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

Most successful protocols for renal transplantation across ABO incompatible (ABOi) barriers have utilized splenectomy as part of the pre-conditioning process. We recently described successful ABOi transplantation using anti-CD20 monoclonal antibody in lieu of splenectomy. In the current study, we hypothesized that plasmapheresis (PP) and low dose CMV hyper-immunoglobulin (CMVIg) alone would be sufficient to achieve successful engraftment of ABOi kidneys. We describe four blood type incompatible patients who received live donor renal transplants from A1 (two patients), A2 (one patient), and B (one patient) donors. All patients started with antihuman globulin (AHG) phase titers of 64 or higher and were pre-conditioned with PP/CMVIg but not splenectomy or anti-CD20. All 4 patients underwent successful transplantation and have a mean current serum creatinine of 1.1 (range: 0.9-1.2). There were no episodes of antibody mediated rejection. Rapid allograft accommodation may limit the need for long-term antibody suppression provided by splenectomy or anti-CD20, thereby eliminating the added infectious risk of these modalities and removing another disincentive to ABOi transplantation.

A national kidney paired donation (KPD) program will substantially increase transplant opportunities for recipients with blood type incompatible or cross-match positive donors. It seems likely that donor-recipient pairs with certain blood types, races or restrictions will wait longer than others for a match, although no data exist to confirm this assumption. We simulated patients and characterized the predicted waiting times for different blood type sub-groups, as well as the effects of patient-imposed restrictions on waiting time. We also compared waiting times of different racial sub-groups. Almost all patients with panel-reactive antibody (PRA) less than 80% match within a few months in a national KPD program, with the longest waiting time seen by O recipients with AB donors. Highly sensitized patients wait considerably longer, especially those unwilling to travel or accept older donors, and those with AB or B donors may not match in a timely manner. Although patients are better served by matching in a combined pool than within their own race, racial inequalities exist and bonus points can offset some of these differences. These data provide the first waiting time predictions that can aid patients with incompatible donors in choosing between KPD and desensitization, and can also facilitate planning for a national KPD program.

BACKGROUND: Outcomes after kidney transplantation using deceased donors with high terminal creatinine are not well described but potentially represent an underutilized source of renal allografts. Utility of renal biopsy of these kidneys is similarly not well established. METHODS: To better understand the posttransplant function of kidneys from donors with high terminal creatinine, we reviewed our database of almost 500 cadaveric kidney transplants. We compared the 65 nonexpanded criteria donors with a final donor creatinine > or = 2.0 mg/dl (range 2.0-4.9 mg/dl) with kidneys procured from donors with terminal creatinine of <1.5. Biopsy results were correlated with graft function. RESULTS: Kidneys from deceased donors with high terminal creatinine performed as well as kidneys from donors with a normal terminal creatinine with respect to primary non-function, acute rejection, 6-year graft and patient survival, and function over the first 48 months. High creatinine kidneys with moderate or severe lesions on biopsy demonstrated poorer function at 6 months and 1 year as compared to those with mild or no histological lesions. CONCLUSIONS: Under select conditions, kidneys from donors with high terminal creatinine can be used safely with excellent results.

The number of renal transplants can be increased by implementing an exchange program involving donor-recipient pairs for whom the donors are each incompatible with their original patient but compatible with each other's patient. The number can be further increased if the exchanges are not limited to ABO incompatible pairs or combinations of two donor-recipient pairs. However, as the number of donor-recipient pairs willing to participate in such a program increases, there is a substantial increase in both the time taken to identify such matches and the potential for error. We have developed a computer program that accounts for ABO and HLA compatibility and is not limited to two-way exchanges. With our database of 60 patients and 83 donors, we have been able to identify 122 two-way and 1230 three-way exchanges with an average run time of 30 s.

Options for utilizing live donor kidneys from those who are blood type incompatible or crossmatch positive with their intended recipients include kidney paired donation (KPD), list paired donation (LPD) and desensitization. KPD provides live donor kidneys for both recipients but requires a match to another incompatible pair, while LPD utilizes the deceased donor pool but is restricted by ethical and logistic concerns. We simulated patients and their potential donors to determine which recipients could receive a kidney through KPD and LPD. With smaller populations (100 pairs or fewer), more kidneys were matched through LPD, although the greatest benefit was derived from a combination of LPD and KPD. With increasing population sizes, more patients were matched through KPD, including almost all patients who would have been eligible for LPD. At population sizes predicted to be achieved by a national paired donation system, the role of LPD became minimal, with only 3.9% of pairs unmatched through KPD eligible for LPD. Considerable overlap was seen between the pairs unmatchable by KPD and those ineligible for LPD, namely less-demanded donors and hard-to-match recipients. For this population, the best option may be desensitization.

An orthotopic liver transplant model in the rat was used to evaluate the role of tumor necrosis factor alpha (TNF-alpha) in liver transplant rejection. There were significantly increased levels of TNF-alpha mRNA and parallel increases in 8-hydroxy-2' deoxyguanosine (8-OHdG) indicative of oxidative DNA damage present 7 to 12 days after transplantation. Cells staining positively for 8-OHdG were localized to the cytoplasm of hepatocytes adjacent to the TNF-alpha expressing inflammatory cells in the portal areas or in patches surrounded by inflammatory cells in the hepatic sinusoids. Significantly more cells staining for 8-OHdG were found in the allogeneic grafts that were strongly rejected than in the syngeneic controls or in the grafts placed in species that accepted the allograft permanently after a rejection episode. TUNEL reactivity lagged 2 days behind peak reactivity for 8-OHdG. On day 12 after transplantation, many cells stained for both 8-OHdG and TUNEL, indicating that the cells suffering oxidative DNA injury were undergoing apoptosis or death. Oxidative injury resulted in mtDNA deletion consisting of 4,834 base-pairs. Studies of hepatocytes cultured from normal rats displayed dose-dependent relationships between TNF-alpha concentration and 8-OHdG and mtDNA mutation. Repetitive intraperitoneal injection of Enbrel, a TNF receptor blocker, significantly decreased hepatocyte 8-OHdG levels and the frequency of deleted mtDNA while greatly extending graft survival time. In conclusion, the data presented implicate TNF-alpha as being capable of causing oxidative DNA damage and mtDNA mutation in hepatocytes.

Antibody-mediated barriers to renal transplantation, including donor specific anti-HLA and anti-blood group antibodies, have become an increasingly important issue over the last forty years as the organ shortage has continued to expand. The inevitable result of the unmet demand for compatible organs has been a continuous increase in recipient waiting times. Over the last decade, two treatment strategies have been developed to address this problem. These regimens rely on the immunomodulatory properties of intravenous immunoglobulin (IVIG) administered alone at relatively high doses, or at lower doses in combination with the non-selective depletion of antibodies from plasmapheresis. Both protocols have been successfully used for desensitization of patients with donor-specific anti-HLA antibody and have allowed for renal transplantation with excellent outcomes. The combined strategy of plasmapheresis/IVIG has also been successfully employed for renal transplantation in recipients of ABO blood group incompatible kidneys. This review will provide an overview of these therapies and their application to incompatible renal transplantation.

CONTEXT: Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE: To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION: We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES: Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS: A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS: The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably.

Antibody to donor HLA antigens is a significant barrier to both access to and outcome of allogeneic transplants. Many attempts have been made to desensitize patients with HLA-specific antibody, but the most effective and durable have been treatment with high-dose pooled human intravenous immunoglobulin (IVIg) and a combination of plasmapheresis and low-dose IVIg. Despite the success of these treatments, low levels of donor-specific antibody (DSA) persist in some patients. We examined factors that may be related to and used to predict the elimination of DSA. The most significant associations have been strength of antibody at initiation of treatment and antibody specificity, although other factors revealed a trend toward association. We demonstrate how the types of data generated here can be used to predict elimination or persistence of DSA.