renal transplantation is regarded as the optimal treatment for patients with end - stage renal disease . however , as long - term graft survival is still limited , most transplant patients will face graft loss after 9 - 10 years . these patients are generally more fragile and in considerable need of new grafts , in comparison to nave patients waiting for their first renal transplantation . it has been reported that the best approach to treat most patients suffering from chronic renal allograft failure is to perform a kidney retransplant , in hopes of avoiding the high risk of morbidity and mortality with a return to dialysis . these patients , however , are commonly human leukocyte antigens- ( hla- ) sensitized because of exposure to previous allograft(s ) ; thus there is a lower chance of their receiving a retransplant . retransplantation accounts for 1315% of the annual transplants performed in usa and only approximately 5% of those performed in europe . renal retransplant patients had high rates of acute rejection , from 33% to 69% , as reported in previous studies [ 46 ] . about two - thirds of these rejections were verified as antibody - mediated rejection ( abmr ) , comprising the primary cause of early graft loss . thus , it is well recognized that the risk of abmr in retransplantation increases markedly and needs to be prevented as much as possible . in contrast , the risk of t - cell mediated rejection ( tcmr ) in retransplantation is less of a concern . compared to first transplant patients , it is unclear whether the incidence of acute tcmr would significantly increase in retransplant patients without early abmr . in other words , if de novo donor - specific antibody ( dsa ) and its mediated abmr could be prevented successfully in retransplantation , would tcmr be brought to the forefront as an important issue ? here , we report on the early transplant outcomes of 33 second , third , and fourth kidney transplants performed at our hospital within the last 3 years . analysis focused particularly on the incidence and patterns of the early acute rejection episodes , as well as one - year graft and patient survival . between january 2013 and december 2015 , a total of 703 kidney transplants were performed at tongji hospital , including 521 transplants from deceased donors ( donation after brain death or cardiac death ) and 182 from living - related donors . of these , 662 ( 94% ) were first transplantations and 41 ( 6% ) were retransplantations . in the current retrospective study , for the retransplant group , we included 33 adult patients , who received a second , third , or fourth renal allograft with thymoglobulin induction therapy and tacrolimus - based maintenance therapy . the exclusion criteria were as the following : ( 1 ) pediatric recipients ; ( 2 ) renal allografts from pediatric donors ; ( 3 ) patients who received no induction therapy or received induction therapy other than thymoglobulin ; ( 4 ) patients who received a multiorgan transplant . for the control group , we selected 90 patients who received a first renal allograft during the same period and fulfilled the same inclusion and exclusion criteria . this study was performed after approval by the ethics committee at tongji hospital , tongji medical school , huazhong university of science and technology . data on transplantations and hospital stays , as well as follow - up data , were collected from hospital records . baseline characteristics , such as recipient age and gender , donor type ( deceased or living ) , number of previous transplants , cold ischemia time , number of hla mismatches , pretransplant panel reactive antibody ( pra ) percentages divided into groups ( 010% , > 10%50% , and 50% ) , and preformed dsa , were collected and analyzed . in addition , early clinical outcomes , including the generation of de novo dsa , rate of delayed graft function ( dgf ) , the frequency and type of acute allograft rejection ( cellular or antibody - mediated rejection ) , and one - year graft and patient survival , were analyzed . dgf was defined as the need for more than 1 dialysis during the first week after transplant . hla class i and ii antibody screenings were performed using flowpra ( one lambda , inc . , canoga park , ca ) , and the specificity determination was measured by luminex using labscreen single antigen beads ( one lambda , inc . , canoga park , ca ) . all patients received induction therapy with thymoglobulin and maintenance immunosuppression with tacrolimus , mycophenolate mofetil , and steroids . because of differences in immunological risk , the dosage and duration of the thymoglobulin administration were slightly different for the retransplant group , compared to the control group . the initial administration of thymoglobulin was finished intraoperatively , before the graft reperfusion , at a dose of 50  mg in the retransplant group and a dose of 25  mg in the control group . then , it was used daily by the retransplant group from day 1 to day 4 , reaching a total dosage of 125150  mg . in the control group , thymoglobulin was given from day 0 to day 2 at a daily dose of 25  mg . the peripheral blood lymphocyte counts were frequently monitored within the first 2 weeks after renal transplantation . methylprednisolone was given intravenously from day 0 to day 2 ( 500  mg / d ) , followed by oral doses of prednisone at 50  mg / d , which was then tapered every other day to a maintenance dose of 10  mg / d . mycophenolate mofetil was administered at a dose of 1.5  g / d and was subsequently reduced to 1  g / d depending on the individual 's white blood cell count . tacrolimus was started at day 3 , with a targeted trough level of 810  ng / ml initially and 68  ng / ml one month after transplantation . in our center , the decision of desensitization was mainly based on the laboratory testing results for pretransplant pra , preformed dsa , hla mismatch ( mm ) , and flow complement - dependent cytotoxicity ( cdc ) . as shown in figure 1 , sensitized patients were not required to be desensitized in the following two situations : ( 1 ) hla 0  mm between donor and recipient and ( 2 ) hla mm  1 , pra < 50% with negative dsa and flow cdc . in contrast , desensitization was suggested for sensitized patients in any of the following conditions : ( 1 ) hla mm  1 , dsa positive , and negative or weakly positive flow cdc ( 1015% ) ; ( 2 ) hla mm  1 and pra  50% with negative dsa and flow cdc . for a few highly sensitized patients with flow cdc  15% , the upcoming transplantation was then avoided due to the limitations of current desensitization therapy . the protocol we used to desensitize patients involved a combination of plasmapheresis ( pp ) , intravenous immunoglobulin ( ivig ) , and/or rituximab ( rtx ) . ivig was used at a dose of 300400  mg / kg each time and rtx was given once at a dose of 200  mg . in general , acute rejection was diagnosed using kidney biopsies upon banff 2007 or 2013 classification . when a tissue analysis was not available , the clinical diagnosis was based on an otherwise unexplained elevation of serum creatinine levels , coupled with appropriate physical signs ( including edema , oliguria , fever , or weight gain ) . all allograft biopsies were routinely stained for hematoxylin and eosin ( he ) and immunohistochemistry for c4d , cd3 , cd4 , and cd8 . the diagnosis of acute tcmr was based on the following criteria : ia , cases with significant interstitial infiltration ( > 25% of parenchyma affected , i2 or i3 ) , and foci of moderate tubulitis ( t2 ) ; ib , cases with significant interstitial infiltration ( > 25% of parenchyma affected , i2 or i3 ) , and foci of severe tubulitis ( t3 ) ; iia , cases with mild - to - moderate intimal arteritis ( v1 ) ; iib , cases with severe intimal arteritis comprising > 25% of the luminal area ( v2 ) ; iii , cases with  transmural  arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation ( v3 ) . acute abmr was defined as a biopsy with or without c4d , evidence of acute renal injury and microvascular inflammation , in the presence of circulating dsa . if an episode of abmr occurred together with acute tcmr , it was also defined as abmr . early acute rejection referred to a rejection that developed < 90 days after transplantation . in our descriptive statistical analysis , results are expressed as numerical values and percentages for categorical variables and as mean values with standard deviation ( sd ) for continuous variables . the retransplant group comprised 28 ( 84.9% ) second , 4 ( 12.1% ) third , and 1 ( 3% ) fourth kidney transplants . the majority of patients received kidneys from deceased donors ( 72.7% in retransplant group and 100% in control group ) . no statistical difference was observed between the two groups in terms of cold ischemia time and the global hla mismatch ( 3.2  1.2 in the retransplant group versus 3.5  1.2 in the control group ) . however , in relation to the pretransplant pra levels , a much higher incidence of hla presensitization was present in the retransplant recipients than in the first transplant recipients ( 57.6% versus 3.3% , p < 0.001 ) . in particular , 11 ( 33.3% ) retransplanted patients were highly presensitized , as evidenced by the high pretransplant pra levels that were detected ( class i or class ii  50% ) . based on our criteria , 7 sensitized patients , including 3 patients with positive preformed dsa , received desensitization therapy to decrease anti - hla antibody levels and ensure a negative flow cdc before their retransplants . early transplant outcomes were then evaluated on the basis of the frequency of dgf and acute rejection , as well as one - year graft and patient survival . the incidence of dgf in both groups was not high , with 12.1% in the retransplant group and 17.8% in the control group ( p > 0.05 ) . the rates of acute abmr in both groups were similarly low , with 6.1% ( 2/33 ) in the retransplant group and 4.4% ( 4/90 ) in the control group ( p > 0.05 ) . in the retransplant group , two patients unexpectedly generated large amounts of de novo dsa in the first week after transplantation , resulting in severe acute abmr of renal allografts and eventual graft loss . in the control group , 3 grafts developed mild or moderate acute abmr , which was successfully reversed by treatment with pp + ivig . unfortunately , severe acute abmr was also seen in the control group , leading to graft loss in 1 patient . in the control group , acute tcmr was only seen in 5.6% ( 5/90 ) of the patients with an induction therapy of low thymoglobulin doses . however , even when a higher total dosage of thymoglobulin was administered , resulting in a satisfactory decline in peripheral blood lymphocyte count ( figure 2 ) , a much higher rate of tcmr was still observed in the retransplant group ( 30.3% versus 5.6% in the control group , p < 0.001 ) . a total of 14 acute tcmr episodes were observed in 10 of 33 retransplant patients . among them , 4 patients had 2 sequential episodes of early acute tcmr . the acute tcmr usually occurred around 2 weeks after the retransplantation and could be successfully reversed by either the high - dose steroid pulse therapy alone or its combination with thymoglobulin . his first renal allograft was from his sister ( half hla match ) , and the graft developed chronic failure after 10 years . his preretransplant pra levels were not significantly elevated ( class i : 18% and class ii : 2% ) . for his second transplant with hla 3  mm , ivig was given at a daily dose of 1020  g from day 0 to day 11 . the second renal graft achieved immediate function with serum creatinine ( scr ) levels decreasing rapidly and reaching normal levels at day 7 . however , increased scr levels were subsequently observed at around day 14 without detected dsa . acute tcmr was the suspected clinical diagnosis , and thus 3 doses of methylprednisolone ( mp , 500  mg / d ) were administered . after the treatment , the patient 's scr levels decreased to 117  mol / l at day 23 . surprisingly , at day 31 after transplantation , the patient once again had elevated scr levels ( 221  mol / l ) , and a biopsy was performed ( figure 3(a ) ) . pathological results indicated acute tcmr , banff 2007 grade iia ( i3 , t2 , v1 , and g0 ) , with extensive t - cell infiltration and negative c4d staining ( figure 3(b ) ) . the patient fully recovered after treatment with thymoglobulin ( 25  mg / d ) for 4 days and subsequent mp doses ( 500  mg / d ) for 3 days ( figure 3(a ) ) . interestingly , almost all the episodes of tcmr were observed in lower presensitized retransplant patients with pretransplant pra < 50% ( table 2 ) . in contrast , only 1 of 10 highly sensitized patients ( pra  50% ) developed acute tcmr . this patient did not receive desensitization due to 0 mm of hla to his donor . furthermore , none of the highly sensitized patients with desensitization therapy ( n = 7 ) developed acute tcmr , indicating that desensitization may have some role in the prevention of early tcmr ( table 2 ) . both groups had high rates of graft and patient survival at the one - year mark ( table 1 ) . in the retransplant group , graft and patient survival at 1 year were 93.9% and 100% , respectively . renal allograft failure was only seen in 2 retransplant patients , as a result of early severe acute abmr . in the control group , one female patient lost her graft in the early period after transplantation because of severe acute abmr . two patients lost their grafts due to renal artery rupture caused by donor - derived infections of candida albicans . additionally , the other 4 patients in the control group died with a functioning graft : 3 patients died from severe interstitial pneumonia which might be cytomegalovirus- ( cmv- ) relevant , while 1 patient died of cardiac arrest during surgery for renal graft rupture . since the recipients of retransplantation are usually sensitized to certain mismatched hla antigens because of exposure to previous allograft(s ) , they are at high risk for the development of acute abmr . this process is mediated by either preformed or induced dsa that is produced as a result of an anamnestic response by memory b cells . consequently , considerable efforts have been made to prevent abmr in kidney retransplantation , including a stringent immunological selection of donors , pretransplant desensitization therapy , and more potent induction therapy . as a result , since the hla presensitization may also result in the generation of alloantigen - specific memory t cells , which could mediate the so - called second - set rejection that is rather difficult to block or inhibit [ 11 , 12 ] , it is important to investigate the incidence and patterns of acute rejection in kidney retransplantation . in the current retrospective study , we included 33 retransplant patients and 90 first transplant patients with similar protocols of induction therapy and maintenance therapy . excellent short - term clinical outcomes were obtained in both groups , as evidenced by high rates of one - year graft and patient survival and low incidences of early acute abmr . even so , a much higher rate of early acute tcmr was observed in the retransplant group than in the first transplant group , which has been rarely reported or emphasized in the literature . it is well known that despite attempts devoted to improving outcomes in highly sensitized patients by using desensitization protocols , acute abmr rates remain high , afflicting about 28%40% of all cases [ 13 , 14 ] . in our cohort , however , a much lower incidence of acute abmr ( 6.1% ) was observed in retransplant patients , leading to significantly improved short - term graft survival . this result is different from previous studies , which could be explained by our cautious selection of patients and donors ( by avoiding flow cdc positive transplantation ) , the expanded indications for desensitization ( patients who had negative dsa and flow cdc but with pra  50% were given desensitization ) , and the lack of routine primary allograft nephrectomies ( implying no massive reduction in immunosuppressive drugs after the return to dialysis ) . in addition , compared to other studies which mainly focused on third and fourth renal transplant patients , the majority of our retransplant population were second graft recipients , who may have fewer anti - hla immunization and memory responses . finally , the ethnic background of our patients differs from caucasian and african american patients , which could influence transplant outcomes as well . notably , even with more potent thymoglobulin induction therapy , the retransplant patients in our study had a much higher incidence of early acute tcmr compared to the first transplant group . one study showed a relatively higher rate of both abmr ( 22% ) and tcmr ( 40% ) in 37 presensitized kidney transplant patients without any desensitization treatment . however , they mainly focused on abmr in their study and did not discuss anything about the problem of acute tcmr . in the present study , we found that the type of acute tcmr had the following characteristics : ( 1 ) usually occurring around 2 weeks after the retransplantation ; ( 2 ) repeated occurrence in some of the patients ; and ( 3 ) the fact that it could be successfully reversed by high - dose steroids and/or thymoglobulin . since almost all these episodes of tcmr were effectively reversed , the short - term clinical outcome was not affected in any way . however , long - term graft survival still warrants further observation . the mechanisms for the elevated occurrence of early acute tcmr in retransplant patients also remain unclear . in retransplant patients , there could be two potential approaches for the generation of alloreactive memory t cells : ( 1 ) direct alloantigenic stimulation of nave t cells during the course of the previous transplantation and ( 2 ) homeostatic proliferation in response to transient lymphopenia resulting from t - cell depletion therapy , which induces the proliferation and differentiation of nave t cells into memory cells . in contrast to nave t cells , memory t cells have lower activation thresholds and are less dependent on costimulation signals , are more resistant to killing by t - cell depletion therapy and regulation by regulatory t cells ( treg ) , and are less susceptible to conventional immunosuppressive agents . these features lead us to speculate that memory t cells may be responsible for the early acute tcmr observed in our retransplant patients . in the future , we will focus on memory t cells and try to provide direct evidence for our hypothesis . additionally , we found that none of the highly presensitized retransplant patients with desensitization therapy developed early acute tcmr , indicating that desensitization may have some role in the prevention of early tcmr . however , we can not draw a clear conclusion due to the small sample size in our current study . in conclusion , our data on kidney retransplantation show excellent clinical outcomes with low incidence of early acute abmr and satisfactory one - year patient and graft survival . however , the retransplant patients are at higher risk for the development of early acute tcmr , which requires accurate diagnosis and prompt treatment .