Perioperative administration of high‐dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta‐analysis

Delayed graft function (DGF) due to ischemia–reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta‐analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high‐dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I² = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47–1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25–11.68, P = 0.02). Perioperative, high‐dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.     

High incidence of delayed graft function in HIV‐infected kidney transplant recipients

Kidney transplantation (KT) outcomes in human immunodeficiency virus (HIV)‐infected recipients are under continuous research. High incidence of early post‐transplant complications such as acute rejection has been observed. A multicenter study including HIV‐infected patients who underwent KT in Spain, from 2001 to 2011, was performed. The study population included 108 recipients, 36 HIV‐infected, and 72 matched HIV‐negative KT recipients. HIV‐infected recipients developed more delayed graft function (DGF) (52% vs. 21%, P < 0.001). One‐ and 3‐year graft survival was 91.6% and 86.2% in HIV‐infected patients, and 97.1% and 94.7% in HIV‐negative patients (P = 0.052). In two‐variate Cox analysis, HIV infection was not a predictor of graft loss after adjusting for time on dialysis, acute rejection, and DGF. Multivariate analysis for DGF revealed HIV‐positive status as independent risk factor. We analyzed the evolution of immunosuppressive and antiretroviral therapy (ART). In HIV‐infected patients tacrolimus trough levels were very high in the first week and significantly lower in the second week post‐transplant (P = 0.042). Post‐transplant ART was significantly changed: protease inhibitors use decreased (P = 0.034) and integrase inhibitor use increased (P < 0.001). DGF is another frequent early complication in HIV‐infected recipients that can affect graft survival. Strategies to prevent DGF and antiretroviral regimes with less drug interactions could improve outcomes.     

Early post‐transplant conversion from tacrolimus to belatacept for prolonged delayed graft function improves renal function in kidney transplant recipients

Prolonged delayed graft function (DGF) in kidney transplant recipients imparts a risk of poor allograft function; tacrolimus may be detrimental in this setting. We conducted a retrospective single center analysis of the first 20 patients converted to belatacept for prolonged DGF as part of a clinical protocol as a novel treatment strategy to treat prolonged DGF. Prior to conversion, patients underwent an allograft biopsy to rule out rejection and confirm tubular injury. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months post‐transplant; secondary outcome was the change in eGFR 30 days post‐belatacept conversion. At 1 year post‐transplant, the mean eGFR was 54.2 (SD 19.2) mL/min/1.73 m². The mean eGFR on the day of belatacept conversion was 16 (SD 12.7) mL/min/1.73 m² and rose to 43.1 (SD 15.8) mL/min/1.73 m² 30 days post‐conversion (P<.0001). The acute rejection rate was 20% with 100% patient survival at 12 months post‐transplant. There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy. Belatacept conversion for prolonged DGF is a novel treatment strategy that resulted in an improvement in eGFR. Additional follow‐up is warranted to confirm the long‐term benefits of this strategy.     

Pre‐existing donor‐specific antibodies are detrimental to kidney allograft only when persistent after transplantation

Donor‐specific antibodies (DSA) increase the risk of allograft rejection and graft failure. They may be present before transplant or develop de novo after transplantation. Here, we studied the evolution of preformed DSA and their impact on graft outcome in kidney transplant recipients. Using the Luminex Single Antigen assay, we analyzed the sera on the day of transplantation of 239 patients who received a kidney transplant. Thirty‐seven patients (15.5%) had pre‐existing DSA detected the day of transplantation. After 5 years, the pre‐existing DSA disappeared in 22 patients whereas they persisted in 12. Variables associated with DSA persistence were age <50 years (P = 0.009), a history of previous transplantation (P = 0.039), the presence of class II DSA (P = 0.009), an MFI of preformed DSA >3500 (P < 0.001), and the presence of two or more DSA (P < 0.001). DSA persistence was associated with a higher risk of graft loss and antibody‐mediated rejection. Previously undetected preformed DSA are deleterious to graft survival only when they persist after transplantation.     

Risk factors for and outcomes of delayed graft function in live donor kidney transplantation – a retrospective study

Delayed graft function (DGF) in deceased donor kidney transplantation is associated with worse outcomes. DGF has been less well studied in live donor transplantation. We aimed to examine the risk factors for DGF, and associations between DGF and short‐ and long‐term outcomes in live donor kidney transplant recipients. Using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we included live donor kidney transplants performed in Australia and New Zealand over 2004–2015 and excluded pediatric recipients (n = 440), pathological donors (n = 97), grafts that failed in the first week (as a proxy for primary non function; n = 38), and grafts with missing DGF data (n = 46). We used multivariable logistic regression to identify the risk factors for DGF and the association between DGF and rejection at 6 months; Cox proportional hazards models to examine the relationship between DGF and patient and graft survival; and linear regression to examine the association between DGF and eGFR at 1 year. DGF occurred in 77 (2.3%) of 3358 transplants. Risk factors for DGF included right‐sided kidney [odds ratio (OR) 2.00 (95% CI 1.18, 3.40)], donor BMI [OR 1.06 per kg/m² (95% CI 1.01, 1.12)]; increasing time on dialysis and total ischemic time [OR 1.09 per hour (1.00, 1.17)]. DGF was associated with increased risk of rejection at 6 months [OR 2.37 (95% CI 1.41, 3.97)], worse patient survival [HR 2.14 (95% CI 1.21, 3.80)] and graft survival [HR 1.98 (95% CI 1.27, 3.10)], and worse renal function at 1 year [Coefficient ‐9.57 (95% CI ?13.5, ?5.64)]. DGF is uncommon after live donor kidney transplantation, but associated with significantly worse outcomes. The only modifiable risk factors identified were kidney side and total ischemic time.     

DCD donor hemodynamics as predictor of outcome after kidney transplantation

Insufficient hemodynamics during agonal phase—ie, the period between withdrawal of life‐sustaining treatment and circulatory arrest—in Maastricht category III circulatory‐death donors (DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen saturation (SpO2‐with pulse oximetry at the fingertip) and systolic blood pressure (SBP‐with arterial catheter) were measured during agonal phase, and were dichotomized into minutes of SpO2 > 60% or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. Outcome measures were and primary non‐function (PNF), delayed graft function (DGF), and three‐year graft survival. Primary non‐function (PNF) rate was 6.6%, delayed graft function (DGF) rate was 67%, and graft survival at three years was 76%. Longer periods of agonal phase (median 16 min [IQR 11‐23]) contributed significantly to an increased risk of DGF (P = .012), but not to PNF (P = .071) and graft failure (P = .528). Multiple logistic regression analysis showed that an increase from 7 to 20 minutes in period of SBP < 80 mmHg was associated with 2.19 times the odds (95% CI 1.08‐4.46, P = .030) for DGF. In conclusion, duration of agonal phase is associated with early transplant outcome. SBP < 80 mmHg during agonal phase shows a better discrimination for transplant outcome than SpO2 < 60% does.     

Laparoscopic sleeve gastrectomy improves renal transplant candidacy and posttransplant outcomes in morbidly obese patients

Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new‐onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single‐center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011‐2016 (n = 20). Post‐LSG kidney recipients were compared with similar‐BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed‐rank test were used to compare groups. Among post‐LSG patients, mean BMI ± standard deviation (SD) was 41.5 ± 4.4 kg/m² at initial encounter, which decreased to 32.3 ± 2.9 kg/m² prior to transplantation (P < .01). No complications, readmissions, or mortality occurred following LSG. After transplantation, one patient (5%) experienced DGF, and no patients experienced NODAT. Allograft and patient survival at 1‐year posttransplantation was 100%. Compared with non‐LSG patients, post‐LSG recipients had lower rates of DGF (5% vs 20%) and renal dysfunction–related readmissions (10% vs 27.5%) (P < .05 each). Perioperative complications, allograft survival, and patient survival were similar between groups. These data suggest that morbidly obese patients with end‐stage renal disease who undergo LSG to improve transplant candidacy, achieve excellent posttransplantation outcomes.     

Polygenic risk score as a determinant of risk of non‐melanoma skin cancer in a European‐descent renal transplant cohort

Renal transplant recipients have an increased risk of non‐melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome‐wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P‐value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P‐value threshold 1 × 10^?5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P‐value threshold 1 × 10^?5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10^?7; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens.     

Discovery of non‐HLA antibodies associated with cardiac allograft rejection and development and validation of a non‐HLA antigen multiplex panel: From bench to bedside

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non‐HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody–negative, endothelial cell crossmatch–positive sera obtained from 12 cardiac allograft recipients at the time of biopsy‐proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non‐HLA antibodies associated with rejection (P < .1) including 4 newly identified non‐HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non‐HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non‐HLA antigens synergize with HLA donor‐specific antibodies and significantly increase the odds of rejection (P < .1). The non‐HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non‐HLA antibodies identifies cardiac transplant recipients at risk of rejection.     

Donor‐specific anti‐HLA antibodies detected by Luminex: predictive for short‐term but not long‐term survival after heart transplantation

In heart transplantation, the clinical significance of pretransplant donor‐specific antibodies (DSA) detected by solid phase assay (SPA), which is more sensitive than the conventional complement‐dependent cytotoxicity (CDC) assays, is unclear. The aim was to evaluate SPA performed on pretransplant sera for survival after heart transplantation. Pretransplant sera of 272 heart transplant recipients were screened for anti‐HLA antibodies using CDC and SPA. For determination of pretransplant DSA, a single‐antigen bead assay was performed. The presence of anti‐HLA antibodies was correlated with survival. Secondary outcome parameters were acute cellular rejection, graft coronary vasculopathy and ejection fraction. In Kaplan–Meier analysis, SPA‐screening did not predict survival (P = 0.494), this in contrast to CDC screening (P = 0.002). However, the presence of pretransplant DSA against HLA class I was associated with decreased short‐term survival compared to non‐DSA (P = 0.038). ROC curve analysis showed a sensitivity of 76% and specificity of 73% at a cutoff of 2000 MFI. In contrast, the presence of anti‐HLA antibodies had no influence on long‐term survival, rejection incidence, and graft function. Thus, detection of DSA class I in pretransplant serum is a strong predictor of short‐term, but not long‐term survival and may help in the early management of heart transplant patients.     

Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients

Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy‐proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high‐risk AA kidney transplant patients over a 2‐year follow‐up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6 months (13% vs 0%; P = .016) compared to 24 months (13% vs 7%; P = .521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12 mg/day) compared to nonexpressers (8 mg/day; P < .001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P = .006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5 mL/min vs 50.0 mL/min; P = .003) at 24 months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.     

Quantitative PCR of INDELs to measure donor-derived cell-free DNA—a potential method to detect acute rejection in kidney transplantation: a pilot study

The quantification of donor-derived cell-free DNA (ddcfDNA) in recipient's plasma is a novel, but technically challenging noninvasive method to assist the diagnosis of acute rejection (AR). A quantitative real-time PCR (qPCR) approach targeting insertion/deletion polymorphisms (INDEL) was adapted to measure ddcfNA in plasma samples from 29 kidney transplant recipients obtained at time of clinically indicated biopsies (eight patients with a histologically verified AR, nine with borderline rejection and 12 without evidence of rejection). Measured ddcfDNA levels of smaller INDEL amplicon targets differed significantly (P = 0.016, Kruskal–Wallis H test) between recipients with biopsy-proven AR (median 5.24%; range 1.00–9.03), patients without (1.50%; 0.41–6.50) and patients with borderline AR (1.91%; 0.58–5.38). Similarly, pairwise testing by Mann–Whitney U-tests revealed significant differences between recipients with AR and without AR (P = 0.012) as well as patients with AR and borderline histology (P = 0.015). Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve for discriminating AR and non-AR biopsies of 0.84 (95% CI: 0.66–1.00). The determined cutoff value of 2.7% ddcfDNA showed a sensitivity of 0.88 (95% CI: 0.63–1.00) and specificity of 0.81 (95% CI: 0.64–0.98). INDEL qPCR represents a novel method to quantify ddcfDNA on standard qPCR instruments within 6–8 h with high sensitivity and specificity to detect AR.     

Effects of expanded allocation programmes and organ and recipient quality metrics on transplant‐related costs in kidney transplantation – an institutional analysis

Expansions of donor pools have a controversial impact on healthcare expenditures. The aim of this study was to investigate the emerging costs of expanded criteria donor (ECD) kidney transplantations (KT) and to identify independent risk factors for increased transplant‐related costs. We present a retrospective explorative analysis of hospital costs and reimbursements of KTs performed between 2012 and 2016 in a German university hospital. A total of 174 KTs were examined, including 92 (52.9%) ECD organ transplantations. The ECD group comprised 43 (24.7%) ‘old‐for‐old’ transplantations. Median healthcare costs were 19 570€ (IQR 18 735–27 405€) in the standard criteria donor (SCD) group versus 25 478€ (IQR 19 957–29 634€) in the ECD group (+30%; P = 0.076). ‘Old‐for‐old’ transplantations showed the highest healthcare expenditures [26 702€ (19 570–33 940€)]. Irrespective of the allocation group, transplant‐related costs increased significantly in obese (+6221€; P = 0.009) and elderly recipients (+6717€; P = 0.019), in warm ischaemia time exceeding 30 min (+3212€; P = 0.009) and in kidneys with DGF or surgical complications (+8976€ and +10 624€; both P < 0.001). Transplantation of ECD organs is associated with incremental costs, especially in elderly and obese recipients. A critical patient selection, treatment of obesity before KT and keeping warm ischaemia times short seem to be crucial, in order to achieve a cost‐effective KT regardless of the allocation group.     

Combined liver–kidney transplantation versus liver transplant alone based on KDIGO stratification of estimated glomerular filtration rate: data from the United Kingdom Transplant registry – a retrospective cohort study

Patient selection for combined liver–kidney transplantation (CLKT) is a current issue on the background of organ shortage. This study aimed to compare outcomes and post‐transplant renal function for patients receiving CLKT and liver transplantation alone (LTA) based on native renal function using estimated glomerular filtration rate (eGFR) stratification. Using the UK National transplant database (NHSBT) 6035 patients receiving a LTA (N = 5912; 98%) or CLKT (N = 123; 2%) [2001–2013] were analysed, and stratified by KDIGO stages of eGFR at transplant (eGFR group‐strata). There was no difference in patient/graft survival between LTA and CLKT in eGFR group‐strata (P > 0.05). Of 377 patients undergoing renal replacement therapy (RRT) at time of transplantation, 305 (81%) and 72 (19%) patients received LTA and CLKT respectively. A significantly greater proportion of CLKT patients had severe end‐stage renal disease (eGFR < 30 ml/min/1.73 m²) at 1 year post‐transplant compared to LTA (9.5% vs. 5.7%, P = 0.001). Patient and graft survival benefit for patients on RRT at transplantation was favouring CLKT versus LTA (P = 0.038 and P = 0.018, respectively) but the renal function of the long‐term survivors was not superior following CLKT. The data does not support CLKT approach based on eGFR alone, and the advantage of CLKT appear to benefit only those who are on established RRT at the time of transplant.     

Former smoking and early and long‐term graft outcome in renal transplant recipients: a retrospective cohort study

Smoking is associated with unfavourable outcome in solid‐organ transplant recipients. Nicotine may predispose to kidney injury by increasing oxidative stress. We hypothesized that former smoking negatively affects graft outcome in kidney transplant recipients and especially those with delayed graft function (DGF). We included adult recipients of a kidney transplant between 1 January 2003 and 1 October 2015 at Ghent University Hospital and recorded outcomes until 31 October 2015. We used Kaplan–Meier and multivariable Cox proportional hazard analysis to examine the relationship between former smoking at the time of transplantation and the incidence of 10‐year graft loss with and without censoring for death in 1013 participants. We evaluated mean differences in eGFR over time by a random intercept and slope model, considering a linear time effect. After adjusting for potential confounders, a history of smoking was associated with an increased hazard of graft loss (adjusted hazard ratio (aHR) 1.60; 95% CI: 1.17–2.17; P = 0.003) and death‐censored graft loss (aHR 2.29; 95% CI: 1.41–3.72; P = 0.001). The linear time trend of eGFR was different between former and never smokers (P = 0.001). To conclude, former smoking exerts long‐lasting negative effects on graft outcome and this independent of DGF.     

Kidney transplant from uncontrolled donation after circulatory death donors maintained by nECMO has long‐term outcomes comparable to standard criteria donation after brain death

Uncontrolled donation after circulatory death (uDCD) increases organ availability for kidney transplant (KT) with short‐term outcomes similar to those obtained from donation after brain death (DBD) donors. However, heterogeneous results in the long term have been reported. We compared 10‐year outcomes between 237 KT recipients from uDCD donors maintained by normothermic extracorporeal membrane oxygenation (nECMO) and 237 patients undergoing KT from standard criteria DBD donors during the same period at our institution. We further analyzed risk factors for death‐censored graft survival in the uDCD group. Delayed graft function (DGF) was more common in the uDCD group (73.4% vs 46.4%; P < .01), although glomerular filtration rates at the end of follow‐up were similar in the 2 groups. uDCD and DBD groups had similar rates for 10‐year death‐censored graft (82.1% vs 80.4%; P = .623) and recipient survival (86.2% vs 87.6%; P = .454). Donor age >50 years was associated with graft loss in the uDCD group (hazard ratio: 1.91; P = .058), whereas the occurrence of DGF showed no significant effect. uDCD KT under nECMO support resulted in similar graft function and long‐term outcomes compared with KT from standard criteria DBD donors. Increased donor age could negatively affect graft survival after uDCD donation.     

Impact of donor age on long‐term outcomes after delayed graft function: 10‐year follow‐up

Delayed graft function (DGF) has a negative impact on graft survival in donation after brain death (DBD) but not for donation after cardiac death (DCD) kidneys. However, older donor age is associated with graft loss in DCD transplants. We sought to examine the interaction between donor age and DGF in DBD kidneys. This is a single‐center, retrospective review of 657 consecutive DBD recipients transplanted between 1990 and 2005. We stratified the cohort by decades of donor age and studied the association between DGF and graft failure using Cox models. The risk of graft loss associated with DGF was not significantly increased for donor age below 60 years (adjusted hazard ratio [aHR] 1.12, 1.51, and 0.90, respectively, for age <40, 41–50 and 51–60 years) but significantly increased after 60 years (aHR 2.67; P = 0.019). Analysis of death‐censored graft failure yielded similar results for donor age below 60 years and showed a substantially increased risk with donors above 60 years (aHR 6.98, P = 0.002). This analysis reveals an unexpectedly high impact of older donor age on the association between DGF and renal transplant outcomes. Further research is needed to determine the best use of kidneys from donors above 60 years old, where DGF is expected.     

Profiling non‐HLA antibody responses in antibody‐mediated rejection following heart transplantation

Antibody‐mediated rejection (AMR) driven by the development of donor‐specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non‐HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single‐center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non‐AMR (n = 21) were tested for reactivity against a panel of 44 non‐HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non‐AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA‐positive AMR patients exhibited greater reactivity to autoantigens compared to DSA‐negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta‐tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non‐AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non‐HLA are associated with DSA‐positive AMR although their specific role in mediating allograft injury is not yet understood.     

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m², respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient ( ClinicalTrials.gov number: 980654).