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United States ports must be prepared for the threat of a small-vessel attack using weapons of mass destruction (WMD). To reduce the risk of such an attack, modeling was conducted at the Savannah River National Laboratory (SRNL) in Aiken, South Carolina, to develop options for redeployment of existing maritime law enforcement resources, deployment of new resources, and optimal use of geographic terrain. Agent-based modeling (ABM) implemented by the Automated Vulnerability Evaluation for Risks of Terrorism (AVERT®) software was used to conduct computer-based simulation modeling. The port-specific models provided estimates for the probability of encountering an adversary based on allocated resources under varying environmental conditions and traffic flow rates. Defensive resources include patrol and response platforms, some of which may be more appropriate in particular environmental conditions. A diverse range of potential adversary and attack scenarios was assessed for a large area port and also for a port with a narrow inlet, thereby identifying vulnerable pathways. For chokepoint operations, the probability of encountering an adversary was estimated for various configurations and operational tempos. As traffic flow increased, the probability of encountering an adversary decreased because the adversary could assimilate into traffic, while security forces were preoccupied inspecting pleasure craft. However, there was a significant increase in the probability of encountering an adversary (P(Encounter)) when additional patrols were added. Noted was a decreasing marginal benefit of additional patrols at low traffic levels. In open water, use of helicopters on patrol substantially increased the P(Encounter) by directing on-water security to target vessels. This capability was due to the far-reaching vision and speed capabilities of helicopters. As a result of ABM, more effective countermeasures can be deployed with available resources to reduce the risk of a small-vessel attack using WMD. The models can be expanded to all ports in the United States using generic models similar to those presented herein that can be matched to any port based on its size and shape.

Background: Limulusanti-lipopolysaccharide (LPS) factor (LALF) is a 102-amino acid LPS-binding protein from the horseshoe crab, Limulus polyphemus. The peptide includes the LPS-binding domain of holoLALF, yet it lacks the loop structure stabilized by disulfide or other covalent bonds that is a common motif in the LPS-binding regions of holo- LALF and several other LPS-binding proteins. Although it neutralizes LPS and is bactericidal against Pseudomonas aeruginosa, the LALF 28-54 portion of LALF is not protective in a murine model of intraperitoneal sepsis compared with holoLALF. We examined the effects of cyclizing this linear peptide to determine if this action would recapitulate the stable loop-type structure and enhance its LPS-neutralization and bactericidal activity in vitro.Methods:Cyclic LALF 28-54 was produced by oxidizing linear LALF 28-54. Each peptide, along with appropriate controls, was assayed for LPS neutralization using the chromogenic Limulusamebocyte lysate (LAL) assay and a bioassay to measure inhibition of LPS-stimulated production of tumor necrosis factor-alpha (TNF-α) by murine macrophages. Bactericidal activity against Pseudomonas aeruginosawas also assessed. Data were analyzed using a two-tailed Student t-test.Results:Polymyxin B and holoLALF exhibited potent endotoxin antagonism in both assays, as well as bactericidal activity. Concordant with prior studies, the linear form of LALF 28-54 exhibited either similar or a slightly lesser degree of activity in all assays. However, cyclization was associated with significantly diminished endotoxin neutralization in both assays (p < 0.05) and decreased bactericidal activity (p < 0.05) compared with linear LALF 28-54.Conclusions:Whereas a synthetic linear peptide based on the endotoxin-binding region of holoLALF retained activity, cyclization was associated with a diminution in potency in vitro. We postulate that cyclization does not constrain the peptide in a manner that recreates the loop structure necessary for potent endotoxin antagonism.

The deep corelipid A DCLA region of gramnegative bacterial lipopolysaccharide LPS is common to most gramnegative pathogens and contains anionic phosphoryl groups plus numerous acyl chains as part of the toxic lipid A moiety. Several disparate agents that antagonize the effects of LPS exhibit extensive physicochemical similarities hydrophobicity, cationic charge within their binding domains. It is presumed that binding to the DCLA region by each of these antagonists—crossreactive antiLPS monoclonal antibodies mAbs, polymyxin B PmB, plus bactericidal permeabilityincreasing protein BPI and LimulusantiLPS factor LALF—may be related to these properties. Therefore, we hypothesized that in addition to secondary and tertiary protein conformation, electrostatic interactions involving the negatively charged phosphoryl groups, hydrophobic interactions involving the acyl chains of lipid A, or both might be important factors that promote LPS antagonism. Binding of PmB, BPI, LALF, or antiDCLA mAb 1B6 to Salmonella minnesotamonophosphoryl lipid A MPLA, diphosphoryl lipid A DPLA, and Salmonella minnesotaRe which possess a common structural moiety, but vary considerably in structure and charge was examined. Highly phosphorylated DNA and bovine serum albumin served as unrelated structural controls. BPI bound MPLA, which is hydrophobic and minimally charged, while mAb 1B6 bound anionic DNA neither PmB nor LALF were reactive with MPLA or DNA. We surmised that hydrophobic interactions play a role in BPI binding to LPS, and although electrostatic interactions appear to be important for binding of mAb 1B6 to DCLA, they may not contribute to as great an extent for PmB, BPI, or LALF. Thus our data support the contention that the contribution of these specific physicochemical factors varies among endotoxin antagonists.

Posttransplant cytomegalovirus (CMV) infection has been directly and temporally correlated with decreased patient and allograft survival. Because of this association, prior dogma has dictated that immunosuppression be decreased or maintained, but not increased, and thus rejection episodes have not been treated during active CMV infection. Since 1987, we have treated a group of patients who developed concurrent (within 1–3 days) mild to moderate acute rejection and mild to moderate tissue invasive CMV disease (TI‐CMV) with antirejection and antiviral therapy simultaneously. 619 patients underwent renal transplantation between 5/7/87 and 12/13/90 [535 kidney (253 living related, 282 cadaver) and 84 kidney‐pancreas]. 18 patients presented with concurrent evidence of TI‐CMV plus acute kidney or pancreas allograft rejection. Treatment consisted of iv ganciclovir (DHPG, 5 mg/kg iv q 12 h, mean = 14.4 days) for TI‐CMV and initial oral or iv steroids (followed by ALG or OKT3 in 13 patients) for rejection. At 30 days, all 18 patients with concurrent TI‐CMV and rejection were successfully treated for CMV without DHPG toxicity, although 2 allografts were lost due to unrelenting rejection requiring nephrectomy. 4 patients developed recurrent TI‐CMV and 1 patient developed recurrent rejection >30 days after simultaneous therapy, all of which were successfully treated. A total of 4 deaths occurred due to the following causes: pulmonary embolus, cerebrovascular accident. Candidasepsis, and Aspergillussepsis, the latter subsequent to treatment of recurrent rejection. We analyzed outcome in patients who developed TI‐CMV post‐rejection (> 14 days) or TI‐CMV without rejection and who received DHPG. and noted that patient and allograft survival was not statistically different compared to patients who received simultaneous therapy for both disease processes (p>0.05). Recipients with or without rejection who never developed TI‐CMV. however, did exhibit increased patient and allograft survival when compared to those who were treated for TI‐CMV alone or simultaneous TI‐CMV plus rejection (p<0.01). Based upon this analysis, we concluded that: 1) simultaneous treatment of concurrent TI‐CMV and acute rejection is feasible, and 2) this docs not magnify the adverse effects related to TI‐CMV alone, and recommended that: 1) antirejection therapy be instituted with simultaneous administration of DHPG in patient with proven rejection and suspected TI‐CMV. 2) the diagnostic work‐up for CMV and other pathogens should be vigorously pursued in this setting, and 3) if evidence of progression of CMV disease occurs (despite absence of this event in this series) that antirejection therapy be withdrawn.

In this report, we describe an aggressive polymorphous monoclonal B‐cell lymphoma that developed in a 34–year‐old diabetic male, 1 month after combined pancreas‐kidney transplantation. A diagnosis of post‐transplant lymphoproliferative disorder (PTLD) was established within 72 hours of admission. The tumor was found to infiltrate the transplanted kidney and peripancreatic lymph nodes, as well as the patient's own liver. Despite early diagnosis and immediate withdrawal of immunosuppression, the clinical course was marked by a “sepsis type” syndrome in which high cardiac output, low systemic vascular resistance, metabolic acidosis, and rapid demise occurred. This case was remarkable for several reasons. First, the tumor involved multiple organs and the clinical course of the patient mimicked Gram‐negative bacterial sepsis with multisystem organ failure. Second, the strikingly accelerated progression of the disease led to death within days of diagnosis, despite standard therapeutic interventions. Third, the malignancy appeared shortly after a 7–d course of anti‐lymphocyte antibody was administered for treatment of biopsy‐proven renal allograft rejection. Review of the literature revealed a small number of similar cases of rapidly fatal PTLD. We analyze the possible pathogenesis of this tumor, and emphasize the need for new, aggressive diagnostic and treatment protocols in the management of fulminant PTLD.

Fifty‐eight consecutive patients who received orthotopic liver transplantation were given triple immunosuppressive therapy (cyclosporine, prednisone and azathioprine) to prevent rejection. Weekly percutaneous biopsy was employed to rapidly diagnose and treat rejection. Mild rejection was initially treated with steroids; moderate‐severe rejection was treated using antilymphoblast globulin with or without steroids depending on severity of the histologic pattern. One‐year actuarial survival was 82% for adult recipients and 65% for pediatric recipients. The incidence of biopsy‐proven rejection was high in both groups (77% in adult patients and 73% in pediatric patients) but relatively easily reversed by individualizing treatment based on the response as gauged by serial biopsy. Rejection was reversed in 12 of 13 patients treated with steroids alone and 21 of 24 patients treated with ALG. Only 2 patients went on to chronic rejection. The incidence of bacterial, fungal and viral infections was similar in patients without rejection and in patients with rejection who were treated with steroids alone. A much higher incidence of infection was seen in patients who received antilymphoblast globulin. Four infectious deaths were related to immunosuppressive therapy. The remainder of infections were readily treated with antimicrobial agents. Thus, triple drug immunoprophylaxis with prompt biopsy‐guided individualized therapy is a satisfactory solution to controlling rejection, without exacerbation of fatal infection.

We compared the incidence of de novotumors developing in 1165 primary adult renal allograft recipients treated with azathioprine (AZA)‐ prednisone (Pred)‐antilymphocyte globulin (ALG) (CONV group) with that in 722 patients receiving cyclosporine (CSA) as part of double (CSA‐ Pred), triple (CSA‐Pred‐AZA), or quadruple‐therapy (CSA‐Pred‐AZA‐ ALG) protocols. Mean±SD follow‐up was 9.5±6.4 years for the CONV group and 6.2±2.7 years for the CSA group. Overall, 124 patients (10.6%) in the CONV group and 34 patients (4.7%) in the CSA group developed malignancies, with nonmelanoma skin cancers and lymphomas comprising 55% and 13% of cancers in the CONV group and 65% and 3% of cancers in the CSA group, respectively. There were no significant differences in overall cancer (p=0.41) or skin cancer (p=0.97) incidence between non‐CSA‐ treated and CSA‐treated patients by Kaplan‐Meier life‐table analysis; however, CONV‐treated patients demonstrated a higher incidence of lymphoma (p=0.05). The mean (SD) time to overall and skin cancer occurrence was significantly shorter in the CSA group: 37 +22 versus 90+ 52 months (p<0.001) and 40±24 versus 92 +52 months, respectively. When the Cox Proportional Hazard Model was utilized to assess the relative importance of age, diabetic status, donor source, sex, and immunosuppressive regimen in determining cancer development, age ≥50 years and nondiabetic status were significant independent prognostic indicators, while immunosuppressive regimen was not. Graft and patient survival were significantly greater in CONV‐treated patients developing cancer than in those who did not. In contrast, there were no significant differences in either patient or graft survival between the small group of CSA‐treated patients who developed de novoneoplasms and the much larger group who did not. In conclusion, we find no significant differences in overall or skin cancer incidence but a decrease in lymphoma incidence in primary adult renal allograft recipients following the introduction of CSA at our institution. Longer follow‐up of renal allograft recipients on CSA therapy may reveal changes in the pattern of cancer development.

We reviewed urologic complications of 1183 consecutive primary or secondary renal transplants performed with bladder anastomoses at the University of Minnesota Hospital between 1985 and 1993. The Politano‐Leadbetter (PL) technique of ureteroneocystostomy was used in 410 patients; the multistitch (MS) extravesical technique modified from the methods of Witzel, Sampson, and Lich in 295; and the extravesical single‐stitch (SS) technique in 478. Urologic complications occurred in 81 patients (6.8%). Of these complications, 68 (5.7%) were early (<4 months) and 13 (1.1%) late; 32 (7.8%) were after PL. 17 (5.8%) after MS, and 32 (6.7%) after SS. A total of 13 patients had an anastomotic leak, 7 (1.7%) after PL, 4 (1.4%) after MS, and 2 (0.0004%) after SS; 49 patients had a ureterovesical obstruction, 16 (4.0%) after PL, 12 (4.0%) after MS, and 21 (4.2%) after SS; 5 patients had a ureteropelvic obstruction, 2 (0.5%) after PL, 2 (0.7%) after MS, and 1 (0.2%) after SS; and 14 patients had hematuria, 7 (1.7%) after PL, 1 (0.34%) after MS, and 6 (1.3%) after SS. Of the 81 patients with urologic complications, one (1%) resolved spontaneously; 30 (37%) were treated with temporary percutaneous nephrostomy, 17 (21%) with dilatation and stent; the 14 (17.3%) with hematuria were treated via cystoscopy; 19 (23%) required reoperation. Only 2 (2.5%) patients lost their graft. For both cadaver and living donor recipients, there was no difference between techniques for early and late complications of leakage, stricture, and hematuria. Each technique has certain advantages. and each should be in every surgeon's repertoire.

Nephrotoxicity remains a concern for patients on long‐term cyclosporine. We have previously reported on renal function in a cohort of kidney transplant recipients followed up to 10 years posttransplant. The current study extends the analysis to 12 years. We find no evidence of cyclosporine‐induced renal failure.

In an effort to define the pathology of transplanted human duodenal tissue, 15 resected human duodenal tissues transplanted as pancreaticoduodenal allografts were reviewed and compared with 12 native jejunal tissues (control tissues) used with segmental pancreatic transplants. Correlation of findings in duodenal and pancreatic tissues was also performed. Features which were present in duodenal allografts but not in control tissues included crypt loss (p = 0.0065), villous atrophy (p = 0.015) and vascular changes (endothelialitis, vasculitis and subintimal thickening). Other findings typical of rejecting duodenal allografts included epithelial cell necrosis, epithelial reactive atypia (p = 0.012), and intraepithelial inflammation. Nine patients had histologic evidence of pancreas rejection. The duodenal allografts from these 9 patients typically showed epithelial necrosis, crypt loss and villous atrophy in the mucosa. These features may be markers of acute pancreatic rejection. CMV infection in the duodenal allografts corresponded to pancreatic CMV infection in 1 of 2 allografts.

A major variable in the cost of kidney transplants is the length of initial hospitalization. Using multivariate analysis, we studied risk factors for hospital stay > 10 d post‐transplant. Between 1 January 1985 and 31 August 1995 a total of 1588 patients underwent first or second kidney transplants at the University of Minnesota. Antibody was used for 1 wk in cadaver donor recipients and for 2 wk in pediatric recipients (resulting in a long stay for all pediatric recipients). Adult living related donor recipients were immunosuppressed with triple therapy. Donor risk factors studied were age (<15, 15‐50, > 50 yr) and, for cadaver recipients, preservation time (< 12, 12‐18, 18‐24, 24‐30, >30 h) and cause of death (trauma, cerebrovascular accident, or cardiac). Recipient risk factors studied were age (< 18, 18‐55, > 55 yr); sex; transplant number; antigen mismatch; peak PRA; PRA at transplant (< 11, 11‐50, >50); diabetic status; pretransplant dialysis (vs. pre‐emptive transplant); pretransplant cardiac, peripheral vascular, or respiratory disease; and delayed graft function (DGF) (dialysis in the first week vs. no dialysis). Risk factors were analyzed separately for living donor and cadaver donor recipients. For cadaver donor recipients, DGF was the major risk factor (p < 0.0001); others were age 55 yr (p=0.03) and diabetes (p=0.02). For living donor recipients, DGF was also a risk factor (p=0.003); others were diabetes (p=0.01), retransplant (p=0.006), PRA at transplant > 50 (p < 0.0001), age > 55 yr (p=0.02), pretransplant respiratory disease (p=0.005), and pretransplant dialysis (p=0.005). Because DGF was the major risk factor for a prolonged stay, we then studied risk factors for DGF using multivariate analysis. For cadaver donor recipients, risk factors were recipient weight > 90 kg (p=0.004), preservation time 24 h (p=0.03), PRA at transplant > 50 (p=0.03), and donor age < 15 or > 50 yr (p=0.002). For living donor recipients, risk factors were recipient age 18 yr (p=0.01), donor age > 50 yr (p=0.03), female sex (p=0.05), pretransplant respiratory disease (p=0.1), pretransplant peripheral vascular disease (p=0.05), and recipient weight > 90 kg (p=0.1). From our data, a profile emerged of recipients likely to have a longer hospital stay. Important variables, either simultaneous with or related to DGF, include donor and recipient age, diabetes, pretransplant recipient weight, PRA at transplant, preservation time, and pretransplant respiratory or peripheral vascular disease.

Use of pediatric cadaver kidneys for transplantation is controversial; reports of outcome following pediatric donor transplantation have shown either similar results or worse results than when adult donors are used. Two techniques have been proposed for use of pediatric donor kidneys ‐ transplantation of a single kidney, or transplantation of both kidneys with a common aorta and cava to a single recipient. Single kidney transplants make optimum use of the donor pool; double transplants provide increased renal mass and therefore more functional reserve in the early posttransplant period. No study from a single institution has compared outcome after double versus single pediatric cadaver kidney transplantation. To investigate this issue, we reviewed our experience with 131 pediatric cadaver kidneys (donor age ≤ 10 years) transplanted between 1971 and 1988. We compared outcome of these transplants to outcome of adult donor kidney transplants. Of the group receiving pediatric kidneys, 33 (25%) received double and 98 (75%) received single pediatric kidney transplants. For double pediatric graft recipients, 5 and 10‐yr patient survival rates were 81% and 75%, respectively, whereas for single graft recipients, 5‐ and 10‐yr patient survival rates were 67% and 54% (NS). Graft survival was 78% (1 yr) and 48% (10 yr) in double kidney transplant recipients, but only 61% (1 yr) and 34% (10 yr) in single kidney transplant recipients (p = 0.07). When compared to adult cadaver kidney recipients, double graft recipients had similar short‐ and long‐term outcome (p = 0.6), whereas single pediatric kidney recipients had significantly decreased graft survival (p = 0.03). Pathogenesis for graft loss was similar in double and single pediatric kidney transplants. However, early graft loss (within first 3 months posttransplant) due to rejection was more frequent in single (16%) than in double (3%) pediatric allograft recipients (NS). We conclude that double pediatric cadaver kidneys provide an overall higher patient and graft survival. However, optimal use of the donor pool may be made by the use of single pediatric kidney transplants.

Cytomegalovirus (CMV)‐induced acute lung injury following heart and lung transplantation carries a substantial mortality and morbidity. This report documents the successful management of a fulminant episode of cytomegalovirus infection occurring I month after double‐lung transplantation. Over a period of 36 hours the recipient progressed from a mild febrile illness without exertional dyspnea to a state requiring mechanical ventilation with 100% oxygen and almost complete opacification of lung fields on chest radiograph. Treatment with dihydroxypropoxy‐methylguanine (DHPG) resulted in rapid defervescence and recovery of gas exchange. Cytomegalovirus hyperimmune globulin was also used. After 5 days of treatment, clinical and radiological deterioration occurred that was consistent with an episode of rejection which was treated with bolus corticosteroids. Following this, the patient made a steady recovery and is well 3 months after the initial infection with near normal lung function studies and normal arterial blood gases. It is concluded that DHPG may be a life‐saving therapy in such cases. The relationship between CMV infection and rejection and further possible sequelae is discussed.

Our prospective, randomized trial comparing cyclosporine (CSA) and prednisone (P) with azathioprine (AZA)‐P‐antilymphoblast globulin (ALG) in cadaveric renal transplant patients from 1980 to 1984 demonstrated that CSA‐P treatment produced slightly higher graft survival rates, fewer acute rejection episodes, less infectious complications, and shorter hospital stays while the AZA‐P‐ALG treatment produced lower serum creatinine levels and a shorter duration of delayed graft function. In an attempt to capture the benefits of each protocol, we began evaluating a CSA‐P‐AZA‐ALG regimen in cadaveric renal allograft recipients. In this report, we compared the 1st year results of this new four‐drug protocol given to 78 patients with the 1st yr results of the two‐drug regimens previously studied (CSA‐P, n = 81 and AZA‐P‐ALG, n = 75). The three groups were matched for age, sex, number of retransplants, and diabetic status, and all patients were followed for at least 1 yr posttransplant. The overall 1‐yr actual patient survival rates were 94% for CSA‐P‐AZA‐ALG, 90% for CSA‐P, and 88% for AZA‐P‐ALG. Actual graft survival rates at 1 yr were 87% for CSA‐P‐AZA‐ALG, 80% for CSA‐P, and 73% for AZA‐P‐ALG. The incidence of acute rejection in the 1st yr was similar for CSA‐P‐AZA‐ALG ‐ and CSA‐P‐treated patients (40% vs33%), but was lower in both of these groups than in the AZA‐P‐ALG‐treated patients (55%). The 1‐yr incidence of infectious complications was 38% for CSA‐P‐AZA‐ALG patients, 30% for CSA‐P patients, and 55% for AZA‐P‐ALG patients. Although the incidence of acute tubular necrosis was not significantly different among the three groups, the duration of oliguria and number of dialyses required were significantly less in the CSA‐P‐AZA‐ALG patients than in the CSA‐P patients. Serum creatinine levels at 1 yr posttransplant were lowest in the AZA‐P‐ALG patients (1.5 ± 0.2 mg/dl), 1.7 ± 0.2 mg/dl for CSA‐P‐AZA‐ALG patients, and 2.0 ± 0.2 mg/dl for CSA‐P patients. In summary, our CSA‐P‐AZA‐ALG immunosuppressive protocol for use in cadaveric renal transplantation has achieved its original goal of reducing the adverse consequences of CSA nephrotoxicity by decreasing the duration of acute tubular necrosis and improving creatinine levels while maintaining high patient and graft survival rates.

Eight patients with end‐stage renal failure due to Wegener's granulomatosis underwent renal transplantation at the University of Minnesota. Seven patients were alive with a functioning graft 40 to 128 months posttransplant (mean follow‐up: 91 months). One patient died 126 months posttransplant with a well‐functioning graft. Posttransplant immunosuppression controlled primary disease in all but 1 patient, who presented with perisinusitis. Recurrent disease was not noted in any of the transplanted organs. We conclude that transplantation is an excellent treatment for renal failure secondary to Wegener's disease.

Between January 1971 and February 1988, 1121 cadaver donor kidney transplants were performed at the University of Minnesota. Of these, 873 (77.9%) were from adult (> 15 years of age) donors, 117 (10.4%) from adolescents (> 10, < = 15) and 131 (11.7%) from pediatric (< = 10) donors. Of the last group, 25% of the patients received double and 75% single pediatric cadaver kidney transplants. We compared outcome of pediatric, adolescent and adult donor transplants. There was no difference in patient survival between recipient groups. One‐ and 5‐yr graft survival was 74% and 54% for recipients of adult kidneys, 68% and 53% for recipients of adolescent kidney, and 65% and 46% for recipients of pediatric cadaver kidneys (p = 0.03). Interestingly, the entire difference could be explained by a subgroup – adult or adolescent retransplant recipients of single pediatric kidneys. There was no statistical difference between any groups when primary transplants alone were considered. For pediatric retransplant recipients, there was no difference in outcome if the graft came from a pediatric or adult donor. For the adult or adolescent retransplant recipient most of the difference in graft survival occurred within the first 3 months after transplantation and this difference was maintained throughout the entire follow‐up. Analysis of graft loss within the first 3 months revealed that both acute and chronic rejection were more frequent in recipients of pediatric donor kidneys (p = 0.008). We conclude that the single pediatric kidney is associated with significantly worse graft survival in the adult retransplant recipient.

During the 25‐year period from 1963 to 1988, 127 patients with end‐stage renal failure (ESRF) secondary to autosomal dominant polycystic kidney disease (ADPKD) received a total of 143 renal transplants. The average follow‐up time was 116 months (range 3 to 300 months). Mean age (45.8 yr) was significantly higher than the average age in our transplant population (31 yr) (p< 0.001). No correlation was found between ADPKD and HLA‐A or ‐B antigen frequency among the patients. Overall patient and graft survival was 90% and 73% at 1 yr, 74% and 53% at 5 yr, 55% and 36% at 10 yr, and 37% and 28% at 15 yr, respectively. When death with a functioning graft was excluded as a cause of graft loss, 15‐yr graft survival was 57%. The most common causes of death were cardiovascular complications (46%) and infections (34%), while graft loss was mainly due to patient death (50%), or rejection (38%). Multivariable analysis showed patient survival to be influenced by the level of panel reacting antibodies at the time of transplantation (PRA) (p = 0.002), while graft survival was affected primarily by the donor status (living related vs. cadaver) (p = 0.02). Outcome in transplant patients with ADPKD was compared to outcome in two matched control groups: diabetic and nondiabctic transplant recipients. There was a lower patient survival rate for the diabetic group (p = 0.0003). Graft survival, however, was similar among the three groups, with the exception of diabetics treated with azathioprine, , ALG and prednisone who appeared to have a lower graft survival rate (p = 0.0002). The cause of patient death and graft loss overall did not differ among the three groups studied; however, ADPKD and diabetic patients showed an increased death rate due to cardiovascular episodes for the time period between the 1st and 5th posttransplant years (p = 0.02). We conclude that, although ADPKD patients are older at the time of transplantation, they are excellent transplant candidates.

Despite the superior patient and allograft survival rates of HLA‐identical sibling renal transplantation, a substantial incidence of acute rejection still occurs with the conventional azathioprine‐prednisone (AZA‐P) or AZA‐P‐antilymphocyte globulin (ALG) immunosuppressive regimens. In an attempt to further improve these results, we compared a cyclosporine (CSA)‐AZA‐P combination with AZA‐P‐ALG in 60 consecutive HLA‐identical sibling renal allograft recipients. The distribution of gender, age and proportion of diabetics was almost identical between the two groups. There was no significant difference (p = 0.51) between the CSA‐AZA‐P versus AZA‐P‐ALG groups in patient or graft survival at 1 year (100% versus 93%). Renal function was also similar when comparing the best (1.0 ± 0.7 vs 1.0 ± 0.3 mg/dl, p = 0.46) and current serum creatinine concentrations (1.4 ± 0.7 vs 1.4 ± 0.3 mg/dl, p = 0.45). The AZA‐P‐ALG treated group had a 40% incidence of rejections at 6 months, while rejections were totally eliminated in the CSA‐AZA‐P group (p < 0.001). Patients who received CSA‐AZA‐P also had a lower incidence of infections at 6 months posttransplant (3% vs 27%, p = 0.05), and shorter mean hospitalization time posttransplant (7.4 ± 4.3 days vs 12.4 ± 7.7 d, p < 0.001). Our results suggest that the CSA‐AZA‐P combination is safe and extremely effective for immunosuppression in HLA‐identical sibling renal transplantation.

To determine whether renal allograft recipients with sustained or transient elevation in hemoglobin (Hgb) level are at increased risk for thromboembolism, we examined the incidence of arterial and venous thromboembolic events in various subgroups of 224 patients who were prospectively randomized and stratified by risk to treatment with either cyclosporine‐prednisone (CSA‐P) (n = 117) or azathioprine‐prednisone‐antilymphocyte globulin (AZA‐P‐ALG) (n = 107). Eleven CSA patients (9.4%) and 4 AZA patients (3.7%) developed posttransplant erythrocytosis (PTE) (p = 0.08). There were no significant differences in the incidence of thromboembolic events among subgroups of phlebotomized or nonphlebotomized, CSA‐ or AZA‐treated, PTE patients, nor did these incidence rates differ significantly from those for the entire AZA and CSA groups. There was no significant increase in the incidence of thromboembolism in any of the CSA‐treated subgroups with “sustained” (≥ 1 year) or transient elevation in Hgb level when compared with the CSA‐P group as a whole or with CSA subgroups with lower Hgb levels. The percentage of AZA‐treated patients with thromboses increased in parallel with sustained Hgb levels, reaching statistical significance when patients with Hgb ≥ 16 g/dl for at least 1 yr were compared to the AZA‐P‐ALG group as a whole (p = 0.02), to AZA subgroups with lower Hgb levels (Hgb ≥ 14 g/dl for at least 1 yr, Hgb never > 17 g/dl, and Hgb never > 14 g/dl; p = 0.02, 0.02, and 0.05, respectively), and to their CSA‐treated counterparts (p = 0.03). Under both immunosuppressive regimens, however, Hgb levels tended to be low precisely at the time when patients in all subgroups had their complications. We conclude that neither transient marked elevations nor modest sustained elevations of Hgb level per seis directly associated with an increased incidence of thromboembolic complications in renal transplant recipients. PTE can be successfully managed without an increase in thromboses if therapeutic phlebotomy is utilized to maintain the hematocrit (HCT) < 50–55% and/or to treat symptoms attributable to polycythemia.

The increasing number of organs required for transplantation has given an impetus to the development of techniques of multiorgan procurement from a single cadaver donor. We studied the effect of these techniques on the short‐term outcome of kidney transplants. Between 1.1985 and 12.1989, 168 kidneys were procured by our team during multiorgan harvests, 166 of which were transplanted in our institution or elsewhere. Follow‐up could be obtained for 161. The pancreas was retrieved simultaneously in 14 cases (9%); the pancreas and the liver in 34 (21%); the pancreas, the liver, and the heart in 73 (45%); the pancreas, the liver, the heart and the lungs in 24 (15%); the pancreas and the heart in 4 (2%); and the pancreas, the heart and the lungs in 2 (1%). We have incomplete information for 10 kidneys (7%). Immediate graft function occurred in 125 grafts (78%) (Group I); 31 kidneys (19%) had delayed graft function (DGF), 4 (2%) had technical failure (TF) (thrombosis), and 1 (1%) was a primary nonfunction (PNF) (Group II). Comparison with historical controls suggests that multiorgan retrieval had no impact on the incidence of DGF. Multivariate analysis demonstrated that the determinant factor in immediate graft function was the length of preservation – 20 ± 8 hours for Group I vs 26 ± 8 for Group II. Patients with DGF had normal creatinine values at 3 and 6 months, similar to those with immediate function. We conclude that the combined simultaneous procurement of the kidney and other organs does not affect the outcome of the kidney transplant. DGF is related to perservation time.

Herpesviruses are a major cause of morbidity and mortality in renal transplant recipients. Recently, a new member of the herpesvirus family, human herpesvirus 6 (HHV‐6), has been identified. We investigated the incidence and clinical manifestations of HHV‐6 infections in 25 hospitalized renal transplant recipients. HHV‐6 infections were documented serologically by comparing pre‐ and post‐transplantation antibody titers using an indirect immunofluorescence assay. Infections caused by cytomegalovirus, Epstein‐Barr virus, herpes simplex virus and varicella‐zoster virus were also studied. During the mean follow‐up period of 3½ months post‐transplant (range, 2 to 6 months), 9 recipients (36%) had serologic evidence of HHV‐6 infection. Two patients seroconverted, suggesting primary HHV‐6 infection. These patients had febrile illnesses, skin rash and malaise. Seven recipients had a non‐primary HHV‐6 infection (reactivation/reinfection) documented by a > 4‐fold rise in antibody titer that was associated with clinical illness in 5 of 7 patients. Two recipients developed primary cytomegalovirus infection and both had evidence of non‐primary HHV‐6 infection. Seven of 9 recipients (77%) who developed HHV‐6 infection had received acyclovir prophylaxis. We conclude that primary and non‐primary HHV‐6 infections occur in renal transplant recipients and can be associated with fever, skin rash and malaise. HHV‐6 infections can occur despite high‐dose oral acyclovir prophylaxis.

Patients with paraproteinemias may have a spectrum of clinical diseases with marked differences in prognosis. We report the course of 3 patients with pretransplant paraproteinemias (1 with multiple myeloma, 1 with light chain deposition disease, 1 with Waldenström's macroglobulinemia) and review 10 patients reported in the literature (6 with multiple myeloma, 4 with light chain deposition disease). Of the 7 patients with multiple myeloma, 2 are alive with functioning grafts. The remaining 5 died with function 14 months to 9.5 years posttransplant; infection was the cause of death in all 5. The patient with Waldenström's macroglobulinemia and 3 of the 5 with light chain disease are alive with function. Although recurrent disease was common, it did not necessarily result in renal dysfunction or graft loss. The collective experience from these 13 patients demonstrates that relatively long patient and graft survival can be achieved in a select group of patients with paraproteinemias. Pretrans‐plant evaluation should exclude the presence of active disease. Patients with “benign monoclonal gammopathy” should undergo serial revaluations for at least 1 yr to exclude the presence of unrecognized multiple myeloma or Waldenström's macroglobulinemia. Posttransplant management should: (1) include a particularly low threshold for detecting infectious complications, especially with fungal pathogens, (2) avoid dehydration, hypercalcemia, hyperuricemia, and nephrotoxic drugs, and (3) maintain close follow‐up for detecting recurrent disease. The data suggests transplantation is an acceptable choice for treating renal failure in patients with paraproteinemias.

Twenty‐five years ago the first case of renal transplantation into an ileal conduit was performed at this institution. Since then, 16 patients (9 females, 7 males) with an average age of 24.8 yr (range 9 to 47 yr) have undergone 19 transplants into intestinal conduits. The indication was neurogenic bladder in 7 cases, major urinary tract abnormalities in 7, and vesicoureteral reflux in 2. In primary transplants, 8 kidneys were from living related donors and 8 from cadaver donors; in retransplants, 1 kidney was from a living related and 2 from cadaver donors. In all but 3 cases the intestinal loop was constructed at least 2 weeks pretransplant. An ileal loop was used in 14 cases; a colon loop in 2. Conduit‐specific complications were: calculi (n = 2), small‐bowel‐to‐ileal‐loop fistula with hyperchloremic hyperkalemic acidosis (n = 1), urinary fistula (n = 1), and recurrent UTIs (n = 12). Urosepsis caused 4 deaths. As of 9/89, 9 of these 16 patients are alive with functioning grafts (1 retransplant), 1 is alive without a functioning graft, and 6 died [urosepsis (4), ARDS (1), pneumonia (1)]. All of the 9 patients have had functioning grafts for more than 1 yr, 5 for more than 5 yr and 3 for more than 10 yr. Of the 9 functioning grafts, 6 were from living related donors and 3 from cadaver donors. Patients were divided into two groups based on time of transplantation: Group I (11/64–4/77) and Group II (5/77–9/89). In Group I, 6 of 9 patients died; 1 is alive, but without a functioning graft, and only 2 still have functioning grafts. In Group II, no patient has died and 6 of 7 primary grafts still are functioning. Improvements in immunosuppression, surgical technique, infection treatment, and selection criteria are responsible for higher graft and patient survival in Group II.

We studied the long‐term morbidity and mortality of 123 consecutive HLA‐ID living‐related kidney transplants performed at a single institution more than 10 years ago. Type I diabetes was the cause of renal failure in 39% of patients; mean age at transplant was 32 ± 12 yr (range 2–64). Immunosuppression consisted of prednisone and Imuran; most patients received ALG perioperatively. For nondiabetics, 10‐, 15‐, and 20‐yr actuarial patient survival was 85%, 75%, and 68%; for diabetics. 10‐ and 15‐yr survival was 65% and 34% (p = 0.0015). Cardiovascular complications were the main cause of death in diabetics, affecting mostly males; sepsis, malignancy, and graft loss were the main cause of death in nondiabetics. Graft survival paralleled patient survival; 76% of grafts lost were due to patient death. Graft survival at 10 and 15 yr was 81% and 73% for nondiabetics; for diabetics, it was 63% and 24%, respectively (p = 0.0031). When death as a cause of graft loss was excluded, there was no difference between diabetics and nondiabetics. Mean serum creatinine at 10 yr was 1.4 ± 0.5. Thirty‐two patients (26%) had one or more acute rejection episodes, most of them occurring within the 1st yr posttransplant. Only 7 grafts have been lost either to acute (4) or chronic (3) rejection. Twenty‐four percent of the patients had no complications. Cardiovascular complications (28%) were the major cause of morbidity and mortality, affecting mostly diabetic males. Sepsis was also a significant problem (19.5%), CMV being the most common pathogen. Malignancy occurred in 12.2% of cases, affecting most frequently the skin. Liver dysfunction, mainly of viral etiology, was the cause of 2 deaths and contributed to several others. Nontraumatic osteonecrosis occurred in 4.9% of the patients; it tended to present in young patients soon after their transplant. We conclude that the long‐term results of HLA‐ID transplantation are excellent when compared to other options in patients with ESRD. Mortality due to the underlying disease (diabetes) and morbidity due to the immunosuppression remain as major obstacles to the long‐term survival and successful rehabilitation of these patients.

The influence of cold storage preservation time on graft survival and metabolic function of pancreatic transplants was studied in 130 recipients of bladder-drained grafts (47 simultaneous with, 33 after, and 50 without a kidney transplant) between October 1, 1984 and May 1, 1989. The recipients were divided into four groups according to the preservation time: < 6 hr (n 11), 6–12 hr (n 24), 12–24 hr (n 75), and > 24 hr (n 20). Twenty-six grafts were procured by other transplant teams and sent to us. Silica gel fractionated plasma was used for preservation in 104 cases and the University of Wisconsin solution in 25 (1 in the < 6 hr, 2 in the 6–12 hr, 16 in the 12–24 hr, and 6 in the > 24 hr groups). The technical failure rate at 1 month was 13 (17 grafts), 1 (9) in the < 6 hr, 5 (21) in the 6–12 hr, 9 (12) in the 12–24 hr, and 2 (10) in the > 24 hr groups. At 1 month, 107 (82) of the grafts were functioning, 10 (91) in the < 6 hr, 18 (75) in the 6–12 hr, 62 (83) in the 12–24 hr and 17 (85) in the > 24 hr groups, the longest preserved for 30 hr. The respective 1-year graft survival rates were 51, 50, 57, and 70. Ninety patients (10 in the < 6 hr, 16 in the 6–12 hr, 51 in the 12–24 hr, and 13 in the > 24 hr groups) had metabolic studies between 2 and 6 weeks posttransplant. The results of 24-hour profiles (14 blood glucose determinations) were similar in each preservation time group; the means of the mean (±SD) profile glucose (mg/dl) values were 130±19, 126±31, 130±24, and 129±30, respectively (P> 0.6). Mean plasma glucose levels at 2 hr during OGTT were 141±32, 145±43,

• Suppression of the gut luminal aerobic flora to reduce nosocomial infections was tested in a prospective, randomized, double-blind, placebo-controlled clinical trial in patients in a surgical intensive care unit who had persistent hypermetabolism. Forty-six patients were randomized to receive either norfloxacin, 500-mg suspension every 8 hours, together with nystatin, 1 million units every 6 hours, or matching placebo solutions administered through a nasogastric tube within 48 hours of surgical intensive care unit admission. Selective gut decontamination with the experimental therapy or placebo solutions continued for at least 5 days or until the time of surgical intensive care unit discharge. Patients were monitored with routine surveillance cultures for the development of nosocomial infections, as defined by criteria from the Centers for Disease Control. All other therapy was given as clinically indicated, including systemic antibiotics. The selective gut decontamination group experienced a significant reduction in the incidence of nosocomial infections and a reduced length of stay. However, these results were not associated with a concomitant decrease in progressive multiple organ failure syndrome, adult respiratory distress syndrome, or mortality.(Arch Surg. 1992;127:163-169)

• To improve our understanding of posttransplant infections, we analyzed bacterial, viral, fungal, parasitic, and other infections in 604 consecutive recipients of kidney (n = 518), kidney-pancreas (n = 82), kidney-liver (n = 3), or kidney-islet (n = 1) allografts (355 cadaveric, 14 living-unrelated, 235 living-related donors) who also received cyclosporine, azathioprine, and prednisone immunosuppression. Recipients of cadaveric grafts received additional induction immunosuppression (antilymphocyte globulin or murine monoclonal antibody OKT3). Rejection episodes were treated with high-dose steroids, and either antilymphocyte globulin or OKT3 was administered when clinically indicated. Perioperative antibiotics and posttransplant prophylactic acyclovir sodium or ganciclovir sodium, trimethoprim-sulfamethoxazole, and clotrimazole or nystatin (Mycostatin) were administered to all recipients. Two hundred thirteen patients (35.3%) were found to have had no identifiable infections, while 391 (64.7%) had either isolated bacterial (97 [16.1 %]), viral (53 [8.8%]), or fungal (34 [5.6%]) infections or combination (concurrent or sequential) infections with bacterial plus viral (46 [7.6%]), bacterial plus fungal (66 [10.9%]), viral plus fungal (20 [3.3%]), bacterial plus viral plus fungal (64 [10.6%]), or bacterial plus viral plus fungal plus parasitic (11 [1.8%]) pathogens in the posttransplantation period. Renal allograft survival (percentage, actuarial method) was diminished in patients with infections at both 1 year (91% vs 83%) and 3 years (81% vs 76%) after transplantation, as was actuarial patient survival (1 year, 97% vs 92%; 3 years, 93% vs 88%). We conclude that infection remains a major cause of both patient demise and allograft loss following successful solid-organ transplantation.(Arch Surg. 1992;127:38-48)

OBJECTIVE: To determine the effect of targeted disruption of the cellular receptors of either tumor necrosis factor α (TNF-α) or interleukin-1β (IL-1β) during experimental gram-negative bacterial infection and endotoxemia. DESIGN: Transgenic (knockout [KO]) mice deficient in either the p55 TNF receptor (TNF RI) or the p80 IL-1 receptor (IL-1 RI) were challenged with intravenous lipopolysaccharide (endotoxin) or intraperitoneal live Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Serum endotoxin levels and quantitative blood cultures were monitored at multiple times during infection. SETTING: Surgical infectious disease research laboratory. MAIN OUTCOME MEASURES: Mortality, results of quantitative blood cultures, and serum endotoxin levels. RESULTS: Both TNF and IL-1 RI KO mice were resistant to endotoxin challenge (0% mortality for both groups) compared with control mice (100% mortality [P&lt;.01]). In contrast, only the IL-1 RI KO mice were resistant to infection caused by viable gram-negative bacteria (43% mortality) compared with control mice (100% mortality [P&lt;.01]). Infection led to 100% mortality in TNF RI KO mice. The IL-1 RI KO mice exhibited less bacteremia and diminished endotoxemia compared with control and TNF RI KO mice 18 and 24 hours after infection. CONCLUSION: The absence of either the TNF or the IL-1 RI receptor prevents cellular activation by each respective cytokine. Absence confers protection against intravenous endotoxin, which stimulates massive rapid release of cytokines into the systemic circulation. However, bacterial infection within the peritoneal cavity is known to cause more delayed cytokine release, and cytokines may act at the site of infection to enhance host defenses. We believe that IL-1 signaling may be more critical in provoking lethal systemic toxic effects than TNF signaling. However, TNF signaling may be an important component of host defense enhancement at the local site of infection.Arch Surg. 1996;131:1216-1221

OBJECTIVES: To generate a recombinant fusion protein (FP) based on the endotoxin-binding domain of bactericidal/permeability-increasing protein (BPI) and the constant domain of IgG and to test its ability to inhibit lipopolysaccharide (LPS)-induced macrophage tumor necrosis factor α (TNF-α) secretion. DESIGN: A murine macrophage cell line, RAW 264.7, was transfected with a BPI-IgG FP before incubation with LPS. The amount of LPS-induced TNF-α protein secreted was measured and compared with that secreted by cells transfected with a control construct. SETTING: Basic science research laboratory. MAIN OUTCOME MEASURE: Secreted TNF-α protein concentration. RESULTS: After transfection, RAW 264.7–cell FP expression was detected in cell lysates and supernatants. At each LPS dose tested, cells transfected with the FP gene secreted less TNF-α than did cells transfected with a control construct. CONCLUSIONS: The FP possesses substantial antiendotoxin activity, as delineated by inhibition of LPS-induced TNF-α secretion by murine macrophages transfected with the fusion gene construct. In the future, such FP may be used as a clinical reagent to reduce the morbidity and mortality associated with serious gram-negative bacterial infections in surgical patients.Arch Surg. 1996;131:1173-1178

OBJECTIVE: To investigate whether previous pancreas graft loss caused by intra-abdominal infection is a risk factor for a subsequent pancreas retransplantation. DESIGN: Retrospective case-series analysis. SETTING: Large university hospital. PATIENTS: Of 97 pancreatic retransplantations (July 1, 1985 to June 30, 1994), 13 (13%) were performed after previous pancreas grafts had been lost because of intra-abdominal infection. MAIN OUTCOME MEASURES: Cause of retransplant graft loss; patient survival. RESULTS: Of 13 cases of pancreatic retransplantations performed after previous grafts had been lost because of intra-abdominal infection, 12 (92%) were again complicated by intra-abdominal infection. Of these 12 retransplantation infections, 10 were caused by the same microbial species that had caused failure of the previous graft 1 to 5 years earlier (8 required graft pancreatectomy [mortality rate, 25%], and 2 were successfully treated) and 2 were caused by different microbial species (both required graft pancreatectomy [mortality rate, 0%]). In 1 of the 13 retransplantations, prophylactic antimicrobial treatment was directed at the microbial species that had caused failure of the previous graft; no recurrent intra-abdominal infection developed. CONCLUSIONS: Intra-abdominal infection after a previous pancreas transplantation is a risk factor for recurrence of infection by the same microbial species after a subsequent retransplantation. For the selected patients who are considered for retransplantation in spite of their previous graft loss caused by intra-abdominal infection, periretransplantation antimicrobial prophylaxis should include a prolonged course of an agent directed against the previously identified microbial species.Arch Surg. 1996;131:1054-1060

OBJECTIVE: To study whether bacterial translocation is more prevalent after small-bowel transplantation with systemic venous drainage (SVD) vs portal venous drainage (PVD) and whether it is influenced by immunosuppression. DESIGN: We performed 15 small-bowel transplantations in pigs. Group 1 (n=5) had SVD and no immunosuppression; group 2 (n=6), PVD and no immunosuppression; and group 3 (n=4), PVD and immunosuppression with tacrolimus and methylprednisolone sodium succinate. Portal and systemic blood, portal and mesenteric lymph nodes, and liver were cultured in donors and recipients on postoperative day 0 (POD 0) and in recipients on postoperative day 3 (POD 3). Jejunal and ileal contents were also sampled at these times. SUBJECTS: Outbred male Yorkshire-Landrace pigs. MAIN OUTCOME MEASURES: (1) Blood and tissue bacterial cultures, (2) blood endotoxin levels, and (3) histopathologic examination. RESULTS: Cultures were positive for bacteria in 32% (16/ 50) of samples on POD 0 and 88% (22/25) on POD 3 in group 1, in 18% (11/60) of samples on POD 0 and 97% (29/30) on POD 3 in group 2, and in 8% (3/40) of samples on POD 0 and 95% (19/20) on POD 3 in group 3. Systemic blood cultures were positive for bacteria on POD 3 in 60% (3/5) of pigs in group 1, 83% (5/6) in group 2, and 100% (4/4) in group 3. Significantly more bacteria were present in the ileum than in the jejunum on POD 0 in group 2; this difference approached significance in groups 1 and 3. Bacterial numbers were identical in the ileum and jejunum by POD 3 in all groups. Circulating endotoxin levels were significantly elevated on POD 3 vs POD 0 only in group 1. Endotoxin levels were not significantly different between the SVD group (group 1) and either PVD group (groups 2 and 3). CONCLUSIONS: Bacterial translocation is prevalent after small-bowel transplantation in pigs whether PVD or SVD is used. Immunosuppression with tacrolimus does not prevent bacterial translocation but may reduce systemic endotoxemia.(Arch Surg. 1996;131:77-84)

Gram-negative bacterial sepsis with the frequent sequelae of shock, multi-system organ failure, and death represents one of the most severe infections that can occur in the surgical patient. Fatality in most series has paralleled the presence and severity of underlying host disease processes, polymicrobial bacteremia, shock, and lack of early appropriate antimicrobial therapy. Even patients with no underlying disease state have a significant mortality (10–20%). Therapy of gram-negative bacterial sepsis and shock at present consists of antimicrobial agents, hemodynamic monitoring, aggressive fluid resuscitation, and metabolic support. The use of these treatment modalities in concert has reduced, but not eliminated, the severe consequences that may ensue. Administration of antibody directed against the comon core lipopolysaccharide antigen of gramnegative microorganisms to patients with gram-negative sepsis represents a means by which the morbidity and mortality of this disease process may be further reduced. This is supported by a large body of experimental evidence, as well as several preliminary clinical studies. It is necessary to determine how the clinical efficacy of such antibody preparations can be maximized. This will entail rigorously controlled studies in which the timing of antibody administration and dose utilized can be correlated with clinical efficacy. Should such antibody preparations continue to prove efficacious as an additive form of therapy, it may be possible to identify high-risk groups of patients who would benefit from antibody prophylaxis.