Pancreas transplantation prevents or retards development of early diabetic glomerular lesions in renal allografts transplanted to patients with insulin-dependent diabetes mellitus (IDDM), but its effect on established renal lesions in native kidneys of such patients is unknown. Renal biopsy samples were taken before and 5 years after pancreas transplantation from 13 non-uraemic IDDM patients and compared with baseline and 5-year biopsy samples from 10 persistently hyperglycaemic IDDM patients who did not undergo transplantation. The two groups were similar in age, duration of diabetes, metabolic control, renal function, and blood pressure. Glomerular structures were measured by standard morphometric techniques. Haemoglobin A1 concentrations fell to within the normal range after pancreas transplantation but did not change in the comparison group. Glomerular basement membrane width did not significantly change in either group. Glomerular volume decreased and mesangial fractional volume increased in the pancreas transplant recipients but there was no significant change in total mesangial volume over 5 years. By contrast, both glomerular volume and mesangial fractional volume increased in the comparison patients, resulting in increased total mesangial volume. Diabetic glomerular lesions in patients with their own kidneys were not ameliorated by pancreas transplantation, despite 5 years of normoglycaemia. Pancreas transplantation can correct severe metabolic instability and thus improve quality of life, but it cannot yet be recommended for the treatment of established lesions of diabetic nephropathy.

Adolescent↗

PubMed1993

Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15-deoxyspergualin.

Islet transplantation has been slow to develop as a therapy for type I diabetes mellitus. Conventional immunosuppression does not protect islet allografts from early failure and by current techniques the yield of purified islets from a single pancreas is inadequate or only marginally in excess of the number needed to sustain normoglycaemia. We transplanted unpurified islets from a single pancreas concomitantly with a kidney to two uraemic diabetic patients. The novel agent 15-deoxyspergualin, along with antilymphocyte globulin, was used for induction immunosuppression, and azathioprine, prednisone, and cyclosporin for maintenance. Islet function has been sustained in both, and the second patient is insulin-independent and euglycaemic more than 6 months after transplantation.

Adult↗

PubMed1993

En bloc kidney and whole pancreaticoduodenal transplantation with bladder drainage in the rat: microsurgical technique and outcome.

A microsurgical technique for en bloc kidney and whole pancreaticoduodenal transplantation with bladder drainage employing triple vascular anastomoses without the need for a vascular cuff is described. Nineteen combined isografts were performed using this technique in inbred male Lewis (RT1:I) rats with streptozotocin-induced diabetes. Six recipients died within 1 month from early complications (two from uremia, two from pancreatitis, one from bleeding, one from peritonitis); the other 13 survived more than 1 month after transplantation with both the pancreas and kidney grafts functioning. Four of the 13 rats died after 1 month (one from uremia secondary to an obstructed ureter, one from unexplained uremia, one from peritonitis after a biopsy, and one of unknown causes). The pancreas isografts of two animals were excised at 1 and 3 months to confirm dependence on the graft; both animals became hyperglycemic after graft pancreatectomy and had immediate declines of urine amylase activity to normal. One animal was sacrificed at 3 months to determine the insulin content of its native and transplanted pancreas; insulin was very low in the former and normal in the latter. The remaining rats survived with both grafts functioning for at least 6 months (normoglycemic, high urinary amylase levels, normal or near-normal plasma creatinine concentrations), before being sacrificed within the context of other experiments and for histological observations. Both the kidney and pancreas isografts were well preserved microscopically.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗

PubMed1993

Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota.

Transplantation began at the University of Minnesota in 1963. Treatment of diabetes and its complications has been emphasized since 1966, when the first pancreas-kidney transplant was done. Of 3,640 kidneys transplanted by 1992, 1,373 were for diabetic recipients, including 658 from living donors and 715 from cadaver donors. The results progressively improved; since 1984, survival rates of kidney grafts have been similar for diabetic and nondiabetic recipients, with three fourths of the grafts functioning at 4 years. As of 1992, 501 pancreas transplants had been done, including 170 simultaneous with a kidney, 142 after a kidney, and 188 alone for nonuremic diabetic patients; again, the results have improved: by the 1990s, graft survival rates were similar in the 3 recipient categories. Successful pancreas transplants have been shown by our coworkers to stabilize or improve neuropathy and prevent recurrence of diabetic nephropathy in kidney grafts. In an attempt to simplify endocrine replacement therapy, we have done 63 human islet transplants, 34 as allografts for patients with type I diabetes and 29 as autografts after total pancreatectomy to treat chronic pancreatitis. Insulin independence occurs for about 50% of islet autograft recipients. Two recent islet allograft recipients treated with 15-deoxyspergualin have had sustained insulin independence. We anticipate that endocrine replacement therapy by transplantation will become routine for diabetic patients as methods to prevent rejection are refined.

Diabetes Mellitus, Type 1↗

PubMed1993

Pancreatic islet transplantation: is purification necessary?

Successful islet allotransplantation in diabetic patients has been slow to develop. In the past, it has been assumed that the low success rates are, in part, due to difficulty in obtaining high-quality human islet preparations. The assumption has been that purified islets are essential because exocrine contamination hampers engraftment and makes islets more vulnerable to rejection by increasing graft immunogenicity. We reviewed the existing experimental data on the consequences of exocrine contamination and concluded that most clinical trials of islet allotransplantation have involved efforts to over-purify the allograft. Until antigen-specific tolerance or the biohybrid artificial pancreas is a reality, the best strategy for clinical trials is to test new immunosuppressive protocols in a search for a more effective way of modifying the host's immune response while maximizing islet yield by using less pure preparations.

Animals↗

PubMed1993

Half-life and risk factors for kidney transplant outcome--importance of death with function.

Transplant center outcome is being increasingly scrutinized, so it is critical to have a consistent approach to data analysis. Standard practice has been to include death with function as a graft loss. But doing so may obscure other important risk factors and make it difficult to compare centers. To document this data analysis problem, we studied half-life and risk factors for long-term graft survival in 2230 kidney transplant recipients who had > or = 1 year of function. Four separate Cox regression analyses were done, differing in how death with function is considered: death with function considered a graft loss (analysis 1); all deaths censored (analysis 2); definitively non-transplant-related deaths censored, i.e., deaths from infection, malignancy, or cardiac problems analyzed as a graft loss (analysis 3); and definitively non-transplant-related as well as cardiac deaths censored (analysis 4). For each analysis, variables included immunosuppressive protocol, age at transplant, donor source, diabetes, gender, transplant number (primary vs. retransplant), and HLA ABDR mismatches (0 vs. > or = 1 mismatch). There were important differences in risk factors, depending on how death with function is considered. For example, when all deaths are considered a graft loss, age > 50, cadaver donor source, diabetes, retransplantation, and > 0 antigen mismatch were found to be risk factors for long-term graft survival. However, when all deaths are censored, age > 50, cadaver donor source, retransplantation, and diabetes were no longer risk factors. In fact, age > 50 was associated with significantly better graft survival when all deaths are censored (analysis 2), suggesting that the increased graft loss seen in these patients is nonimmunologic. Similarly, t1/2 is markedly different for different patient subgroups depending on how death with function is considered. For example, nondiabetic living donor (non-HLA-identical) recipients > 50 have a t1/2 of 9 +/- 1 years when death with function is considered a graft loss; for the same group, t1/2 is 62 +/- 28 years when death with function is considered. For diabetic patients < or = 50, when death with function is considered a graft loss, t1/2 is 9 +/- 0.9 years for living donor recipients and 7 +/- 0.7 years for cadaver donor recipients. For the same patients, when death with function is censored, t1/2 is 27 +/- 4 years for living donor recipients and 24 +/- 4 years for cadaver donor recipients. Our analysis suggests that death with function needs to be considered in analyzing kidney transplant outcomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1993

Early versus late acute renal allograft rejection: impact on chronic rejection.

We studied the effect of acute renal allograft rejection and its timing on the development of chronic rejection and subsequent graft loss. Between January 1, 1987 and April 30, 1991, 424 patients at the University of Minnesota received a primary kidney transplant (minimum follow-up, 1 year). Patients were subdivided by donor source, presence or absence of acute rejection, and the timing of acute rejection onset (early, < or = 60 days vs. late, > 60 days post-transplant). For living donor (LD) transplant recipients (n = 219), the incidence of chronic rejection is 0.8% in those who had no acute rejection (n = 130), 20% in those with acute rejection < or = 60 days (n = 59) (P < 0.001 vs. no acute rejection), and 43% in those with acute rejection > 60 days (n = 30) (P < 0.001 vs. no acute rejection, P = 0.04 vs. early acute rejection). For cadaver (CAD) transplant recipients (n = 205), the incidence of chronic rejection is 0% in those who had no acute rejection (n = 109), 36% in those with acute rejection < or = 60 days (n = 69) (P < 0.001 vs. no acute rejection), and 63% in those with acute rejection > 60 days (n = 27) (P < 0.001 vs. no acute rejection, P = 0.03 vs. early acute rejection). For both LD and CAD recipients, no grafts have been lost to chronic rejection among those who did not first have at least 1 acute rejection episode. In contrast, 23 patients with acute rejection have had graft loss to chronic rejection. For both LD and CAD recipients, those with > 1 acute rejection episode had significantly more chronic rejection than those with only 1 rejection (P < 0.05). There was no significant difference in the incidence of chronic rejection based on whether the first acute rejection episode was steroid resistant or steroid responsive. We conclude that acute rejection is strongly related to the development of biopsy-proven chronic rejection and subsequent graft loss. Patients undergoing their first acute rejection episode > 60 days (vs. < or = 60 days) have an increased incidence of chronic rejection.

Acute Disease↗

PubMed1993

The in vivo and in vitro effect of 15-deoxyspergualin on pancreatic islet function.

15-deoxyspergualin (DSG) is a novel immunosuppressive agent that has been shown to prolong the function of islet allografts in both small and large animal models. The purpose of this study was to investigate the effect of DSG on in vitro glucose-induced insulin secretion by isolated islets and on glucose disposal in vivo. Incubation of human or rat islets for 24 hr in the presence of DSG (1, 2, 5 or 10 micrograms/ml) did not effect their secretory capacity. In addition, glucose disposal and insulin secretion by normal rats was unaffected by the daily administration of DSG (1, 4, or 10 mg/kg) for 1 week. In contrast to cyclosporine, prednisone, and FK506, DSG does not appear to be associated with altered beta cell function or disordered glucose disposal and is an attractive alternative with potential usefulness in clinical islet allo-transplantation.

Animals↗

PubMed1993

Rejection in single versus combined pancreas and kidney transplantation in pigs.

Clinically, the incidence of reversible renal allograft rejection episodes appears to be higher in recipients of simultaneous pancreas/kidney (SPK) than of kidney transplantation alone (KTA); conversely, the rate of irreversible pancreas allograft rejection appears to be higher in pancreas transplant alone (PTA) than SPK recipients. Clinical/histological correlation of graft rejection in these three groups has not been precise. Therefore, we studied the incidence and histological severity of the rejection process in a large animal (pig) model of SPK (n = 36), PTA (n = 31), and KTA (n = 36) allotransplantation. SPK and PTA recipients were made diabetic pretransplant by streptozotocin (150 mg/kg). Pancreas graft exocrine secretions were bladder-drained via a duodenocystostomy for urine amylase (UA) monitoring; endocrine function was monitored by plasma glucose (PG) levels. SPK and KTA recipients underwent native nephrectomy, and renal allograft function was monitored by serum creatinine (CR). Cyclosporine, azathioprine, and prednisone were given in tapering doses from the time of transplantation. Grafts were biopsied weekly to grade histologic severity of interstitial and vascular rejection on light microscopy (LM) and for intensity of T cell infiltration on immunofluorescence. Pancreas graft exocrine function (UA above pretransplant baseline), present in 62% of PTA and 68% of SPK recipients at one week, persisted in only 7% of PTA vs. 64% of SPK pigs at 2 weeks (P = 0.0004). Likewise, pancreas graft endocrine function (PG < 200 mg/dl off insulin) was sustained longer in SPK than PTA recipients (100% vs. 84% at 1 and 91% vs. 27% at 2 weeks; P = 0.0006). However, renal allograft functional survival (serum creatinine < 3.0 mg/dl) was not significantly different (P = 0.471) between SPK and KTA recipients (36% vs. 30% at 1 and 23% vs. 13% at 2 weeks). Graft functional parameters partially correlated with biopsy observations. Pancreas allograft biopsies showed a significantly (P = 0.03 at 1 and P = 0.05 at 2 weeks) lower incidence of moderate/severe interstitial rejection in SPK than PTA recipients (67% vs. 95% at 1 and 57% vs. 92% at 2 weeks); rejection was absent in 8% of SPK and in no PTA biopsies at 1 week. Vascular rejection was moderate/severe in significantly fewer (P = 0.0013 at 1 and P = 0.023 at 2 weeks) SPK than PTA pancreas grafts (13% vs. 37% at 1 and 14% vs. 38% at 2 weeks).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗