J. A. Bradley

Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial.

One third of deceased donor kidneys for transplantation in the UK are donated following cardiac death (DCD). Such kidneys have a high rate of delayed graft function (DGF) following transplantation. We conducted a multicenter, randomized controlled trial to determine whether kidney preservation using cold, pulsatile machine perfusion (MP) was superior to simple cold storage (CS) for DCD kidneys. One kidney from each DCD donor was randomly allocated to CS, the other to MP. A sequential trial design was used with the primary endpoint being DGF, defined as the necessity for dialysis within the first 7 days following transplant. The trial was stopped when data were available for 45 pairs of kidneys. There was no difference in the incidence of DGF between kidneys assigned to MP or CS (58% vs. 56%, respectively), in the context of an asystolic period of 15 min and median cold ischemic times of 13.9 h for MP and 14.3 h for CS kidneys. Renal function at 3 and 12 months was similar between groups, as was graft and patient survival. For kidneys from controlled DCD donors (with mean cold ischemic times around 14 h), MP offers no advantage over CS, which is cheaper and more straightforward.

Defining delayed graft function after renal transplantation: simplest is best.

Background Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF. Methods The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined. Results The incidence of DGF varied widely depending on the definition used (DBD; 24%–70%: DCD; 41%–91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF. Conclusion No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition—the use of dialysis in the first postoperative week—should be universally adopted as the definition of DGF clinically and as a study endpoint.

Early experience of paired living kidney donation in the United kingdom.

Background. Paired living kidney donation became possible in the United Kingdom in 2006 after the introduction of a new legal framework for organ donation. A national matching scheme was subsequently established and we report the early United Kingdom experience of paired donation. Methods. A new national matching algorithm was developed for the introduction of paired donation in the United Kingdom. Initially, all potential two-way exchanges were identified with prioritization according to a points system based on geographical proximity between pairs, calculated human leukocyte antigen antibody reaction frequency (cRF), HLA mismatch of potential transplant, and donor-donor age difference. Three-way exchanges were additionally considered after the first year. Results. The list for paired donation has grown steadily as 3-monthly “matching runs” have been carried out from April 2007, and in July 2008 there were 85 couples registered. Eight paired donor transplants have resulted with a number of identified exchanges unable to proceed. Fewer potential exchanges have been identified than expected due to blood group composition (47 of 85 donors of group A compared with 16 potential recipients [A, AB]) and high levels of cRF (95%–100% in 35% of patients) among listed patients. Conclusions. Paired donation has been introduced successfully in the United Kingdom, adding to living donor transplant activity. The new national program has yielded fewer transplants than initially anticipated but as the scheme evolves, with the use of altruistic, nondirected donors to start a “chain” of transplants, an increase in the number of successful paired donation transplants is anticipated.

Expansion of the Kidney Donor Pool by Using Cardiac Death Donors with Prolonged Time to Cardiorespiratory Arrest

Donation after Cardiac Death (DCD) is an increasingly important source of kidney transplants, but because of concerns of ischemic injury during the agonal phase, many centers abandon donation if cardiorespiratory arrest has not occurred within 1 h of controlled withdrawal of life‐supporting treatment (WLST). We report the impact on donor numbers and transplant function using instead a minimum ‘cut‐off’ time of 4 h. The agonal phase of 173 potential DCD donors was characterized according to the presence or absence of: acidemia; lactic acidosis; prolonged (>30 min) hypotension, hypoxia or oliguria, and the impact of these characteristics on 3‐ and 12‐month transplant outcome evaluated by multivariable regression analysis. Of the 117 referrals who became donors, 27 (23.1%) arrested more than 1 h after WLST. Longer agonal‐phase times were associated with greater donor instability, but surprisingly neither agonal‐phase instability nor its duration influenced transplant outcome. In contrast, 3‐ and 12‐month eGFR in the 190 transplanted kidneys was influenced independently by donor age, and 3‐month eGFR by cold ischemic time. DCD kidney numbers are increased by 30%, without compromising transplant outcome, by lengthening the minimum waiting time after WLST from 1 to 4 h.

A simplified donor risk index for predicting outcome after deceased donor kidney transplantation.

Background. We sought to determine the deceased donor factors associated with outcome after kidney transplantation and to develop a clinically applicable Kidney Donor Risk Index. Methods. Data from the UK Transplant Registry on 7620 adult recipients of adult deceased donor kidney transplants between 2000 and 2007 inclusive were analyzed. Donor factors potentially influencing transplant outcome were investigated using Cox regression, adjusting for significant recipient and transplant factors. A United Kingdom Kidney Donor Risk Index was derived from the model and validated. Results. Donor age was the most significant factor predicting poor transplant outcome (hazard ratio for 18–39 and 60+ years relative to 40–59 years was 0.78 and 1.49, respectively, P<0.001). A history of donor hypertension was also associated with increased risk (hazard ratio 1.30, P=0.001), and increased donor body weight, longer hospital stay before death, and use of adrenaline were also significantly associated with poorer outcomes up to 3 years posttransplant. Other donor factors including donation after circulatory death, history of cardiothoracic disease, diabetes history, and terminal creatinine were not significant. A donor risk index based on the five significant donor factors was derived and confirmed to be prognostic of outcome in a validation cohort (concordance statistic 0.62). An index developed in the United States by Rao et al., Transplantation 2009; 88: 231–236, included 15 factors and gave a concordance statistic of 0.63 in the UK context, suggesting that our much simpler model has equivalent predictive ability. Conclusions. A Kidney Donor Risk Index based on five donor variables provides a clinically useful tool that may help with organ allocation and informed consent.

Copresentation of Intact and Processed MHC Alloantigen by Recipient Dendritic Cells Enables Delivery of Linked Help to Alloreactive CD8 T Cells by Indirect-Pathway CD4 T Cells

In transplantation, direct-pathway CD8 T cells that recognize alloantigen on donor cells require CD4 help for activation and cytolytic function. The ability of indirect-pathway CD4 T cells to provide this help remains unexplained, because a fundamental requirement for epitope linkage is seemingly broken. The simultaneous presentation, by host dendritic cells (DCs), of both intact MHC class I alloantigen and processed alloantigen would deliver linked help, but has not been demonstrated definitively. In this study, we report that following in vitro coculture with BALB/c DCs, small numbers (∼1.5%) of C57BL/6 (B6) DCs presented acquired H-2d alloantigen both as processed allopeptide and as unprocessed Ag. This represented class I alloantigen provides a conformational epitope for direct-pathway allorecognition, because B6 DCs isolated from cocultures and transferred to naive B6 mice provoked cytotoxic CD8 T cell alloimmunity. Crucially, this response was dependent upon simultaneous presentation of class II–restricted allopeptide, because despite acquiring similar amounts of H-2d alloantigen upon coculture, MHC class II–deficient B6 DCs failed to elicit cytotoxic alloimmunity. The relevance of this pathway to solid-organ transplantation was then confirmed by the demonstration that CD8 T cell cytotoxicity was provoked in secondary recipients by transfer of DCs purified from wild-type, but not from MHC class II–deficient, C57BL/6 recipients of BALB/c heart transplants. These experiments demonstrate that representation of conformationally intact MHC alloantigen by recipient APC can induce cytotoxic alloimmunity, but simultaneous copresentation of processed allopeptide is essential, presumably because this facilitates linked recognition by indirect-pathway CD4 Th cells.

Antibody-Mediated Rejection—An Ounce of Prevention Is Worth a Pound of Cure

The presence of preformed, donor‐specific alloantibodies inpatients undergoing renal transplantation is associated with a high risk of hyperacute and acute antibody‐mediated rejection (ABMR), and often limits potential recipients’ access to organs from living and deceased donors. Over the last decade, understanding of ABMR has improved markedly and given rise to numerous, diverse strategies for the transplantation of allosensitized recipients. Antibody desensitization programs have been developed to allow renal transplant recipients with a willing but antibody‐incompatible living donor to undergo successful transplantation, whereas kidney paired exchange schemes circumvent the antibody incompatibility altogether by finding suitable pairs to donors and recipients. Recognizing the complexity of ABMR and the recent developments that have occurred in this important clinical research field, the Roche Organ Transplantation Research Foundation (ROTRF) organized a symposium during the XXIII Congress of The Transplantation Society in Vancouver, Canada, to discuss current understanding in ABMR and ways to prevent it. This Meeting Report summarizes the presentations of the symposium, which addressed key areas that included the interactions between alloantibodies and the complement system in mediating graft injury, technological advancements for assessing antibody‐mediated immune responses to HLA antigens, and the potential benefits and challenges of desensitization and kidney paired donation schemes.

Alloantibody responses after renal transplant failure can be better predicted by donor-recipient HLA amino acid sequence and physicochemical disparities than conventional HLA matching

We have assessed whether HLA immunogenicity as defined by differences in donor–recipient HLA amino‐acid sequence (amino‐acid mismatch score, AMS; and eplet mismatch score, EpMS) and physicochemical properties (electrostatic mismatch score, EMS) enables prediction of allosensitization to HLA, and also prediction of the risk of an individual donor–recipient HLA mismatch to induce donor‐specific antibody (DSA). HLA antibody screening was undertaken using single‐antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The effect of AMS, EpMS, and EMS on the development of allosensitization (calculated reaction frequency [cRF]) and DSA was determined. Multivariate analyses, adjusting for time on the waiting list, maintenance on immunosuppression after transplant failure, and graft nephrectomy, showed that AMS (odds ratio [OR]: 1.44 per 10 units, 95% CI: 1.02–2.10, p = 0.04) and EMS (OR: 1.27 per 10 units, 95% CI: 1.02–1.62, p = 0.04) were independently associated with the risk of developing sensitization to HLA (cRF > 15%). AMS, EpMS, and EMS were independently associated with the development of HLA‐DR and HLA‐DQ DSA, but only EMS correlated with the risk of HLA‐A and ‐B DSA development. Differences in donor–recipient HLA amino‐acid sequence and physicochemical properties enable better assessment of the risk of HLA‐specific sensitization than conventional HLA matching.

Baseline donor chronic renal injury confers the same transplant survival disadvantage for DCD and DBD kidneys.

Histological assessment of baseline chronic kidney injury may discriminate kidneys that are suitable for transplantation, but has not been validated for appraisal of donation after circulatory death (DCD) kidneys. ‘Time‐zero biopsies for 371 consecutive, solitary, deceased‐donor kidneys transplanted at our center between 2006 and 2010 (65.5% DCD, 34.5% donation after brain death [DBD]) were reviewed and baseline chronic degenerative injury scored using Remuzzis classification. High scores correlated with donor age and extended criteria donors (42% of donors), but the spectrum of scores was similar for DCD and DBD kidneys. Transplant outcomes for kidneys scoring from 0 to 4 were comparable (1 and 3 year graft survival 95% and 92%), but were much poorer for kidneys scoring ≥5, with 1 year graft survival only 73%, and 12.5% suffering primary nonfunction. Critically, high Remuzzi scores conferred the same survival disadvantage for DCD and DBD kidneys. On multi‐variable regression analysis, time‐zero biopsy score was the only independent predictor for graft survival, whereas one‐year graft estimated glomerular filtration rate (eGFR) correlated with donor age and biopsy score. In conclusion, the relationship between severity of chronic kidney injury and transplant outcome is similar for DCD and DBD kidneys. Kidneys with Remuzzi scores of ≤4 can be implanted singly with acceptable results.

Early Graft Loss After Kidney Transplantation: Risk Factors and Consequences

Early graft loss (EGL) after kidney transplantation is a catastrophic outcome that is assumed to be more likely after the use of kidneys from suboptimal donors. We therefore examined its incidence, risk factors and consequences in our center in relation to different donor types. Of 801 recipients who received a kidney‐only transplant from deceased donors, 50 (6.2%) suffered EGL within 30 days of transplantation. Significant risks factors for EGL were donation after circulatory death (DCD) (odds ratio [OR] 2.88; pu2009=u20090.006), expanded criteria donor (ECD) transplantation (OR 4.22; pu2009=u20090.010), donor age (OR 1.03; pu2009=u20090.044) and recipient past history of thrombosis (OR 4.91; pu2009=u20090.001). Recipients with EGL had 12.28 times increased risk of death within the first year, but long‐term survival was worse for patients remaining on the waiting list. In comparison with patients on the waiting list but not transplanted, and with all patients on the waiting list, the risk of death after EGL decreased to baseline 4 and 23 months after transplantation, respectively. Our findings suggest that DCD and ECD transplantation are significant risk factors for EGL, which is a major risk factor for recipient death. However, long‐term mortality is even greater for those remaining on the waiting list.