Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism.

Targeting interleukin-6 (IL-6) is a promising strategy to counteract antibody-mediated rejection (ABMR). In inflammatory states, IL-6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub-study of a phase 2 trial of anti-IL-6 antibody clazakizumab in late ABMR (ClinicalTrials.

Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study.

Background And Objectives: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial.

Design, Setting, Participants, & Measurements: In the correction phase, adult outpatients with plasma potassium ≥5.

Characterization of renal biomarkers for use in clinical trials: effect of preanalytical processing and qualification using samples from subjects with diabetes.

Background: Identifying the potential for drug-induced kidney injury is essential for the successful research and development of new drugs. Newer and more sensitive preclinical drug-induced kidney injury biomarkers are now qualified for use in rat toxicology studies, but biomarkers for clinical studies are still undergoing qualification. The current studies investigated biomarkers in healthy volunteer (HV) urine samples with and without the addition of stabilizer as well as in urine from patients with normoalbuminuric diabetes mellitus (P-DM).

Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers.

Background: Several preclinical urinary biomarkers have been qualified and accepted by the health authorities (US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency) for detecting drug-induced kidney injury during preclinical toxicologic testing. Validated human assays for many of these biomarkers have become commercially available, and this study was designed to characterize some of the novel clinical renal biomarkers. The objective of this study was to evaluate clinical renal biomarkers in a typical Phase I healthy volunteer population to determine confidence intervals (pilot reference intervals), intersubject and intrasubject variability, effects of food intake, effect of sex, and vendor assay comparisons.

An open-label, pilot study evaluating the safety and efficacy of converting from calcineurin inhibitors to sirolimus in established renal allograft recipients with moderate renal insufficiency.

This pilot study was designed to evaluate the safety and efficacy of converting from a calcineurin inhibitor (CI) to a sirolimus (SRL)-based regimen in established renal transplant recipients with moderate renal insufficiency. Sixty renal transplant recipients on CI-based immuno-suppression with a serum creatinine (SCr) between 159 and 265 microM (1.8 and 3.

Bcl-XL expression in stem cells facilitates engraftment and reduces the need for host conditioning during bone marrow transplantation.

The prolonged survival of donor hematopoietic stem cells is crucial to the success of bone marrow transplantation. The anti-apoptotic gene Bcl-xL has been shown to promote survival of cells of the erythroid, myeloid and lymphoid lineages. To evaluate a potential therapeutic role for Bcl-xL, we used a retroviral vector to express Bcl-xL in donor cells used for murine bone marrow transplantation.

Notch and the immune system.

Notch proteins are used repeatedly to direct developmental cell fate decisions in multiple organs. During hematopoiesis and immune development, Notch is critical for T/B lineage specification and for generation of splenic marginal zone B cells. In early embryonic development, Notch is crucial for generating hematopoietic stem cells.

Notch signaling augments T cell responsiveness by enhancing CD25 expression.

Notch receptors signal through a highly conserved pathway to influence cell fate decisions. Notch1 is required for T lineage commitment; however, a role for Notch signaling has not been clearly defined for the peripheral T cell response. Notch gene expression is induced, and Notch1 is activated in primary CD4(+) T cells following specific peptide-Ag stimulation.

Immunotherapy as a means to induce transplantation tolerance.

There have been several recent advances in the use of immunotherapy to induce transplantation tolerance. These include newer and safer protocols to create hematopoietic chimerism, the development of more-powerful T cell depleting antibodies, the identification of additional costimlulatory pathways as molecular targets and the identification of a role for suppressor cells in transplant tolerance.