Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification.

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.

Alterations in the Circulating Proteome Associated with Albuminuria.

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.

Testican-2 Is Associated with Reduced Risk of Incident ESKD.

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.

Proteomic cardiovascular risk assessment in chronic kidney disease.

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.

Proteins Associated with Risk of Kidney Function Decline in the General Population.

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 ß-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.

Renal Dysfunction in Heart Failure With Preserved Ejection Fraction: Insights From the RELAX Trial.

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/1.73m2) 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 (VO2) after adjustment for demographics, clinical comorbidities, exercise modality, ejection fraction, and chronotropic index (ß 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 (ß coefficient: -0.26, 95% CI: -0.68, 0.16, P = .22). Hemoglobin mediated 35% of the association between eGFR and peak VO2. Sildenafil therapy was independently associated with worsening eGFR over the trial (ß 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.

Application of echocardiographic data in patients with chronic kidney disease.

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.

Project ECHO Telementoring Intervention for Managing Chronic Pain in Primary Care: Insights from a Qualitative Study.

Objective: Family physicians in Canada receive little training in chronic pain management; concomitantly, they face increasing pressure to reduce their prescribing of opioids. Project ECHO Ontario Chronic Pain/Opioid Stewardship (ECHO) is a telementoring intervention for primary care practitioners that enhances their pain management skills. This qualitative study reports participants' experiences and assessment of ECHO. Design: An opportunistic sample of multidisciplinary primary care providers attending one of three residential weekend workshops participated in focus group discussions. Setting: University or hospital facilities in Toronto, Thunder Bay, and Kingston, Ontario, Canada. Subjects: Seventeen physicians and 20 allied health professionals. Methods: Six focus group discussions were conducted at three different sites during 2014 and 2015. Transcripts were analyzed using a qualitative-descriptive approach involving analytic immersion in the data, reflection, and achieving consensus around themes discerned from transcribed discussions. Results: Findings resolved into five main themes: 1) challenges of managing chronic pain in primary care; 2) ECHO participation and improvement in patient-provider interaction and participant knowledge; 3) the diffusion of knowledge gained through ECHO to participants' colleagues and patients; 4) ECHO participation generating a sense of community; and 5) disadvantages associated with participating in ECHO. Conclusions: Managing patients with chronic pain in primary care can be difficult, particularly in remote or underserved practices. Project ECHO offers guidance to primary care practitioners for their most challenging patients, promotes knowledge acquisition and diffusion, and stimulates the development of a "community of practice."

Simplified guideline for prescribing medical cannabinoids in primary care.

OBJECTIVE: To develop a clinical practice guideline for a simplified approach to medical cannabinoid use in primary care; the focus was on primary care application, with a strong emphasis on best available evidence and a promotion of shared, informed decision making. METHODS: The Evidence Review Group performed a detailed systematic review of 4 clinical areas with the best evidence around cannabinoids: pain, nausea and vomiting, spasticity, and adverse events. Nine health professionals (2 generalist family physicians, 2 pain management-focused family physicians, 1 inner-city family physician, 1 neurologist, 1 oncologist, 1 nurse practitioner, and 1 pharmacist) and a patient representative comprised the Prescribing Guideline Committee (PGC), along with 2 nonvoting members (pharmacist project managers). Member selection was based on profession, practice setting, location, and lack of financial conflicts of interest. The guideline process was iterative through content distribution, evidence review, and telephone and online meetings. The PGC directed the Evidence Review Group to address and provide evidence for additional questions as needed. The key recommendations were derived through consensus of the PGC. The guideline was drafted, refined, and distributed to a group of clinicians and patients for feedback, then refined again and finalized by the PGC. RECOMMENDATIONS: Recommendations include limiting medical cannabinoid use in general, but also outline potential restricted use in a small subset of medical conditions for which there is some evidence (neuropathic pain, palliative and end-of-life pain, chemotherapy-induced nausea and vomiting, and spasticity due to multiple sclerosis or spinal cord injury). Other important considerations regarding prescribing are reviewed in detail, and content is offered to support shared, informed decision making. CONCLUSION: This simplified medical cannabinoid prescribing guideline provides practical recommendations for the use of medical cannabinoids in primary care. All recommendations are intended to assist with, not dictate, decision making in conjunction with patients.

Soluble Guanylate Cyclase Stimulators: a Novel Treatment Option for Heart Failure Associated with Cardiorenal Syndromes?

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.

Associations of tissue Doppler imaging with NT-proBNP and hs-TnT: a pilot study in end-stage renal disease.

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.

Association of segmental wall motion abnormalities occurring during hemodialysis with post-dialysis fatigue.

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.

Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC).

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.

Lignes directrices simplifiées en matière de prescription de cannabinoïdes médicaux en soins de première ligne.

OBJECTIF: Élaborer des lignes directrices de pratique clinique visant à simplifier l'approche à l'emploi de cannabinoïdes à des fins médicales en soins de première ligne; le projet visait l'application en soins de première ligne, en insistant fortement sur les meilleures données probantes disponibles, et la promotion de la prise de décision éclairée et partagée. MÉTHODES: Le Groupe d'examen des données a effectué une revue systématique détaillée de 4 domaines cliniques dotés des meilleures données probantes en matière de cannabinoïdes : douleur, nausées et vomissements, spasticité et événements indésirables. Neuf professionnels de la santé (2 omnipraticiens, 2 médecins de famille spécialisés en gestion de la douleur, 1 médecin de famille en milieu urbain, 1 neurologue, 1 oncologue, 1 infirmière praticienne et 1 pharmacien) et une représentante de patients composaient le Comité des lignes directrices en matière de prescription (CLDP), de même que 2 membres sans droit de vote (pharmaciens gestionnaires de projet). Les membres ont été sélectionnés en fonction de leur profession, et de leur contexte et de leur lieu de pratique, de même qu'en fonction de l'absence d'un conflit d'intérêts de nature financière. Les lignes directrices sont le fruit d'un processus itératif incluant la distribution de contenu, l'examen minutieux des données probantes, et des rencontres téléphoniques et en ligne. Le CLDP a confié au Groupe d'examen des données la responsabilité de répondre aux questions additionnelles et de fournir des données probantes, au besoin. Les principales recommandations découlent d'un consensus au sein du CLDP. Les lignes directrices ont été rédigées, peaufinées et distribuées à un groupe de cliniciens et de patients aux fins de commentaires, puis ont été peaufinées à nouveau et finalisées par le CLDP. RECOMMANDATIONS: Les recommandations consistent à limiter la consommation générale de cannabinoïdes médicaux, mais elles décrivent aussi l'emploi restreint potentiel dans un petit sous-groupe de conditions de santé pour lesquelles des données probantes existent (douleur neuropathique, douleur en soins palliatifs et en fin de vie, nausées et vomissements induits par la chimiothérapie, et spasticité causée par la sclérose en plaques ou une lésion de la moelle épinière). L'article examine en détail d'autres points importants en matière de prescription, et offre du contenu étayant la prise de décision éclairée et partagée. CONCLUSION: Ces lignes directrices simplifiées en matière de prescription de cannabinoïdes médicaux offrent des recommandations pratiques quant à l'emploi de cannabinoïdes en soins de première ligne. Toutes les recommandations visent à contribuer à la prise de décision conjointement avec le patient et non à la dicter.