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Purpose: Between September 20, 1995 and September 20, 1996, 120 patients were entered into a prospective, randomized trial comparing tacrolimus and prednisone with (61) and without (59) 2 gm. mycophenolate mofetil daily to determine whether mycophenolate mofetil was associated with a lower incidence of rejection., Materials and Methods: Mean recipient age plus or minus standard deviation was 50.8+/-14.1 years (range 18.8 to 84.1). Mean donor age was 34.3+/-21.7 years (range 0.01 to 76). Of the donors 18 (15%) were older than 60 years. Mean cold ischemia time was 30.9+/-8.4 hours (range 14.2 to 49). Median followup was 8.6+/-0.5 months., Results: The 6-month actuarial patient survival was 95%, 92% in the double therapy group and 98% in the triple therapy group (not significant). The 6-month actuarial graft survival was 88%, 84% in the double therapy group and 92% in the triple therapy group (not significant). The overall incidence of rejection and steroid resistant rejection was 34.2 and 4.2%, respectively. There was a strong trend toward less rejection in the mycophenolate mofetil group than in the double therapy group (26.2 versus 42.4%). Crossover was common, and was 42.6% from triple to double therapy and 18.6% from double to triple therapy. The reasons for discontinuation of mycophenolate mofetil were gastrointestinal toxicity, primarily diarrhea, or less commonly hematological toxicity, primarily neutropenia or thrombocytopenia. Gastrointestinal toxicity was ameliorated by separating the doses of tacrolimus and mycophenolate mofetil by 2 to 4 hours, and reducing the dose to 1 gm. daily., Conclusions: Mycophenolate mofetil appears to be a useful third agent with tacrolimus in patients undergoing renal transplantation, and is associated with a reduction in the rate of rejection and a low incidence of steroid resistant rejection. There is a high incidence of gastrointestinal toxicity associated with the 2 gm. daily dose but this complication is relatively straightforward to manage.

Between November 1987 and September 1989, 419 cadaveric renal transplants were performed at our university. Of the patients 36 (8.6%) had invasive cytomegalovirus infection documented by gastric or duodenal mucosal biopsy in 23 (64%), bronchoalveolar lavage in 12 (33%), allograft biopsy or nephrectomy specimen in 5 (14%) and/or liver biopsy in 1 (3%). Cytomegalovirus severity was defined as mild in 27 patients, moderate in 6 and severe in 3. Ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)-guanine] was begun once the diagnosis was confirmed by histology or culture at a median of 56 days from transplantation (range 28 to 133 days). Duration of ganciclovir therapy was a minimum of 7 days or until fever was absent for 5 consecutive days (mean 12.2 +/- 3.5 days, range 4 to 21). Ganciclovir was well tolerated and side effects were limited to de novo neutropenia (7 patients), thrombocytopenia (2) and rash (1). Initial clinical improvement was observed in all patients. Two patients had recurrent cytomegalovirus infections that responded to a second course of ganciclovir. The 1-year actuarial patient survival was 100%. At a mean followup of 12.7 +/- 6.2 months 19 patients retained allograft function with a mean serum creatinine of 2.5 mg./dl. (range 1.2 to 4.6). Ganciclovir appears to be a safe and effective drug for the treatment of tissue invasive cytomegalovirus infection in cadaver renal transplant recipients. Prompt institution of this drug at diagnosis of invasive cytomegalovirus may lower the mortality rate formerly associated with this disease.

Renal transplantation (11 cadaveric and 1 living-related donor) was performed in 12 pediatric recipients (mean age 10.8 years) under FK-506 immunosuppression in combination with prednisone therapy. At a mean followup of 6.1 months, patient and graft survival rates were 100% and 92%, respectively. The only graft loss was due to the recurrent hemolytic uremic syndrome 4 days after transplantation. In the functioning grafts the mean serum creatinine is 1.59 +/- 1.27 mg./dl. and the mean blood urea nitrogen is 36.3 +/- 24.6 mg./dl. Three patients take no prednisone, 5 are receiving 0.15 to 0.25 mg./kg. per day and 3 are taking 0.35 to 0.5 mg./kg. per day. There was a total of 8 rejection episodes in 5 patients. All rejection episodes were successfully reversed. Complications of transplantation included an episode of seizures in 1 patient, cytomegalovirus infection in 1 and steroid-induced diabetes mellitus in 1. Since pediatric transplant recipients are a group in whom the reduction or elimination of steroids is highly desirable, FK-506 immunosuppression may be particularly suited for use in this population.

Between January 1982 and August 1989, cadaveric renal transplantation was performed in 22 patients 65 years old or older. Mean recipient age was 68 years (range 65 to 73 years). There were 17 men and 5 women. Additional risk factors included retransplantation (3 patients), high (greater than 30%) panel reactive antibody (4) and diabetes (1). All patients received cyclosporine as part of the immunosuppressive regimen. The 3-year actuarial patient and allograft survival rates were 89% and 71%, respectively. There were 6 graft losses due to chronic rejection (2 patients), renal vein thrombosis (1), myocardial infarction (1), withdrawal of immunosuppression because of sepsis (1) and primary nonfunction (1). Of the 16 patients with a functioning graft 12 currently have a serum creatinine of less than 2.0 mg./dl. These results suggest that cadaveric renal transplantation is an acceptable form of treatment for patients older than 65 years with end stage renal disease.

Metastatic renal cell carcinoma (RCC) remains largely incurable. We used a murine RCC (Renca) in BALB/c mice to investigate the treatment possibilities with chemoimmunotherapy using in vivo boosters of natural killer (NK) activity. Diffuse pulmonary metastases were induced by intravenous (i.v.) inoculation with 100,000 Renca cells. All untreated control animals died within one month from pulmonary metastases. Chemoimmunotherapy using the NK immunostimulator flavonic-8-acetic acid (FAA) at 200 mg./kg. i.v. was given on the third day post tumor inoculation, followed by four consecutive days of twice daily intraperitoneal (i.p.) administration of 10,000 units human recombinant interleukin-2 (rIL-2). This chemoimmunotherapy regimen consistently cured 70% of tumor-bearing animals. Mice cured by this chemoimmunotherapy regimen did not reject subsequent reinoculation with Renca, indicating absence of specific antitumor immunity as a result of the treatment. While FAA and rIL-2 have no demonstrable in vitro cytotoxicity for Renca, they are excellent boosters of in vivo NK activity. These data suggest a potential alternative treatment method for metastatic RCC, a tumor type for which no efficient cytostatic drugs are available.

In this paper we describe the generation of antibody dependent cellular cytotoxicity against a murine renal cell carcinoma. Using human recombinant interleukin-2 and in vitro adherence to plastic, we generated lymphokine activated killer and adherent lymphokine activated killer cells. Adherent lymphokine activated killer cells had significant (p less than 0.05) higher unrestricted cytotoxicity than LAK cells. Using a rabbit antibody against Renca developed in our laboratory, we induced significant (p less than 0.01) antibody dependent cellular cytotoxicity using fresh spleen, lymphokine activated killer and adherent lymphokine activated killer cells. The strongest antibody dependent cellular cytotoxicity killing was mediated by adherent lymphokine activated killer cells and was restricted only to the renal cell carcinoma target. Using FACS cell surface analysis and antibody and complement depletion of selected effector cell subsets, we also demonstrate that the antibody dependent cellular cytotoxicity effector cell population consists of asialoGM1+ Lyt 2.1- natural killer cells. This first description of antibody dependent cellular cytotoxicity against renal cell carcinoma by activated natural killer cells suggests a novel method for more efficient use of cytotoxic effector cells against this type of cancer.

The postoperative management of the highly sensitized renal transplant recipient with delayed graft function on cyclosporine is complicated. Allografts with delayed graft function are reported to have a 20 to 30% poorer 1-year survival than allografts without delayed graft function. Several factors may be implicated in this poorer 1-year survival. A decrease in or cessation of cyclosporine dosage frequently is used in an attempt to minimize nephrotoxicity. Such under-immunosuppression can result in irreversible rejection. Occasionally, a pessimistic view of the prognosis for the transplant may result in early abandonment of the allograft with discontinuation of immunosuppression and allograft nephrectomy. We report on 3 highly sensitized patients whose kidneys had delayed graft function and were deliberately maintained on high doses of cyclosporine throughout the period of delayed graft function. Each graft achieved function (2, 4 and 5 months) after transplantation. The serum creatinine levels 20, 28 and 38 months after transplantation were 2.7, 2.0 and 1.0 mg./dl., respectively. We suggest that the maintenance of high cyclosporine levels throughout the delayed graft function period is useful in highly sensitized recipients and was an important factor in their successful outcome. A management protocol for such patients is proposed.

During a 16-month interval 235 kidneys were recovered from 120 consecutive donors, 15 of which were not transplanted for a variety of reasons. The factors believed to be important in producing a low wastage rate of procured kidneys included careful management of the donor during the brain death period, en bloc resection to avoid damage to vascular structures and the ureter, and avoidance of cold ischemia.

Our experience with 110 cases of ileal conduit construction with autosuture stapling devices is discussed. The technique is described briefly and the results are compared to results with ileal conduits constructed with the conventional suture technique. Analysis of our data revealed a significant reduction in operating time and postoperative morbidity.

We analyzed the case histories of 31 patients who initially had a diagnosis of seminoma and elevated serum levels of alpha-fetoprotein or human chorionic gonadotropin. We concluded that an elevated alpha-fetoprotein level is firm evidence of the presence of non-seminomatous germ cell tumor and that the patient should be treated accordingly. However, if the level of human chorionic gonadotropin alone is elevated the diagnosis may be either non-seminomatous tumor or seminoma. Patients with seminoma and an elevated level of human chorionic gonadotropin do respond well to radiation therapy if they have low stage disease but if metastatic seminoma is present an elevated human chorionic gonadotropin level appears to be a poor prognostic sign if conventional treatment is given. A plan of treatment is proposed for these patients.

From July 1977 to January 1980, 5 cases of pneumonia owing to Pittsburgh pneumonia agent and 4 cases owing to Legionella pneumophila occurred in our renal transplant population. Comparison of the clinical manifestations, laboratory features an radiographic changes demonstrated no unique characteristics that allowed differentiation from other bacterial pneumonias. Diagnosis in all cases required histologic or serologic identification of the infecting organism. We herein present our protocol for establishing rapidly the diagnosis of pneumonia in renal transplant patients with emphasis on the use of open lung biopsy.

The conventional cell-mediated cytotoxicity assay was modified so that more useful estimates of cell-mediated immunity to transitional cell carcimoma of the urinary tract could be obtained. With this modified assay changes in the levels of cell-mediated immunity in transitional cell carcinoma patients to transitional cell carcinoma target cells were measured during the clinical course. Initial results from a small number of patients with invasive and non-invasive tumors showed that anti-transitional cell carcinoma cell-mediated immunity increased after the tumor was removed and during administration of Bacillus Calmette-Guerin.

The effect of human chorionic gonadotropin on the in vitro cytotoxicity of lymphocytes against human transitional cell carcinoma cells was studied in 9 patients using the microcytotoxicity assay. Lymphocytes from 6 patients were cytotoxic against transitional cell carcinoma cells. However, in the presence of human chorionic gonadotropin the cytotoxicity of these lymphocytes against transitional carcinoma cells was diminished. Human chorionic gonadotropin alone or in combination with non-cytotoxic lymphocytes did not change the growth of target cells and human chorionic gonadotropin did not have a direct toxic effect on lymphocytes alone. These results demonstrate that human chorionic gonadotropin can inhibit the cytotoxic action of lymphocytes against human tumor cells in vitro. Human chorionic gonadotropin may contribute to the poor prognosis associated with certain human chorionic gonadotropin-secreting human tumors.

A total of 42 patients who had failed prior renal transplantation underwent repeat cadaveric transplantation using cyclosporin A and low dose steroid immunosuppression. Patient survival at 1 year was 100 per cent. Over-all graft survival was 83 per cent at 1 year, which was significantly better than had been obtainable previously in this high risk group. Repeat cadaver transplantation with cyclosporin A is safe and offers those who have failed previous transplantation an opportunity for existence free of dialysis.

The interaction of antibodies and lymphocytes in their immune reaction against human transitional cell carcinomas was studied using the in vitro microcytotoxicity assay. A non-complement dependent, IgG antibody was detected in the serum of occasional transitional cell carcinoma patients, which induced cytotoxicity against transitional cell carcinoma target cells by lymphocytes from donors with and without transitional cell carcinoma. The observation that lymphocytes from transitional cell carcinoma donors were more sensitive to activation by this anti-transitional cell carcinoma, lymphocyte dependent antibody is compatible with the hypothesis that the surface of lymphocytes from some transitional cell carcinoma donors is coated in vivo with an anti-transitional cell carcinoma lymphocyte dependent antibody and that this antibody may be a significant factor in immunity to transitional cell carcinomas of the urinary tract.

Alpha-fetoprotein and human chorionic gonadotropin levels were measured by radioimmunoassays in 260 patients with genitourinary diseases, including 93 patients with testicular tumors. Elevations of alpha-fetoprotein and human chorionic gonadotropin were associated only with non-seminomatous germ cell testicular tumors. Our 32-month experience with serial measurements of the 2 markers in patients with these tumors shows that alpha-fetoprotein and human chorionic gonadotropin must be determined and that together they serve as accurate and sensitive indicators of metastases and are helpful in determining the effectiveness of therapy. However, they have limited value in the differential diagnosis of scrotal masses.