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Background: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF., Methods and Results: Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR., Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature., Methods and Results: Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio., Conclusions: Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354., (© 2016 American Heart Association, Inc.)

End-stage renal disease (ESRD) patients receiving hemodialysis experience a heavy burden of disease-related symptoms, which lead to reduced quality of life. This review focuses on aspects of ESRD-related pharmacokinetics and on efficacy of drugs for treatment of somatic symptoms. Fatigue, pruritus, insomnia, and cramps are the most common symptoms in ESRD, and studies suggest that they are often undertreated. However, few evidence-based guidelines exist to guide therapy in patients received dialysis. In the context of this review, we examine the role of l-Carnitine in the treatment of fatigue and cramps; human growth hormone analog Norditropin and anabolic steroid Nandrolone for the treatment of fatigue; Gabapentin and other agents for the management of pruritis; Vitamin and creatine supplementation in the management of dialysis-associated cramps, and somnambulates in the treatment of dialysis-related insomnia. Treatment decisions should be made in consultation with patients with a full accounting of the potential risks and benefits of these therapies., (© 2015 Wiley Periodicals, Inc.)