Hand-assisted laparoscopic donor nephrectomy for morbidly obese patients.
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Body Mass Index↗
Biomedical subjects
M D Stegall
Publications and source records attributed to M D Stegall.
Thymoglobulin induction decreases rejection in solitary pancreas transplantation.
BACKGROUND: Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS: Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS: The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS: Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.
Adult↗
alpha4 integrin in islet allograft rejection.
BACKGROUND: Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between alpha4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. METHODS: Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against alpha4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of alpha4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. RESULTS: Treatment with anti-alpha4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-alpha4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, alpha4 integrin+, cytotoxic T cells. CONCLUSIONS: These data show that alpha4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualitatively affecting either T cell activation or migration to the graft. Conversely, anti-alpha4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between alpha4 integrin and its ligands may provide novel forms of immunosuppression.
Animals↗
Cyclosporine elimination in the presence of TOR inhibitors: effects on renal function, acute rejection, and safety.
Sirolimus in combination with cyclosporine reduces the incidence of acute rejection in renal transplant recipients when administered in double- or triple-therapy immunosuppressive regimens. Sirolimus administered as primary therapy has a beneficial effect on renal function, and the frequency of rejection episodes is similar to that of primary immunosuppression with cyclosporine. A strategy that may result in a more benign immunologic course with a substantially beneficial effect on renal function is to administer sirolimus and a calcineurin inhibitor early after transplantation, thereby promoting immunologic adaptation, and then to withdraw the calcineurin inhibitor at some point after transplantation to prevent nephrotoxicity. This article examines the results of this approach in recent studies that evaluated the effect of cyclosporine withdrawal on renal function, acute rejection, and safety in patients treated with sirolimus. Two open-label randomized trials of cyclosporine withdrawal were conducted in the United States, Canada, Europe, and Australia. In one of the studies, graft survival, patient survival, and the incidence of acute rejection at 6 months posttransplantation were not statistically significantly different between the patients receiving cyclosporine and the group that had undergone cyclosporine withdrawal. Furthermore, significantly better renal function was observed in the patients who underwent cyclosporine withdrawal compared with patients who continued to receive full-dose cyclosporine. These studies indicate that cyclosporine withdrawal has a beneficial effect on renal function without a significant increase in the incidence of acute rejection episodes.
Acute Disease↗
Donor scoring system for cadaveric renal transplantation.
We studied early renal function in 241 consecutive patients who received cadaveric renal transplants at two different transplantation centers (group 1, n = 90; group 2, n = 151). Univariate and multivariate analyses of data from group 1 showed a significant correlation between seven donor variables and early renal function after cadaveric renal transplantation. A scoring system was developed from these seven donor variables (cause of death, 0-6 points; history of hypertension, 0-6; final creatinine clearance before procurement, 0-6; age, 0-6; history of diabetes mellitus, 0-3; cold ischemia time, 0-3; and severity of renal artery plaque, 0-3). Data from group 2 were used to validate the donor scoring system and stratify cadaver kidneys on the basis of score: grade A, 0-5 points; grade B, 6-10; grade C, 11-15; and grade D, 16-32. A significant decline in early renal function was observed with increasing donor score and grade of cadaver kidney. In conclusion, a donor scoring system based on information available at the time of procurement can be used to estimate early graft function after cadaveric renal transplantation and may assist in the allocation of marginal organs.
Adolescent↗
Pancreas transplantation for the prevention of diabetic nephropathy.
Diabetic nephropathy is the leading cause of kidney failure in the United States. Poor glycemic control, hypertension, and smoking have been implicated as risk factors for the development and progression of diabetic nephropathy in patients with type 1 diabetes mellitus. Improved medical therapy including angiotensin-converting enzyme inhibitors and tight glycemic control with use of intensive insulin therapy have been shown to reduce the progression of diabetic nephropathy substantially based on albumin excretion rates. Despite these improvements in medical management, many patients still experience progression from early diabetic nephropathy to end-stage renal disease. Successful pancreas transplantation leads to normal glycemic control in patients with type 1 diabetes, but historically it has generally been limited to patients with both kidney failure and diabetes. In this review of the current treatment of diabetic nephropathy, we examine the potential role of preemptive pancreas transplantation in patients with diabetic nephropathy.
Albuminuria↗
Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.
BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.
Adult↗
Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus.
BACKGROUND: The long-term complications of immunosuppressive therapy such as diabetes, hypercholesterolemia, and hypertension are a major source of morbidity in liver transplant recipients. In this prospective, randomized, open-label study we completely withdrew prednisone (PRED) 14 days after liver transplantation in an effort to decrease these metabolic complications. Patients were maintained on mycophenolate mofetil (MMF) in combination with either cyclosporine (CsA; Neoral formulation) or tacrolimus (TAC). Thus, we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy, toxicity, and effect on posttransplant metabolic complications. METHODS: A total of 71 patients were randomized to receive either TAC-MMF (n=35) or CsA-MMF (n=36) after liver transplantation and were analyzed for patient and graft survival. Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes, hypertension, and hypercholesterolemia. RESULTS: The 6-month patient survival rates were 94.4% for CsA-MMF and 88.6% for TAC-MMF. Corresponding 6-month graft survival rates were 88.7% and 85.71% with no immunologic graft losses in either group. The incidence of biopsy-proven acute rejection was 46% for CsA-MMF and 42.3% for TAC-MMF. Six patients were converted from CsA to TAC (four for recurrent rejection) and seven patients were converted from TAC to CsA (four for neurotoxicity). Only one patient (in the TAC-MMF group) developed new-onset posttransplant diabetes. In contrast, four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant. The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group (145.2+/-41.8 mg/dl and 190.3+/-62.2, respectively; P<0.001) and the incidence of hypertension was lower in the TAC-MMF group (12% vs. 30.3% in the CsA-MMF group, P<0.01). Both groups had a lower incidence of metabolic complications compared with a historical group (n=100) maintained on CsA and PRED (10 mg/day at 6 months). CONCLUSIONS: MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses. Early PRED withdrawal decreases posttransplant diabetes, hypercholesterolemia, and hypertension, but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients.
Acute Disease↗
Prednisone withdrawal late after adult liver transplantation reduces diabetes, hypertension, and hypercholesterolemia without causing graft loss.
We prospectively withdrew prednisone in 28 adult patients who had stable graft function more than 2 years after orthotopic liver transplantation (OLTx) and had been on 5 mg/d prednisone for at least 6 months. Prednisone was decreased from 5 mg/d to 2.5 mg/d for 1 month then stopped completely. Cyclosporine monotherapy was maintained at a level of approximately 200 ng/mL (TDX). Nineteen patients had prednisone withdrawn without complications. Four (14.2%) had modest elevations in liver function tests (two biopsy proven mild rejections and two were not biopsied). These four were treated with methylprednisolone boluses and then withdrawal of steroids again. Prednisone was restarted in five patients because of generalized fatigue and body aches (n = 4) and colitis (n = 1). Steroids later were successfully withdrawn in two of these patients. After prednisone withdrawal, three of five insulin-dependent diabetic patients were able to discontinue insulin therapy and their glycosylated hemoglobin levels improved. Four of fourteen hypertensive patients were able to discontinue antihypertensive medicines. Mean serum cholesterol decreased from 222.6 +/- 43.3 to 188.3 +/- 33.3 mg/dL (P < .001). The number of patients with serum cholesterol levels > 220 mg/dL decreased from 13 to 4. A control group of 24 patients maintained on 5 mg/d prednisone at least 2 years after liver transplantation also was studied. In this group during the study period, no diabetic became normoglycemic, no patient decreased their antihypertensive medicine, and the mean serum cholesterol levels did not change significantly. We conclude that prednisone withdrawal using cyclosporine monotherapy late after liver transplantation does not lead to graft loss and decreases the prevalence of diabetes, hypertension, and hypercholesterolemia. Symptoms occurring during withdrawal may be minimized by earlier or slower tapering.
Adult↗
Monitoring human islet allografts using a forearm biopsy site.
OBJECTIVES: Despite the increasing success of whole-organ pancreas transplantation, the success of clinical islet allografts has remained limited. One of the factors limiting the success is the difficulty in monitoring islet allografts after transplantation. The aim of these studies is to develop a method of "biopsying" human islet allografts using a forearm islet implantation site. METHODS: A subtherapeutic number of isolated human islets were placed in the forearm under the muscle fascia in three human recipients with Type I insulin dependent diabetes. All of the recipients had undergone successful cadaveric renal transplantation at least one year prior and were maintained on their baseline immunosuppression. Aliquots of the islet grafts were removed 7 and 14 days to assess engraftment and graft infiltrate. To verify that the islets were viable, 400 were handpicked and transplanted into B6-scid mice made diabetic with streptozotocin. RESULTS: The biopsy site was found in all three cases. In one patient, no islets were recovered. In two other patients, viable islet tissue was recovered 7 days after transplantation. Immunohistology at 7 days showed the presence of both insulin and glucagon-staining cells in the islets. At 14 days in these two patients, a mononuclear cell infiltrate was observed in the explanted islet biopsies. Immunohistology showed the relative absence of insulin-staining cells with intact glucagon-staining cells. This finding is consistent with recurrent autoimmunity in the islet grafts. DISCUSSION: This preliminary study shows that the forearm biopsy site is a useful method to retrieve human islet grafts after transplantation. The islets engraft and are easily found in the first weeks after transplantation. These data suggest that recurrent autoimmunity may affect islet allografts. Further studies will be needed to determine if the histology in the forearm will correlate with the fate of intraportal or intraperitoneal islet allografts. Although they were shown to reduce the incidence of early allograft failure, their influence on the long-term graft survival remains to be proven.
Animals↗
Evidence of recurrent autoimmunity in human allogeneic islet transplantation.
We transplanted 10,000 isolated, handpicked human pancreatic islets into the subfascial compartment of the forearm muscle of a type I diabetic recipient who had received a successful renal transplant one year prior. The recipient was maintained on his usual immunosuppressive therapy of cyclosporine, azathioprine, and prednisone. A biopsy performed 7 days after transplantation showed normal islets with both insulin- and glucagon-staining cells present and no lymphocytic infiltration. A second biopsy performed 14 days after transplantation showed a dense mononuclear cell infiltrate with a preferential loss of insulin-staining cells relative to glucagon-staining cells in the islets. These data are consistent with recurrent autoimmune diabetes in an isolated islet allograft in an immunosuppressed type I diabetic recipient. In addition, this forearm subfascial site may be a useful means to monitor islet rejection and autoimmune recurrence in therapeutic intraportal islet allografts.
Adult↗
Autoimmune destruction of islet grafts in the NOD mouse is resistant to 15-deoxyspergualin but sensitive to anti-CD4 antibody.
Islet allografts transplanted into Type I diabetic recipients may be destroyed by allorejection or recurrent autoimmune diabetes. We studied islet transplantation in three murine models in order to determine the relative sensitivity of autoimmunity and alloimmunity to two immunosuppressive agents that may be useful in clinical islet transplantation: 15-deoxyspergualin (DSG) and anti-CD4 antibody (GK 1.5). In the model in which only allorejection occurs (BALB/c islets transplanted into streptozotocin-induced diabetic CBA or streptozotocin-induced diabetic NOD recipients), both DSG and anti-CD4 antibody treatment led to indefinite survival of allogeneic islets (>100 days in both treatments). In the second model in which only recurrent autoimmunity can destroy islet grafts (islets from NOD donors transplanted into spontaneously diabetic NOD recipients), only anti-CD4 treatment caused prolonged graft survival [MST 36.7 +/- 6.8 days vs 9.8 +/- 1.8 days (controls), P < 0.0002]. Treatment with DSG did not cause any increase in graft survival (MST 12.6 +/- 5.4 days, NS). Finally, using a model in which both autoimmunity and allorejection may occur (BALB/c to spontaneously diabetic NOD mice), treatment with anti-CD4 caused marked graft prolongation [42.0 +/- 14.5 days vs 7.2 +/- 0.8 days (control), P < 0.002] while DSG again did not prolong graft survival with respect to untreated recipients (9.8 +/- 3.0, NS). We conclude that recurrent autoimmunity in the NOD mouse involves a CD4+ T cell that is not sensitive to DSG. Anti-CD4 antibody may be useful in human clinical islet transplantation trials because it seems to prevent both allorejection and recurrent autoimmunity.
Animals↗
Metabolic complications after liver transplantation. Diabetes, hypercholesterolemia, hypertension, and obesity.
We retrospectively studied the incidence of diabetes, hypercholesterolemia, hypertension, and obesity in 123 consecutive adult liver transplant recipients (61 men and 62 women) who were alive at least 1 year after transplantation. We also studied the change in these metabolic complications in 61 patients who subsequently were able to be tapered to 5 mg prednisone per day. One year after transplantation--a point at which almost all patients were on maintenance immunosuppression and had stable graft function--the incidence of diabetes was 13% and hypertension was 69.1%. The overall incidence of hypercholesterolemia (serum cholesterol > 240 ng/ml) was 31% and was more frequent in women than in men (38.7% vs. 23.0%, P < 0.06). The incidence of obesity at 1 year was 41.9% in women and 39.3% in men. With tapering of prednisone from 10 mg to 5 mg per day in 61 patients, the mean serum cholesterol decreased from 224.6 +/- 65.2 mg/dl to 203.3 +/- 65.5 mg/dl, P < 0.005. With steroid tapering, 8 patients were able to discontinue antihypertensive medications and 4 were able to discontinue insulin treatment for diabetes. Five patients became obese during the steroid-tapering period. No patient developed irreversible rejection with steroid tapering and no immunologic graft losses occurred more than a year after transplantation. Nine patients who lived a year subsequently died. Of these, 7 patients were diabetic and 2 died of cardiac disease. We conclude that metabolic complications such as diabetes, hypertension, and hypercholesterolemia are common later after liver transplantation and that these may contribute to patient morbidity and mortality. In addition, we conclude steroid tapering to 5 mg/day does not lead to graft loss and may decrease the incidence and severity of late metabolic complications.
Adult↗
Prolongation of islet allograft survival with an antibody to vascular cell adhesion molecule 1.
BACKGROUND: The purpose of this study was to determine whether an antibody to vascular cell adhesion molecule 1 (VCAM1) prolongs the survival of neovascularized pancreatic islet allografts. METHODS: We treated CBA (H-2k) recipients of BALB/c (H-2d) islet allografts with anti-VCAM1 antibody (400 micrograms/day for 20 days). Sensitized recipients of islet grafts also were treated with anti-VCAM1. To study mechanism we performed mixed lymphocyte reactions (MLRs) with anti-VCAM1 and studied the graft infiltrate in treated recipients. RESULTS: Anti-VCAM1-treated CBA recipients showed prolonged graft survival with indefinite survival in five of nine cases. Anti-VCAM1 prevented proliferation in an MLR but not when added 36 hours after the beginning of the MLR. Anti-VCAM1 did not prolong allograft survival in sensitized recipients and did not prevent lymphocytic infiltration of the graft at 7 days. CONCLUSIONS: Anti-VCAM1 prolongs allograft survival in neovascularized islets in which the donor vascular endothelium plays little or no role in immunogenicity. VCAM1 appears to be important in the afferent phase (lymphocyte activation) of the allograft response. Once activated, either late in an MLR or in sensitized recipients, lymphocytes are not dependent on VCAM1 for function. Finally, anti-VCAM1 does not appear to affect the homing of lymphocytes to the allograft.
Animals↗
When insulin isn't enough.
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Diabetes Mellitus, Type 1↗
Liver transplantation without venovenous bypass.
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Cardiac Output↗
Clinical experience with human anodal trypsinogen (HAT) for detection of pancreatic allograft rejection.
To date one of the major dilemmas in clinical pancreas transplantation is the lack of a reliable indicator for pancreas rejection. In a consecutive series of 52 patients undergoing simultaneous pancreas and kidney (SPK) transplantation with bladder drainage technique between October 1991 and December 1992 a new test using serial levels of serum human anodal trypsinogen (HAT) was evaluated for its efficacy to detect pancreas rejection. Postoperative baseline levels of HAT were compared to peak HAT values at time of rejection. HAT profiles at time of rejection were calculated and compared to profiles of urinary amylase, serum amylase, fasting blood sugar and serum creatinine. In this series one year patient survival was 97%, graft survival of the pancreas 86% and of the kidney 90%. In 71% of the patients at least one rejection episode occurred. At time of kidney-biopsy proven rejection with a concurrent serum creatinine rise a significant HAT level rise to more than 1000 ng/ml was observed from baseline levels of 200 ng/ml (P < 0.001) indicating kidney and pancreas rejection (73%). Urinary amylase levels decreased in the majority of rejection episodes at the same time from baseline levels to less than 20,000 U/l. In 25% of the rejection episodes a significant serum creatinine rise was observed without a HAT rise or urinary amylase decrease indicating kidney-only rejection, while in 2% a urinary amylase decrease and simultaneous HAT also was observed with a negative kidney biopsy indicating pancreas-only rejection. We feel that increase in HAT levels significantly correlates with pancreas rejection. After SPK, determination of HAT is an additional helpful non-invasive test. In pancreas transplantation alone HAT can be a useful indicator to detect rejection and facilitate timing of a pancreas biopsy and initiation of antirejection treatment.
Adult↗
Efficacy of human anodal trypsinogen for detection of rejection in clinical pancreas transplantation.
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Actuarial Analysis↗