George M. Abouna

Long-term function and survival of elderly donor kidneys transplanted into young adults.

BACKGROUND Traditionally, elderly donor kidneys have not been widely accepted for transplantation on the assumption of inferior performance. However, the United Network for Organ Sharing reports an increase in the number of elderly donors from less than 2% in 1982 to 24% in 1995. This trend is commensurate with the increase of older dialysis patients and an overall increase in the elderly population in the United States (1). Optimal utilization of these kidneys is essential to overcome the acute organ shortage. METHODS In this study, we transplanted 25 kidneys from elderly donors (ages 56-72 years) into young adult recipients (ages 20-50 years) (group 1) over a 4-year period. We compared the results with matched recipients of young adult donor kidneys (group 2) with regard to long-term kidney function and graft survival. A pretransplant biopsy of elderly donor kidneys was carried out and a frozen section report was obtained. Only those kidneys showing glomerulosclerosis of less than 20% were accepted for transplantation. All cadaveric kidneys were preserved in University of Wisconsin solution. RESULTS Pretransplant biopsies of elderly donor kidneys showed structural deficits, which included glomerulosclerosis in 85%, arteriolar and/or mesangial thickening in 75%, and interstitial lymphocyte infiltration in 30%. The mean serum creatinine was 2.4+/-0.74, 2.2+/-0.56, and 2.9+/-0.76 mg/100 ml in group 1 and 1.5+/-0.55, 2.3+/-2.24, and 1.7+/-0.62 in group 2 at 1, 3, and 5 years, respectively. The patient survival was 92%, 92%, and 88% in group 1, and 100%, 100%, and 100% in group 2 at 1, 3, and 5 years, respectively. The graft survival was 80%, 64%, and 56% in group 1 and 100%, 96%, and 88% in group 2 at similar time intervals. The differences in the serum creatinine and graft survival between the two groups were statistically significant (P < 0.05). CONCLUSIONS Most of the elderly donor kidneys with structural deficits transplanted into young adults provided suboptimal function and inferior long-term graft survival. To maximize the utilization and optimize the survival of elderly donor kidneys, we propose transplantation of these kidneys into age-matched recipients with similar physiological requirements as those of donors, with regard to kidney function.

RANDOMIZED CLINICAL TRIAL OF ANTITHYMOCYTE GLOBULIN INDUCTION IN RENAL TRANSPLANTATION COMPARING A FIXED DAILY DOSE WITH DOSE ADJUSTMENT ACCORDING TO T CELL MONITORING

Antithymocyte globulin (ATG) has been used successfully for induction therapy as well as for treatment of established allograft rejection. However, this therapy has often been associated with problems of overimmunosuppression and increased costs. In a randomized clinical trial, we compared the immunosuppressive benefits, complication rates, and treatment costs when ATG is given as a fixed daily dose or when the dose is adjusted daily according to its biologic effects on T cells. Forty-five recipients of cadaver renal allografts were randomized into two groups. In group 1 (n=23), ATG (ATGAM) was administered in variable doses to maintain the absolute number of peripheral CDS T cells at 50–100/μl. In group 2 (n=22), ATG was given at a fixed dose of 15 mg/kg/day. All patients received azathioprine and prednisone. ATG was discontinued at 7–14 days when cyclosporine was introduced. In both groups, CD2, CDS, CD4, CDS, and CD19 cells were measured by flow cytometry and the levels of cytokines IL-1β, IL-2R, ICAM-1, IL-6, IL-7, and IL-10 were measured by ELISA. In group 2, the levels of all T cell subsets were profoundly suppressed. In group 1, the number of CDS and other T cells was maintained at about 100 cells/μl, while the CD19 T cells remained unsuppressed. Cytokine levels were greatly suppressed in group 2 compared with group 1, except for IL-10 levels, which remained elevated in the latter group. Patient survival, graft function, and the incidence of acute and recurrent rejections were similar in the two groups. Bone marrow suppression and infective complications were greater in group 2 than in group 1. The mean daily dose and the total quantity of ATG used in group 1 were significantly smaller than in group 2, resulting in a savings of

Extracorporeal liver perfusion system for successful hepatic support pending liver regeneration or liver transplantation: a pre-clinical controlled trial.

2,398.00 per patient per treatment. It is concluded that monitoring of ATG by its biologic effects on T cells is a rational and safe method of regulating the dose of this important agent; in this way, it is possible to reduce the total amount of the drug given to patients with consequent reduction in undesirable complications as well as in the cost of treatment without loss of immunosuppressive benefits.

Function of transplanted human pancreatic allografts after preservation in cold storage for 6 to 26 hours.

BACKGROUND There is a well recognized need for a system capable of providing effective support for patients with hepatic failure pending liver regeneration or liver transplantation. Recent attempts of using bioartificial liver containing encapsulated porcine hepatocytes, the deployment of emergency whole liver, or hepatocyte transplantation are complex and not consistently successful. The technique of ex vivo hepatic perfusion developed and used clinically by Abouna in the 1970s, has now been redesigned in a perfusion circuitry that mimics the physiological conditions of a normal liver. Before clinical application of this system, a preclinical trial was carried out in dogs with induced hepatic failure. METHODS Acute hepatic failure was induced in dogs by an end-to-side porto caval shunt, followed 24 hr later, by a 2-hr occlusion of the hepatic artery. All animals (n=18) were medically supported and were divided into three groups. In the control group (n=6) only medical support was used. In the experimental group (n=12) the animals were connected to the ex vivo liver support apparatus during acute hepatic failure via an AV shunt using a dog liver (n=6) or calf liver (n=6) (after a temporary extracorporeal bovine kidney transplant to remove preformed xeno antibody). Hepatic perfusion was carried out at 37 degrees C through the hepatic artery and portal vein at physiological pressures, and blood flow rate for 6-8 hr. RESULTS All control animals died of progressive hepatic failure at 14-19 hr after clamping the hepatic artery. The animals treated with ex vivo liver showed remarkable clinical and biochemical improvement. Five animals survived for 36-60 hr. Another seven animals recovered completely and became long-term survivors with biochemical and histological evidence of regeneration of their own liver. Biopsy of the allogeneic ex vivo liver at the end of perfusion showed some interstitial edema. Similar biopsy of the xenogeneic calf liver showed only mild and delayed xenograft rejection, which was most likely due to removal of preformed xeno antibody by temporary transplantation of the calf kidney before liver perfusion. CONCLUSIONS The observations and results obtained in this trial strongly confirm that extracorporeal perfusion through a whole liver, using the system described, is very successful and cost effective for the treatment of acute, but reversible hepatic failure, as well as serving as a bridge to liver transplantation. The time has come for this form of liver support technology to be reintroduced and widely used.

Prolongation of allograft survival in diabetic rats treated with cyclosporine by deoxyguanosine pretreatment of pancreatic islets of langerhans

Preservation of cadaveric pancreas allografts has been a difficult problem in clinical pancreas transplantation; most institutions use Collins solution and limit preservation time to less than 6 hr. Longer preservation times have been used at the University of Minnesota. Between August 1983, and December 1985, 47 human cadaveric pancreas grafts were transplanted into Type I diabetic recipients after cold storage at 4°C in a modified, hyperosmolar silica-gel filtered plasma (SGFP), * a solution previously found to allow dog pancreas grafts to be successfully preserved for up to 48 hr. Ten grafts were preserved for 2–5 hr (group 1); 20 for 6–11 hr (group 2; 17 for 12–26 hr (group 3). Graft function and late outcome were compared between these groups and another group of 7 cadaveric grafts (group 4), which were transplanted immediately and without any preservation. Analysis of exocrine pancreatic function early after transplantation showed a maximum mean serum amylase (IU/L) of 557, 440, 429, and 307 in groups 1, 2, 3, and 4, respectively. Primary preservation failure rates of 0, 5%, 5.8%, and 0%, and endocrine graft function rates at 1 month of 80%, 80%, 78%, and 88% were obtained for groups 1, 2, 3, and 4, respectively (P=NS). Only patients who were insulin-independent were counted as having functioning grafts. Detailed functional studies at 1 month showed that mean plasma glucose levels during 24-hr metabolic profiles were in the normal range in 71%, 68%, 72%, and 50%, while oral glucose tolerance test results were within the normal range in 38%, 81%, 76%, and 68% of groups 1, 2, 3, and 4, respectively (P=NS). At 1 year, patient survival rates were 57%, 88%, 75%, and 100% (P=NS), and the graft functional survival rates were 0, 25%, 33%, and 29% (P=NS) in the respective groups. Five patients in group 2, and 8 in group 3 have currently functioning grafts at 4 to 37 months after transplantation. We conclude that cadaver pancreas grafts can be safely preserved for 12–24 hr in modified SGFP solution, thus making the sharing of these organs between different centers practical and the transplant operation less of an emergency procedure.

Brachial Arteriovenous Shunts for Hemodialysis and Extracorporeal Procedures

In vitro pretreatment of islets of Langerhans with deoxyguanosine (dGuo) has been shown to be effective for the prolongation of islet allograft survival in rats. [This study evaluates the effect of pretreatment of islets with dGuo transplanted into CsA-treated recipients.] Transplantation of dGuo-treated islets from Wistar rats into diabetic hooded (PVG) rats resulted in 36% graft survival without immunosuppression (dGuo-group) and 89% islet survival after a short course of cyclosporine was used in recipients (dGuo + CsA group). In contrast, transplantation of untreated islets into rats without immunosuppression (controls) and with CsA (CsA group) immunosuppression resulted in 0 and 56% survival, respectively. The differences in graft survival between dGuo versus control group (P<0.001), (dGuo + CsA) ersus control group (P<0.0001), and CsA versus control group (P<0.002) are statistically significant. Donor-strain skin-graft challenge failed to induce rejection of transplanted normoglycemic rats in (dGuo) and (dGuo + CsA) groups. The results indicate that a state of immunologic unresponsiveness may have been induced in the recipients of dGuo-treated islets, and further treatment with CsA synergistically prolongs islet survival in fully mismatched rats.

Ultrastructure of canine renal autografts following 24 hour hypothermic preservation

Fourteen patients aged 8–47 years were : given brachial arteriovenous shunts. The main indications were a combination of hemodialysis, hepatic assist and intravenous feeding. Five p

Emergency adult to adult living donor liver transplantation for fulminant hepatic failure--is it justifiable?

29 canine kidneys were preserved for 24 h by hypothermic, pulsatile or nonpulsatile perfusion with albumin or cryoprecipitated plasma and were autotransplanted. Electron microscopy of biopsies taken a