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G W Burke

Publications and source records attributed to G W Burke.

At least 19 recordsLinked to original sources
PubMed2005

Immunosuppressive treatment options in renal transplantation.

An overview of the first 4 decades of clinical kidney transplantation would characterize progress primarily in the development of new immunosuppressive agents designed to reduce the incidence and severity of acute rejection to improve short-term outcomes, but with less marked effects on long-term patient and graft survival. The new trend of immunosuppressive therapy is to facilitate long-term allograft and patient survival, and to help to maintain a good quality of life after renal transplantation. To achieve these goals, transplant physicians need to determine the immunosuppressive protocols that will best minimize risk factors associated with reduced allograft/patient survival and quality of life. Recent protocols and clinical experience with modern immunosuppression strategies, as well as the efficacy and safety of various combination protocols, will be reviewed.

Adrenal Cortex Hormones↗
PubMed2003

Daclizumab as induction therapy in kidney and simultaneous pancreas-kidney transplantation.

Acute rejection still remains a major problem in organ transplantation and is a significant risk factor for chronic rejection, and chronic rejection is one of the most important causes of late graft loss. Current new immunosuppressive drugs such as tacrolimus, rapamycin and mycophenolate mofetil have been developed to reduce acute rejection and to improve renal allograft survival. More recently, antihuman antibodies, either monoclonal or polyclonal, have been developed to use for induction therapy at the time of transplantation or to treat rejection. Daclizumab, a new engineered human immunoglobulin monoclonal antibody to the interleukin-2 receptor a-subunit was approved to prevent acute rejection after solid organ transplantation. Data from clinical trials show daclizumab to be well tolerated in solid organ transplantation. It does not increase the incidence of infection, including cytomegalovirus infection.

Adrenal Cortex Hormones↗
PubMed2001

Six-year clinical effect of donor bone marrow infusions in renal transplant patients.

BACKGROUND: To date, several single- and multicenter clinical trials have attempted to induce specific immunological unresponsiveness using donor bone marrow cell infusions to augment solid organ transplantation, but the outcomes have not been definitive. METHODS: Between September 1994 and May 1998, 63 cadaver (CAD) renal transplant recipients of either one or two postoperative donor bone marrow cell (DBMC) infusions were prospectively compared with 219 non-infused controls given equivalent immunosuppression. There was at least a 1 HLA DR antigen match present between donors and recipients. The immunosuppressive regimen included a 10-day course of OKT3 induction, and tacrolimus, mycophenolate mofetil, and methylprednisolone maintenance. A total 7.01x10(8)+/-1.9x10(8) (SD) DBMC/kg was infused into the CAD recipients on either days 4 and 11 (n=42) or one half of that dose on day 4 (n=21) postoperatively. Clinical follow-up has ranged from 2.9 to 6.3 years (mean, 4.7 years). Studies were also performed of humoral immunity and quantitative cellular chimerism. RESULTS: There is clear-cut equivalence in immunosuppressive dosaging and in the other major demographic variables in both groups. However, only 2/63 DBMC recipients had biopsy-proven chronic rejection, whereas 41/219 showed chronic rejection in the controls (P = <0.01). In both groups, mortality was not associated with rejection. The actuarial graft survival at 6.3 years in the CAD DBMC group was 84.3% compared with 72.2% in the control group (not statistically significant). However, if death with a functioning graft was excluded, graft survival was 94.1% in the DBMC group and 79.8% in the controls (P=0.039). Forty patients in the control group continue to have deteriorating renal function (increasing serum creatinine concentrations to 2 mg/dl and higher), compared with 2 patients in the DBMC group (P=0.04). In the DBMC group, chimerism in iliac crest marrow aspirates has increased 3-fold in yearly sequential measurements between 1 and 4 years postoperatively averaging 1.3+/-0.36% (SE) most recently. This has not occurred in the controls. CONCLUSIONS: There now appears to be more solid long-term evidence, in kidney transplant recipients prospectively receiving DBMC infusions, of an improvement in long-term graft survival, and of the degree of chimerism positively correlating with the absence of graft loss.

Adolescent↗
PubMed2001

The use of intravenous tacrolimus and mycophenolate mofetil as induction and maintenance immunosuppression in simultaneous pancreas--kidney recipients with previous transplants.

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In attempting to obtain a low rejection rate without antibody induction therapy, we proceeded with the combination of TAC intravenous (i.v.), MMF, and steroids as induction therapy and as primary immunosuppression for recipients with previous transplants. In this study, we analyzed 10 patients who received previous transplants, treated with low-dose TAC i.v. as induction therapy. Group A consisted of 6 patients with previous transplants that underwent SPK and group B consisted of four recipients with previous SPK that underwent cadaveric kidney transplants. For group A, the previous transplants were: living related kidney (LRK) followed by islet cell (IC) transplant (n=2), LRK transplant (n=1), cadaver kidney (CAD) and IC transplant (n=1), SPK (n=1), and three previous CAD kidney transplants (n=1). In group A, all six kidneys were lost due to recurrent diabetic nephropathy, IC possibly to rejection, and the pancreas due to thrombosis. In group B with previous SPK transplants, three recipients lost their kidney to chronic rejection and one to long-term use of a nephrotoxic antibiotic. Currently, in all group A and B patients, the kidney and the pancreas are functioning, although 1 patient in group A developed type 2 diabetes (normal fasting C-peptide). Two patients in group A developed three rejection episodes that responded to steroid treatment. The results indicate the TAC i.v. in combination with oral TAC, MMF, and steroids offer effective induction therapy in patients with previous transplants.

Adult↗
PubMed2001

Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation.

HYPOTHESIS: Histological grade of hepatocellular carcinoma (HCC) is an important prognostic factor affecting patient survival after orthotopic liver transplantation (OLT). DESIGN: Retrospective analysis. SETTING: University-based teaching hospital. PATIENTS: Of 952 OLTs performed between June 1991 and January 1999, 56 OLT recipients had histologically proven HCC in the explant liver. Of those, 53 patients with complete clinicopathologic data were analyzed. A single pathologist blinded to the outcome of each patient reviewed all histological specimens. RESULTS: Median follow-up was 709 days. Overall survival for patients with tumors sized 5 cm or less at 1, 3, and 5 years was 87%, 78%, and 71%, respectively (Kaplan-Meier). Univariate analysis revealed the size, number, and distribution of tumors; the presence of microscopic vascular invasion and lymph node metastasis; histological differentiation; and pTNM stage to be statistically significant factors affecting survival. Multivariate analysis revealed histological differentiation and pTNM stage to be the independent and statistically significant factors affecting survival (P =.002 and.03, respectively). When pTNM stage was excluded from multivariate analysis, histological differentiation and size remained the significant independent factors (P =.02 and.03, respectively). Three-year survival for patients with small (</=5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 82% and 67%, respectively. Three-year survival for patients with large (>5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 62.5% and 0%, respectively. CONCLUSIONS: In our retrospective experience, histological differentiation had a statistically significant effect on the prognosis of HCC after OLT. However, before altering the current OLT selection criteria for patients with HCC, prospective studies are required to confirm the impact of histological grade on clinical outcome.

Carcinoma, Hepatocellular↗
PubMed2000

Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses.

BACKGROUND: Even though a number of transplant centers have adopted donor-specific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. METHODS: Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living-related-donor (LRD) renal transplant recipients, who had received perioperative donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and functionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. RESULTS: The yield of RdD cells ranged from 0.1 to O.9% of the starting material with the majority being TcRalphabeta, CD3 positive T cells, a substantial percentage of which coexpressed CD28. At 1 year posttransplant almost 50% of the LRD-kidney/DBMC recipients tested so far exhibited donor-specific unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 23 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor MLR and CML responses significantly more strongly than freshly isolated and similarly treated iliac crest bone marrow cells from the donor. RdD cells also inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than specific inhibition. We also established long-term bone marrow cultures stimulated every 2 weeks with irradiated alogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. CONCLUSIONS: These results clearly support the notion that the infused donor cells play a positive role in the induction and/or maintenance of transplant tolerance.

Bone Marrow Transplantation↗
PubMed2000

Involvement of multiple subpopulations of human bone marrow cells in the regulation of allogeneic cellular immune responses.

BACKGROUND: The identity of the cells in the human bone marrow that function as effective regulators of in vitro and possibly in vivo cellular immune responses is not well established. METHODS: Cell subpopulations were isolated from cadaver donor vertebral-body bone marrow cells (DBMC) by using immuno-magnetic microbeads and were tested as inhibitors (modulators) in cell-mediated lympholysis (CML) and mixed lymphocyte reaction (MLR) responses of normal peripheral blood lymphocytes stimulated with irradiated cadaver donor spleen cells. RESULTS: Compared with spleen cells as controls, un-irradiated T-cell depleted DBMC inhibited both the MLR and CML responses of allogeneic responder cells in a dose dependent manner (as in our previous reports). The inhibition was also mediated by a number of purified subpopulations including pluripotent CD34+ stem cells, and their CD34 negative early progeny of both lymphoid and myeloid lineages. These included DBMC enriched for non-T-cell lymphoid precursors (NT-LP/DBMC; i.e., DBMC depleted of CD3, CD15, and glycophorin-A positive cells) and DBMC positively selected for CD38+, CD2+, CD5+, and CD1+ lymphoid cells (all were depleted of CD3+ cells) as well as CD33+ (but CD15 negative) myeloid precursors. However, positively selected CD19+ B-cells and CD15+ myeloid cells did not inhibit the MLR and CML responses. The NT-LP/DBMC that had been repeatedly stimulated with irradiated allogeneic peripheral blood lymphocytes caused the strongest inhibition of the MLR and CML responses of the same allogeneic cells with 200 times fewer modulator cells needed than uncultured DBMC (P<0.001). Flow cytometric analysis revealed that majority of cells in these cell lines had become CD3+ TcR-alphabeta+ CD4+ and CD28+ cells. CONCLUSION: A variety of less differentiated cells of various lineages residing in the human bone marrow are immunoregulatory in vitro. Among them, there is at least one subset that can undergo differentiation in vitro into regulatory T cells that can be maintained in long-term cultures.

Antigens, CD34↗
PubMed2000

Successful surgical salvage of pancreas allografts after complete venous thrombosis.

BACKGROUND: Complete venous thrombosis of the pancreas after simultaneous pancreas-kidney (SPK) transplantation usually results in graft loss. We describe a technique that allows salvage of the graft after complete venous thrombosis. METHODS: A total of 150 patients with insulin dependent diabetes mellitus/end stage renal disease underwent SPK over the past decade at the University of Miami. Of these, three patients developed complete venous thrombosis after induction therapy with antiinterleukin-2R antibody and i.v. tacrolimus. These three patients underwent surgical thrombectomy followed by heparinization and oral anticoagulation. The splenic vein was opened distally at the tail of the pancreas and the superior mesenteric vein at the level of the mesentery or head of the pancreas. Thrombectomy was performed with a Fogarty catheter. The portal anastomosis was not opened or manipulated. The arterial "Y" graft was not clamped and the right iliac vein was controlled proximally with a double wrapped vessel-loop to contain possible thrombus. In one patient, the partially thrombosed splenic artery was opened at the tail of the pancreas and thrombectomy was performed in the same fashion. There were no apparent technical problems. A pancreatic biopsy was not performed, nor was acute rejection treated empirically. RESULTS: Intraoperative and serial Doppler ultrasound showed good flow through the allograft. In all three patients the exocrine and endocrine function of the pancreas was preserved with a mean follow-up of 15 months. CONCLUSIONS: The described surgical thrombectomy followed by systemic anticoagulation may be useful in the salvage of the allograft pancreas in case of complete venous thrombosis.

Adult↗
PubMed2000

Vascular complications following bladder drained, simultaneous pancreas-kidney transplantation: the University of Miami experience.

Vascular complications remain a significant nonimmunologic source of pancreas allograft loss. From February 1993 through January 1998, we performed 98 simultaneous pancreas-kidney transplantations (SPK) using pancreatic exocrine bladder drainage in patients with type 1 insulin-dependent diabetes mellitus and end-stage renal disease. They originally received quadruple immunosuppression, and since May 1997 triple immunosuppression protocol (tacrolimus, mycophenolate mofetil, and steroids). The patients' mean age was 37 years (range 24-53 years), including 50 women and 48 men with a mean follow-up of 42 months. The overall rate of vascular complications was 6% (5 patients). The vascular complications were as follows: late thrombosis of the Y with persistent pancreas allograft function (n = 1), rupture of a pseudoaneurysm of the superior mesenteric artery (PSMA) with an arteriovenous fistula (AVF) (n = 1), thrombosis of the splenic vein (SV) (n = 3), complete thrombosis of the superior mesenteric vein (SMV) and splenic vein (n = 1). The patient with PSMA underwent surgical correction of the AVF and PSMA with preservation of the allograft pancreas function. The other patient with late thrombosis of the Y-graft required no treatment. All 3 patients with SV thrombosis were systemically heparinized followed by oral anticoagulation. The patient with complete thrombosis required surgical thrombectomy of the SMV and SV followed by heparinization and oral anticoagulation. All 6 patients including the 4 with thrombosis had preservation of the pancreas function. Serial pancreas ultrasound showed resolution and improvement with recanalization of the splenic vein and superior mesenteric vein in those patients with thrombosis. We describe our vascular experience with salvage of the pancreatic allograft function. Surgery seems to be the best treatment option in the case of AVF or complete thrombosis of the allograft. Intravenous heparin followed by oral anticoagultion could be a conservative approach for SV thrombosis.

Adult↗
PubMed2000

Use of tacrolimus and mycophenolate mofetil as induction and maintenance in simultaneous pancreas-kidney transplantation.

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus and mycophenolate mofetil have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In an attempt to obtain a low rejection rate without antibody induction therapy, we undertook a prospective study of combined tacrolimus and mycophenolate mofetil and steroids as primary immunosuppression for SPK transplantation. In this study, we analyzed 17 patients who received low-dose intravenous tacrolimus as induction therapy. This was combined with oral tacrolimus, mycophenolate mofetil, and steroids as the primary immunosuppression regimen. There was a significant reduction of empirically and biopsy-proven rejection with an incidence of 23% (4 patients). Leukopenia, gastroparesis, and gastrointestinal side-effects were the cause of discontinuation of mycophenolate mofetil, or low tacrolimus trough level in those patients who developed rejection. All rejection episodes were easy to treat, and none of them required antibody therapy. The combination of tacrolimus with mycophenolate mofetil without antibody induction therapy is effective in preventing early acute rejection. This combination is safe and effective as an alternative immunosuppressive regimen after SPK transplantation.

Adult↗
PubMed2000

Partial venous thrombosis of the pancreatic allografts after simultaneous pancreas-kidney transplantation.

Despite new advances in transplantation, complete venous thrombosis (VT) of the pancreas after simultaneous pancreas kidney (SPK) transplantation usually results in graft loss. Data are limited regarding the outcome and treatment of partial VT of the pancreas allograft. From July 1994 to December 1999, 126 patients with IDDM/end-stage renal disease underwent SPK with systemic bladder drainage at the University of Miami. We retrospectively reviewed our experience regarding the outcome and treatment options of partial VT of the pancreas allografts. From July 1994 to April 1997, partial VT was not seen in the first 66 SPK patients induced with anti-CD3 rnAb and oral or intravenous (i.v.) tacrolimus (TAC) in the operating room. From May 1997 to June 1999, 14 (29%) out of 48 patients had VT. These cases were identified following the i.v. use of TAC with anti-IL-2R antibody-induction therapy (7/15) or without (7/33). Partial thrombosis of the splenic vein (PTSV) was documented in 10 patients, 2 had complete thrombosis of the splenic vein (CTSV), 1 had partial thrombosis of the superior mesenteric vein (PTSMV), and 1 patient had PTSV and PTSMV. These were identified incidentally during routine color Doppler ultrasonography (CDU). None of these SPK recipients demonstrates a change in clinical parameters. The first 8 patients were systemically heparinized, followed by oral anticoagulation, except 1 patient with CTSV. He progressed to complete thrombosis of the pancreas allograft and was treated with percutaneous thrombectomy and urokinase infusion, followed by heparinization and oral anticoagulation. One patient required exploration for bleeding. In an attempt to reduce the morbidity of heparinization, we treated the next 6 patients with PTSV with aspirin followed by serial CDU. All 14 patients had preservation of the endocrine and exocrine pancreatic functions. CDU showed resolution with recanalization of the thrombosed vein(s). From July 1999 to December 1999, 12 SPK recipients were administered TAC orally with or without induction therapy with anti-IL-2R antibody. So far, in this group, VT has not been identified. In summary, a total of 14 out of 126 patients (11%) had isolated VT with a mean follow-up of 36.4 months. Based on our experience, we suggest that extensive VT after pancreas transplantation, including splenic and superior mesenteric VT, be treated with heparin and subsequent oral anticoagulation for 3 months. For more limited, partial splenic VT, aspirin may be sufficient. Follow-up CDU is critical for a successful outcome. The i.v. use of TAC appears to be a risk factor for the increased incidence of VT. Currently, using IL-2rmAb as induction, TAC is started orally on postoperative days 3 or 4 and aspirin on postoperative day 2.

Adult↗
PubMed2000

Current treatment practice in immunosuppression.

New drugs have recently been added that may eventually replace the two-decade dominance of cyclosporin in solid organ transplantation. This cornerstone of immunosuppression was introduced by Borel [1] and Calne [2] in the mid-70s. In 1989, Starzl et al., after 2 years of preclinical experimentation, introduced tacrolimus (originally designated as FK506 by the Fujisawa Pharmaceutical Company of Japan) as a potent immunosuppressant for liver transplants [3]. Also, in recent years, a variety of novel purine and pyrimidine biosynthesis inhibitors have been tested for transplantation therapy. The leading agent which appears to be replacing the 35-year position occupied by azathioprine is the semi-synthetic morpholinoethyl ester of mycophenolic acid (MPA), mycophenolate mofetil (MMF), introduced by Allison [4] and Sollinger [5], and developed by the Syntex Corporation (now Roche Pharmaceuticals). Others, affecting different intra- or intercellular messages amplifying immunity, are in the pipeline.

Antibodies↗
PubMed2000

Allograft pancreatic duct dilatation following bladder drained simultaneous pancreas-kidney transplantation: clinical significance.

OBJECTIVE: Radiologic imaging of the allograft pancreatic duct dilatation is an uncommon multifactorial finding that is not well described. The purpose of this investigation is to determine the clinical correlation of this finding. DESIGN: Retrospective study. SETTING: University Hospital, USA. SUBJECTS: One hundred forty five simultaneous pancreas-kidney transplants have been performed for treatment of type I diabetes mellitus and end-stage renal disease between February 1993 and December 1999 at the University of Miami. MAIN OUTCOME MEASURES: In 5 recipients, the pancreatic duct was noted to be dilated by ultrasound 1-18 months post-transplant. RESULTS: In all 5 recipients a Foley catheter was placed as the first line of treatment. This reduced the size of the pancreatic duct in one patient, who presented with normal serum amylase and lipase and hyperglycemia. A pancreas biopsy done with Foley catheter in place showed fibrosis with no evidence of rejection. Four patients with dilated pancreatic duct presented with increased serum amylase and lipase; however improvement of the pancreatic duct dilatation was seen only after anti-rejection therapy. One of the patients developed recurrence of pancreatic duct dilatation and a video-urodynamic study subsequently demonstrated voiding with abdominal straining and no detrusor activity. He ultimately underwent enteric conversion with resolution of pancreatic duct dilatation. CONCLUSIONS: This infrequent complication of dilated transplant pancreatic duct could be multifactorial. It could suggest the diagnosis of reflux pancreatitis, which should resolve with bladder decompression. In fact, 1 patient presented with reflux pancreatitis caused by external sphincter detrusor pseudodyssynergia. However, this ultrasound finding may also be associated with pancreas rejection (4/5 patients).

Adult↗
PubMed1999

Microangiopathy in kidney and simultaneous pancreas/kidney recipients treated with tacrolimus: evidence of endothelin and cytokine involvement.

BACKGROUND: In the past 3 years, three transplant recipients [one kidney, two simultaneous pancreas/kidney (SPK)] developed a thrombotic thrombocytopenic purpura-like clinical syndrome. This was characterized by an abrupt fall in the hematocrit and platelet count with evidence of hemolysis (fragmented red blood cells and schistocytes) and transplant kidney dysfunction during the first 2 weeks after transplantation. This was also associated with pancreatic dysfunction in the two SPK recipients. In all three patients, elevated tacrolimus levels (>24 ng/ml) occurred. METHODS: Serum cytokine and endothelin levels were determined retrospectively from stored (-70 degrees C) sera. RESULTS: In each case tacrolimus was discontinued, and treatment with plasmapheresis, fresh frozen plasma, steroids, and OKT3 was begun. The clinical courses varied from mild (one patient), to moderate (one patient), to severe (one patient), complicated with seizures and coma. Each patient responded clinically and ultimately was converted to cyclosporine A, and/or mycophenolate mofetil. These clinical events were associated with a rise in serum levels of endothelin and several cytokines. Levels of endothelin were elevated at 209+/-137 pg/ml, particularly in the severe episode where peak levels reached 480 pg/ml (normal 0-20 pg/ml). Peak levels of IL-8 (104+/-36 pg/ml), interleukin- (IL) 10 (238+/-105 pg/ml), and/or IL-12 (306+/-119 pg(ml) mean+/-SE, occurred during or before the clinical event. Serum levels of tumor necrosis factor-a and interferon-gamma were elevated in 2 patients while levels of IL-2, IL-4, and IL-6 were not elevated during the acute phase. CONCLUSIONS: These data are consistent with a mechanism of microangiopathy involving endothelial cell injury (associated with tacrolimus treatment), and accompanied by cytokines (IL-10, IL-12, tumor necrosis factor-a, interferon-gamma) that affect expression of adhesion molecules, chemokines (IL-8) that direct the influx of white blood cells and endothelins that may exacerbate underlying hypertension and increase shear force-related red blood cell destruction.

Adult↗