Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell-mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods.

The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell-mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.

The Predictors and Risk Factors of 2-Year Rejection in Renal Transplant Patients: A Multicenter Case-Control Study.

INTRODUCTION: Kidney transplantation is a definitive treatment for end-stage renal disease. It is associated with improved life expectancy and quality of life. One of the most common complications following kidney transplantation is graft rejection. To our knowledge, no previous study has identified rejection risk factors in kidney transplant recipients in Saudi Arabia. Therefore, this study aimed to determine the specific risk factors of graft rejection. METHODS: A multicenter case-control study was conducted at four transplant centers in Saudi Arabia. All adult patients who underwent a renal transplant between January 1, 2015 and December 31, 2021 were screened for eligibility. Included patients were categorized into two groups (cases and control) based on the occurrence of biopsy-proven rejection within 2 years. The primary outcome was to determine the risk factors for rejection within the 2 years of transplant. Exact matching was utilized using a 1:4 ratio based on patients' age, gender, and transplant year. RESULTS: Out of 1,320 screened renal transplant recipients, 816 patients were included. The overall prevalence of 2-year rejection was 13.9%. In bivariate analysis, deceased donor status, the presence of donor-specific antibody (DSA), intraoperative hypotension, Pseudomonas aeruginosa, Candida, and any infection within 2 years were linked with an increased risk of 2-year rejection. However, in the logistic regression analysis, the presence of DSA was identified as a significant risk for 2-year rejection (adjusted OR: 2.68; 95% CI: 1.10, 6.49, p = 0.03). Furthermore, blood infection, infected with Pseudomonas aeruginosa or BK virus within 2 years of transplant, were associated with higher odds of 2-year rejection (adjusted OR: 3.10; 95% CI: 1.48, 6.48, p = 0.003, adjusted OR: 3.23; 95% CI: 0.87, 11.97, p = 0.08 and adjusted OR: 2.76; 95% CI: 0.89, 8.48, p = 0.07, respectively). CONCLUSION: Our findings emphasize the need for appropriate prevention and management of infections following kidney transplantation to avoid more serious problems, such as rejection, which could significantly raise the likelihood of allograft failure and probably death. Further studies with larger sample sizes are needed to investigate the impact of serum chloride levels prior to transplant and intraoperative hypotension on the risk of graft rejection and failure.

Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation.

Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.

Safety and infectious outcomes in pediatric kidney transplant recipients after COVID-19 vaccination: A pediatric nephrology research consortium study.

BACKGROUND: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID-19 have substantial morbidity and mortality related to SARS-CoV-2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID-19 vaccination series in pediatric KTRs. METHODS: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID-19 were enrolled and data were collected pertaining to SARS-CoV-2 infection incidence and severity, graft outcomes and post-vaccination safety profile, as well as overall patient survival. RESULTS: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5-15). SARS-CoV-2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post-transplant, within the defined follow-up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor-specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA-tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed. CONCLUSIONS: Observationally, infectious outcomes of SARS-CoV-2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort.

Clinical conundrums in pediatric kidney transplantation: What we know about the role of angiotensin II type I receptor antibodies in pediatric kidney transplantation and the path forward.

Antibodies to angiotensin II type 1 receptor (AT1R-Abs) are among the most well-studied non-HLA antibodies in renal transplantation. These antibodies have been shown to be common in pediatric kidney transplantation and associated with antibody-mediated rejection (AMR), vascular inflammation, development of human leukocyte donor-specific antibodies (HLA DSA), and allograft loss. As AT1R-Ab testing becomes more readily accessible, evidence to guide clinical practice for testing and treating AT1R-Ab positivity in pediatric kidney transplant recipients remains limited. This review discusses the clinical complexities of evaluating AT1R-Abs given the current available evidence.

Exploratory associations of tacrolimus exposure and clinical outcomes after lung transplantation: A retrospective, single center experience.

PURPOSE: This study aimed to investigate the potential impact of tacrolimus (TAC) exposure on clinical outcomes after lung transplantation. METHODS: This retrospective observational study enrolled a total of 228 lung transplant recipients. TAC trough levels (C0) were collected for 3 intervals: 0-3 months, 3-12 months, and 12-24 months. The intra-patient variability (IPV) was calculated using coefficient of variation. Genotyping of CYP3A5*3 (rs776746) was performed. Patients were further divided into groups based on the C0 cut-off value of 8 ng/mL and IPV cut-off value of 30%. Cox proportional hazards regression models were used to explore the potential impact of C0 and IPV on outcomes of interests, including de-novo donor-specific antibodies (dnDSA), chronic lung allograft dysfunction (CLAD) and mortality. RESULTS: The influence of CYP3A5*3 polymorphism was only significant for C0 and IPV during the first 3 months. Low C0 (< 8 ng/mL) at 3-12 months increased the risk of dnDSA (hazard ratio [HR] 2.696, 95% confidence interval [CI] 1.046-6.953) and mortality (HR 2.531, 95% CI 1.368-4.685), while High IPV (≥ 30%) during this period was associated with an increased risk of mortality (HR 2.543, 95% CI 1.336-4.839). Patients with Low C0/High IPV combination had significantly higher risks for dnDSA (HR 4.381, 95% CI 1.279-15.008) and survival (HR 6.179, 95% CI 2.598-14.698), surpassing the predictive power provided by C0 or IPV alone. CONCLUSION: A combination of Low C0/High IPV might be considered in categorizing patients towards risk of adverse clinical outcomes following lung transplantation.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients.

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation.

Double filtration plasmapheresis combined with rituximab for donor-specific antibody desensitization in haploidentical haematopoietic stem cell transplantation.

Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical haematopoietic stem cell transplantation (Haplo-HSCT). Double filtration plasmapheresis (DFPP) avoids the unnecessary loss of plasma proteins and increases the efficiency of purification. To investigate the effectiveness of the desensitization protocol including DFPP and rituximab, we conducted a nested case-control study. Thirty-three patients who had positive DSA were desensitized by the protocol and 99 patients with negative DSA were randomly matched as control. The median DSA mean fluorescence intensity values before and after DFPP treatment were 7505.88 ± 4424.38 versus 2013.29 ± 4067.22 (p < 0.001). All patients in DSA group achieved haematopoietic reconstitution and the median neutrophils and platelets engraftment times were 13 (10-21) and 13 (10-29) days respectively. Although the cumulative incidence of II-IV aGVHD (41.4% vs. 28.1%) and 3-year moderate to severe cGVHD (16.8% vs. 7.2%) were higher in DSA cohort than in the control, no statistical significance was observed. The 3-year non-relapse mortality and the overall survival were 6.39% and 72.0%, respectively, in the DSA cohort, which were comparable to the negative control. In conclusion, DFPP and rituximab could be effectively used for desensitization and overcome the negative effects of DSA in Haplo-HSCT.

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

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 862 deceased donors for 1,137 kidney recipients at 13 centers. EXPOSURES: 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. OUTCOMES: 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. ANALYTICAL APPROACH: Multivariable Fine-Gray models with death as a competing risk. RESULTS: 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. LIMITATIONS: BPAR was ascertained through for-cause biopsies, not surveillance biopsies. CONCLUSIONS: 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.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody.

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Kidney transplant from HCV viremic donors to HCV-negative recipients and risk for de novo donor specific antibodies and acute rejection.

BACKGROUND: Kidney transplantation from HCV-viremic donors into uninfected recipients is associated with excellent short-term outcomes. However, concerns regarding an increased risk for the development of de novo donor specific antibodies (DSA) and acute rejection have been raised in single center reports. METHODS: A retrospective study of HCV-negative kidney-only transplant recipients between 2018 and 2020. Patients were grouped based on the donor HCV status into group 1; HCV-viremic donors, and group 2; HCV-negative donors. Inverse probability of treatment weighting (IPTW), with weights derived from the propensity score, were used to estimate the effect of donors' HCV-viremia on the recipients. The primary objective was to compare the 1-year incidence of de novo DSA. Secondary outcomes included group comparison of the incidence of biopsy proven acute rejection (BPAR), 1-year patient and allograft survival, and 1-year renal allograft function. RESULTS: A total of 71 patients were included in the HCV NAT+ group, and 440 in the HCV- negative group. One-year incidence of de novo DSA was higher in the HCV NAT+ group in the IPTW weighted analysis (19% vs. 9%, p = .02). In the unweighted analysis, BPAR occurred in 7% of recipients in the HCV NAT+ group, compared to 3% in the control group (p = .06). However, due to the low event rate in the in the IPTW weighted groups, a statistical significance test could not be performed. Average estimated GFR was higher in the HCV-viremic group at 3 months (61 vs. 53 ml/min/1.73 m2 p = .002), but comparable at 6 (59 vs. 56 ml/min/1.73 m2 , p = .31) and 12 months (60 vs. 55 ml/min/1.73 m2 , p = .07). Patient and allograft survival were comparable between the two groups. CONCLUSION: Kidney transplant from HCV-viremic donors was associated with an increased risk for the development of post-transplant de novo DSA in the first year after transplantation, but no difference in patient and graft survival.

Donor-specific antibodies after heart transplantation for Fontan-associated protein-losing enteropathy.

BACKGROUND: Despite ubiquitous exposure to sensitizing events, most Fontan PLE patients have low panel reactive antibodies (PRA). To assess whether they are at risk for donor-specific antibody (DSA) memory response following heart transplantation (HT) when their PLE resolves, DSA profiles, incidence of rejection, and graft outcomes in Fontan recipients with and without PLE were compared. METHODS: Patient characteristics, appearance of newly detected DSA (nDSA), and graft outcomes were compared between patients with and without PLE using Wilcoxon rank-sum and Chi-squared tests. DSA burden was quantified using titers and time to nDSA, incidence of rejection, and graft outcomes were compared using Kaplan-Meier curves and the log-rank test. RESULTS: Characteristics of patients with and without PLE were similar. Lymphocyte and albumin levels were lower in the PLE group, and flow PRA were comparable. Graft failure, CAV, and ACR were similar between the two groups, but AMR occurred more frequently in the PLE group (p = .03). Nearly 50% of PLE patients experienced class II nDSA by 1-year post-HT, compared to 30% of non-PLE patients, but this difference was statistically not significant. Antibody burden did not differ between groups. CONCLUSIONS: In this cohort, PLE was associated with AMR within the first-year post-HT, despite no significant difference in nDSA. Small patient numbers limited statistical comparison of nDSA in this cohort. PLE may be a risk factor for AMR post-HT, and the possibility of a clinically important DSA memory response remains. Larger studies are necessary to better understand these preliminary findings.

Development of New Donor-Specific and Human Leukocyte Antigen Antibodies After Transfusion in Adult Lung Transplantation.

OBJECTIVES: The development of new human leukocyte antigens (HLAs) and donor-specific antibodies (DSAs) in patients are associated with worse outcomes following lung transplantation. The authors aimed to examine the relationship between blood product transfusion in the first 72 hours after lung transplantation and the development of HLA antibodies, including DSAs. DESIGN: A retrospective observational study. SETTING: At a single academic tertiary center. PARTICIPANTS: Adult lung transplant recipients who underwent transplantation between September 2014 and June 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 380 patients were included in this study, and 87 (23%) developed de novo donor-specific antibodies in the first year after transplantation. Eighty-five patients (22%) developed new HLA antibodies that were not donor-specific, and 208 patients (55%) did not develop new HLA antibodies in the first year after transplantation. Factors associated with increased HLA and DSA development included donor pulmonary infection, non-infectious indication for transplant, increased recipient body mass index, and a preoperative calculated panel reactive antibody value above 0. Multivariate analysis identified platelet transfusion associated with an increased risk of de novo HLA antibody development compared to the negative group (odds ratio [OR; 95% CI] 1.18 [1.02-1.36]; p = 0.025). Cryoprecipitate transfusion was associated with de novo DSA development compared to the negative group (OR [95% CI] 2.21 [1.32-3.69] for 1 v 0 units; p = 0.002). CONCLUSIONS: Increased perioperative transfusion of platelets and cryoprecipitate are associated with de novo HLA and DSA development, respectively, in lung transplant recipients during the first year after transplantation.

Mechanism and treatment for chronic antibody-mediated rejection in kidney transplant recipients.

Chronic antibody-mediated rejection of kidney transplantation is a major cause of late-stage graft loss. Donor-specific antibodies are the main cause of antibody-mediated rejection; in particular, de novo donor-specific antibodies are a risk factor for chronic active antibody-mediated rejection. The level of de novo donor-specific antibodies tends to increase with time throughout long-term graft survival. Donor-specific antibodies induce humoral rejection through complement activation, which results in tissue injury and coagulation. Additionally, complement activation promotes the migration of inflammatory cells through the innate immune response, causing endothelial injury. This inflammatory response may cause persistent glomerulitis and peritubular capillaritis, leading to fixed pathological lesions that impair graft function. No treatment has been established for chronic antibody-mediated rejection, a condition in which antibody-mediated rejection becomes irreversible. Thus, antibody-mediated rejection must be detected and treated while it is still reversible. In this review, we discuss the development of de novo donor-specific antibodies and the mechanisms leading to chronic antibody-mediated rejection and summarize the current treatment options and the latest biomarkers for detecting chronic antibody-mediated rejection at an earlier stage.

Monitoring of Serological, Cellular and Genomic Biomarkers in Transplantation, Computational Prediction Models and Role of Cell-Free DNA in Transplant Outcome.

The process and evolution of an organ transplant procedure has evolved in terms of the prevention of immunological rejection with the improvement in the determination of immune response genes. These techniques include considering more important genes, more polymorphism detection, more refinement of the response motifs, as well as the analysis of epitopes and eplets, its capacity to fix complement, the PIRCHE algorithm and post-transplant monitoring with promising new biomarkers that surpass the classic serum markers such as creatine and other similar parameters of renal function. Among these new biomarkers, we analyze new serological, urine, cellular, genomic and transcriptomic biomarkers and computational prediction, with particular attention to the analysis of donor free circulating DNA as an optimal marker of kidney damage.

Clinical characteristics of 15 cases of renal transplantation with pre-exsiting donor-specific antibody. / 15ä¾‹é¢„å­˜ä¾›è€ ç‰¹å¼‚æ€§æŠ—ä½“é˜³æ€§è‚¾ç§»æ¤çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Currently, patients with pre-exsiting donor-specific antibody (DSA) are prone to antibody-mediated rejection (AMR) after surgery and are at a relatively high risk of postoperative complications and graft failure. The risk of postoperative complications and graft failure is relatively high. This study aims to discuss the clinical outcome of DSA-positive kidney transplantation and analyze the role and safety of preoperative pretreatment in DSA-positive kidney transplantation, providing single-center treatment experience for DSA-positive kidney transplantation. METHODS: We retrospectively analyzed the clinical data of 15 DSA-positive kidney transplants in the Department of Renal Transplantation of First Affiliated Hospital of Zhengzhou University from August 2017 to July 2022. Eight cases were organ donation after citizen's death (DCD) kidney transplant recipients, of which 3 cases in the early stage were not treated with preoperative desensitisation therapy (DCD untreated group, n=3), and 5 recipients were treated with preoperative rituximab desensitisation (DCD preprocessing group, n=5). The remaining 7 cases were living related donors recipients (LRD) who received preoperative desensitisation treatment with rituximab and plasma exchange (LRD preprocessing group, n=7). We observed and recorded the incidence of complications with changes in renal function and DSA levels in the recipients and the survival of the recipients and transplanted kidneys at 1, 3 and 5 years, and to compare the differences in recovery and postoperative complications between 3 groups. RESULTS: All 15 recipients were positive for preoperative panel reactive antibody (PRA) and DSA and were treated with methylprednisolone+rabbit anti-human thymocyte immunoglobulin induction before kidney transplantation. DCD untreated group all suffered from DSA level rebound, delayed renal graft function (DGF) and rejection reaction after surgery. After the combined treatment, DSA level was reduced and the graft renal function returned to normal. The DCD preprocessing group were all without antibody rebound, 1 recipient developed DGF and the renal function returned to normal after plasmapheresis, and the remaining 4 recipients recovered their renal function to normal within 2 weeks after the operation. In the LRD preprocessing group, 2 cases had antibody rebound and 1 case had rejection, but all of them recovered to normal after treatment, and DSA was maintained at a low level or even disappeared. The incidence of DGF and rejection in the DCD untreated group were significantly higher than that in the DCD preprocessing group and the LRD preprocessing group; and there were no significant difference in the incidence of postoperative haematuria, proteinuria, bacterial and fungal infections, and BK virus infection between the 3 groups (all P>0.05). A total of 11 of the 15 recipients were followed up for more than 1 year, 6 for more than 3 years, and 1 for more than 5 years, and the survival rates of both the recipients and the transplanted kidneys were 100%. CONCLUSIONS: Effective preoperative pretreatment with desensitization therapy can effectively prevent antibody rebound in DSA-positive kidney transplantation and reduce perioperative complications.

Two-year outcomes of low-exposure extended-release tacrolimus and mycophenolate mofetil regimen in de novo kidney transplantation: A multi-center randomized controlled trial.

BACKGROUND: Once-daily extended-release tacrolimus (TACER) is commonly administered following kidney transplantation (KTx); however, its optimal dosage remains unknown. METHODS: In this multi-center, randomized controlled trial, 62 living donor KTx recipients were assigned to either standard-exposure (SE; n = 32) or low-exposure (LE; n = 30) TACER (Graceptor®, Astellas Pharm Inc.) groups. All patients received basiliximab and mycophenolate mofetil (MMF). The primary outcomes were acute rejection, graft/patient survival, and the secondary outcomes were incidence of cytomegalovirus infection, and de novo donor-specific antibodies (dnDSA) production. RESULTS: The tacrolimus trough level and estimated area under the blood concentration-time curve (eAUC) were significantly higher in SE than in LE (SE vs. LE; 1 year: 5.0 ± 0.9 ng/ml and 206.9 ± 26.8 ng h/ml vs. 3.4 ± 1.0 ng/ml and 153.9 ± 26.4 ng h/ml; 2 years: 4.8 ± 1.0 ng/ml and 204.9 ± 30.1 ng h/ml vs. 3.8 ± 0.9 ng/ml and 164.4 ± 27.0 ng h/ml). In contrast, the dosage and eAUC of MMF did not differ between groups. Two-year graft and patient survival rates were 100% in both groups, and acute rejection rates were 0% and 10% in the SE and LE, respectively (p = 0.11). The mean estimated glomerular filtration rates did not differ between the groups. Cytomegalovirus infection was slightly lower in the LE (SE: 12.5% and LE: 6.7%, p = 0.37). In the LE, four cases of dnDSA were noted within 2 years of transplantation; no case was observed in the SE (p = 0.034). CONCLUSIONS: Although the LE TACER regimen showed similar rates of acute rejection, as well as graft and patient survival compared with SE after KTx, LE was significantly more associated with dnDSA. Further investigation of its long-term effect on graft survival is warranted. (University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000033089).

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

INTRODUCTION: 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. METHODS: In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first-year post-transplant. RESULTS: 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. CONCLUSION: Overall, we conclude that G-CSF use with or without immunosuppression reduction was not associated with graft outcomes.