Surgical Specialist
29 years of experience

Accepting new patients
University City
Childrens Anesthesiology Assoc
3400 Spruce St
Philadelphia, PA 19175
215-662-2050
Locations and availability (5)

Education ?

Medical School Score Rankings
University of Pennsylvania (1981)
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Kidney Transplantation
Pancreas Transplantation
Castle Connolly's Top Doctors™ (2012 - 2013)
Appointments
University of Virginia School of Medicine
Professor of Surgery
University Of Virginia School Of Medicine - Charlottesville Va
Full Professor
University Of Pennsylvania School Of Medicine - Philadelphia Pa
Assistant Professor
Associations
American Board of Surgery
American College of Surgeons
American Hepato-pancreato-biliary Association

Affiliations ?

Dr. Brayman is affiliated with 4 hospitals.

Hospital Affilations

Score

Rankings

  • Pennsylvania Hospital University PA Health System
    800 Spruce St, Philadelphia, PA 19107
    • Currently 4 of 4 crosses
    Top 25%
  • Children's Hospital of Philadelphia
    324 S 34th St, Philadelphia, PA 19104
    • Currently 2 of 4 crosses
  • Rector and Visitors UVA Health Sciences Center
  • Hospital of the University of Pennsylvania
  • Publications & Research

    Dr. Brayman has contributed to 113 publications.
    Title Adenosine A(2a) Agonist Administration Improves Islet Transplant Outcome: Evidence for the Role of Innate Immunity in Islet Graft Rejection.
    Date November 2010
    Journal Cell Transplantation
    Excerpt

    Activation of adenosine A(2A) receptors inhibits inflammation in ischemia/reperfusion injury, and protects against cell damage at the injury site. Following transplantation 50% of islets die due to inflammation and apoptosis. This study investigated the effects of adenosine A(2A) receptor agonists (ATL146e and ATL313) on glucose-stimulated insulin secretion (GSIS) in vitro and transplanted murine syngeneic islet function in vivo. Compared to vehicle controls, ATL146e (100 nM) decreased insulin stimulation index [SI, (insulin)(high glucose)/(insulin)(low glucose)] (2.36 +/- 0.22 vs. 3.75 +/- 0.45; n = 9; p < 0.05). Coculture of islets with syngeneic leukocytes reduced SI (1.41 +/- 0.17; p < 0.05), and this was restored by ATL treatment (2.57 +/- 0.18; NS). Addition of a selective A(2A)AR antagonist abrogated ATL's protective effect, reducing SI (1.11 +/- 0.42). ATL treatment of A(2A)AR(+/+) islet/A(2A)AR(-/-) leukocyte cocultures failed to protect islet function (SI), implicating leukocytes as likely targets of A(2A)AR agonists. Diabetic recipient C57BL/6 mice (streptozotocin; 250 mg/kg, IP) received islet transplants to either the renal subcapsular or hepatic-intraportal site. Recipient mice receiving ATL therapy (ATL 146e or ATL313, 60 ng/kg/min, IP) achieved normoglycemia more rapidly than untreated recipients. Histological examination of grafts suggested reduced cellular necrosis, fibrosis, and lymphocyte infiltration in agonist-treated animals. Administration of adenosine A(2A) receptor agonists (ATL146e or ATL313) improves in vitro GSIS by an effect on leukocytes, and improves survival and functional engraftment of transplanted islets by inhibiting inflammatory islet damage in the peritransplant period, suggesting a potentially significant new strategy for reducing inflammatory islet loss in clinical transplantation.

    Title Liver X Receptor Agonists Augment Human Islet Function Through Activation of Anaplerotic Pathways and Glycerolipid/free Fatty Acid Cycling.
    Date March 2010
    Journal The Journal of Biological Chemistry
    Excerpt

    Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use.

    Title Extent and Severity of Coronary Disease and Mortality in Patients with End-stage Renal Failure Evaluated for Renal Transplantation.
    Date December 2009
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with >or=50% stenosis, Group 2 (n = 56) had one vessel with >or=50% stenosis and Group 3 (n = 70) had two or more vessels with >or=50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.

    Title Kidney and Pancreas Transplantation in the United States, 1998-2007: Access for Patients with Diabetes and End-stage Renal Disease.
    Date July 2009
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Although the number of candidates on the kidney transplant waiting list at year-end rose from 40 825 to 76 070 (86%) between 1998 and 2007, recent growth principally reflects increases in the number of patients in inactive status. The number of active patients increased by 'only' 4510 between 2002 and 2007, from 44 263 to 48 773. There were 6037 living donor and 10 082 deceased donor kidney transplants in 2007. Patient and allograft survival was best for recipients of living donor kidneys, least for expanded criteria donor (ECD) deceased donor kidneys, and intermediate for non-ECD deceased donor kidneys. The total number of pancreas transplants peaked at 1484 in 2004 and has since declined to 1331. Among pancreas recipients, those with simultaneous pancreas-kidney (SPK) transplants experienced the best pancreas graft survival rates: 86% at 1 year and 53% at 10 years. Between 1998 and 2006, among diabetic patients with end-stage renal disease (ESRD) who were under the age of 50 years, 23% of all and 62% of those waitlisted received a kidney-alone or SPK transplant. In contrast, 6% of diabetic patients aged 50-75 years with ESRD were transplanted, representing 46% of those waitlisted from this cohort. Access to kidney-alone or SPK transplantation varies widely by state.

    Title Adenoviral Graft-nephritis: Case Report and Review of the Literature.
    Date June 2009
    Journal Transplant International : Official Journal of the European Society for Organ Transplantation
    Title Regenerative Medicine and Tissue Engineering: Contribution of Stem Cells in Organ Transplantation.
    Date June 2009
    Journal Current Opinion in Organ Transplantation
    Title The Use of Stem Cells in Liver Disease.
    Date June 2009
    Journal Current Opinion in Organ Transplantation
    Excerpt

    Cell transplantation to restore liver function as an alternative to whole liver transplantation has thus far not been successful in humans.

    Title The Use of Stem Cells in Kidney Disease.
    Date June 2009
    Journal Current Opinion in Organ Transplantation
    Excerpt

    Acute and chronic kidney disease is a leading cause of morbidity and mortality worldwide with overall mortality rates between 50 and 80%. An acute shortage of compatible organs coupled with limited adaptability of current dialysis techniques has created a sense of urgency to investigate new alternatives, and the purpose of this review is to provide a concise overview of current stem cell-based strategies in renal repair following acute kidney injury.

    Title Nocardiosis in a Renal Transplant Recipient Following Rituximab Preconditioning.
    Date April 2009
    Journal Upsala Journal of Medical Sciences
    Title Amplification of Pulsatile Glucagon Counterregulation by Switch-off of Alpha-cell-suppressing Signals in Streptozotocin-treated Rats.
    Date October 2008
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    Glucagon counterregulation (GCR) is a key protection against hypoglycemia that is compromised in diabetes via an unknown mechanism. To test the hypothesis that alpha-cell-inhibiting signals that are switched off during hypoglycemia amplify GCR, we studied streptozotocin (STZ)-treated male Wistar rats and estimated the effect on GCR of intrapancreatic infusion and termination during hypoglycemia of saline, insulin, and somatostatin. Times 10 min before and 45 min after the switch-off were analyzed. Insulin and somatostatin, but not saline, switch-off significantly increased the glucagon levels (P = 0.03), and the fold increases relative to baseline were significantly higher (P < 0.05) in the insulin and somatostatin groups vs. the saline group. The peak concentrations were also higher in the insulin (368 pg/ml) and somatostatin (228 pg/ml) groups vs. the saline (114 pg/ml) group (P < 0.05). GCR was pulsatile in most animals, indicating a feedback regulation. After the switch-off, the number of secretory events and the total pulsatile production were lower in the saline group vs. the insulin and somatostatin groups (P < 0.05), indicating enhancement of glucagon pulsatile activity by insulin and somatostatin compared with saline. Network modeling analysis demonstrates that reciprocal interactions between alpha- and delta-cells can explain the amplification by interpreting the GCR as a rebound response to the switch-off. The model justifies experimental designs to further study the intrapancreatic network in relation to the switch-off phenomenon. The results of this proof-of-concept interdisciplinary study support the hypothesis that GCR develops as a rebound pulsatile response of the intrapancreatic endocrine feedback network to switch-off of alpha-cell-inhibiting islet signals.

    Title Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation.
    Date September 2008
    Journal Endocrine Reviews
    Excerpt

    Although type 1 diabetes cannot be prevented or reversed, replacement of insulin production by transplantation of the pancreas or pancreatic islets represents a definitive solution. At present, transplantation can restore euglycemia, but this restoration is short-lived, requires islets from multiple donors, and necessitates lifelong immunosuppression. An emerging paradigm in transplantation and autoimmunity indicates that systemic inflammation contributes to tissue injury while disrupting immune tolerance. We identify multiple barriers to successful islet transplantation, each of which either contributes to the inflammatory state or is augmented by it. To optimize islet transplantation for diabetes reversal, we suggest that targeting these interacting barriers and the accompanying inflammation may represent an improved approach to achieve successful clinical islet transplantation by enhancing islet survival, regeneration or neogenesis potential, and tolerance induction. Overall, we consider the proinflammatory effects of important technical, immunological, and metabolic barriers including: 1) islet isolation and transplantation, including selection of implantation site; 2) recurrent autoimmunity, alloimmune rejection, and unique features of the autoimmune-prone immune system; and 3) the deranged metabolism of the islet transplant recipient. Consideration of these themes reveals that each is interrelated to and exacerbated by the other and that this connection is mediated by a systemic inflammatory state. This inflammatory state may form the central barrier to successful islet transplantation. Overall, there remains substantial promise in islet transplantation with several avenues of ongoing promising research. This review focuses on interactions between the technical, immunological, and metabolic barriers that must be overcome to optimize the success of this important therapeutic approach.

    Title Pancreas Allografts: Comparison of Three-dimensional Rotational Angiography with Standard Digital Subtraction Angiography.
    Date May 2008
    Journal Journal of Vascular and Interventional Radiology : Jvir
    Excerpt

    PURPOSE: To define the role of three-dimensional (3D) rotational angiography (RA) for the evaluation of pancreas allografts and compare 3D RA to standard digital subtraction angiography (DSA). MATERIALS AND METHODS: DSA and 3D RA were performed in patients with vascular abnormalities diagnosed on contrast medium-enhanced magnetic resonance (MR) angiography. Patency of the allograft vasculature, confidence in the ability to make a therapeutic decision, and value of the study for definition of the optimal projection for an intervention was assessed on a graded scale. RESULTS: Seventeen standard DSA projections (mean, 3.4; range, 2-6) and 10 3D RA images (mean, 2; range, 1-3) were obtained in five patients. An average iodinated contrast agent dose of 14.4 mL (range, 8-22 mL) was administered for DSA. An average CO2 dose of 54 mL (range, 0-120 mL) was administered for 3D RA. Five 3D RA procedures were timed for the arterial phase and five were timed for the arterial and venous phases. Average contrast agent doses were 17.6 mL (range, 11-22 mL) for arterial 3D RA and 24.4 mL (range, 16-34 mL) for arterial- and venous-phase 3D RA. Of 68 vascular segments available for direct comparison of patency, complete concordance was present in 96%. There was no difference in the reviewers' diagnostic confidence (10 +/- 0 for both techniques). Three-dimensional RA was considered significantly superior for planning the optimal projection for intervention (10 +/- 0 for 3D RA vs 7.2 +/- 1.6 for DSA; P = .0052). CONCLUSIONS: Three-dimensional RA of pancreatic allografts is feasible and does not differ in accuracy from conventional DSA. It provides similar reviewer confidence in the ability to make an accurate treatment decision, but its key advantage is its superior ability to define the optimal projection for planned endovascular interventions.

    Title Hiv-infected Liver and Kidney Transplant Recipients: 1- and 3-year Outcomes.
    Date April 2008
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Improvements in human immunodeficiency virus (HIV)-associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9-4.9). One- and 3-year liver recipients' survival was 91% and 64%, respectively; kidney recipients' survival was 94%. One- and 3-year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1- and 3-year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28-75%) and 70% (48-92%), respectively. Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV-related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients cared for at centers with adequate expertise.

    Title Kidney and Pancreas Transplantation in the United States, 1996-2005.
    Date August 2007
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Kidney and pancreas transplantation in 2005 improved in quantity and outcome quality, despite the increasing average age of kidney graft recipients, with 56% aged 50 or older. Geography and ABO blood type contribute to the discrepancy in waiting time among the deceased donor (DD) candidates. Allocation policy changes are decreasing the median times to transplant for pediatric recipients. Overall, 6% more DD kidney transplants were performed in 2005 with slight increases in standard criteria donors (SCD) and expanded criteria donors (ECD). The largest increase (39%) was in donation after cardiac death (DCD) from non-ECD donors. These DCD, non-ECD kidneys had equivalent outcomes to SCD kidneys. 1-, 3- and 5-year unadjusted graft survival was 91%, 80% and 70% for non-ECD-DD transplants, 82%, 68% and 53% for ECD-DD grafts, and 95%, 88% and 80% for living donor kidney transplants. In 2005, 27% of patients were discharged without steroids compared to 3% in 1999. Acute rejection decreased to 11% in 2004. There was a slight increase in the number of simultaneous pancreas-kidney transplants (895), with fewer pancreas after kidney transplants (343 from 419 in 2004), and a stable number of pancreas alone transplants (129). Pancreas underutilization appears to be an ongoing issue.

    Title Glucose Regulation of Insulin Gene Transcription and Pre-mrna Processing in Human Islets.
    Date April 2007
    Journal Diabetes
    Excerpt

    Glucose is the primary regulator of insulin granule release from pancreatic islets. In rodent islets, the role of glucose in the acute regulation of insulin gene transcription has remained unclear, primarily because the abundance and long half-life of insulin mRNA confounds analysis of transcription by traditional methods that measure steady-state mRNA levels. To investigate the nature of glucose-regulated insulin gene transcription in human islets, we first quantitated the abundance and half-lives of insulin mRNA and pre-mRNAs after addition of actinomycin D (to stop transcription). Our results indicated that intron 1-and intron 2-containing pre-mRNAs were approximately 150- and 2,000-fold less abundant, respectively, than mature mRNA. 5' intron 2-containing pre-mRNAs displayed half-lives of only approximately 60 min, whereas all other transcripts displayed more extended lifetimes. In response to elevated glucose, pre-mRNA species increased within 60 min, whereas increases in mature mRNA did not occur until 48 h, suggesting that measurement of mature mRNA species does not accurately reflect the acute transcriptional response of the insulin gene to glucose. The acute increase in pre-mRNA species was preceded by a sixfold increase in histone H4 acetylation and a twofold increase in RNA polymerase II recruitment at the insulin promoter. Taken together, our data suggest that pre-mRNA species may be a more reliable reflection of acute changes to human insulin gene transcriptional rates and that glucose acutely enhances insulin transcription by a mechanism that enhances chromatin accessibility and leads to recruitment of basal transcriptional machinery.

    Title Assessment of Differences in Hla-a, -b, and -drb1 Allele Mismatches Among African-american and Non-african-american Recipients of Deceased Kidney Transplants.
    Date April 2007
    Journal Transplantation Proceedings
    Excerpt

    Among recipients of deceased donor kidney transplants, African-Americans experience a more rapid rate of kidney allograft loss than non-African-Americans. The purpose of this study was to characterize and quantify the HLA-A, -B, and -DRB1 allele mismatches and amino acid substitutions at antigen recognition sites among African-American and non-African-American recipients of deceased donor kidney transplants matched at the antigen level. In recipients with zero HLA antigen mismatches, the degree of one or two HLA allele mismatches for both racial groups combined was 47%, 29%, and 11% at HLA-DRB1, HLA-B, and HLA-A, respectively. There was a greater number of allele mismatches in African-Americans than non-African-Americans at HLA-A (P < .0001), -B (P = .096), and -DRB1 loci (P < .0001). For both racial groups, the HLA allele mismatches were predominantly at A2 for HLA-A; B35 and B44 for HLA-B; but multiple specificities for HLA-DRB1. The observed amino acid mismatches were concentrated at a few functional positions in the antigen binding site of HLA-A and -B and -DRB1 molecules. Future studies are ongoing to assess the impact of these HLA mismatches on kidney allograft loss.

    Title Evaluation of Vascular Complications of Pancreas Transplantation with High-spatial-resolution Contrast-enhanced Mr Angiography.
    Date February 2007
    Journal Radiology
    Excerpt

    PURPOSE: To retrospectively evaluate high-spatial-resolution contrast material-enhanced three-dimensional (3D) magnetic resonance (MR) angiography for assessment of vascular complications of pancreas allografts. MATERIALS AND METHODS: The institutional review board approved the study and waived the requirement for informed patient consent owing to the retrospective nature of the study with use of an anonymous-subject database. The study was HIPAA compliant. The clinical and MR angiography findings in 11 patients (eight men, three women; mean age, 43 years; age range, 30-54 years) who had a history of pancreatic transplant dysfunction and underwent a total of 13 contrast-enhanced 3D MR angiography examinations were retrospectively reviewed. Comparison with conventional angiography findings was possible for four MR angiography examinations, comparison with surgical findings was possible for two examinations, and clinical follow-up was possible for all examinations. Two observers in consensus and blinded to the clinical results performed image analysis of the arterial and venous segments. Classification agreement was assessed with quadratic weighted kappa statistics. RESULTS: Ten MR angiography examinations revealed vascular complications or signs suggestive of rejection. Only three examinations were considered to have completely normal results. All major complications were detected and included complete or partial arterial graft occlusion, stenosis of the arterial Y-graft caused by a kink, complete venous thrombosis, and arteriovenous fistula with pseudoaneurysm formation. For 46 arterial segments and 15 venous segments with angiographic and/or surgical comparison, overall agreement with MR angiography findings was nearly perfect (mean kappa, 0.983; standard error of the mean, 0.128). CONCLUSION: High-spatial-resolution MR angiography of pancreas allografts enables assessment of the arterial and venous vascular anatomy and can be used to reliably identify clinically relevant vascular complications.

    Title Development of Anti-human Leukocyte Antigen Class 1 Antibodies Following Allogeneic Islet Cell Transplantation.
    Date April 2006
    Journal Transplantation Proceedings
    Excerpt

    Currently there is minimal concern that islet allograft failure could result from the development of anti-human leukocyte antigen (HLA) antibodies reactive to the allograft. We report here a case of islet allograft failure where the recipient developed immunoglobulin G anti-HLA class I antibodies reactive to HLA antigens present in two of the three islet cell donors. The patient had no detectable anti-HLA antibodies prior to the transplant but these antibodies were detected approximately 4 months posttransplant. Of concern, these antibodies developed despite induction with anti-IL2R antibodies (Zenapex) prior to intraportal islet cell infusion, low-dose tacrolimus (12-hour troughs 3 to 5 ng/mL) and rapammune (target troughs 12 to 15 ng/mL). The patient was not presensitized with blood products or a previous allograft. Her husband, however, shared antigens present in one of the islet donors and the recipient could have been presensitized to her husband during her two pregnancies. This case clearly demonstrates that islet allografts can lead to development of anti-HLA antibodies, which can cause islet allograft failure, as is the case with solid organ transplants, and hence emphasizes the need to monitor for such antibodies pre- and posttransplant. Additionally it appears that currently recommended immunosuppression may not be sufficient to inhibit a humoral response to both alloantigens and autoantigens.

    Title Race and Electronically Measured Adherence to Immunosuppressive Medications After Deceased Donor Renal Transplantation.
    Date October 2005
    Journal Journal of the American Society of Nephrology : Jasn
    Excerpt

    Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26 to 0.72; P = 0.001). Cause of renal disease, Powerful Others health locus of control, transplant center, and dosing frequency were also associated with adherence. After adjustment for transplant center and dosing frequency, the association between black race and decreased adherence was substantially attenuated (OR, 0.65; 95% CI, 0.38 to 1.14, P = 0.13). Transplant center (P = 0.003) and increased dosing frequency (OR, 0.43; 95% CI, 0.22 to 0.86, for three or four times per day dosing; OR, 2.35; 95% CI, 1.01 to 5.45, for daily dosing; versus two times per day dosing; P = 0.003) remained independently associated with adherence. Other baseline demographic, socioeconomic, medical, surgical, and psychosocial characteristics were not associated with adherence. The transplant center and dosing frequencies of immunosuppressive medications are associated with adherence and explain a substantial proportion of the race-adherence relationship.

    Title Inflammatory Blockade Improves Human Pancreatic Islet Function and Viability.
    Date June 2005
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    The pathogenesis of pancreatic beta-cell death in diabetes mellitus is still under investigation. Inflammation is likely to be one of the factors responsible for beta-cell death during disease development. In this study, we have used a novel antiinflammatory compound, Lisofylline (LSF), to investigate the role of inflammatory blockade in protecting human pancreatic islets. LSF is a small synthetic molecule that reduces inflammatory cytokine production and action, improves beta-cell mitochondrial metabolism, and regulates immune activities. The present study has demonstrated that the treatment of human islets with LSF not only allows the retention of glucose responsiveness and insulin secretion in the presence of multiple proinflammatory cytokines, but also enhances basal insulin secretion of beta cells in vitro. LSF also significantly reduces islet apoptosis, protects beta cells from proinflammatory cytokine damage, and maintains cellular viability. In a mouse transplantation model, insulin independence could be reached in diabetic recipient mice by implantation of 30% fewer islets when LSF was used in islet culture compared to the control group. These results demonstrate that LSF profoundly enhances beta-cell function, and suggest the potential of using inflammatory blockade, such as LSF, to improve beta-cell function for islet transplantation.

    Title Contrast-enhanced Mr Angiography After Pancreas Transplantation: Normal Appearance and Vascular Complications.
    Date April 2005
    Journal Ajr. American Journal of Roentgenology
    Title Victor Satinsky (1912-1997) and the Success of His Partially Occluding Vascular Clamp.
    Date March 2005
    Journal Transactions & Studies of the College of Physicians of Philadelphia
    Title Successful Treatment of Encrusted Cystitis and Pyelitis with Preservation of Renal Graft.
    Date August 2004
    Journal Transplantation
    Title Short Sirolimus Half-life in Pediatric Renal Transplant Recipients on a Calcineurin Inhibitor-free Protocol.
    Date July 2004
    Journal Pediatric Transplantation
    Excerpt

    Immunosuppression with SRL may provide an opportunity to avoid long-term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3-21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m(2)/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12-h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post-transplant. Half-life (T(1/2)) and terminal T(1/2) were 9.7 (7.1-24.6) and 10.8 (4.4-95.2) hours (median, range) respectively at month 1, and were 9.6 (5-17.8) and 12.1 (4.7-71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r(2) = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r(2) = 0.04). During the first 3 months post-transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T(1/2) of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.

    Title Mycophenolic Acid Pharmacodynamics and Pharmacokinetics Provide a Basis for Rational Monitoring Strategies.
    Date January 2004
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Title The Use of Non-heart-beating Donors for Isolated Pancreatic Islet Transplantation.
    Date June 2003
    Journal Transplantation
    Excerpt

    Recent improvements in isolated islet transplantation indicate that this therapy may ultimately prove applicable to patients with type I diabetes. An obstacle preventing widespread application of islet transplantation is an insufficient supply of cadaveric pancreata. Non-heart-beating donors (NHBDs) are generally not deemed suitable for whole-organ pancreas donation and could provide a significant source of pancreata for islet transplantation. Isolated pancreatic islets prepared from 10 NHBDs were compared with those procured from 10 brain-dead donors (BDDs). The success of the isolation for the two groups was analyzed for preparation purity, quality, and recovered islet mass. The function of NHBD and BDD islets was evaluated using in vitro and in vivo assays. On the basis of the results of this analysis, an NHBD isolated islet allograft was performed in a type I diabetic. The recovery of islets from NHBDs was comparable to that of control BDDs. In vitro assessment of NHBD islet function revealed function-equivalent BDD islets, and NHBD islets transplanted to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice efficiently reversed diabetes. Transplantation of 446,320 islet equivalents (IEq) (8,500 IEq/kg of recipient body weight) from a single NHBD successfully reversed the diabetes of a type I diabetic recipient. Normally functioning pancreatic islets can be isolated successfully from NHBDs. A single donor transplant from an NHBD resulted in a state of stable insulin independence in a type I diabetic recipient. These results indicate that NHBDs may provide an as yet untapped source of pancreatic tissue for preparation of isolated islets for clinical transplantation.

    Title Successful Pta and Stenting for Acute Iliac Arterial Injury Following Pancreas Transplantation.
    Date June 2003
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Iliac artery injuries may occur during solid organ transplantation. We describe an approach to an iliac artery clamp injury after pancreatic allotransplantation. The patient is a 48-year-old diabetic male who underwent successful cadaveric pancreatico-duodenal transplantation complicated by a left common iliac artery clamp injury. The injury resulted in both graft and lower leg ischemia. The injury was recognized promptly and diagnosed by magnetic resonance angiogram (MRA). The lesion was successfully treated with percutaneous transluminal angioplasty and stenting with resolution of both graft and leg ischemia. We propose this technique as a minimally invasive approach to an iliac injury that can be used to treat vascular injuries during solid organ transplantation.

    Title Comparison of Open, Laparoscopic, and Hand-assisted Approaches to Live-donor Nephrectomy.
    Date August 2002
    Journal Transplantation
    Excerpt

    BACKGROUND: Minimally invasive donor nephrectomy has become a favored procedure for the procurement of kidneys from live donors. The optimal minimally invasive surgical approach has not been determined. In the current work, we compared the outcome of kidneys procured using the traditional open approach with two minimally invasive techniques: the standard laparoscopic procedure and a hand-assist procedure. METHODS: The function of live-donor kidneys procured by open versus minimally invasive procedures was compared (procedures compared were the traditional open donor nephrectomy [ODN], the standard laparoscopic [LAP] approach, and the hand-assisted [HA] laparoscopic technique). The length of donor operation, donor length of stay in the hospital, surgical complications, and cost of hospitalization for three groups of patients were assessed in a series of 150 live-donor nephrectomies. RESULTS: We found that both minimally invasive procedures yielded kidney allografts with excellent early function and a minimum of complications in the donor. The open procedure was associated with a reduced operative time but increased donor length of stay in the hospital. Resource utilization analysis revealed that both minimally invasive techniques were associated with a slight increase in costs compared with the open procedure, despite a shorter hospital stay. CONCLUSIONS: Minimally invasive donor nephrectomy is safe and effective for procuring normally functioning organs for live-donor transplantation. Of the two minimally invasive approaches examined, the hand-assisted technique was found to afford a number of important advantages, including facilitating teaching of residents and students, that it is more readily mastered by transplant surgeons, and that it may provide an additional margin of safety for the donor.

    Title Neoral Rescue Therapy in Transplant Patients with Intolerance to Tacrolimus.
    Date August 2002
    Journal Clinical Transplantation
    Excerpt

    BACKGROUND: The calcineurin inhibitors, cyclosporine and tacrolimus, are the mainstay of current immunosuppressive regimens for the prevention of acute rejection in organ transplantation. The choice of the individual agent used often depends on the preference of the Transplant Center and patient type. Adverse effects associated with tacrolimus may impact its clinical utility in many patients. This study characterizes the clinical outcomes of transplant recipients who experienced adverse effects from tacrolimus and were converted to cyclosporine-microemulsion-based (Neoral([cyclosporine, USP] MODIFIED) therapy. METHODS: Hepatic or renal allograft recipients unable to maintain adequate immunosuppression with a tacrolimus-based regimen for reasons of toxicity or efficacy were recruited for this study and converted to cyclosporine-microemulsion-based therapy. Data were collected on drug dosing, trough concentrations, and treatment duration, as well as detailed information on tacrolimus-associated toxicities that prompted rescue with cyclosporine-microemulsion. Furthermore, clinical and laboratory data related to the clinical course of the patients after conversion to cyclosporine-microemulsion were recorded for up to 1 yr following conversion. RESULTS: One hundred and fifty-seven transplant recipients were enrolled in this study. Predominant reasons for discontinuation of tacrolimus were neurotoxicity (55%), diabetes (24%), nephrotoxicity (15%), and gastrointestinal intolerance (24%). Patients frequently had multiple symptoms prompting rescue therapy with cyclosporine-microemulsion. Over 70% of subjects had improvement or resolution of their tacrolimus-associated adverse symptoms within 3 months post-conversion. Acute rejection episodes occurred in 27% of patients converted to cyclosporine-microemulsion. CONCLUSIONS: Cyclosporine-microemulsion rescue therapy in patients experiencing adverse clinical effects associated with tacrolimus is an effective treatment option which leads to resolution of these adverse effects in the majority of patients, and allows for satisfactory clinical outcomes.

    Title Intrathymic Islet Transplantation in the Canine: I. Histological and Functional Evidence of Autologous Intrathymic Islet Engraftment and Survival in Pancreatectomized Recipients.
    Date April 2002
    Journal Transplantation
    Excerpt

    BACKGROUND: Although an attractive alternative to daily insulin therapy, allogeneic pancreatic islet transplantation has yielded suboptimal results in clinical trials, in contrast to islet allotransplantation in animal models, which have demonstrated consistent success. The successful transplantation of isolated islets to the thymus, with a single concomitant dose of antilymphocyte serum, has been demonstrated in rodents, and more significantly, such intrathymic islet allografts have been shown to induce recipient tolerance toward subsequent extrathymic donor strain islet allografts. Intrathymic islet autotransplantation has been pursued, as a prelude to studies of allogeneic IT islet transplantation and tolerance induction, in canine, porcine, and non-human primate models, to assess the large animal thymus as a site capable of supporting a viable islet graft. However, little functional or histological evidence has established definitive survival of islets transplanted within the thymus of a phylogenetically advanced species, which may be requisite to tolerance induction. This study describes the successful intrathymic autotransplantation of isolated islets using a canine model. METHODS: Purpose-bred juvenile dogs, aged 4-6 months, underwent partial (n=4), or total pancreatectomy (n=11), and transplantation of autologous islets. The pancreas (or pancreatic limb) was distended with collagenase solution, and digested using a modification of the semiautomated system of Ricordi. Islets were purified by discontinuous gradient centrifugation, using Euroficoll (ficoll in Euro-Collin's kidney preservation solution). Partially pancreatectomized canines underwent IT transplantation of purified autologous islets (8000+/-4000 IEs), and were killed 8 weeks posttransplant. Totally pancreatectomized canines underwent transplantation of autologous islets to the liver (via portal vein embolization, n=5, IPO group) or the thymus (via direct IT injection, n=6, IT group), and were serially evaluated for a period of 8 weeks posttransplant to assess fasting blood glucose (FBG), serum insulin (SI) levels, and i.v. glucose tolerance (IVGTTs). K values (defined as the %-decrease/minute of the log(e) of blood glucose values) were calculated from IVGTT results. RESULTS: After autotransplantation in this cohort of animals, five of five IPO, and three of six IT islet recipients, remained normoglycemic (mean FBG< or =250 mg%) immediately posttransplant, and all recipients exhibited significantly elevated SI levels compared to apancreatic controls (n=10, followed 72 hr postpancreatectomy). Normal k values (=-1.1) were observed in two of five IPO, and in one of six IT recipients, 8 weeks after transplantation, and thymic tissue insulin content was increased compared to non-islet-bearing thymi (93.7+/-48.6 ng/g tissue vs. 0.7+/-0.4 ng/g tissue). At 8 weeks posttransplantation thymi from both partially and totally pancreatectomized animals were resected and processed for histological examination. Microscopic analysis of islet-bearing thymi revealed positive staining for islet-specific hormones (insulin and glucagon) within all IT recipients., Identification of islets within thymi of hyperglycemic IT recipients was problematic as islet beta cells were highly degranulated as a result of the recipients glycemic state. CONCLUSIONS: These results indicate that autologous islets, transplanted to the canine thymus, engraft, function, and survive for up to 8 weeks after islet autotransplantation to the canine thymus and establish the feasibility of intrathymic islet transplantation in a phylogenetically advanced animal model. The ability of islets to survive within the thymic environment for a period of at least 8 weeks after transplantation suggests that the successful induction of specific unresponsiveness secondary to intrathymic transplantation will not be impaired or limited by the inability of a viable islet mass to survive within the thymus for a sufficient period.

    Title Surgical Options for Live-donor Nephrectomy.
    Date March 2002
    Journal Transplantation Proceedings
    Title Pharmacokinetics and Concentration-control Investigations of Mycophenolic Acid in Adults After Transplantation.
    Date March 2002
    Journal Therapeutic Drug Monitoring
    Excerpt

    Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

    Title Clinical Utility of Monitoring Tacrolimus Blood Concentrations in Liver Transplant Patients.
    Date October 2001
    Journal Journal of Clinical Pharmacology
    Excerpt

    The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme-linked immunosorbent assay (ELISA) for monitoring whole-blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7-day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients.

    Title Annual Literature Review--clinical Transplants 2000.
    Date September 2001
    Journal Clinical Transplants
    Title Mechanism of Adenoviral-mediated Ctla4-ig Gene-induced Pancreatic Allograft Tolerance in Rats.
    Date June 2001
    Journal Transplantation Proceedings
    Title Long-term Localized Transgene Expression in the Pancreas Achieved by Intra-arterial Adenoassociated Virus-mediated Gene Transfer.
    Date June 2001
    Journal Transplantation Proceedings
    Title Pharmacokinetic, Pharmacodynamic, and Outcome Investigations As the Basis for Mycophenolic Acid Therapeutic Drug Monitoring in Renal and Heart Transplant Patients.
    Date May 2001
    Journal Clinical Biochemistry
    Excerpt

    Mycophenolate mofetil is widely used in combination with either cyclosporine or tacrolimus for rejection prophylaxis in renal and heart transplant patients. Although not monitored routinely nearly to the degree that other agents such as cyclosporine or tacrolimus, there is an expanding body of experimental evidence for the utility of monitoring mycophenolic acid, the primary active metabolite of mycophenolate mofetil, plasma concentration as an index of risk for the development of acute rejection. The following are important experimentally-based reasons for recommending the incorporation of target therapeutic concentration monitoring of mycophenolic acid: (1) the MPA dose-interval area-under-the-concentration-time curve, and less precisely, MPA predose concentrations predict the risk for development of acute rejection; (2) the strong correlation between mycophenolic acid plasma concentrations and expression of important cell surface activation antigens, whole blood pharmacodynamic assays of lymphocyte proliferation and median graft rejection scores in a heart transplant animal model; (3) the greater than 10-fold interindividual variation of MPA area under the concentration time curve values in heart and renal transplant patients receiving a fixed dose of the parent drug; (4) drug-drug interactions involving other immunosuppressives are such that when switching from one to another (eg, from cyclosporine to tacrolimus or vice-versa) substantial changes in MPA concentrations can occur in patients receiving a fixed dose of the parent drug; (5) significant effects of liver and kidney diseases on the steady-state total and free mycophenolic acid area under the concentration time curve values; (6) the need to closely monitor mycophenolic acid when a major change in immunosuppression is planned such as steroid withdrawal. Current investigations are focused on determination of the most optimal sampling time and for mycophenolic acid target therapeutic concentration monitoring. Further investigations are needed to evaluate the pharmacologic activity of the newly described acyl glucuronide metabolite of mycophenolic acid which has been shown to inhibit, in vitro, inosine monophosphate dehydrogenase.

    Title Reduced No Production Improves Early Canine Islet Xenograft Function: a Role for Nitric Oxide in Islet Xenograft Primary Nonfunction.
    Date February 2001
    Journal Cell Transplantation
    Excerpt

    Isolated canine islets transplanted to hyperglycemic rats fail to restore euglycemia in almost all cases, although the grafted islet tissue appears to be morphologically intact for up to 48 h following transplantation. Cytokines typically produced in the xenograft environment (e.g., IL-1 and TNF) inhibit insulin biosynthesis and secretion from isolated pancreatic islets, and are associated with the production of nitric oxide (NO). To further define the relationship between NO production and islet xenotransplantation, the inhibition of NO in a splenocyte/islet coculture system, and the in vivo effect of this inhibition on canine islet xenotransplantation, was investigated. Splenocytes (SPLC) from Lewis rats were cocultured with canine islets (freshly isolated or cultured 7 days), supernatant removed, and NO concentration (NO2) determined by optical density (Griess reaction, 550 nm, expressed as nmol nitrite/10(6) cells/18 h). Lipopolysaccharide (LPS) was used as a positive control of SPLC production of NO. Stimulation by LPS resulted in maximal NO production (2.20 +/- 0.16 nmol/10(6) cells/18 h, p < 0.001 compared to baseline values of 0.73 +/- 0.04 nmol/10(6) cells/18 h). In the presence of NO inhibitors (NMA, polymyxin B, hydrocortisone, aminoguanidine, DMSO), nitrite levels did not significantly rise above unstimulated values. Freshly isolated canine islets did stimulate NO production (1.26 +/- 0.12 nmol/10(6) cells/18 h, p < 0.001). In contrast, cultured canine islets did not stimulate NO production (0.84 +/- 0.09 nmol/10(6) cells/18 h). Transplantation of freshly isolated canine islets to STZ-diabetic recipient Lewis rats resulted in amelioration of hyperglycemia in only 50% (n = 6) of recipients 12 h posttransplant, with a return to hyperglycemia at all subsequent time points. Transplantation of 7-day cultured canine islets resulted in amelioration of hyperglycemia in 88% of recipients 12 h posttransplant and 63% of recipients 24 h posttransplant [p = 0.028, mean survival time (MST) = 1.0 days, n = 8]. Transplantation of canine islet xenografts with aminoguanidine therapy (BID, n = 11) resulted in amelioration of hyperglycemia in 100% of recipients at 12 h posttransplant, decreasing to 82% by 24 h following transplantation (p = 0.002, MST = 0.9 days). These results demonstrate that freshly isolated canine islets are potent stimulators of NO production by rat SPLC in vitro, and that culture of canine islets, or addition of NO inhibitors, abrogates stimulated NO production. These results also demonstrate a statistically significant improvement (p < 0.001) in early function of canine islet xenografts following 7 days of islet culture prior to transplant, and following recipient treatment with aminoguanidine. These studies suggest that the production of NO in the microenvironment of the graft site may adversely affect engraftment and function of canine islets, and suggest that the abrogation of islet-stimulated NO production may improve engraftment following islet xenotransplantation.

    Title Advances in Therapeutic Drug Monitoring for Immunosuppressants: a Review of Sirolimus. Introduction and Overview.
    Date August 2000
    Journal Clinical Therapeutics
    Title Gene Therapy Strategies to Facilitate Organ Transplantation.
    Date November 1999
    Journal Molecular Medicine Today
    Excerpt

    Organ transplantation is now the definitive therapy for many forms of end-organ disease, but chronic allograft rejection, the side effects of chronic immunosuppressive therapy and the severe donor organ shortage continue to limit its success. Gene therapy has the potential to prevent graft rejection by manipulating the immune response in the microenvironment of the graft or by facilitating the induction of tolerance. Genetic manipulation of stem cells to create transgenic and/or knockout animals that could serve as organ or cell donors could be combined with gene therapy approaches to overcome the problem of limited allogeneic donor organ supply.

    Title The Effect of Renal Insufficiency on Mycophenolic Acid Protein Binding.
    Date August 1999
    Journal Journal of Clinical Pharmacology
    Excerpt

    Mycophenolate mofetil (MMF) is commonly used in solid organ transplant recipients. MMF is converted to mycophenolic acid (MPA) upon reaching the systemic circulation. Many acidic drugs have altered protein binding in renal failure, and it is possible that MPA protein binding may be decreased. The authors studied 23 renal transplant recipients: 8 transplant patients (7 kidney, 1 kidney/pancreas) with chronic renal insufficiency (CRI) and 15 renal transplant patients with preserved renal function. Plasma was obtained for kinetic profiles of total MPA, free MPA, and its glucuronide metabolite (MPAG). Plasma was obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess in vitro differences in MPA protein binding. Average free fraction of MPA in patients with chronic renal insufficiency was more than double that of patients with normal renal function (5.8 +/- 2.7 vs. 2.5 +/- 0.4, p < 0.01). Free MPAAUC was almost doubled in the patients with chronic renal insufficiency versus controls (2.04 +/- .08 vs. 1.03 +/- 0.6, p < 0.01). MPA protein binding is decreased, and free MPA concentrations are increased in patients with chronic renal failure.

    Title Local Production of Ctla4-ig by Adenoviral-mediated Gene Transfer to the Pancreas Induces Permanent Allograft Survival and Donor-specific Tolerance.
    Date April 1999
    Journal Transplantation Proceedings
    Title Analysis, Pharmacokinetics and Therapeutic Drug Monitoring of Mycophenolic Acid.
    Date November 1998
    Journal Clinical Biochemistry
    Title Scientific Principles for Mycophenolic Acid Therapeutic Drug Monitoring.
    Date September 1998
    Journal Transplantation Proceedings
    Title Interaction Between Tacrolimus and Chloramphenicol in a Renal Transplant Recipient.
    Date July 1998
    Journal Transplantation
    Excerpt

    BACKGROUND: The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient. METHODS: An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation. RESULTS: Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicol CONCLUSIONS: Chloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

    Title Race and Delayed Kidney Allograft Function.
    Date May 1998
    Journal Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
    Excerpt

    BACKGROUND: Allograft survival among black recipients is poorer than among whites. Delayed allograft function is associated with a significant reduction in renal allograft survival. The relationship between delayed allograft function and black race is incompletely specified and was the focus of this investigation. METHODS: A non-concurrent study of 325 recipients of cadaveric allografts followed for the occurrence of delayed allograft function defined as dialysis during the first week following transplantation for the principal analysis. A secondary definition of delayed allograft function was formulated based on the serum creatinine 2 weeks after transplantation. Unadjusted and adjusted logistic regression analysis were used to examine the unconfounded relationship between race and delayed allograft function. RESULTS: Fifty-seven of 91 (62.6%) black recipients experienced delayed allograft function compared to 113 of 234 (48.3%) whites. The odds ratio for black race as a predictor of delayed allograft function was 1.80, P=0.02, (95% CI, 1.09, 2.95). This finding was stable despite adjustment for other predictors of delayed allograft function in a multivariate model, but the precision of this estimate was less (P=0.10) because of missing data. Additionally, adjusted models with imputed values for missing covariates, models using a secondary definition of delayed allograft function, and models excluding patients whose cyclosporin therapy was delayed, all consistently demonstrated a similar association between black race and delayed allograft function. CONCLUSIONS: This study demonstrated an increased risk of delayed allograft function among black recipients. This relationship may play a role in the poorer allograft outcomes experienced by black recipients. Given the negative effect of delayed allograft function on allograft survival, efforts to identify its modifiable risk factors should be a high priority.

    Title Pharmacokinetics of Mycophenolic Acid in Renal Transplant Patients with Delayed Graft Function.
    Date May 1998
    Journal Journal of Clinical Pharmacology
    Excerpt

    The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours (AUC0-12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high-performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, were applied to AUC0-12 of MPA and MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC0-12 of MPA increased as a function of time, although it was not possible to fit a statistical model to the data due to considerable among-patient variation in the pattern of increase with time. The AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values. The average creatinine concentration was maximal at day 1 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC0-12 of MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed pharmacokinetics normalized with improving renal function.

    Title Organ Transplantation in the Twenty-first Century.
    Date April 1998
    Journal The Urologic Clinics of North America
    Excerpt

    Major advances in the understanding of the immunologic process responsible for organ or cellular transplant rejection, a dramatic improvement in available immunosuppressive drugs, development of more sophisticated surgical techniques, and important progress in posttransplant intensive care over the last 30 years have led to a remarkable improvement in success following organ transplantation. Whereas excellent short-term survival of most transplanted organs is readily achieved, graft loss because of chronic rejection and the worsening problem of organ donor shortage remain major concerns in the field of transplantation. Recent advances in immunosuppressive drugs, induction of immunologic tolerance, and gene therapy strategies may help to prolong organ allograft survival in the future. Revised criteria for organ donation and xenotransplantation may one day solve the problem of organ supply. Today, as we approach the next millennium, we are optimistic that the elusive goal of immunologic tolerance will be achieved and perhaps applied to animal tissue. Such will certainly be the challenge for the next century.

    Title Prospective Investigations of Concentration-clinical Response for Immunosuppressive Drugs Provide the Scientific Basis for Therapeutic Drug Monitoring.
    Date March 1998
    Journal Clinical Chemistry
    Excerpt

    The performance of prospective concentration-clinical response investigations during the early stages of the development of new therapeutic agents can provide a more rigorous basis for therapeutic drug monitoring than the traditional retrospective review of drug concentrations vs clinical outcome. Here we discuss the application of the multicenter randomized concentration-controlled clinical trial study design, and related study designs, as applied to older commonly used and monitored drugs and to two new immunosuppressant drugs, mycophenolate mofetil and tacrolimus. Such studies can provide a more rigorous basis for assessing the risk/benefit associated with a target drug concentration in the individual patient and for designing future prospective pharmacokinetic and therapeutic drug monitoring investigations.

    Title Decreased Rejection Episodes in African-american Renal Transplant Recipients Receiving Mycophenolate Mofetil/tacrolimus Therapy.
    Date January 1998
    Journal Transplantation Proceedings
    Title Adenoviral Transfection of Isolated Pancreatic Islets: a Study of Programmed Cell Death (apoptosis) and Islet Function.
    Date July 1997
    Journal The Journal of Surgical Research
    Excerpt

    Gene therapy provides a potential technique to modify immunity in vitro and therefore may prolong graft survival in vivo. However, viral infection and gene transfer may damage target cells and interfere with biologic function. Viruses, including adenovirus, are known to be capable of modulating apoptosis and initiating cell death by either inducing or suppressing specific processes, depending on the virus and cell system studied. The effect of adenovirus on islet cell viability and function has not been examined in detail. In this study, the dose-dependent effect of an adenoviral vector on islet cell death and glucose-stimulated insulin secretion (GSIS) was investigated to establish a therapeutic window for the dose of viral vector administered. Isolated pancreatic rat islets were incubated with an adenovirus expressing a beta-galactosidase gene (AdHCMVsp1LacZ) at different viral concentrations [multiplicity of infection (MOI) 1:10, 1:100, and 1:1000]. Transfection rate, in vitro and in vivo islet viability, and occurrence of programmed cell death were determined 1, 3, and 7 days after transfection. Islets, transfected at MOI 1:10 and 1:100, demonstrated apoptosis not significantly different from nontransfected controls. Islets, transfected at MOI 1:1000, demonstrated a significant increase in apoptosis at 24 hr, which decreased over 7 days of culture. The increase in apoptosis was not reflected by a significant decrease in in vitro GSIS of surviving islet cells, as assessed by stimulation index following in vitro perifusion. SCID or nude mice transplanted with AdlacZ-transfected islets (MOI 1:100 and 1:1000) remained normoglycemic for > or = 30 days. These results demonstrate that transfection of islets using adenoviral vectors can be manipulated such that efficient expression of the gene product encoded by the transfected gene (beta-galactosidase) can be achieved at lower transfecting concentrations of the adenoviral vector (MOI 1:10, 20.2%; MOI 1:100, 30.7%) while preserving islet function. This efficiency of transfection may allow pretransplant manipulation of isolated islet cells without vector-specific alteration of islet function. In cases where high virus concentrations are required for efficient gene transfer (adequate expression of the transgene product), a deleterious effect of the vector on islet cell function, with increased cell loss due to increased apoptotic events, is predicted. Using the AdlacZ vector, cell loss by apoptotic mechanisms appears limited to the first days following coculture with high viral concentrations, and does not appear to influence in vitro or in vivo cell function of the surviving islet cells.

    Title Nk Cells, Macrophages, and Humoral Immune Responses Are Dominant in Primary Nonfunction of Islet Grafts in the Dog-to-rat Xenotransplant Model.
    Date July 1997
    Journal Transplantation Proceedings
    Title Il-10 and Tgf-beta Gene Transfer for Xenogeneic Islet Transplantation: Comparison of Effect in Concordant Vs Discordant Combination.
    Date July 1997
    Journal Transplantation Proceedings
    Title Transfer of Genes for Il-10 and Tgf-beta to Isolated Human Pancreatic Islets.
    Date July 1997
    Journal Transplantation Proceedings
    Title Il-10 and Tgf-beta Gene Transfer to Rodent Islets: Effect on Xenogeneic Islet Graft Survival in Naive and B-cell-deficient Mice.
    Date July 1997
    Journal Transplantation Proceedings
    Title Primary Nonfunction of Islet Xenografts in Rat Recipients Results from Non-t-cell-mediated Immune Responses.
    Date June 1997
    Journal Transplantation Proceedings
    Title Increased Dna Fragmentation in Isolated Rat Islets Following 24 Hour Co-culture with Cytokine Transgene-bearing Adenovirus is Dose Dependent, but Does Not Reduce Glucose-stimulated Insulin Secretion.
    Date June 1997
    Journal Transplantation Proceedings
    Title Is the Glucuronide Metabolite of Mpa Pharmacologically Active?
    Date April 1997
    Journal Transplantation Proceedings
    Title Single Center Analysis of Mycophenolate Mofetil and Neoral/prednisone Therapy for Prophylaxis of Rejection in African-american and Caucasian Transplant Recipients.
    Date April 1997
    Journal Transplantation Proceedings
    Title Adenoviral Transfection of Canine Islet Xenografts with Immunosuppressive Cytokine Genes Abrogates Primary Nonfunction and Prolongs Graft Survival.
    Date April 1997
    Journal Transplantation Proceedings
    Title Reversal of Acute Renal Allograft Rejection by Extracorporeal Photopheresis: a Case Presentation and Review of the Literature.
    Date November 1996
    Journal Journal of Clinical Apheresis
    Excerpt

    There is a clear need for well-tolerated immunomodulatory agents that can aid in the prevention of acute solid organ rejection. Extracorporeal photopherosis is an apheresis-based therapy that is currently available at many medical centers worldwide. Preliminary studies utilizing photopheresis with standard immunosuppressives have shown this therapy to successfully reverse acute cellular rejection of cardiac allografts with minimal toxicity. No formal evaluation of the role of extracorporeal photopheresis had been performed in renal transplantation. In this report, photopheresis was successfully utilized to treat acute cellular rejection in a patient with a renal allograft. This lends further support to the existing literature suggesting that photopheresis may be useful for the reversal of acute solid organ rejection. Although our experience with this patient is anecdotal, photopheresis merits further study as treatment for severe renal allograft rejection.

    Title Delayed Function Reduces Renal Allograft Survival Independent of Acute Rejection.
    Date October 1996
    Journal Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
    Excerpt

    BACKGROUND. Mechanisms by which delayed allograft function reduces renal allograft survival are poorly understood. This study evaluated the relationship of delayed allograft function to acute rejection and long-term survival of cadaveric allografts. METHODS. 338 recipients of cadaveric allografts were followed until death, resumption of dialysis, retransplantation, loss to follow-up, or the study's end, which ever came first. Delayed allograft function was defined by dialysis during the first week following transplantation. Multivariate Cox proportional hazards survival analysis was used to assess the relationship of delayed allograft function to rejection and allograft survival. RESULTS. Delayed allograft function, recipient age, preformed reactive antibody levels, prior kidney transplantation, recipient race, rejection during the first 30 days and rejection subsequent to 30 days following transplantation were predictive of allograft survival in multivariate survival models. Delayed allograft function was associated with shorter allograft survival after adjustment for acute rejection and other covariates (relative rate of failure [RR]+1.72 [95% CI, 1.07, 2.76]). The adjusted RR of allograft failure associated with any rejection during the first 30 days was 1.99 (1.23, 3.21), and for rejection subsequent to the first 30 days was 3.53 (2.9 08, 6.00). The impact of delayed allograft function did not change substantially (RR=1.84 [1.15, 2.95]) in models not controlling for acute rejection. These results were stable among several subgroups of patients and using alternative definitions of allograft survival and delayed allograft function. CONCLUSIONS. This study demonstrates that delayed allograft function and acute allograft rejection have important independent and deleterious effects on cadaveric allograft survival. These results suggest that the effect of delayed allograft function is mediated, in part, through mechanisms not involving acute clinical rejection.

    Title Long-term Culture or Complement Inhibition Improves Early Islet Function in Dog to Rat Islet Xenotransplantation.
    Date June 1996
    Journal Transplantation Proceedings
    Title Analytic Requirements for Immunosuppressive Drugs in Clinical Trials.
    Date March 1996
    Journal Therapeutic Drug Monitoring
    Excerpt

    Essential to the evaluation of (1) the pharmacokinetics, (2) concentration-effect relationships, and (3) the application of therapeutic drug monitoring, during new immunosuppressive drug clinical trials, is the development of validated analytical methodology for the measurement of pharmacologically active drug and metabolites in biofluids and tissues. The characteristics of analytical methodology developed for cyclosporines A and G, FK-506, mycophenolate mofetil, and rapamycin during clinical trials will be described. The advantages of establishing validated analytical methodology as early as possible during clinical trials include: (a) early identification of metabolites and their quantitative and pharmacological significance; (b) early development of interpretable PK and PK-PD data; (c) accrual of experience that will be directly useful in patient monitoring after drug approval; (d) optimization of analysis conditions; and (e) early development of reference methodology for therapeutic drug monitoring tests. A suggested set of performance criteria for drug analysis during clinical trials and thereafter will be presented.

    Title Cyclic Amp Phosphodiesterases of Human and Rat Islets of Langerhans: Contributions of Types Iii and Iv to the Modulation of Insulin Secretion.
    Date February 1996
    Journal Biochemical and Biophysical Research Communications
    Excerpt

    This study evaluated the contribution of isozymes of cAMP phosphodiesterase (PDE) to total PDE activity in human and rat islets using type-selective inhibitors. The effects of selected PDE inhibitors on insulin secretion from human and rat islets were also measured in order to assess the contribution of the various PDE isozymes to the modulation of insulin secretion. The data suggest that PDE III is quantitatively the most important PDE isozyme present in islets, accounting for up to 70% of the total activity. Lower, but measurable, levels of PDE IV activity were present. Approximately 20% of islet PDE is not inhibitable by agents selective either for PDE III or IV. Selective inhibition of PDE III stimulated insulin secretion, but inhibition of PDE IV had no effect. The effects of type-selective inhibitors on PDE activity and insulin secretion were similar in human and rat islets.

    Title Streptozotocin-induced Hyperglycemia in Rats: Analysis of Complement Activity After Streptozotocin Administration.
    Date February 1996
    Journal Transplantation Proceedings
    Title Case 3-1995. Three Patients Requiring Both Coronary Artery Bypass Surgery and Orthotopic Liver Transplantation.
    Date October 1995
    Journal Journal of Cardiothoracic and Vascular Anesthesia
    Title Engraftment and Function of Intrathymic Pancreatic Islet Autografts in Dogs.
    Date April 1995
    Journal Transplantation Proceedings
    Title Vancomycin-resistant Enterococci: an Emerging Pathogen in Immunosuppressed Transplant Recipients.
    Date April 1995
    Journal Transplantation Proceedings
    Title Nonimmunogenic Perinatal Islets, Transplanted Intrathymically to Bb/wor Recipients, Do Not Prevent Onset of Autoimmune Diabetes.
    Date January 1995
    Journal Transplantation Proceedings
    Title Microlymphocytotoxicity Assay to Assess Reactivity of Rodent Sera to Large Animal T Lymphocytes.
    Date January 1995
    Journal Transplantation Proceedings
    Title Fk-506 Therapeutic Drug Monitoring.
    Date January 1995
    Journal Clinical Chemistry
    Title Is Induction Therapy Necessary for Successful Simultaneous Pancreas and Kidney Transplantation in the Cyclosporine Era?
    Date November 1994
    Journal Transplantation Proceedings
    Title Cyclosporin A Inhibits Nitric Oxide Production in an in Vitro Xenogeneic Islet/splenocyte Co-culture System.
    Date November 1994
    Journal Transplantation Proceedings
    Title Noninvasive Evaluation of Bladder-drained Whole Pancreaticoduodenal Transplants with Magnetic Resonance Angiography.
    Date June 1994
    Journal Transplantation Proceedings
    Title In Vitro Assessment of Human Islets for Transplantation: a Comparison of Glucose-stimulated Insulin Secretion from Short-term-cultured (< 48 Hours) Versus Long-term-cultured (> 72 Hours) Human Islets.
    Date June 1994
    Journal Transplantation Proceedings
    Title Analysis of Donor Age and Cold Ischemia Time As Factors in Cadaveric Human Islet Isolation.
    Date June 1994
    Journal Transplantation Proceedings
    Title Comparison of Mhc-incompatible Intraportal Islet and Vascularized Whole-pancreas Transplantation in the Prehyperglycemic Phase of Autoimmune Diabetes.
    Date June 1994
    Journal Transplantation Proceedings
    Title Islet Xenografts in Mice and Rats: I. Exocrine Tissue is Detrimental to Engraftment and Survival of Human Islet Xenografts.
    Date June 1994
    Journal Transplantation Proceedings
    Title Islet Xenografts in Mice and Rats: Ii. Mixed Islet-spleen Cell Assay to Analyze Nitric Oxide Production and Inhibition in Xenogeneic Species Combinations.
    Date June 1994
    Journal Transplantation Proceedings
    Title Renal Transplantation at the University of Pennsylvania Medical Center: an Update of Results in the Cyclosporine Era.
    Date August 1993
    Journal Clinical Transplants
    Excerpt

    This chapter presents a summary of living-related, living-unrelated, and cadaver renal transplantation performed at the University of Pennsylvania Medical Center between January 1984 and October 1992. Over the past 9 years, 895 patients (557 males, 338 females, mean age 42 yrs) received 942 renal transplants; 599 patients received kidneys from cadaver donors (n = 627) and 296 patients received kidneys (n = 315) from living donors of all types. During this period, 151 patients were retransplanted, sometimes more than once (159 total retransplants, 124 secondary grafts, and 35 third or more transplants). An analysis of patient ant graft survival rates (calculated by actuarial methods) for different categories of transplant recipients was performed. Black recipients, as a racial subcategory, had the poorest graft outcome, especially when followed over the long term. Graft survival rates for Black recipients who were retransplanted with cadaver grafts were even worse and were noted to be similar to the diabetic population that received cadaver retransplants (66% vs 62% at 1 yr and 32% vs 25% at 5 yrs). Diabetic recipients of living-donor transplants had excellent graft survival results, similar to nondiabetic, living-donor recipients (patient survival rates 98% and 92% vs 97% and 92% at 1 and 5 yrs; graft survival rates 92% and 82% vs 92% and 82% at 1 and 5 yrs). HLA-identical recipients of first cadaver grafts demonstrated the best outcome in the entire cadaver series (graft survival rates 91% and 83% at 1 and 5 yrs, respectively). HLA-identical recipients of second or more cadaver grafts had poorer results than expected (50% graft survival at 1 yr) despite a 100% patient survival rate. HLA-identical recipients of living-related grafts had the best graft survival rates (96% at 1 yr and 94% at 5 yrs) and superior graft survival rates for retransplanted grafts as well (100% at 1 and 5 yrs). We conclude that in the last decade, patient and graft survival rates for cadaveric and living-donor renal transplants have improved dramatically relative to the results obtained in the pre-CsA era. Long-term graft survival in Black recipients remains lower than in other races, suggesting the need to analyze other factors to explain poorer graft survival in this recipient population. Results in diabetic recipients continue to be excellent at our center, encouraging the continuation of our aggressive approach to try to transplant diabetics as early as possible, particularly when a living donor is available.

    Title Occurrence and Prevention of Graft-vs-host Disease After Pancreaticoduodenal Transplantation in the Bb Rat.
    Date March 1993
    Journal Transplantation Proceedings
    Title Intrathymic Islet Allografts Prevent Hyperglycemia and Autoimmune Beta-cell Destruction in Bb Rats Following Transplantation in the Prediabetic Period.
    Date March 1993
    Journal Transplantation Proceedings
    Title Conversion of Exocrine Secretions from Bladder to Enteric Drainage in Recipients of Whole Pancreaticoduodenal Transplants.
    Date January 1993
    Journal Annals of Surgery
    Excerpt

    Between September 1984 and August 1991, 265 whole pancreaticoduodenal transplants were done at our institution, with bladder drainage of exocrine secretions through a duodenocystostomy. Seventeen patients subsequently underwent conversion from bladder to enteric drainage at 2 to 64 months after transplant. Eight conversion procedures were done to correct chronic intractable metabolic acidosis due to bicarbonate loss from the allograft: seven to alleviate severe dysuria, presumed secondary to the action of graft enzymes on uroepithelium; one to prevent recurrent allograft pancreatitis, presumed secondary to back pressure from the bladder; and one because of graft duodenectomy for severe cytomegalovirus duodenitis with perforation. None were done to correct technical complications from the initial transplant operation. The conversions were done by dividing the graft duodenocystostomy, then re-establishing drainage through a graft duodenal-recipient jejunal anastomosis. A simple loop of recipient jejunum was used for the duodenojejunostomy in 15 cases, and a Roux limb in two. One of those two cases had a previously created Roux limb that was available for use. The other was in the patient who underwent graft duodenectomy and subsequent mucosa-to-mucosa anastomosis of the pancreatic duct to a newly created Roux limb of jejunum. All patients experienced relief of their symptoms after operation. Two patients had surgical complications (12%), an enterotomy in one case, which was closed operatively, and an enterocutaneous fistula in the other case, which healed spontaneously with bowel rest and parenteral nutrition. The drawback to conversion is loss of urine amylase as a marker for rejection, particularly in recipients of solitary pancreas grafts (n = 5). In recipients of simultaneous pancreas-kidney (SPK) allografts (n = 12), the kidney can still be used to monitor for rejection (two with follow-up < 1 year, 10 with follow-up > 1 year). None of our solitary pancreas recipients, however, have lost graft function (follow-up, 10 to 36 months). The only pancreas allograft loss was in an SPK recipient who also rejected the kidney 6 months after conversion. She received a second SPK transplant with enteric drainage, and is insulin independent and normoglycemic 10 months after retransplantation. Patients converted for metabolic acidosis tended to have impaired renal function (mean creatinine, 2.14 +/- 0.98 mg/dL at time of conversion) due to chronic rejection, progression of native kidney diabetic nephropathy, or cyclosporine toxicity, and possibly could not compensate for bicarbonate loss from the pancreas allograft.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Neonatal Tolerance Induction in Diabetes-prone Bb Rats As a Model for Donor-specific Pancreas Transplantation During Adulthood.
    Date January 1993
    Journal Transplantation Proceedings
    Title Factors Leading to Improved Outcome Following Pancreas Transplantation--the Influence of Immunosuppression and Hla Matching.
    Date September 1992
    Journal Transplantation Proceedings
    Excerpt

    The results of pancreas transplantation continue to improve and do not appear to have plateaued worldwide. In the United States, pancreas graft survival rates are now similar or better than those for other organ transplants, particularly when the pancreas is transplanted simultaneously with a kidney. Since 1987, more than three fourths of uremic recipients of simultaneous pancreas and kidney grafts are insulin independent and dialysis-free more than 1 year after transplantation. Although there is room for improvement in the results of solitary pancreas transplants, more than half of these patients are insulin independent at 1 year. A successful pancreas transplant results in near normalization of glucose metabolism and lowers glycosylated hemoglobin to normal levels. While a successful pancreas transplant may not elevate all diabetic patients to the level of health and function of the general population, pancreas transplant recipients report a significantly better quality of life than do those patients who remain diabetic. As the success rate of pancreas transplantation continues to improve, this treatment should be considered as a means for restoring a normal glucose level in type I diabetic patients before the development of advanced, disabling complications of the disease. Our recommendation for an approach to minimizing the antirejection response and maximizing graft survival rates in pancreas transplant recipients is to use quadruple immunosuppressive therapy with the induction doses higher than those employed for other organ transplant recipients. For SPK recipients, the allocation of organs should follow the scheme used for that of a kidney alone.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Evaluation of Intrathymic Islet Transplantation in the Prediabetic Period.
    Date August 1992
    Journal Surgery
    Excerpt

    BACKGROUND. Beta-cell destruction in type I diabetes mellitus results from a chronic autoimmune process. Exposure of thymic T cells to islet antigens during the prehyperglycemic phase of diabetes may alter the likelihood of autoimmune damage to beta cells in the native pancreas. Thus we evaluated whether prophylactic major histocompatibility complex (MHC)-incompatible intrathymic islet allografts could prevent hyperglycemia and native pancreatic beta-cell destruction. METHODS. At 4 to 6 weeks of age, diabetes-prone BioBreeding rats received intrathymic injection of 1500 to 2000 noncultured MHC-incompatible Lewis islets. No immunosuppression was administered. Age-matched littermates underwent intrathymic injection of saline solution. RESULTS. None of 13 BioBreeding rat recipients of prophylactic intrathymic Lewis islet allografts became hyperglycemic versus 13 of 13 control rats (p less than 0.001). The age at onset of diabetes in the control group ranged from 77 to 104 days (mean, 86 days). Normoglycemia in recipients of intrathymic islet allografts persisted for greater than 8 months after transplantation, and thymectomy (graft removal) did not precipitate hyperglycemia. CONCLUSIONS. Prophylactic intrathymic MHC-incompatible islet allografts effectively prevent hyperglycemia and native beta-cell destruction in an animal model of autoimmune diabetes. Rejection and autoimmune destruction of intrathymic MHC-incompatible islet allografts were not seen after transplantation in the prediabetic (prehyperglycemic) period. Intrathymic islet allografts at an early age (before puberty) preserve native beta-cell function and may prevent or retard thymic atrophy.

    Title Influence of Pretransplant Cytomegalovirus Serology and Treatment of Rejection Upon Disease After Kidney and Kidney Plus Pancreas Transplantation.
    Date July 1992
    Journal Transplantation Proceedings
    Title Converting Exocrine Drainage from Bladder to Bowel in Recipients of Whole Pancreaticoduodenal Transplants.
    Date July 1992
    Journal Transplantation Proceedings
    Title Exocrine Dysfunction Evaluation of Bladder-drained Pancreaticoduodenal Transplants Using a Transcystoscopic Biopsy Technique.
    Date July 1992
    Journal Transplantation Proceedings
    Title A Comparison of Mice and Rats As Recipients for Canine Islet Xenografts.
    Date May 1992
    Journal Transplantation Proceedings
    Title Analysis of Infectious Complications Occurring After Solid-organ Transplantation.
    Date March 1992
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    To improve our understanding of posttransplant infections, we analyzed bacterial, viral, fungal, parasitic, and other infections in 604 consecutive recipients of kidney (n = 518), kidney-pancreas (n = 82), kidney-liver (n = 3), or kidney-islet (n = 1) allografts (355 cadaveric, 14 living-unrelated, 235 living-related donors) who also received cyclosporine, azathioprine, and prednisone immunosuppression. Recipients of cadaveric grafts received additional induction immunosuppression (antilymphocyte globulin or murine monoclonal antibody OKT3). Rejection episodes were treated with high-dose steroids, and either antilymphocyte globulin or OKT3 was administered when clinically indicated. Perioperative antibiotics and posttransplant prophylactic acyclovir sodium or ganciclovir sodium, trimethoprim-sulfamethoxazole, and clotrimazole or nystatin (Mycostatin) were administered to all recipients. Two hundred thirteen patients (35.3%) were found to have had no identifiable infections, while 391 (64.7%) had either isolated bacterial (97 [16.1%]), viral (53 [8.8%]), or fungal (34 [5.6%]) infections or combination (concurrent or sequential) infections with bacterial plus viral (46 [7.6%]), bacterial plus fungal (66 [10.9%]), viral plus fungal (20 [3.3%]), bacterial plus viral plus fungal (64 [10.6%]), or bacterial plus viral plus fungal plus parasitic (11 [1.8%]) pathogens in the posttransplantation period. Renal allograft survival (percentage, actuarial method) was diminished in patients with infections at both 1 year (91% vs 83%) and 3 years (81% vs 76%) after transplantation, as was actuarial patient survival (1 year, 97% vs 92%; 3 years, 93% vs 88%). We conclude that infection remains a major cause of both patient demise and allograft loss following successful solid-organ transplantation.

    Title Major-histocompatibility-complex Restricted and Nonrestricted Autoimmune Effector Mechanisms in Bb Rats.
    Date November 1991
    Journal Transplantation
    Excerpt

    To investigate whether the immunologic mechanisms of autoimmune pancreatic beta-cell destruction are MHC restricted, we examined the relative vulnerability of islet allografts from a panel of MHC-compatible and -incompatible donors to autoimmune damage after transplantation to spontaneously diabetic BB recipients. To circumvent a potentially confounding allograft response to the foreign islet graft, we utilized two strategies: (1) pretransplant in vitro culture of islets to delete intraislet APCs; and (2) induction of islet donor-specific immunologic tolerance in diabetes-prone BB rats. Experiments employing organ culture to prevent rejection demonstrated that MHC-incompatible grafts were significantly less vulnerable to autoimmunity than MHC-compatible grafts. In contrast, when we used the model of immunologic tolerance to exclude rejection, both MHC-compatible and -incompatible islet grafts were equally susceptible to autoimmune damage. The reason for this discrepancy has not been defined fully but may be related to our observation that tolerant BB animals exhibit increased peripheral blood NK-cell activity. NK cells are known to be cytotoxic to islets in vitro and could play a role in a non-MHC-restricted diabetogenic response in vivo. We conclude that both MHC-restricted and nonrestricted mechanisms are capable of contributing to anti-beta-cell autoimmunity in BB rats.

    Title Long-term Metabolic Function of Pancreas Transplants and Influence of Rejection Episodes.
    Date June 1991
    Journal Transplantation
    Excerpt

    Pancreas grafts, when not rejected, can sustain an insulin-independent state in type I diabetic recipients for indefinite periods. To what extent the metabolic control achieved approaches that of normal individuals, the relationships between graft endocrine and exocrine function, the effect of reversible rejection episodes on subsequent graft function, and the correlation between the results of serial tests of graft function were determined by studies at 1 month, 1 year, and 2 years in a cohort of 39 recipients (29 females, 10 males; mean age (+/- SD), 33 +/- 5 years; mean duration of diabetes, 22 +/- 6 years) of bladder-drained pancreas transplants performed between November 1984 and December 1988. Fifteen patients received a pancreas transplant alone, 8 a pancreas after a kidney, and 16 a simultaneous pancreas/kidney transplant. Graft endocrine function was tested by a 24-hr metabolic profile of blood glucose levels before meals, at 1 and 2 hr after meals, and during the night (14 values in all), by intravenous and oral blood glucose tolerance tests, and by glycosylated hemoglobin levels (HA1 and HA1c). Graft exocrine function was assessed by urine amylase activity (U/hr). The results of the tests in the recipients were subjected to paired comparisons between timepoints and at each timepoint to the results of the same tests in 55 normal nondiabetic control individuals. The means of the mean 24-hr profile glucose (mg/dl) values were significantly lower (P less than 0.05) at 1 and 2 years posttransplant (116 +/- 27 and 115 +/- 15, respectively) than at 1 month (128 +/- 31) in the recipients, but the mean of the mean values in the normal controls (100 +/- 7) was even lower (P less than 0.05). Mean values of individual timepoints during the profile were significantly lower for 6 of the 14 values in the controls than in the recipients. The mean IVGTT K value of the normal controls (-1.9 +/- 0.4%) was significantly lower than the 1-month and 2-year values of the recipients (-1.5 +/- 0.5% and -1.3 +/- 0.6%, respectively), but the comparison with the 1-year value (-1.6 +/- 0.6%) was not significant. The mean glucose levels at zero minutes and between 120 and 300 min of the OGTTs were significantly lower at both 1 and 2 years than at 1 month in the recipients, and the values in the control group were also significantly lower than in the recipients at 1 month but not at 1 and 2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Treatment of Invasive Cytomegalovirus Disease in Solid Organ Transplant Patients with Ganciclovir.
    Date February 1991
    Journal Transplantation
    Excerpt

    The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.

    Title The Organ Donor.
    Date February 1991
    Journal Critical Care Clinics
    Excerpt

    Vascularized organ transplantation is now a widely applied therapy for patients with end-stage diseases of the heart, lungs, liver, kidneys, and pancreas. A critical shortage of donor organs exists in the United States and, as a consequence, prospective transplant recipients die while waiting for a life-saving transplant. The apparent shortage of cadaver organs is, in large part, caused by the reluctance and failure of the physician and the public to promote cadaver organ donation. Educational awareness programs for both professional personnel and the public at large are needed to increase the number of potential donors and multiorgan procurements carried out. All victims of trauma with severe closed head injury or cerebrovascular catastrophe secondary to anoxia should be considered as potential organ donors and referred to the local organ procurement agency for evaluation.

    Title Percutaneous Transluminal Angioplasty: the Procedure of Choice for Renal Allograft Artery Stenosis.
    Date July 1990
    Journal Transplantation Proceedings
    Title Thymic Major Histocompatibility Complex Antigen Expression and Suppressor Cell Sparing by Cyclosporine.
    Date July 1990
    Journal Transplantation Proceedings
    Title Studies of Host Immunomodulation and Prevention of Pancreatic Beta Cell Destruction.
    Date May 1990
    Journal Transplantation Proceedings
    Title Liver Transplantation: Annotated References.
    Date December 1989
    Journal Current Opinion in Immunology
    Title Immunomodulation of Pre-diabetes in Bb Rats for Prevention of the Disease.
    Date July 1989
    Journal Advances in Experimental Medicine and Biology
    Title Studies of Prediabetes in the Spontaneously Diabetic Bb Rat.
    Date July 1989
    Journal Advances in Experimental Medicine and Biology
    Title Prevention of Autoimmune Damage to Islet Grafts in Bb Rats by Antibody Therapy.
    Date May 1989
    Journal Transplantation Proceedings
    Title Thymus Allografts Fail to Improve Lymphopenia or Prevent Autoimmune Diabetes in the Bb Rat.
    Date May 1989
    Journal Transplantation Proceedings
    Title Prevention of Recurrent Diabetes in Bb Rats After Islet Transplantation by Monoclonal Antibody Therapy.
    Date February 1989
    Journal Diabetes
    Excerpt

    Two immune responses imperil pancreatic islet allografts transplanted into subjects afflicted with autoimmune diabetes: 1) the well-described allograft response that is mounted against tissues bearing foreign transplantation antigens and 2) a recurrence of the beta-cell-specific autoimmune process responsible for the primary disease. To define the role of autoimmune response to transplanted islets, the possibility of a rejection response must be prevented. To accomplish this in spontaneously diabetic BB rats, we induced neonatal tolerance. We found that recurrent autoimmunity in tolerant BB rats can be prevented by treatment of recipients with the monoclonal antibody OX8 (specific for cytotoxic T-lymphocytes) but not W3/25 (specific for helper T-lymphocytes). These findings provide direct evidence for the role of OX8-bearing lymphocytes in autoimmune diabetogenesis.

    Title Prophylaxis of Serious Cytomegalovirus Infection in Renal Transplant Candidates Using Live Human Cytomegalovirus Vaccine. Interim Results of a Randomized Controlled Trial.
    Date December 1988
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    We report the interim results of a randomized, double-blind, placebo-controlled, clinical trial of prophylactic, live, attenuated cytomegalovirus (CMV) vaccination (Towne strain of CMV) of renal transplant candidates (RTCs). One hundred seventy-two RTCs were treated and subsequently underwent transplantation and followed up for at least one year and up to five years after transplantation. Eighty-eight RTCs received vaccine, and 84 received placebo. Results were analyzed according to the prevaccination serologic status (anti-CMV antibody titer) of the recipient (R- or R+) and the donor (D- or D+). The overall incidence of CMV disease was highest in the R-D+ group and almost absent in the R-D- group. There was no difference in the incidence of CMV infection or disease between vaccinated and respective placebo control recipients in either the R-D+, R+D+, R+D-, or R-D- groups. In contrast, the severity of CMV disease was significantly decreased in R-D+ vaccinees vs R-D+ placebo-treated recipients. Moreover, in the R-D+ group, one- and five-year cadaver renal allograft actuarial survival rates were 73% and 62%, respectively, for CMV vaccinees vs 40% and 25%, respectively, for control placebo patients. We conclude that seronegative cadaver RTCs may benefit from vaccination with live, attenuated, Towne strain CMV vaccine before transplantation.

    Title Immunoprediction of Diabetes and Evaluation of Pancreatic Islet Transplantation During the Prediabetic Period.
    Date September 1988
    Journal Surgery
    Excerpt

    The autoimmune diabetic syndrome of the biobreeding (BB) rat currently constitutes the best animal model for human type I diabetes. Since prediction of human beings at high risk for development of diabetes by immunologic and physiologic parameters is not possible at present, we investigated the feasibility of immunoprediction of diabetes in normoglycemic BB diabetes-prone (BBdp) rats. Peripheral blood lymphocyte counts (PBLC) accurately predicted future development of diabetes in a cohort of 50 BBdp rats (100% specificity, 95.8% sensitivity for PBLC less than 3800/mm3). We also assessed the fate of normal islets transplanted from MHC-compatible non-diabetes-prone Wistar Furth (WF) donors in the prediabetic milieu of BBdp hosts that were known on the basis of their PBLC destined either to become diabetic or to remain normoglycemic. In 13 BBdp rats in which diabetes was predicted the native pancreatic beta cells were eliminated at 35 days of age with streptozocin and replaced with transplanted WF islets. Neonatally induced tolerance of WF antigens prevented rejection. After successful islet transplantation, spontaneous diabetes occurred in 100% (5/5) of the rats in which the development of diabetes was predicted. The identical protocol in eight rats predicted not to have diabetes resulted in permanent normoglycemia in all. We conclude that normal islets are susceptible to anti-islet autoimmunity after transplantation in the prediabetic period.

    Title Prevention of Recurrent Autoimmune Diabetes in Bb Rats by Anti-asialo-gm1 Antibody.
    Date August 1988
    Journal Diabetes
    Excerpt

    BB rats exhibit a syndrome of spontaneous diabetes that has clinical and pathological characteristics analogous to those found in human insulin-dependent diabetes mellitus (IDDM). Islet tissue transplanted into spontaneously diabetic BB rats is uniformly destroyed by a recurrence of the autoimmune response that destroyed the diabetic subject's native islets. To examine recurrent autoimmune destruction of transplanted islets, it is necessary to exclude islet damage that might result from allograft rejection. We utilized neonatal tolerance induction to prevent rejection of Wistar-Furth (WF) (RT1u) islet allografts by spontaneously diabetic BB recipients. We determined that islet-recipient treatment with anti-asialo-GM1 (anti-AGM1) antibody prevents recurrent autoimmune diabetes that would otherwise destroy transplanted WF islet grafts. Anti-AGM1 therapy significantly decreased peripheral blood natural killer (NK) cell activity. These data suggest a role for NK cells in the pathogenesis of recurrent diabetes in neonatally tolerant BB rats.

    Title The Effect of Phenobarbital and Methylprednisolone on the Biotransformation of Cyclosporine in the Rat.
    Date June 1988
    Journal Transplantation Proceedings
    Title Predominance of Native Cyclosporine over Metabolites in Rat Blood and Tissue.
    Date June 1988
    Journal Transplantation Proceedings
    Title Prevention of Diabetes in Bb Rats by Intermittent Administration of Cyclosporine.
    Date August 1987
    Journal Surgery
    Excerpt

    The successful prevention of spontaneous autoimmune diabetes in biobreeding (BB) rats--the closest animal model to human type I diabetes mellitus--by daily administrations of cyclosporine (CsA) has prompted clinical trials of CsA immunosuppression in human diabetes. Although remissions from hyperglycemia have been achieved in human subjects, nephrotoxicity and recurrence of diabetes after discontinuation of CsA have been observed. Therefore we studied the biologic efficacy of intermittent administration of CsA, a theoretically less dangerous immunosuppressive protocol, in the prevention of spontaneous diabetes in the BB rat. Beginning at 30 to 49 or 50 to 55 days of age, treated animals (n = 86) received daily injections of CsA (15 mg/Kg) for 2 weeks (induction phase) and then twice weekly (maintenance phase) until 160 days of age. A third group of animals (n = 31) received daily CsA for 14 days only. Control littermates (n = 121) were not injected. All animals were followed to 275 days of age. Intermittent administration of CsA was determined to be a biologically effective regimen in the prevention of spontaneous diabetes in the BB rat. Blood levels of CsA and the major CsA metabolites were undetectable intermittently during the course of therapy. Major complications associated with CsA immunosuppression (nephrotoxicity, malignancy, and infection) were not associated with the intermittent CsA protocol. We conclude that spontaneous diabetes can be delayed and often permanently prevented by intermittent administration of CsA. This immunosuppressive regimen deserves further consideration as a biologically effective, but theoretically less toxic, therapeutic regimen.

    Title Salvage of Hyperacute Renal Transplant Hypoperfusion with Stent Placement: a Case Report.
    Date
    Journal Journal of Vascular and Interventional Radiology : Jvir
    Excerpt

    The authors report on a patient who underwent renal artery stent placement 6 hours after transplantation due to acute hypoperfusion of the transplant, which was diagnosed with intraoperative Doppler ultrasonography. Extensive atherosclerotic disease of the cadaveric transplant renal artery necessitated endarterectomy before creation of the anastomosis, and no further surgical options were considered feasible by the transplant surgeon. Six hours after the transplantation, percutaneous transluminal renal angioplasty and stent placement were performed, resulting in restoration of normal arterial flow and rescue of allograft function.

    Title Evidence That Low-grade Systemic Inflammation Can Induce Islet Dysfunction As Measured by Impaired Calcium Handling.
    Date
    Journal Cell Calcium
    Excerpt

    In obesity and the early stages of type 2 diabetes (T2D), proinflammatory cytokines are mildly elevated in the systemic circulation. This low-grade systemic inflammation exposes pancreatic islets to these circulating cytokines at much lower levels than seen within the islet during insulitis. These low-dose effects have not been well described. We examined mouse islets treated overnight with a low-dose cytokine combination commonly associated with inflammation (TNF-alpha, IL-1 beta, and IFN-gamma). We then examined islet function primarily using intracellular calcium ([Ca(2+)](i)), a key component of insulin secretion and cytokine signaling. Cytokine-treated islets demonstrated several features that suggested dysfunction including excess [Ca(2+)](i) in low physiological glucose (3mM), reduced responses to glucose stimulation, and disrupted [Ca(2+)](i) oscillations. Interestingly, islets taken from young db/db mice showed similar disruptions in [Ca(2+)](i) dynamics as cytokine-treated islets. Additional studies of control islets showed that the cytokine-induced elevation in basal [Ca(2+)](i) was due to both greater calcium influx through L-type-calcium-channels and reduced endoplasmic reticulum (ER) calcium storage. Many of these cytokine-induced disruptions could be reproduced by SERCA blockade. Our data suggest that chronic low-grade inflammation produces circulating cytokine levels that are sufficient to induce beta-cell dysfunction and may play a contributing role in beta-cell failure in early T2D.


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