KIDNEY DYSFUNCTION IS ASSOCIATED WITH DIMINISHED SKELETAL MUSCLE MITOCHONDRIAL PLASTICITY IN LIVER TRANSPLANT RECIPIENTS

BACKGROUND: Liver transplant (LT) recipients experience severe weight gain after transplant. This weight gain is driven by myopenia and subsequent metabolic inflexibility that culminates in an exacerbated risk of cardiometabolic disease. The risk of cardiovascular disease is increased in LT recipients with impaired kidney function. We do not fully understand the underlying physiological mechanisms that link kidney dysfunction with cardiometabolic disease in this patient population. Therefore, the purpose of this study was to determine the relationship between renal dysfunction and skeletal muscle mitochondrial plasticity in LT patients. We hypothesized that worse kidney function would be associated with impaired skeletal muscle mitochondrial oxidative capacity. METHODS: LT recipients were recruited from Virginia Commonwealth University Health Systems outpatient clinic visits. Venous blood samples were analyzed as part of routine clinical labs including renal function reported as estimated glomerular filtration rate (eGFR) calculated using the race free CKD-EPI equation. Skeletal muscle mitochondrial capacity of the wrist flexor muscle group was determined using near-infrared spectroscopy coupled with repeated, transient arterial occlusions to measure the recovery kinetics of oxygen consumption following an acute bout of handgrip exercise. The metabolic recovery rate constant (Tc) of muscle metabolism was calculated and reported as an index of mitochondrial oxidative capacity. Statistical associations were conducted using Pearson’s correlation test. RESULTS: 21 LT recipients (11 Male/10 Female; 5 African American/1 Asian/15 Caucasian; Mean ± SD: Age 58±9 years; body mass index 36.5±5.9 kg/m2) were enrolled. Renal function measured by eGFR (54±19 mL/min/1.73m2) was negatively associated with skeletal muscle mitochondrial oxidative capacity (Tc: 79.73±26.47 seconds; r = -0.51, p = 0.02). CONCLUSIONS: Impaired kidney function was associated with diminished skeletal muscle mitochondrial oxidative capacity in LT recipients. Future studies are warranted to establish if the observed impairments in mitochondrial plasticity are the mechanistic underpinning of metabolic inflexibility and cardiometabolic sequelae that are increased in LT recipients with impaired kidney function. FUNDING: Supported by NIH UL1TR00264

The Relationship Between Hypoadiponectinemia and Cardiovascular Events in Liver Transplant Recipients.

BACKGROUND: Cardiovascular disease (CVD) is an important cause of morbidity and mortality after liver transplantation (LT). Serum adiponectin levels inversely correlate with CVD-related outcomes, but the relationship between hypoadiponectinemia and CVD after LT is unknown. Thus, the aim of the present study was to prospectively evaluate this relationship in LT recipients (LTR). METHODS: LTR were prospectively enrolled (N = 130) between January 1, 2012, and January 1, 2014. Baseline adiponectin levels were drawn at enrollment and patients were followed for CVD events. Hypoadiponectinemia was defined as serum adiponectin \u3c10 \u3eµg/mL. The primary endpoint was a composite CVD outcome consisting of myocardial infarction, angina, need for coronary revascularization, stroke, or cardiac death. RESULTS: The mean age was 58 ± 11 years and prevalence of obesity, diabetes, and dyslipidemia was 40%, 35%, and 40%, respectively. A total of 20 CVD events were noted, after median follow up of 45 months. Hypoadiponectinemia was significantly associated with future risk of CVD events (hazard ratio, 3.519; 95% confidence interval, 1.180-10.499, P = 0.024). This association was independent of traditional CVD risk factors including age, gender, obesity, hypertension, diabetes, and choice of immunosuppression. CONCLUSIONS: Hypoadiponectinemia is a strong independent predictor of future cardiovascular events in LTR, which can be incorporated in clinical practice to assess CVD risk assessment after LT

Reduced metabolic flexibility is a predictor of weight gain among liver transplant recipients.

BACKGROUND: Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. METHODS: LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole room calorimetry and is expressed as respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. RESULTS: The clinical, metabolic and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (β-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (β-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (β-coefficient 0.447, p = 0.02) directly correlated with severity of weight gain. No statistically significant relationship between peak RQ, trough RQ and weight change was demonstrated. CONCLUSION: Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity post-LT with potential to develop new diagnostics and therapeutics

Office-Based Weight Loss Counseling Is Ineffective in Liver Transplant Recipients.

BACKGROUND: Weight gain after liver transplantation (LT) is a predictor of major morbidity and mortality post-LT; however, there are no data regarding weight loss following LT. The current study evaluates the effectiveness of standard lifestyle intervention in LT recipients. METHODS: All adult LT recipients with body mass index (BMI) ≥ 25 kg/m RESULTS: A total of 151 patients with 86 (56.0%) overweight and 65 (44.0%) obese patients were enrolled in the study. The mean BMI at baseline increased from 30.2 ± 3.7 to 30.9 ± 4.3 kg/m CONCLUSION: The practice of office-based lifestyle intervention is ineffective in achieving clinically significant weight loss in LT recipients, and additional strategies are required to mitigate post-LT weight gain

Differential fuel utilization in liver transplant recipients and its relationship with non-alcoholic fatty liver disease.

UNLABELLED: Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). METHODS: Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). RESULTS: The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p \u3c .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue. CONCLUSION: Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT

Differential fuel utilization in liver transplant recipients and its relationship with non‐alcoholic fatty liver disease

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT).MethodsPatients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation).ResultsThe two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue.ConclusionReduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT

Differential fuel utilization in liver transplant recipients and its relationship with non‐alcoholic fatty liver disease

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT).MethodsPatients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation).ResultsThe two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue.ConclusionReduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

ObjectiveTo develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP).MethodsWe conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users.ResultsBecause of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made.ConclusionThis guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies