Renal transplantation is the best renal replacement therapy for end-stage renal disease (ESRD).1 In general, a successful kidney transplant (KT) provides substantially longer survival and better quality of life than dialysis.2 Renal allograft survival has increased over past decades due to technical and pharmaceutical progresses, namely with advances in immunosuppression. So, acute rejection (AR) rates during the first year after KT have decreased over the last 15 years to incidences of 10–15%.3 The late rejection rates have also improved over the last years.4 The average survival of a KT is 8 years for deceased and 12 years for living donor transplants.5 Long-term kidney graft survival rates are lower in the United States when compared with Europe (both for deceased and living donor grafts). Between 2005 and 2008, overall 5 and 10 year graft survival rates for deceased donor grafts in Europe were 77 and 56% respectively when compared to American population (Whites, 71 and 46%, Hispanic, 73 and 48%, and African American, 62 and 34%). The reasons why that happens are unknown.6

HLA antibodies are a well-known and serious barrier to successful transplantation and HLA matching is a predictor of allograft and patient survival.7 HLA antibodies usually develop in association with contact to non-self HLA molecules through the exposure to blood products, foreign tissue during transplantation or during pregnancy. It can also happen spontaneously through cross-sensitization from infection and pro-inflammatory events.8,9

Although these antibodies may be donor-specific or non-donor-specific, their presence may increase the risk for acute and chronic rejection. Patients who are highly sensitized face longer waiting times, more graft rejection and consequently poorer graft outcomes.7,10–13

Historically, cytotoxic PRA (panel reactive antibodies) was the main tool to define immunologically high-risk KT recipients.14 An increased PRA means a higher allosensitization and leads to longer waiting times for a second graft. Moreover, it is a strong risk factor for AR and consequently for graft loss after retransplantation.13,15 A few years ago, a study from John Hopkins transplant center suggested, that a more mismatched kidney transplant leads to a higher degree of allosensitization after transplant loss.16 The third most frequent cause for being in the waiting list in United States is a previous failed graft.17 Importantly, over the past decade, the numbers of candidates with PRA≥20%, and particularly ≥80%, have increased18 and this trend particularly affects candidates to a second transplant.19

The authors aimed to evaluate the net change of allosensitization after a first graft failure, its risk factors and impact on retransplantation outcomes.

Renal transplantation is the best renal replacement therapy, however, many recipients face graft loss and must return to dialysis treatment.1 Retransplantation provides the best chance for long-term survival and improved quality of life in these patients as compared to those remaining on dialysis after a graft loss.20,21 It was described that retransplant patients with higher PRA face longer waiting times and have poor retransplantation outcomes.22,23 The impact of HLA matching can be particularly more important in young than older recipients, because the former have a higher likelihood of needing more than one KT during their lifetime.

In our study the proportion of allosensitized patients (PRA>0%) was clearly higher at the second KT and median change in PRA observed between the first and second KT was +10%.

Magee et al. compared a large cohort of kidney graft recipients (more than 2000 second KT versus more than 20,000 first KT), from the Organ Procurement and Transplantation Network registry, and described that retransplant recipients are more allosensitized, even with adjustment for donor and recipient factors (recipient age, race, body mass index, diagnosis, PRA, length of ESRD treatment and level of human leukocyte antigen mismatch) at time of relisting.24

Treébern-Launay et al. compared the long-term patient and graft survival between second and first KT in more than 3000 patients. The transplant patients faced longer time in the waiting list and were also more sensitized when compared with patients at first transplantation. They were more frequently exposed to induction therapy with a lymphocyte-depleting agent,22 as were patients in our study at retransplant. We showed that higher HLA mismatches (A, B, DR HLA), acute rejection in first KT and first graft survival <1 year were risk factors for higher allosensitization (dPRA≥10%) after first graft failure. Some other studies show also that poorer HLA matching at first transplant was associated with higher PRA at retransplant.7,8,23 In contrast, Gritsch et al. found no association between HLA A, B or DR MM at first transplant and PRA at listing for second transplant in a group of 313 pediatric, but they only considered the effect of each of the A, B and DR alleles separately and not the effect of overall HLA mismatching.25

The presence of PRA >0% has been a widely accepted marker for acute rejection risk after kidney transplantation based on retrospective and prospective data.24–27 In our cohort, an increased allosensitization (dPRA>10%) after a first KT failure was associated with higher AR occurrence in the second KT.

Heaphy et al. showed that patients who experienced AR during their first KT were significantly more likely to experience AR during their retransplant with poor graft survival. A higher serum PRA and more A, B or DR HLA mismatches in the second graft were associated with an increased likelihood of AR.28 Coupel et al. analyzed 1174 kidney transplantations, with 233 being second grafts; when long-term second graft survival was examined, they concluded that the number of acute rejections episodes in the first transplant are a risk factor for poor outcomes in the second.26

Magee et al. showed that second KT had more acute rejections in the first graft, with poor outcomes24 which is in agreement with our results. Contrary to our results, Trébern-Launay et al. did not show significant differences in the occurrence of AR between patients who received a first or a second KT; importantly, second KT recipients received better HLA-matched transplants, a finding not observed in our cohort.22

Our results indicated also that shorter time to graft failure in the primary transplant is a risk factor for dPRA>10%, which was associated with retransplant failure. Some other studies showed that graft survival time from the primary transplant significantly predicted graft survival time in the retransplant.28–31

Acute rejection, dPRA≥10% and delayed graft function were independent predictors of retransplant failure. A German study showed that the number of the HLA mismatches and the occurrence of acute rejections episodes, the type of immunosuppression and delayed graft function in the first graft were associated with poor graft survival after second or subsequent renal transplantation.32

Some studies have demonstrated that the higher risk of second graft failure was mainly related to increased levels of preformed HLA antibodies.22,24,27,30,33,34 Others reported a similar graft survival between second and first KT with no differences in the occurrence of AR.35–39 However, these studies have several limitations: the limited number of cohorts analyzed with low statistical power, the single-center design, and the number of adjustment covariates or the short follow-up period.

Kousoulas et al. evaluated patient and graft survival of the 61 renal retransplant recipients with the aim to identify risk factors associated with inferior outcomes and loss of renal graft. They concluded that the number of previous renal transplantations had no effect on graft survival, but it was shown that immunological aspects such as the number of the HLA mismatches and the occurrence of acute rejections episodes were associated with poor graft survival after second or subsequent renal transplantation and on graft survival.37

Our results reflect the major difficulties faced by allosensitized retransplant patients. In order to prevent allosensitization, it is necessary to avoid additional sensitizing events as blood transfusions through the optimization of erythropoietin and iron supplementation. Moreover, immunosuppression withdrawal after kidney graft failure with or without transplantectomy should be cautiously considered, given that it has been shown to be a predictor of allosensitization.38 Donor-specific antibodies (DSAs) appeared frequently when immunosuppressive therapy was discontinued after graft loss. Unfortunately, the information about immunosuppression withdrawal and DSA after a graft failure was not available in our study. Some other limitations of this study must be acknowledged. This is a single center retrospective analysis, which may account for confounding factors. Adjustment for long-term immunosuppression regimens was not done, as it reflects the therapeutic advances over the last 30 years. Our study also failed to consider the effects of some confounding factors such as medication compliance. Historically, the detection of HLA antibodies was based on complement-dependent cytotoxicity (CDC). Its sensitivity for detecting antibodies is low, but the positive predictive value for early antibody mediated rejection is high.15 Currently, HLA antibody screening is carried out on solid phase assays using HLA molecules bound to polystyrene beads using the Luminex platform18. So, the use of cytotoxic PRA as an allosensitization marker is a limitation but it was necessary given the historical nature of our cohort.

In conclusion, this study shows that there is a significant increase in allosensitization after the first kidney failure, particularly in patients experiencing AR and in those transplanted with a higher HLA mismatched graft. Retransplant patients with higher net change of allosensitization, had poorer outcomes after a second KT. We found that AR and higher HLA mismatch were major predictors of increased allosensitization after graft failure. With the advances in immunosuppression therapies, AR has diminished in the last decades, reducing its impact on allosensitization at retransplant nowadays. Differently, reduced HLA mismatching at a first KT remains an important factor for an allosensitization increase at retransplant. So, de-emphasis of HLA matching in current allocation policies may be undesirable, particularly in younger patients, since they have a higher likelihood of needing a second transplant during their lifetime.

Nothing to declare.