Measure Of Kidney Function Research Articles

Serially assessed bisphenol A and phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: A longitudinal cohort study.

Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

Association between kidney function, nutritional status and anthropometric measures in older people

BackgroundDifferent mechanisms connect the nutritional status with the occurrence and the course of chronic kidney disease (CKD). The end-stage renal disease is complicated by catabolic inflammatory reactions and cachexia which leads to malnutrition (undernutrition). On the other hand, obesity is an important risk factor for the development and acceleration of CKD.MethodsIn the SCOPE study, community-dwelling persons aged 75 years and over, from 6 European countries and Israel were examined at the baseline phase. We assessed the relationship between anthropometric measures (Body Mass Index (BMI), circumferences of arm (AC), waist (WC), hip (HC), and calf (CC), waist-to-hip ratio - WHR, waist-to-height ratio - WHtR, risk of malnutrition (Mini Nutritional Assessment - MNA), serum albumin) and estimated glomerular filtration rate (eGFR) calculated by Berlin Initiative Study (BIS) equation.ResultsWe studied 2151 subjects (932 men and 1219 women) with a mean age of 79.5 ± 5.9 years. A total of 1333 (62%) participants had CKD (GRF < 60 ml/min/1.73 m2). Negative correlations between eGFR and weight, AC, WC, HC, CC, BMI, WHtR were observed. Positive correlation occurred between eGFR and MNA score (Spearman’s rho = 0.11) and albumin concentration (rho = 0.09). Higher weight, AC, WC, HC, CC, BMI and WHtR increased the odds ratio of CKD; higher MNA (OR = 0.98, 95% CI 0.94–1.0) and higher serum albumin (OR = 0.73, 95% CI 0.53–1.0) were weakly associated with reduced odds. The risk of malnutrition was the highest with eGFR < 30 as compared to eGFR > 60 (OR = 2.95, 95%CI = 1.77–4.94 for MNA < 24; OR = 5.54, 95%CI = 1.66–18.5 for hypoalbuminemia < 3.5 g/dL).ConclusionThe population of community dwelling people aged 75+ with CKD shows general features of overweight and obesity with a small prevalence of malnutrition. For anthropometric measures, the strongest association with eGFR and the highest odds of CKD were identified using WC, HC, CC and WHtR. Albumin level and MNA, but not MNA Short Form, indicated an increased odds of malnutrition with a decrease in eGFR.

Characterizing dynamics of serum creatinine and creatinine clearance in extremely low birth weight neonates during the first 6 weeks of life

BackgroundCharacterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight (≤ 1000 g; ELBW) neonates remains challenging.MethodsWe performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated.ResultsA total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤ 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth.ConclusionsWe report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population.

Cardiac Biomarkers and Risk of Mortality in CKD (the CRIC Study)

IntroductionCardiovascular disease (CVD) is the leading cause of mortality among individuals with chronic kidney disease (CKD). Cardiac biomarkers of myocardial distention, injury, and inflammation may signal unique pathways underlying CVD in CKD. In this analysis, we studied the association of baseline levels and changes in 4 traditional and novel cardiac biomarkers with risk of all-cause, CV, and non-CV mortality in a large cohort of patients with CKD.MethodsAmong 3664 adults with CKD enrolled in the Chronic Renal Insufficiency Cohort Study, we conducted a cohort study to examine the associations of baseline levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac high-sensitivity troponin T (hsTnT), growth differentiation factor−15 (GDF-15), and soluble ST-2 (sST-2) with risks of all-cause and cardiovascular (CV) mortality. Among a subcohort of 842 participants, we further examined the associations between change in biomarker levels over 2 years with risk of all-cause mortality. We used Cox proportional hazards regression models and adjusted for demographics, kidney function measures, cardiovascular risk factors, and medication use.ResultsAfter adjustment, elevated baseline levels of each cardiac biomarker were associated with increased risk of all-cause mortality: NT-proBNP (hazard ratio [HR] = 1.92, 95% confidence interval [CI] = 1.73−2.12); hsTnT (HR = 1.62, 95% CI = 1.48, 1.78]); GDF-15 (HR = 1.61, 95% CI = 1.46−1.78]); and sST-2 (HR = 1.26, CI = 1.16−1.37). Higher baseline levels of all 4 cardiac biomarkers were also associated with increased risk of CV. Declines in NT-proBNP (adjusted HR = 0.55, 95% CI = 0.36−0.86) and sST2 (HR = 0.55, 95% CI = 0.36−0.86]) over 2 years were associated with lower risk of all-cause mortality.ConclusionIn a large cohort of CKD participants, elevations of NT-proBNP, hsTnT, GDF-15, and sST-2 were independently associated with greater risks of all-cause and CV mortality.

Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD

In a multinational placebo‐controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy’s Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity.

ANGIOTENSIN RECEPTOR BLOCKERS PROVIDE BETTER GLOMERULAR FILTRATION RATES THAN ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN KIDNEY TRANSPLANT RECIPIENTS WITH PROTEINURIA

Introduction: Kidney transplantation is the best renal replacement therapy in CKD whereas preventing measures of kidney function still remains a major problem after transplantation. Proteinuria and hypertension are two major determinants of worsening of kidney function in graft kidneys. Angiotensin converting enzyme inhibitors (ACEI) and Angiotensin receptor blockers (ARB) are the choice of treatment in proteinuria and hypertension. The aim of our study is to compare and evaluate the effectiveness of ACEIs and ARBs in patients with proteinuria higher than 1 gram per day. Materials & Methods: 62 kidney transplant (KT) recipients who have proteinuria over 1 g/day who have been followed up in Baskent University between 2009-2015 were enrolled to our study. The data of 2 years follow-up has been recorded. Patients using ACE-Is (Group 1), patients using ARBs (Group 2) have been compared. The demographic, clinical and laboratory values of the patients were recorded prospectively. At least 1 year of stable kidney function and proteinuria higher than 1 g/day was the inclusion criteria. Results: The initial 24 hours proteinuria levels showed statistically significant decrease in the follow up of 2 years period. The mean proteinuria at the initiation of the study was 2914 ± 2501 mg/d whereas the mean proteinuria declined to 1331 ± 2088 mg/d at the 24th month of the study. Both ACEI group (Group 1)and ARB group (Group 2) showed statistically significant decreasing effect on proteinuria. After 24 months follow-up, the ACEI group showed a significant loss of kidney function that was confirmed as the reducing of creatinine clearance from 88.8 ± 38.1 to 76.9 ± 36.1 mL/min whereas the ARB group maintained the kidney function that was confirmed as preventing the creatinine clearance from 65.2 ± 29.0 to 61.2 ± 29.1 mL/min. Conclusion: Patients who have proteinuria higher than 1 g per day should receive ACEI or ARB therapies. ARBs showed better results in prevention of GFR compared to ACE inhibitors while both protocols showed significant decline in proteinuria regardless of primary etiology.

Metal mixtures and kidney function: An application of machine learning to NHANES data

BackgroundExposure to heavy metals may increase risk of kidney disease, but most studies have examined individual metals or two-way interactions. There is increasing recognition of the importance of studying exposure to metal mixtures and health outcomes. ObjectivesWe used Bayesian kernel machine regression (BKMR) to examine associations between a mixture of four heavy metals and indicators of kidney function. MethodsWe used NHANES 2015-16 data on 1435 adults aged 40 and over to study cross-sectional associations between blood levels of four heavy metals (Co, Cr, Hg and Pb) and kidney function. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and by albumin to creatinine ratio (ACR), measured continuously and dichotomized into indicators of chronic kidney disease (CKD) and albuminuria, respectively. BKMR tested for non-linearity in the exposure-specific responses to evaluate dose-response relationships between mixtures and outcomes and possible interaction effects among exposures. Interactions among continuous outcomes were identified using the NLinteraction package in R. ResultsA higher metals mixture was significantly associated with all four measures of kidney function in dose-response patterns. Pb had the strongest association with eGFR, albuminuria and ACR, and the second strongest association with CKD. We also observed an interaction between Pb and Co for eGFR and an interaction between Pb and Cd for ACR. ConclusionsExposure to a co-occurring heavy metals mixture was associated with indicators of poor kidney function. Within this mixture, Pb, Co and Cd considered singly and jointly made the greatest contributions to the observed effects. Future prospective study is needed to confirm the association between metal mixtures and kidney function.

Postoperative outcomes of 12 cats with ureteral obstruction treated with ureteroneocystostomy.

To report complications and long-term outcomes of cats with benign ureteral obstruction treated with ureteroneocystostomy and to determine the effects of double pigtail catheter (DPT) placement on postoperative outcomes. Retrospective study. Twelve client-owned cats with ureteral urolithiasis treated with ureteroneocystostomy. Records were reviewed for signalment, location of the obstruction, diagnostic tests, surgical technique, perioperative complications, long-term measurements of kidney function, and survival. Cats were divided into two groups; in one group, a DPT was placed at the time of ureteroneocystostomy, and, in the other group, a DPT was not placed at the time of ureteroneocystostomy (NDPT). A DPT was placed in six of 12 cats. The NDPT group included four cats with temporary catheters and two cats with no catheter. Median creatinine concentration decreased from 10.4 mg/dL (range, 1.6-20.3) to 2.2 mg/dL (range, 1.1-3.6) at the time of discharge (P = .015) in all cats. Two cats in the NDPT group required revision surgery for uroabdomen. Eleven cats were discharged from the hospital. Long-term complications (hematuria, pollakiuria, urinary tract infections) were more common in the DPT group (P = .047). Seven cats were alive a median of 329 days (range, 8-1772) after surgery. Median creatinine concentration was 2.0 mg/dL (range, 0.6-6.4) at a median of 157 days (range, 43-1772) after surgery. Ureteroneocystostomy resulted in acceptable long-term outcomes in 11 of 12 cats. The placement of a DPT did not influence the long-term outcome in this small population. Ureteroneocystostomy with or without intraoperative placement of a DPT should be considered to relieve benign ureteral obstructions in cats.

The Relationship Between Immigration Status and Chronic Kidney Disease Risk Factors in Immigrants and US-Born Adults.

Objective:To understand the relationship between nativity and measures of kidney function including estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR).Methods:Seven waves of data from the National Health and Nutrition Examination Survey (2001 – 2014) was analyzed. General linear regression methods were used to assess the relationship between eGFR, ACR and nativity (foreign-born vs US-born). Models were adjusted for length of time in the US, demographic variables, comorbidities, lifestyle factors, and access to healthcare.Results:There were 27,111 individuals representing 217,842,257 US adults included in the study. Approximately 26.1% were immigrants, with 40.4% of immigrants having resided <15 years in the US. Among immigrants with <15 years of residence, 51% were Hispanic, and 54.4% had high school or below education. After controlling for demographics and length of time in the US, immigrants were 26% more likely to have an ACR >= 30mg/g (OR=1.26, 95% CI: 1.08 – 1.47); however, after controlling for demographics, length of time, comorbidities, and lifestyle factors the results were no longer significant. Immigrants were significantly less likely to have an eGFR < 60 (OR=0.42, 95%CI: 0.36 – 0.50), which remained after adjustment (OR=0.75, 95%CI: 0.61 – 0.93).Conclusions:Immigrants had significantly lower odds of having an eGFR < 60 compared to US-born adults. Additionally, immigrants with >= 15 years in the US had mean eGFR values that were less than immigrants < 15 years in the US, indicating that there is some decrease in kidney function as the length of US residence increases.

The Difference Between Cystatin C– and Creatinine-Based Estimated GFR and Associations With Frailty and Adverse Outcomes: A Cohort Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT)

In prior research and in practice, the difference between estimated glomerular filtration rate (eGFR) calculated from cystatin C level and eGFR calculated from creatinine level has not been assessed for clinical significance and relevance. We evaluated whether these differences contain important information about frailty. A cohort analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). 9,092 hypertensive SPRINT participants who had baseline measurements of serum creatinine, cystatin C, and frailty. eGFRs calculated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations (eGFRcys and eGFRcr), and eGFRDiff, calculated as eGFRcys-eGFRcr. A validated 35-item frailty index that included questionnaire data for general and physical health, limitations of activities, pain, depression, sleep, energy level, self-care, and smoking status, as well as medical history, cognitive assessment, and laboratory data. We defined frailty as frailty index score>0.21 (range, 0-1). The incidence of injurious falls, hospitalizations, cardiovascular events, and mortality was also recorded. We used logistic regression to model the cross-sectional association of baseline eGFRDiff with frailty among all SPRINT participants. Adjusted proportional hazards regression was used to evaluate the association of eGFRDiff with adverse outcomes and mortality. Mean age was 68±9 (SD) years, mean eGFRcys and eGFRcr were 73±23 and 72±20mL/min/1.73m2, and mean eGFRDiff was 0.5±15mL/min/1.73m2. In adjusted models, each 1-SD higher eGFRDiff was associated with 24% lower odds of prevalent frailty (OR, 0.76; 95% CI, 0.71-0.81), as well as with lower incidence rate of injurious falls (HR, 0.84; 95% CI, 0.77-0.92), hospitalization (HR, 0.91; 95% CI, 0.88-0.95), cardiovascular events (HR, 0.89; 95% CI, 0.81-0.97), and all-cause mortality (HR, 0.71; 95% CI, 0.63-0.82); P<0.01. Gold-standard measure of kidney function and assessment of muscle mass were not available. The difference between eGFRcys and eGFRcr is associated with frailty and health status. Positive eGFRDiff is strongly associated with lower risks for longitudinal adverse outcomes and mortality, even after adjusting for chronic kidney disease stage and baseline frailty.

Prophylactic Ligature of AV Fistula Prevents High Output Heart Failure after Kidney Transplantation

Background: Arteriovenous (AV) fistulas are considered the gold standard for ensuring safe and long-term vascular access in patients with haemodialysis-dependent end-stage renal disease. However, previous studies demonstrated that high-flow AV fistulas might add additional cardiovascular burden in the post-transplant setting, leading to frequent fistula closure in this population. Currently, there is no consensus regarding management of high-flow fistulas in post-transplant patients with stable kidney function. The present randomized controlled trial examines the effect of prophylactic AV fistula closure on high-output heart failure. Methods: Twenty-eight kidney transplant patients with stable graft function, absence of pre-existing severe cardiac failure, and brachial arterial flow rate of at least 1,500 mL/min were recruited and randomized in a 1:1 ratio to an intervention and control group, respectively. The intervention group was subject to immediate fistula ligature. Patients within the control group were referred to fistula ligature only if the main study endpoint high-output heart failure was reached. The latter was defined by the presence of at least 1 clinical sign (i.e., worsening NYHA score) and at least 2 of the following echocardiographic parameters: diameter of right atrium (major) >53 mm, right atrium (minor) >44 mm, inferior vena cava ≥21 mm, right pulmonary artery >20 mm, TAPSE <16 mm, systolic pulmonal artery pressure >40 mm Hg, and/or left ventricular eccentricity index <1. During a 24-month follow-up period, quarterly measurements of kidney function, NT-proBNP, and lactate dehydrogenase as well as a biannual echocardiographic check-up were performed. Results: High-output heart failure attributable to high-flow fistula was reported in 5 of 13 control patients (38.5%), whereas no patient in the intervention group presented with clinical and echocardiographic signs of high-output heart failure during the follow-up period. Thus, prophylactic ligature of high-flow fistulas avoided high-output heart failure in our patient population (p = 0.013). Three patients in the control group, however, had to undergo fistula ligature due to aneurysm formation (n = 2) and steal phenomenon (n = 1). Median NT-proBNP levels decreased from 317 ng/L pre-ligature to 223 ng/L post-ligature (p = 0.003). Serum creatinine levels did not significantly differ before and after AV fistula ligature (1.69 vs. 1.60 mg/dL, respectively, p = 0.059). Improvement of echocardiographic findings (e.g., a decrease in systolic pulmonary arterial pressure) was found in 7 of 8 ligature patients but did not reach statistical significance. Conclusion: Prophylactic ligature of high-flow AV fistulas after kidney transplantation can avoid high-output heart failure, and a more liberal approach to close AV fistulas might be justified.

Quality use of medicines in patients with chronic kidney disease

BackgroundChronic kidney disease (CKD) affects drug elimination and patients with CKD require appropriate adjustment of renally cleared medications to ensure safe and effective pharmacotherapy. The main objective of this study was to determine the extent of potentially inappropriate prescribing (PIP; defined as the use of a contraindicated medication or inappropriately high dose according to the kidney function) of renally-cleared medications commonly prescribed in Australian primary care, based on two measures of kidney function. A secondary aim was to assess agreement between the two measures.MethodsRetrospective analysis of routinely collected de-identified Australian general practice patient data (NPS MedicineWise MedicineInsight from January 1, 2013, to June 1, 2016; collected from 329 general practices). All adults (aged ≥18 years) with CKD presenting to general practices across Australia were included in the analysis. Patients were considered to have CKD if they had two or more estimated glomerular filtration rate (eGFR) recorded values < 60 mL/min/1.73m2, and/or two urinary albumin/creatinine ratios ≥3.5 mg/mmol in females (≥2.5 mg/mmol in males) at least 90 days apart. PIP was assessed for 49 commonly prescribed medications using the Cockcroft-Gault (CG) equation/eGFR as per the instructions in the Australian Medicines Handbook.ResultsA total of 48,731 patients met the Kidney Health Australia (KHA) definition for CKD and had prescriptions recorded within 90 days of measuring serum creatinine (SCr)/estimated glomerular filtration rate (eGFR). Overall, 28,729 patients were prescribed one or more of the 49 medications of interest. Approximately 35% (n = 9926) of these patients had at least one PIP based on either the Cockcroft-Gault (CG) equation or eGFR (CKD-EPI; CKD-Epidemiology Collaboration Equation). There was good agreement between CG and eGFR while determining the appropriateness of medications, with approximately 97% of the medications classified as appropriate by eGFR also being considered appropriate by the CG equation.ConclusionThis study highlights that PIP commonly occurs in primary care patients with CKD and the need for further research to understand why and how this can be minimised. The findings also show that the eGFR provides clinicians a potential alternative to the CG formula when estimating kidney function to guide drug appropriateness and dosing.

Progression of retinopathy and incidence of cardiovascular disease: findings from the Chronic Renal Insufficiency Cohort Study

PurposeChronic kidney disease (CKD) patients often develop cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess the association between progression of retinopathy and concurrent incidence of...

P1336PROPHYLACTIC CLOSING OF AV FISTULA PREVENTS HIGH OUTPUT HEART FAILURE - A SINGLE-CENTER RANDOMISED CONTROLLED TRIAL

Abstract Background and Aims AV fistulas are the favoured way ensuring a safe long-term access for patients with need for hemodialysis. Various studies, including a prior retrospective trial at our department, showed that AV fistulas are an additional burden on the cardiac-vascular system leading to frequent fistula closure in post-transplant patient. In literature, there is a widespread approach in dealing with high-flow fistulas in post-transplant patients with stable kidney function is reported. Method For this trial, patients with a stable graft function (min. 3 months post-transplant) and a brachial artery flow of min. 1,500 ml/min were recruited. Initially planned for multi-centric analysis, 28 patients were randomised in Innsbruck. Exclusion criteria were a pre-existing cardiac failure with ejection fraction less than 25%, NT-pro-BNP &amp;gt; 1,400 ng/l and NYHA score ≥ III. These patients were randomised in a 1:1 ratio in intervention group with immediate fistula ligature after randomisation, and control group with no surgical intervention. Patients in the control group had fistula ligature only if at least two criteria for ligature occurred. These criteria were selected in agreement with of the department for cardiology and encompassed dilation of right atrium, of inferior vena cava or of pulmonary artery, left-ventricular eccentricity index &amp;lt; 1 or a systolic pulmonary artery pressure of &amp;gt; 35 mmHg. The main endpoint high-output heart failure was defined by min. 2 echocardiographic criteria and signs of congestive heart failure such as worsening in NYHA score. A follow-up procedure of 24 months with quarterly measurements of kidney function, NT-proBNP and lactat dehydrogenase as well as a biannual echocardiographic check-up were performed. Statistics included paired t-test and Wilcoxon-rank test for median/mean comparison and chi-quadrat test for absolute frequency. Results The main endpoint high-output heart failure referable to high fistula flow was reached in five of 13 control patients (38.5%), whereas in the intervention group no study patient showed a worsening in clinical and echocardiographic signs to reach criteria for ligature. Prophylactic ligature of high-flow fistulas avoided right heart failure in our patient collective (p-value 0.013, x?test). Three patients had to undergo ligature due to off-study complications such as progressive aneurysma formation and steal phenomenon. One patient with dyspnoe preferred fistula ligature but was not fulfilling echocardiographic criteria. In total nine patients in the control group were assigned to fistula ligature. Matching all conducted fistula closures median NT-proBNP was 317 ng/l pre-ligature and 223 ng/l post-ligature (p 0.003, Wilcoxon). In total, 18 of 21 patients (excluding 2 patients with lack of data) showed falling NT-proBNP values. Creatinine levels showed a decrease from 1.69 mg/l to 1.60 mg/l (p-value 0.059, paired t-test). The intervention group included 14 patients with a gender ratio of 12 men to 2 women and a mean age of 52.5 years; the same age and gender distribution was seen in the control group. Fistula flow per m?body surface did not differ significantly (980 ml/min vs. 1000 ml/min). Echocardiographic findings showed improvement in ligature patients (e.g. a drop of sPAP in 7/8 ligature patients with available data) but did not reach statistical significance. Conclusion A prophylactic ligature of high-flow AV fistulas can avoid high-output heart failure and a more liberal approach to closure AV fistulas may be discussed in future.

A Randomized, Two-Arm Crossover, Controlled-Feeding Trial Comparing Effects of Pork and Chicken Diets on System Biology, Microbiome and Metabolome Changes in Healthy Adults

Abstract Objectives Majority of Americans practice a meat-based dietary lifestyle. We hypothesized that switching between chicken and pork meats within a nutritionally balanced diet would minimally impact gut microbiota composition, biogenic amine levels, and cardiometabolic health markers in healthy, non-diabetic adults. Methods 36 eligible men and women 50 years or older were randomized into chicken and pork meat groups consuming an isocaloric (1920 kcal/day) diet. The 10 day diet arms were separated by minimum of two weeks washout period. Following the current dietary guidelines for Americans, daily meals consisting of 156 g minimally-processed meat were provided to participants. Stool, urine and blood samples were collected before and after each diet phase followed by 16S targeted metagenomics and hydrophilic interaction chromatography analyses of metabolites. Proposed outcome measures were selected based on their ability to quickly respond to dietary changes and were assessed after overnight fasting. Linear mixed effect and regression models as well as other relevant approach were applied in R studio for data analyses. Results No differential outcome was observed between the chicken and pork diet groups for body weight and body composition features, lipid panel markers, blood pressures, inflammatory and oxidative stress markers, and kidney function measures (all, P &amp;gt; 0.05). Alpha diversity of the gut microbiome was not differential. A small number of OTU level differences in beta diversity measures were present (padj &amp;lt; 0.05). Plasma trimethyl amine-N-oxide, trimethylamine, carnitine, and choline levels were similar between the groups. Ongoing side-by-side examination of the impact of the two meats on an extended array of over hundred biogenic amine species may reveal novel changes. Several within group effects of the intervention were observed that were non-differential between the groups. Conclusions White meat is generally perceived as healthier than red meat. Our comprehensive data suggest minimal differential metabolic impact on the host and the gut microbiota when switched between chicken (white meat) and pork (red meat). Additional assessments are needed to reflect on the long-term metabolic outcome of routine red meat intake in healthy non-vegetarian individuals. Funding Sources National Pork Board and National Institute of Food and Agriculture.

A phase II/III randomized, blinded study of tozuleristide for fluorescence imaging detection during neurosurgical resection of pediatric primary central nervous system (CNS) tumors: PNOC012 (Pacific Pediatric Neuro-oncology Consortium).

TPS2575 Background: Tozuleristide (also known as BLZ-100 or Tumor Paint) is a fluorescent imaging drug designed to specifically label and accumulate in tumor tissue, thus enabling more precise surgical tumor resection intraoperatively. Tozuleristide achieves tumor targeting through the peptide portion of the molecule, a modified chlorotoxin peptide, and its imaging properties from a coupled near-infrared fluorescent dye, an indocyanine green. Tozuleristide has been studied in 4 Phase 1 studies, including a trial in pediatric brain cancer subjects. No tozuleristide SAEs or dose limiting toxicity were observed in the 97 subjects treated in the Phase 1 program at doses up to 30 mg in adults or 17.3 mg/m2 in pediatrics (Hansen S et al, WMIC 2018, P196). Eighty percent of pediatric subjects receiving tozuleristide had tumors considered fluorescence positive, including high and low grade glioma, ependymoma, and medulloblastoma. Methods: This study randomizes subjects in a 1:10 ratio to standard of care or tozuleristide arms. The primary efficacy objectives and endpoints are based on equivocal regions of tissue encountered in surgery. Prior to fluorescence assessment, the surgeon assesses the suspected nature of the tissue (more likely tumor/less likely tumor). Tissue specimens of equivocal regions are collected for blinded central pathology assessment. Sensitivity and specificity of the surgeon’s designation, fluorescence assessment, and ratios of surgeon to fluorescence assessments comprise the primary efficacy analyses. Tozuleristide is given as an IV bolus dose of 15 mg/m2 to pediatric subjects 1 to 36 hours prior to surgery. Subjects must have a MRI documented lesion consistent with a CNS tumor for which resection is planned. Measures of safety include adverse events, laboratory measures of hematology, liver and kidney function and changes in vital signs and ECGs. Pharmacokinetic blood samples are collected up to 3 hr post dose. Fluorescence imaging is assessed during surgery using an investigational “Canvas System” imaging device attached to a surgical microscope. Collected pathology specimens will also be subjected to further genetic, molecular and pathology studies, including fluorescence assessment of frozen tissue sections. SAEs and patient reported outcomes are collected for 3 months. The SMC for the study last reviewed the data for this study in July 2019 and recommended the trial continue as planned. Clinical trial information: NCT03579602 .

Dynamic 2-deoxy-2[18F] fluoro-D-glucose PET/MRI in human renal allotransplant patients undergoing acute kidney injury

Patients after solid organ kidney transplantation (KTX) often suffer from acute kidney injury (AKI). Parameters as serum creatinine indicate a loss of kidney function, although no distinction of the cause and prognosis can be made. Imaging tools measuring kidney function have not been widely in clinical use. In this observational study we evaluated 2-deoxy-2[18F] fluoro-D-glucose (FDG) PET/MRI in thirteen patients after KTX with AKI as a functional assessment of the graft. Twenty-four healthy volunteers served as control. General kidney performance (GKP), initial flow (IF) and renal response function (RF) were calculated by standardized uptake values (SUV) and time activity curves (TAC). The GKP measured for the total kidney and medulla was significantly higher in healthy patients compared to patients after KTX (p = 0.0002 and p = 0.0004, respectively), but no difference was found for the GKP of the cortex (p = 0.59). The IF in KTX patients correlated with renal recovery, defined as change in serum creatinine 10 days after PET/MRI (r = 0.80, p = 0.001). With regard to the RF, a negative correlation for tubular damage was found (r = −0.74, p = 0.004). In conclusion, parameters obtained from FDG PET/MRI showed a possible predictive feature for renal recovery in KTX patients undergoing AKI.

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.

Background As coronavirus disease 2019 (COVID-19) pandemic rages on, there is urgent need for identification of clinical and laboratory predictors for progression towards severe and fatal forms of this illness. In this study we aimed to evaluate the discriminative ability of hematologic, biochemical and immunologic biomarkers in patients with and without the severe or fatal forms of COVID-19. Methods An electronic search in Medline (PubMed interface), Scopus, Web of Science and China National Knowledge Infrastructure (CNKI) was performed, to identify studies reporting on laboratory abnormalities in patients with COVID-19. Studies were divided into two separate cohorts for analysis: severity (severe vs. non-severe and mortality, i.e. non-survivors vs. survivors). Data was pooled into a meta-analysis to estimate weighted mean difference (WMD) with 95% confidence interval (95% CI) for each laboratory parameter. Results A total number of 21 studies was included, totaling 3377 patients and 33 laboratory parameters. While 18 studies (n = 2984) compared laboratory findings between patients with severe and non-severe COVID-19, the other three (n = 393) compared survivors and non-survivors of the disease and were thus analyzed separately. Patients with severe and fatal disease had significantly increased white blood cell (WBC) count, and decreased lymphocyte and platelet counts compared to non-severe disease and survivors. Biomarkers of inflammation, cardiac and muscle injury, liver and kidney function and coagulation measures were also significantly elevated in patients with both severe and fatal COVID-19. Interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin were strong discriminators for severe disease. Conclusions Several biomarkers which may potentially aid in risk stratification models for predicting severe and fatal COVID-19 were identified. In hospitalized patients with respiratory distress, we recommend clinicians closely monitor WBC count, lymphocyte count, platelet count, IL-6 and serum ferritin as markers for potential progression to critical illness.

Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study.

The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population. We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro-B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A1c [Hb A1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016-2017; age 71-94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors. In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44-3.22]; no diabetes: OR, 2.31 [95%CI, 1.76-3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08-1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22-1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A1c (OR, 1.76 [95% CI, 1.22-2.54]), fructosamine (OR, 1.71 [95% CI, 1.19-2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03-2.03]) with PN were significant only among participants with diabetes. Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Acute Kidney Injury During Pregnancy Leads to Memory Impairment but not Anxiety in Rats with a History of Severe Preeclampsia/HELLP Syndrome

OBJECTIVEWomen with hypertensive conditions of pregnancy such as severe PE (preeclampsia)/HELLP (hemolysis, elevated liver enzyme, and low platelets) syndrome are at an increased risk of developing Acute Kidney Injury (AKI). New reports suggest that AKI during pregnancy can lead to the progression of chronic kidney disease (CKD). Between 27–67% of patients with CKD have evidence of depression, cognitive impairment and dementia that is directly linked to renal damage. Among these deficits are impairments in memory, orientation, reasoning and executive function. Incidentally, women with a history of hypertensive disorders with and without AKI have an increased risk of developing mental health and cognitive disorders. Using an established animal model of severe PE/HELLP syndrome we sought to test the hypothesis that AKI in the presence of severe PE/HELLP exacerbates cognitive impairment and anxiety in the postpartum period.STUDY DESIGNOn gestational day (GD) 12, sFlt‐1 and sEng was infused via mini‐osmotic pump into the abdominal space of timed‐pregnant Sprague Dawley rats to induce severe PE/HELLP. A subset of HELLP and normal pregnant (NP) rats underwent bilateral renal ischemia‐reperfusion surgery for 45 minutes on GD18 to induce AKI. All rats delivered on GD21, underwent behavioral testing between postpartum weeks (PPW) 11–13 and were euthanized at PPW15. FITC‐sinistrin which was used to assess glomerular filtration (measure of kidney function), blood pressure via carotid catheter, and urinary creatinine were all measured during PPW15. N’s per group = 7 –10.RESULTSCompared to NP rats (p=0.01), HELLP, NP+AKI and HELLP+AKI rats had significant impairments in learning and memory. HELLP rats spent significantly less time in the open arms of the zero maze compared to NP (p=0.04) and NP+AKI (p=0.04). The time in open arms for HELLP+AKI rats were significantly less, as well, compared to NP (p=0.01) and NP+AKI (p=0.01) rats. Kidney function significantly declined in H+AKI (p= 0.001) and NP+AKI (p=0.009) rats compared to NP rats, as well as HELLP+AKI (p=0.03) rats compared to HELLP rats. Urinary creatinine was significantly increased in HELLP+AKI rats compared to NP (p=0.03) and HELLP (p=0.007) rats as well as NP+AKI (p=0.01) rats to HELLP rats. Blood pressure was significantly increased in NP+AKI (p=0.003), HELLP+AKI (p=0.0007), and HELLP (p=0.02) rats compared to NP rats.CONCLUSIONThe results from this study suggest that HELLP during pregnancy impairs learning and memory and is exacerbated by AKI. Anxiety was only impaired in rats with a history of severe PE/HELLP with/without AKI suggesting that renal injury may lead to selective psychological impairments. Hypertension persisted into the post‐partum period for rats with a history of severe PE/HELLP. Renal function wasn’t recovered into the post‐partum period for rats with history of AKI.Support or Funding InformationThis work was sponsored by P20GM121334 and the UMMC Office of Sponsored Program.