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BACKGROUND: Renal allograft rejection is more frequent under belatacept-based, compared to tacrolimus-based, immunosuppression. We studied kidney transplant recipients experiencing rejection under belatacept-based early corticosteroid withdrawal following T cell depleting induction in a recent randomized trial (BEST Trial, clinicaltrials.gov #NCT01729494) to determine mechanisms of rejection and treatment. METHODS: Peripheral mononuclear cells, serum creatinine levels, and renal biopsies were collected from 8 patients undergoing belatacept-refractory rejection. We used flow cytometry, histology and immunofluorescence to characterize CD8(+) effector memory T cell (T(EM)) populations in the periphery and graft before and after mammalian target of rapamycin (mTOR) inhibition. RESULTS: Here, we found that patients with belatacept-refractory rejection (BRR) did not respond to standard antirejection therapy and had a substantial increase in alloreactive CD8(+) T cells with a CD28(low)/DR(hi)/CD38(hi)/CD45RO(+) T(EM). These cells had increased activation of the mTOR pathway, as assessed by phosphorylated ribosomal protein S6 (p-RPS6) expression. Notably, everolimus (an mTOR inhibitor) treatment of patients with BRR halted the in vivo proliferation of T(EM) cells, their ex vivo alloreactivity, and resulted in their significant reduction in the peripheral blood. The frequency of circulating FoxP3(+) regulatory T cells was not altered. Importantly, everolimus led to rapid resolution of rejection as confirmed by histology. CONCLUSIONS: Thus, while prior work has shown that concomitant belatacept + mTOR inhibitor therapy is effective for maintenance immunosuppression, our preliminary data suggest that everolimus may provide an available means for effecting “rescue” therapy for rejections occurring under belatacept that are refractory to traditional antirejection therapy with corticosteroids and polyclonal antilymphocyte globulin.

This study assesses the impact of a telemedicine-based home management program (THMP) on patient adherence, hospital readmissions, and quality of life (QOL) after liver transplantation (LT).Telemedicine interventions represent an opportunity to personalize care and can lead to improved adherence and patient satisfaction. However, there is limited data on impact of these interventions on outcomes after LT. Therefore, we conducted the first randomized controlled trial (RCT) of a THMP compared to standard of care (SOC) after LT.One hundred six consecutive LT recipients were randomized (1:1) to 1 of 2 posttransplant care strategies: SOC or THMP. The THMP included an electronic tablet and bluetooth devices to support daily text messages, education videos, and video FaceTime capability; data was cyber-delivered into our electronic medical record daily. Endpoints were THMP participation, 90-day hospital readmission rate, and QOL.One hundred patients completed the study with 50 enrolled in each arm. Participation and adherence with telemedicine was 86% for basic health sessions (vital sign recording), but only 45% for using messaging or FaceTime. The THMP group had a lower 90-day readmission rate compared to SOC (28% vs 58%; P = 0.004). The THMP cohort also showed improved QOL in regards to physical function (P = 0.02) and general health (P = 0.05) at 90 days.To our knowledge, this is the first RCT demonstrating the impact of THMP after LT. The magnitude of effect on LT outcomes, hospital readmissions, and QOL suggests that the adoption of telemedicine has great potential for other major operations.

Background Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. Case Report We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up. Conclusion This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.

Hepatitis C (HCV) disease transmission from the use of HCV antibody-positive and HCV nucleic acid test-negative (HCV Ab+/NAT-) kidneys have been anecdotally reported to be absent. We prospectively analyzed kidney transplant (KT) outcomes from HCV Ab+/NAT- donors to HCV naive recipients under T-cell depleting early steroid withdrawal immunosuppression. Allografts from 40 HCV Ab+/NAT- donors were transplanted to 52 HCV Ab- recipients between July 2016 and February 2018. Thirty-three (82.5%) of donors met Public Health Service (PHS) increased risk criteria. De novo HCV infection was detected at 3 months post-KT in one recipient (1.9%). This was a case of transmission from a HCV Ab+ NAT+ donor with an initial false-negative NAT completed using sample collected on donor hospital admission (day 2). At the time of HCV diagnosis, a stored donor sample collected during procurement (day 4) was tested and resulted NAT-positive. Subsequently, sustained virologic response (SVR) was achieved with 12 weeks of glecaprevir/pibrentasvir. One death with functioning graft at 261 days post-KT was determined not related to HCV or donor factors. This experience provides evidence of a low transmission rate of HCV from HCV Ab+/ NAT- kidney donors, thereby arguing for increasing utilization.

Donor-specific antibodies (DSAs) have a deleterious effect on allografts and remain a major immunologic barrier in transplantation. Current therapies to eliminate DSAs are ineffective in highly HLA-sensitized patients. Proteasome inhibitors have been employed as a strategy to target bone marrow plasma cells (BMPCs), the source of long-term antibody production; however, their efficacy has been limited by poorly defined drug-resistance mechanisms. Here, we performed transcriptomic profiling of CD138+ BMPCs that survived in vivo desensitization therapy with the proteasome inhibitor carfilzomib to identify mechanisms of drug resistance. The results revealed a genomic signature that included increased expression of the immunoproteasome, a highly specialized proteasomal variant. Western blotting and functional studies demonstrated that catalytically active immunoproteasomes and the immunoproteasome activator PA28 were upregulated in carfilzomib-resistant BMPCs. Carfilzomib-resistant BMPCs displayed reduced sensitivity to the proteasome inhibitors carfilzomib, bortezomib, and ixazomib, but enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914. Finally, in vitro carfilzomib treatment of BMPCs from HLA-sensitized patients increased levels of the immunoproteasome β5i (PSMB8) catalytic subunit suggesting that carfilzomib therapy directly induces an adaptive immunoproteasome response. Taken together, our results indicate that carfilzomib induces structural changes in proteasomes and immunoproteasome formation.

Background Highly sensitized patients, who produce antibodies against multiple anti-human leukocyte antigens, have significantly reduced chances for renal transplantation. Traditionally, desensitization protocols to reduce the levels of antibodies have relied on the use of intravenous immunoglobulin and plasmapheresis. Results Here we report the case of a patient with a calculated panel-reactive antibody level of 100% who was desensitized using multiple courses of bortezomib, a proteasome inhibitor, in an intravenous immunoglobulin-free regimen. The patient underwent a successful transplantation with an allograft from a living donor and has continued to do well post-transplantation. Conclusions The expression of anti-human leukocyte antigen antibodies decreases the likelihood of transplantation for patients by restricting the available donor pool. New protocols that reduce antibody expression in these patients and allow for renal transplantation are needed. Bortezomib, as used in the patient reported here, represents a promising new medication for successful desensitization and transplantation.

Background Post-transplantation recurrence of primary focal and segmental glomerulosclerosis (FSGS) is estimated to occur in 30%–50% of cases and doubles the risk of allograft failure. Treatment of recurrent FSGS is challenging because specific pathogenic targets are unknown and available therapeutic options have limited efficacy. Case Report We report a case of recurrent FSGS with nephrotic-range proteinuria (urine protein creatinine ratio [UPCR], >50) and debilitating edema that was resistant to rituximab and plasmapheresis. The patient had a remarkable response to adrenocorticotropic hormone (ACTH) gel and achieved complete remission (UPCR, 0.5; serum albumin, 4.1 g/dL; serum creatinine, 1.0 mg/dL) which was maintained over 10 months on this treatment. Conclusions We conclude that ACTH gel is a potential therapeutic option for post-transplantation recurrence of FSGS and warrants further evaluation.

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/m(2) × 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.

Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new-onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single-center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011-2016 (n = 20). Post-LSG kidney recipients were compared with similar-BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed-rank test were used to compare groups. Among post-LSG patients, mean BMI ± standard deviation (SD) was 41.5 ± 4.4 kg/m2 at initial encounter, which decreased to 32.3 ± 2.9 kg/m2 prior to transplantation (P

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax) to peak concentration (Cmax) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, Cmax, Tmax or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, −30%; ER‐Tac:LCPT, −36%. After exposure normalization, Cmax was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; Cmin was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac., This study evaluates the pharmacokinetic profile of three tacrolimus formulations and shows significant differences, highlighting the higher per mg exposure and a lower peak and delayed peak of extended‐release tacrolimus tablets when compared to the two other capsule formulations.

Background. FTY720 (fingolimod), a novel immunomodulator, has demonstrated potential for prevention of acute rejection in combination with cyclosporine.Methods. This study evaluated FTY720 2.5 mg versus mycophenolate mofetil (MMF) in a combination regimen with standard tacrolimus and corticosteroids in de novo renal transplant recipients for the composite efficacy within 6 months of transplantation.Results. Incidence of treated biopsy-proven acute rejection was 22.9% with FTY720 and 18.5% with MMF. Increased incidence of macular oedema, transient decrease in heart rate and low rate of infections were seen in the FTY720 arm.Conclusion. FTY720 combined with tacrolimus and steroids did not show a significant therapeutic advantage over MMF for the prevention of acute rejection in de novo renal transplant recipients. © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

AMR is being recognized with increasing efficiency, but continues to present a significant threat to renal allograft survival. Traditional therapies for AMR (IVIG, plasmapheresis, rituximab, and antilymphocyte preparations) in general have provided inconsistent results and do not deplete the source of antibody production, viz., the mature plasma cell. Recently, the first plasma cell-targeted therapy in humans has been developed using bortezomib (a first in class PI) for AMR treatment in kidney transplant recipients. Initial experience with bortezomib involved treatment of refractory AMR. Subsequently, the efficacy of bortezomib in primary therapy for AMR was demonstrated. In a multicenter collaborative effort, the initial results with bortezomib in AMR have been confirmed and expanded to pediatric and adult heart transplant recipients. More recently, results from a prospective, staged desensitization trial has shown that bortezomib alone can substantially reduce anti-HLA antibody levels. These results demonstrate the significant potential of proteasome inhibition in addressing humoral barriers. However, the major advantage of proteasome inhibition lies in the numerous potential strategies for achieving synergy.

Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1: 2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (+/- standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 +/- 22.3 vs. 49.5 +/- 17.7 mL/min/1.73 m(2), p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.

The continuing organ shortage requires evaluation of all potential donors, including those with malignant disease. In the United States, no organized approach to assessment of risk of donor tumor transmission exists, and organs from such donors are often discarded. The ad hoc Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and held discussions to generate a framework to approach risk evaluation in this circumstance. Six levels of risk developed by consensus. Suggested approach to donor utilization is given for each category, recognizing the primacy of individual clinical judgment and often emergent clinical circumstances. Categories are populated with specific tumors based on available data, including active or historical cancer. Benign tumors are considered in relation to risk of malignant transformation. Specific attention is paid to potential use of kidneys harboring small solitary renal cell carcinomas, and to patients with central nervous system tumors. This resource document is tailored to clinical practice in the United States and should aid clinical decision making in the difficult circumstance of an organ donor with potential or proven neoplasia.

Background: Pseudoaneurysm after renal transplantation is a rare but serious complication. Case Presentation: We report a case of a 76-year-old man who presented six weeks after kidney transplant with a large pseudoaneurysm arising from the renal artery anastomosis, causing renal vein compression and renal allograft dysfunction. Prior to the removal of the transplanted kidney, an in situ cold perfusion of the allograft was performed. The pseudoaneurysm was repaired ex vivo and the renal artery was reconstructed. External iliac vein was reconstructed with deceased donor interposition allograft, and the kidney was then re-implanted. The patient recovered with immediate allograft function. Conclusions: Successful surgical management of a large renal allograft arterial pseudoaneurysm involves avoidance of dissection of the pseudoaneurysm, utilization of in situ cold perfusion and en-bloc removal of the kidney together with pseudoaneurysm, and pseudoaneurysm incision and vascular bypass reconstruction ex vivo

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

Background Long-term outcomes of kidney transplantation with organs from donors with disseminated intravascular coagulation (DIC) are comparable with those from other deceased donors. The use of tranexamic acid to impair fibrinolysis in the treatment of DIC is becoming increasingly frequent, particularly in the trauma setting. However, the effects of tranexamic acid on a transplanted kidney allograft are unknown. Results We report 2 cases of kidney transplantation following administration of tranexamic acid to the donor prior to organ donation. Microthrombi were present in the renal allografts. Both recipients experienced clinically significant hemolytic anemia, which typically occurs at a very low frequency. Conclusions These cases illustrate a potential concern for the use of tranexamic acid in deceased kidney donors with DIC.

Although paired donation, list donation and non-directed donation allow more recipients to receive living donor transplants, policy makers do not know how willing incompatible potential donors are to participate. We surveyed 174 potential donors ruled out for ABO-incompatibility or positive cross-match about their participation willingness. They were more willing to participate in paired donation as compared to list donation where the recipient receives the next deceased donor kidney (63.8% vs. 37.9%, p < 0.001) or non-directed donation (63.8% vs. 12.1%, p < 0.001). Their list donation willingness was greater when their intended recipients moved to the top versus the top 20% of the waiting list (37.9% vs. 19.0%, p < 0.001). Multivariate logistic regression modeling revealed that potential donors' empathy, education level, relationship with their intended recipient and the length of time their intended recipient was on dialysis also affected willingness. For paired donation, close family members of their intended recipient (odds ratio (OR) = 3.01, confidence intervals (CI) = 1.29, 7.02), with high levels of empathy (OR = 2.68, CI = 1.16, 6.21) and less than a college education (OR = 2.67, CI = 1.08, 6.61) were more willing to participate compared to other donors. Extrapolating these levels of willingness nationally, a 1-11% increase in living donation rates yearly (84-711 more transplants) may be possible if donor-exchange programs were available nationwide.

This report summarizes year 1 blinded data from a 5-year prospective, randomized (1:1, stratified by race and donor type), multicenter, double-blind study comparing treatment failure rates between early cessation of corticosteroid therapy and long-term corticosteroid maintenance therapy in 397 primary renal transplant recipients receiving tacrolimus and mycophenolate mofetil with antibody induction. Sixteen (4.1%) patients died or experienced graft loss during year 1 (9 deaths, 6 graft losses, and 1 death with a graft loss). Fifty-nine (15.3%) patients experienced rejection; 40 (10.4%) of these cases were biopsy-confirmed. Values for 10-year predictive risk of coronary heart disease (CHD) estimated from the Framingham Heart Study scores showed a shift from baseline toward a more favorable risk profile. Renal transplant recipients treated with a tacrolimus-based immunosuppressive regimen and either early cessation or maintenance of corticosteroid therapy experienced excellent patient and graft survival, low acute rejection rates, low rate of posttransplantation diabetes mellitus (9.0%), and improved CHD risk profile at 1 year posttransplantation.

Aims Renal transplant (RTX) candidates with pre-formed anti-HLA antibody (HLA-Ab) have lower transplantation rates and increased mortality. Anti-angiotensin II type 1 receptor antibody (AT1R-Ab) has recently been associated with allograft loss and antibody-mediated rejection. The aim of the present study was to evaluate: (1) the prevalence of anti-angiotensin receptor 1 antibody (AT1R-Ab) in RTX candidates with circulating HLA-Ab and (2) AT1R-Ab response to VDS. Methods Thirty-nine patients receiving desensitization therapy had HLA-Ab levels determined by single-antigen bead array (Luminex). Mean fluorescence intensity (MFI) of the strongest HLA-Ab (immunodominant antibody -iDSA) was measured before and after therapy. A successful response was considered when iDSA decreased >50% at nadir versus pre-desensitization. Serum samples were also tested by ELISA for the presence of AT1R-Ab (U/mL after 1:50 dilution), before and after desensitization. Results A high proportion of candidates with HLA-Ab exhibited AT1R-Ab (20/39, 51%). A good response of AT1R-Ab to therapy was observed in 18/20 patients [Figure 1]: 17.4 ± 12.3 pre versus 10.9 ± 13.1 U/mL post therapy, p = 0.0009). iDSA reduction with desensitization was observed in 13/20 patients – 7996 ± 2580 pre versus 4410 ± 2695 MFI post therapy, p = 0.0001). 12/20 patients had both iDSA and AT1R-Ab reduction by therapy, 6/20 responded to AT1R-Ab only, 1/20 responded to iDSA only, and 1/20 was a non-responder. AT1R-Ab levels were more elevated in Caucasians then in African-Americans both before (20.7 ± 14.9 versus 12.3 ± 3.7 U/mL, p = 0.1), and after desensitization (14.7 ± 15.9 versus 5.2 ± 2.9 U/mL, p = 0.1). Conclusions More than half of HLA-sensitized candidates exhibit AT1R-Ab. This initial desensitization experience consistently provided substantial reductions both in HLA-Ab and AT1R-Ab levels in an unselected, highly sensitized kidney transplant candidate population. Download : Download high-res image (380KB) Download : Download full-size image

The endeavor to study desensitization in kidney transplantation hasn't been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive 3 weekly infusions of SG (320mg/Kg). The study was stopped after 5 subjects were enrolled and their data was analyzed after completing a follow up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean(sd) Cmax, Tmax, AUC and half-life of 4.39(0.69)mg/ml, 2.42(0.91)hours, 171.86(52.35)mg.hour/ml and 40.60(11.96)hours respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals. This article is protected by copyright. All rights reserved.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

To the Editor: The recent article by Mj en et al.1 reports that former kidney donors have increased long-term risk of death, cardiovascular death, and end-stage renal disease (ESRD). The authors note the increased risk to be small, and conclude that they will continue to promote living donation. Yet, we are already aware of insurance companies citing these data (in the United States) when denying or charging increased rates for life and health insurance. Despite its strengths (comparing donors with healthy controls), there are weaknesses in the analysis: (1) all postdonation ESRD is in related donors; relatives of those with ESRD are known to have increased ESRD rates.2–4 (2) Most ESRD was due to immunologic disease, which would have affected both kidneys. (3) The statistical analysis is a concern due to the following: (a) 1901 donors are compared with 32,621 controls with much of the data imputed; (b) the reported hazard ratio for ESRD in donors was 11.38, yet only 0.47% of donors developed ESRD; (c) the donors were 8 years older than controls and, in the analysis adjusted for age, cardiovascular death was nonsignificant; (d) there is uncertainty about the randomness of imputed data, especially on key determinants of survival such as smoking; and (e) 9512 potential controls were eliminated because of ‘reduced general health’. (4) Rather than the entire country, the matched controls were from a relatively small, genetically homogenous geographic area. (5) The difference in mortality was about 5% and only seen after 15 years; the number at risk at or beyond this time point was not stated. (6) The donor cohort originated in the 1970s, whereas controls began observation between 1984 and 1988; in the interval, average lifespan increased. Clearly, Mj en et al. make important observations and future candidates need to be informed of the results. However, additional studies, addressing the limitations noted, are needed to validate these findings.

B cells play a complex role in the immune response. In addition to giving rise to plasma cells (PCs) and promoting T cell responses via antigen presentation, they perform immunoregulatory functions. This knowledge has created concerns regarding nonspecific B cell depletional therapy because of the potential to paradoxically augment immune responses. Recent studies now indicate that PCs have immune functions beyond immunoglobulin synthesis. Evidence for a new role for PCs as potent regulatory cells (via IL-10 and IL-35 production) is discussed including the implications for PC-targeted therapies currently being developed for clinical transplantation.

Compatible living donor/recipient pair participation (CPP) in kidney exchange (KE) transplantation may substantially increase transplant volumes and significantly mitigate the O blood group donor shortage in KE. Initial ethical analysis did not support CPP for two primary reasons: (1) KE would be "unbalanced," and (2) the possibility of undue influence experienced by the compatible pair living donor. Recent developments with CPP (modeling studies and small clinical experiences), have demonstrated substantial potential for increasing KE volumes. This encouraged us to reconsider initial ethical concerns, with a focus on the potential for a design of a prospective CPP clinical trial. This ethical reconsideration led us to conclude that the concept of unbalanced kidney exchanges (manifested primarily by differential benefit between compatible and incompatible pairs) is no longer as clear cut as originally conceived. In addition, application of two concepts substantially diminishes ethical concerns including: (1) "quasi-compatible" pairs, and (2) a priori definition of mitigating factors. We conclude that genuine uncertainty exists regarding whether kidney exchange is best performed with or without compatible pair participation and that a clinical trial is therefore warranted.

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/m(2) (range 35.8-67.7 kg/m(2)). Follow-up after LSG was 220 ± 152 days (range 26-733 days) with last BMI of 36.3 ± 5.3 kg/m(2) (range 29.2-49.8 kg/m(2)) with 29 (55.8%) patients achieving goal BMI of 35 kg/m(2) 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/m(2)/month versus 1.1 kg/m(2)/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.

Background One proposal to increase kidney transplantation is to exchange kidneys between pairs of ABO-incompatible (or cross-match-incompatible) living donors and their recipients. One variation that has greater potential exchanges living donor kidneys for cadaveric donor kidneys (indirect exchanges). A primary concern with indirect exchanges is the potential to disadvantage blood group O wait list candidates. Using wait list modeling, we examine whether this proposal would disadvantage cadaveric kidney blood group O wait list candidates, and present an approach for neutralizing these negative effects. Methods A probability model estimated the total number and blood type frequencies of donor-recipient pairs that would participate in indirect exchanges. A supply-to-demand model for the cadaveric kidney wait list estimated the mean wait time under different allocation policies and donor selection mechanisms for candidates on the wait list classified according to the candidates' race and blood type. Results Indirect exchanges will reduce the mean wait time for cadaveric kidney wait list candidates. The mean wait time of blood group O cadaveric kidney wait list candidates increases when the participating living donors self-select and when kidney allocation is determined by efficiency. This is neutralized when the transplant team preferentially selects blood group O living donors and cadaveric kidney allocation is determined by need. Conclusion Indirect exchange programs will significantly shorten the wait times for cadaveric kidney wait list candidates. The wait times of blood group O candidates will not be affected adversely if blood group O living donors are selected preferentially and if allocation is based on need.

Programmed cell death (PCD) is currently one of the most intensively studied areas in cell biology. Substantial evidence now exists demonstrating the integral role of PCD in many fundamental immunologic processes; therefore, understanding the mechanisms of PCD may provide advances with broad implications in immunobiology. This Overview provides a definition of PCD, a description of known PCD biochemical pathways, and finally a discussion of the implications of PCD in transplantation.

BACKGROUND Although signaling via class I MHC molecules has been shown to suppress T-cell responses, the mechanisms by which these effects are mediated have not been delineated. Studies were conducted to examine the possibility that 5H7 (a murine anti-human mAb specific for the alpha3 domain of human class I MHC) induces programmed cell death (PCD). MATERIALS Normal human T cells and lymphocyte tumor lines were used. PCD was assessed by viable cell recovery (VCR) with trypan blue, ethidium bromide/acridine orange staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling techniques. RESULTS 5H7 induced growth inhibition of lymphocyte tumor cell lines as assessed by [3H]thymidine incorporation. 5H7 also induced marked reductions in VCR of lymphocyte tumors and normal human T and B cells, with the most dramatic reductions occurring in B cells and B cell-derived tumors (JY, BeVD, and 521). Reductions in tumor growth observed with 5H7 monoclonal antibody, however, were not observed with other anti-human class I MHC monoclonal antibodies, TP2599 (alpha3 domain specific) and W6/32 (alpha2/alpha3 domain specific). Cells treated with 5H7 demonstrated typical features of PCD including cytoplasmic vacuolization, DNA condensation, and apoptotic body formation. Reduction in VCR was augmented by anti-CD3 monoclonal antibody and was not reversed by exogenous interleukin 2. Induction of PCD was not observed with soluble 5H7 F(ab)'2 fragments alone, but cross-linking of 5H7 F(ab)'2 fragments by F(ab)'2 fragments of human Ig-absorbed goat anti-mouse Ig partially restored PCD induction, indicating that anti-class I MHC monoclonal antibody can induce PCD in an FcR-independent system and that monoclonal antibody cross-linking is necessary for PCD induction. CONCLUSIONS These studies provide the first evidence that class I MHC molecules mediate PCD in human T and B cells.

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.

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.

A long term goal of investigators working in our laboratory has been to develop new mAbs for use as immunosuppressive agents. As a means toward achieving this goal, several new mAbs (hybridomas) have been developed by screening fusions for supernatants that possess T cell-inhibitory properties. Of these new mAbs, one mAb, designated 5H7, has been shown to possess both a unique combination of specificity for a monomorphic determinant of the alpha 3 domain of human class I MHC heavy chains and highly potent T cell inhibitory properties. mAb 5H7 profoundly inhibited T cell proliferation in response to anti-CD3 mAb in primary or secondary allogenic MLR or in primary human anti-mouse xenogenic MLR. mAb 5H7 inhibited expression of an early T cell activation marker, Leu23 (CD69); expression of IL-2Rs; and IL-2 production by both CD4+ and CD8+ T cells. mAb 5H7 inhibited IL-2 release by the Jurkat (E6-1) human T cell leukemia line in response to immobilized anti-CD3 mAb, thus, providing further evidence that 5H7 can inhibit activation directly at the level of the T cell. 5H7 profoundly blocked CD3-dependent (anti-CD3, anti-CD3 plus PMA, or anti-CD3 plus anti-CD28) pathways, but only partially blocked a CD3-independent (anti-CD28 plus PMA) pathway of T cell activation. In conclusion, class I MHC molecules that are expressed on the T cell may regulate early TCR/CD3-dependent signaling events. In addition, 5H7 mAb may provide a reagent for suppression of cellular immunity in vivo.

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/m(2) (range 35.8-67.7 kg/m(2)). Follow-up after LSG was 220 ± 152 days (range 26-733 days) with last BMI of 36.3 ± 5.3 kg/m(2) (range 29.2-49.8 kg/m(2)) with 29 (55.8%) patients achieving goal BMI of

AMR is being recognized with increasing efficiency, but continues to present a significant threat to renal allograft survival. Traditional therapies for AMR (IVIG, plasmapheresis, rituximab, and antilymphocyte preparations) in general have provided inconsistent results and do not deplete the source of antibody production, viz., the mature plasma cell. Recently, the first plasma cell-targeted therapy in humans has been developed using bortezomib (a first in class PI) for AMR treatment in kidney transplant recipients. Initial experience with bortezomib involved treatment of refractory AMR. Subsequently, the efficacy of bortezomib in primary therapy for AMR was demonstrated. In a multicenter collaborative effort, the initial results with bortezomib in AMR have been confirmed and expanded to pediatric and adult heart transplant recipients. More recently, results from a prospective, staged desensitization trial has shown that bortezomib alone can substantially reduce anti-HLA antibody levels. These results demonstrate the significant potential of proteasome inhibition in addressing humoral barriers. However, the major advantage of proteasome inhibition lies in the numerous potential strategies for achieving synergy.

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1-year, randomized, controlled, open-label, exploratory study assessed two belatacept-based regimens compared to a tacrolimus (TAC)-based, steroid-avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept-mycophenolate mofetil (MMF), belatacept-sirolimus (SRL), or TAC-MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty-nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept-MMF, belatacept-SRL and TAC-MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens at 12 months and the calculated glomerular filtration rate was 8-10 mL/min higher with either belatacept regimen than with TAC-MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC-based regimen.

HLA-IDENTICAL living donor renal transplant recipients have superior long-term graft and patient survival. They require less immunosuppression than other living-donor and cadaver-donor recipients. However, early acute rejection episodes occurring in up to 55% of recipients have been reported with azathioprine (AZA) and prednisone immunosuppression. Although acute rejection (AR) rates are significantly lowered by the addition of cyclosporine (CyA) to the immunosuppression regimen, concerns arise regarding the safety of long-term CyA in this group of patients with low immunologic risk and excellent long-term results. The aim of this study is to analyze the AR rate, immunosuppression requirements, posttransplant complications, long-term allograft function, and graft and patient survival rates in HLA-identical living-donor renal transplant recipients. The effects of two immunosuppressive regimens (AZA and prednisone or AZA, CyA, and prednisone) are compared, and the outcome of CyA and/or prednisone withdrawal is also analyzed.