Application of magnetic resonance imaging in pancreas transplant.

Various imaging methods have been used in the differential diagnosis of pancreas-transplant dysfunction. As early as 1977, angiography and radionuclide studies ([75Se]seleno-DL-methionine) were used to evaluate pancreas allografts. More recently, the use of 99mTc-labeled DTPA, computed tomography, and ultrasonography has been described, and abnormal findings associated with rejection have been reported with these imaging methods. However, no attempt has been made to determine the ability of each method to detect rejection and to differentiate graft dysfunction caused by rejection from dysfunction by other causes. We summarize our experience with the application of magnetic resonance imaging (MRI) in pancreas transplantation and a comparative study of radionuclide 99mTc-DTPA scans, ultrasonography, and MRI in the detection and differentiation of pancreas-graft dysfunction.

Liver disease in renal transplant recipients.

Significant liver disease developed in 14 patients after renal transplantation. Nine patients had morphologic and functional evidence of chronic active hepatitis. In general, these patients had few symptoms of liver disease, even though the course of chronic active hepatitis was progressive. Despite large doses of prednisone, cirrhosis ultimately developed in five patients. The cause of chronic active hepatitis could not be related to azathioprine or methyldopa therapy because there was no perceptible change in the course of liver disease after treatment with these drugs was stopped. Three patients were persistently positive for hepatitis B surface antigen. Isolated instances of granulomatous hepatitis (Mycobacterium kansasii) and of prolonged intrahepatic cholestasis were encountered in patients with chronic active hepatitis. Two patients had acute cytomegalovirus hepatitis. There was one episode each of fulminant herpes simplex hepatitis and severe fatty metamorphosis.

Stroke in renal transplant recipients.

Cerebrovascular events are the most common neurological complications seen in renal transplant recipients. Cerebral infarction and transient ischemic attacks are the most common events and may occur years after transplantation. Recipients older than 40 years at the time of transplantation and those with diabetes mellitus are at greater risk. No instances of aneurysmal subarachnoid hemorrhage occurred among 31 patients with polycystic kidney disease who had undergone transplantation.

Elimination of acute GVHD and prolongation of rat pancreas allograft survival with DST cyclosporine, and spleen transplantation.

Allogeneic spleen transplantation has been shown to have a tolerizing effect on pancreas allograft survival in rats. In this study we examined the effect of blood transfusions and cyclosporine administration on both rat pancreas allograft survival and acute graft-versus-host disease in BN recipients of Lewis pancreas-spleen allografts. We found that in this strain combination significant pancreas allograft prolongation occurred when the spleen was included en bloc with the pancreas graft. However, 50% of these recipients developed GVHD and died. A single donor-specific transfusion delivered to BN recipients of Lewis pancreas and pancreas-spleen allografts did not extend graft survival, but precluded the development of GVHD. A short, 6-day, and long, 26-day, course of CsA to recipients of pancreas and pancreas-spleen allografts extended graft and animal survival times, although not indefinitely. All pancreas-spleen recipients of both CsA protocols died following acute GVHD. Combined DST and CsA (short and long-course) administration in pancreas-only allograft recipients was deleterious to graft survival, compared with CsA administration alone. However, in pancreas-spleen recipients, combined DST and CsA had an additive effect. Moreover, in DST and long-course CsA-treated pancreas-spleen recipients, indefinite graft survival occurred with no signs of acute GVHD. The beneficial effect of the spleen allograft on pancreas graft survival was not dependent upon GVHD, since splenic-induced prolongation of pancreas graft survival was observed in the F1-donor to parent-recipient combination.

Metabolic effects of urinary diversion of exocrine secretions in pancreatic transplantation.

We have compared the metabolic consequences of two forms of exocrine drainage for pancreaticoduodenal transplant, duodenojejunostomy (DJ) and duodenocystostomy (DC). DC offered the advantage of avoiding opening of the recipient small intestine with its potential for wound sepsis, as well as a reliable method for early detection of pancreatic rejection as measured by an abrupt fall in urinary amylase and bicarbonate concentration. However, DC led to a large urinary loss of bicarbonate with a concomitant mild metabolic acidosis. During periods of renal dysfunction, the patients with DC developed severe hyperchloremic acidosis. Use of DC for pancreatic exocrine diversion may require patients to take supplemental bicarbonate even with a well-functioning renal transplant.

Abrogation of second-set rejection with cyclosporine.

Cyclosporine was evaluated for its ability to delay or prevent accelerated rejection in a model of the second-set immune response. Lewis rats sensitized by LBN skin grafts or subcutaneous heart fragments experienced accelerated rejection of heterotopic, vascularized LBN hearts with a mean survival time (MST) of approximately 5 days versus MST of 9.5 days for primary grafts. A short course of cyclosporine (10 mg/kg/day for 10 days) significantly prolonged graft survival in presensitized hosts to approximately 12 days (P less than 0.01) as compared with the nontreated controls. Adjunctive splenectomy failed to further extend graft survival; MSTs were 12.0 and 5.7 days with and without cyclosporine, respectively. A comparable abrogation of second-set rejection was also achieved with a short course of antithymocyte serum (MST of 10.6 days). Rejection promptly ensued in all of the above groups shortly after cessation of immunosuppression. In contrast, a maintenance regimen of cyclosporine, given in a tapering dose, markedly extended graft survival to from 77 to 100+ days. Again, however, rejection eventually occurred following withdrawal of the cyclosporine. These data suggest that cyclosporine can indeed effectively prolong allograft survival in presensitized hosts.

Effect of blood transfusions on survival of cadaver and living related renal transplants.

The effect of blood transfusion was analyzed in 194 first cadaver renal transplants and 86 living related renal transplants. The association of blood transfusion with HLA genotyping and poor risk recipients was analyzed. Exclusion of poor risk recipients improved graft survival among the transfused group of patients but not in the small subgroup of nontransfused recipients. No effect of blood transfusion was observed in the living related group. Improved graft survival was observed in both the haplotype-matched and nonhaplotype-matched transfused cadaver recipients. The haplotype-transfused recipients had grafts survival rates of 69 and 66% at 1 and 2 years, respectively. The greatest beneficial effect was seen in the double haplotype-transfused cadaver recipients with graft survival rates of 80 and 71% for the same period. The lack of beneficial effect of transfusion in the living related patients is felt to be a result of the fact that the maximum effect had already been achieved by a far superior donor-recipient histocompatibility than is able to be achieved in a large group of cadaver recipients.

Effect of transfusion of donor on allograft survival.

It has been reported by two European transplant centers that blood transfusion of cadaver donors with third-party blood prior to nephrectomy increases renal allograft survival rates by approximately 30% at 1 year. A retrospective analysis in our center was performed on 293 kidney recipients, 110 of whom received kidneys from untransfused donors. Actuarial analyses revealed no significant differences in graft survival rates between all nontransfused donor kidneys and all transfused donor kidneys. Considering only first transplant recipients, there was no difference in graft survival rates between nontransfused donor kidneys and transfused donor kidneys. In addition, when only preoperatively transfused recipients receiving first transplants were examined, there was no difference in graft survival rates between nontransfused donor kidneys and transfused donor kidneys. Animal studies were performed with (Lewis x Brown Norway)F1 (LBNF1) hybrid rat hearts transplanted heterotopically to the abdomens of Lewis rat recipients. Six LBNF1 heart grafts had a mean survival time of 8.0 +/- 1.1 days. Five LBNF1 rats received 2 ml of heparinized whole blood from Charles River (CD) rats 24 hr before heart transplantation to Lewis recipients. The transfused LBNF1 grafts had a mean survival time of 6.6 +/- 0.9 days. Therefore, donor blood transfusion does not appear to prolong graft survival in this retrospective human study or in the animal model.

A 2-year trial of prospective HLA-DR matching: effects on renal allograft survival and rate of transplantation.

In a 2-year trial at a single center, prospective HLA-DR matching for cadaver renal transplantation exerted a stronger effect than either HLA-A and B matching or blood transfusion. One-year cumulative graft survivals for two-DR-matched organs was 92%. Grafts matched for one DR antigen had a cumulative 1-year graft survival of 65% whereas grafts matched for zero DR antigens had a cumulative 1-year survival of 41%. When all cadavers with less than two identifiable DR antigens were excluded from this analysis, however, the graft survivals of the groups known to be mismatched for one or two DR antigens were similar (61% versus 59%). Grafts matched for three or four HLA-A and B antigens did somewhat better than those matched for only zero, one, or two HLA A and B antigens (74% versus 59%, 1-year survival). This effect was only demonstrable in the zero- and one-DR-matched group. Similarly, prior blood transfusion exerted a modest effect (transfused versus nontransfused, 71% versus 56% 1-year graft survival) that was also most evident in the zero- and one-DR-matched groups. The institution of this trial was also associated with a 35% annual increase in the rate of transplantation and a 50% reduction in median patient waiting time. DR typing of cadaveric donors is feasible and highly desirable. Multicenter pooling of DR-typed donors is thus predicted to lead to optimal matching for a high proportion of renal transplant candidates.

The hemodynamic effects of Cremophor-EL.

A problem associated with parenteral cyclosporine has been the increased incidence of renal toxicity. Cremophor-EL, the vehicle for parenteral cyclosporine has been associated with massive histamine release and anaphylaxis in certain animal models. We investigated the effects of Cremophor-EL on the cardiac output (CO); mean arterial pressure (MAP); and hepatic, renal and pancreatic blood flow in the anesthesized canine model. Doppler flow probes were utilized to calculate individual organ blood flow. Profound adverse affects were noted on the CO, MAP, and hepatic blood flow. There were negative trends noted in the renal and splenic arterial flow that did not reach statistical significance. It was noted that the changes in organ blood flow were partially independent on MAP and the total dose of Cremophor-EL. We therefore conclude that it is prudent to consider the possible adverse hemodynamic role of Cremophor-EL in canine allograft dysfunction.

Results of conversion from cyclosporine to azathioprine in cadaveric renal transplantation.

Between December 1983 and August 1985, 110 cadaver transplants were performed at our institution. All were started on cyclosporine (CsA) and prednisone (P) for immunosuppressive therapy. Of the 110 patients, 46 were converted from CsA to azathioprine (AZA) for a variety of reasons (cost, toxicity, patient preference, prolonged dysfunction posttransplant, or nonresponsive rejection). The course and outcome of these patients are described. The only group of patients who had consistent benefit and stable course following the CsA-to-AZA switch were primary cadaver transplants with stable renal function (serum creatinine less than 2 mg/dl) who were converted an average of 7.97 months posttransplant. All other groups of patients had severe problems or graft loss postconversion.

En bloc pancreas and kidney transplantation in a patient with limited vascular access.

We report a successful en bloc pancreas and kidney transplantation on a type I diabetic patient with advanced peripheral arterial calcific disease, who had frequent life-threatening episodes of hypoglycemia. The en bloc double organ, created by joining the graft renal artery to the arterial Y graft of the pancreas, was implanted to the proximal left common iliac artery, which was the only site available for an arterial anastomosis. Under appropriate circumstances, this procedure would be an option for potential combined pancreas-kidney transplant recipients with severe calcific arterial disease.

Successful DR-incompatible cadaver kidney transplantation. Combined effect of HLA A and B matching and blood transfusion.

The purpose of this retrospective analysis of DR-incompatible cadaver renal transplantation was to evaluate the effect of HLA A and B matching and blood transfusion status on actual one-year graft survival. There were 31 2-DR, 111 1-DR, and 27 0-DR grafts at risk during the study period. First, a comparison was made between preoperative (PRE) and peroperative (PER) transfusions alone. Graft survivals were 70% vs. 92% (2 DR), 67% vs. 52% (1 DR) and 71% vs. 39% (0 DR) for the PRE and PER groups, respectively. Statistical significance was not found between the two values in each DR subgroup, although the difference approached significance in the O DR group (0.1 greater than P greater than 0.05). Matching for greater than or equal to 2 A and B antigens significantly improved graft survival in the 1 DR-matched group when compared with those matched for less than 2 antigens (76% vs. 44%, P less than 0.005). While marked differences between the greater than or equal to 2 and less than 2 A and B matched groups were observed for both the 2 DR (92% vs. 68%, P greater than 0.1) and O DR groups (59% vs. 40%, P greater than 0.3) these differences were not significant. Stratifying the data for transfusion status revealed that the positive influence of HLA A and B matching in the 1 DR group was dependent upon the presence of preoperative blood administration. Graft survival of 87% for the PRE transfused recipients of grafts matched for greater than or equal to 2 A and B antigens was significantly better (P less than 0.001) than the 42% survival observed in similarly transfused recipients of poorer matched organs. Conversely, A and B matching was not significantly beneficial in the 1 DR recipients transfused only at the time of transplant with graft survivals of 57% vs. 43% for those matched for greater than or equal to 2 or less than 2 A and B antigens, respectively (P greater than 0.3). This analysis suggests that a combined effect of both HLA A and B matching and preoperative blood transfusions may allow for highly successful first cadaver renal transplantation in the face of DR incompatibility.

Effect of timing of administration and quantity of blood transfusion on cadaver renal transplant survival.

Graft and patient survival rates were analyzed in 239 consecutive first cadaver renal transplants as a function of time of administration of blood transfusion and the number of units given. There was no statistically significant difference in patient survival in comparing patients who were never transfused, patients not previously transfused who received blood peroperatively, those who received blood before transplantation only, and those who were transfused before transplantation and peroperatively. In fact, the best survival rates were achieved in patients who were not transfused previously. Graft survival rates were significantly better in the prior transfused groups compared to either the never transfused group or the larger no prior transfused group which included the peroperatively transfused patients. Graft survival of the peroperatively transfused patients was intermediate between the never transfused and the prior transfused patients. There was no statistically significant difference between graft survival rates of patients who received more than 6 units of blood with those receiving less than 6 units. Also, the time interval from the last transfusion to transplantation appeared to have no effect on graft survival. Since an intentional transfusion protocol carries the real risk of sensitization and delay or elimination of the transplantation option, a prospective study comparing peroperative with preoperative transfusions is suggested. Such a study would answer the questions of the risk of sensitization with prior transfusion and the value of peroperative transfusions.

Strategies to expand the donor pool for pancreas transplantation.

BACKGROUND: Our organ procurement organization has been forced to liberalize the donor criteria in order to expand the donor pool for pancreas transplantation. In this report, we describe our experience using whole organ pancreatic grafts from "marginal" donors, which include grafts obtained from donors over 45 years of age and from donors who were identified to be hemodynamically unstable at the time of organ retrieval. METHODS: A prospective study was performed between July 1994 and March 1998, during which time 137 pancreas transplants were performed at our center using organs procured by our own surgeons (organs sent by other teams were excluded). The rapid en bloc technique was used exclusively. The use of pancreatic grafts from marginal donors was analyzed for short-term and overall graft survival, and for delayed graft function and complications. RESULTS: Overall pancreas graft survival for our series was 83%, with a mean follow-up of 23 months. There were 22 pancreas grafts from donors over 45 years of age, 13 of whom were greater than 50 years of age. The actual graft survival rate of the over-45 donor group was 86%. Fifty-one grafts were removed from hemodynamically unstable donors on high-dose vasopressors. The actual graft survival in this group was 86%. There was no significant difference found in graft survival between recipients of pancreatic grafts from marginal and nonmarginal donors. Delayed graft function was exhibited by more recipients of grafts from donors on high-dose vasopressors (P<0.05), but this had no effect on long-term graft survival and endocrine function. Recipients of marginal donor grafts did not have higher rates of complication compared to recipients of nonmarginal grafts. CONCLUSIONS: Based on our results, we currently employ a graft selection strategy not limited by donor age or hemodynamic stability. Our selection of pancreas organs for transplantation is based on careful inspection of the pancreas and determination of the adequacy of the ex vivo flush. Our results suggest that the current pancreas donor pool may be expanded substantially.

Spontaneous arterioenteric fistula after pancreas transplantation.

Chronic pancreas transplant rejection with enteric exocrine drainage can lead to significant long-term complications. We report a case of a 47-year-old male insulin-dependent diabetic who survived the complications of peripancreatic abscess, enterocutaneous fistula, and arterioenteric fistula related to pancreas transplantation. To avoid these long-term complications, we now recommend elective removal of nonfunctioning, enterically drained pancreas allografts.

Failure of cyclosporine to prevent in vivo T cell priming in man. Studies in allogeneic spleen transplantation.

Cyclosporine is a potent new immunosuppressive agent utilized in clinical organ transplantation. Available evidence suggest that it interferes with the secretion of interleukin-2. However, the long term efficacy of cyclosporine in preventing allograft rejection may depend on a relative sparing of suppressor cells early in the allogeneic response, allowing them to mature and effect a state of operational tolerance. If this is the case, cyclosporine must not affect antigen priming or recognition. Two patients in our center underwent allogeneic spleen transplant in conjunction with renal and pancreatic transplant. Both patients were treated with therapeutic levels of cyclosporine during the course of transplant. Neither developed any clinical signs of renal or pancreatic transplant rejection. Both patients developed graft-versus-host disease and eventually required allogeneic (donor) splenectomy. Studies performed on the splenocytes recovered from these specimens demonstrate alloantigen-specific cytotoxic T cell precursors. These studies demonstrate that although cyclosporine can prevent allograft rejection it does not necessarily prevent or ameliorate graft-versus-host disease. Furthermore, cyclosporine does not prevent in vivo T cell priming of alloantigen recognition. The primed cytotoxic precursors can be expanded in the presence of exogenous interleukin-2 to become fully active cytoxic cells.

Appearance of type II diabetes mellitus in type I diabetic recipients of pancreas allografts.

To determine the cause of hyperglycemia appearing after pancreas transplantation in type I diabetic recipients, we performed 65 oral glucose tolerance tests with serum insulin and C-peptide determinations in 32 patients with pancreas grafts functioning two or more months following transplantation. We correlated these results with estimates of graft size obtained by magnetic resonance imaging (MRI) and values of urinary amylase as a measure of pancreatic exocrine function. A total of 33 studies were obtained in 20 patients at times of normal glucose tolerance, and normal ranges for serum insulin and C-peptide levels were established; 32 studies in 17 patients during periods of glucose intolerance revealed values of serum insulin and C-peptide that were within the normal range, though the time to peak values was delayed to 2 hr, characteristic of type II diabetes. Only 3 of 17 patients examined by MRI had significant pancreatic allograft atrophy. These patients also had low urinary amylase excretion, and the only values for serum C-peptide that were below the normal range. The other 14 hyperglycemic patients had normalized pancreas grafts, normal urinary amylase excretion, and normal values for serum insulin and C-peptide. In our experience, then, in 76% of patients with hyperglycemia more than 2 months following pancreas transplantation, the cause was appearance of type II diabetes rather than destruction of the allograft with recurrence of type I diabetes. This observation has important implications for the definition of pancreas allograft failure and for the management of pancreas allograft recipients with hyperglycemia.

Incidence and morbidity of cytomegalovirus disease associated with a seronegative recipient receiving seropositive donor-specific transfusion and living-related donor transplantation. A multicenter evaluation.

This retrospective study was conducted to identify the frequency of cytomegalovirus (CMV) disease in seronegative recipients of donor-specific transfusion (DST) and living-related donor (LRD) kidneys from seropositive donors. A total of 151 LRD transplants (TX) were performed at six transplant centers over a 3-year period. A total of 33 patients were identified as having been seronegative (pre-TX) for CMV, yet they had DST and a TX from a seropositive LRD. Of these patients, 12 (36.4%) seroconverted within the first 6 months post-TX and developed clinical CMV disease. Additional patients seroconverted, but did not have evidence of clinical disease and were not tested further. All TX centers, with the exception of one, had seronegative patients that became ill after receiving a seropositive DST/LRD TX. Six patients manifested their disease as a febrile illness with leukopenia and liver enzyme elevations, four had pneumonitis, and two developed CMV ulcerations of the colon (one of whom died from resultant sepsis). Of the 36 seronegative patients who received seronegative DST/LRD TX none became ill with CMV disease. Of the 72 seropositive patients who received DST/LRD TX, only 2 (2.8%) developed CMV illness (one, seropositive into seropositive, the other, seronegative into seropositive). Of the 33 seronegative patients receiving seropositive DST/LRD TX, 17 received antilymphocyte preparations (ALP), and 8 of these became ill (47.1%). Of 16 patients not receiving ALP, 5 (31.3%) developed clinical CMV illness. Of the 33 patients who were identified as having been seronegative for CMV yet received seropositive DST/LRD TX, the 12 who did develop CMV illness had two graft losses, one death, and a serum creatinine for the remaining 9 patients of 2.3 +/- 1.6 at last follow-up. The remaining 21 patients who developed no illness had a serum creatinine of 1.3 +/- 0.6 with no graft losses at the last follow-up. This evidence suggests that a prospective TX recipient who is seronegative for CMV who receives DST/LRD TX from a seropositive family member has a significant risk for developing morbidity related to clinical CMV illness.

Combined simultaneous kidney/bone marrow transplantation.

On the basis of observations in patients with long-term (28-30 years) renal allograft survival, all of whom had evidence of systemic microchimerism, we began a program of combined simultaneous kidney/bone marrow transplantation. Between 12/14/92, and 10/31/94, 36 kidney transplant recipients received 3-5 x 10(8) unmodified bone marrow cells/kg; 6 patients also received pancreatic islets, and 7 patients also received a pancreas. The mean recipient age was 39.0 +/- 10.8 years, and the mean donor age was 31.8 +/- 16.1 years; the mean cold ischemia time was 23.0 +/- 9.1 hr. Twenty control patients received kidneys alone, mainly because of refusal by the donor family to consent to vertebral body recovery; 3 of these patients also received a pancreas. The mean recipient age was 47.9 +/- 11.7 years, and the mean donor age was 41.5 +/- 17.9 years; the mean cold ischemia time was 28.6 +/- 6.2 hr. All patients received tacrolimus-based therapy, without radiation, cytoreduction, or induction antilymphocyte preparations. Blood was drawn prior to and at regular intervals after transplantation for detection of chimerism and for immunologic studies. With a mean follow-up of 11.1 +/- 5.8 months, all 36 study patients are alive, and 33 (92%) have functioning allografts with a mean serum creatinine of 1.9 +/- 1.2 mg/dl and a BUN of 26 +/- 9 mg/dl. Graft vs. host disease was not seen in any patient. The incidence of rejection was 72%; 11% of the patients required OKT3 or ATG for steroid-resistant rejection. The incidence of CMV was 14%, and that of delayed graft function was 17%. A total of 18 (90%) control patients are alive, and 17 (85%) have functioning allografts, with a mean serum creatinine of 2.1 +/- 1.3 mg/dl, and a BUN of 30 +/- 13 mg/dl. The incidence of rejection was 60%, and 10% required OKT3 or ATG. CMV was seen in 15%, and delayed graft function in 20% (P = NS). In the study patients, chimerism was detected in the peripheral blood of 30 of 31 (97%) evaluable patients by either PCR or flow cytometry. In the control patients, chimerism was seen in 9 of 14 (64%) evaluable patients (P < .02). Decreasing donor-specific responsiveness was seen in 6/29 (21%) evaluable study, and 4/14 (29%) evaluable control patients (P = NS). We conclude that combined kidney/bone marrow transplantation is associated with acceptable patient and graft survival, augmentation of chimerism, and no change in the early events after transplantation.