Cyclosporine kinetics in renal transplantation.

The pharmacokinetics of cyclosporine were evaluated in 41 recipients of a cadaveric renal transplant. Cyclosporine was taken by mouth (mean dose 14 mg/kg) on one study day and was intravenously infused over 2 hours (mean dose 4.7 mg/kg) on the next study day. Cyclosporine was extracted from whole blood and analyzed by HPLC. After intravenous infusion, cyclosporine exhibited multicompartmental behavior. The mean (+/- SD) terminal disposition rate constant was 0.065 +/- 0.036 hours-1 and the harmonic mean t 1/2 was 10.7 hours. The harmonic mean total body clearance of cyclosporine was 5.73 ml/min/kg and the mean apparent volume of distribution was 4.5 +/- 3.6 L/kg. The absorption of oral cyclosporine was slow and incomplete. Peak blood cyclosporine concentrations (means = 1,103 ng/ml) were reached between 1 and 8 hours after oral dosing (means = 4 hours). The mean relative bioavailability was 27.6% +/- 20%. Oral bioavailability was less than 10% in 17% of our subjects. The absorption and clearance of cyclosporine were highly variable. We conclude that the variability in the kinetics of cyclosporine makes trough blood level monitoring essential in the management of patients who receive renal transplants.

Evaluation of cardiovascular risk for renal transplantation in diabetic patients.

Cardiovascular disease contributes in a major way to morbidity and mortality in diabetic patients with end-stage renal disease. Sixty patients with type I diabetes were evaluated prior to renal transplantation to determine the risk of cardiovascular complications. On the basis of results of thallium stress testing and/or cardiac catheterization, each patient was assigned to one of five categories. There were no cardiovascular events in the seven patients who had negative results on stress testing. Of the remaining 53 patients, all of whom underwent cardiac catheterization, 30 had normal coronary arteries. None of these 30 patients had any cardiac morbidity, and the two deaths that occurred in this group were not attributable to cardiac causes. Significant coronary artery disease was present in 38 percent of the patients. The overall mortality rate was 5.4 percent in those patients without coronary artery disease and 43.5 percent in those with the disease. In addition, the mortality rate in patients with coronary disease classified as severe was 62 percent, whereas it was 20 percent in those categorized as having moderate disease. The data indicate that patients with diabetes and end-stage renal disease who are at highest risk for cardiovascular events can be identified, and these patients probably should not undergo renal transplantation.

The effect of hypoprolactinemia alone and in combination with cyclosporine on allograft rejection.

Recent evidence suggests that prolactin has a role in regulating immune function. Hypophysectomy or administration of bromocriptine results in suppression of the immune response, which is reversed by the administration of prolactin. Hypoprolactinemia has been shown to augment the immunosuppressive effect of cyclosporine. We studied the effect of hypoprolactinemia induced by a new drug, CQP 201-403, on the survival of heterotopic cardiac allografts in the rat and the ability of peripheral blood lymphocytes to respond in vitro to plant mitogens. CQP treatment alone produced a small increase in graft survival but no change in lymphocyte in vitro proliferation (P less than 0.05). CQP treatment greatly enhanced the immunosuppressive effect of cyclosporine on graft rejection and in vitro lymphocyte function (P less than 0.02). We conclude that modulation of prolactin may be a useful adjunct to cyclosporine immunosuppression.

Influence of DR matching in cadaveric renal transplants performed with cyclosporine. A retrospective analysis of one center.

A retrospective analysis of 300 consecutive cadaveric renal allografts performed at our institution between August 1, 1981, and December 1, 1983, was performed to evaluate the influence of DR typing on graft and patient survival. All patients were treated with low-dose steroids and cyclosporine as the only means of immunosuppression. The group included 246 primary graft recipients and 54 retransplants. DR information was available on the donor and the recipient in 225 of these patients, and it was unavailable on the donor and/or recipient in 75 patients. In 49% of the cases in which information was available, 2 alleles were identified in the donor and in the recipient; in the remainder only 1 allele was identified in either the donor or recipient. The results were analyzed according to HLA/DR match and mismatch. Twelve-month graft survival for the 2-DR-match recipients was 67%, versus 78% for the 1-DR match and 76% for the O-DR match. These differences were not significant. For the O-DR mismatch, the one-year actuarial graft survival was 74%, for the 1-DR mismatch 78%, and for the 2-DR mismatch 79%. Again, there was no significant difference. There was no impact of DR matching on patient or graft survival up to 18 months. Additionally, no difference was found in any of the groups regarding the number of treated rejection episodes per patient or the amount of steroid received per patient at the end of a year. These results suggest that cyclosporine negates the effect of DR matching in cadaveric renal transplantation.

The effect of food on cyclosporine absorption.

The effect of food on the absorption of cyclosporine was evaluated in 18 recipients of cadaveric renal transplants. Cyclosporine was administered orally with a standard hospital breakfast on one study day and without breakfast on the alternate study day. The oral absorption rate as measured by the observed time to peak concentration was not significantly altered by food. The administration of cyclosporine with food resulted in a significant increase in the peak (1465 ng/ml versus 1120 ng/ml) and trough (267 ng/ml versus 228 ng/ml) blood concentrations as well as the area under the blood concentration versus time curve (11430 ng . hr/ml versus 7881 ng . hr/ml). The mean increase in area under the blood concentration versus time curve was 60.6%. The exact mechanism by which food increases the absorption of cyclosporine is not known. Regardless of the mechanism involved, if adequate immunosuppression is achieved with lower doses of cyclosporine taken with food, significant cost savings could be realized.

Comparison of UW solution and Euro-Collins solutions for cold preservation of human liver grafts.

University of Wisconsin solution, a new organ preservation medium, is reported to extend the period of cold storage. In order to evaluate the efficacy of UW solution in human liver preservation we compared 58 donor liver grafts preserved in Euro-Collins (EC) solution. All livers were harvested in a similar manner. Donor and recipient characteristics in the two groups were comparable. The mean preservation time of the UW solution was 11.5 +/- 4.2 hr (range 3-20 hr), significantly longer than the EC mean preservation time of 4.9 +/- 1.6 hr (2-9.6 hr) (P = 0.0001). Evaluation of mean postoperative liver function tests and coagulation factors on days 1-7 showed no statistical difference between the two groups. There was one primary graft nonfunction in the EC group and none with the UW organs. Hepatic artery thrombosis was similar in each group. The incidence of early retransplantation was similar. Three-month graft survival was 81% in the UW group vs. 73% in the EC group. Patient survival at three months was 87% with the UW organs and 84% with the EC organs. We conclude that cold storage of liver grafts in the UW solution has allowed for significantly longer preservation, permitting transplantation to be performed under semielective conditions and procurement of organs from much further distances. Grafts stored in UW solution perform as well as those stored in Euro-Collins, with no significant difference in liver function abnormalities postoperatively.

The significance of a positive flow cytometry crossmatch test in primary kidney transplantation.

This study was conducted to determine the efficacy of the T cell flow cytometry crossmatch (T-FCXM) test in 841 first cadaver donor transplants. Results showed one-year graft survival rates were 82% for T-FCXM-negative patients, compared with 75% for T-FCXM-positive patients (P = 0.01). Early one-month graft failure was 13 percentage points higher in those with a positive T-FCXM than those with a negative T-FCXM. The positive crossmatch patients also had more frequent immunological failures. A positive T-FCXM was found in 39% of the sensitized patients (PRA > 10%) and 8% of those who had not been sensitized. Patients with a positive T-FCXM in either category had a 74% graft survival rate. Thus, most of the T-FCXM-positive results occurred in patients with complement-fixing antibodies. It is suggested that flow cytometry crossmatching (FCXM) be used prospectively, despite the fact that many patients with a positive crossmatch did have successful transplants (TXs). In the current climate of a cadaver kidney scarcity and large recipient waiting pools, utilization of kidneys for patients with the highest probability of success seems a most prudent policy.

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.

Combined cadaveric hepatic and renal organ procurement in infants. Technique for salvage of all organs.

The recent improved success with solid organ transplantation has made multiple-organ procurement from single cadaveric donors a more frequent procedure. The techniques for team procurement have resulted in excellent posttransplant organ function with minimal organ waste. In 12% of the population the right hepatic artery arises from the superior mesenteric artery. When this occurs in an infant or small pediatric combined kidney-liver donor, the aorta is divided below the superior mesenteric artery. Our method salvages the kidneys from these donors for en bloc transplantation without jeopardizing the liver for transplant.

Cyclosporine kinetics in healthy volunteers.

The pharmacokinetics of cyclosporine was studied in five healthy male volunteers following intravenous administration. The subjects received 2.1 mg/kg of cyclosporine as a two-hour intravenous infusion. Blood samples were collected over the subsequent 48 hours. Cyclosporine was extracted from whole blood and analyzed by high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Following the intravenous infusion of cyclosporine, the drug exhibited multicompartmental behavior. The harmonic mean distribution half-life based on HPLC data was 0.45 hours, and the harmonic mean terminal disposition half-life was 6.2 hours. The clearance of cyclosporine based on HPLC cyclosporine concentrations was 3.9 mL/min/kg, and the volume of distribution at steady state of cyclosporine was 1.23 L/kg. Cyclosporine has a shorter half-life, lower clearance, and smaller Vss in healthy persons as compared to patient populations. The differences observed in the pharmacokinetics of cyclosporine in healthy persons as compared to patient populations may be due to differences in hematocrit, lipoprotein profiles, and/or concurrent drug therapy between the groups. Cyclosporine concentrations determined by RIA were consistently higher than those determined by HPLC, resulting in a significantly higher area under the blood concentration versus time curve and lower clearance rate for cyclosporine. We conclude that: (1) kinetic parameter estimates for cyclosporine are different in healthy individuals as compared with organ-transplant recipients, and (2) the kinetic parameters for cyclosporine are different, depending on the assay technique used.

Hypercalcemia in carcinoma of prostate. Its cure by orchiectomy.

A case report of a patient with carcinoma of the prostate and hypercalcemia is presented. We believe this is the first such case documenting ectopic parathormone from this tumor. Resolution of the hypercalcemia followed orchiectomy.

Varicosities of renal venous system.

A forty-four-year-old woman was evaluated for filling defects in the renal pelvis by intravenous pyelography and was found to have varicosities of the renal vein by renal vein angiography.

Sternotomy and portal triad division for cadaver donor nephrectomy.

Modification of the en bloc resection of kidneys for cadaveric kidney transplant patient is described. A median sternotomy and division of the portal triad provide excellent exposure of the upper aorta above the celiac axis. This approach has been used in 40 cadaveric donors with no complications.

Leiomyosarcoma of the vena cava with atrial extension: long-term survival following resection and caval replacement without circulatory arrest.

This is a case report of a primary vena cava sarcoma extending to the atrium in a young woman, which was resected. Cardiopulmonary bypass was used, and the cava replaced with ringed Gore-Tex. She remains alive and well more than 3 years after the surgery with no evidence of recurrence.

Kidney recovery from the multiple organ donor.

Although knowledge of the details of heart, lung, liver, or pancreas dissections is not critical for urologists doing only renal procurement, understanding the principles of multiple organ procurement is important if quality kidneys are to be obtained. The needs of the various recipients must be kept in mind, especially those of heart, lung, and liver recipients, because those organs must function properly every time. Although it may be necessary in an occasional case, especially in small pediatric donors, to remove a heart or liver but not the kidneys, it is not acceptable practice to sacrifice kidneys routinely from multiple organ donors. Low wastage rates of kidneys from multiple organ donors are well documented. Rates of initial nonfunction (ATN) in patients receiving kidneys from multiple organ donors have been about 10 per cent, comparable to the initial nonfunction rates of kidneys from kidney-only donors. Renal procurement operations from cadaver donors will be done frequently in association with procurement of other vital organs. The continued availability of kidneys for transplantation should not be altered by the use of such donors as long as cooperation and careful surgical techniques are employed.

Expanded criteria for cadaver organ donation in renal transplantation.

Although the demand for kidneys has risen steadily, the number of organs available has not increased significantly. In an attempt to alleviate this shortage of organs, the criteria for acceptance of cadaver organs has been expanded. Extremes of donor age and other medical conditions that would have excluded donors in the past are now being accepted cautiously.

The role of whole organ pancreas transplantation in the treatment of type I diabetes.

UNLABELLED: BACKGROUND AND DEMOGRAPHICS: Clinical course was reviewed for 19 whole organ pancreas transplant recipients at UCLA between 11/14/93 and 5/31/95, 18 of which were simultaneous pancreas kidney transplants and 1 of which was an isolated pancreas after kidney transplant. The initial 4 pancreatic grafts were procured by classical warm dissection techniques while the remaining 15 were procured by rapid en bloc technique. Mean recipient age, duration of diabetes, and daily insulin requirements were 38 years, 25 years, and 45 units, respectively. Bladder drainage of exocrine secretions was used primarily in 18 cases and primary enteric drainage in one. RESULTS: All recipients manifested immediate dialysis and insulin independence. Actuarial patient and graft survival were 100% and 89%, respectively, at a mean follow-up of 396 days (range, 150-660 days). Mean maximal serum amylase on the first postoperative day was 366 U/dL. There were no instances of pancreatic graft vascular thrombosis. Three patients experienced pancreatic leaks (16%), 1 of which resulted in graft loss. Six month posttransplant Hgb A1c was within normal range and significantly lower than pretransplantation values (5.1 vs 10.7, P = 0.002). Mean length of initial hospitalization was 15 days, with 100% of patients requiring at least one read mission. Fifty-eight percent of patients experienced rejection episodes. Ninety-one percent of patients responding to a quality of life survey reported improvement in general sense of well-being after transplantation. CONCLUSIONS: It is concluded that high rates of success may be possible with whole organ pancreas transplantation, even in new programs. Rapid en bloc dissection is a safe, expeditious method of pancreas procurement. Successful pancreatic transplantation is associated with freedom from exogenous insulin administration, normalization of glycated hemoglobin, and subjective improvement in quality of life. However, this modality is associated with higher rates of rejection and readmission, and longer duration of hospitalization when compared with isolated kidney transplantation.

The role of combined liver/kidney transplantation in end-stage hepato-renal disease.

The study describes the indications and results of combined liver/kidney transplantation in eight patients suffering from end-stage hepato-renal diseases. The causes of primary renal failure were hyperoxaluria type I (2/8), diabetic nephropathy (2/8), glomerulonephritis (2/8), congenital pyelonephritis (1/8), and polycystic kidneys (1/8). Only five of these patients were on chronic dialysis prior to transplantation. The indication for kidney transplantation in the other three patients was low GFR (< 20 mL/min) and the anticipation of further deterioration of the renal function after liver transplantation as a result of cyclosporine toxicity. The end-stage liver diseases were chronic active hepatitis (4/8) and alcoholic cirrhosis (2/8). There was no evidence for liver failure in two patients undergoing combined transplants for primary hyperoxaluria. The 1-year patient survival rate is 75 per cent, and at that time, kidney and liver function were found to be within normal range. In conclusion, excellent long-term patient survival, as well as kidney and liver graft function, can be achieved in patients suffering from complex end-stage disease of both organs who undergo combined liver and kidney transplantation.

Cyclosporine pharmacokinetic profiles in liver, heart, and kidney transplant patients as determined by high-performance liquid chromatography.

Cs pharmacokinetic profiles using HPLC have aided in predicting necessary dosage alterations for specific groups of transplant patients. Additional information has been gained by HPLC profiles in nontransplant subjects who are healthy or have a stable disease state. The clinician now knows that liver disease not only impairs Cs elimination but may also have a pronounced effect upon drug absorption. While the cardiac failure patient may have reversible inhibition of Cs clearance, other factors may affect the distribution of the drug to lower dosage requirements. Impaired renal function is not an impediment to Cs elimination, but malabsorption similar to that observed in liver and bone marrow transplant patients may still occasionally complicate therapy. Pharmacokinetic information on Cs must be integrated into the complex care plan of a transplant patient to optimally utilize and monitor this pharmacologic agent.