For comprehensive analysis of outcomes from DDKT cohort, our study involved 123 donors and 246 recipients with follow-up period of 2 years at least after transplantation and detected several possible risk factors for TR. In this study, donor profiles were matched to corresponding recipients for analysis, reducing feasible selection biases in evaluation of relationship between risk factors and outcomes, and may provide pragmatic value in clinical practice.
Given the great infectious risk from over-immunosuppression caused by imbalance between immuno-suppressive protocols and occurrence of rejection, appropriate stratification of recipient is important to clinical practices. Not only could be induction regimen individually tailored for each recipient, but also immunosuppression medication be personalized basing on the profile of immunologic hazard. Hence the assessment of risk factors for rejection would be beneficial to improve graft survival and long-term prognosis of patients.
Traditionally, re-transplantation, grafts from deceased donor and high level of panel reactive antibody (PRA) have been reportedly associated with increased risk of graft loss and rejection after transplantation[11, 12]. In current cohort, these risk factors were also evaluated and none of them demonstrated significant relevance with rejection in multivariate analysis. However, apart from HLA-DQ mismatch as an independent predictor of rejection was confirmed (HR 2.197, 95%CI:1.119–4.317, P = 0.022), we also observed that several unexpected indicators from hemato-biochemical work up of recipients showed statistical relevance in regression model. Precisely, UA with cutoff value of 400µmoI/L, PLT with 185*10^9 and ANC with 5.0*10^9 exhibited robust association with TR and maybe the probable risk factors for it.
Platelet, neutrophil and neutrophil-to-lymphocyte ratio (NLR) have been seemed as the surrogates for inflammatory severity which positively correlated prognosis in several diseases[13, 14]. It's speculated that these parameters or ratios could reflect the systemic inflammation which might have adverse impacts on hematologic cell lines and subsequently result in alteration of their ratios[14, 15]. Current study indicated a positive correlation of both PLT and ANC with TR (HR 2.202, 95%CI:1.051–4.617, P = 0.037 and HR 2.164, 95%CI:1.018–4.599, P = 0.045, respectively). Our hypothesis is that elevated preoperative PLT and ANC of recipients maybe represent robust inflammatory response or over-activated immune system by any cause, which may underlie the pathogenesis of rejection. Thus, for recipients with high preoperative PLT and ANC, aggressive regimen of induction and maintenance immunosuppression could be considered to decrease the risk of rejection in these patients.
Another unexpected finding in our analysis was that preoperative UA levels revealed independent association with TR. However, the comprehensive effect of UA on graft outcomes still remains controversial in published studies[16]. Although hyperuricemia could result in deterioration of renal disease by inducing endothelial dysfunction and inflammatory dysregulation, it is hard to identify that UA is a immediate cause of renal disease due to unclear causal link between elevated UA and impaired renal function[17]. It is unclear why UA could be an independent risk factor for TR in our investigation. However, to our knowledge, the association of decreased UA with reduced graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (allo-SCT) has been verified by animal models, and levels of serum UA could be used as predictor for allo-SCT outcome[18]. We therefore assume that higher level of UA from reduced renal clearance might initiate non-infectious inflammation and contribute to immune reconstitution, which increased the risk of rejection. Moreover, it is not unusual that hyperuricemia would be concomitant with end-stage renal diseases. Thus, although further studies are needed to confirm our results, it is necessary to address the hyperuricemia during perioperative period.
In addition to retrospective design, this study has several inherent limitations. On one hand, despite characteristics of donors were matched to paired recipients and analysed with recipients data at once to control potential confounding variables, regression residual is an important and iterative confounding factor in observational studies. On the other hand, for the sake of reducing negative effects of multicollinearity, the stepwise method was adopted in regression model with matched donor-recipient, probably leading some variables were marginalized by those with more statistical weight. Finally, our data originated from single center, which may somewhat limit its feasibility and relevance in other settings. However, although this retrospective study based on a single-center cohort and need further validation, heterogeneity of large dataset from multi-center or even transnational registry could be significantly reduced in current analysis.