Faculty Bibliography

Although the majority of deceased-donor kidneys are donated after brain death, increased recovery of kidneys donated after cardiac death could reduce the organ shortage and is now a national priority. Racial disparities in donations after brain death have been well described for renal transplantation, but it is unknown whether similar disparities occur in donations after cardiac death. In this study, outcomes of adult deceased-donor renal transplant recipients included in the United Network for Organ Sharing database (1993 through 2006) were analyzed. Among black recipients of kidneys obtained after cardiac death, those who received kidneys from black donors had better long-term graft and patient survival than those who received kidneys from white donors. In addition, compared with standard-criteria kidneys from white donors after brain death, kidneys from black donors after cardiac death conferred a 70% reduction in the risk for graft loss (adjusted hazard ratio 0.30; 95% confidence interval 0.14 to 0.65; P = 0.002) and a 59% reduction in risk for death (adjusted hazard ratio 0.41; 95% confidence interval 0.2 to 0.87; P = 0.02) among black recipients. These findings suggest that kidneys obtained from black donors after cardiac death may afford the best long-term survival for black recipients.

BACKGROUND: When the United Network for Organ Sharing changed its algorithm for liver allocation to the model for end-stage liver disease (MELD) system in 2002, highest priority shifted to patients with renal insufficiency as a major component of their end-stage liver disease. An unintended consequence of the new system was a rapid increase in the number of simultaneous liver-kidney transplants (SLK) being performed yearly. METHODS: Adult recipients of deceased donor liver transplants (LT, n=19,137), kidney transplants (n=33,712), and SLK transplants (n=1,032) between 1987 and 2006 were evaluated based on United Network for Organ Sharing data. Recipients were stratified by donor subgroup, MELD score, pre- versus post-MELD era, and length of time on dialysis. Matched-control analyses were performed, and graft and patient survival were analyzed by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: MELD era outcomes demonstrate a decline in patient survival after SLK. Using matched-control analysis, we are unable to demonstrate a benefit in the SLK cohort compared with LT, despite the fact that higher quality allografts are being used for SLK. Subgroup analysis of the SLK cohort did demonstrate an increase in overall 1-year patient and liver graft survival only in those patients on long-term dialysis (> or =3 months) compared with LT (84.5% vs. 70.8%, P=0.008; hazards ratio 0.57 [95% CI 0.34, 0.95], P=0.03). CONCLUSION: These findings suggest that SLK may be overused in the MELD era and that current prioritization of kidney grafts to those liver failure patients results in wasting of limited resources.

Many have reported success with ABO-incompatible kidney transplantation using B-cell ablative therapies such as anti-CD20 and splenectomy. However, splenectomy and anti-CD20 is associated with an increased risk of infection. We show how ABO-incompatible kidney transplants can be accomplished with a low risk of antibody-mediated rejection and graft loss using plasmapheresis preconditioning, low-dose intravenous immunoglobulin, and standard maintenance immunosuppression. The mean follow up for our cohort of 53 patients is 2 years. The mean creatinine clearance at 1 and 3 years is 58 mL/min and 63 mL/min, predicting excellent long-term function. Only long-term follow up of these patients will render definitive answers, however, these data demonstrate that ABO-incompatible kidney transplantation increases the donor pool by providing live donor kidneys that function promptly with minimal risk of early loss. This can be accomplished with a modest, brief escalation of immunosuppression and at a lower cost to the health care system than maintaining the patient on dialysis.

A deceased donor (DD) allocation system incorporating net life survival benefit has been proposed. In this system, many kidneys will be shifted to younger recipients, thereby decreasing their waiting times. The goal of this study was to determine the potential effects of altering waiting times on the likelihood of live donor kidney transplantation (LDKT). We analyzed 93,727 waiting list candidates to determine the association of various patient factors with likelihood of LDKT. The proportion of patients receiving LDKT was compared by the median DD waiting time at that patient's transplant center for someone of that patient's age category and race. LDKT was consistently higher as waiting times became longer. After adjusting for all other factors associated with likelihood of LDKT, waiting time remained a significant, independent predictor. Patients with the longest DD waiting times had 2.3-fold higher odds of LDKT (95% CI 2.11-2.58, p < 0.001). In planning the new DD allocation policy, we must account for resulting alterations in LDKT. It is possible that shifting DD kidneys to younger recipients may decrease LDKT or shift it to older recipients, net effects not consistent with the goal of net life survival benefit.

In kidney paired donation (KPD), incompatible pairs exchange kidneys so that each recipient receives a compatible organ. This modality is underutilized partly because of the difficulty of finding a suitable match among incompatible pairs. Alternatively, recipients with compatible donors might enter KPD arrangements in order to be matched with a donor predicted to give greater allograft durability or for other altruistic reasons. Using simulated donors and recipients, we investigated the impact of allowing recipients and their compatible donors to participate in KPD. For KPD programs of any size, the participation of compatible donor/recipient pairs nearly doubled the match rate for incompatible pairs (28.2% to 64.5% for single-center program, 37.4% to 75.4% for national program). Legal, logistical, and governmental controversies have hampered the expansion of KPD in the United States by delaying the creation of a national program. The inclusion of compatible pairs into small single-center pools could achieve match rates that would surpass that which could be realized by a national list made up of only incompatible pairs. This new paradigm of KPD can immediately be instituted at the single-center level, while the greatest gains will be achieved by incorporating compatible pairs into a national program.

We examined rejection outcome and graft survival in 58 adult patients with acute cellular rejection Banff type I (ARI) or II (ARII), within 1 year after transplantation, with or without CD20-positive infiltrates. Antibody-mediated rejection was not examined. Of the 74 allograft biopsies, performed from 1999 to 2001, 40 biopsies showed ARI and 34 biopsies showed ARII; 30% of all the biopsies showed CD20-positive clusters with more than 100 cells, 9% with more than 200 cells and 5% with more than 275 cells. Patients with B cell-rich (>100 or >200/HPF CD20-positive cells) and B cell-poor biopsies (<50 CD20-positive cells/HPF) were compared. Serum creatinine and eGFR of B cell-rich (CD20 > 100/HPF) and B cell-poor were not significantly different at rejection, or at 1, 3, 6 and 12 months, and during additional 3 years follow-up after rejection, although higher creatinine at 1 year was noted in the >200/HPF group. Graft survival was also not different between B cell-rich and B cell-poor groups (p = 0.8 for >100/HPF, p = 0.9 for >200/HPF CD20-positive cells). Our data do not support association of B cell-rich infiltrates in allograft biopsies and worse outcome in acute rejection type I or II, but do not exclude the possible contribution of B cells to allograft rejection.

Although donation after cardiac death (DCD) kidneys have a high incidence of delayed graft function (DGF) and have been considered marginal, no tool for stratifying risk of graft loss nor a specific policy governing their allocation exist. We compared outcomes of 2562 DCD, 62,800 standard criteria donor (SCD) and 12,812 expanded criteria donor (ECD) transplants reported between 1993 and 2005, and evaluated factors associated with risk of graft loss and DGF in DCD kidneys. Donor age was the only criterion used in the definition of ECD kidneys that independently predicted graft loss among DCD kidneys. Kidneys from DCD donors <50 had similar long-term graft survival to those from SCD (RR 1.1, p = NS). While DGF was higher among DCD compared to SCD and ECD, limiting cold ischemia (CIT) to <12 h decreased the rate of DGF 15% among DCD <50 kidneys. These findings suggest that DCD <50 kidneys function like SCD kidneys and should not be viewed as marginal or ECD, and further, limiting CIT <12 h markedly reduces DGF.

BACKGROUND: Differences in the antibody response to allogeneic transplantation exist between groups defined by race or gender. These differences may reflect differences in immune competency and/or exposure to alloantigens. We have investigated the frequencies and phenotypes of HLA-specific B cells to address those possibilities. METHODS: HLA-specific B cells were identified by staining with HLA tetramers (tet) as described previously and the distribution of CD27 and CD38 among those cells were measured in groups defined by various parameters. Possible correlation between frequencies of HLA-specific B cells and production of HLA-specific antibody after transplantation was also investigated. RESULTS: We found no correlation between the frequencies of CD27+tet+ (33%-44% vs. 34%-36%) or CD38+tet+ (57%-65% vs. 59%-66%) B cells and a previous mismatch for the HLA antigen of the tetramer. However, there was an increase in CD38+tet+ B cells among patients making antibody to the tetramer antigen (67%-72% vs. 53%-56%). Blacks had lower frequencies of CD27+ B cells than did whites (11.8% vs. 28.9%, P=0.003), but had greater increases of these cells among tet+ cells than did whites. There was a higher frequency of tet+ B cells among patients who developed "new" antibody to the HLA antigen (3.9%-8.6%) of the tetramer after transplantation than among those who did not (1.1%-3.7%). CONCLUSIONS: The phenotype of HLA-specific B cells reflects current or historic sensitization to HLA and may reflect inherent differences between groups defined by race and/or gender. The frequencies of HLA-specific B cells may predict patients at risk for production of donor-specific antibody after transplantation.

BACKGROUND: The development of highly sensitive and specific assays for detecting and characterizing HLA-specific antibodies has contributed to an appreciation of the extensive involvement of those antibodies in graft injury and dysfunction. However, understanding the regulatory processes of the humoral response to transplantation and the mechanisms underlying therapeutic agents and protocols for preventing and treating sensitization requires a way to study HLA-specific B cells. METHODS: Lymphocyte preparations enriched for B cells were stained with one or more of three different HLA tetramers. Tetramer-positive (tet+) B cells were enumerated and evaluated for an association of their frequencies with known sensitization. In some cases, tet+ B cells were isolated and placed in culture with supplements known to activate B cells in a nonspecific fashion. RESULTS: For all tetramers used, the frequencies of tet+ B cells were significantly higher (4.1%-5.5%) among sensitized patients than among nonsensitized patients (1.6%-3.2%, P<0.001). Binding of the tetramers occurred by the surface immunoglobulin antigen receptor with little or no binding to antibody captured in the Fc receptor. Cultured tet+ B cells produced antibodies specific for epitopes of the tetramer antigen. There appeared to be a certain amount of crossreactivity in the binding of tetramers. The frequency of CD27+ cells among tet+ B cells was higher, on average (34.4%-38.8%) than among all B cells (26.2%) whereas the frequencies of CD38 were comparable in the two groups. CONCLUSIONS: Staining with HLA tetramers provides a means for identifying, quantifying, and isolating HLA-specific B cells.