Byron H. Smith

32 Doses of Bortezomib for Desensitization Is Not Well Tolerated and Is Associated With Only Modest Reductions in Anti-hla Antibody

Background We previously showed that bortezomib (BTZ) partially depletes plasma cells, yet has limited efficacy for desensitization in kidney transplant candidates when up to 16 doses is given. Methods This study aimed to determine the safety and efficacy of 32 doses of BTZ (1.3 mg/m2 of body surface area) in 10 highly sensitized kidney transplant candidates with alloantibodies against their intended living donor. Results Dose reduction was needed in 2 patients and 2 others completely discontinued therapy for adverse events. Anti-HLA antibodies mean fluorescence intensity (MFI) values were stable prior to BTZ (P = 0.96) but decreased after therapy (mean decrease of 1916 [SE, 425] MFI, P < 0.01). No patient developed a negative crossmatch against their original intended donor, and the calculated panel-reactive antibodies based on MFI of 2000, 4000, and 8000 was unchanged in all patients. Conclusions These data suggest that 32 doses of BTZ monotherapy was not well tolerated and resulted in only a modest reduction in anti-HLA antibodies.

Renal Allograft Histology at 10 Years after Transplantation in the Tacrolimus Era: Evidence of Pervasive Chronic Injury

Improving long‐term renal allograft survival remains an important unmet need. To assess the extent of histologic injury at 10 years after transplantation in functioning grafts, we studied 575 consecutive adult solitary renal transplants performed between 2002 and 2005: 77% from living donors and 81% maintained on tacrolimus‐based immunosuppression. Ten‐year graft survival was 59% and death‐censored graft survival was 74%. Surveillance allograft biopsies were assessed at implantation, 5 years, and 10 years from 145 patients who reached 10 years. At implantation, 5% of biopsies had major histologic abnormalities (chronic transplant glomerulopathy score > 0, other chronic Banff scores ≥ 2, global glomerulosclerosis > 20%, or mesangial sclerosis ≥ 2). This increased to 54% at 5 years and 82% at 10 years. Major lesions at 10 years included the following: arteriolar hyalinosis (66%), mesangial sclerosis (67%), and global glomerulosclerosis > 20% (43%), with 48% of grafts having more than one major lesion. Transplant glomerulopathy and moderate‐to‐severe interstitial fibrosis were uncommon (12% each). Major lesions were associated with increased proteinuria and decreased graft function. In patients with diabetes at baseline, 52% had diabetic nephropathy/mesangial sclerosis at 10 years. We conclude that almost all renal allografts sustain major histologic injury by 10 years after transplantation. Much damage appears nonimmunologic, suggesting that new approaches are needed to decrease late injury.

Progression of Interstitial Fibrosis during the First Year after Deceased Donor Kidney Transplantation among Patients with and without Delayed Graft Function

BACKGROUND AND OBJECTIVES Delayed graft function is a form of AKI resulting from ischemia-reperfusion injury. Our aim was to study the effect of delayed graft function on the progression of interstitial fibrosis after deceased donor kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Our study is a retrospective study of all patients transplanted at our center between July of 2003 and September of 2014 using a kidney from a deceased donor. The primary outcome was the progression of interstitial fibrosis on serial protocol biopsies done during the first year post-transplant. We analyzed the distribution of the change in the Banff interstitial fibrosis (ci) score between the delayed graft function and nondelayed graft function groups for all of the paired biopsies done at time 0 and 12 months post-transplant (Δfibrosis). We also performed a linear mixed model analyzing the difference in the slopes for the progression of mean Banff ci score for all of the biopsies done at time 0 and 1, 4, and 12 months post-transplant. RESULTS There were 343 (36.7%) in the delayed graft function group and 591 in the control group. The biopsy rates for the delayed graft function and nondelayed graft function groups at time 0 were 65.3% (n=224) and 67.0% (n=396), respectively, and at 12 months, they were 64.4% (n=221) and 68.4% (n=404), respectively. Paired biopsies were available for 155 in the delayed graft function group and 283 in the control group. In a risk-adjusted model, Banff ci score >0 on the time 0 biopsy had a higher odds of delayed graft function (odds ratio, 1.70; 95% confidence interval, 1.03 to 2.82). The distribution of the Δfibrosis between 0 and 12 months was similar in delayed graft function and control groups (P=0.91). The slopes representing the progression of fibrosis were also similar between the groups (P=0.66). CONCLUSIONS Donor-derived fibrosis may increase the odds of delayed graft function; however, delayed graft function does not seem to increase the progression of fibrosis during the first year after transplantation.

Importance of Routine Antihuman/Leukocyte Antibody Monitoring: De Novo Donor Specific Antibodies Are Associated With Rejection and Allograft Vasculopathy After Heart Transplantation

The significance of de novo donor-specific antibodies (dnDSAs) after heart transplantation (HTx) on alloimmune injury, including acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy, remains unclear. In this study, we examined the importance of routine solid-phase arrays in detecting dnDSA during long-term follow-up of recipients of HTx. The study protocol was approved by the Mayo Clinic Institutional Review Board, and patients gave informed consent. Between January 2009 and December 2013, 86 of 101 consecutive adult recipients of HTx underwent routine serial antihuman leukocyte antigen (HLA) antibody monitoring before and 1 week, 4 months, 1 year, and annually after HTx using a panel of single-antigen beads (LABScreen, One Lambda, Inc.) read on a Luminex (Luminex Corp.) platform. Mean fluorescence intensity levels ≥2000 were considered positive. According to the International Society for Heart and Lung Transplantation classification, 1546 endomyocardial biopsies scored with severe ACR defined as grade 2R or 3R. Serial 3-dimensional intravascular ultrasound examinations were performed as previously published.1 Cumulative incidences were estimated using the Kaplan-Meier method. Cox-proportional hazard models were used for analysis of time-to-event data. Variables with a P value <0.10 by univariable …

Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo

Plasma cells (PCs) are a major source of alloantibody in transplant patients and are resistant to current therapy. Because receptor-ligand interactions in stromal microenvironments play important roles in the localization, development, and survival of normal PCs, we hypothesized that interfering with CXCR4/CXCL12 interactions with plerixafor might cause PC depletion and enhance the efficacy of the proteasome inhibitor bortezomib. PCs in mouse spleen, bone marrow, and peripheral blood demonstrated CXCR4 expression. We then treated with plerixafor in doses ranging from 240 μg/kg in a single dose to a 1-mg/kg daily dose for 10 days. CXCR4/CXCL12 blockade with plerixafor resulted in increased mobilization of PCs into the peripheral blood. Splenectomy completely abrogated this effect, suggesting that all plerixafor-mobilized cells were from the spleen. The total number of PCs in the spleen and marrow remained constant despite treatment with plerixafor. Bortezomib caused a reduction in PCs, but adding plerixafor did not increase killing. We conclude that CXCR4/CXCL12 interactions are important for the retention of a subpopulation of PCs in the spleen, but this interaction has minimal effect on PCs in the marrow. The lack of enhancement of bortezomib-mediated depletion suggests that factors other than CXCR4/CXCL12 interactions are responsible for drug resistance.

A method to reduce variability in scoring antibody-mediated rejection in renal allografts: implications for clinical trials - a retrospective study

Poor reproducibility in scoring antibody‐mediated rejection (ABMR) using the Banff criteria might limit the use of histology in clinical trials. We evaluated the reproducibility of Banff scoring of 67 biopsies by six renal pathologists at three institutions. Agreement by any two pathologists was poor: 44.8–65.7% for glomerulitis, 44.8–67.2% for peritubular capillaritis, and 53.7–80.6% for chronic glomerulopathy (cg). All pathologists agreed on cg0 (n = 20) and cg3 (n = 9) cases, however, many disagreed on scores of cg1 or cg2. The range for the incidence of composite diagnoses by individual pathologists was: 16.4–22.4% for no ABMR; 17.9–47.8% for active ABMR; and 35.8–59.7% for chronic, active antibody‐mediated rejection (cABMR). A “majority rules” approach was then tested in which the scores of three pathologists were used to reach an agreement. This increased consensus both for individual scores (ex. 67.2–77.6% for cg) and for composite diagnoses (ex. 74.6–86.6% cABMR). Modeling using these results showed that differences in individual scoring could affect the outcome assessment in a mock study of cABMR. We conclude that the Banff schema has high variability and a majority rules approach could be used to adjudicate differences between pathologists and reduce variability in scoring in clinical trials.

Response by Wong et al to Letter Regarding Article, “Importance of Routine Antihuman/Leukocyte Antibody Monitoring: De Novo Donor Specific Antibodies Are Associated With Rejection and Allograft Vasculopathy After Heart Transplantation”

We thank Clerkin et al for their interest in our study addressing the importance of routine monitoring for de novo donor–specific antibodies (dnDSA) not only in predicting cellular and antibody-mediated rejection (AMR) but also for the first time demonstrating its association with allograft vasculopathy detected by intravascular ultrasound.1 Our data were analyzed using a Cox regression survival analysis model accounting for the timing of dnDSA events when predicting subsequent incidence of AMR. In 2 previous studies cited by Clerkin, patients at time of transplant were classified according to posttransplant outcomes such as dnDSA or AMR. Statistical theory does not …

Early Conversion to Belatacept in Kidney Transplant Recipient with Low Glomerular Filtration Rate

Background Our aim was to determine the impact of converting from tacrolimus to belatacept in patients with stable low estimated glomerular filtration rate (eGFR) early after kidney transplant. Methods This is a single-center retrospective case control study. During this study period, we had a clinical protocol to convert patients to belatacept if they had a stable but low GFR and they were at least 1-month posttransplant. Eligible patients had stable but low eGFR usually < 40 mL/min per 1.73 m2. We used direct matching to select 1 control case for each patient converted to belatacept. The primary outcome was the change in eGFR from the point of belatacept conversion to 4 months postconversion (delta eGFR). Results There were 30 patients in the conversion group and 30 in a direct matched control group. The median preconversion eGFR for the entire cohort was 23.0 mL/min per 1.73 m2 with an interquartile range of 15.7 to 31.4. The delta eGFR was 11.0 (12.9) mL/min per 1.73 m2 in belatacept group and 4.8 (10.5) mL/min per 1.73 m2 in the control group (P = 0.045). Acute rejection postconversion occurred in 5 (16.7%) in the conversion group and none of the control group (P = 0.052). Although the delta improvement in eGFR was about 6 mL/min better in the Belatacept group, there was no difference in the slope of inverse creatinine during the 12-month period after conversion between the groups. Conclusions We conclude that early belatacept conversion in kidney transplant recipients with stable low eGFR may only result in a modest increase in GFR.