K. Moudry-Munns

Long-term Glucose Control in Patients with Pancreatic Transplants

OBJECTIVE To evaluate the long-term effect on blood glucose levels of successful transplantation of part or all of an intact human pancreas in patients with insulin-dependent diabetes mellitus (IDDM). DESIGN Cohort study. SETTING Referral medical center. PATIENTS Thirty-seven patients with adequate data, representative of a group of 62 patients with functioning grafts (that is, insulin-independent) at 2 years after transplantation. The 62 patients came from a total of 178 patients in the University of Minnesota series as of July 1987, for a 2-year success rate of 35% (95% Cl, 27.8% to 41.8%). These patients were compared to two diabetic control groups (18 patients with IDDM under standard insulin treatment in a university diabetes clinic and 11 patients with IDDM whose pancreas grafts had failed) and to two nondiabetic groups (14 nondiabetic patients who received immunosuppressive drugs after kidney transplantation and 196 healthy control subjects). MEASUREMENTS Glycosylated hemoglobin was measured by the high-pressure liquid chromatography method, as total A1 (Hb A1) and the A1C subfraction (Hb A1C); results were expressed as a percentage of total hemoglobin. MAIN RESULTS Before pancreas transplantation, the 37 patients in the study group had a mean Hb A1 of 10.8%, consistent with moderate to marked hyperglycemia and not statistically different from the levels in the diabetic control groups. All 37 patients had values above the therapeutic target range of 5.4% to 7.4%. However, at 1 and 2 years after transplantation, the mean Hb A1 value had fallen sharply to 6.7% and 6.5%, respectively, well within target range (Cl of the difference, 3.4% to 4.8%; P less than 0.001). These levels did not differ from the mean Hb A1 in the nondiabetic kidney transplant recipients but were slightly above the 6.2% value for the 196 healthy controls (Cl of the difference at 1 year, 0.2% to 0.8%). Serial values were available on 6 subjects for 5 years; these values were all well within target range. As expected, Hb A1C values were parallel to those of Hb A1. CONCLUSIONS Pancreas transplantation, in our successful cases, lowered glycosylated hemoglobin to normal or near-normal levels that were sustained for as long as 5 years. These results compare favorably with those in our patients on standard treatment, and also with those in similar patients on intensive control reported by others. Further effort to improve transplant methods appears to be warranted.

EVIDENCE THAT COMBINED PROCUREMENT OF PANCREAS AND LIVER GRAFTS DOES NOT AFFECT TRANSPLANT OUTCOME

We compared outcome after pancreas and liver transplantation when both organs were retrieved from the same donor to outcome when only one or the other organ was retrieved. A total of 166 cadaver pancreata were transplanted at our institution between November 1984 and August 1989; 64 were obtained from donors in whom the liver was also donated (LD), and 102 were retrieved from non-liver donors (non-LD). Of the 64 LD pancreata, 53 were the entire organ with a segment of duodenum and 11 were segmental. Both the superior mesenteric artery (SMA) and celiac axis (CA) were retained with the pancreas in 13, while in 40 pancreata the CA was retrieved with the liver and the blood supply to the pancreas was reconstructed [end-to-side anastomosis of splenic artery (SA) to SMA in 11 and a Y-graft of donor iliac bifurcation to SA and SMA in 29]; a graft of common iliac vein was used to extend the portal vein in 10. The technical failure rate was 8/64 (12%) in LD pancreata, and 13/102 (13%) in non-LD pancreata (P greater than 0.1). The overall pancreas allograft survival rate at 1 year was 76% for pancreata obtained from LD (n = 64) and 64% for technically successful transplanted pancreata obtained from non-LD (n = 102, P greater than 0.1). One-year actuarial patient survival was 95% in the LD group and 90% in the non-LD group (P greater than 0.1). Among the 64 livers from pancreas donors (PD), 20 were transplanted at our hospital, 42 were transported to other institutions, and 2 were not transplanted. Follow-up information regarding 47 primary orthotopic adult, whole liver PD recipients (18 at our hospital, 29 at other institutions) was available for analysis and was compared with information concerning 62 adult recipients of primary orthotopic whole livers from non-PD transplanted during the same period at our institution. The total PNF rate among 47 PD liver allografts was 2/47 (4%), compared with 1/62 (1%) for the livers from non-PD (P greater than 0.1). The technical failure rate for the PD group was 1/47 (2%) versus 5/62 (8%) in the non-PD group (P greater than 0.1). The overall liver allograft survival rate at 1 year was 75% for livers obtained from PD (n = 47) and 81% for livers obtained from non-PD (n = 62, P greater than 0.1). One-year actuarial patient survival was 88% in the PD group and 81% in the non-PD group (P greater than 0.1). We concluded that simultaneous procurement of liver and pancreas grafts had no significant detrimental effect on the rate of technical failure, or on allograft or patient survival after either pancreas or liver transplantation.

Pancreas retransplants compared with primary transplants.

The improved results with pancreas transplantation in general, and the emerging evidence that the procedure favorably influences the course of secondary diabetic complications, given an impetus to retransplant patients whose initial graft has failed. In order to determine whether a pancreas retransplant policy is justified, we analyzed the results at our own institution. From 1978 through 1989, 327 pancreas transplants were performed in 261 patients, including 259 primary (79%) and 68 retransplants (21%) after a previous one failed (including 2 primary transplants performed elsewhere), with 48 second (15%), 18 third (5%), and 2 fourth (1%) transplants. The surgical techniques used in the 261 primary PxTxs were open-duct free drainage into the peritoneal cavity in 15 recipients, of whom 3 (20%) were retransplanted: duct occlusion in 34, of whom 9 (26%) were retransplanted intestinal drainage in 78, of whom 23 (29%) were retransplanted; and bladder drainage in 134, of whom 13 (10%) were retransplanted. The surgical techniques used for the 68 pancreas retransplants were duct occlusion in 11 (10 second, 1 third), intestinal drainage in 12 (9 second, 3 third), and bladder drainage in 45 (29 second, 14 third, and 2 forth); bladder drainage has been used nearly exclusively for the most recent pancreas retransplants. The recipient categories in the 261 primary transplants were pancreas alone in 115, of whom 29 (25%) were retransplanted, pancreas after kidney in 81, of whom 17 (21%) were retransplanted, and simultaneous pancreas and kidney transplants in 63, of whom 2 (3%) were retransplanted. Of the 68 pancreas retransplants, 32 (47%) were pancreas alone (26 second, 6 third), 24 (35%) were pancreas after kidney (17 second, 6 third, 1 fourth), and 12 (18%) were simultaneous pancreas and kidney (5 second, 6 third, 1 fourth). Overall patient survival rates were similar (P = 0.48), at 1 month (actual [98% after primary and 94% after retransplantation]) and at 1 year (actuarial [91% vs. 89%]). Overall graft functional rates were also similar, at 1 month (actual [76% for all primary and 79% for all retransplants - P = 0.9]), and at 1 year (actuarial [46% vs. 43% - P = 0.9]). Causes of graft losses at 1 months were similar for primary (18% were technical failures, 6% were rejected) and retransplant (16% were technical failures, 3% were rejected) cases.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of preservation time on outcome and metabolic function of bladder-drained pancreas transplants

The influence of cold storage preservation time on graft survival and metabolic function of pancreatic transplants was studied in 130 recipients of bladder-drained grafts (47 simultaneous with, 33 after, and 50 without a kidney transplant) between October 1, 1984 and May 1, 1989. The recipients were divided into four groups according to the preservation time: less than 6 hr (n = 11), 6-12 hr (n = 24), 12-24 hr (n = 75), and greater than 24 hr (n = 20). Twenty-six grafts were procured by other transplant teams and sent to us. Silica gel fractionated plasma was used for preservation in 104 cases and the University of Wisconsin solution in 25 (1 in the less than 6 hr, 2 in the 6-12 hr, 16 in the 12-24 hr, and 6 in the greater than 24 hr groups). The technical failure rate at 1 month was 13% (17 grafts), 1 (9%) in the less than 6 hr, 5 (21%) in the 6-12 hr, 9 (12%) in the 12-24 hr, and 2 (10%) in the greater than 24 hr groups. At 1 month, 107 (82%) of the grafts were functioning, 10 (91%) in the less than 6 hr, 18 (75%) in the 6-12 hr, 62 (83%) in the 12-24 hr and 17 (85%) in the greater than 24 hr groups, the longest preserved for 30 hr. The respective 1-year graft survival rates were 51%, 50%, 57%, and 70%. Ninety patients (10 in the less than 6 hr, 16 in the 6-12 hr, 51 in the 12-24 hr, and 13 in the greater than 24 hr groups) had metabolic studies between 2 and 6 weeks postransplant. The results of 24-hour profiles (14 blood glucose determinations) were similar in each preservation time group; the means of the mean (+/- SD) profile glucose (mg/dl) values were 130 +/- 19, 126 +/- 31, 130 +/- 24, and 129 +/- 30, respectively (P greater than 0.6). Mean plasma glucose levels at 2 hr during OGTT were 141 +/- 32, 145 +/- 43. 163 +/- 49, and 184 +/- 100 in the respective preservation groups (P greater than or equal to 0.064). According to the National Diabetes Data Group classification, 75% of recipients in the less than 6 hr, 50% in the 6-12 hr, 44% in the 12-24 hr, and 33% in the greater than 24 hr groups had normal OGTT results.(ABSTRACT TRUNCATED AT 400 WORDS)

Pancreas transplants from living related donors

Living related donors (LRDs) were first used for kidney transplantation [1]. The consistently high patient and graft survival rates of LRD kidney transplants have led to their increasing popularity in the United States, accounting for up to 50% of all kidney transplants at some centers. The pancreas was the first extrarenal solid organ in which successful LRD transplants were done [2]. Over the last 5 years, the use of LRDs has received increasing attention for liver [3], lung [4], and intestinal [5] transplantation

LONG-TERM METABOLIC FUNCTION OF PANCREAS TRANSPLANTS AND INFLUENCE OF REJECTION EPISODES

Pancreas grafts, when not rejected, can sustain an insulin-independent state in type I diabetic recipients for indefinite periods. To what extent the metabolic control achieved approaches that of normal individuals, the relationships between graft endocrine and exocrine function, the effect of reversible rejection episodes on subsequent graft function, and the correlation between the results of serial tests of graft function were determined by studies at 1 month, 1 year, and 2 years in a cohort of 39 recipients (29 females, 10 males; mean age (1SD), 33±5 years; mean duration of diabetes, 22±6 years) of bladder-drained pancreas transplants performed between November 1984 and December 1988. Fifteen patients received a pancreas transplant alone, 8 a pancreas after a kidney, and 16 a simultaneous pancreas/kidney transplant. Graft endocrine function was tested by a 24-hr metabolic profile of blood glucose levels before meals, at 1 and 2 hr after meals, and during the night (14 values in all), by intravenous and oral blood glucose tolerance tests, and by glycosylated hemoglobin levels (HA1 and HA1c). Graft exocrine function was assessed by urine amylase activity (U/hr). The results of the tests in the recipients were subjected to paired comparisons between timepoints and at each timepoint to the results of the same tests in 55 normal nondiabetic control individuals. The means of the mean 24-hr profile glucose (mg/dl) values were significantly lower (P<0.05) at 1 and 2 years posttransplant (116± 27 and 115115, respectively) than at 1 month (128±31) in the recipients, but the mean of the mean values in the normal controls (100±7) was even lower (P<0.05). Mean values of individual timepoints during the profile were significantly lower for 6 of the 14 values in the controls than in the recipients. The mean IVGTT K value of the normal controls (-1.9±0.4%) was significantly lower than the 1-month and 2-year values of the recipients (-1.5±0.5% and −1.3±0.6%, respectively), but the comparison with the 1-year value (-1.6±0.6%) was not significant. The mean glucose levels at zero minutes and between 120 and 300 min of the OGTTs were significantly lower at both 1 and 2 years than at 1 month in the recipients, and the values in the control group were also significantly lower than in the recipients at 1 month but not at 1 and 2 years. Mean hemoglobin A1 values at 1 and 2 years (not tested at 1 month) in the recipients (6.6±0.9% and 6.5±0.7%) were not significantly different from the mean values in the control group (6.2±0.4).

Medical Risks and Benefit of Pancreas Transplants from Living Related Donors

The rationale to perform transplants of any organ from living related donors (LRDs) rather than cadaver (Cad) donors is two-fold: there is a shortage of Cad donors for the number in need of a transplant, and the rejection rate will be less with grafts from LRDs. Either reason by itself will justify the use of LRDs, and for kidney transplants both pertain.

Experience with pancreas transplants from living related donors

The rationale to perform transplants of any organ from related donors rather than cadaver donors is twofold: there is a shortage of cadaver (CAD) donors for the number in need of a transplant, and the rejection rate will be less with grafts from living related donor (LRDs). Either of these two alone will justify the use of LRDs, and for kidney transplants both rationales pertain.

International Pancreas Transplantation Registry report

The International Pancreas Transplant Registry (IPTR) has collected information prospectively on all pancreas transplant cases in the world since 1980 (1), and has retrospective information on all cases before 1980 dating back to the first case performed in 1966 (2). Several previous reports of the Registry have been made (3–13). Some of the results of an analysis performed on August 22, 1989, of cases submitted to the Registry as of June 30, 1989, and reported in greater detail elsewhere (14, 15), are summarized here.

Pancreas transplantation in non-uremic diabetic recipients

Most pancreas transplants have been performed in diabetic patients with end-stage nephropathy who also received kidney transplants, either simultaneous with or before the pancreas graft (1). Such patients have been selected for the procedure because they were already obligated to immunosuppression in lieu of the kidney transplant, and the only risk incurred in order to achieve an insulin-independent, normoglycemic state, was that of the surgery itself, a risk that is currently very low (2–8). In addition, in such patients a kidney graft can be used to monitor for rejection episodes that in most instances effect both grafts simultaneously, with a rise in serum creatinine as a manifestation of renal allograft rejection preceding pancreas allograft dysfunction, allowing treatment to be initiated in time to preserve endocrine function. For this reason, pancreas graft survival rates are higher in recipients of simultaneous kidney transplants than in recipients of solitary pancreas transplants (8).