M. Cardi

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.

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.

Pharmacokinetics of mycophenolic acid, tacrolimus and sirolimus after gastric bypass surgery in end-stage renal disease and transplant patients: a pilot study

Abstract:  Background:  Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population.

Improvement and stabilization of chronic kidney disease after gastric bypass

BACKGROUND To more clearly establish the extent to which surgical weight loss can alter the course of established renal disease at a bariatric surgical service at a university-affiliated hospital. METHODS Of a series of 45 nontransplant patients with established renal disease who had undergone gastric bypass, 9 had resolution, improvement, or stabilization of their kidney function. Two of these patients were already receiving, or were ready for, dialysis. Their average age at gastric bypass was 43.0+/-4.3 years, and their mean body mass index was 48.9+/-1.9 kg/m2. Of these 9 patients, 5 had a primary diagnosis of focal segmental glomerulosclerosis, 2 had membranous glomerulonephritis, and 2 had diabetic nephropathy. RESULTS No leaks, splenic injury, transfusions, infections starting in the deep parts of the wound, death, or serious complications occurred. One patient had biopsy-proven membranous glomerulonephritis that completely resolved and has had 9 years of postoperative follow-up. The 2 dialysis patients were able to discontinue dialysis for 27 and 7 months, respectively. The remaining patients had stable renal function for 2-5 years postoperatively. CONCLUSION In some patients with chronic kidney disease, gastric bypass results in stabilization or improvement of their kidney disease. Excess body weight loss seems to have the most positive effect in patients with obesity-related focal segmental glomerulosclerosis.

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).

Laparoscopic donor nephrectomy vs. open live donor nephrectomy: a quality of life and functional study

Abstract:  Background:  Few studies have compared the quality of life (QoL) and functional recuperation of laproscopic donor nephrectomy (LDN) vs. open donor nephrectomy (ODN) donors. This study utilized the SF‐36 health survey, single‐item health‐related quality of life (HRQOL) score, and a functional assessment questionnaire (‘Donor Survey’).

Multivariate Analysis of Risk Factors for Acute Rejection in Early Corticosteroid Cessation Regimens Under Modern Immunosuppression

The purpose of this study was to define risk factors for acute rejection with early corticosteroid withdrawal (CSWD; within 7 days posttransplant) in renal transplantation. Data from prospective, IRB‐approved early CSWD trials were analyzed. Overall acute rejection rate in 308 patients was 17.1%. Acute rejection rates and observed risks (OR) in patients with individual risk factors were: repeat transplants 38.6%; current PRA >25%; 29.4%; African Americans 23.5%; delayed graft function (DGF) 26.1%; HLA DR mismatches >0 17.9%; female gender 19.7%; Thymoglobulin induction 15.3%; type 1 diabetes 30.8%; type 2 diabetes 11.1%; deceased donor recipients 21%; and living donor recipients 14%. Logistic regression analysis provided the following risks (OR) for acute rejection: repeat transplant 2.51; current PRA > 25% 1.53; African Americans 1.47; DGF 1.58; HLA DR mismatches > 0 1.61; female gender 1.43; Thymoglobulin induction 0.61; type 1 diabetes 2.23, type 2 diabetes 0.5, deceased donor recipients 1.11, and living donor recipients 0.9. Risk factors for acute rejection under early corticosteroid withdrawal are similar to those previously defined under chronic corticosteroid therapy. These observations provide implications for future CSWD trials including: use of T cell depleting antibody induction therapy (thymoglobulin) to reduce acute rejection risk, 2) enrollment stratification for high risk groups, and 3) modified immunosuppression for high risk groups.

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.

Body weight alterations under early corticosteroid withdrawal and chronic corticosteroid therapy with modern immunosuppression

Background. Weight gain is a known complication of corticosteroid maintenance therapy. The purpose of the present study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) with that observed under early (i.e., within 7 days posttransplant) corticosteroid withdrawal (CSWD) in renal-transplant recipients. Methods. Renal-transplant recipients who underwent early CSWD under four prospective, institutional review board-approved clinical trials were compared with a historic control group of patients receiving maintenance CCST. Results. One hundred sixty-nine patients with early CSWD were compared with 132 patients who received CCST. Mean population weight gain was significantly higher in CCST patients at 3, 6, and 12 months posttransplant. Race influenced weight gain because white CSWD patients demonstrated greater reductions in weight gain compared with African-American patients. Sex also influenced weight gain: women demonstrated a greater benefit from CSWD than did men. Corticosteroid rejection therapy in CSWD patients completely restored weight gain because these patients showed weight gains similar to the CCST group. Finally, pretransplant body mass index (BMI) also influenced weight gain because patients who were overweight (BMI 25–30) or obese (BMI>30) demonstrated a greater reduction in weight gain with CSWD than did patients of normal weight (BMI<25). Conclusions. Early CSWD minimizes weight gain in renal-transplant recipients. Women, whites, and patients with high pretransplant BMI had greater reductions in weight gain with early CSWD.

African‐American Renal Transplant Recipients Benefit from Early Corticosteroid Withdrawal Under Modern Immunosuppression

African‐Americans (AAs) have historically been considered high‐risk renal transplant recipients due to increased rejection rates and reduced long‐term graft survival. As a result, AAs are often excluded from corticosteroid withdrawal (CSWD) protocols. Modern immunosuppression has reduced rejections and improved graft survival in AAs and may allow successful CSWD. Outcomes in 56 AAs were compared to 56 non‐AAs. All patients were enrolled in one of four early CSWD protocols. Results are reported as AA versus non‐AA. Acute rejection at 1‐year was 23% and 18%; (p = NS); creatinine clearance at 1‐year was 75 versus 80 mL/min (p = NS); patient and graft survival was 96% versus 98% and 91% versus 91%; (p = NS). AAs benefit from early CSWD with significantly improved blood pressure, LDL < 130 mg/dL and HDL > 45 mg/dL at 1‐year, post‐transplant diabetes of 8.7%, and mean weight change at 1‐year of 4.8 ± 7.2 kg. In conclusion, early CSWD in AAs is associated with acceptable rejection rates, excellent patient and graft survival, and improved cardiovascular risk, indicating that the risks and benefits of early CSWD are similar between AAs and non‐AAs. Additional follow‐up is needed to determine long‐term renal function, graft survival, and cardiovascular risk in AAs with early CSWD.