Pharmacokinetic and pharmacogenetic analysis of immunosuppressive agents after laparoscopic sleeve gastrectomy.

BACKGROUND: Severe obesity has been shown to limit access to renal transplantation in patients with end-stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence of tacrolimus products and immunosuppression pharmacokinetics. METHODS: This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended-release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. RESULTS: Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI; 89.6%-119.6%) for AUC0-24 and 92.5% (90% CI; 80.4%-106.4%) for Cmax . PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (P=.004) and Cmax (P=.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (P=.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values vs those with CYP3A5*3/*3 (IR-TACP<.001; ER-TACP=.008). Genotype did not impact MPA PK. CONCLUSION: Dose modification of immunosuppressants post-LSG may not be necessary aside from standard therapeutic drug monitoring.

Reducing Donor-specific Antibody During Acute Rejection Diminishes Long-term Renal Allograft Loss: Comparison of Early and Late Rejection.

BACKGROUND: Reduction in donor-specific antibody (DSA) has been associated with improved renal allograft survival after antibody-mediated rejection (AMR). These observations have not been separately analyzed for early and late AMR and mixed acute rejection (MAR). The purpose of this study was to evaluate long-term responses to proteasome inhibitor-based therapy for 4 rejection phenotypes and to determine factors that predict allograft survival. METHODS: Retrospective cohort study evaluating renal transplant recipients with first AMR episodes treated with proteasome inhibitor-based therapy from January 2005 to July 2015. RESULTS: A total of 108 patients were included in the analysis. Immunodominant DSA reduction at 14 days differed significantly (early AMR 79.6%, early MAR 54.7%, late AMR 23.4%, late MAR 21.1%, P < 0.001). Death-censored graft survival (DCGS) differed at 3 years postrejection (early AMR 88.3% versus early MAR 77.8% versus late AMR 56.7% versus late MAR 54.9%, P = 0.02). Multivariate analysis revealed that immunodominant DSA reduction > 50% at 14 days was associated with improved DCGS (odds ratio, 0.12, 95% CI, 0.02-0.52, P = 0.01). CONCLUSIONS: In summary, significant differences exist across rejection phenotypes with respect to histological and DSA responses. The data suggest that DSA reduction may be associated with improved DCGS in both early and late AMR.

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.

The influence of immunomodulatory diets on transplant success and complications.

BACKGROUND: Animal studies have shown that dietary supplementation with arginine and lipids containing the omega-3 and omega-9 fatty acids prolong allograft survival in animals receiving a short course of low-dose cyclosporine. They also reduce cardiovascular complications and infections in humans. METHODS: Adult renal transplant patients receiving standard immunosuppression were stratified according to gender, diabetic state, donor source (LD or CD), and first versus repeat transplant, and randomized to receive or not receive supplemental arginine and canola oil (containing both omega-3 and omega-9 fatty acids) twice daily. Patients were followed for a minimum of 3 years. RESULTS: Seventy-six patients were randomized to the supplement group (S) and 71 patients to the control group (C). Intent-to-treat analysis revealed that S patients had fewer post-30 day first rejection episodes (5.4%) when compared with the C group (23.7%) (P=0.01) and fewer post-30 day episodes of calcineurin inhibitor (CNI) drug toxicity (9.2% vs. 35.3%, P=0.003). S patients developed new onset diabetes mellitus (NODM) less frequently by 3 years (2.3% vs. 14.5%, P=0.04), had fewer cardiac events (5.0% vs. 17.1%, P=0.05), and fewer episodes of sepsis (6.5% vs. 18.7%, P=0.05). CONCLUSIONS: Dietary supplementation with L-arginine and canola oil is a safe, inexpensive, and unique treatment, which is associated with decreased rejection rates and CNI toxicity after the first month in renal transplant patients. Due to reductions in NODM and cardiac events, long-term benefits for patient survival may be particularly important.

A Banff Component Scoring-based Histologic Assessment of Bortezomib-based Antibody-mediated Rejection Therapy.

BACKGROUND: Histology remains a cornerstone for antibody-mediated rejection (AMR) diagnosis. Little data exist supporting histology for assessing therapeutic responses. This study evaluates histologic components in assessing AMR therapeutic responses. METHODS: Antibody-mediated rejection was diagnosed using Antibody Working Group criteria and Banff component scoring, and C4d staining data were analyzed. Statistics included independent and paired samples t test, χ(2), Fisher exact, or the Wilcoxon-signed rank test. Fifty-five AMR patients were analyzed. Early AMR was defined as occurring within 6 months after transplantation and treated with a single rituximab dose and 4 bortezomib doses preceded by plasmapheresis. Allograft biopsies were performed within 48 hours of treatment; repeat biopsy was performed 14 to 21 days later. RESULTS: Early AMR demonstrated histologic improvement in mean scores for acute Banff components glomerulitis (g), C4d, g+ peritubular capillaritis (ptc) and acute composite score, but showed deterioration in chronic Banff components tubular atrophy and interstitial fibrosis. Late AMR showed improved mean scores for acute Banff components tubulitis, interstitial inflammation, g, ptc, g + ptc, C4d, and acute composite score, but chronic scores did not change. Significant changes in distribution of Banff scores after treatment were observed for g, C4d, tubular atrophy, and interstitial fibrosis scores in early AMR patients and tubulitis, interstitial inflammation, g, ptc, and C4d in late AMR. CONCLUSIONS: These results show that: (1) Banff component scoring provides insights into histologic responses to AMR therapy and may provide a potential endpoint for clinical AMR trials. (2) Early and late AMR demonstrate differences in acute and chronic Banff components at the time of the AMR diagnostic biopsy, as well as differential responses to AMR therapy.

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.