J. Thomas Rosenthal

Evaluation of cardiovascular risk for renal transplantation in diabetic patients

Abstract 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 cardio-vascular 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.

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 t½ 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 (X̄ = 1,103 ng/ml) were reached between 1 and 8 hours after oral dosing (X̄ = 4 hours). The mean relative bioavailability was 27.6% ± 20%. Oral bioavailability was <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.

Anaphylactoid Reactions Associated with Parenteral Cyclosporine Use: Possible Role of Cremophor EL

Acute anaphylactoid reactions occurred immediately after initiation of intravenous infusions of cyclosporine in three patients post-organ transplantation. Shortness of breath, flushing, tachypnea, chest pain, pruritus, or urticaria were noted; rapid recovery followed cessation of drug infusion. Subsequently, oral cyclosporine has been used in each patient without recurrence of the observed reaction. The presence of Cremophor EL as an emulsifying agent in the parenteral dosage formulation of cyclosporine is a likely etiology for this acute adverse reaction, Slowed rates of drug infusion and antihistamine premedication may permit continued intravenous cyclosporine use in affected patients.

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.

Liver and kidney transplantation in children receiving cyclosporin A and steroids

The new immunosuppressive agent, cyclosporin A, was used with low doses of steroids to treat eight patients undergoing hepatic transplantation and three patients undergoing cadaveric renal transplantation. Seven of the eight liver recipients are well, including one who was given two livers. The three kidney recipients who had developed cytotoxic antibodies after previously rejecting grafts with conventional immunosuppressive therapy, have had good results despite conditions which usually preclude attempts at transplantation. The ability to control rejection effectively and safely without chronic high-dose steroid therapy may make the described therapeutic regimen valuable for pediatric recipients of whole organs.

Right Splenorenal Fusion with Associated Hypersplenism

We report the second case of splenorenal fusion and the first occurrence of spleen fusion associated with a right retroperitoneal structure. Hypersplenism was cured by removal of the mass. A concomitant renal cell carcinoma and multiple adenomas within the mass were incidental clinical features. Aside from the rarity of the lesion, its documented occurrence on the right side is significant in that it provides evidence for the possible migration of spleen cells in embryogenesis as an explanation for some other splenic fusion anomalies.

Hypercalcemia in carcinoma of prostate Its cure by

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.

Management of Urinary and Bowel Complications after Ileal Conduit Diversion

Serious urinary and bowel complications after ileal conduit diversion are associated with significant morbidity and mortality rates. We reviewed 9 patients treated at our institution during the last 5 years for sequelae after ileal conduit diversion for bladder cancer. Of these patients 8 are well and 1 died postoperatively of a myocardial infarction. In all, 33 operations were required to treat complications after initial diversion. A variety of surgical procedures, including anastomotic revision, ileal ureter, stomal revision, transverse colon conduit and nephrectomy, was used to treat urinary complications. A treatment outline emphasizing an initial conservative approach, the importance of nutritional support and the appropriate options for reconstruction is presented.