Faculty Bibliography

HYPOTHESIS: The use of kidneys from deceased donors considered at increased infectious risk represents a strategy to increase the donor pool. DESIGN: Single-institution longitudinal observational study. SETTING: Tertiary care center. PATIENTS: Fifty patients who gave special informed consent to receive Centers for Disease Control and Prevention high-risk (CDCHR) donor kidneys were followed up by serial testing for viral transmission after transplantation. Nucleic acid testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus was performed on all high-risk donors before transplantation. Outcomes of CDCHR kidney recipients were compared with outcomes of non-high-risk (non-HR) kidney recipients. MAIN OUTCOME MEASURES: New viral transmission, graft function, and waiting list time. RESULTS: No recipient seroconversion was detected during a median follow-up period of 11.3 months. Compared with non-HR donors, CDCHR donors were younger (mean [SD] age, 35 [11] vs 43 [18] years, P = .01), fewer were expanded criteria donors (2.0% vs 24.8%, P < .001), and fewer had a terminal creatinine level exceeding 2.5 mg/dL (4.0% vs 8.8%, P = .002). The median creatinine levels at 1 year after transplantation were 1.4 (interquartile range, 1.2-1.7) mg/dL for CDCHR recipients and 1.4 (interquartile range, 1.1-1.9) mg/dL for non-HR recipients (P = .4). Willingness to accept a CDCHR kidney significantly shortened the median waiting list time (274 vs 736 days, P < .001). CONCLUSIONS: We show safe use of CDCHR donor kidneys and good 1-year graft function. With continued use of these organs and careful follow-up care, we will be better able to gauge donor risk and match it to recipient need to expand the donor pool and optimize patient benefit.

BACKGROUND AND OBJECTIVES: Kidney transplantation from donors after cardiac death (DCD) provides similar graft survival to donors after brain death (DBD) in adult recipients. However, outcomes of DCD kidneys in pediatric recipients remain unclear, primarily because of limited sample sizes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We identified 137 pediatric (<18 years old) recipients of DCD kidneys between 1994 and 2010 using Scientific Registry of Transplant Recipients data and compared outcomes with 6059 pediatric recipients of DBD kidneys during the same time period, accounting for donor, recipient, and transplant characteristics using time-varying Cox regression and matched controls. Long-term follow-up (4 years or beyond) was available for 31 DCD recipients. RESULTS: Pediatric recipients of DCD kidneys experienced a significantly higher rate of delayed graft function (22.0% versus 12.3%; P = 0.001), although lower than reported delayed graft function rates of DCD grafts in adults. Although DCD and DBD graft survival was equal in the early postoperative period, graft loss among pediatric recipients of DCD kidneys exceeded their DBD counterparts starting 4 years after transplantation. This effect was statistically significant in a multivariate Cox model (hazard ratio = 2.03; 95% confidence interval, 1.21 to 3.39; P = 0.007) and matched-controls analysis (hazard ratio = 2.36; 95% confidence interval, 1.11 to 5.03; P = 0.03). CONCLUSIONS: A significant increase in DCD graft loss starting 4 years after transplantation motivates a cautious approach to the use of DCD kidneys in children, in whom long-term graft survival is of utmost importance.

Careful examination of liver, kidney and heart transplants in human recipients has revealed small numbers of host bone marrow derived stem cells in the graft. If the limited recipient repopulation of a donor graft that is currently observed could be facilitated, it is possible that conversion to a predominantly host phenotype would permit long-term graft function without immunosuppression. We proposed to "engineer" repopulation after transplant in a strain combination (dark agouti [DA] to Lewis green fluorescent protein+[LEW GFP+]) which rejects liver grafts strongly, a model that more closely resembles the situation in humans. Treatment on days 0, 1, 2, 3 and 7 after transplantation with low-dose (0.1 mg/kg) tacrolimus (T) designed to blunt rejection combined with plerixafor (P) to mobilize host stem cells resulted in greater than 180 days graft survival with extensive albeit spotty conversion of a small (50%) DA graft to the recipient LEW GFP+ genotype. Subsequent skin grafting revealed donor-specific graft prolongation. The T plus P treatment resulted in higher levels of Lin-Thy1+CD34+CD133+ stem cells and Foxp3+ regulatory T cells in the blood and liver at day 7. Thus, pharmacological mobilization of host stem cells sustains liver allografts by two mechanisms: repopulation of injured donor cells and regulation of the immune response.

CONTEXT: Many studies have reported that black individuals undergoing dialysis survive longer than those who are white. This observation is paradoxical given racial disparities in access to and quality of care, and is inconsistent with observed lower survival among black patients with chronic kidney disease. We hypothesized that age and the competing risk of transplantation modify survival differences by race. OBJECTIVE: To estimate death among dialysis patients by race, accounting for age as an effect modifier and kidney transplantation as a competing risk. DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study of 1,330,007 incident end-stage renal disease patients as captured in the United States Renal Data System between January 1, 1995, and September 28, 2009 (median potential follow-up time, 6.7 years; range, 1 day-14.8 years). Multivariate age-stratified Cox proportional hazards and competing risk models were constructed to examine death in patients who receive dialysis. MAIN OUTCOME MEASURES: Death in black vs white patients who receive dialysis. RESULTS: Similar to previous studies, black patients undergoing dialysis had a lower death rate compared with white patients (232,361 deaths [57.1% mortality] vs 585,792 deaths [63.5% mortality], respectively; adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.83-0.84; P <.001). However, when stratifying by age and treating kidney transplantation as a competing risk, black patients had significantly higher mortality than their white counterparts at ages 18 to 30 years (27.6% mortality vs 14.2%; aHR, 1.93; 95% CI, 1.84-2.03), 31 to 40 years (37.4% mortality vs 26.8%; aHR, 1.46; 95% CI, 1.41-1.50), and 41 to 50 years (44.8% mortality vs 38.0%; aHR, 1.12; 95% CI, 1.10-1.14; P <.001 for interaction terms between race and each aforementioned age category), as opposed to patients aged 51 to 60 years (51.5% vs 50.9%; aHR, 0.93; 95% CI, 0.92-0.94), 61 to 70 years (64.9% vs 67.2%; aHR, 0.87; 95% CI, 0.86-0.88), 71 to 80 years (76.1% vs 79.7%; aHR, 0.85; 95% CI, 0.84-0.86), and older than 80 years (82.4% vs 83.6%; aHR, 0.87; 95% CI, 0.85-0.88). CONCLUSIONS: Overall, among dialysis patients in the United States, there was a lower risk of death for black patients compared with their white counterparts. However, the commonly cited survival advantage for black dialysis patients applies only to older adults, and those younger than 50 years have a higher risk of death.

BACKGROUND AND OBJECTIVES: Use of incompatible kidney transplantation (IKT) is growing as a response to the organ shortage and the increase in sensitization among candidates. However, recent regulatory mandates possibly threaten IKT, and the potential effect of these mandates cannot be estimated because dissemination of this modality remains unknown. The goal of this study was to better understand practice patterns of IKT in the United States. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Directors from all 187 unique active adult kidney transplant programs were queried about transplantation across the following antibody barriers: positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); positive cytotoxic crossmatch (PCC); and ABO incompatible (ABOi). RESULTS: Responses from 125 centers represented 84% of the live-donor transplant volume in the United States. Barriers of PLNF, PFNC, PCC, and ABOi are being crossed in 70%, 51%, 18%, and 24%, respectively, of transplant centers that responded. Desensitization was performed in 58% of PLNF, 76% of PFNC, 100% of PCC, and 80% of ABOi using plasmapheresis and low-dose intravenous Ig (IVIg) in 71% to 83% and high-dose IVIg in 29% to 46%. CONCLUSIONS: A higher proportion of centers perform IKT than might be inferred from the literature. The rapid dissemination of these protocols despite adequate evidence of a clear advantage of IKT transplants argues for the creation of a national registry and randomized studies.

PURPOSE OF REVIEW: Many sensitized patients have willing live donors but are unable to use them because of a human leukocyte antigen (HLA) incompatibility. The options for these patients include: remaining on the deceased-donor list, entering a kidney-paired donation scheme, or undergoing desensitization with high-dose IVIg or plasmapheresis and low-dose IVIg. RECENT FINDINGS: Mathematical simulations verified by actual data from several national kidney-paired donation (KPD) programs has shed light on which donor/recipient phenotypes are likely to benefit from each transplant modality. Pairs that are easy to match are likely to receive compatible kidneys in a KPD. Those who are hard to match may be better served by desensitization. The phenotype which is both hard to match and hard to desensitize due to board and strong HLA reactivity are most likely to be transplanted by a hybrid modality utilizing desensitization after identifying a more immunologically favorable donor in a KPD. SUMMARY: Recent outcomes from desensitization in which starting donor-specific antibody strength is low have been very good. For broadly sensitized patients with a high-strength cross-match, searching for a better donor in a KPD pool can facilitate a safer, less expensive, and more successful desensitization treatment course.

BACKGROUND: More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. METHODS: We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). RESULTS: In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). CONCLUSIONS: Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

Human immunodeficiency virus (HIV) is no longer a contraindication to transplantation. For HIV-infected patients, HIV-infected deceased donors (HIVDD) could attenuate the organ shortage and waitlist mortality. However, this practice would violate United States federal law. The goal of this study was to estimate the potential impact of legalizing transplantation of HIV-infected organs by quantifying the potential pool of HIVDD. Using Nationwide Inpatient Sample (NIS) data, HIV-infected deaths compatible with donation were enumerated. Using HIV Research Network (HIVRN) data, CD4 count, plasma HIV-1 RNA level, AIDS-defining illnesses and causes of death were examined in potential HIVDD. Using UNOS data, evaluated donors who later demonstrated unanticipated HIV infections were studied. From NIS, a yearly average of 534 (range: 481-652) potential HIVDD were identified, with 63 (range: 39-90) kidney-only, 221 (range: 182-255) liver-only and 250 (range: 182-342) multiorgan donors. From HIVRN, a yearly average of 494 (range: 441-533) potential HIVDD were identified. Additionally, a yearly average of 20 (range: 11-34) donors with unanticipated HIV infection were identified from UNOS. Deceased HIV-infected patients represent a potential of approximately 500-600 donors per year for HIV-infected transplant candidates. In the current era of HIV management, a legal ban on the use of these organs seems unwarranted and likely harmful.

BACKGROUND: Kidney transplants from pediatric donors after cardiac death (PDCD) have quadrupled in the past 9 years, but little data exist on outcomes using these donors. We hypothesized that pediatric organs might be more sensitive to the pathophysiology of cardiac death. METHODS: We evaluated outcomes and rates of discard of more than 12,000 pediatric kidneys recovered between 2000 and 2009. We compared short- and long-term graft function among adult and pediatric recipients of PDCD kidneys compared with recipients of pediatric kidneys from donors after brain death (PDBD). RESULTS: Overall, 6.3% of pediatric kidneys recovered were PDCD and 93.7% were PDBD. Discard rates were higher for PDCD kidneys (adjusted odds ratio=1.69, 95% confidence interval [CI]=1.31-2.18, P<0.001). Delayed graft function (DGF) was twice as common in recipients of PDCD grafts compared with PDBD (26.2% vs. 13.0%, P<0.001); however, among pediatric recipients, DGF rates were half of those observed in adults, and a statistically significant difference in DGF could not be detected between PDBD and PDCD grafts (6.9% vs. 4.9%, P=0.6). Among all recipients, PDCD kidneys had a greater risk of graft loss compared with PDBD kidneys (adjusted hazard ratio=1.32, 95% CI=1.06-1.65, P=0.01), although among pediatric recipients this increased risk was not statistically significant (adjusted hazard ratio=2.01, 95% CI=0.89-4.54, P=0.1). CONCLUSIONS: The differences in outcomes between adult recipients of PDCD and PDBD kidneys, and the attenuation of these differences among pediatric recipients, should be weighed against risks of prolonged waitlist time in recipients being considered for these grafts.

Optimizing the possibilities for kidney-paired donation (KPD) requires the participation of donor-recipient pairs from wide geographic regions. Initially it was envisaged that donors would travel to the recipient center; however, to minimize barriers to participation and simplify logistics, recent trends have involved transporting the kidneys rather than the donors. The goal of this study was to review outcomes of this practice. KPD programs throughout the United States were directly queried about all transplants involving live donor kidney transport. Early graft function was assessed by urine output in the first 8 h, postoperative serum creatinine trend, and incidence of delayed graft function. Between April 27, 2007 and April 29, 2010, 56 live donor kidneys were transported among 30 transplant centers. Median CIT was 7.2 h (IQR 5.5-9.7, range 2.5-14.5). Early urine output was robust (>100 cc/h) in all but four patients. Creatinine nadir was <2.0 mg/dL in all (including the four with lower urine output) but one patient, occurring at a median of 3 days (IQR 2-5, range 1-49). No patients experienced delayed graft function as defined by the need for dialysis in the first week. Current evidence suggests that live donor kidney transport is safe and feasible.