Thomas G. Stewart

Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients

BACKGROUND Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients. METHODS Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models. RESULTS Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease. CONCLUSION These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation. FUNDING This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.

Tissue sodium accumulation and peripheral insulin sensitivity in maintenance hemodialysis patients

Recent data suggest that sodium (Na+) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na+ accumulation would be associated with abnormalities in peripheral insulin action.

High prevalence of non-steroidal anti-inflammatory drug use among acute kidney injury survivors in the southern community cohort study

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been linked to acute kidney injury (AKI), chronic kidney disease (CKD) and cardiovascular disease (CVD). Patients who survive an AKI episode are at risk for future adverse kidney and cardiovascular outcomes. The objective of our study was to examine the prevalence and predictors of NSAID use among AKI survivors.MethodsThe Southern Community Cohort Study is a prospective study of low-income adults aged 40–79 in the southeastern US. Through linkage with Centers for Medicare and Medicaid Services, 826 participants with an AKI diagnosis (ICD-9 584.5-584.9) at any age prior to cohort enrollment were identified. At baseline, data were collected on regular use of prescription and over-the-counter NSAIDs, as well as demographic, medical and other characteristics. Additional comorbidities were ascertained via linkage with CMS or the US Renal Data System.ResultsOne hundred fifty-four AKI survivors (19%) reported regular NSAID use at cohort enrollment (52 prescription, 81 OTC, 21 both) and the percentage of NSAID users did not vary by time since AKI event. Over 58% of users were taking NSAIDS regularly both before and after their AKI event. Hypertension (83%), arthritis (71%), heart failure (44%), CKD (36%) and diabetes (35%) were prevalent among NSAID users. In a multivariable model, history of arthritis (OR: 3.00; 95% CI: 1.92, 4.68) and acetaminophen use (OR: 2.43; 95% CI: 1.50, 3.93) were significantly associated with NSAID use, while prevalent CKD (OR: 0.63; 95% CI: 0.41, 0.98) and diabetes (OR: 0.44; 95% CI: 0.29, 0.69) were significantly inversely associated.ConclusionsNSAID use among AKI survivors is common and highlights the need to understand physician and patient decision-making around NSAIDs and to develop effective strategies to reduce NSAID use in this vulnerable population.

Metabolic Effects of Diet and Exercise in Patients with Moderate to Severe CKD: A Randomized Clinical Trial

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F2-isoprostane concentrations, and peak oxygen uptake (VO2 peak). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F2-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO2 peak, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

Patients Undergoing Parastomal Hernia Repair Using the Americas Hernia Society Quality Collaborative: A Prospective Cohort Study

BACKGROUND Parastomal hernia is the most common complication after stoma creation. It can create significant morbidity and is associated with a lower quality of life. Current parastomal hernia repair techniques and outcomes are not well characterized. We aimed to describe patient characteristics, operative techniques, and outcomes of patients undergoing parastomal hernia repair. STUDY DESIGN Patients in the Americas Hernia Society Quality Collaborative (AHSQC) ≥18 years old, who underwent parastomal hernia repair were identified. Descriptive statistics were performed for patient demographics, preoperative characteristics, operative details, 30-day follow-up, and patient-reported outcomes. The surgical techniques used in parastomal hernia repair and postoperative outcomes were described, and predictors of open vs minimally invasive surgery (MIS) and type of mesh used were analyzed. RESULTS We identified 672 patients in the AHSQC who underwent parastomal hernia repair between 2013 and Nov 2017. Almost all operations were elective, 22% of patents had their stoma reversed, and 94% of repairs used mesh. Elective status and surgeon practice type were associated with use of synthetic mesh. A surgeons preference for MIS, defect size, and age were associated with use of an MIS approach. Quality of life scores improved for patients who completed a postoperative questionnaire. CONCLUSIONS This is the first multi-institutional report of parastomal hernia repair using prospective data complete with operative details. Parastomal hernia repair remains a difficult operation without a clear best practice. Multiple factors appear to influence operative approach. Surgical treatment may improve quality of life at 6 to 12 months postoperatively.

Insulin Resistance is a Significant Determinant of Sarcopenia in Advanced Kidney Disease

Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass-1·min-1 for controls vs. for MHD patients, respectively, P < 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: -83.7 and 64.7) μg·100 ml-1·min-1 for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.