Outcomes of allograft from donor kidney microthrombi and secondary recipient thrombotic microangiopathy: should we consider loosening the belt?

There is currently a huge worldwide demand for donor kidneys for organ transplantation.Consequently,numerous marginal donor kidneys,such as kidneys with microthrombi,are used to save patients'lives.While some studies have shown an association between the presence of microthrombi in donor kidneys and an increased risk for delayed graft function(DGF)(McCall et al.,2003;Gao et al.,2019),other studies have demonstrated that microthrombi negatively impact the rate of DGF(Batra et al.,2016;Hansen et al.,2018),but not graft survival rate(McCall et al.,2003;Batra et al.,2016;Gao et al.,2019).In contrast,Hansen et al.(2018)concluded that fibrin thrombi were not only associated with reduced graft function six months posttransplantation but also with increased graft loss within the first year of transplantation.On the other hand,Batra et al.(2016)found no significant differences in the DGF rate or one-year graft function between recipients in diffuse and focal microthrombi groups.To date,however,the overall influence of donor kidney microthrombi and the degree of influence on prognosis remain controversial,necessitating further research.

Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy

BK polyomavirus-associated nephropathy(BKPyVAN)is a common cause of allograft failure.However,differentiation between BKPyVAN and type I T cell-mediated rejection(TCMR)is challenging when simian virus 40(SV40)staining is negative,because of the similarities in histopathology.This study investigated whether donor-derived cell-free DNA(ddcfDNA)can be used to differentiate BKPyVAN.Target region capture sequencing was applied to detect the ddcfDNAs of 12 recipients with stable graft function,22 with type I TCMR,21 with proven BKPy VAN,and 5 with possible Py VAN.We found that urinary ddcfDNA levels were upregulated in recipients with graft injury,whereas plasma ddcfDNA levels were comparable for all groups.The median urinary concentrations and fractions of ddcfDNA in proven BKPyVAN recipients were significantly higher than those in type I TCMR recipients(10.4 vs.6.1 ng/mL,P<0.001 and 68.4%vs.55.3%,P=0.013,respectively).Urinary ddcfDNA fractions(not concentrations)were higher in the BKPyVAN-pure subgroup than in the BKPyVAN-rejection-like subgroup(81.30%vs.56.64%,P=0.025).With a cut-off value of 7.81 ng/m L,urinary ddcf DNA concentrations distinguished proven BKPyVAN from type I TCMR(area under the curve(AUC)=0.848,95%confidence interval(95%CI):0.734 to 0.963).These findings suggest that urinary ddcf DNA is a non-invasive biomarker which can reliably differentiate BKPy VAN from type I TCMR.

Helper T Cell(CD4^(+))Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity

Antibody-mediated rejection(ABMR)is a major cause of dysfunction and loss of transplanted kidney.The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells.However,the prognosis of patients following current treatment is poor.T follicular helper cells(Tfh)play an important role in allograft-specific antibodies secreting plasma cell(PC)development.Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders,such as transplant rejection and autoimmune diseases.Tacrolimus(Tac),the primary immunosuppressant,prevents rejection by reducing T cell activation.However,its administration should be closely monitored to avoid serious side effects.In this study,we investigated whether Tac delivery to helper T(CD4^(+))cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure.Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development,PC,and donor-specific antibody(DSA)generation without causing severe side effects compared with delivery through the drug administration pathway.This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation.The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.