Outcomes of surgical mitral and aortic valve replacements among kidney transplant candidates: implications for valve selection

Background: Limited literature exists that evaluated outcomes of kidney transplant–eligible patients who are having dialysis and who are undergoing valve replacement. Our main objective in this study was to compare mortality, reoperation, and bleeding episodes between bioprosthetic and mechanical valve procedures among kidney transplant–eligible patients who are having dialysis. Methods and Results: We studied 887 and 1925 dialysis patients from the United States Renal Data System, who underwent mitral valve replacement and aortic valve replacement (AVR) after being waitlisted for a kidney transplant (2000–2015), respectively. Time to death, time to reoperation, and time to bleeding requiring hospitalizations were compared separately for AVR and mitral valve replacement. Kaplan–Meier survival curves, Cox proportional hazards model for time to death, accelerated time to event model for time to reoperation, and counting process model for time to recurrent bleeding were used. There were no differences in mortality (hazard ratio [HR], 0.92; 95% CI, 0.77–1.09) or risk of reoperation or risk of significant bleeding events between bioprosthetic and mechanical mitral valve replacement. However, mechanical AVR was associated with a modestly significant less hazard of death (HR, 0.83; 95% CI, 0.74–0.94) compared with bioprosthetic AVR. There were no differences in time to reoperation, or time to significant bleeding events between bioprosthetic and mechanical AVR. Conclusions: For kidney transplant waitlisted patients who are on dialysis and who are undergoing surgical valve replacement, bioprosthetic and mechanical valves have comparable survival, reoperation rates, and bleeding episodes requiring hospitalizations at both mitral and aortic locations. These findings emphasize that an individualized informed decision is recommended when choosing the type of valve for this special group of patients having dialysis

Obesity Induces Expression of Uncoupling Protein-2 in Hepatocytes and Promotes Liver Atp Depletion

Uncoupling protein 2 (UCP2) uncouples respiration from oxidative phosphorylation and may contribute to obesity through effects on energy metabolism. Because basal metabolic rate is decreased in obesity, UCP2 expression is predicted to be reduced. Paradoxically, hepatic expression of UCP2 mRNA is increased in genetically obese (ob/ob) mice, In situ hybridization and immunohistochemical analysis of ob/ob livers demonstrate that UCP2 mRNA and protein expression are increased in hepatocytes, which do not express UCP2 in lean mice. Mitochondria isolated from ob/ob livers exhibit an increased rate of H+ leak which partially dissipates the mitochondrial membrane potential when the rate of electron transport is suppressed. In addition, hepatic ATP stores are reduced and these livers are more vulnerable to necrosis after transient hepatic ischemia. Hence, hepatocytes adapt to obesity by up-regulating UCP2. However, because this decreases the efficiency of energy trapping, the cells become vulnerable to ATP depletion when energy needs increase acutely

Barriers facing patients referred for kidney transplant cause loss to follow-up

End-stage renal disease affects many Americans; however, transplant is the best treatment option increasing life years and offering a higher quality of life than possible with dialysis. Ironically, many who are eligible for transplant do not follow through on the complex workup protocols required to be placed on the transplant waiting list. Here we surveyed vascular access clinic patients at an academic medical center referred for transplant, who did not follow up on the needed workup to be added to the national transplant waiting list. The most frequent responses of 83 patients for not pursuing transplantation were that the patients did not think they would pass the medical tests, they were scared of getting a transplant, and they could not afford the medicine or the transplantation. These impediments may result from unclear provider communication, misinformation received from peers or other sources, misperceptions related to transplant surgery, or limited health literacy/health decision-making capacity. Thus, patients with end-stage renal disease lost to follow-up after referral for kidney transplant faced both real and perceived barriers pursuing transplantation

A Technique for Autologous Priming of the Veno-Venous Bypass Circuit during Liver Transplantation

Orthotopic liver transplantations (OLT) have been associated with significant blood loss and hemodilution, necessitating significant homologous blood component replacement. Increasing administration of homologous blood products has been found to be inversely related to patient and graft survival. Various methods to reduce the amount of blood products patients receive during OLT, such as antifibrinolytic therapy, thromboelastography-guided transfusion, phlebotomy, reduced central venous pressures intraoperatively, and the use of the veno-venous bypass (VVB) circuit, have been explored. The asanguineous priming volume of the VVB circuit increases the likelihood of the patient receiving homologous blood products due to hemodilution. It was reasoned that autologous priming of the VVB circuit in OLT surgery was a plausible adjunctive blood conservation technique given its application to the extracorporeal circuit during cardiac surgery. We describe our technique of modifying the VVB circuit for autologous priming. This technique adds minimal risk and a small amount of cost to the procedure, requires slightly more communication among members of the surgical team, and with proper sequencing, adds no additional length to the surgical procedure. It is recommended that this technique be considered for addition to the arsenal of blood conservation techniques when VVB is used during OLT

Efficient method of genotyping ob/ob mice using high resolution melting analysis.

OBJECTIVE: Direct health care costs of obesity continue to grow throughout the world and research on obesity disease models are on the rise. The ob/ob mouse is a well-characterized model of obesity and associated risk factors. Successful breeding and backcrossing onto different backgrounds are essential to create knockout models. Ob/ob mice are sterile and heterozygotes must be identified by genotyping to maintain breeding colonies. Several methods are employed to detect the ob mutant allele, a single nucleotide polymorphism (SNP). Gel based methods are time consuming and inconsistent, and non-gel based assays rely upon expensive and complex reagents or instruments. A fast, high-throughput, cost effective, and consistent method to identify Lep(ob) mutation is much needed. DESIGN AND METHODS: Primers to produce an amplicon for High Resolution Melting Analysis (HRM) of the Lep(ob) SNP were designed and validated. RESULTS: Fluorescence normalized high resolution melting curve plots delineated ob/+, ob/ob, and WT genotypes. Genotypes were also confirmed phenotypically. CONCLUSIONS: HRM of the Lep(ob) SNP allows closed-tube identification of the Lep(ob) mutation using a real-time PCR machine now common to most labs/departments. Advantages of this method include assay sensitivity/accuracy, low cost dyes, less optimization, and cost effectiveness as compared to other genotyping techniques

Peroxisomal footprint in the pathogenesis of nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a form of fatty liver disease where benign hepatic steatosis leads to chronic inflammation in the steatotic liver of a patient without any history of alcohol abuse. Mechanisms underlying the progression of hepatic steatosis to NASH have long been investigated. This review outlines the potential role of peroxisomal dysfunctions in exacerbating the disease in NASH. Loss of peroxisomes as well as impaired peroxisomal functions have been demonstrated to occur in inflammatory conditions including NASH. Because peroxisomes and mitochondria co-operatively perform many metabolic functions including O2 and lipid metabolisms, a compromised peroxisomal biogenesis and function can potentially contribute to defective lipid and reactive oxygen species metabolism which in turn can lead the progression of disease in NASH. Impaired peroxisomal biogenesis and function may be due to the decreased expression of peroxisomal proliferator-activated receptor-α (PPAR-α), the major transcription factor of peroxisomal biogenesis. Recent studies indicate that the reduced expression of PPAR-α in NASH is correlated with the activation of the toll-like receptor-4 pathway (TLR-4). Further investigations are required to establish the mechanistic connection between the TLR-4 pathway and PPAR-α-dependent impaired biogenesis/function of peroxisomes in NASH

Development of steatohepatitis in Ob/Ob mice is dependent on Toll-like receptor 4

Background and aim. The etiology of non-alcoholic fatty liver disease (NAFLD) progression, and why some patients develop non-alcoholic steatohepatitis (NASH) vs. uncomplicated NAFLD, is not well understood. Obesity and NAFLD are thought to be associated with high circulating levels of leptin; however, the role of leptin in NASH has been controversial. Secondly, as ob/ob mice are known to have elevated circulating levels of TLR4-stimulating endotoxin secondary to increased intestinal permeability.Material and methods. We evaluated the long-term effects of steatosis on the livers of aleptinemic (OB) mice and the role of TLR4 in the development of hepatic sequelae in these animals.Results. At 20 weeks of age OB animals displayed grossly steatotic livers, but also features of early stage NASH including hepatocellular ballooning and numerous necroinflammatory foci with associated changes in serum aspartate aminotransferase (AST) and alanine transaminase (ALT). TLR4 KO did not affect the development of obesity or steatosis in ob/ob mice, but protected these animals from hepatitis and liver injury.Conclusions. In conclusion, the data presented here indicate that steatohepatitis develops in the absence of leptin, and that TLR4 is integral to the development NASH secondary to hyperphagia

Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4-Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

ABSTRACT Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsisinduced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor g coactivator-1a (PGC-1a), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1a led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/ extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ ERK signaling attenuated renal dysfunction and loss of PGC-1a, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-a [TNF-a], interleukin-1b) expression at 3 hours after LPS exposure. Neutralization of TNF-a also blocked PGC-1a suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-a alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-a signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis