Higher Risk Of Acute Rejection Research Articles

#3036 The influence of first renal graft on second graft rejection and survival: the importance of revisiting histocompatibility and clinical outcomes

Abstract Background and Aims Kidney retransplantation confers a robust survival benefit over dialysis and recent data has shown similar outcomes to first kidney transplant. The number of HLA mismatches is an important predictor of graft loss and sensitization and the presence of donor specific antibodies (DSA) -pre and -post transplant is a major risk factor for rejection and worst outcomes. However, the importance of HLA matching of first graft and the relevance of first donor DSAs on second graft outcomes is less known. Our aim was to identify risk factors to second graft acute rejection and graft loss, related to second and first graft features. Method We performed a retrospective, longitudinal study including all patients submitted to a 2nd kidney transplant between January 2008 and December 2021, excluding patients with more than 2 grafts or multi-organ transplant. Clinical and histocompatibility data from the first and second donor and recipient were collected. HLA antibodies were detected by solid phase assays and considered if MFI >2500. For subsequent kidney transplants, repeated mismatches are not allowed and unacceptable antigens are those for which the patient has pre-formed -A, -B and -DR antibodies, with MFI>1000. Biopsy proven acute rejection was defined according to Banff 2017 criteria. Follow-up was 31st December 2023 for functioning grafts or time to graft failure, with a mean time of 92 ± 53 months. Results We included 114 patients, 73 (64%) males, mostly Caucasians (96%), with a mean age of 43.9 ± 13 years at 2nd transplant. First kidney transplant was performed before 2010 for 99 patients (87%), with a median first graft survival of 82.5 [12.5-144] months and 19 patients (16.7%) presented primary disfunction due to surgical/vascular complications. After graft loss, 43 patients (37.7%) had their graft removed. For second transplant, 11 (9.6%) patients had a living donor. Induction therapy with thymoglobulin occurred in 94 patients (83%) and maintenance therapy with mycophenolic acid, calcineurin inhibitors and steroids was prescribed in 83 patients (73%). During follow-up, 20 patients (17.5%) presented biopsy proven acute rejection, 13 (65%) T cell mediated and 7 (35%) antibody-mediated, the majority during the first-year post-transplant (N = 17, 85%). The risk factors for second graft rejection are summarized in Table 1. Patients with a first graft nephrectomy had a higher risk of acute rejection (OR 3.9, 95% CI [1.4-10.9], p < 0.006) and were more susceptible to the development of second donor post-transplant DSA (58% vs 35%, p = 0.02). Death censored second allograft loss occurred in 24 patients (21%) at follow up and acute rejection was an important risk factors (OR 4.3, 95% CI [1.5-12.1], p = 0.004). First-year graft survival was 93% and a survival at follow up was 79%. On survival analysis the presence of second graft DSA was a major risk factor for graft loss, especially class 2 -DQ and -DR. First transplant total mismatch load, especially on class 1 contributed to worst graft survival. Conclusion Worst outcomes in first kidney transplant were related with an increased risk of acute rejection in second graft and 1st graft nephrectomy increases the risk of the development of 2nd graft DSA and acute rejection. First transplant mismatch load decreased second graft survival.

Pre-transplant immune profile defined by principal component analysis predicts acute rejection after kidney transplantation.

Acute rejection persists as a frequent complication after kidney transplantation. Defining an at-risk immune profile would allow better preventive approaches. We performed unsupervised hierarchical clustering analysis on pre-transplant immunological phenotype in 1113 renal transplant recipients from the ORLY-EST cohort. We identified three immune profiles correlated with clinical phenotypes. A memory immune cluster was defined by memory CD4+T cell expansion and decreased naïve CD4+T cell. An activated immune cluster was characterized by an increase in CD8+T cells and a decreased CD4/CD8 ratio. A naïve immune cluster was mainly defined by increased naïve CD4+T cells. Patients from the memory immune profile tend to be older and to have diabetes whereas those from the activated immune profile were younger and more likely to have pre-transplant exposure to CMV. Patients from the activated immune profile were more prone to experience acute rejection than those from other clusters [(HR=1.69, 95%IC[1.05-2.70], p=0.030) and (HR=1.85; 95%IC[1.16-3.00], p=0.011). In the activated immune profile, those without previous exposure to CMV (24%) were at very high risk of acute rejection (27 vs 16%, HR=1.85; 95%IC[1.04-3.33], p=0.039). Immune profile determination based on principal component analysis defines clinically different sub-groups and discriminate a population at high-risk of acute rejection.

#6369 RESULTS OF KIDNEY TRANSPLANTATION IN PATIENTS WITH LOW MFI PREFORMED DONOR SPECIFIC ANTIBODIES

Abstract Background and Aims Preformed DSA at transplantation, significantly increase risk of antibody-mediated rejection (ABMR). While pre-existing positive DSA with concomitant positive cross-match is a general contra-indication to kidney transplantation, DSA presence with negative crossmatch is still a controversial topic. The presence of DSA with Mean Fluorescence Index (MFI) up to 3.000 and a negative cross-match is not valued as a contraindication to transplantation and is widely accepted. In some transplant centers the chance of transplantation is also offered to DSA positive patients, with MFI up to 5.000. Aim of this study was to analyze graft and patient survival, acute cellular rejection, humoral rejection, renal function and side effects in kidney transplant recipients (KTR) with positive DSA (MFI up to 3.000) and negative cross-match. Method Nineteen pts (age 53+/-11) with chronic renal failure on chronic hemodialysis treatment (8+/-6 years) received a kidney transplant between May 2017 and December 2020. Median PRA was 66%; 100% pts had DSA with average MFI 2122 (min 1039, max 3779). As immunosuppressive therapies all pts received induction with Thymoglobuline plus Rituximab, followed by maintenance immunosuppression with Tacrolimus, MofetilMycoFenolate and Steroids. All patients were on periodic follow up in our Transplant Clinic. Mean follow up was 26.5+/-14.4 months. Results were compared to a concomitant KTR group DSA and crossmatch negative. Results After 2y follow-up, 17/19 pts are alive (89.5%), one patient died (1/19, 5.2%) after treatment for ABMR. Three patients returned to dialysis treatment (15.8%) during the first year post-tx, because of: PNF 1pt; irreversible ABMR rejection 2 pts. One other patient had reversible ABMR. Cumulative one year graft survival was 79% and the cumulative incidence of ABMR was 15.8%. Average 2 years follow-up creatinine was 1.46+/-0.88 mg/dl, median 2 year GFR was 51+/-25 ml/min. Comparing the matched control group (19 pts DSA and cross-match negative) 2 years patient survival, graft survival, GFR, acute rejection were not significantly different. Incidence of acute rejection was higher in the DSA positive group (16% vs 0%), as well as graft loss (21% vs 12%). Conclusion Our data suggest that low dose Thymoglobuline plus Rituximab induction allow kidney transplantation in recipient with high PRA (69%) and positive DSA with low MFI (< 3.000), with higher risk of acute rejection, and graft loss.

Patterns in Use and Transplant Outcomes Among Adult Recipients of Kidneys From Deceased Donors With COVID-19

While the COVID-19 pandemic enters a new phase and the proportion of individuals with a previous COVID-19 diagnosis increases, the national patterns in kidney use and medium-term kidney transplant (KT) outcomes among patients receiving kidneys from active or resolved COVID-19-positive donors remain unknown. To evaluate the patterns in kidney use and KT outcomes among adult recipients of kidneys from deceased donors with active or resolved COVID-19. This retrospective cohort study was conducted using national US transplant registry data from 35 851 deceased donors (71 334 kidneys) and 45 912 adult patients who received KTs from March 1, 2020, to March 30, 2023. The exposure was donor SARS-CoV-2 nucleic acid amplification test (NAT) results, with positive NAT results within 7 days before procurement defined as active COVID-19 and positive NAT results 1 week (>7 days) before procurement defined as resolved COVID-19. Primary outcomes were kidney nonuse, all-cause kidney graft failure, and all-cause patient death. Secondary outcomes were acute rejection (ie, rejection in the first 6 months after KT), transplant hospitalization length of stay (LOS), and delayed graft function (DGF). Multivariable logistic regression analyses were performed for kidney nonuse, rejection, and DGF; multivariable linear regression analyses were performed for LOS; and multivariable Cox regression analyses were performed for graft failure and all-cause death. All models were adjusted for inverse probability treatment weighting. Among 35 851 deceased donors, the mean (SD) age was 42.5 (15.3) years; 22 319 (62.3%) were men and 23 992 (66.9%) were White. Among 45 912 recipients, the mean (SD) age was 54.3 (13.2) years; 27 952 (60.9%) were men and 15 349 (33.4%) were Black. The likelihood of nonuse of kidneys from active or resolved COVID-19-positive donors decreased over time. Overall, kidneys from active COVID-19-positive donors (adjusted odds ratio [AOR], 1.55; 95% CI, 1.38-1.76) and kidneys from resolved COVID-19-positive donors (AOR, 1.31; 95% CI, 1.16-1.48) had a higher likelihood of nonuse compared with kidneys from COVID-19-negative donors. From 2020 to 2022, kidneys from active COVID-19-positive donors (2020: AOR, 11.26 [95% CI, 2.29-55.38]; 2021: AOR, 2.09 [95% CI, 1.58-2.79]; 2022: AOR, 1.47 [95% CI, 1.28-1.70]) had a higher likelihood of nonuse compared with kidneys from donors without COVID-19. Kidneys from resolved COVID-19-positive donors had a higher likelihood of nonuse in 2020 (AOR, 3.87; 95% CI, 1.26-11.90) and 2021 (AOR, 1.94; 95% CI, 1.54-2.45) but not in 2022 (AOR, 1.09; 95% CI, 0.94-1.28). In 2023, kidneys from both active COVID-19-positive donors (AOR, 1.07; 95% CI, 0.75-1.63) and resolved COVID-19-positive donors (AOR, 1.18; 95% CI, 0.80-1.73) were not associated with higher odds of nonuse. No higher risk of graft failure or death was found in patients receiving kidneys from active COVID-19-positive donors (graft failure: adjusted hazard ratio [AHR], 1.03 [95% CI, 0.78-1.37]; patient death: AHR, 1.17 [95% CI, 0.84-1.66]) or resolved COVID-19-positive donors (graft failure: AHR, 1.10 [95% CI, 0.88-1.39]; patient death: AHR, 0.95 [95% CI, 0.70-1.28]). Donor COVID-19 positivity was not associated with longer LOS, higher risk of acute rejection, or higher risk of DGF. In this cohort study, the likelihood of nonuse of kidneys from COVID-19-positive donors decreased over time, and donor COVID-19 positivity was not associated with worse KT outcomes within 2 years after transplant. These findings suggest that the use of kidneys from donors with active or resolved COVID-19 is safe in the medium term; further research is needed to assess longer-term transplant outcomes.

Double Pretransplant Positivity for Autoantibodies to LG3 and Angiotensin II Type 1 Receptor Is Associated With Alloimmune Vascular Injury in Kidney Transplant Recipients.

We performed a retrospective cohort study including consecutive kidney transplant recipients between 2013 and 2017 at a single center. The primary outcome was acute rejection with AVI (Banff grade 2 or 3 T-cell-mediated rejection and/or antibody-mediated rejection) in the first 3 mo posttransplant. The secondary outcome was death-censored allograft loss. The independent variables, anti-LG3 and ATRab, were measured pretransplant. Among the 328 study participants, 68 experienced acute rejection with AVI and 23 experienced graft loss over a median follow-up of 4.5 y. In a multivariable model, double pretransplant positivity for anti-LG3/ATRab was associated with acute rejection with AVI (odds ratio: 2.73, 95% confidence interval: 1.06-7.05). We did not observe an association between double positivity for anti-LG3/ATRab and death-censored graft loss. Double positivity for anti-LG3/ATRabs pretransplant is associated with a higher risk of acute rejection with AVI. Whether therapies that remove antibodies could decrease that risk remains to be studied.Supplemental Visual Abtract: http://links.lww.com/TXD/A494.

CYP3A5 Expressor Genotype of the Transplanted Kidney Increases the Risk of Preterm Graft Loss and Acute Rejection

Introduction: Tacrolimus is metabolized mainly in the liver by the CYP3A enzyme family, with a particularly well-documented role of CYP3A5. CYP3A5 is also expressed in the renal tissue and is present in the transplanted kidney. To date, the association between donor CYP3A5 polymorphisms and transplant outcome remains poorly understood. The aim of this study was to assess the effect of donor CYP3A5 expression on early and long-term transplant outcomes. Methods: A retrospective cohort study including 207 patients who received kidney grafts from 110 deceased donors was conducted at a single Central European Center. Tissue samples from all donors were studied for CYP3A5 single-nucleotide polymorphism (rs776746). Death-censored graft loss within 5-year follow-up, acute rejection occurrence, and kidney function, measured using serum creatinine and MDRD eGFR, were compared between groups of patients with allografts from rs776746 carriers (CYP3A5 expressors) and noncarriers (CYP3A5 nonexpressors). Results: Recipients who received kidneys from CYP3A5 expressors (n = 24) were at significantly higher risk of death-censored graft loss within 5-year follow-up (adjusted HR, 95% CI: 6.82, 2.01–23.12; p = 0.002) and acute rejection within the 1st posttransplant year (adjusted OR, 95% CI: 4.62, 1.67–12.77; p = 0.003) than those who did not (n = 183). The median time to loss of function was 1.93 [IQR; 0.77–3.19] years. Conclusions: Donor CYP3A5 expressor status is associated with worse renal graft survival and a higher risk of acute rejection. Determination of donor CYP3A5 genotype is a potentially useful tool that may improve kidney transplant outcomes.

Abstract 9800: Racial Differences in Donor-Derived and Mitochondrial Cell-Free Dna Could Explain Inferior Outcomes in Black Heart Transplant Patients, on Behalf of the Graft Investigators

Introduction: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. Our group has shown that %donor-derived cell-free DNA (%ddcfDNA) is a sensitive and specific marker of AR in heart transplantation. Cell-free mitochondrial DNA (cfmtDNA) has been linked to allograft dysfunction and may mechanistically implicated in inferior outcomes for Black heart transplant recipients. Hypothesis: Higher levels of allograft injury when quantitated using %ddcfDNA and total cfmtDNA will be seen in Black heart transplant patients as compared to White patients. Methods: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter, prospective, longitudinal cohort study of heart transplant patients transplanted between 2015 and 2021. We included Black and White patients and shotgun sequencing was used to quantitate %ddcfDNA and polymerase chain reaction (PCR) to quantitate total cfmtDNA levels. AR was defined as grade ≥2R cellular rejection or pAMR ≥1 antibody-mediated rejection (AMR). Results: We included 151 patients (73 Blacks and 78 Whites), the median age was 56y (29% Female sex). Patients of both racial groups had comparable baseline characteristics. There were a ~1100 ddcfDNA and cfmtDNA measures included in the analysis. At 18-months, the incidence of AR was 2.8% in White patients and 9.2% in Black patients (p<0.01). The diagnostic accuracy of %ddcfDNA to detect AR was comparable between Black and White patients (0.90 vs. 0.83, p=0.19). The %ddcfDNA and cfmtDNA was higher at serial time points after transplant in Black compared to White patients (Figure). CfmtDNA levels were also elevated with AMR which occurred almost exclusively in Black patients (No rejection: 146,345 copies/ul, AMR: 242,238 copies/ul; p=0.004). Conclusions: Elevated levels of %ddcfDNA and cfmtDNA after heart transplant may explain the higher incidence of AR, AMR, and inferior outcomes in Black heart transplant recipients.

Lower Time in Therapeutic Range Relates to a Worse Kidney Graft Outcome

Tacrolimus has a narrow therapeutic margin. Maintaining tacrolimus blood levels in the appropriate range is difficult because of its intrapatient variability. In fact, greater blood level variability has been related to worse kidney graft outcome, but only measuring variability does not consider the therapeutic range goal. Determining the time in therapeutic range (TTR) using the Rosendaal method allows dose optimization by considering the adverse events associated with both supratherapeutic and subtherapeutic doses. Some previous studies in kidney and lung transplantation have shown that the measurement of TTR has been related to the subsequent graft outcome. We performed a single-center, observational study including 215 consecutive kidney transplants performed in our center. The percentage of time that the patient remained with levels above 6 ng/mL between months 3 and 12 (%TTR3-12) was calculated using the Rosendaal method. A lower %TTR3-12 was associated with a higher risk of acute rejection (area under the receiver operating characteristic curve, 0.614; 95% confidence interval [CI], 0.513-0.714; P=.018) and with a higher risk of having a 1-year glomerular filtration rate < 30 mL/min/1.73 m2 (area under the receiver operating characteristic curve, 0.676; 95% CI, 0.542-0.811; P=.014). The lowest tertile of %TTR3-12 was independently associated with a higher risk of death-censored graft loss (hazard ratio, 10.773; 95% CI, 1.315-88.264; P=.027) after adjusting by 1-year glomerular filtration rate, expanded criteria donation, and acute rejection throughout the first year. To conclude, measuring TTR after kidney transplant is an easy way to estimate the time of exposure to adequate levels of tacrolimus and relates to kidney graft outcome.

232.1: Donor-derived Cell-Free DNA Testing in Kidney Transplantation: Do One-month Values Have Any Prognostic Significance?

Introduction: Percutaneous renal allograft biopsy is the current standard for detecting acute rejection after kidney transplantation (KT). Noninvasive tests such as plasma-based donor-derived cell-free DNA (dd-cfDNA) assays have been proposed as an alternative to biopsy. We sought to examine the value of dd-cfDNA testing at one month following KT in different donor and recipient categories. Methods: We performed a single center retrospective review of all adult KT patients (pts) who underwent dd-cfDNA testing between January 2018 and August 2021. The diagnosis of acute rejection was based on histopathology obtained from percutaneous, ultrasound-guided needle biopsies. Our center’s standard practice included dd-cfDNA testing and performing surveillance kidney biopsies at 1 month following KT. The dd-cfDNA test was considered elevated if >1.0%. Results: During the study period, 3157 dd-cfDNA tests were performed in 695 de novo pts. Higher mean 1-month dd-cfDNA levels were noted in the following categories: Retransplants (n=30, 1.8±2.1); highly sensitized pts (PRA 98-100%, n=27, 1.6±2.0; for highly sensitized retransplants, n=18, 2.0±2.3; for highly sensitized primary KTs, n=9, 0.7±0.5); and pts who underwent early reoperations (n=16, 0.85±0.9). In all other KT categories, mean 1-month dd-cfDNA levels were lower and similar: DCD donor KTs (n=53, 0.56±0.4), living donor KTs (n=51, 0.47±0.4); acute kidney injury (AKI) donor KTs (n=23, 0.47±0.6); standard criteria donor (SCD) KTs (n=91, 0.47±0.4); expanded criteria donor (ECD) KTs (n=44, 0.46±0.5); dual KTs (n=16, 0.45±0.4); and pts with delayed graft function (DGF, n=50, 0.46±0.4). In 58 primary KT pts with negative 1-month surveillance biopsies, corresponding mean 1-month dd-cfDNA levels were 0.49±0.4. In 10 pts with positive 1-month surveillance biopsies, corresponding mean 1-month dd-cfDNA levels were 1.5±1.8. In 26 pts with a 1-month dd-cfDNA level >1.0, the subsequent incidence of acute rejection was 27%; in 22 pts with a 1-month dd-cfDNA level ≥2.0, the subsequent incidence of acute rejection was 50% (mean follow-up 14 months). Conclusions: We noted a bimodal distribution of 1-month dd-cfDNA levels. Higher mean 1-month dd-cfDNA levels (range 0.72-2.2) were associated with retransplants, high PRA pts, and pts with early reoperations; 22-44% of these pts had 1-month dd-cfDNA levels >1.0. Conversely, primary KT alone pts (DCD, living donor, AKI donor, SCD, ECD, dual KT, those with DGF) had lower 1-month dd-cfDNA levels (range 0.45-0.56) and only 7-14% had 1-month dd-cfDNA levels >1.0. One-month surveillance biopsy results correlated with corresponding dd-cfDNA levels. Elevated 1-month dd-cfDNA levels occurred in pts at a higher risk for acute rejection, suggesting that these pts need to be monitored more closely.

Metagenomic Next-Generation Sequencing Reveals the Profile of Viral Infections in Kidney Transplant Recipients During the COVID-19 Pandemic.

BackgroundTo study the clinical application of metagenomic next-generation sequencing (mNGS) in the detection of viral infections in kidney transplant recipients (KTRs) during the COVID-19 pandemic.MethodsUsing mNGS technology, 50 human fluid samples of KTRs were detected, including 20 bronchoalveolar lavage fluid (BALF) samples, 21 urine samples and 9 blood samples. The detected nucleic acid sequences were compared and analyzed with the existing viral nucleic acid sequences in the database, and the virus infection spectrum of KTRs was drawn.ResultsThe viral nucleic acids of 15 types of viruses were detected in 96.00% (48/50) of the samples, of which 11 types of viruses were in BALF (95.00%, 19/20), and the dominant viruses were torque teno virus (TTV) (65.00%; 13/20), cytomegalovirus (CMV) (45.00%; 9/20) and human alphaherpesvirus 1 (25.00%; 5/20). 12 viruses (95.24%, 20/21) were detected in the urine, and the dominant viruses were TTV (52.38%; 11/21), JC polyomavirus (52.38%; 11/21), BK polyomavirus (42.86%; 9/21), CMV (33.33%; 7/21) and human betaherpesvirus 6B (28.57%; 6/21). 7 viruses were detected in the blood (100.00%, 9/9), and the dominant virus was TTV (100.00%; 9/9). Four rare viruses were detected in BALF and urine, including WU polyomavirus, primate bocaparvovirus 1, simian virus 12, and volepox virus. Further analysis showed that TTV infection with high reads indicated a higher risk of acute rejection (P < 0.05).ConclusionsmNGS detection reveals the rich virus spectrum of infected KTRs, and improves the detection rate of rare viruses. TTV may be a new biomarker for predicting rejection.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy in Heart Transplantation: New Strategies and Preliminary Results in Endomyocardial Biopsies

Tacrolimus (TAC) is an immunosuppressant drug approved both in the US and in the EU, widely used for the prophylaxis of organ rejection after transplantation. This is a critical dose drug: low levels in whole blood can lead to low exposure and a high risk of acute rejection, whereas overexposure puts patients at risk for toxicity and infection. Both situations can occur at whole-blood concentrations considered to be within the narrow TAC therapeutic range. We assumed a poor correlation between TAC trough concentrations in whole blood and the incidence of acute rejection; therefore, we propose to study TAC concentrations in endomyocardial biopsies (EMBs). We analyzed 70 EMBs from 18 transplant recipients at five scheduled follow-up visits during the first year post-transplant when closer TAC monitoring is mandatory. We observed five episodes of acute rejection (grade 2R) in three patients (2 episodes at 0.5 months, 2 at 3 months, and 1 at 12 months), when TAC concentrations in EMBs were low (63; 62; 59; 31; 44 pg/mg, respectively), whereas concentrations in whole blood were correct. Our results are preliminary and further studies are needed to confirm the importance of this new strategy to prevent acute rejection episodes.

Transcriptional Changes of Left Ventricle Biopsy During Reperfusion Predict the Outcome of Heart Transplants

<h3>Purpose</h3> Ischemia-reperfusion injury may predispose heart transplant to acute rejection and early mortality. Contemporary treatment possibilities are limited. We hypothesize that investigating transcriptomic changes and the underlying biological processes of ischemia-reperfusion injury could yield information on the outcome of the recipient as well as on possible therapeutic targets. <h3>Methods</h3> RNA was extracted and sequenced from 144 left ventricle biopsies that were procured immediately before and 1 hour after reperfusion of the heart transplant. Primary endpoints of the study were acute rejection and graft-related mortality within 1 year after transplantation. <h3>Results</h3> Next-generation sequencing confirmed that a total of 802 genes had significantly changed their expression 1 hour after reperfusion, of which 590 were upregulated and 212 were downregulated. Alteration of certain differentially expressed gene profiles, such as downregulation of C5AR1, GAA, and MEN1 led to a higher probability of graft-related mortality within 1 year, whereas downregulation of FOSB and FOSL1 were associated with a higher risk of acute rejection. Downregulation of MMP19 were shown to predict both mortality as well as acute rejection (Figure 1). Gene ontology pathway analysis showed that these genes are involved in several biological processes, including neutrophil mediated immunity, regulation of protein serine/threonine kinase activity, and response to corticosteroids. <h3>Conclusion</h3> Our study describes the changes in gene expression of the left ventricle biopsies and their related biological processes associated with ischemia-reperfusion injury after heart transplantation. We have confirmed that alterations in certain gene profiles may predict acute rejection and graft-related mortality within 1 year after transplantation. Understanding the biological pathways associated with these gene profiles could be beneficial for identification of possible therapeutic targets.

Management strategies and outcomes in renal transplant recipients recovering from COVID-19: A retrospective, multicentre, cohort study

SummaryBackgroundThere is an enormous knowledge gap on management strategies, clinical outcomes, and follow-up after kidney transplantation (KT) in recipients that have recovered from coronavirus disease (COVID-19).MethodsWe conducted a multi-center, retrospective analysis in 23 Indian transplant centres between June 26, 2020 to December 1, 2021 on KT recipients who recovered after COVID-19 infections. We analyzed clinical and biopsy-confirmed acute rejection (AR) incidence and used cox-proportional modeling to estimate multivariate-adjusted hazard ratios (HR) for predictors of AR. We also performed competing risk analysis. Additional outcome measures included graft loss, all-cause mortality, waiting time from a positive real-time polymerase test (RT-PCR) to KT, laboratory parameters, and quality of life in follow-up.FindingsAmong 372 KT which included 38(10·21%) ABO-incompatible, 12(3·22%) sensitized, 64(17·20%) coexisting donors with COVID-19 history and 20 (5·37%) recipients with residual radiographic abnormalities, the incidence of AR was 34 (9·1%) with 1(0·26%) death censored graft loss, and 4(1·07%) all-cause mortality over a median (interquartile range) follow-up of 241 (106–350) days. In our cox hazard proportional analysis, absence of oxygen requirement during COVID-19 compared to oxygen need [HR = 0·14(0·03–0·59); p-value = 0·0071], and use of thymoglobulin use compared to other induction strategies [HR = 0·17(0·03–0.95); p-value = 0·044] had a lower risk for AR. Degree of Human leukocyte antigen (HLA) DR mismatch had the highest risk of AR [HR = 10.2(1·74–65·83); p-value = 0·011]. With competing risk analysis, with death as a competing event, HLA DR mismatch, and oxygen requirement continued to be associated with AR. Age, gender, obesity, inflammatory markers, dialysis vintage, steroid use, sensitization and ABO-incompatibility have not been associated with a higher risk of AR. The median duration between COVID-19 real time polymerase test negativity to transplant was 88(40–145) days (overall), and ranged from 88(40–137), 65(42–120), 110(49–190), and 127(64–161) days in World Health Organization ordinal scale ≤ 3, 4, 5, and 6–7, respectively. There was no difference in quality of life, tacrolimus levels, blood counts, and mean serum creatinine assessed in patients with a past COVID-19 infection independent of severity.InterpretationOur findings support that the outcomes of KT after COVID-19 recovery are excellent with absence of COVID-19 sequelae during follow-up. Additionally, there does not seem to be a need for changes in the induction/immunosuppression regimen based on the severity of COVID-19.FundingSanofi

Effect of Early Steroid Withdrawal on Posttransplant Diabetes Among Kidney Transplant Recipients Differs by Recipient Age.

Posttransplant diabetes (PTD), a major complication after kidney transplantation (KT), is often attributable to immunosuppression. The risk of PTD may increase with more potent steroid maintenance and older recipient age. Using United States Renal Data System data, we studied 12 488 adult first-time KT recipients (2010-2015) with no known pre-KT diabetes. We compared the risk of PTD among recipients who underwent early steroid withdrawal (ESW) versus continued steroid maintenance (CSM) using Cox regression with inverse probability weighting to adjust for confounding. We tested whether the risk of PTD resulting from ESW differed by recipient age (18-29, 30-54, and ≥55 y). Of 12 488, 28.3% recipients received ESW. The incidence rate for PTD was 13 per 100 person-y and lower among recipients who received ESW (11 per 100 person-y in ESW; 14 per 100 person-y in CSM). Overall, ESW was associated with lower risk of PTD compared with CSM (adjusted hazard ratio [aHR] = 0.720.790.86), but the risk differed by recipient age (P interaction = 0.09 for comparison between recipients aged 18-29 and those aged 30-54; P interaction = 0.01 for comparison between recipients aged 18-29 and those aged ≥55). ESW was associated with lower risk of PTD among recipients aged ≥55 (aHR = 0.620.710.81) and those aged 30-54 (aHR = 0.730.830.95), but not among recipients aged 18-29 (aHR = 0.811.181.72). Although recipients who received ESW had a higher risk of acute rejection across the age groups (adjusted odds ratio = 1.011.171.34), recipients with no PTD had a lower risk of mortality (aHR = 0.580.660.74). The beneficial association of ESW with decreased PTD was more pronounced among recipients aged ≥55, supporting an age-specific assessment of the risk-benefit balance regarding ESW.

Kidney transplant outcomes in children and adolescents with systemic lupus erythematosus.

Literature supports equivalent kidney transplant outcomes in adults with systemic lupus erythematosus (SLE) compared with those without SLE. However, there are conflicting and scant data on kidney transplant outcomes, as well as controversy over optimal timing of transplantation, in children and adolescents with SLE. Analysis included kidney-only transplant recipients aged 2-21years from 2000 to 2017 enrolled in the Organ Procurement and Transplant Network (OPTN). The relationship between diagnosis (SLE n = 457, non-SLE glomerular disease n = 4492, and non-SLE non-glomerular disease n = 5605) and transplant outcomes was evaluated. The association between dialysis time and outcomes was analyzed in the SLE group only. In adjusted models, SLE had higher mortality compared with non-SLE glomerular recipients (HR 1.24 CI 1.07-1.44) and non-glomerular recipients (HR 1.42 CI 1.20-1.70). SLE was associated with higher graft failure compared with non-SLE glomerular (HR 1.42 CI 1.20-1.69) and non-glomerular disease (HR 1.67 CI 1.22-2.28). SLE had a higher risk of acute rejection at 1year compared with non-glomerular disease (HR 1.39 CI 1.03-1.88). There was a decreased risk of delayed graft function compared with non-SLE glomerular disease (HR 0.54, CI 0.36-0.82). There were no significant associations between dialysis time and transplant outcomes in the SLE group. SLE in children and adolescents is associated with worse patient and graft survival compared with non-SLE diagnoses. Outcomes in children and adolescents with SLE are not associated with dialysis time. Further studies are needed to assess implications of potential earlier transplantation and shorter time on dialysis prior to transplantation.

This Month in Anesthesiology

This Month in Anesthesiology

EFFECT OF LEPTIN CONCENTRATIONS AND LEPTIN RECEPTOR GENE POLYMORPHISMS ON THE OUTCOME OF RENAL TRANSPLANTATION

IntroductionLeptin is a pro-inflammatory adipocytokine implicated in cardiovascular disease, insulin resistance, obesity and chronic kidney disease.Material and methodsIn a cohort of 236 renal transplant recipients, we aimed to determine whether circulating leptin concentrations and/or three polymorphisms in the leptin receptor (LEPR) gene, namely rs1137100, rs1137101 and rs1805094, were related to clinical outcomes in renal transplantation. Plasma leptin concentrations were measured by ELISA. Genetic variants were determined by conventional real-time PCR assays and statistical associations with clinical outcomes were obtained by logistic regression modelling.ResultsPatients with elevated leptin levels were at higher risk of acute rejection [OR=1.03 (1.01–1.05), p=0.03] and displayed worse renal clearance (p=0.001) than patients with lower levels. Leptin levels were not significantly affected by any of the three LEPR SNPs. The rs1137101 G variant showed an inverse association with the risk of delayed graft function (DGF) [OR=0.42 (0.22-0.81), p=0.009], whilst the homozygous rs1805094 CC genotype was associated with increased risk of acute rejection [OR=11.38 (2.15-60.16), p=0.004]. A statistically significant association was also observed between the rs1137100 GG genotype and better renal function [mean difference vs. AA/AG =20.20 (4.91-35.49) ml/min, p=0.010].ConclusionsOur results show that both leptin plasma concentrations and polymorphisms in the LEPR gene may affect clinical outcomes in renal transplant recipients, suggesting that the determination of these parameters could be useful in predicting post-transplant adverse events.

Single-center utilization of donor-derived cell-free DNA testing in the management of heart transplant patients.

Gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single-center experience of combined GEP and dd-cfDNA testing for AR surveillance. GEP and dd-cfDNA are tested together starting at 2months post-OHT. After 6months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd-cfDNA. This approach was compared to using a GEP-only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd-cfDNA usage. A total of 153 OHT patients over a 13-month period underwent 495 combined GEP/dd-cfDNA tests. 82.2% of dd-cfDNA tests were below threshold. Above threshold results identified high-risk patients who developed AR. 378 combined tests ≥6months post-OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody-mediated rejection episodes, and no significant AR ≥6months. Routine dd-cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re-classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd-cfDNA identified patients at higher risk for AR.

Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients

Tacrolimus (TAC) pharmacokinetics is influenced by the donor CYP3A5 genotype and the age of pediatric liver recipients. However, an optimization of a genotype-based algorithm for determining TAC starting is needed to earlier achieve stable target levels. As the graft itself is responsible for its metabolism, the Graft-to-Recipient Weight Ratio (GRWR) might play a role in TAC dose requirements. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. Children < 2 years received grafts with a significantly higher GRWR (4.2%) than children between 2–8 (2.6%) and over 8 (2.7%). TAC concentration/weight-adjusted dose ratio was significantly lower in recipients from CYP3A5*1/*3 donors or with extra-large (GRWR > 5%) or large (GRWR 3–5%) grafts. The donor CYP3A5 genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. Patients with a GRWR > 4% had a higher risk of acute rejection, observed in 20/49 (41%) patients. In conclusion, TAC starting dose could be guided according to the donor CYP3A5 genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection.

The effect of genetic variations for interleukin-10 (IL-10) on the efficacy of immunosuppressive therapy in patients after kidney transplantation

Kidney transplantation is the target method of treating chronic kidney disorders. It improves the comfort of patient life by eliminating the need for repeated dialysis. The aim of the study was to examine the correlation between tacrolimus (TAC) dose and genetic variation for interleukin-10 (IL-10) and its effect on the therapeutic outcome. In addition, the correlations between the IL-10 polymorphism andthe clinical and the biochemical parameters of TAC patients were also analyzed. The study included 209 subjects after kidney transplantation, who received TAC every 12 and 24 h. Drug concentrations in blood, selected morphological and biochemical parameters, and the genetic variation of IL-10 (-1082A > G) which may affect immunosuppressant dosage and risk of acute graft rejection were analyzed. Genetic analyses were performed using real-time PCR. No significant correlations between the clinical and the biochemical parameters and IL-10-1082A > G polymorphism for patients receiving TAC after kidney transplantation were found. The analysis of the correlation between TAC dose and IL-10 genetic variation for the −1082A > G polymorphism revealed that patients with the AA genotype required lower immunosuppressive drug doses (AA: 3.54 ± 2.38 mg/day vs AG: 6.18 ± 5.10 mg/day, GG: 4.44 ± 3.01 mg/day). Furthermore, frequencies of the genotypes for the IL-10 −1082A > G polymorphism were characterized by a significantly higher frequency of the AA genotype among TAC 24 as compared to TAC 12 patients. The results of the study indicated that the IL-10 −1082A > G polymorphism may in fact influence the TAC dose. The biochemical parameters of the renal profile in relation to the IL-10 genetic variations were not indicative of higher risk of acute rejection after transplantation.