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FK506 is a novel immunosuppressive agent which is approximately 100 times as potent as cyclosporine in vitro. In this initial trial, 65 renal transplant patients of high complexity received primary FK506 immunosuppression. Overall, graft and patient survival rates are 80% and 98.5%, respectively. A major advantage of FK506 is its potency with relatively few side effects, which has permitted elimination of steroids in 31 (60%) of these patients. Because of these encouraging results, a randomized trial comparing the therapeutic efficacy and toxicity of FK506 and cyclosporine is currently underway at our institution.

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.

Retrograde transurethral balloon dilatation (RTBD) of the prostate recently has been suggested as alternative therapy for patients with benign prostatic hyperplasia (BPH). Seven patients with documented functional urinary outlet obstruction at the level of the bladder neck or prostatic urethra underwent RTBD of prostate. Each patient had a classic diagnosis of abacterial chronic prostatitis or prostatodynia based on history, physical examination, and localization cultures. Prior to RTBD of prostate, patients underwent cystoscopy, voiding cystourethrogram, urodynamic and uroflow studies. RTBD of prostate was done as an outpatient procedure requiring intravenous sedation or general anesthesia. Dilation was performed with a 25-mm urethroplasty balloon catheter inflated at 3.5 atm of pressure for twenty minutes. Improvement in voiding symptomatology was noted in all patients and graded numerically (0-10 scale), with ten indicating normal voiding. Follow-up to date ranges from one to five months. This technique may have promise as a treatment option in patients with abacterial chronic prostatitis and prostatodynia.

Six groups of two cynomolgus monkeys were treated with escalating intravesicular doses of recombinant human tumor necrosis factor (rHuTNF) for a 6 week interval. The doses of rHuTNF ranged from 10 ng to 1 mg and were instilled weekly. Two monkeys had instillation of saline only and served as controls. The monkeys were weighed and temperatures determined before, immediately after, and 2 days following each treatment. Cystoscopic examination was performed 2 days after each treatment and blood samples were obtained. At the conclusion of the study, animals were killed and necropsy was performed. There was no observable toxicity from treatment with rHuTNF. There was no difference between treated and control monkeys with respect to temperature, weight, or blood measurements. No drug-induced alteration in bladder morphology was found by either cystoscopic or microscopic pathologic examination.

Nonobstructing colonic dilatation has not been commonly reported following renal transplantation, and colon perforations carry a high morbidity and mortality in this population. During a 7-year period, nonobstructing colonic dilatation developed in 13 adults 1 to 13 days after renal transplantation. Twelve (92%) of the 13 had poorly functioning allografts. Five (83%) of the 6 with and 2 (29%) of the 7 without colonoscopy had resolution of nonobstructing colonic dilatation. Of the seven right-sided colon perforations during this period, six were associated with nonobstructing colonic dilatation. An additional 4 patients had diverticular perforations in the left colon. Of a total of 11 patients with colon perforation, 7 had surgery within 24 hours of the perforation and 6 (86%) of these survived. Only 1 (25%) of the 4 having surgery more than 24 hours later survived. Six of the survivors retained functioning allografts. Nonobstructing colonic dilatation seems to be a potential complication of poor graft function after renal transplantation, and colonoscopy is effective in its treatment. In patients with colon perforations, early surgery and reduced immunosuppression are essential in decreasing mortality.

Obesity has generally been thought to increase the risk of operative mortality and postoperative complications in surgical patients. No data examining obesity as a factor in cadaveric renal transplantation were available. We therefore matched obese patients undergoing cadaveric renal transplantation with nonobese control patients and retrospectively analyzed mortality, morbidity, and graft survival in each group. Patients were matched for age, sex, diabetes mellitus, PRA, graft number, cardiovascular disease, date of transplantation, and posttransplant immunosuppression. There were significant differences found in mortality (11% in obese vs. 2% in nonobese patients, P less than or equal to 0.01), immediate graft function (38% in obese vs. 64% in nonobese patients, P less than or equal to 0.01), 1-year graft survival (66% in obese vs. 84% in nonobese patients, P less than or equal to 0.05), and postoperative complications. Wound complications (20% vs. 2%, P less than or equal to 0.01), intensive-care-unit admissions (10% vs. 2%, P less than or equal to 0.01), reintubations (16% vs. 2%, P less than or equal to 0.03), and new-onset diabetes (12% vs. 0%, P less than or equal to 0.02) were all significantly more common in the obese group. These results suggest that an attempt at significant weight reduction is indicated in obese patients prior to renal transplantation.

Multiple organ transplantation has come of age. Indications are that it will continue to grow, if not flourish. The complexity of modern surgical care, its multiperson dependency, and the need for the surgeon to retain knowledge and involvement with his patient's care and problems are nowhere more evident than in multiple organ transplantation. Each organ presents its own associated challenges, the prime solution of which lies with a skillful and dedicated surgeon; but with all organs there are challenges of expectantly waiting patients, housing during the wait and for postoperative observation, procurement, erratic scheduling of the operating room, nursing, social service, immunosuppression, immunopathology, interest of hospital public relations and of the news media, and perennial care. This report concerns the growth and development of the multiple organ transplant program at the University Health Center of Pittsburgh and describes some answers to the challenges presented.

The records of 59 immunocompromised patients with fever and pulmonary infiltrates who underwent open lung biopsy, were reviewed. A specific diagnosis was made by lung biopsy in 49 (83%) patients, and in 32 instances (54%) the diagnosis was a treatable infection. Only two (3.4%) false-negative biopsies occurred. Transplant recipients were more likely to have a specific, treatable pneumonia (74%) than patients with a reticuloendothelial malignancy (42%, P less than 0.05). This was due to a greater frequency of bacterial pneumonias, primarily due to Legionella, in transplant recipients (P less than 0.01). However, obtaining a specific diagnosis by lung biopsy did not appear to improve outcome. Seventeen of 32 (53%) patients with treatable infections survived, compared to 8 of 16 (50%) with specific, but untreatable, diagnosis and 6 of 11 (55%) with nondiagnostic biopsies. Advanced age and a low platelet count were predictive of death in both transplant recipients and patients with leukemia and lymphoma (P less than 0.05); a high serum creatinine was an additional predictor in renal transplant recipients.

In vitro measurements of the immune response in patients with cancer can be divided into those that estimate nonspecific and those that estimate tumor-specific immune responses. Contained herein is a review of these measurements, especially as they relate to studies that have been reported in patients with transitional cell carcinoma (TCC). In vitro tumor-specific immunity has been extensively examined in TCC using the lymphocyte-mediated microcytotoxicity assay, but subsequent observations on this assay have seriously jeopardized the validity of those early findings. Recent modifications of this assay have permitted longitudinal studies of lymphocyte cytotoxicity in TCC patients, and clinical correlations suggest that this modified assay may detect important immunological events. To date, however, a clinically useful classification of the TCC patient based on in vitro measurement of immune responses has not been achieved, although many promising areas still require investigation.

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.

A monoclonal IgM antibody (anti-SSEA-1) and its divalent antigen-binding peptic fragment [F(ab')2 mu] were compared as in vivo tumor localization reagents in mouse teratocarcinomas. F(ab')2 mu is cleared more rapidly than whole antibody from the whole body, blood, and all tested organs (t1/2 for whole antibody approximately 18 hr; t1/2 for F(ab')2 mu, 12 hr). A corresponding average improvement in tumor-to-tissue ratio is observed 48 hr after injection and earlier. However, the affinity of the F(ab')2 mu for antigen is much lower, and a smaller fraction of the antibody fragment is retained in the tumor than with whole antibody. The fragment was not retained by animals bearing nonantigenic tumors.

Techniques have been developed which permit removal of the kidneys, liver, heart and other organs from the same donor without jeopardy to any of the individual grafts. The guiding principle is avoidance with all organs of warm ischemia. This is achieved by carefully timed and controlled infusion of cold solutions into anatomic regions, the limits of which are defined by preliminary dissection.

Eight immunosuppressed patients had pneumonia due to Pittsburgh Pneumonia Agent (PPA), a gram-negative, weakly acid-fast bacterium cultivatable only in embryonated eggs and guinea pigs and distinct from Legionella pneumophila. The diagnosis was established by isolation of the agent from lung or visualization of the organism in lung tissue. The clinical presentations, radiographic abnormalities and pathology were not specific. The most consistent feature associated with the disease was the recent institution of daily high-dose corticosteriod therapy in all patients. Five of the eight patients died despite broad-spectrum antibiotic and antituberculous therapy. Anti-microbial activity against PPA was demonstrated for sulfamethoxazole combined with trimethoprim, for rifampin and for erythromycin with an egg-protection assay. Serologic studies with an indirect fluorescent-antibody technic suggested that seroconversion or high titers may be a sensitive test for PPA disease. PPA appears to be a newly recognized cause of life-threatening bacterial pneumonia in immunosupressed patients.

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.

We investigated the fate of the cadaver renal transplant done with cyclosporine and prednisone immunosuppression into a recipient who had suffered the loss of at least two prior allografts. Nineteen cadaver renal allografts were transplanted into 18 recipients. All 18 recipients had previously rejected at least two prior allografts. One of these rejected an allograft done at our institution with cyclosporine and prednisone and was included a second time in this series when a fourth allograft was received. Nine of 19 allografts were successfully transplanted. Average follow-up time was 39 months. Eight allografts were rejected. One graft was lost to technical complications. In one instance, the recipient died with a functioning graft. Duration of function of previous allografts was not found to be a critical determinant of third or fourth graft survival. Human leukocyte antigen matching was not a statistically significant determinant. Panel reactive antibody was higher in those who rejected the third or fourth allograft, but not with statistical significance. Recipients with the blood type A were less likely to enjoy successful third or fourth cadaver renal transplantation. We concluded that the "two time loser" renal allograft recipient should not be systematically denied subsequent transplantation.

The immunosuppressive effects of three herpesviruses--cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV)--were assessed in 29 renal transplant recipients treated with cyclosporine and prednisone. The ratios of Leu 3-positive ("helper-inducer") to Leu 2-positive ("suppressor-cytotoxic") T lymphocytes in peripheral blood were only moderately and transiently decreased during primary CMV infection, with or without concurrent reactivated EBV and HSV infections. This effect was due to an increase in absolute numbers of Leu 2-phenotypic and decrease in Leu 3-phenotypic T cells and was associated with symptomatic viral illness. Reactivated CMV infection alone or together with reactivated EBV and HSV infections resulted in less significant alterations in T-cell subsets than did primary CMV infection. Lymphocyte blastogenesis was not significantly altered during the herpesvirus infections. The data suggest that cyclosporine treatment inhibits the activation of suppressor cells and depression of cellular immune function that have been associated with herpesvirus infections in renal transplant recipients undergoing conventional immunotherapy.

Murine teratocarcinomas were located in mice by external gamma-ray scintigraphy with an iodine-125-labeled monoclonal antibody specific to the tumors. The specificity of the method was increased by subtracting the radiation produced by an iodine-125-labeled indifferent monoclonal antibody of the same immunoglobulin class as the tumor-specific antibody.

Methotrexate (MTX) conjugates of a monoclonal antibody, anti-SSEA-1, containing an average of 45 mol MTX/mol of immunoglobulin M, were prepared by a carbodiimide coupling reaction. Binding experiments indicate that conjugation does not decrease the affinity of the antibody for its antigen. The conjugate strongly inhibits the growth of SSEA-1-bearing F-9 teratocarcinoma cells, with 50% inhibitory dose of 4.5 nM MTX, which makes it more active than free MTX (50% inhibitory dose of 15 nM). The drug-free antibody is not cytotoxic to F-9 cells at the concentrations used. The high efficacy of the conjugated drug may be due in part to the fact that anti-SSEA-1 antibody is an immunoglobulin M. MTX conjugated to nonspecific immunoglobulin M has little inhibitory effect (50% inhibitory dose of 150 nM). When acting on SSEA-1 negative cells, the two conjugates have only a small but identical effect. Thiamine pyrophosphate, an inhibitor of MTX transport, can prevent the cytotoxicity of the free MTX but not that of the anti-SSEA-1 conjugate. Leupeptin, an inhibitor of lysosomal protease, can partially protect F-9 cells against the antibody conjugate but not against free MTX. These results indicate that the MTX antibody conjugate binds specifically to F-9 cells, and is internalized and intracellularly degraded to release a small molecular active drug. Pretreatments of F-9 cells for 1 h with unlabeled antibody inhibits the subsequent uptake of identical concentration of labeled conjugate. The rate of internalization, however, regains almost normal values within 4 h, indicating a rapid reappearance of free antigenic sites at the cell surface.

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.

Stage-specific embryonic antigen-1 (SSEA-1) was localized on paraffin embedded, formalin fixed specimens of human renal tumors by immunoperoxidase staining using a monoclonal antibody. Of 19 renal cell carcinoma (RCC) samples tested, 12 were positive for SSEA-1; SSEA-1 was also found on distinct elements in two samples of Wilms' tumor. No correlation was found between expression of SSEA-1, and RCC morphology or pattern of growth. Because SSEA-1 is found on proximal tubules in the normal kidney, these results support the hypothesis that RCC arises from the cells of the proximal tubule. Furthermore, since greater than 60% of the RCCs examined expressed SSEA-1, this antigen may prove to be a useful target for immunolocation or therapy of metastatic RCC.

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 need for cadaveric organs other than kidneys for transplantation is increasing. Principles and techniques that allow their procurement without jeopardizing renal recovery are outlined. These include utilization of brain dead donors, careful donor selection, and surgery which minimizes warm ischema while avoiding iatrogenic injury. Utilizing this approach, a variety of combinations of organs have been removed and transplanted resulting in satisfactory functional results.

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.

Methotrexate (MTX) was coupled to an IgM monoclonal antibody specific for stage-specific embryonic antigen-1 (SSEA-1), and the resulting immunoconjugate (MTX-anti-SSEA-1) was used for in vivo drug targeting in mice bearing MH-15 teratocarcinoma. Immunoconjugates having an average of 65 mol MTX/mol antibody retained full antigen-binding capacity. Mice bearing well-established tumors (approx. 1 g) were treated i.v. using the immunoconjugate. MTX-anti-SSEA-1 at 15 mg/kg of drug had significant antitumor activity with no significant systemic toxicity. Neither an irrelevant isotype-matched conjugate, MTX-MOPC-104E, prepared from the MOPC 104E myeloma protein, nor free MTX injected alone or with either antibody had any significant antitumor effect. These results indicate that IgMs can be effective drug carriers for tumor targeting in spite of their high molecular mass, and that antigens that are selectively accessible in tumors, even though present in normal tissues, can be suitable targets for in vivo chemoimmunotherapy.

During 1986, a total of 270 cadaver renal transplantations were performed at the University of Pittsburgh. Kidneys were allocated by a point system that awarded points to recipients for waiting time, antigen matching, antibody analyses, medical urgency, and logistic practicality. Kidneys were given to patients with the highest point totals in 98% of cases. To our knowledge, this is the first such multifactorial system for cadaver kidney allocation. Possibly it may be modified for extrarenal organs.

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.

Both murine and heterotransplanted human nonseminomatous germ-cell tumors have been successfully located by external scintigraphy using radioiodinated anti-SSEA-1, a monoclonal IgM, and its pepsin-derived antigen-binding fragment, F(ab')2 mu. Antibody localization in the tumor is mainly due to antigenic specificity, rather than to nonspecific trapping, and depends strongly on the amount of time after injection. The antibody has been used for drug targeting in vitro and in vivo.

The postoperative convalescence period was analyzed for 42 consecutive patients who had cadaveric renal transplantation under therapy with cyclosporin A and steroids. Twenty-two of the patients underwent transplantation for the first time, and the other 20 had retransplantation. None of the recipients has died. With follow-up period of two to eight months, the survival rate of grafts is 96 per cent after first transplantation and 85 per cent after retransplantation. Immunosuppression with a standard regimen was used for all patients at the outset. Early convalescence was highly variable, often necessitating adjustments of cyclosporin A and steroid dosage to accommodate the possibilities of rejection or cyclosporin A nephrotoxicity, or both, simultaneously. Management problems were more frequent and complex in patients undergoing retransplantation. From the results, a classification of convalescence patterns was evolved, with recommendations about how standardized initial therapy should be adjusted if the renal graft does not function promptly or deteriorates later.

Fourteen of 156 renal-transplant recipients treated with cyclosporine and steroids developed Pneumocystis carinii-related pneumonia (PCP) over a 19-month period. This was a significant change from past experience with this disease in renal-transplant patients receiving azathioprine and steroids (six cases among 179 patients from 1977 to 1981). Epidemiological investigation failed to implicate either person-to-person or nosocomial spread of infection. Cases of PCP occurred more frequently in males. Twelve patients (86%) had onset of disease in the third or fourth months after transplantation. Comparison of cases to matched controls revealed that the cases had received lower doses of steroids and had a higher incidence of cytomegalovirus infection. This suggested that the cases may have been more effectively immunosuppressed than the controls. After institution of prophylaxis with trimethoprim-sulfamethoxazole, no further cases of PCP developed.

From January 1, 1986 to July 30, 1988, 530 consecutive cadaver kidney transplantations were performed with patient selection by a point system that took into account time awaiting an organ, donor-recipient matching, degree of presensitization, and some less important factors. The effect of the system was to diminish judgmental factors in case selection which in the past, had probably operated to the disadvantage of "undesirable" potential recipients, including older ones. Primary 1-year graft survival (74%) and graft survival after retransplantation (71%) were lower than in the earlier time. However, the results with triple-drug therapy using CsA, AZA and P demonstrated 88% 1-year graft survival for primary graft recipients and 74% in highly sensitized patients, with comparable patient mortality. These latter observations provide some assurance that the concepts of equitable access and efficient utilization of a scarce resource are not mutually exclusive.

Stage-Specific Embryonic Antigen-1 (SSEA-1), originally discovered on mouse teratocarcinomas, has since been found on some human non-seminomatous germ-cell tumors and adenocarcinomas, as well as on some adult mouse and human tissues. A monoclonal antibody to this antigen (anti-SSEA-1; IgM, kappa) was used for radioimmunolocation. Nude mice bearing the human choriocarcinoma BeWo, which is SSEA-1 positive, were injected using a mixture of [131I]anti-SSEA-1 and [125I]MOPC 104E, an unselected myeloma protein of the same heavy-chain isotype. Animals were sacrificed at 24 hour intervals; the radioactive deposition due to both antibodies was determined for both tumors and normal organs. Accumulation of anti-SSEA-1 in the tumor was consistantly rapid and specific, while little accumulation of the unselected myeloma protein occurred. At five days after injection, an average of 3% of the initial dose of specific antibody was retained per gram of tumor; the tumor/blood ratio was 11, tumor/muscle was 80. Gamma-camera imaging allowed ready location of the tumors. Tumors could also be imaged using F(ab')2 antibody fragments.