Faculty Bibliography

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.

We evaluated a technique for implantation of right kidneys with short renal veins without the need for venous reconstruction. METHOD: The technique of iliac vein transposition was performed in six recipients who received right kidneys with short renal veins. Two cases were living related donors, two were living unrelated, one was an autotransplant, and one was a cadaver kidney recipient. The common and external iliac veins and arteries of the recipient were thoroughly mobilized, allowing for the lateral transposition of the external iliac vein with respect to the external iliac artery. The renal vessels were subsequently implanted in an end to side fashion onto the corresponding transposed external iliac vessels. After implantation, the iliac vein remained lateral with respect to the iliac artery. CONCLUSIONS: The technique described allows for the implantation of right kidneys without the need for venous reconstruction. Such an approach is especially useful in cases of grafts with short veins.

Many facets of accommodation have been explored since this process was first observed in ABO-incompatible renal allografts over 17 years ago. Intriguing new pieces of the puzzle have emerged to be fitted into the picture in several places. For example, vascular endothelial cells can be stimulated to secrete substantial amounts of blood group A and B antigens linked to von Willebrand factor; the antibody response to A and B antigens stimulated by ABO-incompatible renal allografts can show epitope spreading; complement can inhibit inflammation through actions of some complement split products, particularly iC3b and C3a; endothelial cells can upregulate various cytoprotective mechanisms; and clinically, new protocols for achieving accommodation have been implemented with improved results.

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.

OBJECTIVE: To review a single-institution 6-year experience with laparoscopic live donor nephrectomy detailing the technical modifications, clinical results, as well as the trends in donor and recipient morbidity. SUMMARY BACKGROUND DATA: Since 1995, laparoscopic donor nephrectomy has had a significant impact on the field of renal transplantation, resulting in decreased donor morbidity, without jeopardizing procurement of a high-quality renal allograft. This technique has become the preferred method of allograft procurement for many transplantation centers worldwide but still remains technically challenging with a steep learning curve. METHODS: Records from 381 consecutive laparoscopic donor nephrectomies were reviewed with evaluation of both donor and recipient outcomes. Trends in donor and recipient complications were assessed over time by comparing the outcomes between four equally divided groups. RESULTS: All 381 kidneys were procured and transplanted successfully with only 8 (2.1%) open conversions. Mean operative time was 252.9 +/- 55.7 minutes, estimated blood loss 344.2 +/- 690.3 mL, warm ischemia time 4.9 +/- 3.4 minutes, and donor length of stay was 3.3 +/- 4.5 days. There was a significant decline in total donor complications, allograft loss, and rate of vascular thrombosis with experience. The rate of ureteral complications declined significantly when comparing our early (Group A) versus later (Groups B-D) experience. CONCLUSION: Laparoscopic donor nephrectomy has remained a safe, less invasive, and effective technique for renal allograft procurement. Over our 6-year experience and with specific refinements in surgical technique, we have observed a decline in both donor and recipient morbidity following laparoscopic live donor nephrectomy

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.

During the past few decades, much of the experimental and clinical effort in solid-organ transplantation has been directed toward ameliorating or abrogating T-cell-mediated responses. As a result, universally understood and accepted nomenclature and diagnostic criteria have evolved. Humoral immunity in transplantation has yet to undergo a similar renaissance. Readers of transplant journals regularly find it difficult and often impossible to interpret data on the diagnosis and management of antibody-mediated rejection. The Antibody Working Group was assembled in an attempt to provide guidelines for the standardization of nomenclature, diagnostic criteria, reporting, antibody profiling, and risk assessment.

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.