Subclinical Antibody-mediated Rejection Research Articles

410.5: Donor-derived cell-free DNA identifies subclinical antibody-mediated rejection in de novo donor-specific antibody-positive kidney transplant recipients.

410.5: Donor-derived cell-free DNA identifies subclinical antibody-mediated rejection in de novo donor-specific antibody-positive kidney transplant recipients.

Imlifidase in Highly Sensitized Kidney Transplant Recipients With a Positive Crossmatch Against a Deceased Donor

IntroductionImlifidase is authorized for desensitization of highly sensitized adult kidney transplant candidates with a positive crossmatch against a deceased donor. Here, we report on the results for the first 9 patients transplanted in this context who had at least 3 months of follow-up. MethodsThe eligibility criteria were: calculated panel reactive antibodies (cPRA) ≥ 98%, ≥ 3 years on the waiting list, immunodominant donor specific antibodies (iDSA) with mean fluorescence intensity (MFI) > 6,000 (and < 5,000 at 1:10 dilution) and a negative post-imlifidase complement-dependent cytotoxic crossmatch (CDCXM). ResultsAll 9 patients had been on dialysis for an average of 123±41 months, with cPRA at 99% (n=2) or 100% (n=7). At transplantation, the mean number of DSA was 4.3±1.4. The median iDSA MFI was 9,153 (6,430-16,980). Flow cytometry and CDC XMs before imlifidase were positive in 9 and 2 patients, respectively. After one injection of imlifidase all were negative. Patients received polyclonal antibodies, intravenous immunoglobulins, rituximab, tacrolimus, and mycophenolate. Five patients had a DSA rebound within the first 14 days: 2 had concomitant clinical antibody-mediated rejection (ABMR), 2 had subclinical ABMR, and 1 had isolated positive C4d staining. No ABMR was observed in patients without rebound. CKD-EPI eGFR was 56±22 mL/min/1.73m2 at the last follow-up (7±2.8 months). No graft loss or death were observed. Four patients developed at least one infection. ConclusionThese real-life data demonstrate that the use of imlifidase to desensitize highly sensitized patients can have an acceptable short-term efficacy and safety profile in selected patients.

Targeting CD38 in Subclinical Antibody-mediated Rejection in HLA-incompatible Kidney Transplantation: A Case Report.

Targeting CD38 in Subclinical Antibody-mediated Rejection in HLA-incompatible Kidney Transplantation: A Case Report.

“Pre-Histologic” Antibody-Mediated Rejection Detected by Donor-Derived Cell-Free DNA and a Novel Tissue Gene Expression Assay: A Case Report

Despite its well-characterized association with poor long-term graft outcomes, subclinical antibody-mediated rejection (ABMR) in recipients of kidney transplants continues to pose a significant diagnostic and therapeutic challenge. Specifically, its detection currently relies on invasive histologic surveillance, a relatively uncommon practice among US transplant centers. We describe a subclinical, "pre-histologic" antibody-mediated rejection identified and characterized by a combination of novel molecular tools, donor-derived cell-free DNA (dd-cfDNA), and molecular histology. A 67-year-old kidney transplant recipient was found to have a marked elevation of dd-cfDNA on routine testing at 3 months post-transplant; other laboratory parameters were stable. A biopsy was performed, demonstrating the absence of rejection by traditional histology, but evidence of rejection was seen when tissue was evaluated using a research use molecular histology assay. Four months later, in the setting of persistently elevated dd-cfDNA, the patient developed graft dysfunction and was found to have C4d-negative ABMR, which was treated with improvement in both graft function and dd-cfDNA. This case highlighted the complementary use of dd-cfDNA and molecular histology to aid in the early detection and characterization of graft injury. Hybrid approaches combining these tools may allow more expeditious therapeutic intervention, leading to improved graft and patient outcomes.

Outcomes of untreated subclinical antibody-mediated rejection after heart transplantation

Subclinical antibody-mediated rejection (AMR) is represented by histopathological and/or immunopathological manifestations in the absence of significant cardiac allograft dysfunction. Treatment remains uncertain as there is a lack of data on asymptomatic heart transplant (HT) recipients (HTR) with a positive cardiac biopsy. We sought to determine the impact of untreated subclinical biopsy-proven AMR, regardless of circulating donor-specific antigen (DSA) expression, when diagnosed on surveillance biopsies in the first year after HT. This retrospective case control study evaluated 260 HTR between May 2004 and February 2021. These comprised 231 controls and 29 patients with untreated subclinical AMR. The mortality event rate was higher in controls (2.63 events per 100 person-years) compared to the scAMR Group (1.71 events per 100 person-years), a difference that did not reach statistical significance (hazard ratio 0.66, CI: 0.18–2.36). The combined event rate of cardiac allograft vasculopathy (CAV), graft dysfunction, or mortality was higher in the subclinical AMR group (5.60 events per 100 person-years) than in controls (3.89 events per 100 person-years) but did not reach statistical significance (hazard ratio 1.63, CI: 0.07–40.09). Our results suggest that subclinical AMR diagnosed in the first year after HT on surveillance biopsy is not associated with decreased survival. This may sway the management of subclinical AMR towards a more conservative approach in transplant-capable institutions that currently prioritize treatment, though prospective, randomized studies of such a management strategy are required.

Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories.

Pulmonary antibody-mediated rejection (AMR) consensus criteria categorize AMR by diagnostic certainty. This study aims to define the clinical features and associated outcomes of these recently defined AMR categories. Adjudication committees reviewed clinical data of 335 lung transplant recipients to define clinical or subclinical AMR based on the presence of allograft dysfunction, and the primary endpoints, time from transplant to allograft failure, a composite endpoint of chronic lung allograft dysfunction and/or death. Clinical AMR was subcategorized based on diagnostic certainty as definite, probable or possible AMR if 4, 3, or 2 characteristic features were present, respectively. Allograft injury was assessed via plasma donor-derived cell-free DNA (ddcfDNA). Risk of allograft failure and allograft injury was compared for AMR categories using regression models. Over the 38.5 months follow-up, 28.7% of subjects developed clinical AMR (n=96), 18.5% developed subclinical AMR (n=62) or 58.3% were no AMR (n=177). Clinical AMR showed higher risk of allograft failure and ddcfDNA levels compared to subclinical or no AMR. Clinical AMR included definite/probable (n=21) or possible AMR (n=75). These subcategories showed similar clinical characteristics, ddcfDNA levels, and risk of allograft failure. However, definite/probable AMR showed greater measures of AMR severity, including degree of allograft dysfunction and risk of death compared to possible AMR. Clinical AMR showed greater risk of allograft failure than subclinical AMR or no AMR. Subcategorization of clinical AMR based on diagnostic certainty correlated with AMR severity and risk of death, but not with the risk of allograft failure.

Potential Utility of Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte, and Neutrophil, Lymphocyte, and Platelet Ratios in Differential Diagnosis of Kidney Transplant Acute Rejection: A Retrospective, Propensity Score Matched Analysis.

BACKGROUND Acute kidney transplant rejection can negatively affect long-term graft function. The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio have been proposed as non-invasive predictors of acute rejection in stable kidney transplant recipients. The aim of this study was to validate the predictive value of these ratios, as well as neutrophil, lymphocyte, and platelet ratios in the diagnosis of acute rejection during the early post-transplant period. MATERIAL AND METHODS After propensity score matching, we compared 71 kidney recipients with biopsy-proven acute rejection with 71 patients without rejection and also subjects with different histologic types of rejection. All 3 types of blood cell count-derived ratios were calculated 6 and 3 days prior to biopsy and on the day of biopsy. RESULTS There were 15 patients with T cell-mediated rejection, 33 with vascular rejection, and 23 with antibody-mediated rejection. The values of all examined ratios did not differ between subgroups with and without rejection. However, at all post-transplant study time-points, patients with antibody-mediated rejection had significantly higher values of all analyzed ratios than subjects with other types of rejection. In multivariate regression models, higher values of blood cell count-derived ratios were independently associated with the occurrence of antibody-mediated rejection. CONCLUSIONS In the early post-transplant period, the values of neutrophil-to-lymphocyte, platelet-to-lymphocyte, and neutrophil, lymphocyte, and platelet ratios were similar in patients with and without an acute rejection episode, but significantly higher values were found in subjects with antibody-mediated rejection as compared with other types of rejection and those without rejection. High values of analyzed ratios in patients with satisfactory early kidney graft function may be helpful in selecting subjects with increased risk of subclinical antibody-mediated rejection.

MO1002: Two-Step Desensitization Protocol Consisting of High-Dose Intravenous Immunoglobulin, Plasmapheresis and Rituximab in Highly Sensitized Kidney Transplantation

Abstract BACKGROUND AND AIMS High-dose intravenous immunoglobulin (IVIG) therapy has not only immediate effects but also gradual effects via Fc receptors. To optimize IVIG therapy, we adopted a two-step desensitization protocol in kidney transplantation (KTx) with positive flow cytometry crossmatch (FCXM). METHOD In the first step, rituximab 200 mg and IVIG 2 g/kg were administered 2 months before KTx. In the second step, patients received additional rituximab 200 mg and IVIG 2g/kg for 2 weeks prior to transplantation in combination with plasmapheresis. RESULTS Of the six KTx with positive FCXM, there was no rejection except one (16.7%) subclinical antibody-mediated rejection within 1 month after transplantation. Average graft function was acceptable (serum creatinine level of 1.17 mg/dL). CONCLUSION The two-step desensitization protocol is an effective option for achieving successful transplant outcomes in KTx with positive FCXM, which can spare more aggressive and expensive treatments, such as C5 inhibitors, proteasome inhibitors and imlifidase.

Anti-HLA DQ Antibodies Are Associated with Chronic Lung Allograft Dysfunction in a Pediatric Lung Transplant Population

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) limits long term survival after lung transplantation. Antibody mediated rejection (AMR) has been associated with earlier CLAD development, but studies are limited in children. Clinical AMR can exist on a spectrum from subclinical to definite AMR based on the presence of anti-HLA donor specific antibodies (DSA), allograft dysfunction, and histopathologic findings, with DSA development first to appear. This study aims to describe the relationship of elevated DSA with clinical outcomes in a single center pediatric lung transplant population. <h3>Methods</h3> This was a single center, retrospective study. Pediatric bilateral lung transplant recipients were included from 2002-2020 if they had longitudinal HLA and lung function data for at least 6 months after transplantation. Preliminary analyses with chi-squared or Fisher's exact test for categorical variables and ANOVA or Kruskal-Wallis for continuous variables were used. DSA were detected with single-antigen bead arrays, and elevated DSA was defined as a mean fluorescence intensity level above 500. <h3>Results</h3> 34 patients were included: 19 with elevated DSA and 15 without. Most patients had subclinical AMR (n=10) without allograft dysfunction and two patients had definite AMR, based on the 2018 Banff consensus statement. The proportion of patients who developed CLAD was significantly higher in the elevated DSA group and had an earlier onset of CLAD. Average graft longevity and rates of acute cellular rejection, while not significant, trended towards shorter survival and higher rates of rejection in the elevated DSA group. All persistently elevated DSA were directed against HLA Class II DQ (6 of 14 patients) epitopes. Survival analysis and the significance of different HLA antigens remains ongoing. <h3>Conclusion</h3> The development of persistently elevated HLA Class II DQ DSA is associated with CLAD and likely decreased survival in the pediatric lung transplant population.

Eight-Year Results of an IgA- and IgM-Enriched Human Immunoglobulin-Based Therapy for Early Detectable Anti-HLA Donor Specific Antibodies After Lung Transplantation

<h3>Purpose</h3> The development of anti-HLA donor specific antibodies early after lung transplantation (eDSA) has been associated with antibody-mediated rejection (AMR) and poor graft survival. At our institution, since 2013, successive infusions of IgA- and IgM-enriched human intravenous immunoglobulins (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg once every 4 weeks for a maximum of 6 months) formed the backbone of eDSA therapy. Actually, patients with only evidence of eDSA (possible subclinical AMR) are treated with IgGAM only. Patients with concomitant graft dysfunction (possible clinical AMR) or preformed DSA (positive virtual crossmatch) receive additionally plasmapheresis (PE) or immunoabsorption before the first IgGAM dose, and a single dose of anti-CD20 antibody (Rituximab) thereafter. Aims of this study were to present the 8-year results of the IgGAM-based therapy. <h3>Methods</h3> Records of patients transplanted between 02/2013 and 10/2021 were reviewed. Outcomes were compared between patients with eDSA and treated with IgGAM (IgGAM group) and without eDSA (control group)<i>.</i> Median (IQR) follow-up was 45 (21-72) months. <h3>Results</h3> During the study period, among the 994 transplanted patients, 250 (25%) patients formed the IgGAM group and 721 (73%) the control group. The remaining 23 (2%) patients (14 patients with eDSA but not treated, and 9 patients treated only with tPE and Rituximab) were excluded. Fifty-Five IgGAM patients (22%) showed pre-formed eDSA and 41 (16%) patients showed possible clinical AMR. Median time to eDSA detection was 14 days after transplantation. At follow-up end, treatment was completed in 229 (92%) patients (still on treatment, n=8; in-hospital deaths, n=4; treatment interrupted earlier as intended by protocol, n=9). In these patients, IgGAM treatment cleared eDSA in 208 (91%) patients, 29 (14%) patients showing eDSA recurrence a median of 12 months after treatment end. In IgGAM vs. control patients and at 5- and 8-year follow-up, respectively, graft survival (%) was 77 vs. 76 and 68 vs. 67 (p=0.53), and freedom from CLAD was 73 vs. 72 and 65 vs. 62 (p=0.76), respectively. <h3>Conclusion</h3> After lung transplantation, a treatment protocol for eDSA based on IgGAM yielded high eDSA clearance. Patients with eDSA and IgGAM-treatment have good 8-year graft survival similar to control patients.

Renal allograft DARCness in subclinical acute and chronic active ABMR.

SummaryGene expression profiling of renal allograft biopsies revealed the Duffy antigen receptor for chemokines (DARC) as being strikingly upregulated in antibody‐mediated rejection (ABMR). DARC has previously been shown to be associated with endothelial injury. This study aimed at assessing the value of DARC immunohistochemistry as diagnostic marker in ABMR. The study was performed on 82 prospectively collected biopsies of a clinically well‐defined population (BORTEJECT trial, NCT01873157) of DSA‐positive patients with gene expression data available for all biopsies. Diagnostic histologic assessment of biopsies was performed according to the Banff diagnostic scheme. DARC expression was focally accentuated, on peritubular capillaries (PTC) mostly in areas of interstitial fibrosis and/or inflammation. DARC positivity was associated with diagnosis of ABMR and correlated with DARC gene expression levels detected by microarray analysis. Still, as previously described, a substantial number of biopsies without signs of rejection showed DARC‐positive PTC. We did not observe significantly reduced graft survival in cases showing histologic signs of ABMR and being DARC‐positive, as compared to DARC‐negative ABMR. In summary, the upregulation of DARC, detected by immunohistochemistry, is associated with but not specific for ABMR. We did not observe reduced graft survival in DARC‐positive patients.

Intensity of de novo DSA detected by Immucor Lifecodes assay and C3d fixing antibodies are not predictive of subclinical ABMR after Kidney Transplantation.

De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and allograft loss. We tested Immucor* (IM) Luminex Single-antigen beads (LSAB) assay and C3d-fixing antibodies in the setting of dnDSA and subclinical (s) ABMR. This retrospective multicentric study included 123 patients biopsied because of the presence of subclinical de novo DSA detected by One Lamda* Labscreen (MFI > 1000). In 112 patients, sera of the day of the biopsy were available and tested in a central lab with IM Lifecodes LSAB and C3d fixing antibodies assays. In 16 patients (14.3%), no DSA was detected using Immucor test. In 96 patients, at least one DSA was determined with IM. Systematic biopsies showed active sABMR in 30 patients (31.2%), chronic active sABMR in 17 patients (17.7%) and no lesions of sABMR in 49 KT recipients (51%). Intensitity criteria (BCM, BCR and AD-BCR) of DSA were not statistically different between these 3 histological groups. The proportion of patients with C3d-fixing DSA was not statistically different between the 3 groups and did not offer any prognostic value regarding graft survival. Performing biopsy for dnDSA could not be guided by the intensity criteria of IM LSAB assay. C3d-fixing DSA do not offer added value.

POS-686 UِSE OF BORTEZOMIB IN TREATMENT OF KIDNEY TRANSPLANT SUB-CLINICAL ANTIBODY MEDIATED REJECTION

Subclinical antibody-mediated rejection is defined as the presence of circulating donor HLA specific antibodies with the presence of typical pathological finding of antibody-mediated rejection and no change in graft function. It is known to be associated with poor outcome. Bortezomib is a proteasome inhibitor which has been used recently in treatment of antibody mediated rejection with varying degrees of success. It acts on antibodies producing plasma cells. It is commonly used with intravenous immunoglobulin infusion, therapeutic plasma exchange and rituximab and prednisone.

Seven-Year Clinical Results of an IgA-and IgM-Enriched Human Immunoglobulin-Based Therapy for Antibody-Mediated Rejection after Lung Transplantation

Purpose Development of anti-HLA donor specific antibodies early after lung transplantation (eDSA) has been associated with antibody-mediated rejection (AMR) and poor graft survival. Since 2013, our institution has employed successive infusions of IgA- and IgM-enriched intravenous immunoglobulins (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg once every 4 weeks for a maximum of 6 months) as 1st line treatment in such cases. Asymptomatic eDSA development (possible subclinical AMR) was treated with IgGAM only. Patients with concomitant graft dysfunction (possible clinical AMR) or positive crossmatch additionally receive 5 sessions of plasmapheresis pre-IgGAM, and a single dose of anti-CD20 antibody (Rituximab) afterwards. This study was presents 7-year results of this IgGAM-based protocol. Methods Records of patients transplanted between 02/2013 and 10/2020 were reviewed. Outcomes were compared between patients with eDSA and treated with IgGAM (IgGAM group) and those without eDSA (control group). Median follow-up was 41 (18-64) months. Results he 913 transplanted recipients, 224 (25%) patients were included in the IgGAM group and 667 (73%) the control group. The remaining 22 (2%) patients (13 patients with eDSA but not treated, and 9 patients treated only with tPE and Rituximab) were excluded. Forty-one (18%) IgGAM patients exhibited pre-formed eDSA and 16 (7%) patients showed a positive retrospective crossmatch. Thirty-six (16%) patients showed concomitant graft dysfunction (possible clinical AMR). Median time to eDSA detection was 14 days post-transplant. At follow-up end, treatment was completed in 204 (91%) patients (ongoing treatment, n=7; in-hospital deaths, n=4; treatment prematurely interrupted, n=9). In these 204 patients, IgGAM treatment cleared eDSA in 184 (90%) patients. Twenty-five (12%) patients developed eDSA recurrence at a median of 9 months after completing treatment. Clearance was less effective in patients with preformed eDSA (p Conclusion In lung recipients, treatment of eDSA with IgGAM yielded high eDSA clearance. Patients with eDSA and IgGAM-treatment have good 7-year graft survival similar to control patients.

The Problem of Subclinical Antibody-mediated Rejection in Kidney Transplantation.

Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell-mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.

Double-Filtration Plasmapheresis Plus Low-Dose Anti-thymocyte Globulin and Tacrolimus in Asian Living-Donor Kidney Transplantation With Donor-Specific Anti-HLA Antibody

BackgroundPretransplant desensitization protocols, including plasmapheresis, intravenous immunoglobulin, induction antibody therapy, and intensive maintenance immunosuppression, are generally employed in kidney transplant recipients who have positive status for donor-specific anti-HLA antibody (DSA). To avoid serious infectious complications, the authors designed a novel low-dose protocol in Thai patients undergoing DSA+ living-related kidney transplantation (LRKT). MethodsA retrospective cohort study of the patients who underwent DSA+ LRKT was conducted. The novel protocol consisted of 3 to 5 sessions of pretransplant double-filtration plasmapheresis (DFPP) with or without low-dose intravenous immunoglobulin together with low-dose anti-thymocyte globulin (ATG) induction (1-1.5 mg/kg/d for 3-4 days) and low-dose tacrolimus (Tac) (trough level 5-10 ng/mL), mycophenolate, and prednisolone. ResultsThe study included 17 patients. The lymphocyte crossmatch via complement-dependent cytotoxicity was negative in 12 patients and positive for B cell immunoglobulin M in 5 patients. The novel desensitization protocol resulted in a decrease of at least 50% of DSA mean fluorescence intensity from baseline (from 4320 ± 549 before DFPP to 1601 ± 350 before transplantation, P < .005) and successful kidney transplantation with good allograft function in all cases. Early DSA rebound was observed in 3 patients after transplantation, and kidney biopsy revealed subclinical antibody-mediated rejection in 1 patient and diffuse C4d staining without cell infiltration in 2 patients. There were good long-term outcomes in patient and graft survival (100% and 94.1%, respectively). Only 1 allograft loss occurred because of nonadherence. The majority of patients have stable allograft function with serum creatinine less than 1.5 mg/dL. However, infections, including CMV and other organisms, were commonly observed. ConclusionsDesensitization protocol with DFPP, low-dose ATG, and Tac provides excellent outcomes in living donor kidney transplantation in highly sensitized Asian populations.

COMPARATIVE STUDY OF ATG VS ATG-F (GRAFALON) AS AN INDUCTION AGENT IN ABO INCOMPATIBLE KIDNEY TRANSPLANTATION

Induction therapy is used prior to kidney transplant to prevent rejection. ABO-incompatible(ABOi) transplantation has a high risk of rejection owing to preformed antibodies. Polyclonal antibodies are used as an induction agent in high-risk kidney transplant.Two different forms of polyclonal antibodies are available for use- Rabbit Anti thymocyte globulin(ATG) and anti-human T-lymphocyte immunoglobulin (Grafalon).(1) The aim of this prospective study was to compare the outcome of ABOi living donor kidney transplant (LDKT) recipients who received either Rabbit Anti thymocyte globulin(ATG) and anti-human T-lymphocyte immunoglobulin(Grafalon) as an induction agent. All ABOi HLA-compatible patients that received a Lve donor kidney transplant between January 2017 and December 2018 at Sir Ganga Ram Hospital, New Delhi were included in the study. Twenty-five patients were given ATG and twenty-two patients received Grafalon. Baseline characters were similar between the two groups. Post-transplant immunosuppression was similar between both groups. All patients received Tacrolimus, Mycophenolate mofetil, and Prednisolone. There was no immediate infusion reaction observed with both induction agents. During the follow-up, no PTLD or malignancy occurred in both groups. The incidence of viral and bacterial infections was similar in both groups. The cumulative incidence of clinical and subclinical antibody-mediated allograft rejection, as well as T-cell, mediated allograft rejection during the first year between ATG and Grafalon was similar (20% versus 32%; p = 0.48 and 20% versus 9%;p = 0.36 respectively).within one year,two patients in ATG group and three patients in Grafalon group died. One patient in the ATG group underwent graft nephrectomy. Kaplan Meier survival analysis was done which showed survival was greater in the ATG group in comparison to Grafalon.

Mid-Term Outcomes After Treatment for Antibody-Mediated Rejection by De Novo Donor-Specific HLA Antibody in Renal Transplant Recipients: Does Early Treatment Lead to Better Outcomes?

BackgroundDe novo donor-specific HLA antibody (DSA) and antibody-mediated rejection (ABMR) are strongly associated with late allograft loss in renal transplant recipients. However, the impact of therapeutic intervention with the current treatment options for ABMR remains unclear. This study aimed to elucidate the efficacy of treatment for ABMR. MethodsSixty-seven patients who had de novo DSAs underwent diagnostic biopsy for ABMR, and these patients were classified into 3 groups: ABMR-free group (n = 40), clinical ABMR group (n = 15), and subclinical ABMR group (n = 12). The ABMR-positive groups were treated mainly with double-filtration plasmapheresis followed by rituximab and corticosteroid pulse. The patient characteristics and graft outcomes were compared between groups. ResultsThe clinical and subclinical ABMR groups were younger and had a higher number and mean fluorescence intensity (MFI) of de novo DSAs than the ABMR-free group. The graft survival in the clinical ABMR group was significantly lower than that in the ABMR-free group, but the subclinical ABMR group had a surprisingly good graft survival rate compared to the ABMR-free group (43.3% vs 100% vs 94.2% 5 years after diagnostic biopsy in the clinical ABMR, subclinical ABMR, and ABMR-free groups, respectively, P < .001). ConclusionsOur findings indicated that early therapeutic intervention for patients with de novo DSAs may improve graft survival.

Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers.

Subclinical rejection (SCR) screening in kidney transplantation (KT) using protocol biopsies and noninvasive biomarkers has not been evaluated from an economic perspective. We assessed cost-effectiveness from the health sector perspective of SCR screening in the first year after KT using a Markov model that compared no screening with screening using protocol biopsy or biomarker at 3 months, 12months, 3 and 12months, or 3, 6, and 12months. We used 12% subclinical cellular rejection and 3% subclinical antibody-mediated rejection (SC-ABMR) for the base-case cohort. Results favored 1-time screening at peak SCR incidence rather than repeated screening. Screening 2 or 3 times was favored only with age <35years and with high SC-ABMR incidence. Compared to biomarkers, protocol biopsy yielded more quality-adjusted life years (QALYs) at lower cost. A 12-month biopsy cost $13318/QALY for the base-case cohort. Screening for cellular rejection in the absence of SC-ABMR was less cost effective with 12-month biopsy costing $46370/QALY. Screening was less cost effective in patients >60years. Using biomarker twice or thrice was cost effective only if biomarker cost was <$700. In conclusion, in KT, screening for SCR more than once during the first year is not economically reasonable. Screening with protocol biopsy was favored over biomarkers.

Significance of revised criteria for chronic active T cell-mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P<.001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P<.001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.