Peter A. McCullough M.D.

McCullough, P. A., E. Bennett-Guerrero, L. S. Chawla, T. Beaver, R. L. Mehta, B. A. Molitoris, A. Eldred, G. Ball, H. J. Lee, M. T. Houser and S. Khan (2016). “Abt-719 for the prevention of acute kidney injury in patients undergoing high-risk cardiac surgery: A randomized phase 2b clinical trial.” J Am Heart Assoc 5(8): 1-11.

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BACKGROUND: Patients undergoing cardiac surgeries with cardiopulmonary bypass (on-pump) have a high risk for acute kidney injury (AKI). We tested ABT-719, a novel alpha-melanocyte-stimulating hormone analog, for prevention of AKI in postoperative cardiac surgery patients. METHODS AND RESULTS: This phase 2b randomized, double-blind, placebo-controlled trial included adult patients with stable renal function undergoing high-risk on-pump cardiac surgery in the United States and Denmark. Participants received placebo (n=61) or cumulative ABT-719 doses of 800 (n=59), 1600 (n=61), or 2100 mug/kg (n=59). Primary outcome was development of AKI based on Acute Kidney Injury Network (AKIN) criteria, measured utilizing preoperative creatinine value and maximum value within 48 hours and urine output within the first 42 hours postsurgery. Secondary outcomes included incidence of AKI based on maximal changes from baseline in novel AKI biomarkers over a 72-hour period after clamp release and length of intensive care unit stays through 90 days postsurgery. A total of 65.5%, 62.7%, and 69.6% of patients in the 800-, 1600-, and 2100-mug/kg groups, respectively, developed AKI (stages 1, 2, and 3 combined) versus 65.5% in the placebo group (for each pair-wise comparison with placebo, P=0.966, 0.815, and 0.605, respectively). Adverse events occurred at a similar rate in all treatment groups. CONCLUSIONS: ABT-719 treatment did not lower AKI incidence using AKIN criteria, influence the elevations of novel biomarkers, or change 90-day outcomes in patients after cardiac surgery.

Fallahzadeh, M. K. and P. A. McCullough (2015). “Cardiac electromechanical abnormalities in hemodialysis patients: Indicators of cardiomyopathy and future risk.” Am J Nephrol 42(3): 237-238.

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Cardiovascular diseases (CVDs) are more common in chronic kidney disease and end-stage renal disease (ESRD) patients as compared with general population and are a major of cause of morbidity and mortality in this population [1,2]. CVD accounts for approximately 50% of mortality in ESRD patients. In addition to the increased chance of coronary artery disease, the chance of developing arrhythmic events and sudden cardiac death is also higher in ESRD patients [3,4]. The underlying pathophysiology behind this increased chance of arrhythmic event in hemodialysis patients is not clearly understood. Previous studies have shown that hemodialysis patients have lower left ventricular ejection fraction and higher atrial diameters as compared with general population [5,6,7]. Using the timing of electrocardiogram and tissue Doppler on echocardiography, the time from electrical activation to muscular contraction can be assessed. Atrial electromechanical delay (AEMD) times have been reported to be longer in ESRD patients and have been shown to improve after each hemodialysis session [6,7,8]. Additionally, prolonged atrial conduction times are considered as predisposing factors for atrial fibrillation [9]. In this issue of Journal, Turkmen et al. [10] from Turkey have compared the cardiac electromechanical characteristics and biochemical profile of 60 hemodialysis patients versus 44 healthy controls. They also followed the hemodialysis patients for 2 years and compared the characteristics of 19 patients who died within this 2-year period versus 41 living hemodialysis patients.

Zhang, J. and P. A. McCullough (2016). “Lipoic acid in the prevention of acute kidney injury.” Nephron 134(3): 133-140.

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Hypoxia, reactive oxygen species (ROS) and oxidative stress contribute to contrast-induced acute kidney injury (CI-AKI) and ischemic reperfusion injury (IRI) in the kidney and heart. Imbalance between the increased formation of ROS by hypoxia in the cardiac and renal tissue and the low availability of endogenous antioxidants is a common cause of cellular and tissue damage. Therefore, a strategy to inhibit ROS generation or to scavenger free radicals becomes an important intervention to prevent CI-AKI and myocardial IRI. Evidence has shown that a naturally occurring cellular antioxidant lipoic acid (LA) (1,2-dithilane-3-pentanoic acid) acts as a free radical scavenger of ROS and reactive nitrogen oxide species for cardioprotection and renoprotection. The mechanisms whereby LA exerts its protective effects are not entirely understood, but may be related to the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway and the PI3-kinase/Akt pathways. This review will provide the current information of LA as an exogenous antioxidant for cardioprotection and renoprotection, with emphasis on antioxidant functions of LA and multiple signaling pathways underlying protective effects of LA on CI-AKI as well as cardiac and renal IRI.

Grodzinsky, A., A. Goyal, K. Gosch, P. A. McCullough, G. C. Fonarow, A. Mebazaa, F. A. Masoudi, J. A. Spertus, B. F. Palmer and M. Kosiborod (2016). “Prevalence and prognosis of hyperkalemia in patients with acute myocardial infarction.” Am J Med 129(8): 858-865.

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BACKGROUND: Hyperkalemia is common and potentially dangerous in hospitalized patients; its contemporary prevalence and prognostic importance after acute myocardial infarction are not well described. METHODS: In 38,689 consecutive patients with acute myocardial infarction from the Cerner Health Facts database, we evaluated the association between maximum in-hospital potassium levels and in-hospital mortality. Patients were stratified by dialysis status and grouped by maximum potassium as follows: <5 mEq/L, 5 to <5.5 mEq/L, 5.5 to <6.0 mEq/L, 6.0 to <6.5 mEq/L, and >/=6.5 mEq/L. Multivariable logistic regression was used to adjust for multiple patient and site characteristics. The relationship between the number of hyperkalemic values and the in-hospital mortality was evaluated. RESULTS: Of 38,689 patients with acute myocardial infarction, 886 were on dialysis. The rate of hyperkalemia (maximum potassium >/=5.0 mEq/L) was 22.6% in patients on dialysis and 66.8% in patients not on dialysis. Moderate to severe hyperkalemia (maximum potassium >/=5.5 mEq/L) occurred in 9.8% of patients. There was a steep increase in mortality with higher maximum potassium levels. In-hospital mortality exceeded 15% once maximum potassium was >/=5.5 mEq/L regardless of dialysis status. The relationship between higher maximum potassium and increased mortality risk persisted after multivariable adjustment. In addition, patients with a greater number of hyperkalemic values (vs a single value) experienced higher in-hospital mortality. CONCLUSIONS: Hyperkalemia is common in patients who are hospitalized with acute myocardial infarction. Higher maximum potassium levels and number of hyperkalemic events are associated with a steep mortality increase, with higher risks for adverse outcomes observed even at mild levels of hyperkalemia. Whether more intensive management of hyperkalemia may improve outcomes in patients with acute myocardial infarction merits further study.

McCullough, P. A., A. Afzal and P. Kale (2016). “Goal-directed heart failure care in patients with chronic kidney disease and end-stage renal disease.” JACC Heart Fail 4(8): 662-663.

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Investigators have long recognized that renal function and cardiac performance are integrally linked through hemodynamic, neural, humoral, cell signaling, proteomic, and metabolomic pathways (1). Among risk factors for the development of heart failure (HF), chronic kidney disease (CKD) is the most powerful because it contributes to the three fundamental mechanisms of left ventricular failure: 1) pressure overload; 2) volume overload; and 3) cardiomyopathy (2). When CKD progresses to end-stage renal disease (ESRD), these three mechanisms driving HF become more difficult to control because patients undergoing dialysis have on average higher blood pressures; poor volume control only partially addressed by thrice weekly hemodialysis in most cases; and a well-described form of cardiomyopathy characterized by severe left ventricular hypertrophy, marked cardiac fibrosis, reduced capillary density, and calcific deposits on the mitral and aortic valves (3).