Risk Prediction for Delayed Allograft Function: Analysis of the Deterioration of Kidney Allograft Function (DeKAF) Study Data.

BACKGROUND: Delayed graft function (DGF) of a kidney transplant results in increased cost and complexity of management. For clinical care or a DGF trial, it would be ideal to accurately predict individual DGF risk and provide preemptive treatment. A calculator developed by Irish et al has been useful for predicting population but not individual risk. METHODS: We analyzed the Irish calculator (IC) in the DeKAF prospective cohort (incidence of DGF = 20.4%) and investigated potential improvements. RESULTS: We found that the predictive performance of the calculator in those meeting Irish inclusion criteria was comparable with that reported by Irish et al. For cohorts excluded by Irish: (a) in pump-perfused kidneys, the IC overestimated DGF risk; (b) in simultaneous pancreas kidney transplants, the DGF risk was exceptionally low. For all 3 cohorts, there was considerable overlap in IC scores between those with and those without DGF. Using a modified definition of DGF-excluding those with single dialysis in the first 24 h posttransplant-we found that the calculator had similar performance as with the traditional DGF definition. Studying whether DGF prediction could be improved, we found that recipient cardiovascular disease was strongly associated with DGF even after accounting for IC-predicted risk. CONCLUSIONS: The IC can be a useful population guide for predicting DGF in the population for which it was intended but has limited scope in expanded populations (SPK, pump) and for individual risk prediction. DGF risk prediction can be improved by inclusion of recipient cardiovascular disease.

The "oldest and coldest" shipped living donor kidneys transplanted through kidney paired donation.

To date, thousands of living donor kidneys have been shipped through kidney paired donation (KPD). To expand on this growing segment of living donor transplantation, we evaluated the effect of advanced age donation ("oldest kidneys") and prolonged cold ischemia time ("coldest kidneys") on graft function and survival using the National Kidney Registry database from February 2008 to May 2018. Donors were stratified by age at time of donation (<65 or ≥65 years) and kidneys were stratified by cold ischemia time (<16 or ≥16 hours). We evaluated delayed graft function and death-censored graft failure (DCGF) for up to seven posttransplant years. Of the 2363 shipped living donor kidney transplants, 4.1% of donors were ≥65 years and 6.0% of transplanted kidneys had cold ischemia times ≥16 hours. Delayed graft function and DCGF occurred in 5.2% and 4.7% of cases. There were no significant associations between delayed graft function and donor age (P = .947) or cold ischemia (P = .532). Donor age and cold ischemia time were not predictive of delayed graft function (OR = 0.86,1.20; P = .8, .6) or DCGF (HR = 1.38,0.35, P = .5, .1). These findings may alleviate concerns surrounding the utilization of kidneys from older donors or those originating from distant transplant centers.

Late graft failure after kidney transplantation as the consequence of late versus early events.

Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long-term death-censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new-onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 ± 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P < .001) and elevated Cr at Day 90 (HR = 2.56, P < .0001) were associated with increased risk of DCGF; however, later-onset dysfunction requiring IBx had far greater impact (HR = 13.8, P < .0001). At 90 days, neither clinical characteristics nor early events distinguished those who subsequently did or did not undergo IBx or suffer DCGF. To improve long-term kidney allograft survival, management paradigms should promote prompt diagnosis and treatment of both early and later events.

Current methodologies for detecting sensitization to HLA antigens.

PURPOSE OF REVIEW: Advances in solid-phase tests for antibodies directed against HLA antigens have opened new areas of sophistication in detecting and characterizing the antibodies and have improved access to transplantation for sensitized candidates. In considering desensitization as an option for sensitized patients, determining specificities and strengths of antibodies and the risk they pose before and after therapeutic interventions are critical. This review focuses on the tests that are used today to detect sensitization and their relevance to assessing risk for transplant candidates and recipients. RECENT FINDINGS: There are conflicting reports of the clinical relevance of antibodies that are detected in solid-phase assays, which provide exquisite levels of precision and sensitivity for antibody detection. There is growing evidence that low levels of donor-reactive antibody need not be always considered a contraindication to transplant. New tools for determining isotype and complement fixation in solid-phase tests may also resolve some disparities. SUMMARY: Solid-phase tests for HLA antibodies now play a key role in transplantation laboratories and are widely utilized by transplant programs around the world. Although there are not rigid standards for their use and interpretation, transplant patients are benefiting from the use of these tests.

HLA and MICA: targets of antibody-mediated rejection in heart transplantation.

BACKGROUND: The goal of this study was to determine whether antidonor antibodies directed against human leukocyte antigen (HLA) or endothelial cells (ECs) expressed antigens, including major histocompatibility complex class I chain-related antigens A (MICA) are associated with the diagnosis of antibody-mediated rejection (AMR) in heart transplant recipients. METHODS: We studied posttransplant antidonor HLA antibodies in 168 heart allograft recipients transplanted from October 2001 to December 2005. Among them, there were 37 AMR+ patients and 131 age- and sex- matched AMR- controls. Sera were collected at the time of protocol biopsies and tested for the presence of HLA antibodies. Seventy-two of the 168 patients were genotyped for donor and recipient MICA alleles and were tested for the presence of anti-MICA antibodies. Thirty-one patients who never developed antibodies to HLA or MICA were further tested for anti-EC antibodies. RESULTS AND CONCLUSIONS: Of 37 AMR+ patients, 22 (60%) developed donor-specific antibodies (DSA) to HLA compared with 6 of 131(4%) AMR- patients (P<0.0001). Of the remaining 15 AMR+ patients, 5 had anti-HLA antibodies that were not donor specific and 10 did not show any HLA antibodies. In the subgroup of 72 patients, all 19 AMR+ patients had clearly demonstrable antibodies reactive with donor HLA, MICA or with nondonor-derived ECs, with 30% of them showed antibodies directed to non-HLA antigens. The incidence of transplant coronary artery disease was significantly higher in patients who had DSA to HLA and MICA compared with patients without DSA.

Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure.

BACKGROUND: Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF. METHODS: One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3+/-6.0 years) had a baseline serum creatinine level of 1.4+/-0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7+/-1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations. RESULTS: Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF. CONCLUSIONS: Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

One kidney transplant center's experience: linking process improvements and Medicare/Medicaid conditions of participation.

CONTEXT: An institutional priority toward transplantation, dedicated team dynamics, aggressive clinical growth, and optimal care practices are essential for delivering exceptional care to transplant patients. The importance of multidisciplinary integration of these priorities throughout the continuum of patient care is widely recognized in the transplant arena as well as by the Centers for Medicare and Medicaid Services (CMS). In fact, it is the collaboration within these aspects of care that is necessary for certification by CMS. OBJECTIVES: To establish institution-wide practices, systems, and mechanisms to optimize performance of transplant centers through the use of evidence-based protocols, clinical innovation, and data-driven quality improvements. To develop training programs and competency based orientation addressing the topics needed for transplant nurses, multidisciplinary caregivers, and clinical transplant coordinators who provide care to transplant patients. To comply with the CMS conditions of participation for transplant centers. METHODS: Formation of a renal transplant council and multidisciplinary care team. Flow chart of hospital course from admission to discharge, carefully examining patients' progression through the continuum of care, assessing for barriers to care and knowledge deficits of transplant practitioners. RESULTS: Development of multiple clinical process improvements resulting in the creation of an environment for continuous learning, optimal transplant care, and exceptional outcomes in transplantation as well as compliance with CMS conditions of participation for transplant centers.

Transplant tourism in the United States: a single-center experience.

BACKGROUND AND OBJECTIVES: Transplant "tourism" typically refers to the practice of traveling outside the country of residence to obtain organ transplantation. This study describes the characteristics and outcomes of 33 kidney transplant recipients who traveled abroad for transplant and returned to University of California, Los Angeles (UCLA) for follow-up. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Posttransplantation outcomes were compared between tourists and a matched cohort of patients who underwent transplantation at UCLA (matched for age, race, transplant year, dialysis time, previous transplantation, and donor type). Median follow-up time was 487 d (range 68 to 3056). RESULTS: Compared with all patients who underwent transplantation at UCLA, tourists included more Asians and had shorter dialysis times. Most patients traveled to their region of ethnicity with the majority undergoing transplantation in China (44%), Iran (16%), and the Philippines (13%). Living unrelated transplants were most common. Tourists presented to UCLA a median of 35 d after transplantation. Four patients required urgent hospitalization, three of whom lost their grafts. Seventeen (52%) patients had infections, with nine requiring hospitalization. One patient lost her graft and subsequently died from complications related to donor-contracted hepatitis B. One-year graft survival was 89% for tourists and 98% for the matched UCLA cohort (P = 0.75). The rate of acute rejection at 1 yr was 30% in tourists and 12% in the matched cohort. CONCLUSIONS: Tourists had a more complex posttransplantation course with a higher incidence of acute rejection and severe infectious complications.

Kidney transplantation in the United States.

This chapter summarizes data on 159,119 deceased donor (DD) and 83,471 living donor (LD) kidney transplants reported to the OPTN/ UNOS registry during the 20-year period between 1988 and 2007. The 15-year graft survival rates for transplants performed during 1991-1995 were 25% for 32,327 DD and 40% for 13,992 LD recipients. Graft survival rates improved modestly (4% for DD and 2% for LD) transplants performed during 1996-2005. Graft half-lives rose from 8 to 10 years for DD and from 12 to 18 years for LD transplant recipients during the study period. The number of DD kidney recipients over age 50 increased from 1,620 in 1988 to 4,492 in 2007 with no corresponding increase in the number of younger transplants. Annual LD kidney transplants increased from 1,816 in 1988 to 6,273 in 2004, but the rapid growth in LD transplants leveled off in 2001-2002 and may be falling in more recent years. The growth and slowdown of LD transplants occurred at different times for different groups of LD according to their relationship to the patient. Parent donor transplants have not increased substantially, whereas offspring-to-parent graft, spouse and sibling transplants increased rapidly in the early to mid-1990's donors and leveled off in 2001-2002. Other unrelated LD transplants began to rise in 1995 and continued to increase until 2005. Parent-to-child transplants have declined 33% since the new UNOS prioritization of pediatric recipients for young adult DD kidneys in 2005. The difference in 10-year DD kidney survival between the best and worst HLA-matched combinations was 10%, with halflives ranging from 11.6 years to 8.6 years. Nearly one-third of DD transplants performed during 1996-2005 were completely HLA mismatched (5-6 HLA-A,B,DR mismatches) compared with 15% of transplants with no HLA antigens mismatched. About 11% of LD transplants were HLA-matched (most HLA-identical siblings) and 10-year graft survival was 74% compared with 58% for HLA mismatched transplants. There was no survival difference associated with increasing HLA mismatches among LD kidney recipients. The graft half-lives were 27 years for HLA-matched and 15 years for HLA-mismatched LD transplants The increasing use of newer solid-phase tests for HLA-antibodies appears to have inflated recent PRA estimates for sensitized patients as suggested by the increasing percentage of highly sensitized (80+% PRA) patients transplanted since 2003 (from 25 to 40% of retransplanted patients). Three-year graft survival rates for broadly sensitized recipients during 2004-2007 was 77% (vs 79% for less sensitized) compared with 74% (vs 80% for less sensitized) during 1999-2003, which was more similar to the less sensitized patients in either period. There was considerable variability among centers in the percentage of broadly sensitized patients that were transplanted during each period, but most centers reported transplanting more sensitized patients between 2004-2007. Cold ischemia times (CIT) for DD kidney transplants have been reduced over the past 20 years from an average of 24 hours during 1988-1992 to 18 hours in 2003-2007. Despite this reduction in CIT, the incidence of delayed graft function has remained at 25% each year since 1990. The effect of prolonged CIT (> 30 hours) on graft survival was a 1% reduction over 10 years for DD kidneys under age 35 and a 4% reduction for DD kidneys over age 55 compared with the graft survival results for DD kidneys in either age group transplanted within 18 hours.

Could more effective use of kidneys recovered from older deceased donors result in more kidney transplants for older patients?

In the face of a severe shortage of kidneys from deceased organ donors that limits access to transplantation for many patients, about one of every seven kidneys (more than 1,500 each year) recovered from deceased donors in the United States are not transplanted. Eurotransplant, which coordinates organ distribution for six countries and a population of about 118 million, discards only one of every 20 kidneys procured for transplantation. We compared kidney procurement, transplants, and discards between January 2000 and June 2003 in the United States and in the Eurotransplant region using the Organ Procurement and Transplantation Network/United Network for Organ Sharing and Eurotransplant databases to examine differences that might account for this wide disparity.

Preformed cytotoxic antibodies in potential allograft recipients: recent data.

Presensitization to donor human leukocyte antigen (HLA) remains a major barrier to cell and organ transplantation, thereby contributing to patient mortality. The risks associated with transplantation in the presence of preformed antidonor HLA antibodies range from hyperacute rejection and increased frequency and severity of rejection to no appreciable effect on transplant outcome. Recent evidence has emphasized the importance of immunologic history, anti-HLA antibody class and titer, and differential organ susceptibility to antibody-mediated damage to explain differences in risk for antibody-mediated rejection. Furthermore, in studies of endothelial cells, ligation of class I molecules by subsaturating concentrations of antibodies stimulated expression of cell survival proteins, raising the possibility that, under certain conditions, antibodies promote graft accommodation providing a mechanism for the endothelium to resist immune and inflammatory damage. The discovery of capillary-bound C4d as a robust diagnostic marker for antibody-mediated rejection, coupled with the development of solid-phase assays for the identification of HLA-specific antibodies, has enhanced our ability to detect antibody-mediated rejection and interpret cross-match results. With new diagnostic tools and immunosuppression regimens such as plasmapheresis and intravenous immunoglobulin therapy targeting the humoral immune response, it is time for a concerted effort to reassess the role of alloantibodies in acute and chronic rejection.

The OPTN/UNOS Renal Transplant Registry.

The 10-year graft survival rates for first renal transplants performed during 1990-1994 and 1995-1999 and reported to the OPTN/UNOS Renal Transplant Registry increased from 57-58% for living donor transplants, from 42-46% for deceased donors aged 60 or under, and from 22-28% for donors over age 60 comparing the 2 intervals. These modest increases were accompanied by a 2% decline in 10-year patient survival for recipients of living and younger deceased donor grafts and a 1% improvement in patient survival for recipients of older donor kidneys. The 5-year graft and patient survival rates for transplants performed between 2000 and 2004 were 80% and 90% for living donor, 69% and 90% for standard criteria deceased donor and 55% and 82% for expanded criteria donor transplants, respectively. There was no significant improvement when compared to the 1995-1999 period for any of these groups and patient survival had declined by 1% among recipients of living or standard criteria deceased donors. recipients of living or standard criteria deceased donor kidneys had a 6-7% higher 5-year survival rate and longer graft half-lives than recipients of HLA mismatched kidneys. The number of local HLA-DR matched transplants (excluding zero-HLA-ABDR mismatched grafts) has been declining since 1998 and was affected by the activity of the local donation service area (presumably reflecting the size of the waiting list). There was a modest increase in the percentage of broadly sensitized recipients transplanted during 2002-2004 from 8-10% of standard deceased donor The median age for recipients of primary standard criteria deceased donor transplants increased from 43 during the period 1990-1994 to 51 during 2000-2004 and may explain the lack of improvement in long-term graft survival rates. When patients aged 19-35 were analyzed separately during the 3 periods, there was a 3-4% increase in actuarial or projected 10-year graft survival for recipients of living or younger deceased donor kidneys during each interval (p < 0.001). Changes to the kidney allocation algorithm that affect the role of HLA matching have not had a striking impact on the number or percentage of zero HLA-ABDR mismatched SCD transplants, which account for 16-17% of SCD transplants each year. The number and percentage of HLA-matched ECD transplants declined from 113 (12%) in 2001 to 63 (4%) in 2004. The 56% 5-year graft survival rate for recipients of HLA-matched ECD kidneys was not significantly better than that for HLA-mismatched grafts, whereas HLA-matched and from 2-4% of living donor kidney recipients that was temporally associated with improved technologies for detecting anti-HLA antibodies. The presence of panel reactive antibodies had almost no effect on 5-year graft survival among retransplanted patients. The number of transplants between spouses leveled off in 2001 at about 700 transplants each year. The number of non-spouse unrelated living donor transplants has increased 10-fold over the past 10 years to 1,341 in 2004 and does not appear to be slowing.

Trends in donation after cardiac death.

The deceased cardiac donor (DCD) can provide organs that are suitable for transplantation. However, in order to increase recovery and utilization of this under-utilized organ donor source, a number of issues remain to be resolved. First, the public understanding is essential for support of this end-of-life option to donate after cardiac death. Extensive education of donor hospitals will be needed to identify potential donors and arrange for their care. Organ procurement organizations will have to commit to the extra effort required to identify and manage these donors and to design recovery techniques to maximize procurement of abdominal and thoracic organs. Pulsatile machine perfusion may be needed for assessing viability of DCD kidneys, although the evidence is lacking that pump preservation improves survival of DCD kidneys that are transplanted. It will also be important to identify transplant centers and suitable patients within those centers that will accept DCD organs. Preselecting recipients will speed allocation as has been the case for expanded criteria donors. Special efforts to minimize reperfusion injury should be made initially to protect what might be more "injury-prone" DCD organs and calcineurin inhibitors should probably be avoided during the early posttransplant period. The graft survival rates for DCD kidneys and pancreata have been comparable to those for conventional deceased donor grafts, whereas graft survival rates for DCD liver recipients have been significantly poorer than with conventional livers. Thus, we need to continue exploring approaches to improve patient and graft survival for DCD liver transplant recipients.

Impact of portal venous pancreas graft drainage on kidney graft outcome in simultaneous pancreas-kidney recipients reported to UNOS.

Clinical data on the potential immunologic impact of portal (PD) vs. systemic (SD) venous pancreas graft drainage on outcome remains controversial. We reviewed the UNOS database to study the effect of PD vs. SD on the incidence of kidney graft rejection and survival in first cadaveric simultaneous pancreas-kidney (SPK) recipients transplanted 1994-2001. We studied three groups: all SPK (n=6629, 13% PD) (group I), SPK on tacrolimus (n=3563, 17% PD) (group II), and SPK on tacrolimus performed at centers with significant PD experience (n=948, 46% PD) (group III). The cumulative kidney graft rejection incidence for PD vs. SD was only significantly different in group I (for PD vs. SD, respectively: at 6 months, 31% vs. 36% [p=0.015]; at 1 year, 37% vs. 43% [p=0.006]). Kidney graft survival was similar in all groups for PD vs. SD. Multivariate analysis of group III showed only transplantation during the earlier era (1994-96), but not SD, to be an independent risk factor for kidney graft rejection. Portal venous pancreas graft drainage does not affect kidney graft rejection and survival in SPK recipients on tacrolimus. Our data suggests that the efficacy of current immunosuppressive protocols and increasing center experience are clinically much more relevant than any potential immunologic advantage of portal venous drainage in SPK recipients.