinical decisions regarding prediction of eligibility of individual patients for TKI treatment, real-time monitoring, or adjustment of treatment regimens and tracking resistance. The appropriate use of plasma EGFR mutation testing has been shown to deliver both clinical and economic benefits to stakeholders across the entire care pathway; especially in clinical situations where biopsy material is inadequate or unavailable and where it leads to fewer tissue biopsies.

"Malignant" Left Ventricular Hypertrophy Identifies Subjects at High Risk for Progression to Asymptomatic Left Ventricular Dysfunction, Heart Failure, and Death: MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND: As heart failure (HF)-associated morbidity and mortality continue to escalate, enhanced focus on prevention is increasingly important. "Malignant" left ventricular (LV) hypertrophy (LVH): LVH combined with an elevated cardiac biomarker reflecting either injury (high-sensitivity cardiac troponin T), or strain (amino-terminal pro-B-type natriuretic peptide) has predicted accelerated progression to HF. We sought to determine whether malignant LVH identified community-dwelling adults initially free of cardiovascular disease at high risk of asymptomatic decline in LV ejection fraction or a clinical cardiovascular event. METHODS AND RESULTS: A total of 4985 of 6814 individuals without prevalent cardiovascular disease underwent baseline cardiac magnetic resonance for LVH in combination with measurement of plasma high-sensitivity cardiac troponin T and amino-terminal pro-B-type natriuretic peptide as part of MESA (Multi-Ethnic Study of Atherosclerosis) and were subsequently divided into 4 groups: (1) No LVH, no elevated biomarkers (n=2206; 44.3%); (2) No LVH, ≥1 elevated biomarkers (n=2275; 45.7%); (3) LVH, no elevated biomarkers (n=153; 3.0%); and (4) LVH, ≥1 elevated biomarkers (malignant LVH; n=351; 7.0%). Cardiac magnetic resonance was repeated 10 years later (n=2831) for assessment of LV ejection fraction <50%. Median follow-up was 12.2 years. Malignant LVH was associated with 7.0-, 3.5-, and 2.6-fold adjusted increases in incidence of HF, cardiovascular death, and asymptomatic LV dysfunction, respectively, versus group 1. New-onset HF was predominately HF with reduced ejection fraction (9.5-fold increase). CONCLUSIONS: Malignant LVH is predictive of progression to asymptomatic LV dysfunction, HF (particularly HF with reduced ejection fraction), and cardiovascular death. Consequently, malignant LVH represents a high-risk phenotype among individuals without known cardiovascular disease, which should be targeted for increased surveillance and more-aggressive therapies.

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis.

BACKGROUND: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction. AIM: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates. METHODS: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines. RESULTS: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism. CONCLUSIONS: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.

Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis.

The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P <0.0001). Erythronate (R = 0.594, P <0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P <0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P <0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism.

Lipoprotein Biomarkers and Risk of Cardiovascular Disease: A Laboratory Medicine Best Practices (LMBP) Systematic Review.

BACKGROUND: Controversy exists about the incremental utility of nontraditional lipid biomarkers [e.g., apolipoprotein (apo) B, apo A-I, and non-HDL-C] in improving cardiovascular disease (CVD) risk prediction when added to a conventional model of traditional risk factors (e.g., total cholesterol, LDL cholesterol, HDL cholesterol, sex, age, smoking status, and blood pressure). Here we present a systematic review that was conducted to assess the use of nontraditional lipid biomarkers including apo B, apo A-I, apo B/A-I ratio, and non-HDL-C in improving CVD risk prediction after controlling for the traditional risk factors in populations at risk for cardiovascular events. CONTENT: This systematic review used the Laboratory Medicine Best Practices (LMBP™) A-6 methods. A total of 9 relevant studies published before and including July 2015 comprised the evidence base for this review. Results from this systematic review indicated that after the adjustment for standard nonlipid and lipid CVD risk factors, nontraditional apolipoprotein biomarkers apo B (overall effect = relative risk: 1.31; 95% CI, 1.22-1.40; 4 studies) and apo B/apo A-I ratio (overall effect = relative risk: 1.31; 95% CI, 1.11-1.38; 7 studies) resulted in significant improvement in long-term CVD risk assessment. SUMMARY: Available evidence showed that nontraditional lipid biomarkers apo B and apo B/apo I ratio can improve the risk prediction for cardiovascular events after controlling for the traditional risk factors for the populations at risk. However, because of insufficient evidence, no conclusions could be made for the effectiveness of apo A-I and non-HDL-C lipid markers to predict the CVD events, indicating a need for more research in this field.

Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines.

BACKGROUND & AIMS: Equations used to estimate glomerular filtration rate (GFR) are not accurate in patients with cirrhosis. We aimed to develop a new equation to estimate the GFR in subjects with cirrhosis and compare its performance with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C and creatinine-cystatin C equations, which were derived in populations without cirrhosis. METHODS: From 2010 through 2014, we measured GFR in 103 subjects with cirrhosis based on non-radiolabeled iothalamate plasma clearance. We measured blood levels of creatinine, cystatin C, ß-trace protein, ß2-microglobulin, L-arginine, and symmetric and asymmetric dimethylarginines simultaneously with GFR. Multivariate linear regression analysis was performed to develop models to estimate GFR. Overall accuracy, defined by the root mean square error (RMSE) of our newly developed model to estimate GFR, was compared with that of the CKD-EPI equations. To obtain an unbiased estimate of our new equation to estimate GFR, we used a leave-one-out cross-validation strategy. RESULTS: After we considered all the candidate variables and blood markers of GFR, the most accurate equation we identified to estimate GFR included serum levels of creatinine and cystatin C, as well as patients' age, sex, and race. Overall, the accuracy of this equation (RMSE = 22.92) was superior to that of the CKD-EPI cystatin C equation (RMSE = 27.27, P = .004). Among subjects with cirrhosis and diuretic-refractory ascites, the accuracy of the equation we developed to estimate GFR (RMSE = 19.36) was greater than that of the CKD-EPI cystatin C (RMSE = 27.30, P = .003) and CKD-EPI creatinine-cystatin C equations (RMSE = 23.37, P = .004). CONCLUSIONS: We developed an equation that estimates GFR in subjects with cirrhosis and diuretic-refractory ascites with greater accuracy than the CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin C equation.

Traditional Risk Factors Versus Biomarkers for Prediction of Secondary Events in Patients With Stable Coronary Heart Disease: From the Heart and Soul Study.

BACKGROUND: Patients with stable coronary heart disease (CHD) have widely varying prognoses and treatment options. Validated models for risk stratification of patients with CHD are needed. We sought to evaluate traditional and novel risk factors as predictors of secondary cardiovascular (CV) events, and to develop a prediction model that could be used to risk stratify patients with stable CHD. METHODS AND RESULTS: We used independent derivation (912 participants in the Heart and Soul Study) and validation (2876 participants in the PEACE trial) cohorts of patients with stable CHD to develop a risk prediction model using Cox proportional hazards models. The outcome was CV events, defined as myocardial infarction, stroke, or CV death. The annual rate of CV events was 3.4% in the derivation cohort and 2.2% in the validation cohort. With the exception of smoking, traditional risk factors (including age, sex, body mass index, hypertension, dyslipidemia, and diabetes) did not emerge as the top predictors of secondary CV events. The top 4 predictors of secondary events were the following: N-terminal pro-type brain natriuretic peptide, high-sensitivity cardiac troponin T, urinary albumin:creatinine ratio, and current smoking. The 5-year C-index for this 4-predictor model was 0.73 in the derivation cohort and 0.65 in the validation cohort. As compared with variables in the Framingham secondary events model, the Heart and Soul risk model resulted in net reclassification improvement of 0.47 (95% CI 0.25 to 0.73) in the derivation cohort and 0.18 (95% CI 0.01 to 0.40) in the validation cohort. CONCLUSIONS: Novel risk factors are superior to traditional risk factors for predicting 5-year risk of secondary events in patients with stable CHD.

A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.

BACKGROUND: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics. METHODS: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites). RESULTS: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and ß2-microglobulin performed better compared to Cr in estimating RPF, ß-trace protein, ß2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index. CONCLUSION: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.

Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis.

UNLABELLED: Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by nonradiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the "bias," "precision," and "accuracy" of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG), and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores (differences between mGFR and estimated GFR [eGFR] or between mGFR and CrCl, or between mGFR and CG equation for each subject) (RMSE = 23.56) was significantly better than that of CrCl (37.69, P = 0.001), CG (RMSE = 36.12, P = 0.002), and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P = 0.024), CG (P = 0.0001), 4-variable MDRD (P = 0.027), and CKD-EPI creatinine 2009 (P = 0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%. CONCLUSION: The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.

Prevalence of proteinuria and elevated serum cystatin C among HIV-Infected Adolescents in the Reaching for Excellence in Adolescent Care and Health (REACH) study.

OBJECTIVE: In the United States, kidney dysfunction is prevalent in almost 30% of HIV-infected patients and is an independent predictor of mortality. Proteinuria and elevated serum cystatin C (eCysC) are used as markers of kidney disease in the general population; however, the prevalence of these markers in HIV-infected adolescents is largely unknown. METHODS: This study includes 304 HIV-infected adolescents from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort, an observational study of adolescents recruited from 13 US cities. Clinical and demographic characteristics of participants were evaluated as correlates of proteinuria, a urine protein to creatinine ratio of ≥200 mg/g. Select univariate predictors were assessed to determine the association with urinary protein excretion and serum cystatin C in multivariable linear regression models and proteinuria and eCysC (eCysC ≥ 75th percentile) in multivariable logistic regression models. RESULTS: Overall, 19.1% of the participants had proteinuria, whereas 23.7% had an eCysC. Low CD4 T-lymphocyte counts (<200 cells/mm) were significantly associated with a greater urine protein to creatinine ratio in linear models and with proteinuria in logistic regression models. CD4 T-lymphocyte counts <500 cells/mm were significantly associated with a greater serum cystatin C concentration in linear models and with eCysC in logistic regression models. CONCLUSIONS: Proteinuria among HIV-infected adolescents in the REACH cohort was approximately 2-fold greater than healthy US adolescents. Both proteinuria and eCysC are associated with CD4 T-lymphocyte counts. Further studies investigating early markers of kidney disease and the association with immune status and inflammation in HIV-infected adolescents are needed.