Oxidative phosphorylation provides most of the ATP that higher animals and plants use to support life and is responsible for setting and maintaining metabolic homeostasis. The pathway incorporates ...three consecutive near equilibrium steps for moving reducing equivalents between the intramitochondrial NAD+/NADH pool to molecular oxygen, with irreversible reduction of oxygen to bound peroxide at cytochrome c oxidase determining the net flux. Net flux (oxygen consumption rate) is determined by demand for ATP, with feedback by the energy state (ATP/ADPPi) regulating the pathway. This feedback affects the reversible steps equally and independently, resulting in the rate being coupled to (ATP/ADPPi)3. With increasing energy state, oxygen consumption decreases rapidly until a threshold is reached, above which there is little further decrease. In most cells, ATP and Pi are much higher than ADP and change in ADP is primarily responsible for the change in energy state. As a result, the rate of ATP synthesis, plotted against ADP, remains low until ADP reaches about 30 μm and then increases rapidly with further increase in ADP. The dependencies on energy state and ADP near the threshold can be fitted by the Hill equation with a Hill coefficients of about −2.6 and 4.2, respectively. The homeostatic set point for metabolism is determined by the threshold, which can be modulated by the PO2 and intramitochondrial NAD+/NADH. The ability of oxidative phosphorylation to precisely set and maintain metabolic homeostasis is consistent with it being permissive of, and essential to, development of higher plants and animals.
Integration of oxidative phosphorylation into cellular metabolism made possible the evolutionary development of higher organisms. Progressive improvements in control of oxidative phosphorylation supported the increasing demands of specialized tissues, in particular muscles and neurons. One of these improvements, replacing arginine kinase with creatine kinase, was permissive of the evolutionary development of vertebrates.
Abstract Background It is widely believed that a reduced cardiac index (CI) is a significant contributor to renal dysfunction in patients with heart failure (HF). However, recent data have challenged ...this paradigm. Objectives This study sought to determine the relationship between CI and renal function in a multicenter population of HF patients undergoing pulmonary artery catheterization (PAC). Methods Patients undergoing PAC in either the randomized or registry portions of the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial were included (n = 575). We evaluated associations between CI and renal function across multiple subgroups and assessed for nonlinear, threshold, and longitudinal relationships. Results There was a weak but significant inverse correlation between CI and estimated glomerular filtration rate (eGFR), such that higher CI was paradoxically associated with worse eGFR (r = −0.12; p = 0.02). CI was not associated with blood urea nitrogen (BUN) or the BUN to creatinine ratio. Similarly, no associations were observed between CI and better renal function across multiple subgroups defined by indications for PAC or hemodynamic, laboratory, or demographic parameters. A nonlinear or threshold effect could not be identified. In patients with serial assessments of renal function and CI, we were unable to find within-subject associations between change in CI and eGFR using linear mixed modeling. Neither CI nor change in CI was lower in patients developing worsening renal function (p ≥ 0.28). Conclusions These results reinforce evidence that reduced CI is not the primary driver for renal dysfunction in patients hospitalized for HF, irrespective of the degree of CI impairment or patient subgroup analyzed.
Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional ...diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations.
Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated.
Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (
<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%;
=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%;
=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL interquartile range, -536 to 153 mL versus -14 mL interquartile range, -282 to 335 mL;
=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL;
=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (
=0.02) and all other neurohormones were similar (
<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (
=0.20) or renal dysfunction (
>0.11 for all biomarkers), whereas both serum magnesium (
<0.001) and uric acid levels (
=0.008) improved.
Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.
It is hypothesized that glucokinase (GCK) is the glucose sensor not only for regulation of insulin release by pancreatic β-cells, but also for the rest of the cells that contribute to glucose ...homeostasis in mammals. This includes other cells in endocrine pancreas (α- and δ-cells), adrenal gland, glucose sensitive neurons, entero-endocrine cells, and cells in the anterior pituitary. Glucose transport is by facilitated diffusion and is not rate limiting. Once inside, glucose is phosphorylated to glucose-6-phosphate by GCK in a reaction that is dependent on glucose throughout the physiological range of concentrations, is irreversible, and not product inhibited. High glycerol phosphate shuttle, pyruvate dehydrogenase, and pyruvate carboxylase activities, combined with low pentose-P shunt, lactate dehydrogenase, plasma membrane monocarboxylate transport, and glycogen synthase activities constrain glucose-6-phosphate to being metabolized through glycolysis. Under these conditions, glycolysis produces mostly pyruvate and little lactate. Pyruvate either enters the citric acid cycle through pyruvate dehydrogenase or is carboxylated by pyruvate carboxylase. Reducing equivalents from glycolysis enter oxidative phosphorylation through both the glycerol phosphate shuttle and citric acid cycle. Raising glucose concentration increases intramitochondrial NADH/NAD
and thereby the energy state (ATP/ADPPi), decreasing Mg
ADP and AMP. Mg
ADP acts through control of K
channel conductance, whereas AMP acts through regulation of AMP-dependent protein kinase. Specific roles of different cell types are determined by the diverse molecular mechanisms used to couple energy state to cell specific responses. Having a common glucose sensor couples complementary regulatory mechanisms into a tightly regulated and stable glucose homeostatic network.
Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. ...Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
Cardiopulmonary exercise testing (CPET) is used as a preoperative risk-stratification tool for patients undergoing non-cardiopulmonary intra-abdominal surgery. Previous studies indicate that CPET may ...be beneficial, but research is needed to quantify CPET values protective against poor postoperative outcome mortality, morbidity, and length of stay (LOS).
This systematic review aimed to assess the ability of CPET to predict postoperative outcome. The following databases were searched: PubMed, EMBASE, PEDro, The Cochrane Library, Cinahl, and AMED. Thirty-seven full-text articles were included. Data extraction included the following: author, patient characteristics, setting, surgery type, postoperative outcome measure, and CPET outcomes.
Surgeries reviewed were hepatic transplant and resection (n+7), abdominal aortic aneurysm (AAA) repair (n+5), colorectal (n+6), pancreatic (n+4), renal transplant (n+2), upper gastrointestinal (n+4), bariatric (n+2), and general intra-abdominal surgery (n+12). Cardiopulmonary exercise testing-derived cut-points, peak oxygen consumption ( V˙O2\,peak), and anaerobic threshold (AT) predicted the following postoperative outcomes: 90 day–3 yr survival (AT 9–11 ml kg−1 min−1) and intensive care unit admission (AT <9.9–11 ml kg−1 min−1) after hepatic transplant and resection, 90 day survival after AAA repair ( V˙O2\,peak 15 ml kg−1 min−1), LOS and morbidity after pancreatic surgery (AT <10–10.1 ml kg−1 min−1), and mortality and morbidity after intra-abdominal surgery (AT 10.9 and <10.1 ml kg−1 min−1, respectively).
Cardiopulmonary exercise testing is a useful preoperative risk-stratification tool that can predict postoperative outcome. Further research is needed to justify the ability of CPET to predict postoperative outcome in renal transplant, colorectal, upper gastrointestinal, and bariatric surgery.
Highlights • The validity of using changes in serum creatinine as surrogate endpoints for outcomes in heart failure was examined in 301 patients in the DOSE trial. • Decreases in serum creatinine, ...when incorrectly assumed to be linearly related to outcomes, were paradoxically associated with a substantially increased risk for adverse events. • Worsening in serum creatinine during the randomized intervention was not associated with an increase in adverse outcomes. • Improvement in renal function during the randomized intervention was strongly associated with poor outcomes. • The practice of using mild to moderate-sized changes in serum creatinine as an endpoint in heart failure clinical trials may be inappropriate.
Tools that measure patients’ experiences and perceptions of disease are increasingly being recognized as important components of a multidisciplinary personalized approach to care. These ...patient-reported outcome measures (PROMs) have the ability to provide clinicians, researchers, and policymakers with valuable insights into patients’ symptoms and experiences that are unable to be ascertained by laboratory markers alone. If developed rigorously, studied systematically, and used judiciously, PROMs can effectively incorporate the patient voice into clinical care, clinical trials, and health care policy. PROMs have continued to gain attention and interest within the nephrology community, but key challenges and opportunities for their seamless uptake and integration remain. In this narrative overview, we provide nephrologists with a comprehensive list of existing PROMs developed for adults with kidney disease with information on their gaps and limitations; a rationale to support the continued incorporation of PROMs into nephrology clinical trials, clinical care, and health care policy; and a summary of ongoing initiatives and future opportunities to do so.
To determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury.
Double blinded, ...multicenter, parallel, randomized controlled trial.
Six hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers.
6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria.
An electronic health record based "pop-up" alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient's medical record.
A composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury.
6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group
8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes.
Alerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury.
ClinicalTrials.gov NCT02753751.
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