Deceased Donor Kidney Transplant Recipients Research Articles

Donor-specific antibodies present at the time of kidney transplantation in immunologically unmodified patients increase the risk of acute rejection

BackgroundHuman leukocyte antigens (HLA) class II donor-specific antibodies (DSAs) are associated with microcirculation inflammation, transplant glomerulopathy and ultimately graft loss. There is however no data on allograft outcomes in deceased donor kidney transplant recipients who have not received any desensitization prior to transplantation. MethodsWe prospectively evaluated the association of HLA DR and DQ DSAs on rejection and short-term graft survival in patients who did not receive desensitization prior to transplantation. On the basis of their cumulative strength of HLA DR and/or DQ DSA, the patients were dichotomized into: 1) median fluorescence intensity (MFI)<1000 and 2) MFI≥1000. ResultsIn the two year study period, 50 consecutive patients with HLA DR and/or DQ sensitization were transplanted in our two centers. Post-transplantation, the incidence of acute rejection was significantly greater in the MFI≥1000 group (35%; 8/22) compared to the MFI<1000 group (7%; 2/28) (p<0.001). There were two graft losses, both in the MFI≥1000 group. ConclusionThe strength of DR and/or DQ DSA at the time of renal transplantation influences the risk of rejection in non-desensitized recipients with HLA class II DSA.

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients.

The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

Deceased donor kidney transplantation across donor-specific antibody barriers: predictors of antibody-mediated rejection

Apheresis-based desensitization allows for successful transplantation across major immunological barriers. For donor-specific antibody (DSA)- and/or crossmatch-positive transplantation, however, it has been shown that even intense immunomodulation may not completely prevent antibody-mediated rejection (ABMR). In this study, we evaluated transplant outcomes in 101 DSA+ deceased donor kidney transplant recipients (transplantation between 2009 and 2013; median follow-up: 24 months) who were subjected to immunoadsorption (IA)-based desensitization. Treatment included a single pre-transplant IA session, followed by anti-lymphocyte antibody and serial post-transplant IA. In 27 cases, a positive complement-dependent cytotoxicity crossmatch (CDCXM) was rendered negative immediately before transplantation. Seventy-four of the DSA+ recipients had a negative CDCXM already before IA. Three-year death-censored graft survival in DSA+ patients was significantly worse than in 513 DSA- recipients transplanted during the same period (79 versus 88%, P = 0.008). Thirty-three DSA+ recipients (33%) had ABMR. While a positive baseline CDCXM showed only a trend towards higher ABMR rates (41 versus 30% in CDCXM- recipients, P = 0.2), DSA mean fluorescence intensity (MFI) in single bead assays significantly associated with rejection, showing 20 versus 71% ABMR rates at <5000 versus >15 000 peak DSA MFI. The predictive value of MFI was moderate, with the highest accuracy at a median of 13 300 MFI (after cross-validation: 0.72). Other baseline variables, including CDC assay results, human leukocyte antigen mismatch, prior transplantation or type of induction treatment, did not add independent predictive information. IA-based desensitization failed to prevent ABMR in a considerable number of DSA+ recipients. Assessing DSA MFI may help stratify risk of rejection, supporting its use as a guide to organ allocation and individualized treatment.

Socioeconomic deprivation and barriers to live-donor kidney transplantation: a qualitative study of deceased-donor kidney transplant recipients

ObjectivesSocioeconomically deprived individuals with renal disease are less likely to receive a live-donor kidney transplant than less-deprived individuals. This qualitative study aimed to identify reasons for the observed socioeconomic disparity...

Reduced Racial Disparity in Kidney Transplant Outcomes in the United States from 1990 to 2012

Earlier studies reported inferior outcomes among black compared with white kidney transplant (KT) recipients. We examined whether this disparity improved in recent decades. Using the Scientific Registry of Transplant Recipients and Cox regression models, we compared all-cause graft loss among 63,910 black and 145,482 white adults who received a first-time live donor KT (LDKT) or deceased donor KT (DDKT) in 1990-2012. Over this period, 5-year graft loss after DDKT improved from 51.4% to 30.6% for blacks and from 37.3% to 25.0% for whites; 5-year graft loss after LDKT improved from 37.4% to 22.2% for blacks and from 20.8% to 13.9% for whites. Among DDKT recipients in the earliest cohort, blacks were 39% more likely than whites to experience 5-year graft loss (adjusted hazard ratio [aHR], 1.39; 95% confidence interval [95% CI], 1.32 to 1.47; P<0.001), but this disparity narrowed in the most recent cohort (aHR, 1.10; 95% CI, 1.03 to 1.18; P=0.01). Among LDKT recipients in the earliest cohort, blacks were 53% more likely than whites to experience 5-year graft loss (aHR, 1.53; 95% CI, 1.27 to 1.83; P<0.001), but this disparity also narrowed in the most recent cohort (aHR, 1.37; 95% CI, 1.17 to 1.61; P<0.001). Analyses revealed no statistically significant differences in 1-year or 3-year graft loss after LDKT or DDKT in the most recent cohorts. Our findings of reduced disparities over the last 22 years driven by more markedly improved outcomes for blacks may encourage nephrologists and patients to aggressively promote access to transplantation in the black community.

Pretransplant Recipient Circulating CD4+CD127lo/- Tumor Necrosis Factor Receptor 2+ Regulatory T Cells: A Surrogate of Regulatory T Cell-Suppressive Function and Predictor of Delayed and Slow Graft Function After Kidney Transplantation.

Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long-term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI. In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/- and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture. The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P < 0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality. Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics.

Stabilization of estimated glomerular filtration rate in kidney transplantation from deceased donors with acute kidney injuries

AIMTo evaluate and compare the outcomes of kidney transplant (KT) from deceased donors among standard criteria, acute kidney injury (AKI) and expanded criteria donors (ECDs).METHODSThis retrospective study included 111 deceased donor kidney transplant recipients (DDKT). Deceased donors were classified as standard criteria donor (SCD), AKI donor and ECD. AKI was diagnosed and classified based on change of serum Cr by acute kidney injury network (AKIN) criteria. Primary outcome was one-year estimated glomerular filtration rate (eGFR) calculated from Cr by CKD-EPI. Multivariate regression analysis was done by adjusting factors such as type of DDKT, %Panel-reactive antibodies, cold ischemic time, the presence of delayed graft function and the use of induction therapy. Significant factors that can affect the primary outcomes were then identified.RESULTSECD group had a significantly lower eGFR at one year (33.9 ± 17.3 mL/min) when compared with AKI group (56.6 ± 23.9) and SCD group (63.6 ± 19.9) (P < 0.001). For AKI group, one-year eGFR was also indifferent among AKIN stage 1, 2 or 3. Patients with AKIN stage 3 had progressive increase of eGFR from 49.6 ± 27.2 at discharge to 61.9 ± 29.0 mL/min at one year. From Kaplan-Meier analysis, AKI donor showed better two-year graft survival than ECD (100% vs 88.5%, P = 0.006). Interestingly, AKI group had a stable eGFR at one and two year. The two-year eGFR of AKI group was not significantly different from SCD group (56.6 ± 24.5 mL/min vs 58.6 ± 23.2 mL/min, P = 0.65).CONCLUSIONKidney transplantations from deceased donors with variable stage of acute kidney injuries were associated with favorable two-year allograft function. The outcomes were comparable with KT from SCD. This information supports the option that deceased donors with AKI are an important source of organ for kidney transplantation even in the presence of stage 3 AKI.

The Canadian experience using the expanded criteria donor classification for allocating deceased donor kidneys for transplantation.

BackgroundAlthough the outcomes of transplantation with expanded criteria donor (ECD) kidneys are inferior to non-ECD transplants in the USA, the impact of the ECD classification on Canadian kidney transplant recipients is not known.ObjectivesThe objective of the study was to assess the performance of the US-derived ECD classification among deceased donor kidney transplant recipients in a Canadian setting.DesignThis study was a population-based cohort study.SettingThe study was conducted in all adult kidney transplant centers in the province of Ontario.PatientsThe patients were incident-deceased donor kidney transplant recipients from January 1, 2005 to March 31, 2011.MeasurementsStudy subjects were identified through the Trillium Gift of Life Network and linked to healthcare databases in Ontario. ECD status was based on age, hypertension, kidney function, and stroke-related death. Outcomes of interest included graft loss, death, and delayed graft function.MethodsThe Kaplan-Meier product limit method was used to graphically assess time to graft loss or death. Multivariable Cox proportional hazards models were used to assess graft loss or death as a function of ECD status. Multivariable logistic regression models were fitted for the outcome of delayed graft function.ResultsOf 1422 deceased donor kidney transplants, 325 (23 %) were from ECDs. The median donor age was 63 vs. 42 years for ECD vs. non-ECD, respectively. The 5-year cumulative incidence of total graft loss was 29.2 % in ECD and 20.7 % in non-ECD kidney transplants. The relative hazards for total graft loss (HR 1.48 [95 % CI, 1.10; 2.00]) and death-censored graft loss (HR 1.80 [95 % CI, 1.19, 2.71]) were increased in ECD vs. non-ECD transplants. Increased relative risks were also observed for death and delayed graft function, albeit not statistically significant.LimitationsAlthough comprehensive in coverage and outcome ascertainment, the available details on covariate data may be limited in large healthcare databases.ConclusionsThe ECD classification identifies kidneys at increased risk for graft loss in Canadian patients. The performance of more granular measures of donor risk (e.g., Kidney Donor Risk Index) and its impact on organ allocation/utilization in Canadian patients requires further study.Electronic supplementary materialThe online version of this article (doi:10.1186/s40697-016-0106-9) contains supplementary material, which is available to authorized users.

Better the donor you know? A qualitative study of renal patients' views on ‘altruistic’ live-donor kidney transplantation

BackgroundIn the UK there is a short-fall between individuals requiring a renal transplant and kidneys available for transplantation. Non-directed ‘altruistic’ living kidney donation has emerged as a strategy for bridging this gap between supply and demand, with the number increasing each year. ObjectiveThis study aimed to explore the views of potential recipients towards non-directed ‘altruistic’ live-donor kidney transplantation. MethodsSemi-structured interviews with 32 UK deceased-donor kidney transplant recipients were performed. Interviews explored willingness to consider directed and non-directed live-donor kidney transplants (LDKTs). Interviews were recorded, transcribed verbatim and transcripts were analysed using the constant comparison method described in Grounded Theory. ResultsFor those not willing to accept a non-directed ‘altruistic’ LDKT, the following themes were identified: i) Prioritising other recipients above self; ii) Fear of acquiring an unknown donor's characteristics, and iii) Concern for the donor – unnecessary risk. For those willing to accept a non-directed ‘altruistic’ LDKT the following themes were identified: iv) Prioritising known above unknown persons, v) Belief that they are as deserving as other potential recipients, and vi) Advantages of a LDKT. ConclusionsDrawing on ‘gift exchange theory’, this study contributes to our understanding of the experience of the intended recipient of a gift. The anonymity of the donor-recipient appears to be seen as a benefit of non-directed ‘altruistic’ live-donor transplants, freeing recipients from the obligations of the gift. However, those who feel unworthy of the ‘gifted transplant’ are concerned about the donor and by the lack of opportunity for direct reciprocity. Highlighting the ‘reciprocal benefits’ reported by donors may allow individuals whose preference is a live-donor transplant to accept one if offered. These insights provide the transplant community with targets for intervention, through which the concerns of potential recipients might be addressed.

The TALKS study to improve communication, logistical, and financial barriers to live donor kidney transplantation in African Americans: protocol of a randomized clinical trial.

BackgroundLive donor kidney transplantation (LDKT), an optimal therapy for many patients with end-stage kidney disease, is underutilized, particularly by African Americans. Potential recipient difficulties initiating and sustaining conversations about LDKT, identifying willing and medically eligible donors, and potential donors’ logistical and financial hurdles have been cited as potential contributors to race disparities in LDKT. Few interventions specifically targeting these factors have been tested.Methods/DesignWe report the protocol of the Talking about Living Kidney Donation Support (TALKS) study, a study designed to evaluate the effectiveness of behavioral, educational and financial assistance interventions to improve access to LDKT among African Americans on the deceased donor kidney transplant recipient waiting list. We adapted a previously tested educational and social worker intervention shown to improve consideration and pursuit of LDKT among patients and their family members for its use among patients on the kidney transplant waiting list. We also developed a financial assistance intervention to help potential donors overcome logistical and financial challenges they might face during the pursuit of live kidney donation. We will evaluate the effectiveness of these interventions by conducting a randomized controlled trial in which patients on the deceased donor waiting list receive 1) usual care while on the transplant waiting list, 2) the educational and social worker intervention, or 3) the educational and social worker intervention plus the option of participating in the financial assistance program. The primary outcome of the randomized controlled trial will measure potential recipients’ live kidney donor activation (a composite rate of live donor inquiries, completed new live donor evaluations, or live kidney donation) at 1 year.DiscussionThe TALKS study will rigorously assess the effectiveness of promising interventions to reduce race disparities in LDKT.Trial registrationNCT02369354.

Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

Organ quality metrics are a poor predictor of costs and resource utilization in deceased donor kidney transplantation

The desire to provide cost-effective care has lead to an investigation of the costs of therapy for end-stage renal disease. Organ quality metrics are one way to attempt to stratify kidney transplants, although the ability of these metrics to predict costs and resource use is undetermined. The Scientific Registry of Transplant Recipients database was linked to the University HealthSystem Consortium Database to identify adult deceased donor kidney transplant recipients from 2009 to 2012. Patients were divided into cohorts by kidney criteria (standard vs expanded) or kidney donor profile index (KDPI) score (<85 vs 85+). Length of stay, 30-day readmission, discharge disposition, and delayed graft function were used as indicators of resource use. Cost was defined as reimbursement based on Medicare cost/charge ratios and included the costs of readmission when applicable. More than 19,500 patients populated the final dataset. Lower-quality kidneys (expanded criteria donor or KDPI 85+) were more likely to be transplanted in older (both P < .001) and diabetic recipients (both P < .001). After multivariable analysis controlling for recipient characteristics, we found that expanded criteria donor transplants were not associated with increased costs compared with standard criteria donor transplants (risk ratio [RR] 0.97, 95% confidence interval [CI] 0.93-1.00, P = .07). KDPI 85+ was associated with slightly lower costs than KDPI <85 transplants (RR 0.95, 95% CI 0.91-0.99, P = .02). When KDPI was considered as a continuous variable, the association was maintained (RR 0.9993, 95% CI 0.999-0.9998, P = .01). Organ quality metrics are less influential predictors of short-term costs than recipient factors. Future studies should focus on recipient characteristics as a way to discern high versus low cost transplantation procedures.

Center-level variation in the development of delayed graft function after deceased donor kidney transplantation.

Patient-level risk factors for delayed graft function (DGF) have been well described. However, the Organ Procurement and Transplantation Network definition of DGF is based on dialysis in the first week, which is subject to center-level practice patterns. It remains unclear if there are center-level differences in DGF and if measurable center characteristics can explain these differences. Using the 2003 to 2012 Scientific Registry of Transplant Recipients data, we developed a hierarchical (multilevel) model to determine the association between center characteristics and DGF incidence after adjusting for known patient risk factors and to quantify residual variability across centers after adjustment for these factors. Of 82,143 deceased donor kidney transplant recipients, 27.0% developed DGF, with a range across centers of 3.2% to 63.3%. A center's proportion of preemptive transplants (odds ratio [OR], 0.83; per 5% increment; 95% confidence interval [95% CI], 0.74-;0.93; P = 0.001) and kidneys with longer than 30 hr of cold ischemia time (CIT) (OR, 0.95; per 5% increment; 95% CI, 0.92-;0.98; P = 0.001) were associated with less DGF. A center's proportion of donation after cardiac death donors (OR, 1.12; per 5% increment; 95% CI, 1.03-;1.17; P < 0.001) and imported kidneys (OR, 1.06; per 5% increment; 95% CI, 1.03-;1.10; P < 0.001) were associated with more DGF. After patient-level and center-level adjustments, only 41.8% of centers had DGF incidences consistent with the national median and 28.2% had incidences above the national median. Significant heterogeneity in DGF incidences across centers, even after adjusting for patient-level and center-level characteristics, calls into question the generalizability and validity of the current DGF definition. Enhanced understanding of center-level variability and improving the definition of DGF accordingly may improve DGF's utility in clinical care and as a surrogate endpoint in clinical trials.

Long-Term Survival (>25 Years) of Deceased Donor Kidney Transplant Recipients: A Single-Center Experience

IntroductionThe aim of this preliminary work is to analyze the clinical features of 52 patients with a functional transplanted kidney for >25 years (all first transplant and all deceased donor recipients) and to compare with a similar though more complete study from Hôpital Necker-Paris 2012. MethodsThe mean graft survival at 25 years is 12.7% and at 30 years is 10%. The actual mean serum creatinine concentration is 1.3 mg/L. We analyzed recipient age (mean, 35.9 years) and gender (29 men and 23 women). Donor age was 26.7 ± 10.3 years. Seven patients (13.4%) were transplanted with 1 HLA mismatch, 42.3% with 2 mismatches, and 44.2% with 3 mismatches. Mean cold ischemia time was 15.45 ± 7.7 hours. Of the recipients, 76% had immediate graft function; 38% experienced 1 acute rejection episode and 4 patients had 2 rejection crises. The initial immunosuppressive regimen was azathioprine (AZA) + prednisolone (Pred) in 14 patients, cyclosporin (CSA) + Pred in 13 patients, and CSA + AZA + Pred in 25 patients. Of these patients, 19% maintained their initial regimen, and 54% (28 patients) were very stable on a mixed CSA regimen for >25 years. ResultsWe present the major complications (diabetes, neoplasia, and hepatitis C virus positivity). ConclusionOur results in deceased donor kidney recipients for >25 years are similar to the mixed population (deceased donors and living donors) presented by the Necker group, although 54% of our patients remain on CSA immunosuppression, contradicting the idea that its use is not compatible with good long-term kidney function in transplant recipients.

Graft and patient outcomes of zero-human leucocyte-antigen-mismatched deceased and live donor kidney transplant recipients.

Greater compatibility of human leucocyte antigen (HLA) alleles between kidney donors and recipients may lead to improved graft outcomes. This study aimed to compare the incidence of acute rejection and graft failure in zero-HLA-mismatched recipients of living-related (LD) and deceased donor (DD) kidney transplants. Using data from the Australia and New Zealand Dialysis and Transplant Registry, we compared the risk of any acute rejection and biopsy-proven acute rejection (BPAR) and graft failure in recipients of zero-HLA-mismatched kidneys between LD and DD using logistic and Cox regression models. Of the 931 zero-HLA-mismatched recipients transplanted between 1990 and 2012, 19 (2.0%) received kidneys from monozygotic/dizygotic twins (twin), 500 (53.7%) from nontwin LD and 412 (44.3%) from DD. Twin kidney transplant recipients did not experience rejection. Compared to DD transplant recipients, the risk of any acute rejection (adjusted odds ratio 0.52, 95%CI 0.34-0.79, P = 0.002) and overall graft failure (adjusted hazard ratio 0.55, 95%CI 0.41-0.73, P < 0.001) was significantly lower in LD recipients independent of initial immunosuppression, but not for BPAR (adjusted odds ratio 0.52, 95%CI 0.16-1.64, P = 0.263). Zero-HLA-mismatched DD kidney transplant recipients have a significantly higher risk of any acute rejection episodes and graft loss compared to zero-HLA-mismatched LD kidney transplant recipients. A cautious and careful approach in reducing immunosuppression appears to be warranted in this group of transplant recipients.

Role of steroid maintenance in sensitized kidney transplant recipients.

To evaluate whether there is a threshold sensitization level beyond which benefits of chronic steroid maintenance (CSM) emerge. Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, we compared the adjusted graft and patient survivals for CSM vs early steroid withdrawal (ESW) among patients who underwent deceased-donor kidney (DDK) transplantation from 2000 to 2008 who were stratified by peak-panel reactive antibody (peak-PRA) titers (0%-30%, 31%-60% and > 60%). All patients received perioperative induction therapy and maintenance immunosuppression based on calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF). The study included 42851 patients. In the 0%-30% peak-PRA class, adjusted over-all graft-failure (HR 1.11, 95%CI: 1.03-1.20, P = 0.009) and patient-death (HR 1.29, 95%CI: 1.16-1.43, P < 0.001) risks were higher and death-censored graft-failure risk (HR 1.06, 95%CI: 0.98-1.14, P = 0.16) similar for CSM (n = 25218) vs ESW (n = 7399). Over-all (HR 1.04, 95%CI: 0.85-1.28, P = 0.70) and death-censored (HR 0.97, 95%CI: 0.78-1.21, P = 0.81) graft-failure risks were similar and patient-death risk (HR 1.39, 95%CI: 1.03-1.87, P = 0.03) higher for CSM (n = 3495) vs ESW (n = 850) groups for 31%-60% peak-PRA class. In the > 60% peak-PRA class, adjusted overall graft-failure (HR 0.90, 95%CI: 0.76-1.08, P = 0.25) and patient-death (HR 0.92, 95%CI: 0.71-1.17, P = 0.47) risks were similar and death-censored graft-failure risk lower (HR 0.84, 95%CI: 0.71-0.99, P = 0.04) for CSM (n = 4966) vs ESW (n = 923). In DDK transplant recipients who underwent perioperative induction and CNI/MMF maintenance, CSM appears to be associated with increased risk for death with functioning graft in minimally-sensitized patients and improved death-censored graft survival in highly-sensitized patients.

Urine YKL-40 is associated with progressive acute kidney injury or death in hospitalized patients.

BackgroundA translational study in renal transplantation suggested YKL-40, a chitinase 3-like-1 gene product, plays an important role in acute kidney injury (AKI) and repair, but data are lacking about this protein in urine from native human kidneys.MethodsThis is an ancillary study to a single-center, prospective observational cohort of patients with clinically-defined AKI according to AKI Network serum creatinine criteria. We determined the association of YKL -40 ≥ 5 ng/ml, alone or combined with neutrophil gelatinase-associated lipocalin (NGAL), in urine collected on the first day of AKI with a clinically important composite outcome (progression to higher AKI stage and/or in-hospital death).ResultsYKL-40 was detectable in all 249 patients, but urinary concentrations were considerably lower than in previously measured deceased-donor kidney transplant recipients. Seventy-two patients (29%) progressed or died in-hospital, and YKL-40 ≥ 5 ng/ml had an adjusted odds ratio (95% confidence interval) for the outcome of 3.4 (1.5-7.7). The addition of YKL-40 to a clinical model for predicting the outcome resulted in a continuous net reclassification improvement of 29% (P = 0.04). In patients at high risk for the outcome based on NGAL concentrations in the upper quartile, YKL-40 further partitioned the cohort into moderate-risk and very high-risk groups.ConclusionsUrine YKL-40 is associated with AKI progression and/or death in hospitalized patients and improves clinically determined risk reclassification. Combining YKL-40 with other AKI biomarkers like NGAL may further delineate progression risk, though additional studies are needed to determine whether YKL-40 has general applicability and to define its association with longer-term outcomes in AKI.

Effect of Donor and Recipient Gender/Race Disparity On Kidney Transplant Outcomes.

Background: The influence of donor/recipient gender and race in kidney transplantation on graft and patient outcomes is still controversial, with a lack of consensus in the reported literature. The aim of this study is evaluate the effect of gender and racial disparities on outcomes in deceased donor kidney transplant recipients. Methods: This was a retrospective analysis of deceased donor kidney transplants performed between 2005 and 2010. All patients received calcineurin inhibitor based immunosuppression with patients followed for up to 5 years post-transplant. Donor and recipient race stratification was limited to African American (AA) and Caucasian (C). Three year graft and patient survival, acute rejection rates, and renal function (e12, 24, and 36 month) were reported. Multivariate analysis will be performed. Results: A total of 261 consecutives deceased donor renal transplant were stratified into the following groups: donor AA to recipient C (n=21), AA to AA (n=61), C to AA (n=118), and C to C (n=61). Mean follow up time was 4.1+/- 1.8 years. Three year death censored graft function for each group was worse in AA recipients (AA to C 94.7%; AA to AA 86.8%; C to C 93.4%; and C to AA 90.7%). Three year patient survival for each group demonstrate worse survival in the C to AA patients (AA to C 94.7%; AA to AA 95.1%; C to C 93.4%; and C to AA 89%). Three year acute rejection rates were comparable between groups: AA to C 5.3%; AA to AA 6.6%; C to C 13.1%; and C to AA 11.9%. Renal function as determined by the estimated glomerular filtration rates (ml/min/1.73m2) was similar between groups at 12 months (AA to C 51±24, AA to AA 51±21, C to AA 57±22, C to C 53±17), at 24 months (AA to C 62±26, AA to AA 53±25, C to AA 58±21, C to C 47±17), and at 36 months (AA to C 54±27, AA to AA 44±22, C to AA 54±26, C to C 47±16). Stratifying by both gender and race demonstrated that 3 year death censored graft survival was worse in AA female donors to AA recipients (male: 81.0% and female 81.8 %) as compared to the other donor groups. Conclusions: Preliminary results suggest that AA kidney transplant recipients have impaired clinical outcomes regardless of donor race/gender. However, AA kidney transplant recipients (regardless of gender) from female AA donors appear to have worse graft function at 3 years as compared to other donor types. Additional analysis is needed to further evaluate this relationship.

Donor and Recipient Angiotensin II Type 1 Receptor Polymorphisms and Haplotypes and Allograft Outcome in Renal Transplantation.

We investigated the association between single nucleotide polymorphisms and haplotypes of the Angiotensin II Type 1 receptor (AGTR1), and long term kidney allograft outcome. Three thousand adult, deceased donor kidney transplant recipients and paired donors (transplanted 1988 to 2010) were randomly selected from Caucasian recipient and donor pairs in the Collaborative Transplant Study DNA bank. DNA specimens were genotyped for 6 single nucleotide polymorphisms (SNPs) of the AGTR1. The selected polymorphisms were tag SNPs within the two haplotype blocks (1 and 2) of the AGTR1 gene (haplotype 1: rs2933249, rs10935724, rs4681443; haplotype 2: rs718858, rs1492099, rs12721331). The primary outcome was 10-year allograft survival (Kaplan-Meier survival censored for death). We analysed outcomes by individual recipient and donor genotypes and haplotypes (wild-type versus remainder) as well as groups (presence or absence of minor allele), according to the recipient and donor AGTR1 genotype and haplotype. The selected sample was representative of the DNA bank (recipient age ≥18 years, Caucasian recipient and donor and initially on a calcineurin inhibitor). The mean transplant year was 1996. 437 (15%) of recipients were retransplants. Overall, median (interquartile range) follow up time was 7.5 (3.3-13.0) years and the mean 10-year death censored graft survival rate was 69.5%. The recipient mean (standard deviation, SD) age was 48 (13) yrs with 38% female. The donor mean (SD) age was 41 (17) yrs with 40% female. There were no significant (p<0.05) associations between donor or recipient AGTR1 SNPs and recipient allograft outcome. Similarly, neither haplotype of the donor nor recipient was significantly associated with recipient allograft outcome. When grouping the donor and recipient for individual AGTR1 SNP (p=0.29-0.97) or haplotype (p=0.68, p=0.93), again there was no significant association with the primary outcome. These individual SNPs or haplotypes of the AGTR1, whether in the donor, recipient or any combination of donor-recipient, were not associated with 10-year allograft outcome in the recipient following deceased donor kidney transplantation.

Impact of steroid maintenance on the outcomes in first-time deceased donor kidney transplant recipients: Analysis by induction type.

To analyze the impact of steroid maintenance on the outcomes in kidney transplant recipients stratified by induction agent received. Patients who underwent first-time deceased donor kidney transplantation between 2000 and 2008 after receiving induction therapy with rabbit-antithymocyte globulin (r-ATG), alemtuzumab or an interleukin-2 receptor blocker (IL-2B) and discharged on a calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)-regimen along with or without steroids were identified from the Organ Procurement and Transplant Network/United Network of Organ Sharing database. For each induction type, adjusted overall and death-censored graft as well as patient survivals were compared between patients discharged on steroid vs no steroid. Among r-ATG induced patients, analysis was repeated after splitting the group into low and high immune risk groups. Among the 37217 patients included in the analysis, 17863 received r-ATG (steroid = 13001, no-steroid = 4862), 3028 alemtuzumab (steroid = 852, no-steroid = 2176) and 16326 IL-2B (steroid = 15008, no-steroid = 1318). Adjusted overall graft survival was inferior (HR = 1.16, 95%CI: 1.06-1.27, P = 0.002) with similar death-censored graft survival (HR = 0.99, 95%CI: 0.86-1.14, P = 0.86) for steroid vs no-steroid groups in r-ATG induced patients. Both adjusted overall and death-censored graft survivals for steroid vs no-steroid groups were similar in alemtuzumab (HR = 0.92, 95%CI: 0.73-1.15, P = 0.47 and HR = 0.87, 95%CI: 0.62-1.22, P = 0.43 respectively) and IL-2B (HR = 1.05, 95%CI: 0.91-1.21, P = 0.48 and HR = 0.94, 95%CI: 0.75-1.18, P = 0.60 respectively) induced groups. Adjusted patient survivals were inferior for steroid vs no-steroid groups in r-ATG induced (HR = 1.31, 95%CI: 1.15-1.49, P < 0.001) but similar in alemtuzumab (HR = 1.02, 95%CI: 0.75-1.38, P = 0.92) and IL-2B (HR = 1.17, 95%CI: 0.97-1.40, P = 0.10) induced patients. Among the r-ATG induced group there were 4346 patients in the low immune risk and 13517 patients in the high immune risk group. Adjusted overall graft survivals were inferior for steroid vs no steroid groups in both low immune (HR = 1.34, 95%CI: 1.09-1.64, P = 0.001) and high immune (HR = 1.18, 95%CI: 1.07-1.30, P = 0.005) risk groups. Adjusted death-censored graft survivals for steroid vs no steroid groups were similar in both low (HR = 1.06, 95%CI: 0.78-1.45, P = 0.70) and high (HR = 1.04, 95%CI: 0.98-1.20, P = 0.60) immune risk groups. Adjusted patient survivals were inferior for steroid vs no steroid groups in both low immune (HR = 1.54, 95%CI: 1.18-2.02, P < 0.001) and high immune (HR = 1.32, 95%CI: 1.16-1.51, P = 0.002) risk groups. Overall, there were significantly higher deaths from infections and cardiovascular causes in patients maintained on steroids. Our study showed an association between steroid addition to a CNI/MMF-maintenance regimen and increased death with functioning graft in patients receiving r-ATG induction for first-time deceased donor kidney transplantation.