Faculty Bibliography

Efforts to expand kidney paired donation have included matching nondirected donors (NDDs) to incompatible pairs. In domino paired donation (DPD), an NDD gives to the recipient of an incompatible pair, beginning a string of simultaneous transplants that ends with a living donor giving to a recipient on the deceased donor waitlist. Recently, nonsimultaneous extended altruistic donor (NEAD) chains were introduced. In a NEAD chain, the last donor of the string of transplants initiated by an NDD is reserved to donate at a later time. Our aim was to project the impact of each of these strategies over 2 years of operation for paired donation programs that also allocate a given number of NDDs. Each NDD facilitated an average of 1.99 transplants using DPD versus 1.90 transplants using NEAD chains (p = 0.3), or 1.0 transplants donating directly to the waitlist (p < 0.001). NEAD chains did not yield more transplants compared with simultaneous DPD. Both DPD and NEAD chains relax reciprocality requirements and rebalance the blood-type distribution of donors. Because traditional paired donation will leave many incompatible pairs unmatched, novel approaches like DPD and NEAD chains must be explored if paired donation programs are to help a greater number of people.

BACKGROUND: Thousands of patients with chronic renal failure die yearly without a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to permit ABO-incompatible (ABO-I) kidney transplants, but little is known about how well TPE reduces ABO antibodies or complications related to TPE in this clinical setting. STUDY DESIGN AND METHODS: This retrospective study evaluated 46 individuals that received TPE to permit ABO-I kidney transplant. The number of TPE treatments was based on a goal ABO titer at the anti-human globulin (AHG) phase of 16 or less before surgery. RESULTS: Before TPE, the median titer of recipient was 32 (range, 2-128) at room temperature (RT) phase and 64 (range, 4-1024) at AHG phase. The first TPE reduced the total agglutination reactivity score at AHG phase by 10.2 percent. Before transplantation, there was a mean of 6.2 +/- 2.5 TPE treatments and total agglutination reactivity score at AHG phase was reduced by 53.5 percent. The median titer remained reduced at 3 to 6 months after transplantation at 4 (range, 0-64) at RT phase and 8 (range, 1-64) at AHG phase. TPE complications were minimal. During at least one procedure, 15 (32.6%) individuals had either urticaria or pruritus, 18 (39.1%) individuals experienced mild citrate-induced hypocalcemia, 5 (10.2%) individuals had hypotension, 6 (13.0%) individuals had nausea or vomiting, and 1 (2.2%) individual had West Nile virus encephalitis. CONCLUSIONS: With current infectious disease blood screening protocols, TPE has minimal complications and can reduce ABO antibody titers to permit ABO-I renal transplantation.

BACKGROUND: Desensitization protocols, which frequently use lymphocyte depleting agents have increased access to successful transplantation for sensitized candidates. Here, we report on the reconstitution of human leukocyte antigen (HLA)-specific B lymphocytes in renal transplant patients after treatment with B-lymphocyte depletion. METHODS: Sixteen renal transplant candidates were included in the study. Eleven patients were treated with anti-CD20 monoclonal antibody (Ab), four of whom also underwent splenectomy perioperatively. Five patients who did not undergo B-cell depletion were studied as controls. Blood samples were obtained before any treatment and transplant, and at later time points up to 44 months posttransplant. HLA-specific B-cell subpopulations were identified by staining with fluorochrome-labeled HLA tetramers and anti-CD19, CD27, and CD38 monoclonal Abs. RESULTS: Total circulating B lymphocytes repopulated within 12 months post-B-cell depletion. The majority of the recovering cells had the phenotype of transitional CD38 B cells and the percentages of mature, memory CD27 B cells remained significantly depressed. There was a sustained reduction in the proportion of HLA-specific CD27 memory B cells, whereas the HLA-specific CD38 B-cell population returned to near pretreatment levels by 12 months. The presence of mismatched HLA antigens seemed to affect the reconstitution kinetics. The delay in reconstitution of HLA-specific CD27 memory B cells was greater for donor-specific compared with third party. CONCLUSIONS: A delay in functional maturity of repopulating HLA-specific B cells, and in particular those specific for donor HLA, after B-lymphocyte depletion treatment in renal transplant recipients may contribute to the efficacy of desensitization protocols.

Fears of infectious transmission from CDC high-risk donors (HRDs) remain a significant disincentive, and the potential for human immunodeficiency virus/hepatitis C virus (HIV/HCV) nucleic acid testing (NAT) to allay these fears remains unstudied. We hypothesized that NAT, which narrows the window period between infection and detectability compared to the standard ELISA, might lead to increased provider willingness to use HRDs. Between January and April 2008, we performed two national surveys: one of current NAT practice among organ procurement organizations (OPOs); a second of HRD use among transplant surgeons. Surgeons who reported accepting 10% or more offers for a given HRD behavior and organ type were classified as 'high utilizers' of that subgroup. We built hierarchical models to examine associations between OPO NAT performance and provider utilization. Providers who ranked medical risks of HIV or HCV as important disincentives to HRD use had significantly lower odds of being high utilizers (HIV odds ratio 0.22, HCV odds ratio 0.41, p < 0.005). Furthermore, both HIV and HCV NAT performance were associated with significantly higher odds of being high utilizers (HIV odds ratio 1.58, HCV 2.69, p < 0.005). The demonstrated associations between OPO NAT performance and high provider utilization of HRDs should be considered in the ongoing debate about NAT in transplantation.

Single-center studies have reported equivalent outcomes of kidney allografts recovered with histidine-tryptophan-ketoglutarate (HTK) or University of Wisconsin (UW) solution. However, these studies were likely underpowered and often unadjusted, and multicenter studies have suggested HTK preservation might increase delayed graft function (DGF) and reduce graft survival of renal allografts. To further inform clinical practice, we analyzed the United Network for Organ Sharing (UNOS) database of deceased donor kidney transplants performed from July 2004 to February 2008 to determine if HTK (n = 5728) versus UW (n = 15 898) preservation impacted DGF or death-censored graft survival. On adjusted analyses, HTK preservation had no effect on DGF (odds ratio [OR] 0.99, p = 0.7) but was associated with an increased risk of death-censored graft loss (hazard ratio [HR] 1.20, p = 0.008). The detrimental effect of HTK was a relatively late one, with a strong association between HTK and subsequent graft loss in those surviving beyond 12 months (HR 1.43, p = 0.007). Interestingly, a much stronger effect was seen in African-American recipients (HR 1.55, p = 0.024) than in Caucasian recipients (HR 1.18, p = 0.5). Given recent studies that also demonstrate that HTK preservation reduces liver and pancreas allograft survival, we suggest that the use of HTK for abdominal organ recovery should be reconsidered.

The requirements for potent immunosuppression coupled with the formidable risk of irreversible antibody-mediated rejection (AMR) have thus far limited the expansion of ABO incompatible (ABOi) kidney transplantation. We present a retrospective review of our single-center experience with 60 consecutive ABOi kidney transplants and describe the evolution of our treatment protocol to one that consists only of a brief escalation in immunosuppression without long-term B-cell suppression from splenectomy or anti-CD20. The 1-, 3-, and 5-year graft survival rates for the cohort were 98.3%, 92.9%, and 88.7%, respectively, which is comparable with United Network for Organ Sharing data for compatible live donor transplants. No instances of hyperacute rejection were observed, and no grafts were lost secondary to AMR. In fact, fewer than 15% of the patients experienced a clinical episode of AMR, and rejections were mild. Elimination of B-cell ablative therapies did not result in an increased incidence of AMR. Excellent graft function persists with a current median creatinine clearance of 60 mL/min. The findings of this study and the relatively simple therapeutic regimen used should facilitate widespread application of ABOi kidney transplantation resulting in one of the most rapid escalations in access to organs in the modern era of kidney transplantation.

BACKGROUND: The purpose of this study was to examine the incidence of oxalate deposits in native and renal allograft biopsies, and its impact on graft function. METHODS: The renal biopsy files at The Johns Hopkins University between 2000 and 2006 were searched to identify biopsies with oxalate deposits, determine the density of oxalate deposits in renal graft biopsies, compare graft histology and function between allograft recipients with oxalate in the graft biopsies, and a control group of recipients without oxalate in the graft. RESULTS: Oxalate crystal deposits were observed in 61 of 5160 biopsies of native kidneys, and in 76 of 1621 renal allograft biopsies, with a frequency of 1 and 4%, respectively. Sixty-three (9%) of 680 transplant recipients showed oxalate in graft biopsies obtained within the first year from transplantation, with 1.3 +/- 1.2 average number of oxalate deposits per mm(2) of biopsy tissue. The high oxalate density and decreased renal function were correlated in the first 2 years post-transplant (P = 0.037-0.05). Compared with a control group of 70 kidney graft recipients, the renal function was significantly lower in the oxalate group at 1 year, but not at 2 years post-transplant. High tubulo-interstitial scarring (P < 0.0001) was noted in repeated biopsies in the oxalate group, and was significantly greater than that in the control group (P = 0.027). No significant difference in graft loss was observed between oxalate and control groups, and although mortality was higher in the oxalate group, the difference was not significant. CONCLUSIONS: In summary, this study defines the frequency of oxalate deposition in native and allograft kidney biopsies, and suggests its possible negative impact on graft function beyond the early post-transplant period.

We report a chain of 10 kidney transplantations, initiated in July 2007 by a single altruistic donor (i.e., a donor without a designated recipient) and coordinated over a period of 8 months by two large paired-donation registries. These transplantations involved six transplantation centers in five states. In the case of five of the transplantations, the donors and their coregistered recipients underwent surgery simultaneously. In the other five cases, "bridge donors" continued the chain as many as 5 months after the coregistered recipients in their own pairs had received transplants. This report of a chain of paired kidney donations, in which the transplantations were not necessarily performed simultaneously, illustrates the potential of this strategy.

Outcomes after heart and lung transplants have improved, and many recipients survive long enough to develop secondary renal failure, yet remain healthy enough to undergo kidney transplantation. We used national data reported to United Network for Organ Sharing (UNOS) to evaluate outcomes of 568 kidney after heart (KAH) and 210 kidney after lung (KAL) transplants performed between 1995 and 2008. Median time to kidney transplant was 100.3 months after heart, and 90.2 months after lung transplant. Renal failure was attributed to calcineurin inhibitor toxicity in most patients. Outcomes were compared with primary kidney recipients using matched controls (MC) to account for donor, recipient and graft characteristics. Although 5-year renal graft survival was lower than primary kidney recipients (61% KAH vs. 73.8% MC, p < 0.001; 62.6% KAL vs. 82.9% MC, p < 0.001), death-censored graft survival was comparable (84.9% KAH vs. 88.2% MC, p = 0.1; 87.6% KAL vs. 91.8% MC, p = 0.6). Furthermore, renal transplantation reduced the risk of death compared with dialysis by 43% for KAH and 54% for KAL recipients. Our findings that renal grafts function well and provide survival benefit in KAH and KAL recipients, but are limited in longevity by the general life expectancy of these recipients, might help inform clinical decision-making and allocation in this population.

Women have less access to kidney transplantation than men, but the contributions of age and comorbidity to this disparity are largely unknown. We conducted a national cohort study of 563,197 patients with first-onset ESRD between 2000 and 2005. We used multivariate generalized linear models to evaluate both access to transplantation (ATT), defined as either registration for the deceased-donor waiting list or receiving a live-donor transplant, and survival benefit from transplantation, defined as the relative rate of survival after transplantation compared with the rate of survival on dialysis. We compared relative risks (RRs) between women and men, stratified by age categories and the presence of common comorbidities. Overall, women had 11% less ATT than men. When the model was stratified by age, 18- to 45-yr-old women had equivalent ATT to men (RR 1.01), but with increasing age, ATT for women declined dramatically, reaching a RR of 0.41 for those who were older than 75 yr, despite equivalent survival benefits from transplantation between men and women in all age subgroups. Furthermore, ATT for women with comorbidities was lower than that for men with the same comorbidities, again despite similar survival benefits from transplantation. This study suggests that there is no disparity in ATT for women in general but rather a marked disparity in ATT for older women and women with comorbidities. These disparities exist despite similar survival benefits from transplantation for men and women regardless of age or comorbidities.