Sarwat B. Ahmad

Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration.

Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LTαβ rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NFκB signalling via LTβR. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression.

T-bet Regulates Natural Regulatory T Cell Afferent Lymphatic Migration and Suppressive Function.

T-bet is essential for natural regulatory T cells (nTreg) to regulate Th1 inflammation, but whether T-bet controls other Treg functions after entering the inflammatory site is unknown. In an islet allograft model, T-bet−/− nTreg, but not induced Treg, failed to prolong graft survival as effectively as wild-type Treg. T-bet−/− nTreg had no functional deficiency in vitro but failed to home from the graft to draining lymph nodes (dLN) as efficiently as wild type. T-bet regulated expression of adhesion- and migration-related molecules, influencing nTreg distribution in tissues, so that T-bet−/− nTreg remained in the grafts rather than migrating to lymphatics and dLN. In contrast, both wild-type and T-bet−/− CD4+ conventional T cells and induced Treg migrated normally toward afferent lymphatics. T-bet−/− nTreg displayed instability in the graft, failing to suppress Ag-specific CD4+ T cells and prevent their infiltration into the graft and dLN. Thus, T-bet regulates nTreg migration into afferent lymphatics and dLN and consequently their suppressive stability in vivo.

Recreational marijuana use is not associated with worse outcomes after renal transplantation

As marijuana (MJ) legalization is increasing, kidney transplant programs must develop listing criteria for marijuana users. However, no data exist on the effect of MJ on kidney allograft outcomes, and there is no consensus on whether MJ use should be a contraindication to transplantation. We retrospectively reviewed 1225 kidney recipients from 2008 to 2013. Marijuana use was defined by positive urine toxicology screen and/or self‐reported recent use. The primary outcome was death at 1 year or graft failure (defined as GFR<20 mL/min/1.73 m2). The secondary outcome was graft function at 1 year. Using logistic regression analyses, we compared these outcomes between MJ users and non‐users. Marijuana use was not associated with worse primary outcomes by unadjusted (odds ratio 1.07, 95% CI 0.45–2.57, P=.87) or adjusted (odds ratio 0.79, 95% CI 0.28–2.28, P=.67) analysis. Ninety‐two percent of grafts functioned at 1 year. Among these, the mean creatinine (1.52, 95% CI 1.39–1.69 vs 1.46, 95% CI 1.42–1.49; P=.38) and MDRD GFR (50.7, 95% CI 45.6–56.5 vs 49.5, 95% CI 48.3–50.7; P=.65) were similar between groups. Isolated recreational MJ use is not associated with poorer patient or kidney allograft outcomes at 1 year. Therefore, recreational MJ use should not necessarily be considered a contraindication to kidney transplantation.

Extra-Corporeal Membrane Oxygenation (ECMO) following traumatic injury.

BACKGROUND The use of extracorporeal membrane oxygenation (ECMO) for acute respiratory failure after injury is controversial and poorly described. METHODS We reviewed our single-center experience with use of ECMO from January 2006 to November 2015 at a Level 1 primary adult resource center for trauma to determine the association of in-hospital mortality with patient demographics and clinical variables. RESULTS Forty-six patients were treated with ECMO. Patients requiring venoarterial ECMO (n = 7) were excluded. Thirty-nine (85%) were cannulated for venovenous ECMO. Of these, 44% patients survived to discharge. Median age was 28 years. Survivors had a lower BMI and PaCO2 at time of cannulation. Nonsurvivors were more severely injured (median Injury Severity Score, 41 vs. 25; p = 0.03), had a lower arterial pH on arrival, and a shorter length of stay (11 vs. 41 days; p = 0.006). Neither mechanism of injury nor indication for ECMO was associated with mortality. Forty-one percent developed at least one ECMO-related complication, but this was not associated with mortality. Ninety-four percent of the survivors were anticoagulated with heparin versus 55% of nonsurvivors (p = 0.01). Median Injury Severity Score and presence of TBI were not significantly different between survivors and nonsurvivors who were anticoagulated. CONCLUSION The use of venovenous ECMO for acute lung injury after trauma should be considered in special patient populations. Ability to tolerate systemic anticoagulation was associated with improved survival. LEVEL OF EVIDENCE Therapeutic study, level V.

Live Donor Renal Transplant With Simultaneous Bilateral Nephrectomy for Autosomal Dominant Polycystic Kidney Disease Is Feasible and Satisfactory at Long-term Follow-up.

Background Timing of bilateral nephrectomy (BN) is controversial in patients with refractory symptoms of autosomal dominant polycystic kidney disease (APKD) in need of a renal transplant. Methods Adults who underwent live donor renal transplant (LRT) + simultaneous BN (SBN) from August 2003 to 2013 at a single transplant center (n = 66) were retrospectively compared to a matched group of APKD patients who underwent LRT alone (n = 52). All patients received general health and polycystic kidney symptom surveys. Results Simultaneous BN increased operative duration, estimated blood loss, transfusions, intravenous fluid, and hospital length of stay. Most common indications for BN were pain, loss of abdominal domain, and early satiety. There were more intraoperative complications for LRT + SBN (6 vs 0, P = 0.03; 2 vascular, 2 splenic, and 1 liver injury; 1 reexploration to adjust graft positioning). There were no differences in Clavien-Dindo grade I or II (39% vs 25%, P = 0.12) or grade III or IV (7.5% vs 5.7%, P = 1.0) complications during the hospital course. There were no surgery-related mortalities. There were no differences in readmission rates (68% vs 48%, P = 0.19) or readmissions requiring procedures (25% vs. 20%, P = 0.51) over 12 months. One hundred percent of LRT + SBN allografts functioned at longer than 1 year for those available for follow-up. Survey response rate was 40% for LRT-alone and 56% for LRT + SBN. One hundred percent of LRT + SBN survey responders were satisfied with their choice of having BN done simultaneously. Conclusions Excellent outcomes for graft survival, satisfaction, and morbidity suggest that the combined operative approach be preferred for patients with symptomatic APKD to avoid multiple procedures, dialysis, and costs of staged operations.

Outcomes of primary fascial closure after open abdomen for nontrauma emergency general surgery patients

BACKGROUND Emergency general surgery patients are increasingly being managed with an open abdomen (OA). Factors associated with complications after primary fascial closure (PFC) are unknown. METHODS Demographic and operative variables for all emergency general surgery patients managed with OA at an academic medical center were prospectively examined from June to December 2013. Primary outcome was complication requiring reoperation. RESULTS Of 58 patients, 37 managed with OA achieved PFC. Of these, 14 needed re-exploration for dehiscence, compartment syndrome, infection, or other. Complications after PFC were not associated with age, type of operative intervention, time to closure, re-explorations, comorbidities, or mortality. Complications correlated with higher body mass index (P = .02), skin closure (P = .04), plasma infusion (P = .01), and less intraoperative bleeding (P = .05). Deep surgical site infection correlated with fascial dehiscence (P = .02). CONCLUSIONS Reoperation after PFC was more likely in obese and nonhemorrhagic patients. Recognition of these factors and strategies to reduce surgical site infection may improve outcomes.

Current status of the microbiome in renal transplantation.

Purpose of reviewAn imbalance between pathogenic and protective microbiota characterizes dysbiosis. Presence of dysbiosis may affect immunity, tolerance, or disease depending on a variety of conditions. In the transplant patient population, the need for immunosuppression and widespread use of prophylactic and therapeutic antimicrobial agents create new posttransplant microbiota communities that remain to be fully defined. Recent findingsStudies in mice have demonstrated significant bidirectional interactions between microbiota-derived products and host immune cells. The stimulation of regulatory T cell and T helper cell type 17 cells by specific products leads to maintenance of immune homeostasis versus activation of inflammation, respectively. Dysbiosis may lead to development of antigen cross-reactivity, which may affect alloreactivity. Certain immunologic sequelae of microbiota are pronounced in chronic kidney disease, because of uremia and renal metabolism of microbiota metabolites. Dietary modifications, probiotics, and fecal microbiota transplant have been investigated for alteration of microbiota in humans. SummaryResearchers have begun to identify dysbioses associated with clinical conditions, including chronic kidney disease, posttransplant infection, and rejection. This information will allow clinicians not only to select at-risk patients for early intervention, but also to develop therapies that restore the microbiota to a state of homeostasis or tolerance.

Sequential kidney–liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency

Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end‐stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency.

Innovations in Kidney Transplant Research

The future of transplantation research depends on finding ways to refine immunomodulatory protocols so that they not only suppress the inflammatory cells that lead to rejection, but also activate antiinflammatory mechanisms that shift the immune milieu towards tolerance. In this chapter, we describe three emerging areas of interest in the field of transplant immunology. The newly discovered innate lymphoid cells (ILCs) regulate T-cell function and uniquely participate in both innate and adaptive immunity. ILCs interact with antigen such as the commensal bacteria (microbiota) that reside on mucosal surfaces to resist infection and activate immunity. Microbiota sequencing has shown us that various pathological processes, both inflammatory and antiinflammatory, are modulated by microbiota. Similarly, the stromal cells that structurally organize a lymph node can dynamically regulate the immune response. Therapies that target ILCs, microbiota composition, and/or stromal cell function may confer enhanced graft protection and concomitantly bolster host defense mechanisms against opportunistic infection.