Faculty Bibliography

CONTEXT: First proposed 2 decades ago, live kidney paired donation (KPD) was considered a promising new approach to addressing the shortage of organs for transplantation. Ethical, administrative, and logistical barriers initially proved formidable and prevented the implementation of KPD programs in the United States. OBJECTIVE: To determine the feasibility and effectiveness of KPD for the management of patients with incompatible donors. DESIGN, SETTING, AND PATIENTS: Prospective series of paired donations matched and transplanted from a pool of blood type or crossmatch incompatible donors and recipients with end-stage renal disease (6 conventional and 4 unconventional KPD transplants) at a US tertiary referral center (between June 2001 and November 2004) with expertise in performing transplants in patients with high immunologic risk. INTERVENTION: Kidney paired donation and live donor renal transplantation. MAIN OUTCOME MEASURES: Patient survival, graft survival, serum creatinine levels, rejection episodes. RESULTS: A total of 22 patients received transplants through 10 paired donations including 2 triple exchanges at Johns Hopkins Hospital. At a median follow-up of 13 months (range, 1-42 months), the patient survival rate was 100% and the graft survival rate was 95.5%. Twenty-one of the 22 patients have functioning grafts with a median 6-month serum creatinine level of 1.2 mg/dL (range, 0.8-1.8 mg/dL) (106.1 micromol/L [range, 70.7-159.1 micromol/L]). There were no instances of antibody-mediated rejection despite the inclusion of 5 patients who were highly sensitized to HLA antigens due to previous exposure to foreign tissue. Four patients developed acute cellular rejection (18%). CONCLUSIONS: This series of patients who received transplants from a single-center KPD pool provides evidence that recipients with incompatible live donors, even those with rare blood type combinations or high degrees of HLA antigen sensitization, can receive transplants through KPD with graft survival rates that appear to be equivalent to directed, compatible live donor transplants. If these results can be generalized, broader availability of KPD to the estimated 6000 patients with incompatible donors could result in a large expansion of the donor pool

Early and accurate detection of acute cellular rejection (ACR) is important in the management of liver allograft recipients. We hypothesized that expression of allograft inflammatory factor (AIF)-1 would be associated with liver allograft rejection as previous studies have shown that a relationship exists between kidney and heart transplantation. Indeed using rat orthotopic transplant models we found that the expression of allograft inflammatory factor-1 (AIF-1) can be detected in both allograft and peripheral blood leukocytes with peak levels detected 7 days following liver transplantation. Interestingly, AIF-1 expression increased 2-fold in acutely rejecting liver allografts compared to chronically accepted livers on days 5, 7 and 10 after transplantation. AIF-1 expression in peripheral blood leukocytes was also significantly greater in the rejection model than in the acceptance model. Flow cytometric analysis of peripheral blood leukocytes demonstrated that AIF-1 was expressed in ED2-positive cells, a marker for Kupffer cells. In vitro studies showed that AIF-1 expression in Kupffer cells was up-regulated by coculture with Th1 cytokines. However, neither LPS nor Escherichia coli (E. coli) administration had an affect on AIF-1 expression. These data indicate that high levels of AIF-1 expression reflect aggressive liver allograft rejection and suggest a role for monitoring AIF-1 in peripheral blood leukocytes as a monitor for increased immunosuppression.

An increasing number of individuals with end-stage renal disease have become sensitized to human leukocyte antigens (HLA). Sensitization can have a profound impact on the likelihood of obtaining a requisite negative crossmatch (-XM) with a potential donor. Technologic breakthroughs in our ability to diagnose antibody-mediated rejection (AMR) and monitor anti-HLA antibodies has set the stage for a renascence in the understanding and treatment of individuals who harbor donor-specific antibody (DSA). Promising early results from single institutions that have developed preconditioning protocols allowing successful transplantation of XM (+) patients have encouraged other centers to adopt these protocols. Sensitized patients represent a great challenge for the clinician and there is much that remains unknown about the assessment and treatment of these patients. We have successfully preconditioned and transplanted more than 80 patients over a 5-yr period. As our understanding of these patients has increased, we have progressed from a 'one size fits all' approach to therapy to more rational, individualized treatment plans that take into account the varying immunologic risk that each patient possesses. In this article we have summarized our evolving experience with the assessment, treatment, transplantation, and monitoring of patients who undergo preconditioning for a (+) XM with a live donor.

BACKGROUND: Perioperative treatment with plasmapheresis and intravenous immunoglobulin (IVIG), combined with a tacrolimus-based immunosuppressive regimen, has been used successfully to allow renal transplantations in cross-match-positive recipients. A common finding in biopsy specimens of these allografts is isometric vacuolization of proximal tubular epithelium. This finding presents a diagnostic dilemma because it may occur secondary to IVIG treatment or tacrolimus nephrotoxicity. METHODS: We compared the frequency and severity of isometric tubular vacuolization in renal allograft biopsy specimens obtained during the first 10 days after transplantation in 24 patients who received one or more postoperative treatments with IVIG (100 mg/kg; as part of a desensitization protocol also involving plasmapheresis) with specimens obtained in 91 patients who did not receive IVIG. All patients received tacrolimus. Isometric vacuolization was graded on a 0 to 4 scale based on the fraction of proximal tubules involved: 0, none; 1, less than 10%; 2, 10% to 25%; 3, 26% to 50%; 4, more than 50%. RESULTS: There was a higher frequency of isometric tubular vacuolization (71 % vs. 31%) and more widespread involvement in patients who received IVIG and tacrolimus versus tacrolimus alone, although mean tacrolimus levels were not significantly different between these groups. In control, but not IVIG, biopsy specimens, there was a significant association between vacuolization score and blood tacrolimus level on the day of biopsy. CONCLUSIONS: Isometric tubular vacuolization is a common finding in renal transplant biopsy specimens of patients who receive low-dose IVIG and in many cases is likely to be related, at least in part, to IVIG. In these patients, this finding should not necessarily be interpreted as indicative of tacrolimus (or cyclosporine) nephrotoxicity.

The majority of preconditioning protocols developed to allow ABO-incompatible (ABOi) renal transplantation include concurrent splenectomy as a prerequisite to successful engraftment. Our center has developed a preconditioning protocol that includes plasmapheresis (PP), low-dose CMV hyperimmune globulin (CMVIg), and anti-CD20 monoclonal antibody (rituximab) to allow ABOi renal transplantation without splenectomy. Our initial experience has included treatment of six recipients and successful transplantation from blood group A(1), A(2), and group B living donors. Mean (+/- SD) serum creatinine was 1.3 +/- 0.1 mg/dL among the six recipients and no episodes of antibody-mediated rejection (AMR) occurred at a median follow-up of 12 months. ABO antibody titers have remained below pretreatment levels. The absence of AMR and stable allograft function in this series show the potential of this preconditioning protocol to increase ABOi renal transplantation. The use of rituximab, allowing avoidance of splenectomy, may further remove one of the significant disincentives to ABOi transplantation, and eliminate the risk of post-splenectomy infections.

The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding humoral rejection. Though humoral rejection may result from different factors, discussion focused on a paradigm caused by antibodies, typically against donor HLA antigens, leading to the term 'antibody-mediated rejection' (AMR). Conference deliberations were separated into four workgroups: The Profiling Workgroup evaluated strengths and limitations of different methods for detecting HLA reactive antibody, and created risk assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical, pathologic, and serologic criteria for assessing AMR in renal, heart and lung transplant recipients; The Treatment Workgroup discussed advantages, limitations and possible mechanisms of action for desensitization protocols that may reverse AMR; and The Basic Science Workgroup presented animal and human immunologic models for humoral rejection and proposed potential targets for future intervention. This work represents a comprehensive review with contributions from experts in the fields of Transplantation Surgery, Medicine, Pathology, Histocompatibility, Immunology, and clinical trial design. Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation.

We describe a case of West Nile virus encephalitis in a 54-year-old kidney transplant recipient. The clinical course was rapid and fatal. Serial CSF samples showed an evolving mononuclear pleiocytosis and serial MRIs showed increasing signs of cytotoxic edema in her basal ganglia. Seroepidemiological testing indicated that the infection was most likely acquired from transfusion of fresh frozen plasma at the time of transplantation.