G. Mogilishetty

Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection.

Background. Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. Methods. Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. Results. Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient. Conclusions. Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

Reducing De Novo Donor‐Specific Antibody Levels during Acute Rejection Diminishes Renal Allograft Loss

The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single‐antigen beads. Fifty‐two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow‐up was 27.0 ± 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA >20% (current) and/or >50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6‐fold increased allograft loss risk, p = 0.017) to be significant. Four‐year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/C4d) (65%) or antibody‐mediated rejection (35%) (p < 0.001). Patients with >50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.

Proteasome Inhibitor-Based Primary Therapy for Antibody-Mediated Renal Allograft Rejection

Background. Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented. Methods. Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m2) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform. Results. Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination. Conclusions. Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.

Early and Late Acute Antibody-Mediated Rejection Differ Immunologically and in Response to Proteasome Inhibition

Background. The efficacy of plasma cell targeted therapies for antibody-mediated rejection (AMR) has not been defined in detail. The purpose of this study was to compare early and late acute AMR in terms of immunologic characteristics and responses with proteasome inhibitor (PI) therapy. Methods. Renal transplant recipients with acute AMR were treated with PI-based regimens. Early acute AMR was defined as occurring within 6 months posttransplant. Immunodominant donor-specific antibody (iDSA) was defined as the DSA with the highest level. Results. Results are expressed as early or late acute AMR. Thirty AMR episodes (13 early, 17 late) were treated in 12 and 16 patients. Early but not late AMR was associated with presensitization. Late AMR iDSA levels were higher, and specificities were primarily class II (DQ being most frequent). Early AMR patients demonstrated greater reduction in iDSA at 7, 14, and 30 days and at the posttreatment nadir (81.5%+21.2% vs. 51.4%+27.6%; P<0.01). Early AMR patients were more likely to demonstrate histologic resolution/improvement (87.5% vs. 53.8%; P=0.13). Both groups demonstrated significant improvement in renal function. Conclusions. Early and late AMR exhibit distinct immunologic characteristics and respond differently to PI therapy.

Cardiovascular risk, cardiovascular events, and metabolic syndrome in renal transplantation: comparison of early steroid withdrawal and chronic steroids

Abstract: Background:  Cardiovascular disease (CVD) is the leading cause of death with a functioning graft in renal transplant recipients. The purpose of this study was to compare Framingham Risk Score (FRS), metabolic syndrome (MS), and cardiovascular events (CVE) in patients receiving early corticosteroid withdrawal (ECSWD), or chronic corticosteroid therapy (CCS).

Prospective Iterative Trial of Proteasome Inhibitor-Based Desensitization

A prospective iterative trial of proteasome inhibitor (PI)‐based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m2 × 6–8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty‐four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRβ3, HLA DRβ4 and HLA DRβ5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI‐based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin‐based desensitization.

Addressing Morbid Obesity as a Barrier to Renal Transplantation With Laparoscopic Sleeve Gastrectomy

Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25‐month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 ± 10.0 years with an average preoperative BMI of 43.0 ± 5.4 kg/m2 (range 35.8–67.7 kg/m2). Follow‐up after LSG was 220 ± 152 days (range 26–733 days) with last BMI of 36.3 ± 5.3 kg/m2 (range 29.2–49.8 kg/m2) with 29 (55.8%) patients achieving goal BMI of <35 kg/m2 at 92 ± 92 days (range 13–420 days). The mean percentage of excess weight loss (%EWL) was 32.1 ± 17.6% (range 6.7–93.8%). A segmented regression model was used to compare medical therapy versus LSG. This revealed a statistically significant increase in the BMI reduction rate (0.3 kg/m2/month versus 1.1 kg/m2/month, p < 0.0001). Patients also experienced a 40.9% decrease in anti‐hypertensive medications (p < 0.001) and a 49.7% decrease in total daily insulin dose (p < 0.001). LSG is a safe and effective means for addressing obesity in kidney transplant candidates in the context of a multidisciplinary approach.

Randomized controlled pilot study of B cell-targeted induction therapy in HLA sensitized kidney transplant recipients.

Optimal induction regimens for patients at high risk for antibody and/or cell–mediated rejection have not been established. This pilot, prospective, randomized study evaluated addition of B cell/plasma cell–targeting agents to T cell–based induction with rabbit antithymocyte globulin (rATG) in high immunologic risk renal transplant recipients. Patients were randomized to induction with rATG, rATG + rituximab, rATG + bortezomib or rATG + rituximab + bortezomib. Inclusion criteria were: (1) current cytotoxic panel reactive antibody (PRA) ≥20% or peak cytotoxic PRA ≥50% or (2) T or B cell positive flow crossmatch with donor‐specific antibody (DSA) or (3) historical positive serologic or cytotoxic crossmatch or DSA to donor or (4) prior allograft loss with more than one acute rejection. Median overall follow‐up was 496 days: 1‐year and overall acute rejection were 25% and 27.5%, and 25% of patients developed de novo DSA within 1 year. One‐year and overall patient survival were 97.5% and 92.5%, and 1‐year and overall death‐censored allograft survival were 97.5% and 95%. Renal allograft function posttransplant was similar among all arms. Eight of nine cases of peripheral neuropathy were mild, whereas one case was moderate and required a narcotic prescription. In conclusion, addition of rituximab and/or bortezomib to rATG induction has an acceptable safety/toxicity profile in a high immunologic risk renal transplant population.

A Prospective Trial of a Steroid-Free/Calcineurin Inhibitor Minimization Regimen in Human Leukocyte Antigen (HLA)-Identical Live Donor Renal Transplantation

Background. Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transplantation exist. This prospective study evaluated a corticosteroid (CS)-free, calcineurin inhibitor (CNI) minimization immunosuppressive regimen in HLA-identical LD renal transplant recipients. Methods. Twenty HLA-identical LD recipients were prospectively enrolled. Immunosuppression included mycophenolate mofetil (MMF) (2 g/day), tacrolimus (target trough 4–8 ng/mL), sirolimus (target trough 6–10 ng/mL), and no pre- or postoperative steroids. In the absence of prior rejection, tacrolimus was discontinued at posttransplant day 120 and sirolimus at 1 year, leaving patients on MMF monotherapy. Results. Tacrolimus was successfully withdrawn in 94% of patients (16/17). One hundred percent (15/15) of patients who reached 1-year posttransplant had sirolimus discontinued. Ninety-four percent (17/18) of patients remain off CSs. Mean serum creatinine at 6, 12, and 24 months were 1.38±0.32, 1.35±0.37, and 1.25±0.29 mg/dL; corresponding mean calculated creatinine clearance estimates were 70±18, 73±17, and 72±15 mL/min. Acute cellular rejection, chronic allograft nephropathy, and CNI toxicity were not observed. Death-censored graft survival was 100% at last follow-up. Conclusions. A CS-free, CNI minimization immunosuppressive regimen with weaning to MMF monotherapy provides excellent renal function, graft survival, and patient survival in HLA-identical LD renal transplant recipients.

Late Acute Rejection After Allograft Limbal Stem Cell Transplantation: Evidence for Long-Term Donor Survival.

Purpose: To describe the clinical presentation and management of late (>3.0 years) acute graft rejection in keratolimbal allograft (KLAL) recipients. Methods: This was a multicenter, retrospective observational case series. Six eyes of 6 patients with ocular surface transplant at a mean age of 36.2 years were seen at 3 tertiary referral centers for acute graft rejection between 2007 and 2013. Main outcome measures included strength of systemic immunosuppression (SI) at the time of rejection, time to rejection, and clinical presentation of rejection. Results: Preoperative diagnoses included total limbal stem cell deficiency because of aniridia (n = 2) or chemical injury (n = 4). After an initially successful outcome, patients experienced late acute graft rejection at a mean time of 67.8 ± 24.1 months (range: 41–98) after KLAL while receiving suboptimal levels of SI because of medication taper (n = 5) or noncompliance (n = 1). Objective findings included an epithelial rejection line (n = 6), edema (n = 2), corneal epithelial irregularities (n = 2), and neovascularization (n = 1). Antirejection management consisted of topical corticosteroids (n = 6) and augmentation of SI therapy (n = 5). Conclusions: These cases of late acute graft rejection in KLAL patients support the notion that allodonor cells can persist over the long run and remain at risk for immunologic rejection. It further underscores the fact that long-term success with KLAL may require extension of SI beyond the first few years, albeit at lower levels individualized to each patient.