George Kyriakides

Long-Term Study of Vascularized Free-Draining Intraperitoneal Pancreatic Segmental Allografts in Beagle Dogs

The purpose of the present study was to evaluate the significance of immunogenetic factors on the survival of pancreatic allografts in beagle dogs. Donors and recipients were leukocyte antigen (DLA)-typed and mixed lymphocyte culture (MLC)-tested. Recipients were made diabetic by total pancreatectomy and immediately implanted intraperitoneally with a vascularized, free-draining (duct unligated) pancreatic segmental (FDPS) allograft. Two groups of dogs were studied. In group I consisting of donor-recipient littermates, recipients were immunosuppressed with prednisone and azathioprine (n = 16 dogs), or not immunosuppressed (n = 4). In group II, recipients were made specifically unresponsive by total body radiation, autologous marrow implantation, and kidney transplantation from DLA-MLC identical donors, 1 yr before FDPS transplantation from the corresponding original kidney donors. Survival of the FDPS grafts in group I was inversely related to pretransplant MLC reactivity, irrespective of DLA genotyped match between donor and recipient. Thus, immunosuppressed high MLC reactors (n = 8) rejected FDPS grafts between 7 and 14 d, whereas immunosuppressed low MLC reactors (n = 8) accepted grafts for 25 to 260+ days, and nonimmunosuppressed low MLC reactors (n = 4) accepted grafts for 9-55 d. Rejection (hyperglycemia) of FDPS grafts was sudden, permanent, and unpredictable despite weekly intravenous glucose tolerance tests with measurements of glucose disappearance rates and serum insulin responses. Nevertheless, serial in vitro cell-mediated lymphocytotoxicity (CML) assays revealed increases in CML before graft rejection in low MLC reactors, and decreases in both CML and MLC responses before graft rejection in high MLC reactors. FDPS graft survival was indefinite (>6 mo) in group II dogs, despite low-grade MLC reactivity (2:4 dogs) and CML responses (4:4 dogs). Biopsies of FDPS grafts at 6 mo in normoglycemic dogs showed disappearance of exocrine tissue and coalescence of islets in both groups I and II, but with less fibrosis in group I (immunosuppressed). These results indicate that (a) pancreatic islets in vascularized grafts (FDPS) may survive indefinitely in the presence of a good tissue match best predicted by MLC testing, (b) tissue specific histocompatibility factors appear to be common enough between kidney and pancreas to allow for long-term survival of both organs transplanted from the same donor, at least in appropriate recipients (group II), and (c) immunosuppression is associated with less fibrosis in FDPS allografts.

Gastrinoma associated with common bile duct obstruction and the ectopic production of ACTH.

A case of adrenocortical hyperfunction due to ectopic production of ACTH by a gastrin-producing tumor of the pancreas is described. Cushings syndrome preceded the appearance of the overt Zollinger-Ellison syndrome by 2 years and was treated by bilateral adrenalectomy. The Zollinger-Ellison syndrome was initially treated with cimetidine, which successfully reduced the secretion of gastric acid. Because the pancreatic gastrinoma continued to grow, causing obstruction of the common bile duct, biliary diversion and total gastrectomy were performed. There is evidence that the pancreatic gastrinoma was the source of the ectopic production of ACTH and possibly secretion. The role of Histamine-2 blocking agents as therapy in the Zollinger-Ellison syndrome is discussed.

Long-Term Follow-up of Canine Segmental Pancreatic Autografts

The functional and morphologic characteristics of freedraining, pancreatic segmental autografts (FDPS) were studied in 8 beagle dogs that had survived longer than 4 yr. After pancreatectomy, animals received FDPS autografts of the left pancreatic limb, representing approximately one-third of the total pancreas with iliac vessel anastamoses. The grafted recipients were given pancreatic enzyme supplements (Viokase). After transplantation (tx), all 8 animals sustained fasting euglycemia with no evidence of microvascular complications. After 4 yr, IVGTT revealed K-values (%/min) that were not significantly different from age-matched controls (2.9 ± 0.5 versus 3.7 ± 0.6, P > 0.05). Mean fasting serum insulin levels were significantly greater in the tx animals (49 ± 5 μU/ml versus 12.2 μU/ml, P < 0.001), although the incremental response to i.v. glucose (0.5 g/kg) was less than in controls (P < 0.05). Mean fasting plasma C-peptide levels (0.09 ± 0.01 pmol/ml versus 0.21 ± 0.5 pmol/ml) and peak C-peptide responses to i.v. glucose were both significantly less than in controls. Sequential pancreatic biopsies up to 2.5 yr post-tx showed atrophy of the exocrine pancreas with coalescence of islets and mild fibrosis that did not progress with time. Immunoperoxidase stains confirmed the presence of insulin, glucagon, and somatostatin within nests of islet cells. Four years after transplantation of FDPS autografts in pancreatectomized dogs, excellent function is retained. The consequences of peripheral hyperinsulinemia remain to be determined.

Discussion: Renal Replacement Therapy Progression of Renal Disease and Transplantation

The Einstein Group in the 1960’s had an abstract showing that the rate of increase of GFR in infants after birth was influenced by the level of protein intake. What the study did not do was look at the parallel effect of increases of sodium and other nutrients that go along with the protein. In the human studies, have people controlled sodium intake, mineral content intake, and so on?

SERUM LIPID ABNORMALITIES AFTER SUCCESSFUL RENAL TRANSPLANTATION (TX)

Hyperlipidemia (HL) with increase in triglycerides (TG) is frequently seen in uremic patients before TX. In order to assess the lipid abnormalities following renal TX, 22 patient (15 females) [xmacr ] age 17 years (range 5-21), with a functioning renal allograft (serum creatinine [xmacr ] 1.13 mg/dl, range 0.7-2.6) were studied at [xmacr ] 26 months (range 2-55) after renal TX. Serum total cholesterol (TC), TG, and lipoproteins VLDL, LDL and HDL were determined and compared to normal age and sex matched controls. Results ([xmacr ] mg/dl ± SD) are shown in table (†p <0.01).TC and TG were >95 percentile in 68% and 32% of the patients respectively. A significant correlation between HL and daily Prednisolone dose was found (r=0.55; p <0.01). These results demonstrate: 1) HL is commonly present following renal TX;2)HL is mainly due to increased TC, but with a significant elevation of HDL and maintenance of normal HDL/LDL ratios. Based on the findings of normal HDL/LDL ratios, the presence of HL following successful renal TX in children may not increase their risk of premature atherosclerosis.