Biopsy-proven Acute Rejection Research Articles

Longitudinal Evaluation of Donor-Derived Cellfree DNA in Pediatric Kidney Transplantation.

Donor-derived cellfree DNA (cfDNA) is a less-invasive marker of allograft injury compared with kidney biopsy. However, donor-derived cfDNA has not yet been extensively tested in children, where the test may have different characteristics. We assayed donor-derived cfDNA (AlloSure; CareDx) from 290 stored plasma samples from a prospective biobank at our center, collected from 57 children monthly in the first year postkidney transplant between January 2013 and December 2019. We assessed the kinetic changes in donor-derived cfDNA levels within the first year post-transplant. We analyzed donor-derived cfDNA levels for associations with biopsy-proven acute rejection using area under the receiver operating characteristic curve to longitudinal plasma and urine BK viral loads using linear mixed models. We analyzed the prognostic effect of an elevated donor-derived cfDNA level on the eGFR 30 days after the assay via Kolmogorov-Smirnov two-sample tests or on measured GFR or interstitial fibrosis at 12 months post-transplant. The donor-derived cfDNA levels in children remained persistently elevated for at least 4 months post-transplant, more so if there is greater disparity in size between the donor and the recipient, before reaching a steady low level. A donor-derived cfDNA level of >1% discriminated between biopsy-proven acute rejection with a receiver operating characteristic area under the curve of 0.82 (95% confidence interval, 0.71 to 0.93). During BK viruria or viremia, patients had a significantly higher median donor-derived cfDNA than before or after and a significant rise within the same patient. A donor-derived cfDNA of >0.5% predicted a wider spread in the eGFR over the next 30 days but not the 12-month outcomes. In children, donor-derived cfDNA is a valuable, less invasive biomarker for assessment of allograft rejection and injury. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_10_27_CJN03840322.mp3.

Individualised immunosuppression with intravenously administered donor-derived modified immune cells compared with standard of care in living donor kidney transplantation (TOL-2 Study): protocol for a multicentre, open-label, phase II, randomised controlled trial

IntroductionDonor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in...

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients.

Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort. The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

Isolated Hepatic Chronic Ductopenic Rejection Requiring Liver Retransplant in the Absence of Kidney Graft Rejection After Combined Liver-Kidney Transplant: A Case Report

The liver is considered the most immunotolerant organ among all solid-organ transplants. Liver transplant recipients have a lower incidence of rejection and better outcomes after episodes of rejection, with spontaneous operational tolerance developing in up to 20%. In multiorgan transplants, a protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been demonstrated. We describe an unusual case of isolated liver allograft rejection in a patient with polycystic liver and kidney disease who received a combined liver-kidney transplant from the same donor. After initial discharge from the hospital, our patient had 2 episodes of biopsy-proven late acute cellular rejections, despite higher levels of immunosuppression required for her kidney allograft, which were addressed with pulsed steroid therapy. She had no evidence of ischemic cholangiopathy on imaging. Later, a subsequent liver biopsy demonstrated features consistent with chronic ductopenic rejection. She was eventually listed for liver retransplant and has recently received a second liver transplant while continuing to have no concerns with her kidney allograft function. Examination of the explanted liver confirmed graft loss from chronic ductopenic rejection. The exact reasons why our patient developed acute graft rejection progressing to chronic end-stage rejection of the liver allograft despite not developing graft rejection in the kidney allograft from the same donor remains elusive. Our experience demonstrates that graft tolerance in multiorgan transplant recipients can be organ specific and despite the belief of "immunologic privilege," isolated liver allograft rejection can occur in multiorgan transplant, resulting in graft loss.

The combination of exposure to Tacrolimus, mycophenolic acid, Inosine 5'-Monophosphate Dehydrogenase activity and inhibition in the first week define early histological outcomes in renal transplant recipients.

Therapeutic drug monitoring is routine for Tacrolimus, while levels are not routinely monitored for mycophenolic acid (MPA). This study investigated the effect of early post-transplant pharmacokinetics (PK) of MPA and Tacrolimus along with the pharmacodynamics (PD) of MPA on biopsy-proven acute rejection (BPAR) after renal transplantation. A prospective PK/PD study with limited sampling (three blood samples) was conducted in renal transplant recipients on week 1, around Day 6 (n=42) and at the 3rd-month biopsy on Day 90 (n=23). The partial exposures (area under curve [AUC]0-3.5h ) of both MPA and Tacrolimus obtained during the first week were more predictive of rejection (combined clinical and subclinical rejection) by Day 90 than their trough concentrations or Day 90 exposures. Patients with rejection had significantly worse renal function (eGFR) and a comparatively lower exposure to MPA during the first post-transplant week. The lower MPA exposure was also associated with sub-optimal inosine monophosphate dehydrogenase (IMPDH) inhibition in patients with rejection, and the probability of rejection was higher in the presence of an increased pre-transplant IMPDH activity. A composite of parameters, including MPA exposure and IMPDH activity was found to predict acute rejection and may be beneficial along with tacrolimus monitoring early after renal transplantation.

Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry

BackgroundRandomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far.MethodsIn this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554).ResultsMost baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable.ConclusionsIn conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children.

Background.Transcriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. The purpose of this article is to test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection after LT.Methods.Paired peripheral blood DNA samples were obtained before and after LT from 17 children, including 4 rejectors (Rs) and 13 nonrejectors (NRs), and assayed with MethylC capture sequencing approach covering 5 million CpGs in immune-cell–specific regulatory elements. Differentially methylated CpGs (DMCs) were identified using generalized linear regression models adjusting for sex and age and merged into differentially methylated regions (DMRs) comprising 3 or more DMCs.Results.Contrasting Rs versus NRs, we identified 2238 DMCs in post-LT and 2620 DMCs in pre-LT samples, which clustered in 216 and 282 DMRs, respectively. DMCs associated with R were enriched in enhancers and depleted in promoters. Among DMRs, the proportion of hypomethylated DMRs increased from 61/282 (22%) in pre-LT to 103/216 (48%, P < 0.0001) in post-LT samples. The highest-ranked biological processes enriched in post-LT DMCs were antigen processing and presentation via major histocompatibility complex (MHC) class I, MHC class I complex, and peptide binding (P < 7.92 × 10−17), respectively. Top-ranked DMRs mapped to genes that mediate B-cell receptor signaling (ADAP1) or regulate several immune cells (ARRB2) (P < 3.75 × 10−08). DMRs in MHC class I genes were enriched for single nucleotide polymorphisms (SNPs), which bind transcription factors, affect gene expression and splicing, or alter peptide-binding amino acid sequences.Conclusions.Dynamic methylation in distal regulatory regions reveals known transplant-relevant MHC-dependent rejection pathways and identifies novel loci for future mechanistic evaluations in pediatric transplant subcohorts.

Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients: A Multicenter Cohort

Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. Prospective cohort. 862 deceased donors for 1,137 kidney recipients at 13 centers. We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. Multivariable Fine-Gray models with death as a competing risk. Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. BPAR was ascertained through for-cause biopsies, not surveillance biopsies. In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.

Association Between the Intracellular Tacrolimus Concentration in CD3 + T Lymphocytes and CD14 + Monocytes and Acute Kidney Transplant Rejection.

Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC [PBMC] ) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3 + T lymphocytes (TAC [CD3] ) and CD14 + monocytes (TAC [CD14] ) with acute rejection after kidney transplantation. From a total of 61 samples in this case-control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3 + T lymphocytes and CD14 + monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured. The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC [CD3] was significantly lower than TAC [CD14] (median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC [PBMC] (48.5 versus 44.4 pg/million cells; P = 0.82), TAC [CD3] (13.4 versus 12.5 pg/million cells; P = 0.28), and TAC [CD14] (90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC [PBMC] than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors. Differences in TAC [CD3] and TAC [CD14] between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC [PBMC] between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.

311.1: Real-Life Tacrolimus Levels Are Associated With Biopsyproven Acute Rejection After the First Year Post-kidney Transplantation

311.1: Real-Life Tacrolimus Levels Are Associated With Biopsyproven Acute Rejection After the First Year Post-kidney Transplantation

410.2: Outcomes of Living Donor Kidney Transplantation After SARS-CoV-2 Infection in Both the Donor and the Recipient: A Multicenter Study Running Title - LDKT in COVID-19 Survivors

Introduction: The evidence for living donor kidney transplantation (LDKT) when both donor-recipient (D-R) pair had a history of COVID-19 infection is scarce. Methods: We explored the protocol, outcome, and follow-up of 64 LDKT when D-R pair had recovered from COVID-19 in a retrospective, multicentre (n = 12) study from India between October 29, 2020, to December 1, 2021. There was no change in induction/ immunosuppression regimen in the study among different COVID-19 severity and is similar to standard practice. Results: Clinical severity in patients and donors was asymptomatic/ mild without requiring oxygen therapy in 77%(n=49), 95.4%(n=63) and moderate/ severe 4.6%(n=1) illness requiring oxygen therapy in 23%(n=15) and 4.6%(n=1), respectively. The mean ± SE(SD) waiting time from first documented RT-PCR negative to surgery for recipient and donor was 90.9 ± 9.27(74.1) and 47±4.5 (29.2) days respectively. Six (9.3%) episodes of biopsy-proven acute rejection (BPAR) were reported at follow-up of 214 ± 14.8(119) days and median (IQR) of 227(109-309) days. The locally weighted scatter plot smoothing curve for creatinine during follow-up in the D-R pair showed no trends of raised creatinine in the context of waiting time from COVID-19 to surgery. No graft loss, death, reactivation/reinfection, and any complications relating to surgery or COVID-19 were reported in the study. Conclusions: Our report shows excellent outcomes and follow-up data of LDKT in recovered D-R pairs with the standard immunosuppression protocol. To date, this remains the first and the largest study of LDKT when D-R pair had prior COVID-19.

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients

Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. The cumulative incidence ratio of non-melanoma skin cancer has been estimated to be > 60% compared to the general population. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Retrospective study of kidney transplant recipients, suffering from advanced cSCC treated with cemiplimab. Sept patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. 3 patients were on corticosteroid monotherapy, 1 patient on tacrolimus monotherapy and 3 patients were on at least 2 immunosuppressive treatments at start of cemiplimab. The ORR was 42.8%, SD was seen in 14.3% and PD was found in 42.8% of the patients, respectively. Biopsy-proven acute renal allograft rejection was observed in 1 patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in 1 patient of the cohort ( Fig. 1 ). The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to conventional treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance. Cemiplimab may therefore be a feasible treatment for KTR with advanced cSCC and this treatment should therefore not be withheld in this difficult to treat patient population.

Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study.

To report 5-year outcomes of the CERTITUDE study. An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n=55; tacrolimus [TAC], n=64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p=.051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p=.370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n=4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

P16.37: Outcomes of COVID-19 Vaccination Among Kidney Transplant Recipients Admitted for COVID-19 at the National Kidney And Transplant Institute: A Retrospective Study

Background: Kidney transplant recipients are immunocompromised hosts of COVID-19 with a higher risk of infection and severe disease due to underlying CKD and long-term immunosuppression, thus vaccination against COVID is strongly recommended. However, studies indicate that transplant recipients mount lower antibody responses following vaccination compared with healthy individuals. Due to limited information on the outcomes of COVID-19 vaccination on transplant recipients, this study will examine the efficacy of vaccination in preventing severe to critical COVID in this immunocompromised population. Objective: To determine the outcomes of kidney transplant recipients admitted for COVID-19 at the National Kidney and Transplant Institute and the impact of COVID-19 vaccination status on their survival. Methods and Materials: A retrospective study of 131 kidney transplant recipients admitted for COVID-19 from March 2020 to December 2021. Descriptive statistics were used to summarize the clinical characteristics and outcomes of the participants. Results: The median age was 51 years old with a male gender distribution of 54.5%. Chronic glomerulonephritis was the most common primary renal disease. Diabetes, hypertension, and cardiovascular disease were the most common co-morbidities. Patients belonging to the critical COVID group were observed to have older kidney allografts with a median age of 120 months. Among 131 kidney transplant recipients, 24.8% were fully vaccinated and 74.2% were either unvaccinated or partially vaccinated. Of the 32 patients in the vaccinated group, 3 were vaccinated with Astra Zeneca, 5 received Janssen, 7 from Moderna, 10 from Pfizer, 1 received Sputnik and 12 received Coronavac (Sinovac). Among the vaccinated group, those who received Moderna and Pfizer vaccines were observed to have moderate COVID-19 disease progression only with 57.1% from the Moderna group and 40% from the Pfizer group. Among patients who progressed to critical COVID-19, it was observed that a significant number of them came from the Coronavac group. The need for oxygenation was observed in 64% of patients, of which 65.5% were unvaccinated. Acute kidney injury was reported in 43.5% of the overall population, 63.2% of which were observed in the unvaccinated group. Of the 16% who had graft loss during COVID-19 admission, 57.1% were unvaccinated. The incidence of death was lower among fully vaccinated than those in the partial and unvaccinated groups. Likewise, the probability of survival is highest among fully vaccinated than those partially vaccinated and unvaccinated. Renal graft biopsy on patients with COVID-19 has not been practiced at NKTI thus rendering rates of biopsy-proven acute rejection a limitation of the study. Conclusion: Our experience shows that lack of COVID-19 vaccination among kidney transplant recipients demonstrates a higher rate of mortality associated with COVID-19. Key words: COVID-19, renal transplantation, survival, Philippines.

Long-term immunological outcomes of early subclinical inflammation on surveillance kidney allograft biopsies

The long-term impact of early subclinical inflammation (SCI) through surveillance biopsy has not been well studied. To do this, we recruited a prospective observational cohort that included 1000 sequential patients who received a kidney transplant from 2013-2017 at our center. A total of 586 patients who underwent a surveillance biopsy in their first year post-transplant were included after excluding those with clinical rejections, and those who were unable to undergo a surveillance biopsy. Patients were classified based on their biopsy findings: 282 with NSI (No Significant Inflammation) and 304 with SCI-T (SCI and Tubulitis) which was further subdivided into 182 with SC-BLR (Subclinical Borderline Changes) and 122 with SC-TCMR (Subclinical T Cell Mediated Rejection, Banff 2019 classification of 1A or more). We followed the clinical and immunological events including Clinical Biopsy Proven Acute Rejection [C-BPAR], long-term kidney function and death-censored graft loss over a median follow-up of five years. Episodes of C-BPAR were noted at a median of two years post-transplant. Adjusted odds of having a subsequent C-BPAR was significantly higher in the SCI-T group [SC-BLR and SC-TCMR] compared to NSI 3.8 (2.1-7.5). The adjusted hazard for death-censored graft loss was significantly higher with SCI-T compared to NSI [1.99 (1.04-3.84)]. Overall, SCI detected through surveillance biopsy within the first year post-transplant is a harbinger for subsequent immunological events and is associated with a significantly greater hazard for subsequent C-BPAR and death-censored graft loss. Thus, our study highlights the need for identifying patients with SCI through surveillance biopsy and develop strategies to prevent further alloimmune injuries.

Impact of antimetabolite discontinuation following cytomegalovirus or BK polyoma virus infection in kidney transplant recipients.

Cytomegalovirus (CMV) and BK polyoma virus (BKV) infection following kidney transplantation have been associated with allograft dysfunction and allograft loss. Reduction in immunosuppression is a mainstay of management yet has been associated with increased risk of rejection. According to international consensus guidelines, one approach to management of these viral infections is to discontinue the antimetabolite. Little is known surrounding long-term outcomes in these patients, and it remains unclear if consideration should be given to resuming the antimetabolite as variable re-escalation strategies have been reported. The objective was to describe episodes of rejection and identify risk factors for rejection following antimetabolite withdrawal after CMV or BKV DNAemia in kidney transplant recipients. This single-center, retrospective review evaluated adult kidney transplant recipients with a serum CMV or BKV DNA PCR ≥500 copies/ml who underwent antimetabolite discontinuation. The primary outcome assessed was the incidence of biopsy-proven acute rejection (BPAR). One hundred fifty-nine patients were included. Overall, 14 patients (8.8%) experienced BPAR at a median of 1.6 years after antimetabolite discontinuation. Compared to CMV, discontinuation after BKV DNAemia was associated with a higher incidence of BPAR. Characteristics observed more frequently in patients with BPAR included younger age, female sex, higher initial viral load, and development of de novo donor-specific antibody (DSA). These findings suggest that antimetabolite discontinuation after CMV or BKV DNAemia in kidney transplant recipients is a reasonable and safe approach. Further prospective studies investigating optimal immunosuppression management following CMV or BKV DNAemia in kidney transplant recipients are warranted.

Predictors of Short-Term Outcomes in Living Donor Renal Allograft Recipients: A Prospective Study From a Tertiary Care Center in North India.

BackgroundRenal transplantation is the optimal treatment for patients of all ages with end-stage kidney disease. The long-term outcomes of renal transplantation are assessed by graft and patient survival rates. These outcomes are, in turn, influenced by post-transplant events such as delayed graft function, rejections, post-transplant infections, and post-transplant diabetes mellitus (PTDM). Each of these short-term outcomes is, in turn, determined by the interplay of various factors in the pre-, peri-, and post-transplant period. This prospective study was designed to understand the factors affecting short-term outcomes in living donor transplantation and their effect on graft and patient survival.MethodologyA total of 86 patients underwent live donor renal transplantation between January 1, 2015, and March 31, 2016, at a tertiary care hospital in north India. Of these, five were lost to follow-up, and the remaining 81 patients were prospectively followed up to December 31, 2017.ResultsThe majority of the recipients were males (91%) and the donors were females (74%). Spousal and related donors comprised 49% and 51% of donations, respectively. The mean estimated glomerular filtration rate (eGFR) of donors was 98 ± 9.2 mL/minute/1.73m². Induction therapy with basiliximab was given to 21/81 (26%) recipients. The majority of recipients (68/81, 84%) received triple-drug immunosuppression with prednisolone, tacrolimus, and mycophenolate mofetil. Delayed graft function (DGF) occurred in 4/81 (4.9%) cases. Biopsy-proven acute rejections (BPARs) occurred in 15/81 (18.5%) cases, two-thirds of which were acute antibody-mediated rejections (ABMRs). During the follow-up period, 50 episodes of infections occurred in 35/81 (43.2%) recipients, with the most common being urinary tract infection (23/81, 28.5%). PTDM was diagnosed in 22/81 (27.2%) patients beyond six weeks of transplant. On multivariate logistic regression analysis, the most significant predictor of DGF was acute rejections and vice versa. Acute rejections also predicted the occurrence of post-transplant infections. Pre-transplant hepatitis C virus (HCV) infection and cyclosporine-based therapy were significant predictors of PTDM. At the six-month follow-up, 10/81 (12.3%) patients developed graft dysfunction. The predictors of graft dysfunction at six months were recipients of related donors and rural patients. One-year graft survival, death-censored graft survival, and patient survival rates were 85.2%, 92.6%, and 91.3%, respectively. The most common cause of death was post-transplant infections (5/7, 71.4%) of which the majority (4/5, 80%) were fungal infections. On multivariate logistic regression analysis, the most significant predictor of graft loss and patient loss was low pre-transplant donor eGFR and PTDM, respectively.ConclusionsGraft and patient survival in living donor kidney transplantation are influenced by a multitude of interdependent factors during the pre-transplant (donor eGFR, type of donor, socioeconomic status, HCV infection in recipient, type of immunosuppression) and the post-transplant (DGF, rejections, infections, and PTDM) period.

Granulocyte colony-stimulating factor with or without immunosuppression reduction in neutropenic kidney transplant recipients.

Neutropenia post-kidney transplantation is associated with adverse graft and patient outcomes. We aimed to analyze the effect of granulocyte colony-stimulating factor (G-CSF) use with and without immunosuppression reduction on graft outcomes in neutropenic recipients. In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first-year post-transplant. Of these, 45.0% underwent no intervention, 17.5% had immunosuppression reduced, 18.3% were only given G-CSF, and 19.2% had both interventions. Overall, 61 patients experienced the composite outcome of de-novo DSA, biopsy-proven acute rejection, and all-cause graft failure and the cumulative incidence of this outcome did not vary by any of the four interventions (p=.93). When stratifying the cohort by G-CSF use alone, those who received G-CSF were more likely to have had severe neutropenia (<500/mm3 : 51.1% vs. 12.0%, p<.001), and immunosuppression reduction (51.1%vs. 28.0%, p=.003). However, the composite outcome was not different in the G-CSF and no G-CSF cohort (53.3%vs. 49.3%, p=.67), and in a multivariate model, G-CSF use was not associated with this outcome (aHR=1.18, 95% CI: .61-2.30). However, a trend towards higher DSA production was noted in the G-CSF cohort (87.5%vs. 62.2%) and this observation warrants prospective evaluation. Overall, we conclude that G-CSF use with or without immunosuppression reduction was not associated with graft outcomes.

A Multicenter Cohort Study From India of ABO-Incompatible Kidney Transplantation in Post–COVID-19 Patients

BackgroundThere is a dearth of data regarding the consequences of ABO-incompatible kidney transplant (ABOiKTx) among post–COVID-19 candidates.MethodsThe study was designed as a retrospective, multicentric cohort study across 11 sites in India, from August 2020 to December 2021. The data for ABOiKTx conducted for post–COVID-19 candidates were investigated. The primary outcome of biopsy-proven acute rejection was compared with the ABO protocol implemented through Kaplan-Meier analysis. The secondary outcomes were graft loss, patient survival, and infections.ResultsA total of 38 ABOiKTx with candidates of median (interquartile range) age of 38.5 (31.25-47.5) years were performed. Nineteen cases had mild COVID-19 severity, while 9 cases (23.6%) had an oxygen requirement. Six (15.7%) donors also were post–COVID-19. The most common ABO incompatibility reported was A to O in 14 (36.8%) pairs followed by B to O in 10 (26.3%) pairs. The maximum isoagglutinin titer cutoff was 1:2048 and 1:64 for baseline and pretransplant levels, respectively. The median time from COVID-19 infection to surgery was 130 (63.2-183) days. Biopsy-proven acute rejection, graft loss, and mortality were 13.1%, 2.6%, and 2.6%, respectively. The Breslow-Wilcoxon's P value in Kaplan-Meier plots were 0.57 and 0.93 for thymoglobulin-based induction and high dose rituximab-based regimen, respectively. The incidence of reinfection was 2.6%. Two (5.2%) urinary tract infections were reported. No cytomegalovirus or BK polyomavirus infection was reported. The median serum creatinine at 1 year of follow-up was 1.1 (0.8-1.3) mg/dL.ConclusionsOur report implies that ABOiKTx in post–COVID-19 candidates can be successfully performed with no major deviation from standard ABO protocol.

Antithymocyte globulin versus basiliximab induction for kidney transplantation in elderly patients: matched analysis within the Korean multicentric registry.

BackgroundBasiliximab (BSX) and antithymocyte globulins (ATGs), are two major immunosuppressive agents commonly used as induction therapy for kidney transplant (KT) recipients. The superiority of ATG over BSX has not been well established, especially in elderly KT recipients with low immunological risk.MethodsA total of 847 elderly (≥60 years old), low-risk KT patients in the Korean Organ Transplantation Registry were propensity score-matched at a 1:2 ratio and compared according to ATG or BSX induction therapy. The primary outcome was patient and graft survival and biopsy-proven acute cellular rejection. The secondary outcome was graft function, BK virus nephropathy, infection, cancer, new-onset diabetes mellitus after transplantation (NODAT), and delayed graft function.ResultsIn total, 165 patients in the ATG group were matched with 298 patients in the BSX group with average ages of 64.3 and 64.2 years, respectively. During a follow-up of 28.5 ± 10.4 months, the cumulative probabilities of death-censored graft failure at 3 years posttransplantation were 1.3% and 1.4% in ATG and BSX groups, respectively, without a significant difference (p = 0.72). The cumulative probability of NODAT at 3 years posttransplantation was significantly higher in the BSX group (35.6% vs. 21.6%, p = 0.02). The median tacrolimus trough level was significantly lower at 6 months after KT in the ATG group (5.7 ng/mL vs. 6.4 ng/mL, p = 0.001). There were no differences in the other evaluated outcomes.ConclusionCompared with BSX, in elderly, low-risk KT patients, ATG reduced tacrolimus and steroid requirements without differences in all-cause mortality, rejection, or infection, resulting in a reduced NODAT incidence.