Novel therapies for treatment of antibody-mediated rejection of the kidney.

PURPOSE OF REVIEW: We aim to discuss current literature on novel therapies for antibody-mediated rejection (AMR) in kidney transplantation with a focus on chronic AMR. RECENT FINDINGS: IL-6/IL-6 receptor blockers appear promising in the treatment of chronic AMR. Blocking this pathway was shown to reduce human leucocyte antigen-antibodies, improve histologic inflammation and increase T-regulatory cells. Based on experience in desensitization, IgG degrading endopeptidase, imlifidase, could be effective in AMR. There have been case reports describing the successful use of plasma cell/natural killer-cell-directed anti-CD38 antibody in the treatment of AMR. Off-target effects have been noted and strategies to mitigate these will be needed when using these agents. Complement inhibitors could be an effective add-on strategy to antibody-depleting therapies but their role in AMR needs to be better defined. Combining proteasome inhibitors and costimulation blockers has shown encouraging results in the prevention of AMR in animal models and is now being investigated in humans. Other novel strategies such as Fc neonatal receptor blockers which inhibit the recycling of pathogenic IgG and bispecific antibodies against B-cell maturation antigen/CD3+ T cells warrant further investigation. SUMMARY: There are now a number of emerging therapies with varied targets and mechanism(s) of action that hold promise in the management of AMR and improving allograft survival.

An Assessment of the Value of Donor-derived Cell-free DNA Surveillance in Patients With Preserved Kidney Allograft Function.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is a biomarker validated to detect rejection when measured to assess kidney allograft dysfunction. However, it remains unclear whether routine surveillance with dd-cfDNA provides additional information over standard monitoring of kidney allografts with creatinine and donor-specific antibodies (DSAs), particularly among those with little suspicion of rejection or injury. We investigated the value of measuring dd-cfDNA in patients with preserved allograft function and describe its association with future events. METHODS: Three-hundred seventeen kidney transplant recipients with a creatinine ≤1.5 mg/dL, no current DSA, and no prior rejection were assessed with dd-cfDNA and categorized into low (dd-cfDNA <0.5%; n = 239), moderate (dd-cfDNA 0.5% to <1.0%; n = 43), and high (dd-cfDNA ≥1.0%; n = 35) groups. The occurrence of rejection, DSA, graft loss, and change in estimated glomerular filtration rate over time after dd-cfDNA assessment was compared. RESULTS: Over follow-up, rejections were more commonly found among patients with high vs low dd-cfDNA (17% versus 5%; P = 0.01); a similar nonsignificant trend was observed among patients with moderate compared to low dd-cfDNA (12% versus 5%; P = 0.13). DSA development was uncommon and not different between groups (low: 4%; moderate: 3%; high: 0%; P = 0.52). There was only 1 graft loss in a patient with low dd-cfDNA, and dd-cfDNA was not associated with graft dysfunction over time. CONCLUSIONS: Most patients with elevated dd-cfDNA in conjunction with preserved allograft function remained stable over follow-up without deterioration in function or graft loss. Studies are needed to differentiate patients with elevated dd-cfDNA who will develop adverse outcomes from those who will remain clinically stable.

A Banff-based histologic chronicity index is associated with graft loss in patients with a kidney transplant and antibody-mediated rejection.

Antibody-mediated rejection (AMR) is the major cause of graft loss in kidney transplant recipients. The Banff classification defines two classes of AMR, active and chronic active but over time this classification has become increasingly complex. To simplify the approach to AMR, we developed activity and chronicity indices based on kidney transplant biopsy findings and examined their association with graft survival in 147 patients with active or chronic active AMR, all of whom had donor-specific antibodies and were treated for AMR. The activity index was determined as the sum of Banff glomerulitis (g), peritubular capillaritis (ptc), arteritis (v) and C4d scores, with a maximum score of 12. The chronicity index was the sum of interstitial fibrosis (ci), tubular atrophy (ct), chronic vasculopathy (cv), and chronic glomerulopathy (cg) scores, the latter doubled, with a maximum score of 15. While the activity index was generally not associated with graft loss, the chronicity index was significantly associated with graft loss with an optimal threshold value of 4 or greater for predicting graft loss. The association of the chronicity index of 4 or greater with graft loss was independent of other parameters associated with graft loss, including the estimated glomerular filtration rate at the time of biopsy, chronic active (versus active) AMR, AMR with de novo (versus persistent/rebound) donor-specific antibodies, Banff (g+ptc) scores, concurrent T cell-mediated rejection and donor-specific antibody reduction post-biopsy. The association of the chronicity index of 4 or greater with graft loss was confirmed in an independent cohort of 61 patients from Necker Hospital, Paris. Thus, our findings suggest that the chronicity index may be valuable as a simplified approach to decision-making in patients with AMR.

Evaluation of Clazakizumab (Anti-Interleukin-6) in Patients With Treatment-Resistant Chronic Active Antibody-Mediated Rejection of Kidney Allografts.

Introduction: Interleukin-6 (IL-6) is an important mediator of inflammation and activation of T cells, B cells, and plasma cells. Excessive IL-6 production is linked to human diseases characterized by unregulated antibody production, including alloimmunity, where persistence of donor-specific antibodies (DSAs), chronic active antibody-mediated rejection (cAMR), and graft loss are noted. Here, we report our experience investigating clazakizumab, a novel IL-6 inhibitor, in treating human leukocyte antigen (HLA)-sensitized patients with cAMR. Methods: Between February 2018 and January 2019, 10 adults with biopsy-proven cAMR were enrolled in a phase 2, single-center, open-label study. Patients received clazakizumab 25 mg subcutaneously (s.c.) monthly for 12 months, with a 6-month protocol biopsy. Primary end points included patient survival, graft survival, estimated glomerular filtration rate (eGFR), and safety. Secondary end points assessed immune markers (DSAs, IgG, T-regulatory [Treg] cells). At 12 months, stable patients entered a long-term extension (LTE). Results: LTE patients received clazakizumab for >2.5 years. Mean eGFRs showed significant declines from -24 months to study initiation (0 months) (52.8 ± 14.6 to 38.11 ± 12.23 ml/min per 1.73 m2, P = 0.03). However, after initiation of clazakizumab, eGFR stabilized at (41.6 ± 14.2 and 38.1 ± 20.3 ml/min per 1.73 m2, at 12 and 24 months, respectively). Banff 2017 analysis of pre- and post-treatment biopsies showed reductions in g+ptc and C4d scores. DSA reductions were seen in most patients. Adverse events (AEs) were minimal, and 2 graft losses occurred, both in patients who discontinued clazakizumab therapy at 6 months and 12 months after study initiation. Conclusion: In this small cohort of patients with cAMR, clazakizumab treatment showed a trend toward stabilization of eGFR and reductions in DSA and graft inflammation. No significant safety issues were observed. A randomized, placebo-controlled clinical trial (IMAGINE) of clazakizumab in cAMR treatment is underway (NCT03744910).

Assessment of humoral and cellular immune responses to SARS CoV-2 vaccination (BNT162b2) in immunocompromised renal allograft recipients.

BACKGROUND: Assessing the composition of immune responses to SARS-CoV-2 vaccines is critical for our understanding of protective immunity, especially for immune compromised patients. The Pfizer (BNT162b2) vaccination showed >90% efficacy in protecting individuals from infection. However, these studies did not examine responses in immunocompromised kidney transplant patients (KT). Subsequent reports in KT have shown severe deficiencies in Spike-specific immunoglobin G (IgG) responses prompting booster vaccinations, but a broader understanding of T-cell immunity to vaccinating is lacking. METHODS: We examined SARS-CoV-2 Spike IgG and CD4+/CD8+ Spike-specific T-cell responses in 61 KT patients maintained on different immunosuppressive protocols (ISP) (Tac + mycophenolate mofetil + prednisone) versus (belatacept + MMF + prednisone) and compared to 41 healthy controls. We also examined cytomegalovirus-cytotoxic T-cell responses (CMV-Tc) in both groups to assess T-cell memory. RESULTS: Our data confirmed poor Spike IgG responses in vaccinated KT patients with both ISP (21% demonstrating Spike IgG 1M post-second dose of BNT162b2 vs. 93% in controls). However, 35% of Spike IgG (-) patients demonstrated CD4+ and/or CD8+ T-cell responses. All but one CMV-IgG+ patient demonstrated good CMV-Tc responses. No differences in T-cell immunity by ISP were seen. CONCLUSION: Immunocompromised KT recipients showed severe defects in humoral and T-cell immune response after vaccination. No differences in immune responses to SARS-CoV-2 Spike peptides were observed in KT patients by ISP post-vaccination. The detection of Spike-specific T-cell immunity in the absence of Spike IgG suggests that vaccination in immunocompromised KT patients may provide partial immunity, although not preventing infection, T-cell immunity may limit its severity.

Clazakizumab for desensitization in highly sensitized patients awaiting transplantation.

Alloantibodies are a significant barrier to successful transplantation. While desensitization has emerged, efficacy is limited. Interleukin-6 (IL-6) is an important mediator of inflammation and immune cell activation. Persistent IL-6 production increases the risk for alloantibody production. Here we report our experience with clazakizumab (anti-IL-6) for desensitization of highly HLA-sensitized patients (HS). From March 2018 to September 2020, 20 HS patients were enrolled in an open label pilot study to assess safety and limited efficacy of clazakizumab desensitization. Patients received PLEX, IVIg, and clazakizumab 25 mg monthly X6. If transplanted, graft function, pathology, HLA antibodies and regulatory immune cells were monitored. Transplanted patients received standard immunosuppression and clazakizumab 25 mg monthly posttransplant. Clazakizumab was well tolerated and associated with significant reductions in class I and class II antibodies allowing 18 of 20 patients to receive transplants with no DSA rebound in most. Significant increases in Treg and Breg cells were seen posttransplant. Antibody-mediated rejection occurred in three patients. The mean estimated glomerular filtration rate at 12 months was 58 ± 29 ml/min/1.73 m2 . Clazakizumab was generally safe and associated with significant reductions in HLA alloantibodies and high transplant rates for highly-sensitized patients. However, confirmation of efficacy for desensitization requires assessment in randomized controlled trials.

Infectious Complications in Tocilizumab-treated Kidney Transplant Recipients.

BACKGROUND: Tocilizumab is an interleukin-6 receptor antagonist recently described as a promising treatment for antibody-mediated rejection. We compared infectious complications among tocilizumab-treated kidney transplant patients with those receiving intravenous immunoglobulin (IVIG)/rituximab. METHODS: Infections occurring among 148 kidney recipients treated with tocilizumab 8 mg/kg IV monthly (n = 83) or IVIG/rituximab (n = 65) for donor-specific antibodies and antibody-mediated rejection through 1 year after treatment cessation were reviewed. Incidence rates of infections were compared using Poisson regression. RESULTS: There were 106 infections observed over 190.1 person-years, yielding an incidence rate of 558 infections/1000 patient-years. A lower incidence rate of infections was observed among tocilizumab-treated compared with IVIG/rituximab-treated patients (463 infections/1000 patient-years versus 730 infections/1000 patient-years; P = 0.02). Twenty-five of 49 infections (51%) in the IVIG/rituximab group required hospitalization compared with 31 of 57 (54%; P = 0.85) in the tocilizumab group. There were no infection-related deaths in either group. Urinary tract infections and pneumonia were the most common types of infections, whereas gastrointestinal, blood, skin/soft tissue, viral, and fungal infections were less common. On multivariable Poisson regression, there was a lower incidence rate of infections associated with tocilizumab compared with IVIG/rituximab (incidence rate ratio, 0.63; 95% confidence interval, 0.43-0.93). CONCLUSIONS: Among kidney transplant patients treated with tocilizumab, there was no excess risk of infections compared with standard therapy with IVIG/rituximab.

Approach to Highly Sensitized Kidney Transplant Candidates and a Positive Crossmatch.

Human leukocyte antigen (HLA)-incompatible kidney transplantation offers survival benefit compared with ongoing dialysis. There have been considerable advances in the last decade to allow for increased access to transplant for the HLA-sensitized kidney transplant candidates. These include increased priority in the kidney allocation system, kidney paired donation, and novel desensitization strategies. A better understanding of the role of B cells, plasma cells, and complement and inflammatory cytokines in the pathophysiology of HLA antibody-mediated allograft injury has led to the use of novel therapeutics for desensitization and treatment of antibody-mediated rejection. Here we discuss current approaches to kidney transplantation in HLA-sensitized kidney transplant candidates.

Donor-derived Cell-free DNA Combined With Histology Improves Prediction of Estimated Glomerular Filtration Rate Over Time in Kidney Transplant Recipients Compared With Histology Alone.

Higher Banff inflammation and chronicity scores on kidney transplant biopsies are associated with poorer graft survival, although histology alone has limitations in predicting outcomes. We investigated if integrating donor-derived cell-free DNA (dd-cfDNA, Allosure; CareDx, Inc.) with Banff biopsy scores into a predictive model for estimated glomerular filtration rate over time can improve prognostic assessment versus histology alone. METHODS: We identified 180 kidney transplant patients with dd-cfDNA assessed within 1 mo of biopsy. Using linear mixed-effects models, a prediction model of Banff histology scores and dd-cfDNA on estimated glomerular filtration rate over time was derived. Nested models were compared using the likelihood-ratio test, Akaike Information Criterion, and Bayesian Information Criterion to assess if inclusion of dd-cfDNA into a model consisting of Banff biopsy scores would improve model fit. RESULTS: Univariate models identified significant covariate-by-time interactions for cg = 3 versus <3 (coefficient: -1.3 mL/min/1.73 m2/mo; 95% confidence interval [CI], -2.4 to -0.2; P = 0.02) and ci + ct ≥ 3 versus <3 (coefficient: -0.7 mL/min/1.73 m2/mo; 95% CI, -1.3 to -0.1; P = 0.03) and a trend toward significant covariate-by-time interaction for dd-cfDNA (coefficient: -0.5 mL/min/1.73 m2/mo; 95% CI, -1.0 to 0.1; P = 0.08). Addition of acute inflammation (i, t, and v), microvascular inflammation (g and ptc), and inflammation in area of interstitial fibrosis and tubular atrophy scores to chronicity scores (cg ≥ 3 and ci + ct ≥ 3) did not improve model fit. However, a model including dd-cfDNA with cg and ci + ct with covariate-by-time interactions had a better model fit compared with cg and ci + ct alone (likelihood-ratio test statistic = 21.1; df = 2; P < 0.001). CONCLUSIONS: Addition of dd-cfDNA to Banff biopsy scores provided better prognostic assessment over biopsy characteristics alone.

The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection.

Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell-directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody-mediated rejection (AMR) treatment by targeting CD20 found on B-lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model. RESULTS: Three deaths occurred among C1 esterase inhibitor-treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor-treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor-treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (-4 ml/min per 1.73 m2 per year; 95% confidence interval, -8 to -0.1) but was stable in C1 esterase inhibitor-treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, -4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2). CONCLUSIONS: Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

Outcomes of Conversion From Calcineurin Inhibitor to Belatacept-based Immunosuppression in HLA-sensitized Kidney Transplant Recipients.

BACKGROUND: The efficacy and safety of belatacept when converted from calcineurin inhibitors (CNI) in HLA-sensitized (HS) kidney transplant recipients has not been established. METHODS: The study included 108 kidney transplant recipients converted from CNI to belatacept between July 1, 2012, and September 30, 2017. Rejection-free, patient, and graft survival over 5 years follow-up were compared between HS and non-HLA-sensitized (non-HS) recipients using the Kaplan-Meier product-limit method. The estimated glomerular filtration rate slope postconversion was compared using linear mixed effects models. RESULTS: There were 29 HS and 79 non-HS recipients included. Rejections after conversion were mostly cell-mediated. There was no difference in rejection-free survival (log-rank P = 0.30; at 5 y, HS: 82%; non-HS: 84.6%); however, rejection-free survival was lower among HS recipients converted within the first-year posttransplant compared to non-HS recipients (log-rank P = 0.03; at 5 y, HS: 55.6%; non-HS: 75.0%). There was no difference in patient survival (log-rank P = 0.75; at 5 y, HS: 85.7%, non-HS: 83.7%) or graft survival (log-rank P = 0.17; at 5 y, HS: 78.5%, non-HS: 89.8%) in the 2 groups. On average, estimated glomerular filtration rate slope improved postconversion in non-HS (0.28 mL/min/1.73 m/y [0.03 to 0.53]) but declined in HS recipients (-0.44 mL/min/1.73 m/y [-0.85 to -0.03]). CONCLUSIONS: There was no difference in rejection-free, patient, or graft survival after conversion to belatacept over 5 years among HS and non-HS recipients. However, rejection-free survival was lower in HS recipients converted to belatacept within the first-year posttransplant. Conversion from CNI to belatacept should be done cautiously in high immunologic risk patients.

Allocation of the Highest Quality Kidneys and Transplant Outcomes Under the New Kidney Allocation System.

RATIONALE & OBJECTIVE: Increased access to transplantation for highly sensitized candidates following implementation of the kidney allocation system (KAS) has been mostly due to higher use of organs with a lower kidney donor profile index (KDPI; a quality metric for donated kidneys), although changes in allocation of these organs was not intended. It is unclear whether clinical outcomes have changed in association with these changes. We investigated the use of kidneys with low and high KDPI scores over time and whether KDPI score affects patient and graft survival differently across varying levels of allosensitization. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adult (aged ≥18 years) recipients of a deceased donor kidney transplant between October 1, 2009, and September 30, 2017 (Organ Procurement and Transplantation Network/United Network for Organ Sharing database; n = 84,451). PREDICTORS: Calculated panel-reactive antibody (cPRA) level (0%, 1%-79%, 80%-89%, 90%-98%, and 99%-100%) and KDPI score (≤20%, 21%-85%, and >85%). OUTCOMES: Death, graft loss. ANALYTICAL APPROACH: Time to event. RESULTS: Allocation of kidneys with KDPI scores ≤ 20% and KDPI scores of 21% to 85% to recipients with cPRA levels ≥ 99% increased 4-fold following implementation of the KAS with little change in allocation of kidneys with KDPI scores > 85%. Patient survival and graft loss were strongly associated with KDPI score, whereas the association with cPRA level was minimal. There was no evidence of a differential effect of KDPI scores across the range of cPRA levels on patient survival (P for interaction=0.06-0.9) or graft loss (P for interaction=0.5-0.9). Patient survival at 5 years among the 5 cPRA groups ranged from 87.2% to 89.8% for recipients of kidneys with KDPI scores ≤ 20% (P=0.2), 82.8% to 85.5% for KDPI scores of 21% to 85% (P=0.04), and 70.2% to 79.2% for KDPI scores > 85% (P=0.2). Cumulative incidence of graft loss by cPRA level ranged from 7.7% to 10.6% for recipients of kidneys with KDPI scores ≤ 20% (P=0.2), 11.8% to 15.0% for KDPI scores of 21% to 85% (P < 0.001), and 19.8% to 29.7% for KDPI scores > 85% (P = 0.4). LIMITATIONS: Lack of data for crossmatches, donor-specific antibodies, and immunomodulation. CONCLUSIONS: Highly sensitized recipients received kidneys with lower KDPI scores following implementation of the KAS, reducing access to these kidneys by less-sensitized candidates. KDPI score has a stronger association with patient survival and graft loss than cPRA level. The association of KDPI score with these outcomes was not modified by the recipient's level of sensitization. The impact of the redistribution of kidneys with low KDPI scores on outcomes among less-sensitized recipients needs further evaluation.

Clinical Relevance of Posttransplant DSAs in Patients Receiving Desensitization for HLA-incompatible Kidney Transplantation.

BACKGROUND: Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA- at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA- patients. METHODS: From January 2013 to October 2016, 90 HS patients (PRA > 80%, DSA+ = 50 versus DSA- = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant. RESULTS: Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/- (n=19), DSA-/+ (n=10), and DSA-/- (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/- (11%), and DSA-/- (10%) patients (P < 0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar. CONCLUSIONS: Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.

Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients.

Donor-derived cell-free DNA (dd-cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd-cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor-specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd-cfDNA was higher among patients with antibody-mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%-1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%-1.10%; P < .001) and cell-mediated rejection (CMR; median: 0.27%, IQR: 0.19%-1.30%; P = .01). The dd-cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17-0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71-0.93) and a dd-cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd-cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection.

Modification of pathogenic antibodies for autoimmune diseases illuminated the biologic relevance of B cells, plasma cells, and pathogenic antibodies in autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines. Repurposing these drugs from autoimmunity and cancer immunotherapy has yielded important advancements in the care of antibody-mediated rejection patients and novel drug development aimed at HLA desensitization have recently emerged. We now stand on an important threshold that promises many advances in the care of our allosensitized patients. We hope that these initial advances will encourage basic scientist, clinical investigators, industry, National Institutes of Health, our academic societies, and the Food and Drug Administration to continue support of these important objectives. These advances clearly have implications for sensitized patients receiving solid organ transplants and antibody-mediated rejection treatment. Modification of alloimmunity and alloantibodies will also have relevance to xenotransplantation where the xenoantibodies present a formidable obstacle to advancement of this important therapy. Working together, we can advance transplant therapeutics where biologic agents are likely to play novel and important roles. Here, we discuss novel drugs emerging in this area.

Desensitization: Overcoming the Immunologic Barriers to Transplantation.

HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection.

Rare Synchronous Gastrointestinal Plasmacytomas of Colon and Stomach.

Gastrointestinal (GI) plasmacytomas, though relatively uncommon, can occur with or without multiple myeloma. The small intestine is the most commonly involved GI site, followed by stomach, colon, and esophagus. Synchronous plasmacytomas involving 2 anatomically distinct regions of gastrointestinal tract have never been reported in the literature. We report a case of a multiple myeloma patient who had acute-onset hematochezia and was found to have synchronous plasmacytomas of the colon and stomach.