Kenneth A. Newell

Acute Renal Failure in Endotoxemia Is Caused by TNF Acting Directly on TNF Receptor-1 in Kidney

Bacterial endotoxin (LPS) is responsible for much of the widespread inflammatory response seen in sepsis, a condition often accompanied by acute renal failure (ARF). In this work we report that mice deficient in TNFR1 (TNFR1−/−) were resistant to LPS-induced renal failure. Compared with TNFR1+/+ controls, TNFR1−/− mice had less apoptosis in renal cells and fewer neutrophils infiltrating the kidney following LPS administration, supporting these as mediators of ARF. TNFR1+/+ kidneys transplanted into TNFR1−/− mice sustained severe ARF after LPS injection, which was not the case with TNFR1−/− kidneys transplanted into TNFR1+/+ mice. Therefore, TNF is a key mediator of LPS-induced ARF, acting through its receptor TNFR1 in the kidney.

Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression.

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

Complications in 100 living-liver donors

OBJECTIVEnA review of 100 living-liver donors was performed to evaluate the perisurgical complications of the procedure and thus to help quantify the risks to the donor.nnnSUMMARY BACKGROUND DATAnDespite the advantages of living-donor liver transplantation (LDLT), the procedure has received criticism for the risk it imposes on healthy persons. A paucity of data exists regarding the complications and relative safety of the procedure.nnnMETHODSnOne hundred LDLTs performed between November 1989 and November 1996 were reviewed. Donor data were obtained by chart review, anesthesia records, and the computerized hospital data base. Patient variables were compared by Fishers exact test and the Students t test.nnnRESULTSnThere were 57 women and 43 men with a median age of 29. Donors were divided into two groups: group A (first 50 donors), and group B (last 50 donors). There were 91 left lateral segments and 9 left lobes. There were no deaths. Fourteen major complications occurred in 13 patients; 9 occurred in group A and 5 in group B. Biliary complications consisted of five bile duct injuries (group A = 4, group B = 1) and two cut edge bile leaks. Complications were more common in left lobe resections (55%) than in left lateral segment grafts (10%). Minor complications occurred in 20% of patients. A significant reduction in overall complications (major and minor) was observed between the groups (group A, n = 24 [45%] vs. group B, n = 10 [20%]). In addition, surgical time and hospital stay were both significantly reduced.nnnCONCLUSIONSnAlthough the procedure is safe, many LDLT donors have a perisurgical complication. Surgical experience and technical modifications have resulted in a significant reduction in these complications, however. To minimize the risks for these healthy donors, LDLT should be performed at institutions with extensive experience.

Portal vein thrombosis and stenosis in pediatric liver transplantation.

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P<0.0005 vs. reduced graft and < 0.03 vs. other LDLT groups). The incidence of late portal vein stenosis or thrombosis was significantly higher in the LDLT Group 2, (51%) than any of the other groups (LDLT 1, 16%; LDLT Group 3, 9%; RLT 4%;P<0.005 vs. cadaveric and < 0.02 vs. LDLT Group 1 and LDLT Group 3). Five year arterial graft and patient survival for patients who have experienced portal vein thrombosis or stenosis is 61% and 67%, respectively, versus 67% and 71% for those patients who have not experienced portal vein pathology, P=ns. Based on this experience, we recommend avoiding the use of cryopreserved iliac vein for portal vein reconstruction in liver transplantation. Every effort should be taken to eliminate the need for venous conduits in liver transplantation. If venous conduits must be utilized, cryopreserved femoral veins seem to provide superior patency rates. Careful clinical and ultrasonopraphic monitoring of patients at high risk for late venous thrombosis permits therapy with excellent graft and patient survival.

Clinical course and management of inflammatory bowel disease after liver transplantation.

BACKGROUNDnPrevious reports investigating the clinical course and management of inflammatory bowel disease (IBD) after orthotopic liver transplant (OLT) have revealed conflicting results.nnnMETHODSnTo determine the natural history and course of therapy for liver transplant patients with IBD, we reviewed the records of 35 patients, who underwent OLT between 1985 and 1996 and who had a history of either IBD (29 patients) or primary sclerosing cholangitis (PSC) without evidence of IBD before OLT (6 patients). Of 29 patients with IBD before OLT, 25 had a history of ulcerative colitis (UC) and 4 had Crohns disease. Six patients had undergone total colectomy, one subtotal colectomy, and three partial colectomy before OLT. Mean follow-up after OLT was 37+/-6.4 months. Immunosuppression included cyclosporine, prednisone, and azathioprine in 34 patients and tacrolimus and prednisone in 1 patient.nnnRESULTSnAfter OLT, 17 patients (49%) had quiescent disease and were receiving no additional medications other than standard immunosuppression to prevent organ rejection. Five patients (14%) had mild flares controlled with initiation of 5-aminosalicylates (5-ASA), and two patients (6%) required an increase in oral prednisone. Only one patient with PSC, without evidence of IBD before OLT, developed IBD after OLT. No patients required intravenous steroids or surgical intervention for active IBD.nnnCONCLUSIONSn(1) Standard postOLT immunosuppressive agents in patients undergoing OLT with IBD were able to adequately control disease activity after OLT in the majority of patients. (2) IBD flares after OLT were generally well controlled with aminosalicylates or oral steroids. (3) Aminosalicylates were helpful in the clinical management of IBD, even when patients were taking standard doses of steroids, azathioprine, and cyclosporine.

Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation

Vancomycin-resistant Enterococcus (VRE) has become a significant nosocomial pathogen. For this study, the records of 325 patients who underwent orthotopic liver transplantation (OLT) were reviewed. Thirty-four patients were infected by VRE (incidence of 10.5%, 14% in adults vs. 5% in children, P < 0.01). Common features of patients who developed infections with VRE included previous antibiotic use (25 patients, 15 of whom received vancomycin), co-infection by other pathogens (28 patients), and relaparotomy following OLT (20 patients). Pulmonary and/or renal failure preceded infection by VRE in 11 and 4 adult patients, respectively. Biliary complications were exceedingly common in patients infected by VRE (28 patients) and significantly increased the risk of infection by VRE (21.5% vs. 3.1% for patients without biliary complications, P < 0.0001). Mortality associated with VRE infections was high (56% vs. 19% for patients not infected by VRE, P < 0.0005). The most frequent cause of death was sepsis (16 of 19 patient deaths), often polymicrobial. The high incidence of infection by VRE following OLT, the lack of effective antibiotics for the treatment of VRE, and the association of VRE with patient mortality emphasizes the need to define the risk factors associated with VRE infection. We suggest early surgical intervention to treat complications that may predispose patients to infection by VRE.

Comparison of pancreas transplantation with portal venous and enteric exocrine drainage to the standard technique utilizing bladder drainage of exocrine secretions.

Although bladder drainage of pancreatic exocrine secretions has been reported to decrease morbidity and improve pancreas allograft survival, significant complications remain associated with this technique. Furthermore, this technique requires systemic venous drainage of pancreas allografts. Evidence suggests that portal venous drainage of pancreas grafts prevents hyperinsulinemia and improves lipoprotein composition. This report documents our initial experience with portal venous and enteric exocrine drainage of pancreas allografts (portal/enteric technique) and compares it with the standard technique of systemic venous and bladder exocrine drainage (systemic/bladder technique). Patient and allograft survival, as well as allograft function, were comparable for the two procedures. There were no significant technical complications in this pilot series. Enteric exocrine drainage was associated with a significant reduction in the incidence of acidosis and dehydration when compared with bladder drainage (P<0.005). The portal/enteric technique also avoided reoperation for enteric conversion, as was required by 33% of patients in the systemic/bladder group. The incidence and outcome of allograft rejection were similar for the two techniques. These data suggest that combined pancreas/kidney transplantation with portal venous and enteric exocrine drainage is safe and results in outcomes similar to the standard technique, while eliminating many complications of bladder drainage. These findings should encourage additional studies to determine the consequences of portal venous drainage.

Absence of host B7 expression is sufficient for long-term murine vascularized heart allograft survival.

CD28 antagonists have been shown to promote long-term graft survival and induce donor-specific tolerance. In this study, the role of CD28/B7 costimulation and the relative importance of host versus donor B7 expression in allograft rejection was assessed in a murine abdominal vascularized heterotopic heart transplant model. Wild-type, CD28-deficient, or B7-1/B7-2-deficient C57BL/6 (B6) mice were grafted with allogeneic wild type or B7-1/B7-2-deficient hearts. The results demonstrate allogeneic heart grafts survive long-term in mCTLA4Ig-treated B6 and untreated B7-1/B7-2-deficient B6 recipients but not CD28KO B6 mice. B7-1/B7-2KO B6 recipients treated with anti-CD28 (PV-1) or recombinant human IL-2 rejected the heart transplants indicating that these mice are immunologically competent to reject grafts if costimulatory signals are supplied or bypassed. Finally, there was no difference in rejection between normal animals transplanted with wild-type versus B7-1/B7-2-deficient hearts. These results support a critical role for B7-expressing host antigen presenting cells in the rejection of heart allografts in mice and differences among B7KO and CD28KO animals.

Long-term outcome of kidney-pancreas transplant recipients with good graft function at one year.

To assess the long-term outcome of kidney/pancreas transplantation, patients were identified who had good graft function at one year posttransplant and a minimum of 3 years follow-up. Fifty recipients from 1987-92 met these criteria. Records were reviewed for graft survival, graft function, readmissions, and medical complications. Psychosocial adjustment and quality of life were assessed using the SCL-90-R and SIP surveys, respectively. Patient, kidney, and pancreas survivals were 94%, 86%, and 85% at five years (Kaplan-Meier), with a mean follow-up of 4.3 years. The 3 deaths were due to 2 sudden arrests at home (presumed to be cardiac events) and 1 episode of sepsis. Other graft losses were due to rejection, except for one case of sepsis. The remaining patients are normoglycemic (glucose 92 +/- 23 mg/dl) and have a creatinine of 1.8 +/- 0.6 mg/dl. Mortality after the first year was 0.9%/year. Estimated kidney and pancreas half-lives were 15 +/- 2 and 23 +/- 7 years, respectively. Hospitalization, acute rejection, graft pancreatitis, dehydration, and severe infections all decreased dramatically after the first year. While CMV was the most common infection in the first year, foot infections predominated thereafter. Retinal hemorrhage was infrequent. Sudden death (presumably cardiac) was the chief cause of mortality, while peripheral vascular disease resulted in several amputations. Fractures were common, suggesting the need for increased attention to bone demineralization. Psychosocial and quality of life evaluations were within normal limits. In conclusion, most complications specifically related to transplantation occur in the first year, but underlying disease renders these patients susceptible to a variety of cardiovascular, bone, and other disorders.

The role of CD8 and CD4 T cells in intestinal allograft rejection: a comparison of monoclonal antibody-treated and knockout mice.

BACKGROUNDnThe relative contribution of CD8 and CD4 T cells to allograft rejection remains an unresolved issue. Experimental results suggest that the relative importance of these T-cell subsets may vary depending on the model used and the organ studied. We have previously shown that treatment of murine recipients of intestinal allografts with a depleting anti-CD8 or a depleting anti-CD4 monoclonal antibody (mAb) significantly inhibited allograft rejection. This study was undertaken to further examine the contribution of CD8 and CD4 T cells to the rejection of intestinal allografts.nnnMETHODSnIntestinal allografts from B6C3F1/J (C57BL/6 x C3H/HeJ) mice were transplanted into C57BL/6 recipients. Recipient groups included mice with an acquired deficiency in CD8 or CD4 T cells caused by treatment with depleting mAb or mice genetically deficient in CD8 or CD4 T cells as a result of disruption of the genes encoding major histocompatibility complex (MHC) class I, MHC class II, CD8, or CD4. In all cases, rejection was assessed histologically at predetermined time points. In some recipient groups, graft function was also assessed using a maltose absorption assay.nnnRESULTSnRejection, assessed between days 10 and 28 after transplantation, was significantly inhibited in mice deficient in CD8 or CD4 T cells after treatment with depleting mAb. In contrast, mice genetically deficient in either CD8 T cells (MHC class I or CD8 knockouts) or CD4 T cells (MHC class II or CD4 knockouts) rejected intestinal allografts promptly. Both histologic and functional evaluation of anti-CD8 mAb-treated mice on day 60 showed that the inhibition of rejection persisted even after the return of a substantial number of CD8 T cells. Although intestinal allografts from anti-CD8 mAb-treated mice displayed little to no evidence of rejection on day 60 after transplantation, these mice were able to reject both donor and third-party skin grafts.nnnCONCLUSIONSnThese results demonstrate that the inhibition of intestinal allograft rejection associated with mAb treatment is not attributable solely to depletion of CD8 or CD4 T cells. Furthermore, anti-CD8 mAb administration did not induce donor-specific tolerance or cause nonspecific immune suppression, as indicated by the skin-grafting experiments. Our findings suggest that at least some depleting mAbs mediate their protective effect on allograft rejection via an alternative mechanism such as the induction of a regulatory cell population(s).