Feasibility of Interleukin-6 Receptor Blockade in Cardiac Antibody-mediated Rejection.

BACKGROUND: Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. METHODS: This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. RESULTS: All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. CONCLUSIONS: These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies.

Impact of Angiotensin Blockade on Development of Chronic Lung Allograft Dysfunction.

Background: The renin-angiotensin-aldosterone system (RAAS) is responsible for a multitude of physiological functions, including immunological effects such as promotion of TGF-ß and upregulation of IL-6 and IL-8 which are also implicated in the development of chronic lung allograft dysfunction (CLAD). Blockade of the RAAS pathway in pre-clinical models has demonstrated a decrease in these cytokines and pulmonary neutrophil recruitment. Objective: This study sought to evaluate whether use of RAAS inhibitor (RAASi) in lung transplant recipients impacted CLAD-free survival. Methods: In this retrospective, single-center study, 35 lung transplant recipients who received a RAASi post-transplant were compared to 70 lung transplant recipients not exposed to a RAASi and were followed for up to 5 years post-transplant. Results: The incidence of CLAD did not differ based on RAASi treatment (34.3% in RAASi vs 38.6%, P-value .668). This was confirmed with a multivariable Cox proportional hazards model with RAASi initiation as a time-varying covariate (RAASi hazard ratio of 1.01, P-value .986). Incidence of hyperkalemia and acute kidney injury were low in the RAASi group. Conclusions: This study demonstrated no association between post-transplant RAASi use and decreased risk of CLAD development. RAASi were also well tolerated in this patient population.

Tocilizumab for antibody-mediated rejection treatment in lung transplantation.

Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR.

Diagnosis and Treatment of Fungal Infections in Lung Transplant Recipients.

Fungal infections are a significant source of morbidity in the lung transplant population via direct allograft damage and predisposing patients to the development of chronic lung allograft dysfunction. Prompt diagnosis and treatment are imperative to limit allograft damage. This review article discusses incidence, risk factors, and symptoms with a specific focus on diagnostic and treatment strategies in the lung transplant population for fungal infections caused by Aspergillus, Candida, Coccidioides, Histoplasma, Blastomyces, Scedosporium/Lomentospora, Fusarium, and Pneumocystis jirovecii. Evidence for the use of newer triazole and inhaled antifungals to treat isolated pulmonary fungal infections in lung transplant recipients is also discussed.

Impact of antimetabolite discontinuation following cytomegalovirus or BK polyoma virus infection in kidney transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) and BK polyoma virus (BKV) infection following kidney transplantation have been associated with allograft dysfunction and allograft loss. Reduction in immunosuppression is a mainstay of management yet has been associated with increased risk of rejection. According to international consensus guidelines, one approach to management of these viral infections is to discontinue the antimetabolite. Little is known surrounding long-term outcomes in these patients, and it remains unclear if consideration should be given to resuming the antimetabolite as variable re-escalation strategies have been reported. The objective was to describe episodes of rejection and identify risk factors for rejection following antimetabolite withdrawal after CMV or BKV DNAemia in kidney transplant recipients. METHODS: This single-center, retrospective review evaluated adult kidney transplant recipients with a serum CMV or BKV DNA PCR ≥500 copies/ml who underwent antimetabolite discontinuation. The primary outcome assessed was the incidence of biopsy-proven acute rejection (BPAR). RESULTS: One hundred fifty-nine patients were included. Overall, 14 patients (8.8%) experienced BPAR at a median of 1.6 years after antimetabolite discontinuation. Compared to CMV, discontinuation after BKV DNAemia was associated with a higher incidence of BPAR. Characteristics observed more frequently in patients with BPAR included younger age, female sex, higher initial viral load, and development of de novo donor-specific antibody (DSA). CONCLUSION: These findings suggest that antimetabolite discontinuation after CMV or BKV DNAemia in kidney transplant recipients is a reasonable and safe approach. Further prospective studies investigating optimal immunosuppression management following CMV or BKV DNAemia in kidney transplant recipients are warranted.

Association of bleeding with serotonergic antidepressants in patients receiving left ventricular assist device support.

STUDY OBJECTIVE: This study sought to determine whether SA use is associated with bleeding in patients receiving CF-LVAD support. DESIGN: A retrospective cohort analysis was conducted of all adult patients who received CF-LVAD implantation at our institution. SETTING: Barnes-Jewish Hospital between July 1, 2009, and October 1, 2018. PATIENTS: Patients at least 18 years of age who received a HVAD™ (HeartWare Corp.), HeartMate II™ (St. Jude Medical), or HeartMate 3™ (St. Jude Medical) CF-LVAD and survived for at least 30 days postoperatively were included. INTERVENTION: Patients who received SAs (n = 203) were compared to those who did not (n = 391) from 30 days to 18 months following implantation. The primary outcome was the incidence of first bleeding events including gastrointestinal bleed (GIB), epistaxis, or intracerebral hemorrhage (ICH). MEASUREMENTS AND MAIN RESULTS: During follow-up, 219 patients had bleeding events: 93 of 203 (45.8%) in the SA group versus 126 of 391 (32.2%) in the control group (p = 0.001). After adjustment for age, angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) use, history of bleeding events, history of smoking, and CF-LVAD type, SA use remained associated with bleeding (adjusted odds ratio: 1.75, 95% confidence interval: 1.22-2.51, p = 0.002). HeartMate 3™ patients experienced less bleeding than HeartMate II™ patients (adjusted odds ratio 0.46, 95% confidence interval: 0.23-0.90, p = 0.024). CONCLUSIONS: In this single-center, retrospective cohort of patients supported with CF-LVADs, SA use was associated with the incidence of first bleeding events, primarily driven by GIB. Further studies are needed to assess any differential risk of bleeding among SA agents and to assess the utility of altering antithrombotic strategies.

Clinical Experience with Extended-Release Tacrolimus in Older Adult Kidney Transplant Recipients: A Retrospective Cohort Study.

BACKGROUND: Extended-release tacrolimus (LCP-Tac) prescribing information states that there is insufficient data in older adult patients from which to make recommendations on use in this population. This study sought to provide information on de novo use of LCP-Tac in the older adult kidney transplant population. METHODS: This single-center retrospective study had two distinct objectives; to determine if weight-based doses of LCP-Tac differ based on recipient age and to compare safety and efficacy between LCP-Tac and immediate-release tacrolimus (IR-Tac) in older adult transplant recipients. Data was obtained through electronic chart review up to 2 years after transplant with censoring for graft loss and death. RESULTS: Weight-based doses were compared between patients aged ≥ 65 years (n = 84), 36-64 years (n = 64), and ≤35 years (n = 44). LCP-Tac weight-based doses were lower at all time points in patients ≥ 65 years of age. Both age and race significantly impacted required dose on linear regression. The doses required to achieve therapeutic tacrolimus troughs were significantly lower in all age groups compared with the current FDA de novo dosing recommendation. In the older adult population, graft outcomes and infectious and metabolic complications were compared between recipients of LCP-Tac (n = 84) and IR-Tac (n = 42). Within this cohort, there were no differences between LCP-Tac and IR-Tac on graft function, rejection, graft loss, death, cytomegalovirus viremia, BK viremia, hypertension, diabetes, alopecia, or tremor up to 2 years after transplant. CONCLUSIONS: Older adult recipients required significantly lower LCP-Tac doses compared with younger recipients and with the FDA-labeled starting dose. There were no differences in graft outcomes or adverse effects in older adult patients who received LCP-Tac versus IR-Tac.

Choice of Acid Suppressant Therapy and Long-Term Graft Outcomes After Kidney Transplantation.

STUDY OBJECTIVE: The purpose of this study was to comprehensively evaluate the long-term adverse effects of proton pump inhibitors (PPIs) compared with histamine-2 receptor antagonists (H2RAs) in kidney transplant recipients. METHODS: This retrospective cohort compared 582 patients treated with PPI with 705 patients treated with H2RA and evaluated adverse effects throughout their course of acid suppressant therapy to a maximum of nine years posttransplant. The primary outcome of interest was renal function at 1 year posttransplant; secondary outcomes included renal function at 30 days, 3, 5, and 9 years posttransplant as well as rejection, electrolyte and laboratory abnormalities, osteoporosis, pneumonia, and Clostridium difficile infections. RESULTS: Renal function did not significantly differ at any timepoint posttransplant. Rejection rates and Clostridium difficile infections were similar between groups; osteoporosis and pneumonia rates were numerically higher in the PPI treated arm but did not reach statistical significance. Proton pump inhibitor (PPI) treated patients were more likely to experience hypomagnesemia requiring supplementation. High dose PPI treated patients had significantly higher rates of pneumonia and osteoporosis compared with H2RA treated patients. Patients were maintained on PPI therapy for an average of 5 years and H2RA therapy for 3 years posttransplant, the majority without a clear indication for therapy. CONCLUSIONS: There was no difference in renal function, rejection, or graft loss between PPI and H2RA treated patients. The majority of patients were maintained on PPI therapy for several years posttransplant without a clear indication; critical evaluation of ongoing need for acid suppressant therapy in the posttransplant course should be an area of future focus.

Impact of Reported ß-Lactam Allergy on Management of Methicillin-Sensitive Staphylococcus aureus Bloodstream Infections.

BACKGROUND: Antistaphylococcal ß-lactams antibiotics are the preferred treatment for methicillin-sensitive Staphylococcus aureus (MSSA) infections. Patient-reported ß-lactam allergies may complicate antibiotic decision-making and delay optimal therapy, with potential implications on patient outcomes. OBJECTIVE: To determine the impact of reported ß-lactam allergies on the receipt of optimal therapy and outcomes for MSSA bloodstream infections (BSI). METHODS: Retrospective, matched cohort of MSSA BSI patients with and without a reported ß-lactam allergy. The primary end point was receipt of optimal therapy, defined as an antistaphylococcal ß-lactam. RESULTS: Two hundred twelve patients were included: 53 with reported ß-lactam allergy and 159 without ß-lactam allergy. Commonly reported ß-lactam allergies were 26 (49%) immune-mediated reaction and 8 (15%) intolerance, with 19 (36%) having no documented reaction. Optimal antibiotics were given to 135 patients without a ß-lactam allergy and 37 patients with a reported ß-lactam allergy (85% vs 70%, P = .015). Among reported ß-lactam allergy patients, those without a documented reaction were less likely to receive optimal therapy (47% vs 79%, P = .042). Reported ß-lactam allergy was not associated with clinical response (P = .61) or MSSA-related mortality (P = .83). When adjusting for immunosuppression, variables independently associated with optimal therapy were ß-lactam allergy (adjusted odds ratio [adjOR], 0.3; 95% confidence interval [CI], 0.1-0.6) and infectious diseases consultation (adjOR, 6.1; 95%CI, 2.7-13.9). Optimal antibiotic use was associated with decreased all-cause 90-day mortality (adjOR, 0.23; 95%CI, 0.09-0.54). CONCLUSIONS: Patients with reported ß-lactam allergies, particularly those without a documented reaction, were less likely to receive optimal antibiotics for MSSA BSI. Patient outcomes may be improved with enhanced quality of allergy history and routine infectious disease consultation.

Rabbit antithymocyte globulin for the treatment of chronic lung allograft dysfunction.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. Several treatments have been used to prevent the progression or reverse the effects of CLAD. Cytolytic therapy with rabbit antithymocyte globulin (rATG) has previously shown to be a potential option. However, the effect on patients with restrictive allograft syndrome (RAS) versus bronchiolitis obliterans syndrome (BOS) and the effect of cumulative dosing are unknown. METHODS: The charts of lung transplant patients treated with rATG at Barnes-Jewish Hospital from 2009 to 2016 were retrospectively reviewed. The primary outcome was response to rATG; patients were deemed responders if their FEV1 improved in the 6 months after rATG treatment. Safety endpoints included incidence of serum sickness, cytokine release syndrome, malignancy, and infectious complications. RESULTS: 108 patients were included in this study; 43 (40%) patients were responders who experienced an increase in FEV1 after rATG therapy. No predictors of response to rATG therapy were identified. Serum sickness occurred in 22% of patients, 15% experienced cytokine release syndrome, and 19% developed an infection after therapy. CONCLUSION: 40% of patients with CLAD have an improvement in lung function after treatment with rATG although the improvement was typically minimal.

Tacrolimus Concentration-to-Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes.

INTRODUCTION: One factor impacting tacrolimus interpatient variability is the presence of CYP3A5 polymorphisms. Low tacrolimus concentration-to-dose ratios (CDRs), or rapid metabolizers (RMs), have been associated with poor graft function outcomes and higher biopsy-proven acute rejection (BPAR) rates in a predominantly white population. Pretransplant CYP genotyping is not routinely conducted, and therefore only a small number of studies have assessed the use of tacrolimus CDRs as a surrogate for metabolism. We explored differences in outcomes between patients with low tacrolimus CDRs and high tacrolimus CDRs (i.e., nonrapid metabolizers [NRMs]) in a diverse patient population. OBJECTIVE: To determine the relationship between tacrolimus CDRs and graft and patient outcomes in kidney transplant recipients at a large transplant center between 2006 and 2016. METHODS: Inclusion criteria consisted of adult kidney transplant recipients who received rabbit antithymocyte globulin induction followed by a maintenance regimen of tacrolimus, mycophenolate, and prednisone. The primary end point was BPAR at 1 year. Secondary end points included graft survival, patient survival, and toxicities. Determination of clusters was conducted using the two-step cluster analysis with a defined two-cluster distribution. Kaplan-Meier survival curves were created using the log-rank test. RESULTS: The NRM cluster consisted of 322 patients with a mean CDR of 2.91 ng/ml/mg. The RM cluster consisted of 932 patients with a mean CDR of 1.14 ng/ml/mg. The BPAR at 1 year posttransplant was 3.7% in the NRM cluster and 3.6% in the RM cluster (p=0.95). Death at 5 years was higher in the NRM group compared with the RM group for unknown reasons (p=0.03). Differences in the incidence of posttransplant toxicities were not statistically significant at any time point, except for increased rates of cutaneous cancer at 5 years and cardiovascular disease overall in the NRM group. CONCLUSION: Tailoring tacrolimus therapy early posttransplant based on CDR is not supported by the findings in this study.

Synthesis and in vivo evaluation of gallium-68-labeled glycine and hippurate conjugates for positron emission tomography renography.

The objective of this study was to evaluate four new (68) Ga-labeled 1,4,7,10-cyclododeca-1,4,7,10-tetraacetic acid (DOTA)/1,4,7-triazacyclononane-1,4,7-triacetic acid derived (NODAGA)-glycine/hippurate conjugates and select a lead candidate for potential application in positron emission tomography (PET) renography. The non-metallated conjugates were synthesized by a solid phase peptide synthesis method. The (68) Ga labeling was achieved by reacting an excess of the non-metallated conjugate with (68) GaCl4 (-) at pH -4.5 and 10-min incubation either at room temperature for NODAGA or 90 °C for DOTA. Radiochemical purity of all (68) Ga conjugates was found to be >98%. (68) Ga-NODAGA-glycine displayed the lowest serum protein binding (0.4%) in vitro among the four (68) Ga conjugates. Biodistribution of (68) Ga conjugates in healthy Sprague Dawley rats at 1-h post-injection revealed an efficient clearance from circulation primarily through the renal-urinary pathway with <0.2% of injected dose per gram remaining in the blood. The kidney/blood and kidney/muscle ratios of (68) Ga-NODAGA-glycine were significantly higher than other (68) Ga conjugates. On the basis of these results, (68) Ga-NODAGA-glycine was selected as the lead candidate. (68) Ga-NODAGA-glycine PET renograms obtained in healthy rats suggest (68) Ga-NODAGA-glycine as a PET alternate of (99m) Tc-Diethylenetriaminepentaacetic acid (DTPA).