Initial results of solitary pancreas transplants performed without regard to donor/recipient HLA mismatching

BACKGROUND: We hypothesized that solitary pancreas transplants could be performed successfully even in the presence of poor HLA matching if an aggressive approach were taken with regard to immunosuppressive protocol and the performance of allograft biopsy. METHODS: Seven pancreas-after-kidney transplants and seven pancreas transplants alone were performed without consideration given to the degree of HLA mismatching (MM) using tacrolimus (FK506)/mycophenolate mofetil (MMF)/prednisone maintenance therapy. Mean (+/-SD) total HLA MM was 4.8+/-1.2. All patients were followed for at least 6 months. The first four cases were induced with ATGAM for 7 to 10 days. In the remaining 10 cases, an ultrasound-guided percutaneous needle biopsy was attempted on a protocol basis 10 days after completing induction with OKT3 for 7 (n=2) or 14 (n=8) days. RESULTS: Overall patient survival, graft survival, and incidence of acute rejection requiring treatment were 86, 79, and 50%, respectively. Two patients receiving ATGAM developed grade III-IV rejection at 3 weeks. Both patients receiving OKT3 for 7 days developed early grade III rejection. However, only three of eight patients receiving OKT3 for 14 days developed rejection requiring treatment. Protocol biopsy was successfully performed in six of seven patients and uncovered three cases of otherwise undetectable grade III-IV rejection. CONCLUSIONS: Although based on a small number of cases, our results suggest that solitary pancreas transplants with a poor HLA match can be performed with an acceptable rejection incidence and graft survival rate using an OKT3/FK506/MMF/prednisone regimen with protocol biopsy.     

Percutaneous ultrasound-guided pancreas allograft biopsy: a single-center experience

Percutaneous ultrasound-guided pancreas allograft biopsy is the preferred technique for evaluating pancreas allograft rejection. Experience from large centers has shown it to be safe and effective. We report our experience with 120 percutaneous allograft biopsies performed at a single center. Biopsy tissue was obtained in 54 patients. Thirty-three patients received simultaneous pancreas and kidney transplants, 14 received isolated pancreas transplants, and 7 received a pancreas transplant after kidney transplantation. Biopsies were performed by pancreas transplantation surgeons with the assistance of radiologists under ultrasound guidance using an Acuson XP 128/10 ultrasound machine. One hundred twenty allograft biopsies were performed in 54 patients. Twenty-seven (50%) patients underwent multiple biopsies. In 102 (85%) biopsies the specimens were adequate for examination. Eighteen (15%) biopsy samples had no pancreatic tissue and showed surrounding fat and small bowel. 1 (1.8%) patient bleeding developed that required transfusion of 3 units of packed red blood cells, but no surgical intervention was necessary. One (1.8%) patient had a pancreatic fistula, which healed with nonoperative management. Biochemical evidence of pancreatitis was noted in 5 (9.2%) patients, but none of these patients had clinical signs of pancreatitis. Percutaneous ultrasound-guided pancreas allograft biopsy is a safe procedure with a low complication rate and a high tissue yield for histopathologic examination.     

Pilot study of early corticosteroid elimination after pancreas transplantation

Early corticosteroid withdrawal has recently been shown to be possible in recipients of simultaneous pancreas kidney transplants; however, its feasibility in solitary pancreas recipients has not been documented. In the present study, we provide evidence that early withdrawal can be achieved in pancreas as well as pancreas-kidney recipients. METHODS: Twenty type I diabetics underwent 13 pancreas-kidney transplants and 7 pancreas-only transplants with early withdrawal (methylprednisone 6-day taper). Additional immunosuppression consisted of tacrolimus, mycophenolate mofetil, and thymoglobulin induction (five doses). RESULTS: Transplants included 13 pancreas-kidney, 6 pancreas after kidney transplant, and 1 pancreas after islet transplant. Overall mean follow-up was 7.3 months. One episode of pancreas transplant rejection after pancreas-only transplant was detected on protocol biopsy without biochemical abnormalities. One renal allograft rejection occurred 65 days posttransplant in a pancreas-kidney recipient and was graded as a Banff IA rejection. A single pancreas graft loss occurred due to thrombosis 6 days after pancreas-kidney transplantation. CONCLUSIONS: These results indicate that relatively short thymoglobulin induction (five doses) with tacrolimus and mycophenolate mofetil can allow early withdrawal in both pancreas-kidney and pancreas-only transplant recipients.     

Technical and Immunosuppressive Advances in Transplantation forInsulin-Dependent Diabetes Mellitus

Pancreas transplantation has emerged as the single most effective way to achieve normal glucose homeostasis inpatients with type I insulin-dependent diabetes mellitus. Optimal immunosuppressive strategies for pancreas transplantation continue to evolve with the use of newer, more potent immunosuppressive agents,particularly tacrolimus, mycophenolate mofetil, and rapamycin. These agents have contributed to substantially lower rates of allograft rejection and improved graft survival. Regimens designed to avoid nephrotoxicity or spare corticosteroid therapy are emerging as the variety of drug options grows. Also contributing to progressively better results for solitary pancreas transplants are reductions in early graft loss rates and the development of safe, effective biopsy techniques, permitting accurate diagnosis of rejection. Collectively,these factors have allowed solitary pancreas allograft recipients, a group of patients with historically poor long-term graft survival, to enjoy successes nearly equivalent to those of combined kidney-pancreas transplants. Consequently, the American Diabetes Association strongly endorses pancreas transplantation in diabetic patients who have received prior kidney transplants and who have life-threatening metabolic lability.     

Analysis of allograft biopsy specimens from long-term surviving patients with stable renal function: predictive value of long-term graft prognosis

Abstract: Chronic allograft dysfunction is multi-factorial, and histology of long-term renal allograft shows variable findings. It is important to characterize the pathological features of graft kidneys with normal function to understand the natural course of transplants, which in turn would contribute to elucidate the causes of chronic allograft nephropathy (CAN). To address this issue, we performed 'non-episode' biopsies on well-functioning renal allografts, and evaluated the correlation between clinical outcome and histopathological findings. Patients who underwent a non-episode biopsy had a serum creatinine concentration less than 2.0 mg/dL, urinary protein of less than 500 mg/day and a stable clinical course. In total, 90 such biopsies were performed. Mean follow-up period after biopsy was 29 ± 16 months. We evaluated the histopathological findings and clinical outcome on each finding. Moreover, we compared the findings in the patients on tacrolimus with those of patients taking cyclosporin. Twenty-three biopsy specimens were essentially normal. Graft dysfunction during the follow-up period was recognized more frequently in patients showing more than one pathological process than in those with isolated findings. Graft outcome was not associated with drug-induced nephropathy, but with acute rejection ( P  = 0.0193) and CAN ( P  = 0.0032). Patients found to have CAN-b had a worse outcome than those with CAN-a. CAN-b was less common in the tacrolimus group than in the cyclosporin group. Non-episode biopsy has a predictive value of the long-term outcome of a renal allograft. CAN is associated with graft dysfunction; neither is drug-induced nephropathy. Patients treated with tacrolimus had lower rates of CAN-b than did cyclosporin-treated subjects.     

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.     

Conversion of exocrine secretions from bladder to enteric drainage in recipients of whole pancreaticoduodenal transplants.

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)     

Portal enteric-drained solitary pancreas transplantation without surveillance biopsy: is it safe?

BACKGROUND: Most solitary pancreas transplants (SPTx) fail due to unrecognized rejection episodes. Consequently, SPTx are monitored by drainage into the bladder or by surveillance biopsies. METHODS: Between April 2001 and June 2003, a consecutive series of 48 SPTx were performed using portal enteric drainage (PED). Rejection episodes were diagnosed empirically, based on the elevated pancreatic enzymes without a surveillance biopsy. Immunosuppression consisted of basiliximab (n = 42) or ATG (n = 6), low-dose steroids, MMF, and tacrolimus. Donors (mean age 28.9 year; range 9 to 54 year) were selected according to standard criteria irrespective of HLA match, although the best HLA matching was considered at the time of graft allocation. RESULTS: After a mean cold ischemia time of 676 minutes (range 475 to 900 minutes), all but two pancreata (95.8%) functioned immediately. Relaparotomy was required in seven cases (14.6%). Three grafts were lost in the early posttransplant period due to hyperacute rejection. Two additional grafts were lost later due to arterial thrombosis or to chronic rejection. After a median follow-up period of 12.2 months (range 0.2 to 27 months) three further recipients were diagnosed with rejection episodes that were reversed with steroid boluses. Actuarial 1-year patient and graft survival rates were 100% and 93.1% and 2-year figures 100% and 88.7%, respectively. At the longest follow-up no recipient was diagnosed with a malignancy. CONCLUSIONS: With current immunosuppression protocols SPTx achieves high rates of insulin independence even without surveillance biopsy or routine use of T-cell-depleting therapies.     

Percutaneous biopsy of bladder-drained pancreas transplants.

Percutaneous biopsy is a valuable investigation in the management of allograft rejection for all solid organs. Pancreas transplants have not been biopsed percutaneously, though open and percystoscopic biopsies have proved useful. We have compared percutaneous needle core biopsy with fine-needle aspiration cytology for the diagnosis of rejection in 18 patients receiving combined kidney and pancreas transplants and in one who was transplanted with the pancreas alone. Percutaneous needle core biopsy was successful in 37 of 40 attempts (93%), while fine-needle aspiration yielded diagnostic material on 33 of 47 attempts (70%). Transient hyperamylasemia occurred in 29%, returning to baseline in three days. One patient twice developed transient macroscopic hematuria. There was agreement between needle core biopsy and fine-needle aspiration on the diagnosis of rejection on six occasions and for the absence of rejection on 16. There was an 8% false-positive rate for fine-needle aspiration. In 13 instances of histologically proved renal rejection, concurrent pancreas biopsy revealed rejection in 69%. Pancreas rejection was not, however, seen in the absence of renal rejection. In this pilot study, percutaneous biopsy of the bladder-drained pancreas allograft was shown to be a practicable and valuable investigation without major complications.     

Management of complications of simultaneous kidney–pancreas transplantation with temporary venting jejunostomy

Abstract: Background/Aims: The majority of simultaneous kidney–pancreas (SPK) transplants are being performed with portal-enteric drainage, which does not allow easy access to the donor pancreas. By adding a temporary venting jejunostomy (TVJ) we have been able to closely monitor patients for bleeding, anastomotic leak and rejection.
Methods: Retrospective chart review of 29 patients undergoing SPK with PE drainage from December 1996 to December 2001.
Results: Median follow-up was 32 months. Patient, kidney and pancreas graft survival were 93%, 90% and 93%, respectively. The most common early complications were wound infections and bleeding. No patient suffered vessel thrombosis. The most common late (greater than 3 months post-transplant) complication was gastro-intestinal bleeding. Adequate tissue was obtained for biopsy in 100% of patients with suspected pancreatic rejection. The TVJ allowed one patient to undergo donor pancreas ERCP that demonstrated the site of a pancreatic duct leak. Duodenal stump leak and anastomotic bleeding were diagnosed in one patient each via the TVJ. The median time to takedown of the TVJ was 14 months.
Conclusion: TVJ allows patients an easy method of graft surveillance, is well tolerated, and has an acceptable complication rate. The TVJ allows access to diagnose anastomotic leak, cauterize bleeding mucosa, perform ERCP and biopsy the pancreas allograft.     

Scoring of skin rejection in a swine composite tissue allograft model.

BACKGROUND: For the first time, we define and correlate visual and histologic grading systems of composite tissue allograft (CTA) skin rejection in a large-animal model and determine the utility of these grading systems for early diagnosis and monitoring of rejection. MATERIALS AND METHODS: Sixteen pairs of outbred swine underwent transplant of a forelimb osteomyocutaneous free flap. Group I (n = 6) did not receive immunosuppressive therapy. Group II (n = 10) received oral cyclosporin A, mycophenolate mofetil, and prednisone. The flap was visually inspected and protocol skin biopsies were taken at frequent intervals over a 90-day period. Visual Grades 0 (no rejection) to 4 (severe rejection) were assigned based on skin color, bleeding from biopsy site, and blister formation. Histologic Grades 0 to 4 were assigned based on the degree of vasculitis, folliculitis, dermal inflammation, and epidermal degeneration present. RESULTS: All Group I animals progressively rejected their graft by Day 7. Group II grafts survived from 19 and 90 days; 93% of 115 biopsy specimens were read to be within +/-1 histologic score of their assigned flap visual grade. Visual assessment carried an 8% false positive and 39% false negative rate with regard to biopsy-proven rejection. However, 81% of missed rejection specimens were histologic Grade 1. Biopsy, when visually indicated, would detect all rejection episodes when histologically Grade 1 or 2 and still potentially reversible. CONCLUSIONS: Visual scoring of CTA skin serves as a useful tool for initially detecting rejection, but repeated histologic evaluation is necessary for monitoring the subsequent course of the graft.     

The importance of glomerular deposits of von Willebrand factor in human renal allografts

OBJECTIVE: The aim of this study was to evaluate the importance of glomerular expression of von Willebrand factor (vWF) in human renal allografts. METHODS: We investigated graft biopsies from 72 renal transplant recipients, 40 with acute rejection (AR) and 32 with chronic allograft nephropathy (CAN). All biopsy specimens were immunostained with vWF and CD68 and graded using 3-tiered scales. The follow-up biopsies of patients with AR were reevaluated for development of glomerular sclerosis. RESULTS: A significant difference was found between type 1 and type 2 AR with regard to glomerular vWF expression (P < 0.01). None of the patients with type 1 AR showed mesangial vWF expression, but 36.4% of patients with type 2 AR showed segmental mesangial vWF expression. In follow-up biopsies, 18 of 40 patients developed significant glomerular sclerosis, and patients with mesangial vWF expression (grade 3 GvWF) showed glomerular sclerosis earlier than did others (P < 0.01). In addition, the outcome for grafts that showed grade 3 glomerular vWF was significantly worse than was the outcome noted for grafts that showed grade 1 or grade 2 glomerular vWF (P < 0.001). Half of the biopsy specimens in the CAN group showed global mesangial vWF expression. Glomerular macrophage infiltration was correlated with degree of glomerular vWF expression both in the AR and in the CAN groups (P < 0.05, P= 0.001, respectively). CONCLUSION: We hypothesized that the increasing amount of glomerular vWF may be used as a marker of acute vascular rejection and may help for the evaluation of renal allograft biopsies without sufficient arteries. In addition, it can also be a marker for development of early glomerular sclerosis and may help us determine which patients are in need of further treatment.     

The fate of C4d positive kidney allografts lacking histological signs of acute rejection

BACKGROUND: C4d deposits in renal transplants are known to be an independent risk factor of graft failure. The current analysis evaluates the impact of C4d deposits on graft function and survival in renal transplants without morphological signs of rejection. METHODS: We retrospectively analyzed diagnostic transplant biopsies performed due to allograft dysfunction from June 1994 to June 2001 at the University Hospital in Basel. STUDY GROUP: Grafts/patients with focal or diffuse positivity of C4d along peritubular capillaries; absence of morphological signs of acute cellular and/or humoral rejection; up to 3 year follow-up analysis post index biopsy. Patients treated with anti-rejection therapy or an increase in maintenance immunosuppression post biopsy (intervention group = IG) were compared to patients with unaltered immunosuppression (standard group = SG). RESULTS: Study group: 22 biopsies/patients out of 400 biopsies (5%) were included into the study, 17 in the SG and 5 in the IG. Patient survival (1-/3-years): SG: 100/94%, IG: 80/80%; graft survival censored for death (1-/3-years): SG: 82.5/68.8%, IG: 100/100%; serum creatinine (micromol/l) at index biopsy/1-year/3-years: SG: 221 +/- 70/231 +/- 103/245 +/- 124, IG: 217 +/- 100/143 +/- 28/177 +/- 55; acute rejection episodes within 1 year post index biopsy: SG: 4 (4 patients), IG: 1 (1 patient); all differences not significant. Lowest serum creatinine within 4 weeks post index biopsy (IG vs. SG): 108 +/- 25 vs. 181 +/- 61, p = 0.02. CONCLUSIONS: C4d positivity in kidney transplants lacking histological evidence of acute rejection is not associated with rapid functional graft deterioration, even in untreated cases. However, anti-rejection therapy results in the improvement of kidney function. Thus, even in grafts with normal histology, the detection of C4d in diagnostic biopsies can be interpreted as a sign of "smoldering" rejection that benefits from therapy.     

Longitudinal analysis of chronic allograft nephropathy: clinicopathologic correlations

BACKGROUND: Loss of the allograft from chronic allograft nephropathy and death of the patient from vascular, malignant, or infective disease are the major problems in renal transplantation today. Protocol biopsy of the long-term kidney has provided new data with which to develop strategies for prevention and treatment of chronic allograft nephropathy. METHODS: Two series of long-term protocol biopsies are reviewed. In the first, renal biopsies were obtained at time 0, and at 3 months and 12 months, and the recipients of the renal allografts were followed up for up to 15 years. In the second, the kidneys of recipients of simultaneous pancreas kidney transplants were biopsied annually for 10 years, and the results correlated with clinical events. RESULTS: Chronic allograft nephropathy is caused by acute and chronic immune-mediated damage, as well as by chronic calcineurin inhibitor nephrotoxicity. Both immune and nonimmune mechanisms exacerbate pre-existing donor disease and ischemia-reperfusion injury. Established interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerular sclerosis and eventual loss of the graft. CONCLUSION: Protocol biopsies have shown that clinical parameters of renal function underestimate the severity of chronic graft damage. Strategies for preventing or treating chronic renal allograft dysfunction and subsequent graft loss must better control rejection and simultaneously avoid nephrotoxicity.     

Graft dysfunction in simultaneous pancreas kidney transplantation (SPK): Results of concurrent kidney and pancreas allograft biopsies

Simultaneous pancreas and kidney transplants offer significant therapeutic advantages but present a diagnostic approach dilemma in the diagnosis of rejection. Because both organs are from the same donor, the kidney has been treated traditionally as the “sentinel” organ to biopsy, presumably representing the status of both allografts. Truly concurrent biopsy studies, however, are needed to confirm this hypothesis. We examined 101 concurrent biopsies from 70 patients with dysfunction in either or both organs. Results showed concurrent rejection in 23 of 57 (40%) of cases with rejection; 19 of 57 (33.5%) and 15 of 57 (26.5%) showed kidney or pancreas only rejection, respectively. The degree and type of rejection differed in the majority (13 of 23, 56.5%) of cases with concurrent rejection, with the pancreas more often showing higher rejection grade. Taking into account pancreas dysfunction, a positive kidney biopsy should correctly predict pancreas rejection in 86% of the instances. However, the lack of complete concordance between the 2 organs, the discrepancies in grade and type of rejection, and the tendency for higher rejection grades in concurrent or pancreas only rejections, all support the rationale for pancreas biopsies. The latter provide additional data on the overall status of the organ, as well as information on nonrejection‐related pathologies.     

Banff Schema for Grading Pancreas Allograft Rejection: Working Proposal by a Multi-Disciplinary International Consensus Panel

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined.
The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.     

Experience with OKT3 in vascularized pancreas transplantation

With refinements in technical aspects of whole organ pancreas transplantation, allograft rejection is currently the major cause of graft failure. The monoclonal antibody OKT3 has emerged as a highly effective antirejection therapy in renal and hepatic allograft recipients, but its efficacy in pancreas transplantation remains to be determined. During a 12-month period, 28 vascularized whole organ pancreas transplants were performed with pancreatico-cystostomy. Sixteen episodes of allograft rejection were treated with monoclonal antibody OKT3. Indications for OKT3 use included steroid- or antilymphocyte globulin (ALG)-resistant allograft rejection in isolated pancreas (n = 8) or simultaneous kidney-pancreas (n = 8) transplants. A total of 34 rejection episodes occurred in the 16 patients (mean, 2.1; range, one to five). The diagnosis of rejection was based on clinical criteria, a reduction in urinary amylase clearance, radionuclide scanning, hyperglycemia, or associated renal allograft dysfunction in combined engraftments. Postoperative immunosuppression consisted of cyclosporine, prednisone, azathioprine, and prophylactic ALG. OKT3 was administered for a full 14-day course concomitant with low-dose steroids, azathioprine, and cyclosporine. The mean age of the patient population was 32.1 years (range 24 to 39) with a mean duration of insulin-dependent diabetes mellitus (IDDM) of 20.9 years. Monoclonal antibody therapy was instituted in two clinical settings: early rejection (within 3 months of transplant, n = 10); and late rejection (after 3 months, n = 6). OKT3 successfully reversed allograft rejection in ten (62.5%) cases, including six early (60%) and four late (66.7%) episodes. In isolated pancreas transplants, OKT3 therapy reversed pancreas allograft rejection in only two patients (25%).(ABSTRACT TRUNCATED AT 250 WORDS)     

A three-year experience with serum anodal trypsinogen as a biochemical marker for rejection in pancreatic allografts. False positives, tissue biopsy, comparison with other markers, and diagnostic strategies.

Serum values of immunoreactive anodal trypsinogen (sAT) have been claimed to correlate well with rejection occurring in pancreatic allografts. We have studied the behavior of sAT in serial serum samples obtained from 39 type I diabetics undergoing whole-organ pancreas transplantation during the past 3 years. Patients had either received a pancreatic allograft simultaneously with a transplanted kidney (SPK, n = 33) or after a previous kidney transplant (pancreas after kidney [PAK] n = 6). The behavior of sAT was studied in relation to the clinical diagnosis of rejection. Graft amylase output for all 39 patients and serum creatinine for the 33 SPK recipients were also studied. Tissue biopsies were obtained from 11 patients with elevated sAT values and a presumptive diagnosis of rejection. Nine of these patients had SPK grafts and simultaneously elevated creatinine values. Tissue was obtained from the simultaneously transplanted kidney; all specimens revealed rejection. Two of the 11 patients had PAK allografts. Biopsies performed on the graft duodenum were consistent with acute rejection. Three additional patients with unchanged sAT values had biopsies for other reasons; these biopsies failed to demonstrate signs of acute rejection. Thus graft biopsy correlated exactly with sAT behavior in every case in which rejection was suspected. Five patients had elevations of sAT not associated with rejection: one resulted from direct trauma, two had outlet obstruction, and two had clinical diagnoses of graft pancreatitis. The sAT was more sensitive and specific than GAO and as sensitive as creatinine for SPK recipients. These studies confirm that sAT is a reliable, graft-specific biochemical marker for the early diagnosis of pancreatic rejection. The use of sAT should allow for the proper timing of graft biopsies and the judicious use of immunosuppressive agents, which will result in increased allograft survival for PAK and pancreas-alone allografts.     

Reduced dose Thymoglobulin,tacrolimus, and mofetil mycophenolate results in excellent solitary pancreas transplantation outcomes

BACKGROUND: Graft survival following solitary pancreas transplantation has traditionally lagged behind that of simultaneous pancreas-kidney transplants. Thymoglobulin (TMG), a polyclonal rabbit-derived antilymphocyte antibody was originally introduced as treatment for acute rejection of renal allografts. However, data regarding the efficacy of TMG induction in solitary pancreas transplants is lacking. We present the 1-yr graft survival and acute rejection rate of 22 solitary pancreas transplants performed at the McGill University Health Centre using reduced dose TMG induction with lower dose tacrolimus and mophetil mycophenolate. PATIENTS AND METHODS: Eighteen pancreas after kidney and four pancreas transplants alone were performed between January 1998 and October 2000 at McGill University. Induction therapy with TMG at a starting dose of 1.5 mg/kg/d was started 12 h post-operatively. The daily dose of TMG was held if the total leukocyte count was <2,500/mm3 or if the lymphocyte count was <100/mm3. Maintenance therapy was initiated with steroids (tapered to 20 mg prednisone orally once a day) tacrolimus (2 mg twice a day), and mofetil mycophenolate (1 g daily). RESULTS: Patients received three to seven doses of TMG over the first seven post-operative days at a dose of 0.85 +/- 0.27 mg/kg/d (mean +/- SD). The mean follow-up was 1.28 +/- 0.14 yr. The 1-yr patient and graft survival was 100% (22 of 22) and 96% (21 of 22), respectively. The 1 yr acute rejection rate was 27.3% (six of 22). Five of the six rejections responded to steroid boluses. One was refractory to steroids and TMG resulting in graft loss. Presumed rejections were diagnosed on the basis of decreasing urine amylase and/or hyperglycemia. DISCUSSION: Monitoring the total leukocyte and lymphocyte count resulted in a 43% reduction in the amount of TMG used compared with the recommended dosing. Despite the reduced amounts, patient and graft survival were excellent with acute rejection rates comparing favorably to other published series.