Transmission of HCV by organ transplantation.
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Adolescent↗
Biomedical subjects
F O Belzer
Publications and source records attributed to F O Belzer.
Urea and protein synthesis in cold-preserved isolated rat hepatocytes.
We used an isolated-hepatocyte model to study how hypothermic storage (simulating liver preservation) affects metabolism after prolonged preservation. Rat hepatocytes were stored in the University of Wisconsin solution for up to 72 hr. After each day of storage, protein synthesis, urea synthesis, ATP content and lactate dehydrogenase release were determined in rewarmed (37 degrees C) and oxygenated hepatocytes. Protein synthesis ([3H]-leucine incorporation into protein) was depressed by 16% +/- 4%, 54% +/- 6% and 69% +/- 4% after 24 hr, 48 hr and 72 hr, respectively. Urea synthesis, ATP synthesis and lactate dehydrogenase release were similar to those in control hepatocytes (no preservation). Fasting of the rats before isolation of hepatocytes caused more rapid loss of protein-synthesis capabilities (59% in 24 hr) with no significant loss of lactate dehydrogenase, urea synthesis or ATP synthesis. Hepatocyte viability (lactate dehydrogenase release) as judged by membrane permeability, ATP synthesis and potassium content can be maintained after up to 6 days of cold storage. However, protein synthesis is depressed after only 48 hr of cold storage. Thus hypothermic storage of the liver causes a change in the metabolic capabilities of the hepatocytes, and the timing of the loss of protein synthesis is similar to the limits of successful cold storage of the whole liver (48 hr). Thus a limit to long-term storage of the liver may be related to loss of protein synthesis. In liver transplantation, one indication of poor preservation is a decrease in serum albumin and clotting factors with increased tissue edema and bleeding diathesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Loss of mitochondrial respiratory function and its suppression during cold ischemic preservation of rat livers with University of Wisconsin solution.
Preservation of the liver involves a period of cold (0 degrees to 4 degrees C) ischemia; the longer the ischemic period, the greater the injury to the liver. The mechanisms for cold-induced ischemic injury are not known, but it is clear that after preservation the liver has a reduced capacity to regenerate high-energy phosphate compounds (ATP). One cause for the delayed rate of ATP synthesis could be injury to the mitochondria. The effects of long-term (more than 24 hr) preservation on liver mitochondrial function have not been previously studied. In this study, rat livers were preserved in University of Wisconsin solution at 4 degrees C for up to 96 hr. After preservation, mitochondrial respiratory function was assayed in a homogenate and in isolated mitochondria. We saw a progressive increase in oligomycin-sensitive respiration with time of preservation (from 1.2 +/- 0.09 mumol.min-1.gm tissue-1 at 0 hr to 3.8 +/- 0.2 mumol.min-1.gm tissue-1 after 96 hr). The increase after 24-hr preservation (2.1 +/- 0.2 mumol.min-1.gm tissue-1) was also significantly greater than 0 time values (p less than 0.05). No decrease was found in uncoupler-stimulated respiration for up to 48 hr of preservation; only a small decrease was seen after 72 hr of preservation (about 30%). The cause of the increase in oligomycin-sensitive respiration appeared to be related to free fatty acids (or another uncoupling factor) generated during preservation. This was suggested from the fact that bovine serum albumin prevented the increase in oligomycin-sensitive respiration after all periods of preservation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
Improved myocardial ischemic tolerance by contractile inhibition with 2,3-butanedione monoxime.
Contracture of the arrested myocardium during prolonged storage of the heart results in both systolic and diastolic dysfunction, and is a major limitation to extended preservation. We studied the effects of a reversible contractile inhibitor, 2,3-butanedione monoxime (BDM), on myocardial ischemic tolerance. Isolated rabbit hearts were flushed with University of Wisconsin (UW) solution with and without 30 mmol/L BDM and 1 mmol/L CaCl, stored at 4 degrees C for 24 hours, and subsequently reperfused for 60 minutes. Left ventricular pressure-volume relationships and adenine nucleotide content were determined before reperfusion. Left ventricular systolic pressure, diastolic volume, and adenine nucleotide content were measured after reperfusion. Hearts stored in UW solution underwent contracture and adenosine triphosphate (ATP) depletion during storage, and exhibited systolic dysfunction, impaired diastolic relaxation, and poor ATP regeneration upon reperfusion. The addition of calcium worsened contracture and ATP depletion (p < 0.005) and slightly improved function and ATP regeneration (p = not significant). Hearts stored in the presence of BDM experience no contracture during storage; ATP was preserved (10.7 versus 15.7 nmol/mg; p < 0.05), and left ventricular systolic pressure and ATP content recovered to 74% and 93% of control on reperfusion, respectively (p < 0.005). Left ventricular diastolic volume remained depressed, however, although less than with UW solution (0.87 versus 0.45 mL; p < 0.001). When both BDM and calcium were included in the UW solution, calcium-stimulated ATP hydrolysis and contracture were prevented, left ventricular systolic pressure returned to 87% of control, and left ventricular diastolic volume and ATP content returned to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenine Nucleotides↗
Factors affecting renal allograft function in long-term recipients.
The natural history of renal allograft function in long-term recipients is not known. To characterize renal allograft function and the factors that affect it, we reviewed the records of all patients who received a renal allograft at the University of Wisconsin between 1965 and 1981 and selected those who had annual data on renal function for at least 10 years. We identified 155 patients--78 with living-related donors and 77 with cadaveric donors. All patients were adults receiving azathioprine and prednisone. Renal function was estimated by calculated creatinine clearances (Ccr), which correlated well with measured 24-hour creatinine clearances. The creatinine clearance data for each patient were plotted versus time. In 73% of patients, the creatinine clearance increased for several years before reaching a peak value. After the peak, the creatinine clearance declined in a linear manner. Stepwise regression analyses indicated that allografts from cadaveric donors had a greater increase in creatinine clearance from the value at year 1 to the peak than allografts from living-related donors (0.35 +/- 0.25 v 0.21 +/- 0.23 mL/s [21.4 +/- 15.0 v 12.7 +/- 13.8 mL/min]; P less than 0.001). The average time to reach the peak value of creatinine clearance was longer in cadaveric allografts (6.8 +/- 3.5 v 4.6 +/- 4.0 years; P less than 0.001). Postpeak, the rate of decline in creatinine clearance was faster in cadaveric allografts than in living-related ones (0.06 +/- 0.05 v 0.04 +/- 0.04 mL/s/yr [3.50 +/- 2.99 v 2.55 +/- 2.16 mL/min/yr]; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The use of UW solution in clinical transplantation. A 4-year experience.
The development of the University of Wisconsin (UW) cold storage solution has extended safe preservation of the liver and pancreas from 6 to 24 hours or more. From May 1987 until November 1991, 288 livers and 163 simultaneous pancreas/kidney transplants were performed using UW solution. The mean preservation times were: liver, 12.7 +/- 4.4 hours, pancreas 17.2 +/- 4.4 hours, and kidney, 19.2 +/- 4.3 hours. Included in this series were 35 reduced-sized liver transplants, 7 cluster transplants, and 132 combined liver/pancreas retrievals. No differences in allograft function or graft-related complications were seen in organs preserved for less than or longer than 12 hours or in grafts from combined liver/pancreas retrievals. All pancreas/kidney transplants and most liver transplants were performed semi-electively. Actuarial 1-month patient and graft survival after liver transplantation was 91.4% and 80.2%, and at 4 years was 74.0% and 62.0%, respectively. After pancreas/kidney transplantation, the actuarial patient survival at 1 month and 4 years was 99.4% and 90.5%, respectively, whereas pancreatic and renal allograft survival at 1 month was 97.5% and 96.8%, and at 4 years was 83.0% and 83.4%, respectively. The ability to extend preservation times with UW solution has many advantages; however, the most important contribution of UW solution to clinical transplantation has been the increased utilization of scarce donor organs for more recipients because the previously imposed constraints on preservation time have been removed.
Adenosine↗
RS-61443 (mycophenolate mofetil). A multicenter study for refractory kidney transplant rejection.
RS-61443 (mycophenolate mofetil) inhibits a key enzyme of the de novo synthesis of purine nucleotides in T and B lymphocytes. The purpose of this study was to evaluate the efficacy of RS-61443 in patients with refractory renal allograft rejection. Patients eligible for the study had previously undergone anti-rejection therapy with high-dose steroids or OKT3 monoclonal antibody. All rejection episodes were proven by renal biopsy. Successful rescue was achieved in 52 (69%) patients. Rescue was more successful when patients were entered with a creatinine of 4 mg/dL or lower (79%), versus a 52% rescue rate in patients entered with a creatinine of 4 mg/dL or above. Major side effects were predominantly gastrointestinal, but there was no overt nephrotoxicity, hepatotoxicity, or bone marrow suppression. The overall infection rate was 40%, with the spectrum of infections characteristic for the highly immunocompromised patient. The conclude that this pilot study suggests that RS-61443 is effective in refractory kidney allograft rejection. Based on this study, prospectively randomized multi-center trails have been planned and are in progress.
Adolescent↗
Limitations of heart preservation by cold storage.
Clinical heart preservation is currently limited to only 4-6 hr, while the kidney, liver, and pancreas can tolerate 24-48 hr of cold ischemia. A fundamental difference between these organs is that the heart is contractile, containing large quantities of actin and myosin, and is susceptible to contracture-induced injury caused by energy deprivation. We have quantified and correlated the onset of contracture with levels of ATP and glycogen during cold storage in rabbit hearts flushed with UW solution, with and without 1 mM calcium (Ca), or 3 mM iodoacetate (IAA). A fluid-filled left ventricular balloon was used to generate pressure-volume curves (compliance) at 1, 6, 12, 18, and 24 hr of cold storage. Onset of contracture occurred in UW stored hearts at 18 hr, contracture in hearts exposed to Ca occurred between 6 and 12 hr. Compliance was significantly less in hearts exposed to Ca at 12, 18, and 24 hr (P less than .01) than in hearts without Ca. ATP levels were well maintained for up to 18 hr in the hearts preserved in UW solution (78%), but fell more rapidly in the presence of Ca at 12 hr (P less than .005), 18 hr (P less than .005), and 24 hr (P less than .05). In comparison, the ATP supply of the liver and kidney was exhausted by only 4 hr of cold storage. Onset of myocardial contracture correlated with a decrease in ATP to less than 80% of control, and contracture accelerated ATP decline 3-6-fold. IAA caused nearly complete myocardial contracture and ATP depletion within 2 hr. Isolated heart function was 77% and 73% at 6 and 12 hr of storage, but fell to 54% and 42% at 18 and 24 hr, respectively, coinciding with development of contracture. We conclude that ischemic contracture in this model is a major cause of myocardial damage during cold storage, and is accelerated by the presence of Ca. Other organs can be successfully stored despite exhaustion of ATP reserves. Thus successful cold-storage of the heart is highly ATP-dependent. Since cold storage inevitably leads to ATP depletion, extension of myocardial ischemic tolerance will depend on either reversible inhibition of ATP hydrolysis during storage, reversible uncoupling of contracture development from ATP depletion, or maintaining ATP production by continuous hypothermic perfusion.
Adenosine↗
RS-61443--a phase I clinical trial and pilot rescue study.
RS-61443, a morpholinoethyl ester of mycophenolic acid, inhibits the synthesis of guanosine monophosphate, which plays a pivotal role in lymphocyte metabolism. The drug blocks proliferative responses of T and B lymphocytes, and inhibits antibody formation and the generation of cytotoxic T cells. In vivo, RS-61443 prolongs the survival of islet allografts in mice, heart allografts in rats, and kidney allografts in dogs. Reversal of ongoing acute rejection was demonstrated in rat heart allografts and kidney allografts in dogs. Preliminary evidence suggests that the drug prevents chronic rejection. The purpose of this study was to test the safety and tolerance in patients receiving primary cadaver kidneys. RS-61443 in doses from 100 mg/day p.o. to 3500 mg/day p.o. was given to patients in combination with cyclosporine and prednisone. Further study goals were to evaluate the pharmacokinetics of RS-61443, watch for the occurrence of opportunistic infections and acute rejection, and establish dosages for further clinical trials. Forty-eight patients were entered, with six patients in each dose group. RS-61443 was well tolerated in all dose groups, with only one adverse event possibly related to the drug (hemorrhagic gastritis). There was a statistically significant correlation between rejection episodes and dose (P = 0.022), patients with rejection episodes versus dose (P = 0.038), and number of OKT3/prednisone courses versus dose (P = 0.008). There was no overt nephrotoxicity or hepatotoxicity. Preliminary results of a rescue trial in 20 patients with kidney transplants will also be presented.
Adult↗
The importance of a colloid in canine pancreas preservation.
The role of hydroxyethyl starch (HES), the colloid component of the UW solution, was tested in canine pancreas preservation. Segmental pancreatic autografts were preserved for 48 hr cold storage with UW solution with HES (group 1) or UW solution without HES (group 2). After preservation, the pancreas was transplanted, and survival, serum glucose, serum amylase, intravenous glucose tolerance tests, tissue water content, and histology were compared between groups. In group 1 (with HES), 9/10 dogs were long-term survivors with one dog dying due to causes unrelated to preservation failure. In group 2 (without HES), 3/6 dogs died due to graft loss within one week posttransplant (P = 0.01). No graft failure occurred in group 1 (0/9) versus graft loss in 4/6 dogs in group 2 (P = 0.04). All animals in group 1 (with HES) showed normal serum glucose and amylase concentrations postoperatively, normal tissue water values after preservation, k values comparable to those observed after segmental autotransplantation without preservation, and relatively good histology. In group 2 (without HES), in 4/6 dogs graft failure occurred that led to the death (3 dogs) of the animals or to a diabetic state (1 dog). After 48-hr cold storage without HES, a significant increase in tissue water content, glucose and amylase levels was seen. After transplantation, hyperglycemia, hyperamylasemia, and clinical diabetes were observed in 4/6 dogs. Autopsy and histological evaluation showed evidence of thrombosis and ischemic insult. Two of 6 dogs in group 2 remained normoglycemic during follow-up with borderline k values. The results suggested that for consistently successful 48-hr preservation of the pancreas, HES is an important component of the UW solution. Although a colloid may not be essential for short-term preservation of kidney and liver, it appears to be an important factor in successful pancreas preservation.
Adenosine↗
A comparison of histidine-lactobionate and UW solution in 48-hour dog liver preservation.
Many modifications of the UW solution have been reported to yield successful results in rat liver preservation and transplantation. One solution used histidine, in combination with lactobionate (HL-I), and gave superior preservation of the rat liver when compared with the UW solution. In this study we have compared the HL-I solution with 90 mM histidine, HL-II solution with 30 mM histidine, and the UW solution in dog liver preservation and transplantation. Dog livers were preserved for 48 hr in one of the three solutions and transplanted. The peak AST and ALT values were highest in livers preserved in HL-I, intermediate in UW solution, and lowest in HL-II. However, there were no significant differences among survival rates (average 5-7 days per group), posttransplant serum concentration of liver enzymes (AST, ALT, LDH, and alk-phos), clotting factors (PT and PTT), bilirubin, and fibrinogen concentration for each group. Dogs were sacrificed or died within 5-7 days due to rejection in nonimmunosuppressed dogs. Also, rat livers were preserved in the HL-II solution or in a solution in which histidine was replaced by isoleucine (IL-I). Isoleucine is an amino acid with a molecular mass similar to that of histidine, but is not as good a hydrogen ion buffer as histidine at the pH used for liver preservation (7.4). The buffer capacity of the IL-I solution was similar to the UW solution, but about one-half as much as the HL-II solution. Rats receiving a liver preserved for 30 hr in HL-II or IL-I were 100% viable. Rats receiving a liver preserved for 40-44 hr in HL-II or IL-I showed less survival (33% and 25%, respectively). This shows that histidine can be effectively replaced by isoleucine in a preservation solution and gives equivalent preservation results. Thus, the mechanism of improvement of liver preservation with histidine is not due to its action as a hydrogen ion buffer. These studies show that, although the HL solutions are superior for preservation of the rat liver, they are not superior to the UW solution for preservation of the dog liver. However, as others have shown in the rat liver transplant model, a simplified UW solution (HL-II) appears effective in dog liver preservation. The dog liver transplant model remains a more appropriate model for testing new preservation solutions prior to initiation of clinical trials.
Adenosine↗
Hyperlipidemia and transplantation: etiologic factors and therapy.
Hyperlipidemia is a well-recognized complication of renal transplantation. In long-term survivors of renal transplantation, cardiovascular disease accounts for the majority of patient deaths. In the cyclosporine era, cardiovascular disease has surpassed infection as the number one cause of death. Risk factors in the transplant population for hyperlipidemia include age, male sex, diabetes, prednisone dose, graft impairment, obesity, and antihypertensive therapy. Recently, cyclosporine has been implicated as an aggravating factor in the development of hyperlipidemia after transplantation, although its role has been controversial. Because renal transplant recipients have other significant risk factors for the development of coronary artery disease, the amelioration of hyperlipidemia may improve long-term patient survival. Because most late deaths occur in patients with a functioning graft, long-term graft survival could also be improved. The role of corticosteroids in the development of hyperlipidemia is well established. Recent studies employing corticosteroid withdrawal after transplantation have shown a marked reduction in cholesterol despite the use of cyclosporine. Data on corticosteroid withdrawal in living related transplants at our center show a significant reduction in total cholesterol after steroid withdrawal. Data from heart transplant recipients under corticosteroid-free protocols show a similar reduction in total cholesterol. Other treatments for hyperlipidemia include diet and cholesterol-lowering agents, such as Mevacor (lovastatin; Merck Sharp & Dohme, West Point, PA). The efficacy of lowering cholesterol in this high-risk population is unknown.
Adrenal Cortex Hormones↗
Energy metabolism and renal ischemia.
In renal preservation, the longer the organ is cold stored the greater the damage to the organ. The mechanism of hypothermic-induced kidney injury is not known. In this study the effects of long-term preservation (up to 120 h) of the dog kidney on mitochondrial functions in an homogenate of kidney cortex tissue was investigated. Kidneys were exposed to either warm ischemia (0 to 90 min) cold ischemia (0, 72, 96, and 120 h). The mitochondrial oxygen uptake was measured in an homogenate. In both warm and cold ischemia there were changes in the mitochondrial utilization of oxygen. The changes were characterized as a decrease in uncoupler stimulated oxygen uptake by up to 40%, an increase in oligomycin-sensitive respiration by up to about 150%, and a decrease in the respiratory control ratio (uncoupler control ratio) from about 3 to 1. These changes in mitochondrial utilization of oxygen were partially reversed by including albumin in the respiration medium. Albumin binds free fatty acids and these may originate, during ischemia, from the action of phospholipases during ischemia. The changes in mitochondrial oxygen uptake may result from both the loss of membrane-bound phospholipids and the accumulation of free fatty acids. The changes in mitochondrial activity between 72 h (viable kidneys on transplantation) and 96 to 120 h preservation (nonviable kidneys) were not significant. Furthermore, reperfusion of kidneys preserved for 72 to 120 h resulted in a restoration of mitochondrial oxygen uptake to near normal (control) values. Thus, it does not appear that the limitation of successful long-term renal preservation is due to mitochondrial injury caused by cold ischemia.
Animals↗
Indications for enteric conversion after pancreas transplantation with bladder drainage.
BACKGROUND: Bladder drainage has become the procedure of choice for 94% of transplant centers in North America. Bladder drainage is superior to other techniques as far as graft survival and technical success are concerned; however, the procedure is associated with significant urologic problems that might necessitate conversion to enteric drainage. This review summarizes the indications and results for enteric conversion at this institution. METHODS: Between June 1982 and January 1992 a total of 240 pancreas transplantations were performed at our center. In 229 cases exocrine secretions were drained into the bladder. These cases were reviewed, and those with enteric conversions were further analyzed to delineate indications, complications, and results. RESULTS: Sixteen (7%) were converted to enteric drainage (side-to-side duodenojejunostomy). The reasons for conversion were urethral disruption (six), recurrent urine leaks (five), bleeding (four), and chronic urinary tract infection (one). Enteric conversions were performed between 1 1/2 and 32 months after the initial transplantation. With the exception of one anastomotic leak resulting in an intraabdominal abscess, no complications occurred. All patients undergoing enteric conversions had resolution of their problems and, in addition, were able to discontinue use of oral bicarbonate. CONCLUSIONS: We conclude that enteric conversion after pancreas transplantation with bladder drainage is safe and effective in the correction of urologic problems. Based on our experience, we recommend early enteric conversion if urologic problems do not resolve after an appropriate period of conservative therapy.
Duodenum↗
Management of the common duct in extended preservation of the liver.
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Adenosine↗
Liver-intestinal transplantation: report of a case.
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Cyclosporine↗
A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation. Side effects of trimethoprim-sulfamethoxazole, interaction with cyclosporine.
Questions have been raised regarding the safety of trimethoprim-sulfamethoxazole (TMP-SMZ) in organ transplantation, particularly adverse interactions with azathioprine and cyclosporine. In a prospective randomized, double-blind, trial in 132 patients that encompassed 33,876 patient-days, long-term prophylaxis with TMP-SMZ was found to significantly reduce the incidence of bacterial infection after renal transplantation. Prophylaxis was very well tolerated; none of the 66 recipients of TMP-SMZ, who took the drug for an average of 8.9 months, was withdrawn from the study because of hypersensitivity or toxic side effects. Serial measurements of hematologic parameters and liver function tests after transplantation in the two groups showed no significant differences. Recipients of cadaveric transplants, who were all given cyclosporine, randomized to receive TMP-SMZ had serum creatinine levels approximately 15% higher than those in control patients receiving cyclosporine (p less than 0.01); comparison of renal function by 24-hour endogenous creatinine clearances and technetium 99m-labeled diethylenetriamine-penta-acetic acid glomerular filtration rates in 17 patients crossed over to the alternate treatment group for 7 weeks, however, shows that the observed differences are reversible and represent inhibition of tubular excretion of creatinine by TMP in the presence of cyclosporine. Prophylaxis with TMP-SMZ had no discernable effect on cyclosporine pharmacokinetics: recipients of TMP-SMZ had blood levels of cyclosporine similar to those in patients in the placebo group. Episodes of graft rejection occurred at a similar frequency in the two groups (placebo, 50; TMP-SMZ, 44). We conclude that long-term prophylaxis with TMP-SMZ does not produce discernable hematologic, renal, or hepatic toxicity in renal transplant recipients nor does it augment nephrotoxicity with cyclosporine or increase the risk of rejection. TMP-SMZ may be used safely and is highly cost-beneficial for prophylaxis of infection in renal transplantation.
Creatinine↗
The role of oxygen free radicals in organ preservation.
There is controversy over the role of oxygen free radical-induced damage in preserved organs following reperfusion. Furthermore, there has been no definitive study that shows a dramatic improvement in organ functions, delayed graft functions, or improved longevity in organ transplants with oxygen free radical scavenger therapy. However, the presence of glutathione in a new organ preservation solution (University of Wisconsin, UW, solution) yields improved preservation of the liver and heart. The beneficial effect of glutathione may involve in scavenging of cytotoxic products of oxygen metabolism. The results discussed here show that glutathione improves liver preservation. Also, it is shown that glycine, and amino acid component of glutathione, can also give cytoprotection to the rabbit and dog liver tested by either isolated perfusion or orthotopic transplantation. Thus, there may be an involvement of oxygen free radicals in damage to organs hypothermically preserved and transplanted. The injury may occur within the cells or may be due to oxygen within the cells or may be due to oxygen free radicals generated in the extracellular environment.
Adenosine↗