Stegall, Mark

Background. Microvascular inflammation (MVI) is a key feature of antibody-mediated rejection (AMR) among patients with HLA donor-specific antibody (DSA), but MVI at AMR thresholds (Banff glomerulitis [g] + peritubular capillaritis [ptc] score ≥ 2) without DSA has been increasingly recognized. We aimed to determine the incidence of MVI among highly sensitized kidney transplant recipients without DSA. Methods. We performed a single-center, retrospective, matched cohort study comparing outcomes of kidney transplant recipients with cPRA ≥90% with preexisting DSA (n = 49), cPRA ≥90% without preexisting DSA (n = 47), and matched controls with cPRA = 0 without preexisting DSA (n = 49). Controls were matched by age, donor type, and transplant date. Indication and surveillance biopsies combined with annual de novo DSA screening were obtained. Results. Kidney transplant recipients with a cPRA ≥90% and no evidence of preexisting or de novo DSA had a higher incidence of MVI (glomerulitis + peritubular capillaritis ≥ 2) than patients with cPRA = 0 [35% (17/49) versus 12% (6/49), P = 0.0003] over a median (interquartile range) follow-up of 5 (4–6) y posttransplant. Among this cPRA ≥90% group without DSA, MVI persisted in 54% of cases on follow-up biopsy (7/13), and 24% (4/13) of cases developed transplant glomerulopathy (Banff cg score > 0). Conclusions. Highly sensitized transplant recipients have a high incidence of persistent and progressive MVI, even without DSA. The mechanisms underlying these histologic features needs to be elucidated, but this information is important to consider when making decisions about transplantation among highly sensitized individuals.

Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell–based strategies for the enhancement of operational tolerance in transplantation patients.

Significance Statement There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. Background Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. Methods This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. Results Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. Conclusions In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. Clinical Trial registration number NCT04294459.

Background. Few studies have addressed immunosuppression management after allograft failure (AF). Immunosuppression withdrawal to minimize complications must be balanced with the risk of sensitization and potentially reduced retransplantation. We aimed to determine relationships between immunosuppression, death, sensitization, and retransplantation among patients with AF. Methods. We performed a single-center retrospective study of patients transplanted from October 2007 to May 2017 with AF. We collected data on demographics, immunosuppression, calculated panel reactive antibody (cPRA) levels, death, retransplantation, and dialysis. Cox regression models were used to evaluate factors associated with death and retransplantation. Results. From October 2007 to May 2017, 1354 solitary ABO-compatible transplants were performed, of which 97 failed. Ten percent of patients received a preemptive retransplant. Among those who returned to dialysis (n = 87), 35% died, 25% received another transplant, and 30% remained on dialysis. After AF, 46% of patients discontinued immunosuppression. The cPRA was unchanged if immunosuppression was maintained, but immunosuppression discontinuation was associated with increased cPRA from a median (interquartile range) of 18 (0–99) to 96 (88.5–100.0; P = 0.003). Age at failure (hazard ratio, 1.1; confidence interval, 1.0-1.1) and cardiovascular disease were associated with death (hazard ratio, 2.9; confidence interval, 1.2-7.0) in multivariate analysis. Importantly, immunosuppression maintenance was not associated with increased death or retransplantation despite the increase in cPRA that occurred when immunosuppression was discontinued. Conclusions. Kidney transplant recipients with AF have a high mortality rate after dialysis initiation. Although immunosuppression withdrawal was associated with increased cPRA, it was not associated with reduced retransplantation. Therefore, it is reasonable to discontinue immunosuppression after AF despite sensitization if retransplantation is delayed.

AbstractBackgroundCurrent therapy for Type 1 diabetes (T1D) is characterized by significant glucose variability (GV). Pancreas transplantation (PT) is performed in certain T1D patients with and without end‐stage renal disease. To date, GV has been examined to a limited extent after PT.MethodsWe investigated GV using continuous glucose monitoring (CGM) 3‐6 weeks after PT.ResultsEleven patients had simultaneous kidney pancreas transplantation (SPK), nine pancreas after kidney (PAK), and six pancreas transplantation alone (PTA). Mean CGM showed no difference between SPK, 126.5 ± 13.9, PAK 119.9 ± 12.8, and PTA 131.1 ± 29 mg/dL (P value .6). Percentage of time in range (TIR, 70‐180 mg/dL) was 92% for SPK, 93.4% in PAK, and 88.5% in PTA with only 0.3%, 1.5%, and 0.3% of time <70 mg/dL. Percentage >180 mg/dL was 7.9% for SPK, 4.9% PAK, and 11% in PTA. Other measures of GV were similar in the three cohorts. In six patients, CGM was performed before and after PT and improved significantly. GV was also better compared with a matched cohort of T1D patients.ConclusionsAll 3 types of PT resulted in excellent glucose control 3‐6 weeks post‐procedure. CGM outcomes represent an important objective outcome after PT.

Significance Statement Targeting plasma cells to reduce the risk of antibody-mediated rejection and decreased allograft survival due to anti-HLA donor-specific antibodies has not been explored in transplantation. After sensitizing eight rhesus macaques with two sequential mismatched skin allografts, the authors desensitized four with daratumumab (anti-CD38 mAb) and plerixafor (anti-CXCR4) before transplant. Compared with controls, the daratumumab-treated animals had significantly reduced donor-specific antibody levels and prolonged renal graft survival; however, this reduction was not maintained. Two patients treated with daratumumab—one with therapy-resistant acute kidney antibody-mediated rejection and a highly sensitized heart transplant candidate—exhibited a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and heart graft access. These findings suggest daratumumab merits investigation as a potential therapeutic strategy, although further research is needed. Background Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. Methods To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. Results The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P <0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P <0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell–mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access. Conclusions Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.

Background The concepts that obesity is merely a consequence of overeating, and that metabolic health then reflects obesity, may be insufficient and potentially flawed. The role of fructose intake and metabolic endotoxemia has gained attention recently, but data in kidney transplantation are lacking. This study evaluated the risk factors for metabolic syndrome (MS), its components, and other associated markers in kidney transplant recipients (KTRs), focusing particularly on fructose intake and systemic endotoxemia. Methods This cross-sectional observational study enrolled 128 KTRs longer than 1 year posttransplantation. Clinical, biochemical, anthropometric, and questionnaire assessments were undertaken. Results Obesity (body mass index, ≥30 kg/m2) and MS (International Diabetes Federation Definition) were found in 36.7% and 50% of KTRs, respectively. Both increased fructose intake (P = 0.01) and endotoxin level (P = 0.02) were independently associated with MS; and higher fructose intake was independently associated with obesity (P < 0.001). Specifically, increased fructose intake was associated with the central obesity (P = 0.01) and hyperglycemia (P < 0.001) criteria of MS, whereas higher endotoxin level was associated with the hypertriglyceridemia (P = 0.003) and low HDL cholesterol concentration (P = 0.002) criteria of MS. Neither saturated fat nor total caloric intakes were independently associated with obesity and MS; and neither obesity nor central obesity were independently associated with the dyslipidemia and hyperglycemia criteria of MS. Principal component analysis demonstrated relationships between higher levels of endotoxin, soluble endothelial selectin, triglycerides, and insulin resistance (r > 0.6), as well as relationships between increased fructose intake, inflammation, and blood glucose (r > 0.6). Conclusions Dietary modifications through decreasing fructose intake and addressing systemic endotoxemia are plausible targets for improving metabolic health of KTRs.