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Background: The authors reviewed their long-term experience with pediatric renal transplantation into a dysfunctional lower urinary tract to evaluate the results of contemporary lower urinary tract evaluation and management on graft survival and function., Methods: Between 1990 and 1996, 21 renal transplants were performed in 20 children with dysfunctional lower urinary tracts and 61 transplants were performed in 61 patients with normal lower urinary tracts. The minimum follow-up was 36 months (mean, 62.0 +/- 19.6 months). The cause of lower urinary tract dysfunction included posterior urethral valves (n=13), prune belly syndrome (n=4), meningomyelocele (n=2), and urogenital sinus abnormality (n=1). Urodynamics were performed on all children with dysfunctional lower urinary tracts. Using these perioperative assessments, lower tract management strategies were devised, including timed voiding alone (n=6), clean intermittent catheterization (n=8), bladder augmentation (n=4), and supravesical urinary diversion (n=2)., Results: Overall 5-year actuarial patient and graft survival rates were 100% versus 95% (P=not significant [NS]) and 83% versus 69% in the dysfunctional and normal urinary tract groups (P=NS), respectively. Mean serum creatinine levels in dysfunctional and normal urinary tract patients with functioning grafts at 3 years were 1.3 +/- 0.5 and 1.3 +/- 0.7 mg/dL, respectively (P=NS). However, 35% of patients with a dysfunctional lower urinary tract experienced urologic complications., Conclusions: Pediatric renal transplantation into a dysfunctional lower urinary tract yields outcomes comparable to transplantation into the normal lower urinary tract. Because of the high urologic complication rates, careful surveillance of lower urinary tract function by urodynamic evaluation is essential to optimize these outcomes.

We report on the diagnosis and minimally invasive management of Fraley's syndrome using helical CT with volume-rendering techniques in an 18-year-old patient. Three-dimensional images were generated rapidly and allowed safe planning and execution of a laser infundibulotomy of the upper-pole calix. After 24 months of follow-up, the patient remains pain free.

Background: Despite the recent advances in immunosuppression, steroid-resistant rejection remains a difficult problem in renal transplant recipients., Methods: We reviewed our experience with i.v. immunoglobulin (IVIG) in the treatment of steroid- and antilymphocyte antibody-resistant rejection in renal transplant patients. Between September 1996 and March 1999, 17 patients were treated with IVIG to reverse steroid- or antilymphocyte antibody-resistant rejection. A total of 2 g/kg of IVIG was administered to patients during each treatment course., Results: With a mean follow-up of 21.5+/-9.5 months from the time of IVIG administration, patient and graft survival rates were 94% (16/17) and 71% (12/17), respectively. The baseline mean serum creatinine level prior to rejection was 2.2+/-0.7 mg/dl and peaked at 3.3+/-1.1 mg/dl at the time of the diagnosis of refractory rejection. IVIG therapy was associated with a fall in the mean creatinine to 2.8+/-1.1 mg/dl. The most recent serum creatinine in patients with functioning grafts was 2.8+/-1.6 mg/dl. In 82% of allograft biopsies after IVIG, reversal or reduction in the severity of rejection was demonstrated. In addition, IVIG therapy rescued three of four patients with antilymphocyte antibody-resistant rejection., Conclusions: IVIG rescue therapy for steroid- or antilymphocyte antibody-resistant rejection is associated with resolution or improvement of rejection severity, stable renal function, and reasonable graft survival.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2+/-2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Background: Corticosteroids have always been an integral part of immunosuppressive regimens in renal transplantation. The primary goal of this analysis was to assess the safety of steroid withdrawal in our pediatric renal transplant recipients receiving tacrolimus-based immunosuppression., Methods: Between December 1989 and December 1996, 82 renal transplantations were performed in pediatric patients receiving tacrolimus-based immunosuppression. Two of these patients lost their grafts within 3 weeks of transplantation (and were still on steroids at the time of graft loss), and were excluded from further analysis. Seventy-four patients (92.5%) were taken off prednisone a median of 5.7 months after transplantation. Of these 74, 56 (70%) remained off prednisone (OFF), and 18 (22.5%) were restarted on prednisone a median of 14.8 months after discontinuing steroids (OFF --> ON). 6(7.5%) were never taken off prednisone (ON). The mean follow-up was 59 +/- 23 months., Results: The 1-, 3-, and 5-year actuarial patient survival rates in the OFF group were 100%, 98%, and 96%, respectively; in the OFF --> ON group, they were 100%, 100%, and 100%, and in the ON group, they were 100%, 83%, and 83%. The 1-, 3-, and 5- year actuarial graft survival rates in the OFF group were 100%, 95%, and 82%, respectively; in the OFF --> ON group, they were 100%, 89%, and 83%; and in the ON group, they were 100%, 50%, and 33%. Two of the six graft losses in the OFF group, three out of four in the OFF --> ON Group, and two out of five in the ON group, were to chronic rejection. A time-dependent Cox regression analysis showed that the hazard for graft failure for those who came and stayed off prednisone was 0.178 relative to those who were never withdrawn from prednisone (P=0.005). Patients who were 10 years of age or younger were withdrawn from prednisone earlier (median: 5 months) than those older than 10 years (median: 7.3 months, P=0.02). In addition, patients who never had acute rejection were withdrawn from steroids earlier (median: 5 months) than those who had one or more episodes of acute rejection (median: 7.6 months, P=0.001). There was no effect of donor age, race, sex, recipient race, sex, cadaveric versus living donor, 48-hr graft function, panel reactive antibody, and total HLA mismatches or matches on the likelihood of being weaned off steroids. Serum creatinine at most recent follow-up in the OFF group was 1.2 +/- 0.5 mg/dl; in the OFF --> ON group, it was 1.8 +/- 0.9 mg/dl, and in the ON group it was 2.0 mg/dl (P<0.003). The incidence of rejection in the OFF, OFF --> ON, and ON groups was 39%, 77%, and 100%, respectively (P<0.05)., Conclusion: These data suggest that steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression is associated with reasonable short- and medium-term patient and graft survival, and acceptable renal function. Patients who discontinue and then resume steroids had patient and graft survival rates comparable with those in patients who discontinue and stay off steroids, but had a higher serum creatinine and a higher incidence of rejection.

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

Kidney transplantation has become a reasonable treatment option for selected patients aged 60 years or older, and a number of different immunosuppressive drug protocols have been described. This article concerns 230 recipients who were aged 60 years or older and who were undergoing kidney-only transplantation at the University of Pittsburgh between January 1990 and April 1997. All recipients were treated with a tacrolimus-based immunosuppression regimen. The median follow-up was 31.5 months (range, 1-86). The 1-, 3-, and 5-year actuarial patient survival rates were 90%, 83%, and 76%, respectively. There were 42 (19%) deaths, cardiovascular disease (50%) and infection (38%) being the main causes. Death with a functioning kidney occurred in 28 (67%) patients. The 1-, 3-, and 5-year actuarial graft survival rates were 84%, 74%, and 64%, respectively. The delayed graft function rate was 33%. Rejection was seen in 57 (25%) elderly patients. The mean serum creatinine was 2.6 +/- 2.7 mg/dL and the serum urea nitrogen was 35 +/- 22 mg/dL. The mean tacrolimus level was 8.5 +/- 3.8 ng/mL. These results suggest that renal transplantation in older recipients under tacrolimus-based immunosuppression is associated with reasonable outcomes, and can be offered to appropriately selected patients.

Background: Kidneys from older donors exhibit a series of changes characterized by glomerular, vascular, and tubular senescence. These changes may be aggravated by atherosclerosis, hypertension, or diabetes, which are highly prevalent in older individuals., Methods: We analyzed the outcome after transplantation in 230 recipients over the age of 60, who received transplants between February 1990 and December 1996. We assessed the 1- and 5-year patient and graft survival, the quality of renal function, tacrolimus levels, the incidence of rejection, and the incidence of delayed graft function, and compared the outcomes in recipients of kidneys from donors over the age of 60 (group 1, n = 40) with those in recipients of kidneys from donors under the age of 60 (group 2, n = 190). There were no differences between the two groups in terms of recipient sex, race, age, and cold ischemia time. Immunosuppression was with tacrolimus and steroids in 61% of cases; in the remainder of the patients, a third agent, either azathioprine, cyclophosphamide (for 1 week), or mycophenolate mofetil was administered as well. The median follow-up was 31.5 months (range: 1-86)., Results: In recipients over the age of 60 receiving tacrolimus-based immunosuppression, overall patient survival at 1 and 5 years was 90% and 76%, and was not significantly compromised in recipients receiving a kidney from a donor over the age of 60. The overall 1-and 5-year actuarial graft survival was 84% and 64%; in recipients from donors over the age of 60, it was 73% and 52%, whereas in recipients of kidneys from donors under the age of 60, it was 87% and 66% (P<0.05). Most of the effect on graft survival was seen by 1 year. The mean serum creatinine was 2.6+/-2.7 mg/dl, without any difference between the two groups. Although the incidence of delayed graft function was higher in recipients of kidneys from donors over the age of 60, this difference did not reach statistical significance., Conclusions: Although the overall outcomes of transplantation in older recipients remain reasonable, the inferior outcomes with older donor kidneys call into question proposals to utilize older donor kidneys preferentially in older recipients.

Background: Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection., Methods: The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months., Results: The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups., Conclusions: This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids.

Advances in the surgical techniques, preservation solutions, and methods for predicting eventual long-term renal function from expanded donors will be critical in allowing precise selection criteria for kidneys for transplantation, resulting in the optimum use of a scarce and precious resource. Until other options such as xenotransplantation or tissue engineering become realistic, the challenge for the millennium will be to identify which donor organs previously considered suboptimal can be safely used to expand the organ donor pool.

Background: Tacrolimus has been used as a primary immunosuppressive agent in adult and pediatric renal transplant recipients, with reasonable outcomes. Methods. Between December 14, 1989 and December 31, 1996, 82 pediatric renal transplantations alone were performed under tacrolimus-based immunosuppression without induction anti-lymphocyte antibody therapy. Patients undergoing concomitant or prior liver and/or intestinal transplantation were not included in the analysis. The mean recipient age was 10.6+/-5.2 years (range: 0.7-17.9). Eighteen (22%) cases were repeat transplantations, and 6 (7%) were in patients with panel-reactive antibody levels over 40%. Thirty-four (41%) cases were with living donors, and 48 (59%) were with cadaveric donors. The mean donor age was 27.3+/-14.6 years (range: 0.7-50), and the mean cold ischemia time in the cadaveric cases was 26.5+/-8.8 hr. The mean number of HLA matches and mismatches was 2.8+/-1.2 and 2.9+/-1.3; there were five (6%) O-Ag mismatches. The mean follow-up was 4.0+/-0.2 years., Results: The 1- and 4-year actuarial patient survival was 99% and 94%. The 1- and 4-year actuarial graft survival was 98% and 84%. The mean serum creatinine was 1.1+/-0.5 mg/dl, and the corresponding calculated creatinine clearance was 88+/-25 ml/min/1.73 m2. A total of 66% of successfully transplanted patients were withdrawn from prednisone. In children who were withdrawn from steroids, the mean standard deviation height scores (Z-score) at the time of transplantation and at 1 and 4 years were -2.3+/-2.0, -1.7+/-1.0, and +0.36+/-1.5. Eighty-six percent of successfully transplanted patients were not taking anti-hypertensive medications. The incidence of acute rejection was 44%; between December 1989 and December 1993, it was 63%, and between January 1994 and December 1996, it was 23% (P=0.0003). The incidence of steroid-resistant rejection was 5%. The incidence of delayed graft function was 5%, and 2% of patients required dialysis within 1 week of transplantation. The incidence of cytomegalovirus was 13%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 12%. The incidence of early Epstein-Barr virus-related posttransplant lymphoproliferative disorder (PTLD) was 9%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 4%. All of the early PTLD cases were treated successfully with temporary cessation of immunosuppression and institution of antiviral therapy, without patient or graft loss., Conclusions: These data demonstrate the short- and medium-term efficacy of tacrolimus-based immunosuppression in pediatric renal transplant recipients, with reasonable patient and graft survival, routine achievement of steroid and anti-hypertensive medication withdrawal, gratifying increases in growth, and, with further experience, a decreasing incidence of both rejection and PTLD.

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.

The need to reduce the costs associated with the initial hospitalization for kidney transplantation has led to the development of outpatient facilities in which patients can be seen on a daily basis. The implementation of a kidney transplant intensive outpatient unit (IOPU) is described. Prior to the opening of the IOPU, the median and mean lengths of stay after kidney transplantation in our program were 14.0 and 18.9 d, respectively. Subsequent to the opening of the IOPU, the median and mean lengths of stay after kidney transplantation have gradually decreased and are currently 5.0 and 7.5 d, respectively. The median inpatient cost of transplantation, excluding organ acquisition charges, has decreased by 54%, from $25516 to $11616. Patient satisfaction has exceeded 80%. The IOPU represents an effective means of reducing the cost associated with transplantation, without sacrificing the quality of care.

Monoclonal antibodies to two different targetable antigens were conjugated to each of four commercially available cyanine fluorochromes. Equal amounts of all four antibodies were coinjected into tumor-bearing animals and imaged. Small, superficial tumors were adequately labeled using all four fluorochromes. Large tumors were labeled well only by Cy7, probably due to self-masking and dilution effects. Cy7 was superior to other cyanine fluorochromes for visualizing structures located deep within the animal.

Tumor localization using fluorescence has been made practical by current improvements in tumor targeting molecules, especially monoclonal antibodies and their derivatives, by the development of convenient near-infrared emitting fluorochromes and by the availability of digital cameras having high sensitivity in this spectral region. Recent studies in animals have demonstrated that fluorochrome labeling of monoclonal antibodies confers adequate sensitivity and improved resolution. Distribution and catabolism of fluorochrome-labeled and radiolabeled antibodies are similar. Simultaneous localization of multiple reagents is made possible by labeling with several different near-infrared emitting fluorochromes; thus background subtraction and differential labeling of multiple tumor-associated components can be performed. Difficulties in using the fluorochrome labels are mainly related to light scattering and absorption in tissues, but detection of small tumors at depths of several millimeters is feasible. The major medical use of this new technology is likely to be endoscopic location of tumors. Scientific uses include studies of tumor metastasis, uptake and distribution of drugs and tumor-targeting molecules by tumors, and migration patterns of near-infrared labeled cells in vivo.

The expression of stage-specific embryonic antigen 1 (SSEA-1) in transitional cell carcinomas of the bladder (TCCB) has been reported to correlate with tumor grade and the likelihood of lymphatic metastases. We examined the expression of this antigen in TCCBs to evaluate if staining correlated with grade, stage, recurrence, progression and response to intravesical chemotherapy. We studied the expression of SSEA-1 in TCCBs from 74 patients by staining with two different monoclonal antibodies (Mabs), P-12 and anti-SSEA-1, to evaluate if staining correlated with grade, stage and tumor recurrence. Staining was considered as positive or negative irrespective of the intensity of staining. Extent of tumor staining was measured in quartiles of 100% (25, 50, 75 and 100). Follow-up was available in 47/74 (63%) patients and ranged from 6 months to 13 years (median 2 years). Staining with one or both Mabs was observed in 57/75 (76%) tumors. None of the grade I tumors showed > 50% staining while 26% of grade II and only 33% of grade III tumors showed staining of > 50% of cells. 21% of patients whose tumors showed staining with both Mabs were free of recurrence after resection of the primary tumor; 41% of patients with tumors staining negative with both Mabs showed no recurrence. Expression of SSEA-1 does correlate with tumor recurrence especially in grade II tumors, but the correlation is not very strong (0.05 < p < 0.1). Expression of this antigen is a weak indicator of recurrence in superficial TCCBs.

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3+/-5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0+/-14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0+/-9.4 hr. The antigen match was 2.7+/-1.2, and the mismatch was 3.1+/-1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32+/-20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2+/-0.8 mg/dl, and the calculated creatinine clearance was 82+/-26 ml/min/1.73 m2. The mean tacrolimus dose was 0.22+/-0.14 mg/ kg/day, and the level was 9.5+/-4.8 ng/ml. The mean prednisone dose was 2.1+/-4.9 mg/day (0.07+/-0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158+/-54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.

Far-red-emitting cyanine fluorochromes have many properties desirable for in vivo imaging: absorption and emission at wavelengths where blood and tissue are relatively transparent, high quantum yields, and good solubility even at high molar ratios of fluorochrome to antibody. Potentially, conjugation by multiple linkages should minimize hydrolysis in vivo. We conjugated two tumor-targeting monoclonal antibodies: anti-SSEA-1 (IgM, kappa) at ratios of 1.2-35 mol dye/mol antibody and 9.2.27 (IgG2a, kappa) at 0.6-6 mol dye/mol antibody, using the cyanine fluorochromes Cy3.18, Cy5.18, and Cy5.5.18. Nude mice were inoculated using the SSEA-1-expressing MH-15 teratocarcinoma or the 9.2.27 antigen-expressing SK-MEL-2 melanoma to give tumors at several sites. Conjugated antibody was injected, and mice were imaged immediately after injection and at appropriate intervals thereafter using a standard camera lens, dissecting microscope, or endoscopes. Images were acquired using either an image-intensified video camera or cooled CCD cameras. Immediately after injection, major blood vessels and the heart, liver, and kidneys were readily visualized. After 1 day, tumor-targeting antibody conjugates were concentrated in tumors and there was little circulating conjugate; however, the bladder and kidneys were still visible. Tumors labeled by specific antibody were the most fluorescent tissues at 2 days after injection, but non-specific antibody conjugates did not concentrate in the tumors. The small intestine was weakly visualized by both specific and non-specific antibody conjugates. These data support the possibility of visualizing tumor metastasis by optical means, including currently available endoscopes.

Objective: Cadaveric kidneys from donors less than 5 years old, previously considered inferior graft material, are now being successfully transplanted en bloc into children and adults. On the basis of our experience with 132 patients, we describe the general principles of the procedure and review the spectrum of normal and abnormal imaging findings in patients who have undergone this promising transplantation procedure., Materials and Methods: Paired cadaveric kidneys obtained from donors less than 5 years old (mean age, 24 months) were transplanted en bloc to 132 patients (mean age, 37 years) at our institution between 1981 and 1991. All available medical, surgical, pathologic, and imaging records were retrospectively reviewed to define the surgical technique, 1-year survival rate of the graft, appearance of the transplant on postoperative imaging studies, and the prevalence of and imaging findings caused by vascular, urinary, infectious, and neoplastic complications after transplantation. Complications were confirmed by a definitive imaging study, surgical exploration, or study of a pathologic specimen., Results: Paired donor kidneys were transplanted en bloc extraperitoneally into the recipient's right or left iliac fossa, with intact portions of the donor aorta and inferior vena cava anastomosed to the recipient's external iliac artery and vein. One-year graft survival was 70% during the first 8 years of the study and 78% during the last 2 years. Postoperative imaging, particularly sonography and scintigraphy, clearly depicted the normal individual kidneys, urinary collecting systems, and en bloc vasculature. Postoperative complications were vascular (arterial stenoses and thromboses, venous thromboses, and pseudoaneurysms) in 18%, urinary (obstruction and anastomotic leak) in 11%, infectious (caliceal fungal balls) in 1%, and neoplastic (posttransplant lymphoma) in 1%. The complications involved one kidney in 60% of the patients and both kidneys in 40%. The imaging findings caused by these complications were similar to those caused by complications occurring after transplantation of single cadaveric kidneys; however, their detection was more difficult because of the complexity of the en bloc graft., Conclusion: Because of the shortage of available donor organs, en bloc renal transplantation will most likely become increasingly popular. Familiarity with the imaging appearance of the normal transplant and of posttransplantation complications will allow radiologists to perform effective postoperative imaging evaluations.

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.

Transplantation of kidneys from donors over the age of 60 yr is controversial. However, as the demand for cadaveric kidneys far exceeds the supply, exploration of the usefulness of kidneys outside the currently accepted donor pool is necessary. Between January 1987 and July 1989, 31 (5.5%) of the 558 cadaveric renal transplants performed at the University of Pittsburgh utilized organs from donors older than 60 yr. Median recipient age was 41 yr (range 24-71 yr); 4 recipients were diabetic and 6 had panel-reactive antibody levels greater than 20% at the time of transplant. All recipients were treated with cyclosporine, prednisone and azathioprine. The 1-yr allograft survival was 65% which was less than but not statistically different from the graft survival of 80% in a retrospective selected control group who received grafts from younger donors aged 11 to 50 yr. However, the 1-yr graft survival of older donor kidneys with cold ischemia time greater than 48 hours was 38%, which was significantly poorer than the 78% 1-yr graft survival seen with cold ischemia times less than 48 h (p=0.04 Breslow). The mean serum creatinine was significantly higher in the older donor kidneys at 1, 3, and 12 months post-transplant than in the control kidneys even when kidneys with greater than 48 h of cold ischemia time were excluded. In summary, transplantation of cadaver kidneys from donors older than 60 yr results in acceptable graft survival rates. These kidneys are more susceptible to cold ischemic injury and function with a higher serum creatinine than kidneys from younger donors. Expansion of the donor pool by the use of older donor kidneys in selected recipients could have an impact on alleviating the chronic national cadaver kidney shortage.

Methotrexate (MTX) was coupled to the tumor-targeting monoclonal IgM, anti-SSEA-1 and the non-targeting myeloma IgM, MOPC 104E. At 24-h intervals following injection, drug deposition in MH-15 teratocarcinomas and in several normal tissues was followed by immunoperoxidase microscopy using the M16 monoclonal antibody to MTX. MTX-anti-SSEA-1 was deposited on the surface and in the interior of living tumor cells 24 h after injection; at 48 h and after, only low-level binding to necrotic tissue was found. There was no significant gradation in staining from the outside to the interior of the tumors. In tumors, the control MOPC 104E immunoconjugate was detectable only in necrotic tissue. Binding to SSEA-1-expressing normal tissues was undetectable, except for pericryptal fibroblasts in the small intestine. No significant pathology was found in normal tissues that are SSEA-1 positive. High levels of the immunoconjugate were detected in the liver, where MTX was found predominantly in Kupffer cells and possibly in hepatocytes; again, no significant morphological changes were associated with this retention. Thus tumor-associated antigens can be suitable targets for antibody-drug conjugates even when present in normal tissues and in large quantities, provided that the antigens in normal tissues are inaccessible. Moreover, deposition in viable tumor tissue can be assessed using monoclonal antibodies to methotrexate.

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.