Protective Role of Kynurenine 3-Monooxygenase in Allograft Rejection and Tubular Injury in Kidney Transplantation.

Renal tubular epithelial cells (TECs) are the primary targets of ischemia-reperfusion injury (IRI) and rejection by the recipient's immune response in kidney transplantation (KTx). However, the molecular mechanism of rejection and IRI remains to be identified. Our previous study demonstrated that kynurenine 3-monooxygenase (KMO) and kynureninase were reduced in ischemia-reperfusion procedure and further decreased in rejection allografts among mismatched pig KTx. Herein, we reveal that TEC injury in acutely rejection allografts is associated with alterations of Bcl2 family proteins, reduction of tight junction protein 1 (TJP1), and TEC-specific KMO. Three cytokines, IFN γ , TNFα, and IL1ß, reported in our previous investigation were identified as triggers of TEC injury by altering the expression of Bcl2, BID, and TJP1. Allograft rejection and TEC injury were always associated with a dramatic reduction of KMO. 3HK and 3HAA, as direct and downstream products of KMO, effectively protected TEC from injury via increasing expression of Bcl-xL and TJP1. Both 3HK and 3HAA further prevented allograft rejection by inhibiting T cell proliferation and up-regulating aryl hydrocarbon receptor expression. Pig KTx with the administration of DNA nanoparticles (DNP) that induce expression of indoleamine 2,3-dioxygenase (IDO) and KMO to increase 3HK/3HAA showed an improvement of allograft rejection as well as murine skin transplant in IDO knockout mice with the injection of 3HK indicated a dramatic reduction of allograft rejection. Taken together, our data provide strong evidence that reduction of KMO in the graft is a key mediator of allograft rejection and loss. KMO can effectively improve allograft outcome by attenuating allograft rejection and maintaining graft barrier function.

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection.

In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ, with marked increases in tumor necrosis factor (TNF)-α, TNF-ß and interleukin 1ß. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.

Feasibility and Benefit of Incorporating a Multimedia Cadaver Laboratory Training Program into a Didactics Curriculum for Junior and Senior Surgical Residents.

OBJECTIVE: As operative experience in general surgery decreases and work hour limitations increase there is less exposure of surgical residents to advanced vascular and trauma exposures. Many institutions have demonstrated benefits of cadaver laboratory courses. We have incorporated a multimedia cadaver laboratory course into our general surgery residency didactics curriculum with the objective to demonstrate a benefit of the program as well as the feasibility of incorporation. STUDY DESIGN: This is a prospective study at a tertiary care institution including general surgery residents within our residency program. A curriculum was designed, requiring residents to complete multimedia learning modules before both a trauma cadaver laboratory and vascular exposure cadaver laboratory. Outcome measures included self-efficacy/confidence (precourse and postcourse 5-point Likert surveys), knowledge (net performance on precourse and postcourse multiple choice examinations), and resident perception of the curriculum (postcourse 5-point Likert survey). Data were analyzed using ANOVA paired t-tests. RESULTS: For the vascular cadaver laboratory, resident knowledge improved overall from an average of 41.2% to 50.0% of questions correct (p = 0.032) and self-efficacy/confidence improved by 0.59 from 1.52 to 2.11 out of 5 (p = 0.009). Median confidence is 1.37 out of 5 and 2.32 out of 5, before and after course, respectively. Wilcoxon nonparametric test reveals a p = 0.011. Resident's perception of the usefulness of the laboratory evaluation was 3.85 out 5. There were 85.71% agreed that the laboratory is useful and 14.29% were disagree. The Z-score is -0.1579 (means 0.1579 standard deviations a score of 3.85 below the benchmark). The percentile rank is 56.27%. The coefficient of variation is 24.68%. For the trauma cadaver laboratory, resident knowledge improved overall from an average of 55.89% to 66.17% of questions correct (p = 0.001) and self-efficacy/confidence improved by 0.75 from 1.68 out of 5 to 2.43 out of 5 (p = 0.011). Median confidence level is 1.41 out of 5 before the training course and 2.64 out of 5 after the training course. Wilcoxon signed rank test gives a p value of 0.008. Resident's perception of the usefulness of the laboratory evaluation was 3.94 out 5. There were 72.22% agreed that the laboratory is useful and 27.78% were neutral. The Z-score is -0.098 (means 0.098 standard deviations a score of 3.94 below the benchmark). The percentile rank is 53.90%. The coefficient of variation is 15.48%. CONCLUSIONS: Incorporating a multimedia cadaver laboratory into a residency education didactics curriculum was both feasible and beneficial for resident education. We demonstrate an improvement in knowledge and self efficacy/confidence following both cadaver laboratory courses.

Descriptive Analysis of Venous Thromboembolism in Georgia Trauma Centers Compared with National Trauma Centers Participating in the Trauma Quality Improvement Program.

This study was designed to compare the incidence of venous thromboembolism (VTE) in Georgia trauma centers with other national trauma centers participating in the Trauma Quality Improvement Program (TQIP). The use of chemoprophylaxis and characteristics of patients who developed VTE were also examined. We conducted a retrospective observational study of 325,703 trauma admissions to 245 trauma centers from 2013 to 2014. Patient demographics, rate of VTE, as well as the use, type, and timing of chemoprophylaxis were compared between patients admitted to Georgia and non-Georgia trauma centers. The rate of VTE in Georgia trauma centers was 1.9 per cent compared with 2.1 per cent in other national trauma centers. Overall, 49.6 per cent of Georgia patients and 45.5 per cent of patients in other trauma centers had documented chemoprophylaxis. Low molecular weight heparin was the most commonly used medication. Most patients who developed VTE did so despite receiving prophylaxis. The rate of VTE despite prophylaxis was 3.2 per cent in Georgia and 3.1 per cent in non-Georgia trauma centers. Mortality associated with VTE was higher in Georgia trauma centers compared with national TQIP benchmarks. The incidence of VTE and use of chemoprophylaxis within Georgia trauma centers were similar to national TQIP data. Interestingly, most patients who developed VTE in both populations received VTE prophylaxis. Further research is needed to develop best-practice guidelines for prevention, early detection, and treatment in high-risk populations.

Differences in the Management of Perforated Appendicitis in Children by Race and Insurance Status.

This study was conducted to assess whether race and socioeconomic status influence the management method used to treat pediatric perforated appendicitis. Nonelective pediatric admissions with a primary diagnosis of appendicitis were analyzed using data from the 2001-2010 Nationwide Inpatient Sample. Bivariate and multivariate analyses were used to determine the association between race, insurance status, median household income, rural/metropolitan location, and the risk adjusted odds of undergoing surgery, laparoscopic appendectomy, percutaneous drainage, or neither surgery nor percutaneous drainage. A total of 46,211 admissions of perforated appendicitis were identified. Surgery was performed in 90.5 per cent of them. Black children were less likely to have surgery [adjusted odds ratio (AOR) = 0.53] and more likely to be managed nonsurgically with percutaneous drainage (AOR = 1.79). Self-pay patients were less likely to have laparoscopic surgery (AOR = 0.80). Children from rural counties were more likely to undergo surgery than those from larger metropolitan areas (AOR = 1.30). Higher estimated household income did not predict the method of treatment. Although previous studies have attributed racial disparities in outcomes for appendicitis to different rates of perforation and access to care, these findings demonstrate significantly dissimilar management strategies for patients presenting with a similar disease process.

A model of acute renal allograft rejection in outbred Yorkshire piglets.

Pigs represent a desirable animal model for the study of rejection in kidney transplantation with inbred Yucatan miniature swine (YMS) the most commonly studied strain due to well defined swine leukocyte antigen (SLA) genotypes. However, limitations to YMS may include cost and availability. Outbred Yorkshire pigs are widely available and significantly cheaper than YMS. Recent advances in SLA genotyping have allowed its application to outbred strains. On this basis, we theorized that Yorkshire pigs would be a viable alternative to YMS for the study of rejection in kidney transplantation. To address this question, we performed auto (Auto) and allotransplants (Allo) in 24 Yorkshire pigs, and assessed SLA genotypes and acute rejection after 72h. At sacrifice, and when compared to autotransplants, allotransplants had significant elevations in serum creatinine (8.4±1.3 vs 2.8±2.0mg/dL for Allo vs autotransplants, respectively) and BUN (61±9 vs 19.2±15mg/dL for Allo vs autotransplants, respectively). Warm ischemia times between the two groups did not differ (24±2.3 vs 26.4±1.4min for Auto vs Allo, respectively). There were 16 distinct SLA haplotypes identified from pigs undergoing allotransplantion, no matched donor-recipient pairs, and all allografts demonstrated rejection. Type IIA cellular rejection (Banff) was the most common. One allograft demonstrated hyperacute rejection due a blood group incompatibility. Histologically, the expression of regulatory Tcells and dendritic cells was increased in allografts. These data suggest that Yorkshire pigs may be a useful model for the study of acute rejection in experimental kidney transplantation.

Racial disparities in the use of laparoscopic surgery to treat colonic diverticulitis Are not fully explained by socioeconomics or disease complexity.

BACKGROUND: Several studies have demonstrated favorable outcomes for laparoscopic surgery over open surgery for the treatment of diverticular disease. This study was designed to analyze the relationship between race, socioeconomic status and the use of laparoscopy to address diverticulitis. METHODS: A retrospective analysis of 53,054 diverticulitis admissions was performed using data from the 2009-2013 National Inpatient Sample (NIS). The primary outcome was the use of laparoscopic versus open colectomy. Bivariate analysis and multivariable logistic regression were used to determine the raw and adjusted odds by race, insurance status, and median household income. RESULTS: Overall, 41.6% of colectomies involved the use of laparoscopy. Black patients were 19% less likely than White patients to undergo laparoscopic surgery. Hispanic patients were no more or less likely to undergo laparoscopic colectomy. Lacking private insurance was a strong predictor of undergoing open surgery. Lower income patients were 33% less likely to receive minimally invasive colectomies. CONCLUSIONS: These results demonstrate disparities in surgical treatment. Further research is warranted to understand and ameliorate treatment differences which can contribute to outcome disparities.

Brief tool to measure risk-adjusted surgical outcomes in resource-limited hospitals.

OBJECTIVES: To develop and validate a risk-adjusted tool with fewer than 10 variables to measure surgical outcomes in resource-limited hospitals. DESIGN: All National Surgical Quality Improvement Program (NSQIP) preoperative variables were used to develop models to predict inpatient mortality. The models were built by sequential addition of variables selected based on their area under the receiver operator characteristic curve (AUROC) and externally validated using data based on medical record reviews at 1 hospital outside the data set. SETTING Model development was based on data from the NSQIP from 2005 to 2009. Validation was based on data from 1 nonurban hospital in the United States from 2009 to 2010. PATIENTS: A total of 631 449 patients in NSQIP and 239 patients from the validation hospital. MAIN OUTCOME MEASURES: The AUROC value for each model. RESULTS: The AUROC values reached higher than 90% after only 3 variables (American Society of Anesthesiologists class, functional status at time of surgery, and age). The AUROC values increased to 91% with 4 variables but did not increase significantly with additional variables. On validation, the model with the highest AUROC was the same 3-variable model (0.9398). CONCLUSIONS: Fewer than 6 variables may be necessary to develop a risk-adjusted tool to predict inpatient mortality, reducing the cost of collecting variables by 95%. These variables should be easily collectable in resource-poor settings, including low- and middle-income countries, thus creating the first standardized tool to measure surgical outcomes globally. Research is needed to determine which of these limited-variable models is most appropriate in a variety of clinical settings.