Temporal trends and current use of de novo belatacept in kidney transplant recipients in the United States.

The adoption of de novo belatacept in kidney transplant (kTx) recipients was hampered by an increased risk of acute cellular rejection (ACR) with variation in adopted belatacept based immunosuppressive therapies across centers. We used data from the Scientific Registry of Transplant Recipients (SRTR) to evaluate the temporal trends in belatacept use and describe the associated induction and maintenance regimens in US adult kTx recipients transplanted between June 2011 and December 2018. The number of patients receiving de novo-belatacept based immunosuppressive therapy increased from .74% in 2011 to 3.11% in 2016. In 2016, 66/207 centers used de novo belatacept-based regimen with 3.03% using it in over 50% of their patients. The use of T-cell depleting agents increased with time. Since 2012, the rate of calcineurin inhibitor (CNI) use in combination with belatacept remained stable around 50% and ∼30% remained under belatacept/CNI combination at 1-year post-transplantation. The adoption of belatacept as de novo immunosuppressive regimen has been slow and its use remains low in the United States. Various regimens have been used to modulate the risk of ACR. Further studies evaluating the long-term outcomes of these regimens and assessing their safety especially with regard to the risk of infection are needed.

CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept.

INTRODUCTION: Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of belatacept on CMV infection remains understudied. In this study, we assessed the impact of belatacept on patient and graft survivals. METHODS: CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan-Meier method, log-rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under belatacept vs tacrolimus were compared. RESULTS: Among 308 CMV seronegative recipients, 168 CMV high-risk and 203 belatacept-treated patients were included. High-risk CMV status was associated with lower patient survival and graft survival. Among the CMV high-risk group, patients treated with belatacept presented a higher incidence of CMV viremia, a higher rate of first-line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival. CONCLUSION: Belatacept-based maintenance immunosuppression is associated with an increased risk of CMV primary-infection and a prolonged course of viral replication in CMV high-risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high-risk patients treated with belatacept and whether it is explained by the higher risk of CMV reactivation and infection.

The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients.

Recent evidence suggests that belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ≥98% to 100%, the impact of belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on belatacept consecutively for at least 6 months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in belatacept-treated patients compared to controls who did not receive belatacept. Specifically, significant HLA antibody reduction was evident for class I (P < .0009). Posttransplant belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P < .01). Collectively, these findings suggest belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.

Utility of Prostate Cancer Screening in Kidney Transplant Candidates.

Screening recommendations for prostate cancer remain controversial, and no specific guidelines exist for screening in renal transplant candidates. To examine whether the use of prostate-specific antigen (PSA)-based screening in patients with ESRD affects time to transplantation and transplant outcomes, we retrospectively analyzed 3782 male patients ≥18 years of age undergoing primary renal transplant evaluation during a 10-year period. Patients were grouped by age per American Urological Association screening guidelines: group 1, patients <55 years; group 2, patients 55-69 years; and group 3, patients >69 years. A positive screening test result was defined as a PSA level >4 ng/ml. We used univariate analysis and Cox proportional hazards models to identify the independent effect of screening on transplant waiting times, patient survival, and graft survival. Screening was performed in 63.6% of candidates, and 1198 candidates (31.7%) received kidney transplants. PSA screening was not associated with improved patient survival after transplantation (P=0.24). However, it did increase the time to listing and transplantation for candidates in groups 1 and 2 who had a positive screening result (P<0.05). Furthermore, compared with candidates who were not screened, PSA-screened candidates had a reduced likelihood of receiving a transplant regardless of the screening outcome (P<0.001). These data strongly suggest that PSA screening for prostate cancer may be more harmful than protective in renal transplant candidates because it does not appear to confer a survival benefit to these candidates and may delay listing and decrease transplantation rates.

Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation.

After a brief period of antigenic stimulation, T cells become committed to a program of autonomous expansion and differentiation. We investigated the role of antigen-specific T cell precursor frequency as a possible cell-extrinsic factor impacting T cell programming in a model of allogeneic tissue transplantation. Using an adoptive transfer system to incrementally raise the precursor frequency of antigen-specific CD8(+) T cells, we found that donor-reactive T cells primed at low frequency exhibited increased cellular division, decreased development of multifunctional effector activity, and an increased requirement for CD28- and CD154-mediated costimulation relative to those primed at high frequency. The results demonstrated that recipients with low CD4(+) and CD8(+) donor-reactive T cell frequencies exhibited long-term skin graft survival upon CD28/CD154 blockade, whereas simultaneously raising the frequency of CD4(+) T cells to approximately 0.5% and CD8(+) T cells to approximately 5% precipitated graft rejection despite CD28/CD154 blockade. Antigenic rechallenge of equal numbers of cells stimulated at high or low frequency revealed that cells retained an imprint of the frequency at which they were primed. These results demonstrate a critical role for initial precursor frequency in determining the CD8(+) T cell requirement for CD28- and CD154-mediated costimulatory signals during graft rejection.

Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways.

We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulation blockade regimen achieved sustained insulin independence (median survival, >140 days) without evidence of porcine endogenous retrovirus dissemination. Thus, neonatal porcine islets represent a promising solution to the crucial supply problem in clinical islet transplantation.

The impact of renal function on outcomes of bariatric surgery.

The effect of CKD on the risks of bariatric surgery is not well understood. Using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File, we analyzed 27,736 patients who underwent bariatric surgery from 2006 through 2008. Before surgery, 34 (0.12%) patients were undergoing long-term dialysis. Among those not undergoing dialysis, 20,806 patients (75.0%) had a normal estimated GFR or stage 1 CKD, 5011 (18.07%) had stage 2 CKD, 1734 (6.25%) had stage 3 CKD, 94 (0.34%) had stage 4 CKD, and 91 (0.33%) had stage 5 CKD. In an unadjusted analysis, CKD stage was directly associated with complication rate, ranging from 4.6% for those with stage 1 CKD or normal estimated GFR to 9.9% for those with stage 5 CKD (test for trend, P<0.001). Multivariable logistic regression demonstrated that CKD stage predicts higher complication rates (odds ratio for each higher CKD stage, 1.30) after adjustment for diabetes and hypertension. Although patients with higher CKD stage had higher complication rates, the absolute incidence of complications remained <10%. In conclusion, these data demonstrate higher risks of bariatric surgery among patients with worse renal function, but whether the potential benefits outweigh the risks in this population requires further study.

Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection.

Numerous microbes establish persistent infections, accompanied by antigen-specific CD8 T cell activation. Pathogen-specific T cells in chronically infected hosts are often phenotypically and functionally variable, as well as distinct from T cells responding to nonpersistent infections; this phenotypic heterogeneity has been attributed to an ongoing reencounter with antigen. Paradoxically, maintenance of memory CD8 T cells to acutely resolved infections is antigen independent, whereas there is a dependence on antigen for T cell survival in chronically infected hosts. Using two chronic viral infections, we demonstrate that new naive antigen-specific CD8 T cells are primed after the acute phase of infection. These newly recruited T cells are phenotypically distinct from those primed earlier. Long-lived antiviral CD8 T cells are defective in self-renewal, and lack of thymic output results in the decline of virus-specific CD8 T cells, indicating that newly generated T cells preserve antiviral CD8 T cell populations during chronic infection. These findings reveal a novel role for antigen in maintaining virus-specific CD8 T cells during persistent infection and provide insight toward understanding T cell differentiation in chronic infection.

Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial.

As part of the Spare-the-Nephron trial, we evaluated the combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for the preservation of renal function in renal allograft recipients. This 2-year, open-label, multicenter trial randomized 299 patients of which 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine). Baseline characteristics including measured (iothalamate) glomerular filtration rate (GFR) were similar between groups. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Calculated creatinine clearance and GFR were significantly greater with MMF/SRL at 2 years within which biopsy-proven acute rejection (BPAR) occurred in 14 MMF/SRL-treated patients (3 graft losses) and in 17 receiving the MMF/CNI (6 graft losses). Significantly, no patients receiving MMF/SRL but five treated with MMF/CNI died. Thus, compared with MMF/CNI treatment, a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.

Anti-CD40 monoclonal antibody synergizes with CTLA4-Ig in promoting long-term graft survival in murine models of transplantation.

Blockade of the CD40/CD154 signaling pathway using anti-CD154 Abs has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems, although side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 Abs may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 Ab (7E1) for characteristics and effects mirroring those of anti-CD154: 7E1-G1 (an IgG1 isotype); and 7E1-G2b (an IgG2b isotype). In vitro proliferation assays to measure the agonist properties of the two anti-CD40 Abs revealed similar responses when plate bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. 7E1-G2b was as effective as anti-CD154 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimerism and skin graft survival, whereas 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40-bearing APCs. These data suggest that an appropriately designed anti-CD40 Ab can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens.

Bedside ultrasound diagnosis of a traumatic bladder rupture.

BACKGROUND: Urinary bladder rupture is a complication of both blunt and penetrating trauma. Significant morbidity and mortality can result from a missed rupture and its ensuing complications. Patients who are at risk for traumatic bladder rupture should undergo appropriate testing to expedite the diagnosis. Current diagnostic modalities include computed tomography (CT) cystography, and retrograde cystography. Although these modalities carry a sensitivity and specificity of 95-99% and 95-100%, their utility is limited by the resources and staff available. Furthermore, both techniques require that a potentially hemodynamically unstable trauma patient be transported out of the Emergency Department for the entire duration of the procedure. OBJECTIVE: The following case report reviews the incidence and management of traumatic bladder rupture and describes how emergency physicians (EP) can use ultrasound to make this diagnosis quickly and safely at the bedside. CASE REPORT: The case report describes a patient involved in a motor vehicle collision with a history concerning for urinary bladder injury. A bedside ultrasound study performed by the EP was used to establish the diagnosis of urinary bladder rupture. The ultrasound demonstrated a small contracted urinary bladder with copious free fluid anterior to the bladder wall. The diagnosis was confirmed by CT and the patient was taken expeditiously to the operating room. CONCLUSION: This case provides an example of how bedside ultrasound can be used to make an accurate and timely diagnosis of urinary bladder rupture and help expedite patient care.

Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols.

PURPOSE: To retrospectively determine the incidence of nephrogenic systemic fibrosis (NSF) in patients on dialysis administered either a lower dose high-relaxivity linear gadolinium-chelate, gadobenate dimeglumine (MultiHance, MH), compared to a standard dose linear gadolinium chelate, gadodiamide (Omniscan, OM). MATERIALS AND METHODS: This study was Health Insurance Portability and Accountability Act (HIPAA)-compliant and Institutional Review Board (IRB)-approved. As per institution standardized contrast-enhanced magnetic resonance imaging (MRI) protocols, patients on dialysis were imaged using either MH, between 2/2007 to 9/2008, or OM between 10/2003 and 1/2007. Rates of NSF were compared using 95% score-based confidence intervals (CI). The Wilcoxon rank sum test was used to test similarity/difference between contrast doses given to each patient group. RESULTS: Overall, 312 patients on dialysis received OM and eight (2.6%) developed NSF (95% CI: 1.30%-4.98%). In all, 784 patients on dialysis received MH at a mean cumulative dose of 0.11 mmol/kg (0.05-0.75 mmol/kg) and no cases of NSF were identified (upper 95% confidence bound of 0.45%). The mean cumulative dose of OM was 0.16 mmol/kg (0.1-0.9 mmol/kg) for all patients and 0.28 mmol/kg (0.1-0.8 mmol/kg) for the patients with NSF. The median OM dose was greater in patients who developed NSF (P = 0.03), and was greater than the median MH dose (P < 0.005). CONCLUSION: NSF incidence in at-risk patients receiving contrast-enhanced MRI can be reduced after changing contrast administration protocols that includes changing the type and dose of contrast agent.

Belatacept and CD28 Costimulation Blockade: Preventing and Reducing Alloantibodies over the Long Term.

Purpose of Review: Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. Recent Findings: The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. Summary: A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next generation CD28 blockers to prevent and reduce alloantibodies over the long-term.

Kinetics of antibody response to influenza vaccination in renal transplant recipients.

Annual vaccination is routinely used in organ transplant recipients for immunization against seasonal influenza. However, detailed analysis of the kinetics of vaccine-induced immune responses in this population is lacking. In this study, we investigated the kinetics of vaccine strains-specific antibody responses to trivalent influenza vaccine in a group of renal transplant recipients and a control group. First, we found that the geometric mean hemagglutination inhibition titer against all 3 vaccine strains in the transplant cohort was significantly low when compared to control subjects. Next, whereas the control group sera showed significantly higher HA-specific IgG and isotype IgG1 antibodies at all four time points, a similar increase in the transplant group was delayed until day 28. Interestingly, within the transplant group, subjects receiving belatacept/MMF/prednisone-based regimen had significantly lower levels of total IgG and HA-specific IgG when compared to tacrolimus/MMF/prednisone-based regimen. Even though IgG-ASC response in both cohorts peaked at day 7 post-vaccination, the frequency of IgG-ASC was significantly low in the transplant group. Taken together, our studies show delayed kinetics and lower levels of influenza vaccine-specific antibody responses in renal transplant recipients and, more importantly, indicate the need to probe and improve current vaccination strategies in renal transplant recipients.

Transplant Center Patient Navigator and Access to Transplantation among High-Risk Population: A Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVES: Barriers exist in access to kidney transplantation, where minority and patients with low socioeconomic status are less likely to complete transplant evaluation. The purpose of this study was to examine the effectiveness of a transplant center-based patient navigator in helping patients at high risk of dropping out of the transplant evaluation process access the kidney transplant waiting list. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: We conducted a randomized, controlled trial of 401 patients (n=196 intervention and n=205 control) referred for kidney transplant evaluation (January 2013 to August 2014; followed through May 2016) at a single center. A trained navigator assisted intervention participants from referral to waitlisting decision to increase waitlisting (primary outcome) and decrease time from referral to waitlisting (secondary outcome). Time-dependent Cox proportional hazards models were used to determine differences in waitlisting between intervention and control patients. RESULTS: At study end, waitlisting was not significantly different among intervention (32%) versus control (26%) patients overall (P=0.17), and time from referral to waitlisting was 126 days longer for intervention patients. However, the effectiveness of the navigator varied from early (<500 days from referral) to late (≥500 days) follow-up. Although no difference in waitlisting was observed among intervention (50%) versus control (50%) patients in the early period (hazard ratio, 1.03; 95% confidence interval, 0.69 to 1.53), intervention patients were 3.3 times more likely to be waitlisted after 500 days (75% versus 25%; hazard ratio, 3.31; 95% confidence interval, 1.20 to 9.12). There were no significant differences in intervention versus control patients who started evaluation (85% versus 79%; P=0.11) or completed evaluation (58% versus 51%; P=0.14); however, intervention patients had more living donor inquiries (18% versus 10%; P=0.03). CONCLUSIONS: A transplant center-based navigator targeting disadvantaged patients improved waitlisting but not until after 500 days of follow-up. However, the absolute effect was relatively small.

Intravital microscopy identifies selectins that regulate T cell traffic into allografts.

T cell homing to sites of injury and inflammation is a critical step for adaptive immune responses. While much has been learned regarding T cell homing to lymphoid tissues, few studies have directly observed trafficking events during an effector response. In this study, we developed a model that uses intravital fluorescence videomicroscopy to determine the molecules critical to T cell rolling within skin allograft microvasculature during the effector phase of the rejection response. Additional studies were performed to quantify T cell infiltrates as rejection progressed. We found that P-selectin and E-selectin expressed on postcapillary venules play overlapping roles in the recruitment of activated T cells in a SCID reconstitution model of skin graft rejection and are important in T cell accumulation at the graft site. Surprisingly, we also found that naive T cells are recruited and accumulate via constitutive T cell L-selectin and upregulated L-selectin ligands on rejecting allograft vasculature. These data indicated that a specific retinue of molecules is upregulated during the rejection response, and they suggest potential future therapeutic targets.

Heterologous immunity provides a potent barrier to transplantation tolerance.

Many strategies have been proposed to induce tolerance to transplanted tissue in rodents; however, few if any have shown equal efficacy when tested in nonhuman primate transplant models. We hypothesized that a critical distinction between specific pathogen-free mice and nonhuman primates or human patients is their acquired immune history. Here, we show that a heterologous immune response--specifically, virally induced alloreactive memory--is a potent barrier to tolerance induction. A critical threshold of memory T cells is needed to promote rejection, and CD8(+) "central" memory T cells are primarily responsible. Finally, treatment with deoxyspergualin, an inhibitor of NF-kappa B translocation, together with costimulation blockade, synergistically impairs memory T cell activation and promotes antigen-specific tolerance of memory. These data offer a potential explanation for the difficulty encountered when inducing tolerance in nonhuman primates and human patients and provide insight into the signaling pathways essential for memory T cell activation and function.

Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.