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Progress in deceased donor intervention research has been limited. Development of an in silico model of deceased donor physiology may elucidate potential therapeutic targets and provide an efficient mechanism for testing proposed deceased donor interventions. In this study, we report a preliminary in silico model of deceased kidney donor injury built, calibrated, and validated based on data from published animal and human studies. We demonstrate that the in silico model behaves like animal studies of brain death pathophysiology with respect to upstream markers of renal injury including hemodynamics, oxygenation, cytokines expression, and inflammation. Therapeutic hypothermia, a deceased donor intervention studied in human trials, is performed to demonstrate the model's ability to mimic an established clinical trial. Finally, future directions for developing this concept into a functional, clinically applicable model are discussed.

In kidney transplantation, BK virus infection has historically resulted in high rates of graft dysfunction and graft loss. Unlike other opportunistic infections, no therapies have been shown to prevent BK. The purpose of the current study was to evaluate the safety and efficacy of ciprofloxacin for the prevention of BK viremia in kidney transplant recipients. Two hundred kidney transplant recipients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial comparing a 3-month course of ciprofloxacin (n = 133) vs placebo (n = 67) for the prevention of BK viremia. The primary endpoint of BK viremia at month 6 posttransplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P = .03). Higher rates of BK viremia (23.3% vs 11.9%; P = .06) and BK nephropathy (5.8% vs 1.5%; P = .26) remained at 12 months in the ciprofloxacin group. Ciprofloxacin use was associated with a significantly higher rate of fluoroquinolone-resistant gram-negative infections (83.3% vs 50%; P = .04). A 3-month course of ciprofloxacin was ineffective at preventing BK viremia in kidney transplant recipients and was associated with an increased risk of fluoroquinolone-resistant infections. Clinical trial registration number: NCT01789203.

BACKGROUND Careful donor-recipient matching and reduced ischemia times have improved outcomes following donation after circulatory death (DCD) liver transplantation (LT). This study examines a single-center experience with DCD LT including high-acuity and hospitalized recipients. METHODS DCD LT outcomes were compared to a propensity score-matched (PSM) donation after brain death (DBD) LT cohort (1:4); 32 DCD LT patients and 128 PSM DBD LT patients transplanted from 2008 to 2018 were included. Analyses included Kaplan-Meier estimates and Cox proportional hazards models examining patient and graft survival. RESULTS Median MELD score in the DCD LT cohort was 22, with median MELD of 27 for DCD LT recipients with decompensated cirrhosis. No difference in mortality or graft loss was found (p

In patients with portal hypertension, ectopic varices can develop at any site along the gastrointestinal tract outside the classically described gastroesophageal location. Like esophageal variceal hemorrhage, bleeding from ectopic varices can be life-threatening. Diagnosis and treatment of ectopic varices can be challenging; to date, no effective treatment algorithm has been described. A systematic teamwork approach to diagnosing and treatment of ectopic varices is required to successfully manage hemorrhage from ectopic varices.

Modern-day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed-dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV-infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction-induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat-containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV-positive transplant recipients and their providers.

Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-β (TRβ)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings.Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and β-cell area were assessed.GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRβ selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD-GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in β-cell area.Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear.In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study.Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded.This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Introduction The assessment of the glomerular filtration rate (GFR) in kidney donor candidates is required for determining donor candidate acceptability. This assessment can be done using an estimated GFR (eGFR) or a measured GFR (mGFR). The primary objective of the present study was to compare, in healthy adult kidney donor candidates, GFR measured by the clearance of iothalamate to GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and to determine if eGFR was a suitable stand-alone assessment. A secondary objective was to explore demographic factors that affect the relationship of the eGFR and the mGFR. Methods A retrospective review of kidney donor candidates' records at the J. C. Walter, Jr., Transplant Center, Houston Methodist Hospital, from January 2013 to March 2016 was undertaken. GFR was measured by the plasma clearance of radioisotopic iothalamate and estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Results The median mGFR was 108 mL/min/1.73 m2. The eGFR underestimated the mGFR by 11.5%. The underestimation was greatest in subjects with an mGFR of ≥90 mL/min/1.73 m2. The eGFR overestimated the mGFR in donor candidates of black race. Conclusions The Chronic Kidney Disease Epidemiology Collaboration eGFR can be used for screening potential kidney donors restricting the use of iothalamate (mGFR) to those donors with an eGFR below the transplant centers' acceptable GFR threshold for donation, thereby effecting cost savings and greater donor convenience. The eGFR in black donor candidates should be used with caution.

Background The advent of tumor-size–based criteria (Milan and University of California, San Francisco [UCSF]) for the transplantation of hepatocellular carcinomas (HCC) has facilitated tumor patients' access to transplantation. Recent success in transplanting patients with larger tumors (beyond UCSF) necessitates an understanding of the patient, the tumor, and biological criteria that determine successful outcomes for HCC transplantation across all size criteria. Methods We analyzed 11,928 patients who received OLT between 2002 and 2013 from the United Network for Organ Sharing Standard Transplant Analysis and Research file. Clinical outcomes were compared by tumor size at transplant; Milan (n = 11,555), beyond Milan within UCSF (n = 291), and beyond both Milan and UCSF (n = 82). A statistical analysis was conducted to determine the factors impacting survival. Results There were no statistically significant differences in the 1-, 3-, and 5-year survival rates between the 3 patient groups (within Milan 91.1%, 74.8%, and 60.3%; beyond Milan within UCSF, 92.7%, 71.1%, and 51.6%; and beyond Milan and UCSF 95.8%, 75.9%, and 58.1%). In a multivariate analysis, factors significantly affecting survival included, AA race, AFP >3000, and hepatitis C infection, while age, diabetes and largest tumor diameter had a more modest impact. Total tumor burden and time to transplantation were not significant predictors of survival. Conclusions These data indicate that, based on current clinical selection criteria, a small number of large tumors can be successfully treated by transplantation and points to the need to include markers of HCC biologic behavior beyond size and tumor burden to transplant criteria.

The osteoblast-specific hormone osteocalcin (OC) was found to regulate glucose metabolism, fat mass, and β-cell proliferation in mice. Here, we investigate the effect of decarboxylated OC (D-OC) on human β-cell function and mass in culture and in vivo using a Nonobese diabetic-severe combined immunodeficiency mouse model. We found that D-OC at dose ranges from 1.0 to 15 ng/mL significantly augmented insulin content and enhanced human β-cell proliferation of cultured human islets. This was paralleled by increased expression of sulfonylurea receptor protein; a marker of β-cell differentiation and a component of the insulin-secretory apparatus. Moreover, in a Nonobese diabetic-severe combined immunodeficiency mouse model, systemic administration of D-OC at 4.5-ng/h significantly augmented production of human insulin and C-peptide from the grafted human islets. Finally, histological staining of the human islet grafts showed that the improvement in the β-cell function was attributable to an increase in β-cell mass as a result of β-cell proliferation indicated by MKI67 staining together with the increased β-cell number and decreased α-cell number data obtained using laser scanning cytometry. Our data for the first time show D-OC-enhanced β-cell function in human islets and support future exploitation of D-OC-mediated β-cell regulation for developing useful clinical treatments for patients with diabetes.

Congenital absence of the portal vein (CAPV) is a rare congenital anomaly in which the superior mesenteric veins (SMV) and splenic veins converge and bypass the liver, effectively draining directly into the systemic venous circulation via the inferior vena cava (IVC), or alternatively the renal or iliac vein, creating a native portosystemic shunt. Portosystemic shunting results in clinical manifestations of hepatic encephalopathy as well as a predisposition to focal nodular hyperplasia and tumors, including adenomas, hepatoblastoma, and hepatocellular carcinoma (HCC), by the disruption of enterohepatic blood flow. Historically, CAPV has been thought to be a rare condition found mainly at autopsy, however, in recent years due to advances in radiological techniques, CAPV detection has increased. Herein we describe a patient with known CAPV who initially underwent hepatic resection for HCC. During surveillance, additional masses were discovered and were identified as recurrent HCC. Unfortunately, this patient was not a candidate for further resection or locoregional therapy. We demonstrate that transplantation is a challenging but technically viable option for treatment of HCC complicating adenomatosis-associated CAPV.

This study aimed to assess kidney dysfunction in general surgical patients and examine the effect on postoperative mortality and morbidity.An estimated 13% of the US population has chronic kidney disease (CKD), but awareness among patients and caregivers is lacking.The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) data sets for 2005-2007 were analyzed. Preoperative kidney function was assessed by the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate (eGFR) and staged according to National Kidney Foundation. Cross-sectional analyses were performed for 30-day mortality (Cox proportional hazard) and incidence of major complications (nominal logistic regression). A case-control cohort of colectomy cases was analyzed comparing patients in the stage 4 CKD group and the no CKD group (no-CKD).Sixty-four percent of evaluable patients had reduced eGFR, but eGFR was not evaluable in 28% of the surgical cases. In the 260,352 evaluable cases, adjusted hazard ratio for 30-day mortality was 2.30 [95% confidence interval (CI), 2.11-2.51] for stage 3 CKD; 3.37 (95% CI, 3.01-3.76) for stage 4 CKD; and 3.05 (95% CI, 2.68-3.47) for stage 5 CKD compared with no-CKD (P0.0001). CKD was an independent risk factor for having major complications postsurgery [stage 3, odds ratio (OR) = 1.24 (95% CI, 1.19-1.29); stage 4, OR = 1.65 (95% CI, 1.52-1.78); and stage 5 CKD, OR = 1.40 (95% CI, 1.30-1.51); P0.0001]. The case-control for colectomy was confirmatory: increased 30-day mortality in stage 4 CKD versus no-CKD (hazard ratio = 2.58, 95% CI, 1.13-5.92; P = 0.025).Renal insufficiency may be underrecognized in the general and vascular (noncardiac) surgery population, is a leading independent predictor of poor early postoperative outcomes, and should be routinely assessed in the preoperative setting.

BACKGROUND Kidney transplant candidates undergo rigorous testing prior to clearance for transplantation. Because kidney transplant candidates may be at increased risk for carotid artery stenosis because of arteriosclerosis and atherosclerosis secondary to hypertension, vascular calcification, and diabetes, carotid ultrasound is often performed with the intent of preventing a cerebrovascular accident in the perioperative or posttransplant period. To our knowledge, there has not been a study investigating the utility of screening carotid ultrasonography in pretransplant candidates. The purpose of the present study was to investigate the yield of carotid ultrasonography in end-stage renal disease patients, at high risk for having clinically significant vascular disease evaluated at our center for kidney transplantation during the years 2009 to 2014. METHODS Data for carotid ultrasound findings and risk factors for carotid artery disease were extracted from the medical records. RESULTS A total of 882 patients were included in our study of which only 13 patients (1.47% of the cohort) had significant carotid artery stenosis (>70%) on ultrasound testing. Using multiple logistic regression on the outcome of carotid stenosis, congestive heart failure (adjusted odds ratio, 5.2), and peripheral vascular disease (adjusted odds ratio, 4.4) were positively associated with carotid stenosis. CONCLUSIONS The prevalence of significant carotid artery stenosis was only 1.47% in our cohort of kidney transplant candidates, and the routine use of carotid ultrasound testing in this population may not be an efficient use of clinical resources. Use of risk factors, such as congestive heart failure or peripheral vascular disease, may identify patients who are more likely to benefit from carotid ultrasonography screening.

Pancreas transplant recipients experience graft loss in spite of improvements in immunosuppressant therapies and diagnostic technologies. Therefore, a method to improve detection and management of acute rejection is needed. This longitudinal study investigated the usefulness of three biomarkers, granzyme B, perforin, and HLA-DR, measured by real-time PCR on peripheral blood mononuclear cells, for their ability to detect acute rejection and its resolution in 13 recipients of pancreas allograft. Data demonstrated that pre-transplant baseline expression of biomarkers decreased following the initiation of immunosuppression. Throughout follow-up (range 3–27 months), individuals without acute rejection episodes had little variation in their biomarker levels. Recipients with biopsy-proven rejection had a significant increase in the levels of biomarkers as early as 5 weeks before clinical rejection diagnosis. Furthermore, all seven patients with biopsy-proven rejection demonstrated a decrease in the levels of granzyme B and perforin following the increased immunosuppression for the treatment of rejection. This is the first clinical serial measurement of biomarkers in pancreas patients. The data demonstrate that upregulation of granzyme B, perforin, and HLA-DR in peripheral blood mononuclear cells are sensitive to changes in the immune environment and could possibly be used to identify those patients at higher risk of rejection.

The effect of reaming velocity on the pressure distribution within the bone was investigated numerically by solving the full three-dimensional momentum equations together with the continuity equation using the finite element technique. Viscosity was also varied to obtain a pressure envelope. It was found that all the experimental data follow the same trends as the envelopes predicted by the finite element model. It was clear that an increase in either the implant insertion rate or the viscosity resulted in an increase in pressure in the intramedullary canal.

Background—A major problem in the islet field is the high selectivity exercised in accepting cadaveric pancreas for islet isolation. This practice is based on experience that indicates that islet yield and posttransplant function are related to donor demographics and injury mechanisms.Objective—To examine factors influencing islets recovery and in vivo function with emphasis on donor-related factors.Methods—Islets were isolated from 99 human donor pancreata, and islet yield was reported as islet equivalent per gram pancreatic tissue. Donor, procurement, and isolation factors were collected for each isolation and correlation statistics were performed between these variables and islet yield.Results—Results indicated a differential effect of enzyme mixes on yield with Collagenase P digestion most suitable for increased ischemic time (R2 = 0.1; P

Ex vivo gene therapy approaches can improve the outcome of islet transplantation for treating type I diabetes. We have previously shown the improvement in islet function and vascularization following ex vivo transfection for human vascular endothelial growth factor (hVEGF) gene expression. In this study, we tested the hypothesis that co-expression of two genes, which target different challenges faced by islets post-transplantation, supplement each other to improve the survival and function of islets. We determined whether there is an additive effect of hVEGF and human interleukin-1 receptor antagonist (hIL-1Ra) gene expression in human islets.Human islets were co-infected with adenoviral vectors encoding hVEGF and hIL-1Ra. Islets were then incubated with a cocktail of inflammatory cytokines (IL-1beta+TNFalpha+IFNgamma), and islet viability and function were determined. In vivo function was evaluated by transplanting islets under the kidney capsules of streptozotocin-induced non-obese diabetic severe combined immunodeficient (NOD-SCID) mice.Infection of human islets with Adv-hVEGF and/or Adv-hIL-1Ra inhibited expression of inducible nitric oxide synthase (iNOS), decreased the production of nitric oxide (NO), and prevented the loss of in vitro glucose-stimulated insulin response and viability. Moreover, co-expression of hVEGF and hIL-1Ra reduced the blood glucose level of mice, and increased the level of blood insulin and c-peptide upon glucose challenge.Our results indicated that co-expression of genes that target different insults to transplanted islets can improve the outcome of islet transplantation better than either gene alone.

Background An in vitro method to assess human islets could prevent transplantation of nonviable islets and facilitate the optimization of islet preparation. We hypothesize that glucose-stimulated cytochrome c reduction and oxygen consumption by human islets can be used as predictors of transplant success. Methods Isolated human islets were obtained from research-grade pancreata. Using a previously developed islet flow culture system, the response of cytochrome c reduction and oxygen consumption to glucose was compared to the ability of islets transplanted into nondiabetic NOD-SCID mice to secrete C-peptide in response to a glucose tolerance test conducted 7 days following transplant (n=10). Results In vitro responses by human islets were qualitatively similar to those seen in rat islets: glucose increased both oxygen consumption and cytochrome c reduction. However, the responses were smaller in magnitude and quite variable. Scatter plots of C-peptide and quantiles for ln(C-peptide) indicated that 12 ng/ml could be used as threshold of transplant success with which to evaluate the diagnostic potential of cytochrome c and oxygen consumption. Data was analyzed by generating receiver operating curves and the area under the curve was 0.889 (95% CI: 0.645-1.000) and 0.738 (95% CI: 0.413-1.000) for cytochrome c reduction and oxygen consumption respectively (1 indicates absolute predictive capability and 0.5 indicates no predictive capability). Conclusions The detection of glucose-stimulated cytochrome c reduction and oxygen consumption may have utility as criteria for the assessment of human islet quality.

Islet transplantation is limited by islet graft failure due to poor revascularization, host immune rejection and nonspecific inflammatory response. Delivery of human vascular endothelial growth factor (hVEGF) gene to the islets is likely to promote islet revascularization and survival. We used a bicistronic adenoviral vector encoding hVEGF and CpG-free allele of green fluorescent protein (Adv-GFP-hVEGF) and introduced into human pancreatic islets by transfection. We found that transfection efficiency and apoptosis were dependent on the multiplicity of infection (MOI). Compared to Adv-GFP transfected and nontransfected islets, the levels of hVEGF secreted from Adv-GFP-hVEGF transfected islets were higher and exhibit a linear relationship between hVEGF expression and MOI (10-5000). Persistent, but low level expression of hVEGF from nontransfected islets was also observed. This may be due to expression of the endogenous hVEGF gene under hypoxic conditions. The levels of DNA fragmentation determined by ELISA of islet lysates were dependent on the MOI of Adv-GFP-hVEGF. On glucose challenge, insulin release from transfected islets was comparable to nontransfected islets. Immunohistochemical staining for hVEGF was very high in Adv-GFP-hVEGF transfected islets. Weak staining was also observed for hCD31 in both transfected and nontransfected islets. These findings suggest that Adv-GFP-hVEGF is a potential candidate for promoting islet revascularization.

This pilot study examined associations among patterns of gastric myoelectrical activity, symptoms of gastroparesis, years of diabetes, months of dialysis, and use of gastrointestinal medications in gastroparetic kidney-pancreas (KP) transplant recipients. Electrogastrography (EGG) and gastric symptom data were obtained from 42 transplant recipients before and after transplant (6, 12, and 24 months). Recipients were 38 +/- 7 yr of age, 88% Whites, and 60% male; 97% had hypertension. All had functioning grafts post-transplant (mean creatinine, 1.59 +/- 0.66 mg/dL, and serum glucose 91.97 +/- 24.92 mg/dL). Sixteen subjects had normal EGG (2.7-3.2 cycles per minute, cpm); two were tachygastric (>3.2 cpm) at all time points; one remained bradygastric (

Numerous case reports describe patients with previously documented immunity developing active hepatitis B virus (HBV) infection after transplantation. However, the risk of reactivation of HBV under long-term immunosuppression in hepatitis B core antibody (HBcAb)-positive, hepatitis B surface antigen (HBsAg)-negative transplant recipients has not been clearly described. Herein, we present a long-term follow-up for 49 HBcAb-positive, HBsAg-negative recipients (27 liver, 18 kidney, 4 pancreas) transplanted between June 1996 and April 2001. Among these, 37 recipients (76%) were HBsAb positive at transplantation. Immunosuppression consisted of various antibody induction regimens in 20 (41%) of the recipients with either tacrolimus (33 [67%])- or cyclosporine (16 [33%])-based maintenance immunosuppression. The incidence and duration of HBV prophylaxis was not significant. No patient received hepatitis B immunoglobulin (HBIG) before or after transplantation. Additionally, only two patients received lamivudine, which was started post transplant without clinical indication. The mean length of follow-up was 3.1±1.4 years. At the last follow-up, overall patient and graft survival were 98% and 96%, respectively. Patient survival was 96% in liver, 100% in kidney, and 100% in pancreas transplant recipients. The graft survival for each organ type was 93% in liver, 100% in kidney, and 75% in pancreas transplant recipients at the end of follow-up. There was no incidence of HBV reactivation defined as recurrence of HBsAg and/or HBV DNA positivity. These data suggest that the risk of reactivation of HBV in HBcAb-positive, HBsAg-negative transplant recipients under immunosuppression is negligible, regardless of immunosuppressive regimen, lamivudine prophylaxis, or HBsAb status. These patients should have access to transplantation as they enjoy excellent patient and graft survival rates.

Sirolimus is the first of a group of mammalian target of rapamycin inhibitors to be introduced for clinical use in the United States. At the University of Tennessee in Memphis, we have evolved strategies for the use of sirolimus in kidney transplant recipients; which utilize the drug as a primary immunosuppressant and exploit its potential for preserving renal function. Conversions from the calcineurins to sirolimusbased immunosuppression established the efficacy of calcineurin-free immunosuppressants in selected high-risk patients. The conversion experience stimulated the design of protocols for primary use of sirolimus. Posttransplant use of sirolimus was associated with low incidence of rejection whether sirolimus was used with low-dose Prograf or in calcineurin-free protocols. Primary use with full-dose Prograf was associated with a high incidence of calcineurin-related nephrotoxicity and was abandoned in our program. Hematologic and lipid side effects were manageable, as was an observed increase in wound-healing problems and lymphocele formation. Continuous modifications of the sirolimus protocols to increase our benefit-to-risk ratio are ongoing and indicate a continued role for the drug in posttransplant immune suppression.

Soft tissue injuries with associated bone defects are difficult to manage and often require prolonged treatment with repeated interventions. Frequently, a free flap is applied as a first step and bone grafting is carried out in a second procedure. Ideally, these two procedures are combined in one operation, utilizing a soft tissue flap with an attached vascularized bone fragment. The lateral arm flap can provide such an osteoseptocutaneous flap and has been utilized clinically with success; however, the vascular anatomy of the flap, especially the humeral fragment, has not been described in detail previously, and there is broad disagreement concerning its innervation. In this study, the arteries and nerves of 24 fresh cadaver arms were dissected after injection of colored latex. The levels of origin of the periosteal arteries of the humerus were also documented. The lateral arm flap has a consistent arterial supply from three septocutaneous perforating branches that are arranged in a predictable pattern. The lateral supracondylar ridge of the humerus is vascularized by direct branches of the posterior branch of the radial collateral artery and by arteries that arise from muscular branches supplying adjacent muscles. The innervation of the lateral arm flap is by the inferior lateral cutaneous nerve of the arm. Knowledge of the consistent vascular anatomy of the lateral humerus and soft tissue of the donor site allows an osteoseptocutaneous flap to be raised safely with an appropriate technique. We recommend use of the lateral arm flap with a humeral fragment for the treatment of combined soft tissue and bone defects when a single step surgical solution is indicated.

Purpose. To report the incidence and clinical characteristics of polyomavirus (PV) nephritis in kidney (KTX) and kidney–pancreas transplant (KPTX) recipients. Methods. Single center retrospective analysis of all cases of PV nephritis in KTX and KPTX patients transplanted between 1994 and 1999. Results. Thirteen (5 KTX and 8 KPTX) patients (2.1%) had PV nephritis diagnosed on multiple biopsies (n = 22) among 504 KTX and 106 KPTX recipients. The incidence of PV nephritis was higher in cadaver donor transplants (2.6% cadaver vs. 0.7% living donors), after KPTX (1% KTX vs. 7.5% KPTX), in males (3.3% male vs. 0.7% female), and in diabetic patients (4.4% diabetic vs. 0.8% nondiabetic). The mean time to diagnosis of PV nephritis was 18 (range 6–48) months after KTX and 17 (range 9–31) months after KPTX. Three KTX patients and 5 KPTX patients had calcineurin inhibitor toxicity on biopsy prior to developing PV nephritis. Reduction in immunosuppression occurred in 100% of KTX and 63% of KPTX patients. Three patients (23%) developed rejection within 3 months of diagnosis of PV, 1 after a reduction in immunosuppression. Despite multiple antiviral treatment regimens, renal allograft failure requiring dialysis occurred in 60% of KTX and 50% of KPTX patients. All KPTX patients remain insulin independent and 2 were successfully retransplanted with living donor kidneys. 2 patients (15%) died but there was no mortality directly related to the virus. Conclusions. Polyomavirus nephritis may be increasing in incidence and appears to be unresponsive to either conventional antiviral agents or a reduction in immunosuppression. Most of our cases occurred in male diabetic patients undergoing cadaveric donor transplantation and were preceded by biopsy-proven nephrotoxicity. Further studies are needed to better define the pathogenesis of PV and effective antiviral treatment.

Passive immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is important to prevent recurrence of hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) for chronic HBV cirrhosis. With availability of lamivudine (3TC), the use of combination prophylaxis with long-term HBIG/3TC has been shown to prevent short-term HBV recurrence. This report compares HBV recurrence rates between groups receiving no/short-term HBIG, long-term HBIG alone, or HBIG/3TC prophylaxis, and describes HBIG requirements during the first 6 and 12 months in the latter two groups. This study involved patients undergoing OLT at the University of Tennessee-Memphis between May 1990 and July 2001. During this period, 388 liver transplants were performed at our center. All hepatitis B surface antigen (HBsAg)-positive recipients (n = 27) were included in this retrospective analysis. The groups were similar with regard to pre-transplant demographic characteristics such as age, gender, weight, and pre-transplant diagnosis. Owing to the retrospective study design, median follow-up was longer for the no-prophylaxis (5.6 years) and the HBIG-alone (6.0 years) groups compared to the HBIG/3TC group (4.2 years). Patient survival was 50% in the no-prophylaxis and 71% in the HBIG-alone groups compared to 100% in the HBIG/3TC group (P = 0.09). When censored for death with a functioning graft, graft survival was 50% in the no-prophylaxis and 86% in the HBIG-alone group compared to 100% in the HBIG/3TC group (P = 0.07). The overall incidence of HBV recurrence in the no-prophylaxis era was 100% and 21% in the HBIG-alone era compared to 0% in the HBIG/3TC era (P < 0.001), despite similar mean and median HBIG trough titers in the HBIG-alone and HBIG/3TC groups. The incidence of HBV recurrence in HBV DNA-positive recipients was 100% in the no-prophylaxis era, 30% in the HBIG-alone era, and 0% in the HBIG/3TC era (P < 0.001). Recipients in the HBIG-alone group had a nearly two-fold increase in HBIG requirement at 6 and 12 months in order to maintain similar HBIG trough titers post-transplant compared to recipients in the HBIG/3TC group despite similar pre-transplant HBV serology. This increased HBIG requirement in the HBIG-alone group resulted in a marked increase in the mean overall cost of HBV prophylaxis in this group ($47,367 US dollars at 6 months; $84,280 US dollars at 12 months) compared to the HBIG/3TC group ($25,931 US dollars at 6 months; $49,599 US dollars at 12 months). These data demonstrate an improvement in patient and graft survival rates in the group receiving combination HBIG/3TC prophylaxis compared to the HBIG-alone and no-prophylaxis groups. There was a significant reduction in HBV recurrence in the group receiving combination HBIG/3TC when compared to the groups receiving HBIG alone or no prophylaxis. Furthermore, we demonstrated that the addition of 3TC to the long-term HBIG regimen led to elimination of the disparity previously described in HBV recurrence rates between HBV DNA-positive and HBV DNA-negative recipients. Importantly, our data demonstrates a complete lack of HBV recurrence in the HBIG/3TC group at a median follow-up of 4.2 years. Additionally, the data show that the addition of 3TC to the post-operative prophylaxis regimen resulted in a reduction in the requirement of HBIG at 6 and 12 months, which markedly reduced the overall cost of post-transplant HBV prophylaxis.

AIM: To define the value of digital radiography with a clinical flat panel detector system for evaluation of wrist fractures in comparison with state of the art storage phosphor radiography. MATERIAL AND METHODS: Hard copy images of 26 fractured wrist specimens were acquired with the same exposure dose on a state of the art storage phosphor radiography system and a clinical flat panel detector. Image features like cortical bone surface, trabecular bone, soft tissues and fracture delineation were independently analysed by 4 observers using a standardised protocol. Image quality ratings were evaluated with an analysis of variance (ANOVA). RESULTS: Flat panel detector radiographs were rated superior with respect to cortical and trabecular bone representation as well as fracture evaluation, while storage phosphor radiographs produced better soft tissue detail. CONCLUSION: In some of the observed image quality aspects, the performance of caesium iodide/amorphous silicon flat panel detector exceeds state of the art storage phosphor radiography. This makes it well suited for skeletal imaging particularly in trauma as seen in the detection of wrist fractures . Peer, S. et al . (2002). Clinical Radiology 57 , 258–262.

We report the case of a pancreas-alone transplant recipient who developed Rhodococcus equi pneumonia after receiving multiple courses of antilymphocyte therapy for the treatment of recurrent acute pancreas allograft rejection. We also review and discuss the diagnosis, clinical course, and treatment of 18 cases of R. equi infection reported in solid organ transplant recipients. The lung is the most common primary site of infection, but R. equi infection is difficult to diagnose because of the pleomorphic, gram-positive, and partially acid-fast nature of the organism. Treatment usually involves a combination of antibiotics including rifampin, macrolides, vancomycin, and ciprofloxacin. The optimal duration of therapy is unknown, but relapse is common if the duration of treatment is less than 14 days. The duration of therapy should be guided by clinical recovery, culture results, and radiographic findings. Monitoring levels of immunosuppressive agents—such as tacrolimus and cyclosporine—is needed in order to avoid clinically significant drug interactions with rifampin or the macrolides when these agents are used in order to treat R. equi infection in the transplant population.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

Background In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. Methods We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. Results In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1–9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log10copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P

Background. Renal transplant recipients with de novo DSA (dDSA) experience higher rates of rejection and worse graft survival than dDSA-free recipients. This study presents a single-center review of dDSA monitoring in a large, multi-ethnic cohort of renal transplant recipients. Methods. The authors performed a nested case-control study of adult kidney and kidney-pancreas recipients from July 2007 through July 2011. Cases were defined as dDSA-positive whereas controls were all DSA-negative transplant recipients. DSA were determined at 1, 3, 6, 9, and 12 months posttransplant, and every 6 months thereafter. Results. Of 503 recipients in the analysis, 24% developed a dDSA, of whom 73% had dDSA against DQ antigen. Median time to dDSA was 6.1 months (range 0.2Y44.6 months). After multivariate analysis, African American race, kidney-pancreas recipient, and increasing numbers of human leukocyte antigen mismatches were independent risk factors for dDSA. Recipients with dDSA were more likely to suffer an acute rejection (AR) (35% vs. 10%, PG0.001), an antibody-mediated AR (16% vs. 0.3%, PG0.001), an AR ascribed to noncompliance (8% vs. 2%, P=0.001), and a recurrent AR (6% vs. 1%, P=0.002) than dDSA-negative recipients. At a median follow-up of 31 months, the deathcensored actuarial graft survival of dDSA recipients was worse than the DSA-free cohort (P=0.002). Yet, for AR-free recipients, there was no difference in graft survival between cohorts (P=0.66). Conclusions. Development of dDSA was associated with an increased incidence of graft loss, yet the detrimental effect of dDSA was limited in the intermediate term to recipients with AR.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15–2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71–6.77, p

Persons with end-stage renal disease have an accelerated risk for cardiovascular (CV) morbidity and mortality. Unfortunately, their accelerated CV risk persists even after kidney transplantation associated with pretransplant and post-transplant vascular disease. number of rejections treated with high-dose steroids, prolonged use of immunosuppressive therapy post-transplant, effects of comorbid chronic conditions and male gender. Unhealthy, modifiable lifestyle practices often augment their CV risk. The purpose of this study was to examine health-related lifestyle behaviors and estimate CV risks of men 1 year following kidney transplantation. Using the Healthier People Network Health Risk Appraisal (HPN-HRA), we examined CV risk characteristics of 34 men (M age=47.3 years) enrolled in an urban, mid-southern transplant center. Participants were assessed via self-administered paper-and-pencil questionnaires and medical record review provided biological data for analyses. HPN-HRA software was used to analyze biological and behavioral characteristics to compute CV risk estimates. Data were analyzed using descriptive, inferential and correlational analyses. The majority of participants reported smoke cessation (n= 19) or never having smoked (n = 8), and consumption of one or less alcoholic drinks per week (n=28). On the other hand, increased risk for heart attack and stroke were associated with advancing age (P

The Internet is a global communication network used by more than 17.6 million adults as a major source of current health information. Both the number of health-related Web sites and the number of Web users are increasing exponentially as well as reports indicating a growth in the number of persons who access the Internet specifically to retrieve information about organ transplantation. However, few are using this medium for posttransplant educational or psychosocial purposes. Armed with this information, as well as a commitment from the transplant team, we chose to develop a Web-based educational program to facilitate posttransplant care for our transplant recipients. The purpose of this article is to describe the planning, development, and implementation of a Web-based education program for transplant recipients.

Background Tacrolimus, a substrate of CYP3A, has low and variable bioavailability similar to cyclosporine. Co-administration of ketoconazole, potent inhibitor of gut and hepatic CYP3A, has been shown to increase tacrolimus bioavailability in healthy volunteers. The purpose of this study is to assess the role of gut metabolism in the overall bioavailability of tacrolimus in a renal transplant population. Methods We prospectively studied 19 adult renal transplant recipients who were receiving tacrolimus as part of a quadruple, sequential immunosuppression regimen. Each patient received tacrolimus (4-hr intravenous dose of 0.04 mg/kg between postoperative days 2 and 4). Whole blood samples were collected over 24 hr. After a 24-hr washout period, a single oral dose of ketoconazole (400 mg) was administered followed by the same intravenous dose of tacrolimus, and subsequent samples were obtained. Steady state oral pharmacokinetic profiles were obtained between 1 and 3 months after transplant while patients were receiving twice daily dosing of tacrolimus to maintain whole blood levels between 10 and 20 ng/ml. Two days later, 400 mg of ketoconazole was administered orally 2 hr before to the morning dose. Whole blood samples were collected over 12 hr. Results In the absence of ketoconazole, 8.0% of the tacrolimus dose underwent first pass metabolism (E(H)), whereas in the presence of ketoconazole, first pass metabolism was 6.2% (P=0.01). Based on this difference in first pass metabolism, an increase of 2% in bioavailability is expected, but an increase of 47% is observed (P=0.001). Conclusions This indicates that the gut metabolism of tacrolimus is extensive and contributes significantly to its bioavailability.

Human ehrlichioses are tick-borne infections caused by bacteria in the genus Ehrlichia of the family Rickettsiaceae. To date there have been three cases of ehrlichiosis reported in the transplant population, a human monocytic ehrlichiosis (HME) infection in a liver transplant recipient and two cases of human granulocytic ehrlichiosis (HGE) in kidney transplant recipients. We report three pancreas transplant patients who developed HGE in the last two years at a single southeastern center in the United States. All three patients had clinical, laboratory, and pathophysiologic findings on bone marrow biopsy and peripheral blood smears consistent with HGE, and responded to doxycycline therapy. In the setting of potent immunosuppression, ehrlichiosis should be considered in the differential diagnosis of transplant patients presenting with persistent fever, pancytopenia, and abnormal liver function. Patients with ehrlichiosis infection may be at risk for developing other opportunistic infections or lymphoproliferative disease.

Background: The impact of tacrolimus (TAC), mycophenolate mofetil (MMF) and steroid immunosuppression on cytomegalovirus (CMV) infection in combination with ganciclovir prophylaxis in simultaneous kidney-pancreas transplantation (SKPT) has not been well studied. Methods: A retrospective analysis was made of 75 SKPTs performed between 1 January 1996 and 7 January 1999. All patients received ganciclovir for 3 months, but CMV donor (D)+ / recipient (R)- patients received ganciclovir for 6 months. Results: 16/74 (22%) were CMV D+/R-, 25 (33%) D+/R+, 16 (22%) D-/R+, and 17 (23%) D-/R- (1 patient with unknown donor serology was excluded). The mean time to CMV infection was 198 days post-transplant. The incidence of either CMV infection or tissue invasive CMV disease was 16/74 (22%), including 9 (12%) with CMV infection and 7 (10%) CMV disease. The one-year patient, kidney, and pancreas graft survival rates were 91%, 89%, and 83%, respectively The mean follow-up was 29 months (minimum of 12 months). CMV infection was not associated with an increased incidence of graft failure or mortality. The D+/R- group had the highest incidence of CMV infection (44%) compared with the other serologic groups (17%, P=0.02). Concurrent CMV and rejection occurred more frequently in the D+/R- than the other serologic groups (25% vs. 7%, P= 0.03). The D-/R- group had the best outcomes, with no CMV infection, improved kidney graft survival at the end of follow-up (82% VS. 72%, P= 0.04) and the highest event-free survival (no CMV infection, rejection, or graft loss) when compared to the other groups (76% vs. 33%, P

Kidney–pancreas (KP) transplantation has been shown to improve left ventricular (LV) geometry and function 6–24 months after the procedure, yet whether these improvements are sustained in long-term survivors has not been demonstrated. This study examined whether early improvements in LV geometry and function were sustained 3–5 years after KP transplantation. Left ventricular function and geometry were prospectively evaluated prior to, and at 1, 2, and 3–5 years posttransplant using two-dimensional, M-mode, echocardiography with Doppler interrogation in the parasternal and apical views. The sample included 21 KP and a comparison group of 12 diabetic kidney-alone (KA) recipients. Long-term (3–5 years) data were obtained for KP recipients only. Although KA recipients had a longer duration of dialysis and worse diastolic function pretransplant, the groups were similar on other baseline measures. KA recipients experienced minimal improvements while KP recipients had significant improvements in cardiac function and geometry, both in terms of mean values and the percentage of KP recipients who experienced normalization posttransplant (p < 0.05). KP recipient improvements were also sustained at 3–5 years posttransplant on three of five measures, with 75% of long-term KP recipients achieving normal LV mass posttransplant compared with 31% pretransplant. Data indicate that significant impairments in cardiac geometry and function occur in diabetic KA and KP recipients. Though both groups experienced early improvements posttransplant, KP recipients achieved more dramatic and clinically significant improvements at 1, 2, and 3–5 years posttransplant. Additional studies are needed to examine the relevance of these findings with regard to the cardiac morbidity and mortality of these patients.

A prospective evaluation of 37 kidney and 20 kidney-pancreas transplant recipients was conducted to assess the relationship between pre-to posttransplant changes in heart rate variability (HRV) and quality of life (QoL). Assessments of 24-hour interbeat variability (pNN50 and rMSSD, SDNN, SDANN) and power spectral analysis of total, low (sympathetic), and high (parasympathetic) frequency components of HRV were performed. The Sickness Impact Profile was used to assess three dimensions of QoL (physical, psychosocial, and total functioning) prior to and at 6 months following transplantation. Changes in vagally mediated time domain measures of HRV were related to changes in physical and total functioning. Stronger correlations occurred between biobehavioral measures in kidney-pancreas recipients, with the strongest relationships occurring between changes in HRV frequency domain measures and changes in physical functioning. Findings indicate that changes in HRV and QoL are related, suggesting that interventions that enhance transplant recipients’ HRV may also enhance their QoL.

Acute pancreatitis (AP) is characterized by release of proteolytic enzymes from the pancreas and a powerful inflammatory cytokine cascade that mediates the systemic manifestations and contributes to the mortality of the disease. The purpose of this study was to examine a potential link between pancreatic proteolytic enzymes, which are increased in AP, and cytokine production. To evaluate this, we incubated rat peritoneal macrophages (PMO) with increasing concentrations of trypsin and measured cytokine production. Supernatants from the cell cultures were assayed for TNF-alpha and IL-1beta, and the PMO were collected for the evaluation of cytokine mRNA by polymerase chain reaction (PCR). Further to evaluate the role of pancreatic proteases in triggering the cytokine cascade in AP, trypsin was injected into the peritoneal cavity of Sprague-Dawley rats, and the production of cytokines was measured in the peritoneal fluid. Controls included injection of inactivated trypsin. Incubation of PMO with trypsin in vitro resulted in a dose-dependent increase in TNF-alpha production with maximal response (2,660.5+/-748.8 pg/mL) at 10 microg/mL protease. Peak TNF-alpha and IL-1beta release was noted 16 h after stimulation of the PMO (2,759.5+/-698.0 pg/mL and 160,596+/-4,065 cpm, respectively). Trypsin-induced TNF-alpha production was not due to release of cell-associated cytokine, inasmuch as activation of PMO with this protease causing an increase in TNF-alpha mRNA by 30 minutes, reaching a 14-fold increase at 4 h. Trypsin-injected animals produced TNF-alpha-containing ascitic fluid in a dose-dependent manner with peak TNF-alpha at 2 h (371.3+/-180 pg/mL) versus control (53.8+/-11.2 pg/mL; p < 0.022). No TNF-alpha was found in ascites of rats injected with heat-inactivated trypsin. Histologic examination of trypsin-injected animals revealed evidence of pulmonary inflammation at 2 and 4 hours. We conclude that the proteolytic enzyme trypsin stimulates cytokine production from macrophages in vitro and in vivo. This model demonstrates for the first time that trypsin is a potential mediator of the cytokine response seen during AP.

Lung injury is a major cause of patient morbidity in acute pancreatitis. The purpose of this study was to examine the mechanism of pulmonary infiltration and lung injury in acute pancreatitis. Mice were fed a choline-deficient/ethionine-supplemented (CDE) diet for 144 hours to induce severe acute pancreatitis. Serum samples were collected for measurement of biochemical markers of disease and for the detection of tumor necrosis factor-alpha (TNF-α). Cell surface adhesion molecule expression was quantified by the sensitive radiolabeled dual monoclonal antibody technique. Neutrophil sequestration in lung tissue was measured by the myeloperoxidase assay. Lung injury was determined histologically and lung edema was assessed by wet/dry ratios. Pancreatic injury was demonstrated to occur in all CDE-fed mice, which developed significant hyperamylasemia and hypoglycemia by 48 hours (P

Cardiac autonomic function has been associated with mortality in patients with end-stage renal disease. It is unknown whether end-stage renal disease patients who have succumbed to sudden cardiac death can be better identified by a newer test of heart rate variability that uses spectral analysis, rather than laboratory evoked measures.This series of studies sought to characterize cardiac autonomic function in patients awaiting kidney transplantation, identify factors associated with heart rate variability, identify tests which distinguish patients at-risk for death, and compare evoked measures with 24-hour heart rate variability measures.Data were collected on 184 nondiabetics, 60 type 1 diabetics, and 34 type 2 diabetics with end-stage renal disease, all of whom had been referred for kidney transplantation.The 278 patients and 67 healthy control subjects underwent evoked tests (changes in heart rate with deep breathing and Valsalva maneuver) and 24-hour heart rate variability Holter monitoring (time and frequency domains). Five patients had sudden cardiac deaths during the study.Data showed that end-stage renal disease patients, particularly diabetics, had compromised autonomic function. The standard deviation of all R-to-R intervals for the electrocardiogram recording (50 minutes in 60% of the deceased patients), a 24-hour heart rate variability time domain measure, holds the promise of identifying patients at increased risk for death. Exercise was identified as a factor associated with better autonomic function. Examining relationships between 24-hour heart rate variability and characteristics of patients who succumb to death could make quantification of the mortality risk for individual pretransplant end-stage renal disease patients possible, much as it has in other populations. The data from this study may also make it possible to design interventions, such as exercise, aimed at reducing mortality risk.

In an effort to ameliorate the problem of orthostatic hypotension in pancreas transplant patients, current medical management consists of maximizing the patient's hydration, altering antihypertensives, increasing sodium intake, initiation of fludrocortisone, compression stockings, and behavioral modifications. Despite these medical interventions, a subset of patients remains symptomatic. Midodrine (ProAmatine), an alpha-adrenergic agonist, was approved for the treatment of symptomatic orthostatic hypotension in the US. This preliminary report attempts to assess the safety and efficacy of midodrine use in kidney/pancreas (KP) or pancreas alone (PA) transplant recipients. A retrospective review was performed of 7 KP and 1 PA recipient experiencing symptomatic postural hypotension after maximizing other medical treatments. Blood pressure, serum creatinine (SrCr), and objective responses to postural hypotension were assessed at routine intervals. Pre-midodrine monitoring revealed a mean orthostatic change in systolic blood pressure from sitting to standing of 43 mmHg (range 20-100 mmHg). Patients received a mean starting midodrine dose of 18 mg/d, which was titrated to a maximum dose of 30 mg/d. Systolic blood pressure monitoring revealed a mean orthostatic change of 27 mmHg (range 0-81 mmHg) after initiation of treatment with midodrine and a mean follow-up of 3.2 months. All study patients reported improvement in symptoms of orthostatic hypotension. SrCr was not affected based upon comparison of pre-treatment and current SrCr values of 1.4 and 1.3 mg/dL, respectively. The most common side effect experienced was supine hypertension. These preliminary results suggest that midodrine is safe and effective in transplant recipients; however, the dosage should be titrated to symptomatic relief or a maximum dose of 30 mg. Careful monitoring for supine hypertension is necessary.