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Background: Cardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulat

Background and Aims: Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed., Methods: In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events); secondary outcomes included 4-year HF (183 events), HF with reduced ejection fraction (137 events), and HF with preserved ejection fraction (165 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multi-protein risk models was compared to the PCP-HF risk score., Results: Over 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10-5. After adjustment for covariates including N-terminal pro-B-type natriuretic peptide, 17 proteins remained associated at P < 1 × 10-5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C-statistic (95% confidence interval [CI]) for the 48-protein model in CRIC was 0.790 (0.735, 0.844) vs. 0.703 (0.644, 0.762) for the PCP-HF model (P = .001). C-statistic (95% CI) for the protein model in ARIC was 0.747 (0.707, 0.787)., Conclusions: Large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with kidney failure suffer high mortality, and we currently lack markers for risk stratification for these patients. We carried out a quality control study of a modified aptamer assay (SomaScan v.4.0) that measures ~ 5000 proteins, in preparation for a larger study using this platform in cohorts with kidney failure., Methods: Forty participants from the Cardiac, Endothelial Function and Arterial Stiffness in End-Stage Renal Disease (CERES study) were selected to analyze technical and short-term biological variability, orthogonal correlations and differential protein expression in plasma from patients who died during 2.5 year follow-up. Long-term (one year) variability was studied in 421 participants in the Chronic Renal Insufficiency Cohort. We evaluated 4849 aptamers (4607 unique proteins) using data formats including raw data and data formatted using Adaptive Normalization by Maximum Likelihood (ANML), an algorithm developed for SomaScan data in individuals with normal kidney function., Results: In ANML format, median[IQR] intra-assay coefficient of variation (CV) was 2.38%[1.76, 3.40] and inter-assay CV was 7.38%[4.61, 13.12]. Short-term within-subject CV was 5.76% [3.35, 9.72]; long-term CV was 8.71%[5.91, 13.37]. Spearman correlations between aptamer and traditional assays for PTH, NT-proBNP, FGF-23 and CRP were all > 0.7. Fold-change (FC) in protein levels among non-survivors, significant after Bonferroni correction, included SVEP1 (FC[95% CI] 2.14 [1.62, 2.82]), keratocan (1.74 [1.40, 2.15]) and LanC-like protein 1 (0.56 [0.45, 0.70]). Compared to raw aptamer data, technical and short-term biological variability in paired samples was lower in ANML-formatted data. ANML formatting had minimal impact on orthogonal correlations with traditional assays or the associations of proteins with the phenotype of mortality., Conclusions: SomaScan had excellent technical variability and low within-subject short-term variability. ANML formatting could facilitate comparison of biomarker results with other studies that utilize this format. We expect SomaScan to provide novel and reproducible information in patients with kidney failure on dialysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression., (© 2023. Springer Nature Limited.)

Aims: Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models., Methods and Results: Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis., Conclusion: In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population., Competing Interests: Conflict of interest P.G. serves on a medical advisory board to SomaLogic, Inc. for which he accepts no salary, honoraria, or any other financial incentives. J.C. is a scientific advisor to SomaLogic, Inc. S.L.S. serves as a consultant to Agios, FORMA Therapeutics, Global Blood Therapeutics, NOVARTIS, and ORIC Pharmaceuticals., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Significance Statement: We describe circulating proteins associated with albuminuria in a population of African American Study of Kidney Disease and Hypertension with CKD (AASK) using the largest proteomic platform to date: nearly 7000 circulating proteins, representing approximately 2000 new targets. Findings were replicated in a subset of a general population cohort with kidney disease (ARIC) and a population with CKD Chronic Renal Insufficiency Cohort (CRIC). In cross-sectional analysis, 104 proteins were significantly associated with albuminuria in the Black group, of which 67 of 77 available proteins were replicated in ARIC and 68 of 71 available proteins in CRIC. LMAN2, TNFSFR1B, and members of the ephrin superfamily had the strongest associations. Pathway analysis also demonstrated enrichment of ephrin family proteins., Background: Proteomic techniques have facilitated understanding of pathways that mediate decline in GFR. Albuminuria is a key component of CKD diagnosis, staging, and prognosis but has been less studied than GFR. We sought to investigate circulating proteins associated with higher albuminuria., Methods: We evaluated the cross-sectional associations of the blood proteome with albuminuria and longitudinally with doubling of albuminuria in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; mean GFR 46; median urine protein-to-creatinine ratio 81 mg/g; n =703) and replicated in two external cohorts: a subset of the Atherosclerosis Risk in Communities (ARIC) study with CKD and the Chronic Renal Insufficiency Cohort (CRIC)., Results: In cross-sectional analysis, 104 proteins were significantly associated with albuminuria in AASK, of which 67 of 77 available proteins were replicated in ARIC and 68 of 71 available proteins in CRIC. Proteins with the strongest associations included LMAN2, TNFSFR1B, and members of the ephrin superfamily. Pathway analysis also demonstrated enrichment of ephrin family proteins. Five proteins were significantly associated with worsening albuminuria in AASK, including LMAN2 and EFNA4, which were replicated in ARIC and CRIC., Conclusions: Among individuals with CKD, large-scale proteomic analysis identified known and novel proteins associated with albuminuria and suggested a role for ephrin signaling in albuminuria progression., (Copyright © 2023 by the American Society of Nephrology.)

Background: We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD)., Methods: Plasma samples were selected from 2 sources: (a) 24 participants from the Chronic Renal Insufficiency Cohort (CRIC) and (b) 49 patients from the Brigham and Women's Hospital-Kidney/Renal Clinic. We calculated intra-assay variability from both sources and examined short-term biological variability in samples from the Brigham clinic. We also measured correlations of aptamer measurements with traditional biomarker assays., Results: A total of 4656 unique proteins (4849 total aptamer measures) were analyzed in all samples. Median (interquartile range [IQR] intra-assay CV) was 3.7% (2.8-5.3) in CRIC and 5.0% (3.8-7.0) in Brigham samples. Median (IQR) biological CV among Brigham samples drawn from one individual on 2 occasions separated by median (IQR) 7 (4-14) days was 8.7% (6.2-14). CVs were independent of CKD stage, diabetes, or albuminuria but were higher in patients with systemic lupus erythematosus. Rho correlations between aptamer and traditional assays for biomarkers of interest were cystatin C = 0.942, kidney injury model-1 = 0.905, fibroblast growth factor-23 = 0.541, tumor necrosis factor receptors 1 = 0.781 and 2 = 0.843, P < 10-100 for all., Conclusions: Intra-assay and within-subject variability for SomaScan in the CKD setting was low and similar to assay variability reported from individuals without CKD. Intra-assay precision was excellent whether samples were collected in an optimal research protocol, as were CRIC samples, or in the clinical setting, as were the Brigham samples., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with eGFR and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of ESKD is unknown., Methods: Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n =703), the Chronic Renal Insufficiency Cohort (CRIC) study ( n =3196), and the Atherosclerosis Risk in Communities (ARIC) study ( n =4378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD., Results: Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (model 1) and model 1+mGFR or eGFR+comorbidities (model 2). In model 3 (model 2+proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were AASK (hazard ratio [HR]=0.84 [0.72 to 0.98], P =0.023), CRIC (HR=0.95 [0.89 to 1.02], P =0.14), ARIC (HR=0.54 [0.36 to 0.83], P =0.0044), and meta-analysis (HR=0.92 [0.86 to 0.98], P =0.0073)., Conclusions: Across three cohorts spanning >8000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD., (Copyright © 2022 by the American Society of Nephrology.)

Introduction: We lack cardiovascular (CV) markers for patients with end-stage renal disease (ESRD), and left atrial (LA) strain has not been studied definitively in this population. We examined associations of LA reservoir, conduit, and booster strain with major adverse cardiovascular events (MACE) among stable patients with ESRD on dialysis., Methods: One hundred and ninety patients in the Cardiac, Endothelial and Arterial Stiffness in ESRD study underwent echocardiography, including strain imaging. The primary outcome was 2-year composite non-fatal MACE or CV death. We performed Cox proportional hazards regression for LA strain measures, adjusting for demographics, comorbidities, left ventricular global longitudinal strain (LV GLS), E/e' and LA volume index., Findings: Mean ± SD LA reservoir strain was 24.1 ± 7.0%, and LA conduit strain 11.9 ± 5.1%. In age-adjusted analyses, lower LA reservoir strain and LA conduit strain were associated with the primary outcome (HR per 1-SD worsening LA strain parameter = 1.57 [95% CI 1.2-2.1], p = 0.003 and 1.68 [95% CI 1.2-2.3], p = 0.002, respectively). After adjusting for comorbidities, LA reservoir strain remained associated with the primary outcome and with deaths alone, and LA conduit strain with the primary outcome and hospitalizations alone (p < 0.05 for all). Associations of LA conduit strain were independent of LV GLS. Associations were stronger in participants with serum albumin <3.6 mg/dl (p for interaction 0.008)., Discussion: Left atrial reservoir strain and conduit strain were independently associated with MACE among patients with ESRD. Our study provides unique ascertainment of CV hospitalizations not attributed to missed dialysis, and LA conduit strain was a strong marker for this outcome., (© 2022 The Authors. Hemodialysis International published by Wiley Periodicals LLC on behalf of International Society for Hemodialysis.)

Background: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD., Methods: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR., Results: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and β -trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2)., Conclusions: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline., (Copyright © 2021 by the American Society of Nephrology.)

Objectives: Fibroblast growth factor (FGF)-23 is a key regulator of mineral metabolism and has been linked with left ventricular hypertrophy in animal models. Most existing epidemiologic studies evaluated a C-terminal FGF23 assay which measures both the intact (active) hormone and inactive fragments. The relationship of intact FGF23 with cause-specific mortality is unknown., Design: Prospective analyses of data from Health, Aging, & Body Composition (HABC) study., Setting: Community-living adults aged 70 to 79 years with longitudinal follow up., (© 2021 The American Geriatrics Society.)

Background: A better understanding of the pathophysiology involving coronary artery calcification (CAC) in patients on hemodialysis (HD) will help to develop new therapies. We sought to identify the differences in metabolomics profiles between patients on HD with and without CAC., Methods: In this case-control study, nested within a cohort of 568 incident patients on HD, the cases were patients without diabetes with a CAC score >100 ( n =51), and controls were patients without diabetes with a CAC score of zero ( n =48). We measured 452 serum metabolites in each participant. Metabolites and pathway scores were compared using Mann-Whitney U tests, partial least squares-discriminant analyses, and pathway enrichment analyses., Results: Compared with controls, cases were older (64±13 versus 42±12 years) and were less likely to be Black (51% versus 94%). We identified three metabolites in bile-acid synthesis (chenodeoxycholic, deoxycholic, and glycolithocholic acids) and one pathway (arginine/proline metabolism). After adjusting for demographics, higher levels of chenodeoxycholic, deoxycholic, and glycolithocholic acids were associated with higher odds of having CAC; comparing the third with the first tertile of each bile acid, the OR was 6.34 (95% CI, 1.12 to 36.06), 6.73 (95% CI, 1.20 to 37.82), and 8.53 (95% CI, 1.50 to 48.49), respectively. These associations were no longer significant after further adjustment for coronary artery disease and medication use. Per 1 unit higher in the first principal component score, arginine/proline metabolism was associated with CAC after adjusting for demographics (OR, 1.83; 95% CI, 1.06 to 3.15), and the association remained significant with additional adjustments for statin use (OR, 1.84; 95% CI, 1.04 to 3.27)., Conclusions: Among patients on HD without diabetes mellitus, chenodeoxycholic, deoxycholic, and glycolithocholic acids may be potential biomarkers for CAC, and arginine/proline metabolism is a plausible mechanism to study for CAC. These findings need to be confirmed in future studies.

In this review of the application of proteomics and metabolomics to kidney disease research, we review key concepts, highlight illustrative examples, and outline future directions. The proteome and metabolome reflect the influence of environmental exposures in addition to genetic coding. Circulating levels of proteins and metabolites are dynamic and modifiable, and thus amenable to therapeutic targeting. Design and analytic considerations in proteomics and metabolomics studies should be tailored to the investigator's goals. For the identification of clinical biomarkers, adjustment for all potential confounding variables, particularly GFR, and strict significance thresholds are warranted. However, this approach has the potential to obscure biologic signals and can be overly conservative given the high degree of intercorrelation within the proteome and metabolome. Mass spectrometry, often coupled to up-front chromatographic separation techniques, is a major workhorse in both proteomics and metabolomics. High-throughput antibody- and aptamer-based proteomic platforms have emerged as additional, powerful approaches to assay the proteome. As the breadth of coverage for these methodologies continues to expand, machine learning tools and pathway analyses can help select the molecules of greatest interest and categorize them in distinct biologic themes. Studies to date have already made a substantial effect, for example elucidating target antigens in membranous nephropathy, identifying a signature of urinary peptides that adds prognostic information to urinary albumin in CKD, implicating circulating inflammatory proteins as potential mediators of diabetic nephropathy, demonstrating the key role of the microbiome in the uremic milieu, and highlighting kidney bioenergetics as a modifiable factor in AKI. Additional studies are required to replicate and expand on these findings in independent cohorts. Further, more work is needed to understand the longitudinal trajectory of select protein and metabolite markers, perform transomics analyses within merged datasets, and incorporate more kidney tissue-based investigation., (Copyright © 2020 by the American Society of Nephrology.)

Background: Patients with heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) represent a high-risk phenotype. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial enrolled a high proportion of CKD participants, allowing investigation into differences in HFpEF by CKD status., Methods and Results: Among 212 participants, we investigated the associations of CKD with biomarkers, cardiac structure, and exercise capacity, and identified predictors of change in estimated glomerular filtration rate (eGFR) over trial follow-up. CKD participants (eGFR ≤60 mL/min/1.73m 2 ) were older, had more comorbidities, and had worse diastolic function. Lower eGFR was associated with higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide, aldosterone, uric acid, and biomarkers of fibrosis (P < .05 for all). Whereas lower eGFR was associated with worse peak oxygen consumption (VO 2 ) after adjustment for demographics, clinical comorbidities, exercise modality, ejection fraction, and chronotropic index (β coefficient per 1 SD decrease in eGFR: -0.61, 95% CI: -1.01, -0.22, P = .002), this association was attenuated after further adjustment for hemoglobin (β coefficient: -0.26, 95% CI: -0.68, 0.16, P = .22). Hemoglobin mediated 35% of the association between eGFR and peak VO 2 . Sildenafil therapy was independently associated with worsening eGFR over the trial (β coefficient: -2.79, 95% CI: -5.34, -0.24, P = .03)., Conclusion: Renal dysfunction in HFpEF is characterized by echocardiographic and biomarker profiles indicative of more advanced disease, and reduced hemoglobin is a strong mediator of the association between renal dysfunction and low exercise capacity. Sildenafil therapy was associated with worsening of renal function in RELAX., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Patients with end-stage renal disease (ESRD) have reduced endothelial function, but whether macro- and microvascular endothelial function correlate with baseline risk factors and cardiovascular outcomes in this population is not well understood., Methods: Among 146 participants of the Cardiac, Endothelial Function and Arterial Stiffness in ESRD (CERES) study, we evaluated macro- and microvascular endothelial dysfunction as flow-mediated dilation (FMD) and velocity time integral (VTI), respectively. We examined cross-sectional correlations of baseline characteristics, inflammatory and cardiac markers with FMD and VTI. We followed participants for the composite outcome of cardiovascular hospitalization or all-cause death over fourteen months. Cox survival analyses were adjusted for demographics, comorbidities, medications, systolic blood pressure, inflammation, high-sensitivity troponin T (hs-TnT), and N-terminal pro B-type natriuretic peptide (NT-proBNP)., Findings: Impaired VTI was associated with older age and Black race (P < 0.05), as well as female gender, atherosclerosis, and hemodialysis (as opposed to peritoneal dialysis) (P < 0.2). Myocardial injury, measured as hs-TnT, inflammatory markers and NT-proBNP correlated with impaired VTI. In unadjusted analyses, VTI was significantly associated with the composite outcome (HR per SD VTI 0.65 [95%CI 0.45, 0.95]), but FMD was not (HR per SD FMD 0.97 [95%CI 0.69, 1.4]). When VTI was calculated as the ratio of (hyperemic VTI-baseline VTI)/baseline VTI, its association with the outcome persisted after multivariable adjustment., Discussion: Microvascular function was associated with higher rates of cardiovascular hospitalizations and all-cause mortality among individuals with ESRD on dialysis. Further research is needed to learn whether novel therapies that target microvascular endothelial function could improve outcomes in this high-risk population., (© 2019 International Society for Hemodialysis.)

Background: Patients with chronic kidney disease (CKD) are at increased risk for heart failure (HF). We aimed to investigate differences in proteins associated with HF hospitalizations among patients with and without CKD in the Heart and Soul Study., Methods and Results: We measured 1068 unique plasma proteins from baseline samples of 974 participants in The Heart and Soul Study who were followed for HF hospitalization over a median of 7 years. We sequentially applied forest regression and Cox survival analyses to select prognostic proteins. Among participants with CKD, four proteins were associated with HF at Bonferroni-level significance (p<2.5x10(-4)): Angiopoietin-2 (HR[95%CI] 1.45[1.33, 1.59]), Spondin-1 (HR[95%CI] 1.13 [1.06, 1.20]), tartrate-resistant acid phosphatase type 5 (HR[95%CI] 0.65[0.53, 0.78]) and neurogenis locus notch homolog protein 1 (NOTCH1) (HR[95%CI] 0.67[0.55, 0.80]). These associations persisted at p<0.01 after adjustment for age, estimated glomerular filtration and history of HF. CKD was a significant interaction term in the associations of NOTCH1 and Spondin-1 with HF. Pathway analysis showed a trend for higher representation of the Cardiac Hypertrophy and Complement/Coagulation pathways among proteins prognostic of HF in the CKD sub-group., Conclusions: These results suggest that markers of heart failure differ between patients with and without CKD. Further research is needed to validate novel markers in cohorts of patients with CKD and adjudicated HF events., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: Patients with chronic kidney disease (CKD) are at a high risk for cardiovascular events and mortality, particularly heart failure. Echocardiography is the most commonly used diagnostic imaging modality for heart failure. The purpose of this review is to summarize recent literature that demonstrates how echocardiography may be used to define cardiac structure and function in the CKD population and to identify echocardiographic abnormalities that have utility in predicting clinical outcomes in this population., Recent Findings: Recent studies have highlighted the high prevalence of echocardiographic abnormalities in this population, and the challenge of identifying specific echocardiographic criteria for heart failure. There have been advances in application of strain echocardiography for evaluating systolic function in patients with normal ejection fraction, understanding pulmonary hypertension and identifying echocardiographic correlates of albuminuria. Additional studies have focused on diastolic dysfunction, left ventricular hypertrophy and echocardiographic findings in children with CKD., Summary: Recent studies demonstrate the utility of echocardiography in characterizing heart structure and function and in providing potential tools for risk stratification in the high-risk CKD population.

Introduction: Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and urinary kidney injury molecule-1 (uKIM-1) are established markers of subclinical acute kidney injury. In persons with reduced estimated glomerular filtration rate (eGFR) and albuminuria who are at high risk for end-stage renal disease (ESRD) and death, the associations of these urinary markers with incident ESRD or death is an area of active investigation., Methods: Among 1472 black and white participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study with eGFR ≤60 ml/min per 1.73 m 2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin, 2012) and albumin-to-creatinine ratio (ACR) ≥30 mg/g, we evaluated the associations of baseline uNGAL and uKIM-1 with progression to ESRD and all-cause death. Cox models were sequentially adjusted for urinary creatinine, traditional risk factors, C-reactive protein, ACR, and eGFR., Results: There were 257 ESRD events and 819 deaths over a median follow-up of 5.7 and 6.5 years, respectively. In demographic adjusted models, higher levels of uNGAL were associated with increased risk of ESRD and death, but these associations were attenuated in fully adjusted models including baseline eGFR for both ESRD (hazard ratio [HR] = 1.06 per doubling, 95% confidence interval [CI] 0.98-1.14) and death (HR = 1.04, 95% CI = 1.00-1.08). Higher levels of uKIM-1 were associated with increased risk of ESRD and death in demographic-adjusted models, and although attenuated in fully adjusted models, remained statistically significant for both ESRD (HR = 1.24 per doubling, 95% CI = 1.08-1.42) and death (HR = 1.10, 95% CI =1.03-1.19)., Conclusion: In this cohort of high-risk patients with baseline eGFR ≤60 ml/min per 1.73 m 2 and albuminuria, renal tubular injury is associated with higher mortality and progression to ESRD. Further studies are necessary to investigate the mechanism underlying this increased risk.

Introduction: Recent studies suggest that women with end-stage renal disease (ESRD) may have higher rates of mortality than men, but it is unknown whether sex differences in vascular function explain this disparity. The cardiac, endothelial function, and arterial stiffness in ESRD (CERES) study is an ongoing, prospective observational study designed to investigate vascular function, myocardial injury, and cardiovascular outcomes in ESRD., Methods: Among 200 CERES participants (34% women), we evaluated arterial wave reflections as augmentation index normalized to a heart rate of 75 (AIx75), arterial stiffness as pulse wave velocity, and macro- and microvascular endothelial dysfunction as flow-mediated dilation and velocity time integral (VTI). Over a median of 14 months, participants were followed for the composite outcome of cardiovascular hospitalization or all-cause death., Findings: Women had higher arterial wave reflection (Mean, SD AIx75 30% ± 9% for women vs. 21% ± 10% for men; P < 0.001) and worse microvascular function (VTI 55 ± 30 cm for women vs. 70 ± 27 cm for men; P = 0.007). After multivariable adjustment, female sex remained associated with a 0.5-SD higher AIx75 (95% CI [0.01, 0.9]) and 0.3-SD lower VTI (95%CI [0.1, 0.7]). Women experienced higher adjusted rates of the composite outcome (HR 2.5; 95%CI [1.1, 5.6]; P = 0.03), and further adjustment for arterial wave reflection attenuated this risk., Discussion: Vascular dysfunction may partly explain the association of female sex with higher cardiovascular risk and mortality in patients with ESRD. Further studies are needed to explore whether sex differences in vascular function predict long-term outcomes, and whether hormonal or inflammatory factors explain these associations., (© 2017 International Society for Hemodialysis.)

Background and Objectives: Heart failure is the most frequent cardiac complication of CKD. Left ventricular hypertrophy is common and develops early in CKD, but studies have not adequately evaluated the association of left ventricular mass index with heart failure incidence among men and women with CKD., Design, Setting, Participants, & Measurements: We evaluated echocardiograms of 2567 participants without self-reported heart failure enrolled in the Chronic Renal Insufficiency Cohort Study. Two-dimensional echocardiograms were performed at the year 1 study visit and interpreted at a central core laboratory. Left ventricular mass index was calculated using the linear method, indexed to height 2.7 , and analyzed using sex-specific quartiles. The primary outcomes of incident heart failure and all-cause mortality were adjudicated over a median of 6.6 (interquartile range, 5.7-7.6) years., Results: Among 2567 participants, 45% were women, and 54% were nonwhite race; mean (SD) age was 59±11 years old, and mean eGFR was 44±17 ml/min per 1.73 m 2 . During a median follow-up period of 6.6 years, 262 participants developed heart failure, and 470 participants died. Compared with participants in the first quartile of left ventricular mass index, those in the highest quartile had higher rates of incident heart failure (hazard ratio, 3.96; 95% confidence interval, 1.96 to 8.02) and mortality (hazard ratio, 1.86; 95% confidence interval, 1.22 to 2.85), even after adjustment for B-type natriuretic peptide, troponin T, mineral metabolism markers, and other cardiovascular disease risk factors. Those in the lowest quartile of ejection fraction had higher rates of incident heart failure (hazard ratio, 3.01; 95% confidence interval, 1.94 to 4.67) but similar mortality rates (hazard ratio, 1.18; 95% confidence interval, 0.89 to 1.57) compared with those in the highest quartile. Diastolic dysfunction was not significantly associated with heart failure or death., Conclusions: Among persons with CKD and without history of cardiovascular disease, left ventricular mass index is strongly associated with incident heart failure, even after adjustment for major cardiovascular risk factors and biomarkers., (Copyright © 2016 by the American Society of Nephrology.)

Patients with end-stage renal disease (ESRD) suffer high rates of heart failure and cardiovascular mortality, and we lack a thorough understanding of what, if any, modifiable factors contribute to cardiac dysfunction in these high-risk patients. To evaluate endothelial function as a potentially modifiable cause of cardiac dysfunction in ESRD, we investigated cross-sectional associations of macro- and microvascular dysfunction with left and right ventricular dysfunction in a well-controlled ESRD cohort. We performed comprehensive echocardiography, including tissue Doppler imaging and speckle-tracking echocardiography of the left and right ventricle, in 149 ESRD patients enrolled in an ongoing prospective, observational study. Of these participants, 123 also underwent endothelium-dependent flow-mediated dilation of the brachial artery (macrovascular function). Microvascular function was measured as the velocity time integral of hyperemic blood flow after cuff deflation. Impaired flow-mediated dilation was associated with higher left ventricular mass, independently of age and blood pressure: per 2-fold lower flow-mediated dilation, left ventricular mass was 4.1% higher (95% confidence interval, 0.49-7.7; P=0.03). After adjustment for demographics, blood pressure, comorbidities, and medications, a 2-fold lower velocity time integral was associated with 9.5% higher E/e' ratio (95% confidence interval, 1.0-16; P=0.03) and 6.7% lower absolute right ventricular longitudinal strain (95% confidence interval, 2.0-12; P=0.003). Endothelial dysfunction is a major correlate of cardiac dysfunction in ESRD, particularly diastolic and right ventricular dysfunction, in patients whose volume status is well controlled. Future investigations are needed to determine whether therapies targeting the vascular endothelium could improve cardiac outcomes in ESRD., (© 2016 American Heart Association, Inc.)

Heart failure in the setting of chronic kidney disease (CKD) is an increasingly common scenario and carries a poor prognosis. Clinicians lack tools for primary or secondary heart failure prevention in patients with cardiorenal syndromes. In patients without CKD, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) and statins mitigate cardiovascular risk in large part due to salutary effects on the endothelium. In the setting of CKD, use of these therapies is limited by adverse effects of hyperkalemia in pre-dialysis CKD (ACE-I/ARB), or potential increased risk of stroke in end-stage renal disease (statins). The soluble guanylate cyclase (sGC) stimulators are a novel class of medications that promote endothelial and myocardial function with no known risk of hyperkalemia or stroke. In this review, we discuss the evidence emerging from recent clinical trials of sGC stimulators in pulmonary hypertension and heart failure, the diseased pathways involved in cardiorenal syndromes likely to be restored by sGC stimulators, and several strategies for designing future clinical trials of cardiorenal syndromes that might shorten the timeline for discovery and approval of effective cardiovascular therapies in these high-risk patients.

Aims: Chronic kidney disease (CKD) is associated with worse outcomes in heart failure with preserved ejection fraction (HFpEF). Whether this association is due the effect of CKD on intrinsic abnormalities in cardiac function is unknown. We hypothesized that CKD is independently associated with worse cardiac mechanics in HFpEF., Methods and Results: We prospectively studied 299 patients enrolled in the Northwestern University HFpEF Program. Using the creatinine-based CKD-Epi equation to calculate estimated glomerular filtration rate (eGFR), study participants were analysed by CKD status (using eGFR <60 mL/min/1.73 m(2) to denote CKD). Indices of cardiac mechanics (longitudinal strain parameters) were measured using speckle-tracking echocardiography. Using multivariable-adjusted linear and Cox regression analyses, we determined the association between CKD and echocardiographic parameters and clinical outcomes (cardiovascular hospitalization or death). Of 299 study participants, 48% had CKD. CKD (dichotomous variable) and reduced eGFR (continuous variable) were both associated with worse cardiac mechanics indices including left atrial (LA) reservoir strain, LV longitudinal strain, and right ventricular free wall strain even after adjusting for potential confounders, including co-morbidities, EF, and volume status. For example, for each 1-SD decrease in eGFR, LA reservoir strain was 3.52% units lower (P < 0.0001) after multivariable adjustment. Reduced eGFR was also associated with worse outcomes [adjusted hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.61 per 1-SD decrease in eGFR; P = 0.039]. The association was attenuated after adjustment for indices of cardiac mechanics (P = 0.064)., Conclusion: In HFpEF, CKD is independently associated with worse cardiac mechanics, which may explain why HFpEF patients with CKD have worse outcomes., Trial Registration: NCT01030991., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Diastolic dysfunction is common and associated with higher mortality in the end-stage renal disease (ESRD) population. E/E', a measure derived from tissue Doppler imaging (TDI), is a correlate of left ventricular (LV) filling pressures. E/E' may be viewed as a confirmatory marker of diastolic dysfunction, but it is not routinely used to quantify diastolic dysfunction. Whether E/E' is associated with N-terminal brain natriuretic peptide (NT-proBNP) or high sensitivity troponin T (hs-TnT) in this population is not known., Methods: We performed echocardiograms and serology prior to the 2nd or 3rd dialysis session of the week on 35 chronic hemodialysis patients. We compared TDI parameters (E/E' and E' alone), traditional categories of diastolic function (normal, impaired, pseudonormal or restrictive), and ejection fraction (EF) as potential predictors of the outcomes NT-proBNP and hs-TnT., Results: Higher E/E' was associated with higher NT-proBNP (rho 0.48, P = 0.004) and hs-TnT (rho 0.37, P = 0.03). EF did not have statistically significant associations with NT-proBNP (rho -0.2, P = 0.4) or hs-TnT (rho -0.24, P = 0.16). As compared to patients with normal diastolic function, those with impaired or pseudonormal filling patterns did not have significantly different levels of NT-proBNP (P = 0.46); patients in traditional categories of worsened diastolic function actually had lower hs-TnT (P = 0.02). The associations of E/E' with higher NT-proBNP and hs-TnT persisted after multivariate adjustment for EF, LV mass, and volume status., Conclusions: Tissue Doppler imaging may be more useful in evaluating cardiac function than traditional measures of diastolic dysfunction in the ESRD population., (© 2014, Wiley Periodicals, Inc.)

Patients who demonstrate worsening of cardiac wall motion (WM) during hemodialysis have higher 1-year mortality. We sought to identify risk factors for dialysis-induced WM abnormalities. Additionally, we examined the effects of hemodialysis on other parameters of cardiac function. Forty patients underwent echocardiography directly before dialysis and during the last hour of dialysis (79 dialysis sessions). Candidate predictors for intradialytic worsening of WM included age, a history of heart failure (HF) or coronary artery disease, changes in blood pressure or heart rate, high sensitivity cardiac troponin T and N-terminal brain natriuretic peptide. Among 40 patients, WM worsened segmentally in eight patients (20%), worsened globally in one patient (3%), and improved segmentally in four patients (10%). Diastolic function worsened in 44% of patients, and left ventricular ejection fraction was largely unchanged during dialysis. The case of globally worsened WM occurred in the setting of intradialytic hypertension in a patient without HF. Surprisingly, history of coronary artery disease, hemodynamics, and serologic factors were not associated with worsened segmental WM during dialysis. After adjustment for history of coronary artery disease and other cardiac risk factors, patients with a history of HF had a threefold higher risk of worsening segmental WM during dialysis (RR 3.1, 95% CI [1.1, 9], p = 0.04). In conclusion, patients with a history of clinical HF were at higher risk of intradialytic worsening of segmental WM. Further studies are needed to determine the mechanism of this association and whether cardioprotective medications could ameliorate this adverse cardiac effect of hemodialysis., (© 2013 International Society for Hemodialysis.)

Background: Cardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulatory patients. We sought to determine the distribution and predictors of hs-TnT in CKD patients without overt cardiovascular disease (CVD)., Methods: We studied 2464 participants within the multi-ethnic Chronic Renal Insufficiency Cohort (CRIC) who did not have self-reported CVD. We considered renal and non-renal factors as potential determinants of hs-TnT, including demographics, comorbidities, left ventricular (LV) mass, serologic factors, estimated glomerular filtration rate (eGFR) and albumin to creatinine ratio., Results: Hs-TnT was detectable in 81% of subjects, and the median (IQR) hs-TnT was 9.4 pg/ml (4.3-18.3). Analysis was performed using Tobit regression, adjusting for renal and non-renal factors. After adjustment, lower eGFR was associated with higher expected hs-TnT; participants with eGFR < 30 ml/min/1.73 m(2) had 3-fold higher expected hs-TnT compared to subjects with eGFR > 60. Older age, male gender, black race, LV mass, diabetes and higher blood pressure all had strong, independent associations with higher expected hs-TnT., Conclusions: Knowledge of the determinants of hs-TnT in this cohort may guide further research on the pathology of heart disease in patients with CKD and help to stratify sub-groups of CKD patients at higher cardiovascular risk.

Background: Post-dialysis fatigue (PDF) is a common, debilitating symptom that remains poorly understood. Cardiac wall motion abnormalities (WMAs) may worsen during dialysis, but it is unknown whether WMA are associated with PDF., Methods: Forty patients were recruited from University of California San Francisco-affiliated dialysis units between January 2010 and February 2011. Participants underwent echocardiograms before and during the last hour of 79 dialysis sessions. Myocardial segments were graded 1-4 by a blinded reviewer, with four representing the worst WMA, and the segmental scores were summed for each echocardiogram. Patients completed questionnaires about their symptoms. Severe PDF (defined as lasting >2 h after dialysis) was analysed using a generalized linear model with candidate predictors including anemia, intradialytic hemodynamics and cardiac function., Results: Forty-four percent of patients with worsened WMA (n=9) had severe PDF, compared with 13% of patients with improved or unchanged WMA (P = 0.04). A one-point increase in the WMA score during dialysis was associated with a 10% higher RR of severe PDF [RR: 1.1, 95% CI (1.1, 1.2), P < 0.001]. After multivariable adjustment, every point increase in the WMA score was associated with a 2-fold higher risk of severe PDF [RR: 1.9, 95% CI (1.4, 2.6), P < 0.001]. History of depression was associated with severe PDF after adjustment for demographics and comorbidities [RR: 3.4, 95% CI (1.3, 9), P = 0.01], but anemia, hemodynamics and other parameters of cardiac function were not., Conclusions: Although cross-sectional, these results suggest that some patients may experience severe PDF as a symptom of cardiac ischemia occurring during dialysis.

Objective: To estimate the prevalence of type 2 diabetes mellitus (DM2) in 9-18 year-old children with diabetic ketoacidosis (DKA) and to describe the presenting biochemical characteristics and response to standardized DKA treatment., Methods: Data were collected from a consecutive sample of 9-18 year-old children presenting with DKA. DKA was defined as hyperglycemia and ketosis with an initial pH <7.3, or bicarbonate <15 mmol/l. Patients were classified as having DM2 if they had negative autoantibody status and normal or elevated fasting C-peptide., Results: The prevalence of DM2 in patients with DKA was 13.0% (6.1-23.3%). There was no significant difference in the presenting pH (7.14 vs 7.15), but blood glucose was higher (735 vs 587 mg/dl) in patients with DM2, than in patients with type 1 DM (DM1). The duration of insulin infusion until resolution of acidosis (17.3 vs 13.2 h) and intensive care unit stay (2.4 vs 1.6 days) were longer in patients with DM2. Seven of the nine patients with DM2 did not require insulin at 1-year follow-up., Conclusions: Children with DM2 can present with DKA and constitute a significant percentage in the above 9-year age group. The need for insulin must be carefully re-evaluated as DKA resolves in these patients. Adolescents with DM2 and their families need to be educated about DKA.

Lactoferrin and lysozyme are important antimicrobial compounds of airway surface liquid, derived predominantly from serous cells of submucosal glands but also from surface epithelium. Here we compared release of these compounds from the following human cell cultures: primary cultures of tracheal epithelium (HTE), Calu-3 cells (a lung adenocarcinoma cell line frequently used as a model of serous gland cells), 16HBE14o- cells (an SV40 transformed line from airway surface epithelium), T84 cells (a colon carcinoma cell line), and human foreskin fibroblasts (HFF). For lysozyme, baseline secretory rates were in the order Calu-3 > 16HBE14o- > HTE T84 > HFF = 0; for lactoferrin, the only cell type showing measurable release was HTE; for mucus, HTE > Calu-3 > 16HBE14o- T84 > HFF = 0. A wide variety of neurohumoral agents and inflammatory stimuli was without effect on lactoferrin and lysozyme release from HTE or Calu-3 cells, although forskolin did stimulate secretion of water and lysozyme from Calu-3 cells. However, the concentration of lysozyme in the forskolin-induced secretions was much less than in airway gland secretions. Thus our data cast doubt on the utility of Calu-3 cells as a model of airway serous gland cells but do suggest that HTE could prove highly suitable for studies of mucin synthesis and release.