Organ shortage crisis: problems and possible solutions.

The demand for organ transplantation has rapidly increased all over the world during the past decade due to the increased incidence of vital organ failure, the rising success and greater improvement in posttransplant outcome. However, the unavailability of adequate organs for transplantation to meet the existing demand has resulted in major organ shortage crises. As a result there has been a major increase in the number of patients on transplant waiting lists as well as in the number of patients dying while on the waiting list. In the United States, for example, the number of patients on the waiting list in the year 2006 had risen to over 95,000, while the number of patient deaths was over 6,300. This organ shortage crisis has deprived thousands of patients of a new and better quality of life and has caused a substantial increase in the cost of alternative medical care such as dialysis. There are several procedures and pathways which have been shown to provide practical and effective solutions to this crisis. These include implementation of appropriate educational programs for the public and hospital staff regarding the need and benefits of organ donation, the appropriate utilization of marginal (extended criteria donors), acceptance of paired organ donation, the acceptance of the concept of "presumed consent," implementation of a system of "rewarded gifting" for the family of the diseased donor and also for the living donor, developing an altruistic system of donation from a living donor to an unknown recipient, and accepting the concept of a controlled system of financial payment for the donor. As is outlined in this presentation, we strongly believe that the implementation of these pathways for obtaining organs from the living and the dead donors, with appropriate consideration of the ethical, religious and social criteria of the society, the organ shortage crisis will be eliminated and many lives will be saved through the process of organ donation and transplantation.

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

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 degrees 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%, 76%, and 86% 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 66% 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 6 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.

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

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 less than 0.001), (dGuo + CsA) versus control group (P less than 0.0001), and CsA versus control group (P less than 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.

Factors necessary for successful 48-hour preservation of pancreas grafts.

Thirty-nine canine segmental pancreatic autografts were preserved at 4 degrees C for 48 hr prior to transplantation using five different preservation solutions: modified silica gel-filtered plasma (SGFP) (n = 10); modified PPF (n = 9); modified Collins' solution (n = 8); partially modified plasma protein fraction (PPF) (n = 6), and unmodified PPF (n = 6). These modifications were with respect to osmolality, pH, protein, and potassium content. Graft function was assessed by daily fasting blood sugar and serum amylase, and by intravenous glucose tolerance test (IVGTT) and insulin output at 14-21 days. Viable preservation was deemed successful if normoglycemia was maintained for at least 5 days. Modified SGFP was successful in 80% of the animals, modified PPF in 100%, partially modified PPF in 60%, unmodified PPF in 50% and modified Collins' solution in 37%. The difference between modified PPF and the latter three solutions was significant (P less than 0.05). The causes of graft failure were primary nonfunction, graft pancreatitis, and focal necrosis in some of the grafts preserved by Collins' solution. Graft function in the surviving animals, as determined by the IVGTT and K value, was similar regardless of the method of preservation and was comparable to that previously obtained with fresh and unpreserved segmental pancreatic autografts. It is concluded that modified PPF solution is as effective as modified SGFP in the preservation of pancreatic grafts for 48 hr. The essential elements in this modification appear to be high pH and high oncotic pressure in a hyperosmolar and moderately hyperkalemic solution. Since PPF is readily available and is much cheaper than SGFP, it may be the solution of choice for clinical preservation of pancreas allografts for periods of 24-48 hr.

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 CD3 T cells at 50-100/microliters. 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, CD3, CD4, CD8, and CD19 cells were measured by flow cytometry and the levels of cytokines IL-1 beta, IL-2R, ICAM-1, IL-6, IL-7, and levels of cytokines IL-1 beta, IL-2R, ICAM-1, IL-6, IL-7, and levels of cytokines IL-1 beta, 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 CD3 and other T cells was maintained at about 100 cells/microliters, 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 $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.

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

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.

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.

Lymphocyte activation: changes in intracellular adenosine triphosphate and deoxyribonucleic acid synthesis.

Stimulation of human lymphocytes from 20 individuals with phytohaemagglutinin (PHA) for 60 min resulted in a fall in intracellular adenosine triphosphate (ATP) of 35% compared to unstimulated controls of 19% (p less than 0.001). There was a significant (p less than 0.01) correlation (r = 0.57) between ATP decrease at 60 min and deoxyribonucleic acid (DNA) synthesis at 72 h in PHA-stimulated cells. The technique described here is simple, rapid and has possible application in immunodiagnosis and immunologic monitoring.

The place of Sugiura operation for portal hypertension and bleeding esophageal varices.

Fifty patients with portal hypertension and bleeding varices aged 10 months to 72 years were treated with a modified Sugiura, nonshunt operation (n = 26) or shunting procedures (n = 24) in accordance with the following predetermined therapeutic protocol: after resuscitation and diagnostic endoscopy, an emergency mesocaval shunt procedure was carried out if bleeding could not be stopped (group 1, n = 10). When bleeding could be stopped, the patients underwent full investigation and were then treated with either the distal splenorenal (DSR) shunt if the criteria of Warren were satisfied (group 2, n = 14) or with a modified Sugiura procedure in all other circumstances (group 3, n = 26). Patients were evaluated at 1.5 to 6 years. The rates for operative deaths, recurrent hemorrhage, encephalopathy, late deaths, and actuarial patient survival at 6 years were as follows: 20%, 30%, 30%, 20%, and 60% for group 1; 14.3%, 14.3%, 14.3%, 7.2%, and 79% for group 2; and 7.7%, 3.4%, 0%, 0%, and 93% for group 3, respectively. Within 3 months after the Sugiura operation, varices disappeared in 95% of patients and hypersplenism was relieved in all. Major complications were gastric and esophageal leaks in two patients (fatal in one) and temporary dysphagia in six. We conclude that the modified Sugiura nonshunt operation is probably the preferable treatment for variceal hemorrhage in the nonalcoholic patient because it is effective in arresting hemorrhage, has low operative mortality, low recurrence rate, no encephalopathy, and excellent survival rates.

Site for unpurified islet transplantation is an important parameter for determination of the outcome of graft survival and function.

Transplantation of unpurified islets into the liver, unlike that of purified islets, causes portal hypertension and coagulopathy. The aim of this project was to determine the most suitable alternative site for transplantation of unpurified pancreatic islets in autotransplanted dogs. Twenty-five female mongrel dogs were divided into 5 groups depending on the site of islet transplantation: liver (3), spleen (7), skeletal muscle (5), omental pouch (6), and renal subcapsule (4). Pancreatic digestion of the total pancreatectomized specimen was carried out by distension of the pancreas with 1.5 mg/mL collagenase suspended in 250 mL Hanks' balanced salt solution using a semiautomatic method. The total number of islets equivalent isolated from 25 dogs was 90948 +/- 6053. Only islets > 60 microns in diameter were counted, and the mean islet equivalent transplanted per kg body wt was 6762 +/- 429. Islet function was achieved with transplantation into spleen in 71%, omental pouch in 50%, and muscle in 20%, but none in the renal subcapsule or liver groups. Glucose tolerance test at 30 d showed a mean K Value (decline in glucose, %/min) of 1.94 +/- 0.73, 0.79 +/- 0.15 and 1.02 in the splenic, omental pouch and muscle groups, respectively. All animals in the liver group, 2 from the splenic group, and 2 from the renal subcapsule group died of diffuse bleeding. Four out of 5 dogs in the muscle group developed necrosis at the site of transplantation and the islets never functioned. This study demonstrates that in dogs, spleen and omental pouch appear to be suitable sites for transplantation of unpurified islets.

Negative impact of trading in human organs on the development of transplantation in the Middle East.

PIP: With recent advances in transplanting human organs, increasing numbers of people in need of replacement organs are opting for transplantation. These medical advances and the subsequent public demand have, however, led to a supply-demand problem in which more patients request replacement organs than the number which are readily available. A flourishing international trade in human organs has developed in response to the comparatively high demand for organs. Organs in demand are bought from the poor for transplantation to wealthy clientele. For their contacts and services, brokers, private hospitals, and physicians earn enormous profits. It is estimated that more than 2000 kidneys since 1990 have been sold annually in India to wealthy recipients from the Middle East, the Far East, and Europe. The phenomenon has alarmed the medical profession, the public, and many governments and has been condemned by all major religions and most transplant societies. The author also condemns the sale of human organs as being damaging to the cause of transplantation as well as many other moral, religious, and ethical values and beliefs of society. The sale of organs negatively affects their altruistic donation by the public as well as the development of local cadaver procurement programs by national governments. All forms of paid organ donation should therefore be made illegal in all countries of the world. Sections consider the donor, the recipient, local transplant programs, the medical profession, and the impact upon society.^ieng

Limiting factors in successful preservation of cadaveric kidneys with ischemia time exceeding 50 hours.

The results of 61 cadaveric allografts preserved for 30 to 76 hours were analyzed to determine the effect of cold ischemia time, the method of preservation, and the type of immunosuppression on early graft viability and long-term graft survival. Preservation in cold storage up to 50 hours gave a low incidence of nonfunction (4%) and of posttransplant dialysis (20%) and a high rate of function both at 1 month (96%) and at 2 years (60%). Cold ischemia time greater than 50 hours caused a significantly increased need for dialysis (58%) but without appreciable difference in graft function at 1 month or at 2 years. Preservation by machine had no advantage over preservation by simple cold storage when the cold ischemia time was less than 50 hours. When cold ischemia time exceeded 50 hours, machine preservation was associated with a significantly reduced incidence of posttransplant dialysis but without significant differences in long-term function at 2 years. With up to 50 hours of cold ischemia and providing there was no ATN, CsA had little nephrotoxicity and gave excellent graft function at 1 month and at 2 years. However, the nephrotoxicity of CsA was markedly increased when the preservation interval exceeded 50 hours, resulting in a significantly increased rate of primary nonfunction and the need for dialysis with a significant decrease in graft function at 1 month and at 2 years. The nephrotoxicity of CsA was considerably decreased or eliminated without affecting its powerful immunosuppressive property when initial immunosuppression was begun with azathioprine with sequential conversion to CsA when graft function was fully established. It is recommended that when cold ischemia is long or when there is ATN, CsA should be used as a sequential therapy to azathioprine after graft diuresis or, alternatively, in much smaller doses as part of a combination therapy with azathioprine.