Research Spotlight

McCullough, P.A., Rahimi, G. and Tecson, K.M. (2021). “Ambulatory Worsening of Renal Function in Heart Failure With Preserved Ejection Fraction.” J Am Coll Cardiol 77(9): 1222-1224.

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The emergence of new pharmacological therapies for heart failure (HF) patients, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor–neprilysin inhibitors, has improved the life expectancy of those living with this disease markedly. [No abstract; excerpt from article].

McCullough, P.A. (2021). “Anemia of cardiorenal syndrome.” Kidney Int Suppl (2011) 11(1): 35-45.

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Cardiorenal syndrome includes a spectrum of disorders of the kidneys and heart in which loss of function in one organ contributes to reduced function in the other organ. Cardiorenal syndrome is frequently complicated by comorbid anemia, which leads to reciprocal and progressive cardiac and renal deterioration. The triad of heart failure, chronic kidney disease (CKD), and anemia is termed cardiorenal anemia syndrome (CRAS). There are currently no evidence-based recommendations for managing patients with CRAS; however, the treatment of these patients is multifactorial. Not only must the anemia be controlled, but heart failure and kidney injury must be addressed, in addition to other comorbidities. Intravenous iron and erythropoiesis-stimulating agents are the mainstays of treatment for anemia of CKD, addressing both iron and erythropoiesis deficiencies. Since erythropoiesis-stimulating agent therapy can be associated with adverse outcomes at higher doses in patients with CKD and is not used in routine practice in patients with heart failure, treatment options for managing anemia in patients with CRAS are limited. Several new therapies, particularly the hypoxia-inducible factor-prolyl hydroxylase inhibitors, are currently under clinical development. The hypoxia-inducible factor-prolyl hydroxylase inhibitors have shown promising results for treating anemia of CKD in clinical trials and may confer benefits in patients with CRAS, potentially addressing some of the limitations of erythropoiesis-stimulating agents. Updated clinical practice guidelines for the screening and management of anemia in cardiorenal syndrome, in light of potential new therapies and clinical evidence, would improve the clinical outcomes of patients with this complex syndrome.

Mahmud, N., Asrani, S.K., Reese, P.P., Kaplan, D.E., Taddei, T.H., Nadim, M.K. and Serper, M. (2021). “Race Adjustment in eGFR Equations Does Not Improve Estimation of Acute Kidney Injury Events in Patients with Cirrhosis.” Dig Dis Sci Mar 24. [Epub ahead of print].

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BACKGROUND: Accuracy of glomerular filtration rate estimating (eGFR) equations has significant implications in cirrhosis, potentially guiding simultaneous liver kidney allocation and drug dosing. Most equations adjust for Black race, partially accounted for by reported differences in muscle mass by race. Patients with cirrhosis, however, are prone to sarcopenia which may mitigate such differences. We evaluated the association between baseline eGFR and incident acute kidney injury (AKI) in patients with cirrhosis with and without race adjustment. METHODS: We conducted a retrospective national cohort study of veterans with cirrhosis. Baseline eGFR was calculated using multiple eGFR equations including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both with and without race adjustment. Poisson regression was used to investigate the association between baseline eGFR and incident AKI events per International Club of Ascites criteria. RESULTS: We identified 72,267 patients with cirrhosis, who were 97.3% male, 57.8% white, and 19.7% Black. Over median follow-up 2.78 years (interquartile range 1.22-5.16), lower baseline eGFR by CKD-EPI was significantly associated with higher rates of AKI in adjusted models. For all equations this association was minimally impacted when race adjustment was removed. For example, removal of race adjustment from CKD-EPI resulted in a 0.1% increase in the association between lower eGFR and higher rate of AKI events per 15 mL/min/1.73 m(2) change (p < 0.001). CONCLUSIONS: Race adjustment in eGFR equations did not enhance AKI risk estimation in patients with cirrhosis. Further study is warranted to assess the impacts of removing race from eGFR equations on clinical outcomes and policy.

Mack, M.J., Fullerton, D.A. and Fann, J.I. (2021). “The Answers You Get Depend On the Questions You Ask: Insights from the Recent EXCEL Trial Controversy.” Ann Thorac Surg Mar 6;S0003-4975(21)00447-1. [Epub ahead of print].

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The SYYNTAX authors found that the impact of these “enzyme-driven events” on time-to-event curves and the composite endpoints was greater in the surgical cohort. PMIs after PCI were associated with 10-year mortality regardless of definition, whereas their impact on mortality after CABG was limited to 1 year, leading to the conclusion that “the rates of PMI are highly dependent on their definition, which affects time-to-event curves, composite endpoints, and their lethal prognostic relevance”. This serves to stress the importance of engagement of all investigators during the design phase of a trial because of the importance of the decisions at that time in determining trial outcomes. [No abstract; excerpt from article].

Luxton, J.J., McKenna, M.J., Lewis, A.M., Taylor, L.E., Jhavar, S.G., Swanson, G.P. and Bailey, S.M. (2021). “Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning.” J Pers Med 11(3).

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The ability to predict a cancer patient’s response to radiotherapy and risk of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measurements, to predict post radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.