Obesity is associated with a higher incidence of rejection in patients on belatacept: A pooled analysis from the BENEFIT/BENEFIT-EXT clinical trials.

Though belatacept is administered with a weight-based dosing schema, there has been higher clearance reported in obese patients. Therefore, we evaluated the association between body mass index (BMI) and transplant outcomes in kidney transplant recipients who were randomized to cyclosporine- or belatacept-based immunosuppression in the BENEFIT and BENEFIT-EXT randomized clinical trials. A total of 666 and 543 patients underwent randomization and transplantation in BENEFIT and BENEFIT-EXT, respectively, of which 1056 had complete data and were included in this analysis. Patients were grouped categorically according to BMI: <25, 25 to <30, and ≥30 kg/m2. BMI did influence both the incidence and severity of acute rejection. Obese patients with BMI >30 kg/m2 in the low intensity belatacept group experienced significantly more rejection at 12 months than did patients with BMI <25 kg/m2 or BMI 25 to <30 kg/m2. In both the moderate intensity belatacept and low intensity belatacept groups, obese patients with BMI >30 kg/m2 experienced significantly more severe acute rejection than did patients with BMI < 25 kg/m2 or BMI 25 to <30 kg/m2. These results suggest that obese kidney transplant recipients are at an increased risk for acute rejection when under belatacept-based immunosuppression when compared to nonobese patients.

Impact of peri-operative red blood cell transfusions for treatment of anemia on acute rejection in renal transplant recipients.

INTRODUCTION: Anemia occurs before and after kidney transplantation. Determining the impact of perioperative transfusion on post-transplant outcomes can help determine best management of anemia. PROJECT AIM: The current study aims to describe clinical outcomes associated with packed red blood cell transfusions in the peri-operative management of anemia after transplantation. DESIGN: This was a single-center, retrospective study of adult kidney recipients with anemia at the time of transplantation. 1271 patients were stratified by donor-type due to the potential variability in underlying recipient and transplant characteristics; living donor (n = 698, 62%) or deceased donor (n = 573, 38%). RESULTS: Living donor recipients that received blood during the index hospitalization were more likely to experience rejection within 30 days (18% vs. 10%, p = 0.008) and 1 year of transplant (32% vs. 16%, p = 0.038). In multivariate analysis, receiving both blood and darbepoetin (HR: 1.89 [1.20,3.00], p = 0.006), age at transplant (HR: 0.98 [0.97, 0.99], p = 0.02), number of HLA mismatches (HR: 1.17 [1.05,1.30], p = 0.003), and whether the case was a repeat transplant (HR: 2.77 [1.93,3.97], p < 0.01) were significantly associated with hazard of rejection. For deceased donor recipients, there were no differences in acute rejection, graft failure or mortality at 30 days or 1 year. When analyzing hazard of rejection in a multivariate model, treatment received was not found to be significantly associated with rejection. CONCLUSION: Our findings suggest there may be a role for more aggressive pre-transplant treatment of anemia for those patients undergoing living donor transplants.

Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients.

OBJECTIVE: Posaconazole is used for prophylaxis and treatment of invasive fungal infections in lung transplant recipients (LTR). Previous studies have not described the relationship between elevated posaconazole trough concentrations and adverse drug reactions in this population. METHODS: This IRB-approved, retrospective cohort study at NewYork-Presbyterian Hospital included LTR who had posaconazole trough concentrations measured. The primary aim of this study was to evaluate elevated posaconazole trough concentrations and changes in liver function tests as well as QTc interval. A secondary aim of this study was to identify patient factors associated with elevated posaconazole trough levels. RESULTS: A total of 109 LTR were included. The average age was 58.1 years (IQR, 48-65), the majority were male (56%). A total of 932 trough levels were assessed with a median number of 8 (IQR, 5-15) levels per patient. The median posaconazole trough concentration was 1.7 mg/L (IQR, 1.1-2.5). Hepatotoxicity, as defined by common terminology criteria for adverse events (CTCAE), was observed in 73.4% of subjects, with the majority classified as grade 1 (67.5%). However, there was no correlation between elevated posaconazole levels and aspartate aminotransferase (r = .03), alanine aminotransferase (r = .04), alkaline phosphatase (r = .04), and total bilirubin (r = .02). There was also no correlation between posaconazole trough concentrations and QTc interval (r = .03). CONCLUSION: This analysis demonstrates that no correlation exists between whole blood posaconazole levels and hepatotoxicity or QTc prolongation. Based on these results, posaconazole dose reductions may not be warranted for posaconazole levels that are significantly above the therapeutic target to avert risk for hepatotoxicity or QTc prolongation.

Immune cell function assay and T lymphocyte counts lack association with rejection or infection in pediatric heart transplant recipients.

INTRODUCTION: Immune cell function assay (ICFA) and CD3 lymphocyte counts have been considered to be useful in discerning the overall intensity of immunosuppression in pediatric orthotopic heart transplant (OHT) recipients. METHODS: The aim of this retrospective analysis was to evaluate trends of ICFA and CD3 lymphocyte counts and their association with adverse outcomes post-OHT. RESULTS: A total of 381 ICFA and 493 CD3 laboratory values obtained in 78 patients within six months post-OHT were analyzed. There were 14 patients treated for biopsy-proven acute rejection, four of whom had ISHLT grade 2R/3A rejection. In patients with rejection versus those without, CD3 and ICFA values were 122 (IQR 74.5-308) cells/mm2 and 224.5 (IQR 132-343.5) ng/ml compared to 231.8 (IQR 68-421) cells/m2 and 191 (IQR 81.5-333) ng/mL (p = NS for both). Twenty-six patients had at least one detectable cytomegalovirus or Epstein-Barr virus DNAemia within the study timeframe. In patients with viremia versus those without, CD3 and ICFA values were 278.5 (IQR 68-552) cells/mm2 and 130 (IQR 48-284) ng/ml compared to 195 (IQR 74.5-402.5) cells/mm2 and 212 (IQR 89-342) ng/ml (p = NS for both). CONCLUSIONS: No association was found between these immune markers and adverse outcomes. In the absence of larger pediatric studies justifying the role of these tests in identifying elevated risk profiles post OHT, we do not recommend their routine use.

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients.

Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.

COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era.

Treatment outcomes associated with the use of novel COVID-19 therapeutics in solid organ transplant recipients (SOTR) are not well described in the literature. The objective of this analysis was to characterize 30-day hospitalization and other key secondary endpoints experienced by outpatient SOTR with mild-moderate COVID-19 treated with nirmatrelvir/ritonavir (NR), sotrovimab, or no SARS-CoV-2 specific treatment. This IRB-approved, retrospective study included 154 SOTR with a documented positive SARS-CoV-2 infection between December 16, 2021 and January 19, 2022 (a predominant Omicron BA.1 period in New York City). Patients who received NR (N = 28) or sotrovimab (N = 51) experienced a lower rate of 30-day hospitalization or death as compared to those who received no specific treatment (N = 75) (p = .009). A total of three deaths occurred, all among patients who initially received no specific treatment prior to hospitalization. These results suggest a role for SARS-CoV-2 specific agents in the treatment of SOTR with COVID-19, and that there does not appear to be any difference in effectiveness when comparing NR versus sotrovimab.

Comparing weight-based dosing of tacrolimus XR in obese and non-obese renal transplant recipients.

The recommended initial weight-based dose of extended-release (XR) tacrolimus (Envarsus XR) in kidney transplant recipients (KTR) is 0.14 mg/kg/day. However, no data exist regarding dosing recommendations for obese patients specifically. The aim of this study was to evaluate weight-based dosing requirements in a cohort of obese KTR who were initiated on de novo tacrolimus XR post-transplantation. The primary outcome was weight-based dosing requirements (mg/kg/day) on post-operative day (POD) 7 and 14. Of the 254 KTR, 81 (31%) were obese. The median therapeutic dose on POD7 was 0.1 versus 0.12 vs. 0.14 mg/kg/day in the BMI > 30 kg/m2 , BMI 25-30 kg/m2 , and BMI < 25 kg/m2 , respectively, (p = .0001). This result was similar on POD14; median therapeutic dose was 0.09 versus 0.11 versus 0.15 mg/kg/day in the BMI > 30 kg/m2 , BMI 25-30 kg/m2 , and BMI < 25 kg/m2 , respectively, (p < .001). Therapeutic dose on POD7 and POD14 based on ideal body was similar in all cohorts (p = .238, p = .923, respectively). This finding was supported by a strong linear relationship between ideal body weight (IBW) and therapeutic dose (r = .929). In both obese and non-obese KTR, IBW had a stronger correlation with the therapeutic dose for tacrolimus XR.

The Safety and Efficacy of Desmopressin in Patients With Intracranial Hemorrhage and a History of Alcohol Use.

BACKGROUND: Patients with a history of alcohol use disorder are at an increased risk of hematoma expansion following intracranial hemorrhage (ICH) due to the effects of alcohol on platelet aggregation. Desmopressin (DDAVP) improves platelet aggregation and may decrease hematoma expansion in patients with ICH. However, DDAVP may also increase the risk of hyponatremia and thrombotic events. Evidence is limited regarding the safety and efficacy of DDAVP in alcohol use (AU)-associated ICH. METHODS: This was a retrospective chart review of adult patients with radiographic evidence of ICH and a confirmed or suspected history of alcohol use upon admission. Patients were categorized into groups based on DDAVP administration. Safety outcomes included hyponatremia (serum sodium <135 mEq/L or decrease in serum sodium of ≥ 5 mEq/L for patients with baseline sodium <135 mEq/L) within 24 hours of ICH and thrombotic events within 7 days of ICH. The primary efficacy outcome was the incidence of hematoma expansion, defined as any expansion of the hemorrhage noted on repeat imaging within 32 hours. RESULTS: In total, 52 patients were included in the safety analysis (27 DDAVP and 25 non-DDAVP). Although hyponatremia was numerically higher in the DDAVP group, there was no significant difference between groups (19.2% vs 4.2%, P = 0.192). Thrombotic complications were similar between the DDAVP and non-DDAVP groups (11.1% vs. 8%, P = 1.0). Thirty-nine patients met criteria for hemostatic efficacy analysis. There was no difference in hematoma expansion between the DDAVP and non-DDAVP groups (23.1% vs 34.6%, P = 0.71) and these findings were consistent after adjusting for differences in baseline characteristics (OR 0.63, 95% CI 0.1-3.3). CONCLUSION: The administration of DDAVP was not associated with adverse safety events, but did not significantly reduce the incidence of hematoma expansion in patients with AU-associated ICH.

Concomitant tacrolimus and ketorolac therapy in pediatric liver transplant recipients: Teaching old dogma new tricks.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketorolac, are effective analgesic medications, but concerns for nephrotoxicity have limited their role for pain control following pediatric liver transplantation (LT). Calcineurin inhibitors (CNIs) and NSAIDs share a similar mechanism of nephrotoxicity, and concomitant administration is traditionally discouraged. A retrospective review of pediatric LT recipients was conducted between 1/1/2015 and 12/31/2019 at a single center. Patients were stratified based on receipt of ketorolac. The primary outcome was the incidence of acute kidney injury (AKI). Secondary outcomes included serum creatinine, urine output, estimated glomerular filtration rate, bleeding incidence, oral morphine milligram equivalents, and hospital length of stay (LOS). The incidence of AKI was similar between the two groups with 25.8% of patients in the ketorolac group versus 29.2% of patients in the nonketorolac group (p = .475) meeting criteria in the first 10 days post-transplant. Opioid requirements were less in the ketorolac group (p < .001), who also demonstrated shorter LOS compared with nonketorolac patients (p = .033). Concurrent CNI and ketorolac use did not result in an increased incidence of AKI in the early post-LT period and resulted in significantly lower opioid requirements along with a decreased hospital LOS.

Less bleeding associated with apixaban versus other direct acting oral anticoagulation in solid organ transplant recipients.

BACKGROUND: The purpose of this study was to evaluate outcomes of bleeding and thrombosis resulting from the use of direct oral anticoagulants (DOACs) in a large cohort of solid organ transplant (SOT) recipients. METHODS: This was a single center, retrospective cohort study of adult kidney, heart, lung, and liver transplant recipients transplanted between August 2009 and May 2018. Patients were stratified into two groups: those who received apixaban (apixaban group) or those patients receiving either rivaroxaban or dabigatran (non-apixaban group). The primary endpoint was the cumulative incidence of bleeding while receiving DOAC therapy. The secondary endpoints were incidence of major bleeding and thrombosis at any time while receiving DOAC therapy. RESULTS: A total of 106 patients were included; 70 patients received apixaban and 36 patients received non-apixaban anticoagulation. Cumulative incidence of any bleeding was lower in the apixaban group compared to the non-apixaban group at both 90 days (4.9% vs. 16.1%) and 180 days (11.4% vs. 24.9%, P = .034). Cumulative incidence of major bleeding (P = .686) and thrombosis (P = .515) were similar between groups. DOAC dosing congruent with the package insert(s) was associated with a lower risk of thrombosis. CONCLUSION: Apixaban-based anticoagulation was associated with a lower cumulative incidence of any bleeding compared to non-apixaban DOACs.

An evaluation of PJP prophylaxis and anemia among renal transplant recipients.

BACKGROUND: Dapone and atovaquone are therapeutic options for PJP prophylaxis in renal transplant recipients. The objective of this study was to evaluate the incidence of anemia in renal transplant recipients receiving these agents. METHODS: This is an IRB-approved, retrospective analysis of adult renal transplant recipients who received either dapsone or atovaquone. The primary endpoint was the change in hemoglobin within 90 days of drug initiation. Other endpoints of interest included incidence and management of anemia at multiple time points post-transplant. Categorical variables were compared with Pearson's chi-squared or Fischer's exact test and continuous data were compared utilizing Wilcoxon rank-sum test. Statistical analyses were performed using Stata 14.2. RESULTS: A total of 478 patients were screened for inclusion; 50 patients were evaluated in both the dapsone and atovaquone groups. In the dapsone and atovaquone groups, the median age was 52 and 50.5 years, 44% and 42% were Caucasian, and median time to treatment initiation was 27 and 39 days post-transplant, respectively. All patients receiving dapsone had normal G6PD function. There was no difference in baseline hemoglobin between groups (9.7 g/dL vs 9.8 g/dL, P = .83). The median nadir hemoglobin values were 8.6 g/dL and 9.6 g/dL in the dapsone and atovaquone groups, respectively (P = .047). The median decrease in hemoglobin from baseline to nadir was 1.3 g/dL in dapsone patients and 0.2 g/dL in atovaquone patients (P = .001). Dapsone was discontinued in 46% of patients, whereas atovaquone was discontinued in 18% (P = .001). CONCLUSION: Among renal transplant recipients with normal G6PD activity, dapsone is associated with greater hemoglobin reductions and rates of drug discontinuation as compared to atovaquone.

Management of Hepatic Coagulopathy in Bleeding and Nonbleeding Patients: An Evidence-Based Review.

Patients with varying degrees of hepatic dysfunction often present with presumed bleeding diathesis based on interpretation of routine measures of coagulation (prothrombin time [PT], international normalized ratio [INR], and activated partial thromboplastin time). However, standard markers of coagulation do not reflect the actual bleeding risk in this population and may lead to inappropriate administration of hemostatic agents and blood products. The concept of "rebalanced hemostasis" explains both the risk of bleeding and clotting seen in patients with liver dysfunction. The role of pharmacologic agents and blood products for prevention of bleeding during high-risk procedures and treatment of clinically significant bleeding remains unclear. Viscoelastic measurements of the clotting cascade provide information about platelets, fibrinogen/fibrin polymerization, coagulation factors, and fibrinolysis that might better represent hemostasis in vivo and may better inform management strategies. Due to the paucity of available data, firm recommendations for the use of blood products and pharmacologic agents in patients with hepatic coagulopathies are lacking, and thus, these products should not be routinely administered. Traditional laboratory tests such as PT/INR should not be the sole determinant of potential interventions. Rather, clinicians should assess factors such as the severity of bleed or bleeding risk of the procedure, the patient's risk of thromboembolism, and the strength of available evidence for specific agents and blood products to guide decision-making.

Utilization of direct-acting oral anticoagulation in solid organ transplant patients: A national survey of institutional practices.

The safety and efficacy of direct-acting oral anticoagulants (DOACs) and reversal strategies are not well established in the solid organ transplant population. This was a survey of pharmacists to assess DOAC and urgent reversal practices among adult transplant programs in the United States. A 27-question survey was distributed to members of transplant pharmacy organization listservs between 5/28/19 and 6/30/19. A total of 115 responses were received from kidney (43.5%), heart (20.0%), lung (18.3%), liver (13.9%), and pancreas (4.4%) transplant programs. DOAC use prior to transplant was mostly prohibited in thoracic programs (77.3%) but more permissive in kidney transplant programs (64.0%). If permitted, apixaban (57.8%) was most preferred. At transplant surgery, reversal of DOAC was performed "as needed" (20.9%) or was not routine (18.3%). DOAC use post-transplant was more permissive (94.3%). A majority of responders follow FDA recommended dosing in the setting of drug-drug interactions (51.1%). Major factors influencing DOAC prescribing decisions included renal function, drug-drug interactions, and insurance. High clinical practice variability exists regarding DOAC utilization and urgent reversal strategies in pre-, peri-, and post-transplant stages. While more research is needed to refine the clinical landscape, many institutions are using DOAC therapy under the perception that they pose a similar risk of bleeding compared to a non-transplant population.

Delayed calcineurin inhibitor introduction and renal outcomes in liver transplant recipients receiving basiliximab induction.

BACKGROUND: To investigate the impact of delayed calcineurin inhibitor (CNI) initiation in liver transplant recipients (LTR) with peri-operative renal insufficiency receiving basiliximab induction, we compared renal outcomes of LTR stratified by the degree of achieved post-operative renal recovery (RR) prior to CNI initiation. METHODS: All adult LTR transplanted between 01/2007 and 12/2015 who received basiliximab were included. Patients who received multi-organ transplantations, were repeat transplant recipients, or expired prior to post-operative day (POD) 90 were excluded. The primary outcome of our retrospective analysis was renal function at POD 90. RESULTS: A total of 210 patients were included in our final analysis. Most patients were Caucasian males undergoing liver transplantation for liver disease secondary to hepatitis C virus. Baseline characteristics were similar among the evaluable population. Estimated GFR was significantly higher among patients with the greatest degree of post-operative renal recovery at POD 90; however, this difference did not persist at POD 180. There was no significant difference in incidence or severity of biopsy-proven acute rejection (BPAR) at any measured time point. CONCLUSIONS: Delayed CNI initiation following liver transplantation in patients with post-operative renal insufficiency who receive basiliximab induction does not adversely affect the incidence of BPAR or long-term renal outcomes.