Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study.

INTRODUCTION: Envarsus XR® (LCPT), a once daily dosage formulation of tacrolimus, is an FDA-approved medication in adult renal transplant recipients (RTRs). There are limited data on its pharmacokinetics (PK) in adolescent RTRs. We report here the PK profile of LCPT in adolescent RTRs. METHODS: The dose of LCPT was determined using a dose conversion ratio targeting 0.7 relative to the total daily immediate-release tacrolimus (IR-Tac) dose. On day 7 after converting to LCPT, patients had an abbreviated PK assessment with sampling at: 0 h (pre-dose), 8-, and 12-h post-dose. The PK data analysis was performed using Bayesian estimators. Our results were compared to those of published adult PK data for LCPT and pediatric PK data for IR-Tac and extended release tacrolimus (ER-Tac) formulation (Advagraf). RESULTS: PK data from three adolescent patients on LCPT were evaluated. The mean (±SD) area under the time-concentration curve (AUC) was 240 (±20.22) h*ng/mL. The mean Tmax was 9.01 ± 2.12 h, and the % fluctuation was 77.71 ± 3.96%. The AUC, Tmax , and % fluctuation were similar to reported results in adult patients taking LCPT. The AUC was higher and the Tmax was longer than what has been reported in pediatric patients taking IR-Tac and ER-Tac. In addition, the LCPT group showed a lower % fluctuation than patients receiving ER-Tac. CONCLUSION: The PK evaluation of LCPT in adolescent RTRs showed similar results to adults. Adolescents taking LCPT had a higher AUC, a more attenuated Tmax , and a lower fluctuation than that seen with ER-Tac in pediatrics.

IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages.

The mechanisms by which IL-6 contributes to the pathogenesis of chronic inflammatory diseases and cancer are not fully understood. We previously reported that cyclooxygenase-2 (Cox-2)-dependent PGE2 synthesis regulates macrophage matrix metalloproteinase (MMP)-9 expression, an endopeptidase that participates in diverse pathologic processes. In these studies, we determined whether IL-6 regulates the Cox-2→PGE2→MMP-9 pathway in murine macrophages. IL-6 coinduced Cox-2 and microsomal PGE synthase-1, and inhibited the expression of 15-hydroxyprostaglandin dehydrogenase, leading to increased levels of PGE2. In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE2. However, inhibition of PGE2 synthesis partially suppressed IL-6-mediated induction of MMP-9. In the canonical model of IL-6-induced signaling, JAK activation triggers STAT and MAPK(erk1/2)-signaling pathways. Therefore, the ability of structurally diverse JAK inhibitors to block IL-6-induced MMP-9 expression was examined. Inhibition of JAK blocked IL-6-induced phosphorylation of STAT3, but failed to block the phosphorylation of MAPK(erk1/2), and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6-induced phosphorylation of MAPK(erk1/2) and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6-induced MMP-9 expression is dependent on the activation of MAPK(erk1/2) and is restrained by a JAK-dependent gene product. Using pharmacologic and genetic approaches, we identified JAK-dependent induction of IL-10 as a potent feedback mechanism controlling IL-6-induced MMP-9 expression. Together, these data reveal that IL-6 induces MMP-9 expression in macrophages via Cox-2-dependent and -independent mechanisms, and identifies a potential mechanism linking IL-6 to the pathogenesis of chronic inflammatory diseases and cancer.

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation.

INTRODUCTION: Autoantibody to angiotensin II type 1 receptor (AT1R-Ab) has been recognized as a non-human leukocyte antigen (HLA) antibody relevant in transplantation. Endothelin type A receptor antibody (ETAR-Ab) has been strongly associated with AT1R-Ab, but the data in kidney transplantation are scarce. METHODS: We examined the relationship of ETAR-Ab and AT1R-Ab with clinical outcomes, biopsy findings, inflammatory cytokines, and HLA donor-specific antibody (DSA) in a cohort of pediatric renal transplant recipients. Sixty-five patients were longitudinally monitored for ETAR-Ab, AT1R-Ab, HLA DSA, interleukin (IL)-8, tumor necrosis factor-α, IL-1ß, interferon-γ, IL-17, IL-6, renal dysfunction, hypertension, rejection, and allograft loss during the first 2 years post-transplant. RESULTS: Fifteen patients (23%) had AT1R-Ab alone, 1 (2%) had ETAR-Ab alone, 23 (35%) had both ETAR-Ab and AT1R-Ab, and 26 (40%) were negative for both antibodies at all timepoints. Having both ETAR-Ab and AT1R-Ab was associated with >30% decline in estimated glomerular filtration rate (P = 0.024), arteritis (P = 0.016), and elevated IL-8 levels (P = 0.010), but not rejection, HLA DSA, or allograft loss. Having both antibodies resulted in greater increases in IL-8 compared with AT1R-Ab alone, even when controlled for additional clinical factors, including HLA DSA (P = 0.012). CONCLUSION: Our study demonstrates that, in pediatric kidney transplantation, ETAR-Ab is highly associated with AT1R-Ab, but there are a subset of patients with AT1R-Ab alone. Having both antibodies is significantly associated with arteritis, elevated IL-8, and decline in renal function, and our results suggest possible interaction effects. Better understanding of this interaction may be informative in developing protocols for testing, treatment, and prevention of allograft injury.

Linkage to Primary Care and Survival After Hospital Discharge for HIV-Infected Adults in Tanzania: A Prospective Cohort Study.

INTRODUCTION: Little is known about outcomes after hospitalization for HIV-infected adults in sub-Saharan Africa. We determined 12-month, posthospital mortality rates in HIV-infected vs. uninfected adults and predictors of mortality. METHODS: In this prospective cohort study, we enrolled adults admitted to the medical wards of a public hospital in northwestern Tanzania. We conducted standardized questionnaires, physical examinations, and basic laboratory analyses including HIV testing. Participants or proxies were called at 1, 3, 6, and 12 months to determine outcomes. Predictors of in-hospital and posthospital mortality were determined using logistic regression. Cox regression models were used to analyze mortality incidence and associated factors. To confirm our findings, we studied adults admitted to another government hospital. RESULTS: We enrolled 637 consecutive adult medical inpatients: 38/143 (26.6%) of the HIV-infected adults died in hospital vs. 104/494 (21.1%) of the HIV-uninfected adults. Twelve-month outcomes were determined for 98/105 (93.3%) vs. 352/390 (90.3%) discharged adults, respectively. Posthospital mortality was 53/105 (50.5%) for HIV-infected adults vs. 126/390 (32.3%) for HIV-uninfected adults (adjusted P = 0.006). The 66/105 (62.9%) HIV-infected adults who attended clinic within 1 month after discharge had significantly lower mortality than the other HIV-infected adults [adjusted hazards ratio = 0.17 (0.07-0.39), P < 0.001]. Adults admitted to a nearby government hospital had similar high rates of posthospital mortality. CONCLUSIONS: Posthospital mortality is disturbingly high among HIV-infected adult inpatients in Tanzania. The posthospital period may offer a window of opportunity to improve survival in this population. Interventions are urgently needed and should focus on increasing posthospital linkage to primary HIV care.