Delayed graft function complicated by spontaneous renal allograft rupture without acute rejection

We report a young male patient who developed spontaneous renal allograft rupture 7 days after cadaveric renal transplant, complicated by delayed graft function, without evidence of rejection on allograft biopsy.     

Risk factors for acute rejection in renal transplant recipients experiencing delayed graft function

Acute rejection (AR) superimposed upon delayed graft function (DGF) following renal transplantation worsens graft outcomes. However, risk factors for AR in patients displaying DGF remain unclear. In this study, 71 patients displaying DGF >/= 5 d were investigated. All received cyclosporine, adjunctive azathioprine or mycophenolate mofetil (MMF), and corticosteroids, with 43 receiving anti-CD25 monoclonal antibody induction. AR episodes were seen in 20 of 71 (28%) patients. Higher C2 levels at days 3 and 5 and the use of MMF were associated with a reduced incidence of AR, with increased HLA-DR mismatch associated with an increased risk for AR. C2 levels at days 3 and 5 below 885 and 1096 ng/mL, respectively, showed best discriminatory values for AR. C2 levels showed no correlation with DGF duration. This study suggests that optimizing immunosuppression in patients with DGF (by ensuring adequate calcineurin inhibitor exposure and the use of potent adjunctive immunosuppression) may reduce the incidence of AR without prolonging the duration of dialysis requirement.     

The relative influence of delayed graft function and acute rejection on renal transplant survival

Three hundred and eight cadaveric renal transplants were analysed to establish the effects of acute rejection in the first 90 days and delayed graft function (DGF) on graft outcome. There were 120 patients (39%) with no DGF and no rejection (group 1), 101 patients (33%) with rejection but no DGF (group 2), 41 patients (13%) with DGF but no rejection (group 3) and 46 patients (15%) with both rejection and DGF (group 4). The actuarial 4-year graft survival rates for groups 1,2,3 and 40.4%, respectively. The acute rejection rate was 101/221 (46%) in patients with initial graft function compared with 46/87 (53%) for those with DGF (²=1.02, P=0.31). Cox stepwise logistic regression analysis demonstrated that DGF was a more powerful predictive factor for poor graft survival (P=0.001) than acute rejection occurring in the first 90 days post-transplant (P=0.034). Further efforts at improving graft outcome should concentrate on reducing the incidence of DGF.     

Perioperative blood pressure control,delayed graft function,and acute rejection after renal transplantation

BACKGROUND: Blood pressure (BP) control immediately after renal transplantation is poorly understood, with patients experiencing both high and low BP levels. Donor kidneys lack the ability to autoregulate their blood flow, meaning high pressures are directly translated to the graft endothelium, whereas reduced perfusion may augment ischemic injury. We hypothesize that early BP control may therefore influence the early alloimmune response. METHODS: A total of 276 patients undergoing primary cadaveric renal transplantation who received cyclosporine-based therapy were followed; standard transplant variables were identified. BP was serially recorded before, during, and after reperfusion until 50 hr after surgery. Variables predicting acute rejection and delayed graft function were identified using Cox and logistic regression models. RESULTS: The mean (SD) BP after surgery was 161(19) mm Hg systolic and 73(12) mm Hg diastolic. Forty-two percent had perioperative hypertension defined by conventional parameters. Increasing postoperative systolic BP, measured as standardized area-under-the-curve, was associated with an increased risk for acute rejection (hazard ratio [per mm Hg]=1.008), independent of other covariables including the preoperative BP level. Diastolic BP was inversely associated with the risk of delayed graft function (odds ratio [per mm Hg]=0.956). CONCLUSIONS: Early hypertension is common after renal transplantation. Early BP control has the potential to influence the risk of allograft rejection and delayed graft function.     

Acute graft pyelonephritis: a potential cause of acute rejection in renal transplant

Acute graft pyelonephritis is a common complication in renal transplant recipients. The consequences of this complication on kidney allograft survival remain controversial. Bacterial infection is likely to activate the immune system, potentially leading to acute or chronic rejection. Here, we report for the first time two documented cases of acute rejection occurring shortly after acute graft pyelonephritis, suggesting that pyelonephritis can initiate acute rejection. The immunologic process leading to the alloimmune response is discussed. These reports suggest that acute rejection should be questioned in case of atypical graft outcome in the context of acute graft pyelonephritis.     

Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute renal graft rejection

BACKGROUND: The panel reactive antibody test (PRA) is an established method for assessing posttransplant risk of immune-mediated graft injury. The panel of reactive T cell assay (PRT) in which transplant candidates' peripheral blood mononuclear cells are tested for reactivity to a panel of allogenic stimulator cells by the IFN-gamma enzyme-linked immunosorbent spot assay analogously assesses the strength of the pretransplant effector-memory alloreactive T cell repertoire. METHODS: PRT assays were performed in 30 kidney transplant candidates and results were correlated with acute rejection (AR). A positive PRT assay was defined as a response to at least 75% of the stimulators tested. RESULTS: A positive pretransplant PRT test was observed in 11 of 30 (37%) patients, and AR within 1 year posttransplantation was seen in 7 of 30 (23%) subjects. Six of the seven (86%) patients with AR were PRT-positive (P=0.01) whereas only one of seven (14%) patients with a PRA greater than 15% had AR. The mean pretransplant PRT percentage was 40% for patients with no AR versus 81% for patients with AR (P=0.01). Estimated glomerular filtration rate (mL/min/1.73 m2) showed a trend towards a lower value in PRT-positive (48+/-15) versus PRT-negative (55+/-13) individuals. CONCLUSIONS: The data suggest that pretransplant PRT screening can identify patients at risk for posttransplant cellular immune mediated graft injury despite the absence of humoral allosensitization. Once confirmed by larger prospective trials, PRT screening could be used to guide clinical decision-making with regard to choosing donor organs and individualizing immunosuppression regimens.     

Effect of immunosuppressive regimen on acute rejection and liver graft function

Despite the use of modern immunosuppressive drugs, acute liver rejection (AR) continues to affect up to 70% of transplant recipients. The aim of this retrospective study was to assess the incidence of acute rejection episodes in patients treated with different immunosuppressive protocols. In our series, 37.3% of patients developed a clinical episode of AR. Analysis of immunosuppression has shown that the most effective immunosuppressive protocols, with regard to prevention of AR, include: antibody anti-IL-2R (anti-IL-2R) + tacrolimus (Tac) + mycophenolate mofetil (MMF) + prednisolone (Pred); anti-IL-2R + tacrolimus (Tac) + Pred; or Tac + Pred (25% vs 28.6% vs 30.4%, respectively). The highest rate of AR (66.6%) was observed among patients with anti-IL-2R and Tac but no steroid treatment, mostly (77.7%) in the initial period after liver transplantation. There were no statistical differences in liver function tests between the group treated with a CsA-based versus a Tac-based therapy. Strong immunosuppression contributed to a relatively low incidence of clinical AR in our series. The lowest rate of AR was observed among patients treated with anti-IL-2R antibody. Tac, and Pred. Deprivation of steroids in the early phase after liver transplantation substantially increased the risk of acute rejection episodes despite the use of anti-CD25. There were no statistically significant differences in liver function tests among those treated with Tac versus CsA in the short-term follow-up.     

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte‐depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti‐thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2‐receptor antagonists (IL2‐RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1‐year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2‐Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte‐depletion induction when the anticipated risk of DGF is increased.     

Interleukin-10-1082 G/a polymorphism and acute renal graft rejection: a meta-analysis

Objective: The aim of this study was to investigate the association between interleukin (IL)-10-1082 (G/A) promoter polymorphism and acute rejection (AR) in renal transplant recipients. Methods: We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register from the inception to March 2015 for relevant studies. Data concerning publication information, population characteristics, and transplant information were extracted. Odds ratios (ORs) was calculated for the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. Results: This meta-analysis included 22 case–control studies including 2779 cases of renal transplant recipients. The pooled estimate showed that the IL-10-1082 GG genotype was not significantly associated with AR risk (OR_random=1.07, 95% CI 0.80–1.43, p?=?0.64). Similarly, the pooled estimate showed that the IL-10-1082 G allele was not significantly associated with AR risk (OR_fixed=1.02, 95% CI 0.90–1.16, p?=?0.74). None of subgroup analyses yielded significant results in the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. Meta-regression confirmed that there was no significant correlation between the pre-selected trial characteristics and our study results. Conclusions: This meta-analysis suggests that IL-10-1082 G/A polymorphism is not significantly associated with AR risk in renal transplant recipients.     

Delayed function reduces renal allograft survival independent of acute rejection

BACKGROUND: Mechanisms by which delayed allograft function reduces renalallograft survival are poorly understood, This study evaluatedthe relationship of delayed allograft function to acute rejectionand long-term survival of cadaveric allografts. METHODS: 338 recipients of cadaveric allografts were followed until death,resumption of dialysis, retransplantation, loss to follow-up,or the study's end, whichever came first. Delayed allograftfunction was defined by dialysis during the first week followingtransplantation, Multivariate Cox proportional hazards survivalanalysis was used to assess the relationship of delayed allograftfunction to rejection and allograft survival. RESULTS: Delayed allograft function, recipient age, preformed reactiveantibody levels, prior kidney transplantation, recipient race,rejection during the first 30 days and rejection subsequentto 30 days following transplantation were predictive of allograftsurvival in multivariate survival models. Delayed allograftfunction was associated with shorter allograft survival afteradjustment for acute rejection and other covariates (relativerate of failure [RR]=1.72 [95% CI, 1.07, 2.76]). The adjustedRR of allograft failure associated with any rejection duringthe first 30 days was 1.99 (1.23, 3.21), and for rejection subsequentto the first 30 days was 3.53 (2.08, 6.00). The impact of delayedallograft function did not change substantially (RR=1.84 [1.15,2.95]) in models not controlling for acute rejection. Theseresults were stable among several subgroups of patients andusing alternative definitions of allograft survival and delayedallograft function. CONCLUSIONS: This study demonstrates that delayed allograft function andacute allograft rejection have important independent and deleteriouseffects on cadaveric allograft survival. These results suggestthat the effect of delayed allograft function is mediated, inpart, through mechanisms not involving acute clinical rejection.     

Non-invasive diagnosis of acute rejection in kidney transplants with delayed graft function

Delayed graft function (DGF) often occurs in kidney transplants from deceased donors. We wanted to provide studies giving more accurate non-invasive tests for acute rejection (AR). Using real-time PCR, we examined the expression of cytolytic molecules such as perforin, granzyme B, and fas-ligand along with serpin proteinase inhibitor-9. We also measured the expression of FOXP3, a characteristic gene of T-regulatory cells known to be involved in AR. These studies were conducted on peripheral blood monocytes, urinary cells, and 48 surveillance kidney biopsies taken from a total of 35 patients with DGF. Of these patients, 20 had a histopathological diagnosis of AR, whereas other 28 had characteristics of acute tubular necrosis (ATN). Expression of cytolytic and apoptotic-associated genes in the biopsy tissue, peripheral blood leukocytes, and urinary cells was significantly higher in patients with AR than that in patients with ATN. Diagnostic parameters associated with FOXP3 gene expression were most accurate in peripheral blood leukocytes and urine cells with sensitivity, specificity, positive and negative predictive values, and accuracy between 94 and 100%. Our study shows that quantification of selected genes in peripheral blood leukocytes and urinary cells from renal transplant patients with DGF may provide a useful and accurate non-invasive diagnosis of AR.     

Analysis of urinary donor-derived DNA in renal transplant recipients with acute rejection

Abstract: In renal transplantation we usually diagnose an acute rejection by based on the results of a needle biopsy; however, this takes time and findings in some cases are not definite. We analysed the urine of renal recipients for the presence of donor DNA in an attempt to establish a diagnostic means of acute rejection. Sixty-four renal transplant recipients were examined. Thirty-seven patients had no trouble after transplantation and 22 patients developed acute rejection, diagnosed based on serum creatinine levels and/or needle biopsy findings of the graft. Five patients had drug-induced renal dysfunction. In female recipients with a male graft we examined urine for the presence of Y-chromosome (SRY and DYZ-1) and in recipients receiving a HLA mismatched graft we investigated the HLA-DR gene (DRB1) by the polymerase chain reaction (PCR) method. Among female recipients with a male graft there were 14 patients with stable renal function and SRY and DYZ-1 on Y-chromosome were negative in 13 (93%) and positive in one, whereas SRY and DYZ-1 of urine were positive in the four female patients with acute rejection and these DNA fragments disappeared in three after rejection therapy. One patient was subjected to haemodialysis. Among 23 recipients of a graft from HLA mismatched donors with stable renal function, DRB1 was negative in 21(91%). Among 18 patients with acute rejection DRB1 was positive in 16 (93%) and negative in two. These DNA fragments disappeared in 13 patients after rejection therapy. In all patients with drug-induced renal dysfunction donor-derived DNA was negative. Presence of donor-specific DNA in the urine of the recipient is associated strongly with acute rejection and analysis of DNA derived from donor cells in urine might be an effective and accurate method for the diagnosis of acute rejection of a renal transplant.