Ixazomib for Desensitization (IXADES) in Highly Sensitized Kidney Transplant Candidates: A Phase II Clinical Trial.

Key Points: Ixazomib treatment resulted in decreases in B-cell subsets and bone marrow lymphocytes. Ixazomib treatment resulted in modest decreases in certain anti-HLA antibody specificities. Ixazomib treatment was tolerated, with modest adverse events.

Dysregulation of the sensory and regulatory pathways controlling cellular iron metabolism in unilateral obstructive nephropathy.

Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in and mice, we asked if iron regulatory proteins (IRPs), the central regulators of cellular iron metabolism and suppressors of EPO production, contribute to the etiology of anemia in kidney failure.

B-cell Deficiency Attenuates Transplant Glomerulopathy in a Rat Model of Chronic Active Antibody-mediated Rejection.

Background: Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear.

Methods: We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG.

Short-term Immunopathological Changes Associated with Pulse Steroids/IVIG/Rituximab Therapy in Late Kidney Allograft Antibody Mediated Rejection.

Background: B-cell depletion is a common treatment of antibody-mediated rejection (ABMR). We sought to determine the specific immunopathologic effects of this therapeutic approach in kidney transplantation.

Methods: This was a prospective observational study of kidney transplant recipients diagnosed with late ABMR (>3 months after transplant).

Oxidized-ATP Attenuates Kidney Allograft Rejection By Inhibiting T-Cell, B-Cell, and Macrophage Activity.

Background: Extracellular ATP binds to purinergic receptors and promotes inflammatory responses. We tested whether oxidized ATP (oATP), P2X7 receptor antagonist can attenuate acute kidney allograft rejection.

Methods: Brown Norway kidney allografts were transplanted into Lewis recipients.

An in vitro model of antibody-mediated injury to glomerular endothelial cells: Upregulation of MHC class II and adhesion molecules.

Chronic active antibody-mediated rejection is a major cause of allograft failure in kidney transplantation. Microvascular inflammation and transplant glomerulopathy are defining pathologic features of chronic active antibody-mediated rejection and are associated with allograft failure. However, the mechanisms of leukocyte infiltration and glomerular endothelial cell injury remain unclear.

Desensitization and treatment with APRIL/BLyS blockade in rodent kidney transplant model.

Alloantibody represents a significant barrier in kidney transplant through the sensitization of patients prior to transplant through antibody mediated rejection (ABMR). APRIL BLyS are critical survival factors for mature B lymphocytes plasma cells, the primary source of alloantibody. We examined the effect of APRIL/BLyS blockade via TACI-Ig (Transmembrane activator calcium modulator cyclophilin lig interactor-Immunoglobulin) in a preclinical rodent model as treatment for both desensitization ABMR.

Autologous Mesenchymal Stromal Cells Prevent Transfusion-elicited Sensitization and Upregulate Transitional and Regulatory B Cells.

Background: We hypothesized that immunomodulatory properties of mesenchymal stromal cells (MSC) may be considered for desensitization.

Methods: Autologous or allogeneic bone marrow derived MSC were infused tail vein at 0.5 M (0.

Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages in a Rat Kidney Transplant Model.

Background: Increasingly, it is being appreciated that B cells have broad roles beyond the humoral response and are able to contribute to and regulate inflammation. The specific role of B cells in the pathogenesis of early allograft inflammation remains unclear.

Methods: To address this question, we generated B cell-deficient (B) Lewis rats via clustered regularly interspaced short palindromic repeats (CRISPR) technology.

Evaluation of renal metabolic response to partial ureteral obstruction with hyperpolarized C MRI.

Hyperpolarized C magnetic resonance imaging (MRI) may be used to non-invasively image the transport and chemical conversion of C-labeled compounds in vivo. In this study, we utilize hyperpolarized C MRI to evaluate metabolic markers in the kidneys longitudinally in a mouse model of partial unilateral ureteral obstruction (pUUO). Partial obstruction was surgically induced in the left ureter of nine adult mice, leaving the right ureter as a control.

Nox2 and Cyclosporine-Induced Renal Hypoxia.

Background: We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia.

Methods: We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity.

Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody-Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients.

Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use.

Calcineurin Inhibitor Minimization With Ixazomib, an Investigational Proteasome Inhibitor, for the Prevention of Antibody Mediated Rejection in a Preclinical Model.

Background: There is a need for new immunosuppression strategies to minimize calcineurin inhibitor (CNI) toxicity while effectively preventing antibody-mediated rejection (AMR).

Methods: We tested the efficacy of an investigational proteasome inhibitor, ixazomib, alone and in a CNI minimization strategy in a rat kidney transplant model of transfusion-elicited acute AMR. Nonsensitized (naïve) and sensitized allograft recipients were randomized into 4 treatment groups (8 groups total, n = 3 to 6 in each group) and treated for 1 week.

Tubular expression of heat-shock protein 27 inhibits fibrogenesis in obstructive nephropathy.

Morphological changes that occur during kidney injury involve actin skeleton remodeling. Here we tested whether heat-shock protein 27 (HSP27), a small stress response protein involved in cytoskeletal remodeling, protects the kidney from tubulointerstitial fibrosis in obstructive nephropathy. Tubular cell HSP27 immunostaining was significantly increased in human kidneys with ureteropelvic junction obstruction, supporting the clinical relevance of our studies.

Contributing factors to complications and surgical success in mouse kidney transplantation.

Purpose: Mouse kidney transplantation is a challenging technique for novice microsurgeons. Factors that affect transplant outcomes for a clinical surgeon starting microsurgery have not yet been investigated.

Materials And Methods: 110 consecutive mouse kidney transplants were performed over a 9-month period.

Serum HSP27 is associated with medullary perfusion in kidney allografts.

Background: Heat shock protein 27 (HSP27) is a small HSP up-regulated in response to stress in the kidney. The relationship between HSP27 and intrarenal oxygenation in patients with native and transplant kidney disease is unknown.

Methods: We compared HSP27 levels, intrarenal oxygenation measured by blood oxygen-level dependent (BOLD) imaging using R(2)* values, and perfusion determined by arterial spin labeling (ASL) magnetic resonance imaging (MRI), between patients with native and transplant kidney disease (n=28).

Mycophenolic acid may delay allograft fibrosis by inhibiting transforming growth factor-beta1-induced activation of Nox-2 through the nuclear factor-kappaB pathway.

Background: We evaluated the role of renal tubular Nox-2 in the pathogenesis of epithelial-to-mesenchymal transition (EMT) in kidney allografts.

Methods: We examined this question in the human kidney allografts with interstitial fibrosis and tubular atrophy not otherwise specified (IFTANOS), in the Fisher to Lewis rat transplant model, and in the in vitro model of transforming growth factor-beta1-induced EMT in normal rat kidney epithelial cells (NRK52E).

Results: We first demonstrated that Nox-2 and alpha-smooth muscle actin (SMA) were increased in renal tubules from kidney transplant recipients on calcineurin inhibitors, mycophenolic acid (MPA), and prednisone with IFTANOS, suggestive of EMT (n=6).

The Pin 1 inhibitor juglone attenuates kidney fibrogenesis via Pin 1-independent mechanisms in the unilateral ureteral occlusion model.

Background: Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E).

HSP27 is involved in the pathogenesis of kidney tubulointerstitial fibrosis.

We hypothesized that heat shock protein 27 (HSP27), a small heat shock protein with actin-remodeling properties, is involved in the pathogenesis of kidney tubulointerstitial fibrosis. We first examined its expression in the rat unilateral ureteral obstruction (UUO) model of kidney fibrosis and epithelial-to-mesenchymal transition (EMT). Immunoblot analyses showed that UUO resulted in significant upregulation of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), total and phosphorylated HSP27, and phosphorylated p38MAPK.

BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction.

Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) uses deoxyhemoglobin as an endogenous contrast agent for the noninvasive assessment of tissue oxygen bioavailability. We hypothesized that intrarenal oxygenation was impaired in patients with chronic allograft nephropathy (CAN). Ten kidney-transplant recipients with CAN and nine healthy volunteers underwent BOLD-MRI.

Heat shock protein 27 in chronic allograft nephropathy: a local stress response.

Background: Heat shock protein (HSP) 27 plays a cytoprotective role through its antioxidant, antiapoptotic, and actin-stabilizing properties during cell stress. The authors hypothesized that HSP27 is involved in chronic allograft nephropathy (CAN), a chronic state of inflammation and stress.

Methods: The authors used the Fisher 344-to-Lewis model of CAN.

Enteral feeding preserves gut Th-2 cytokines despite mucosal cellular adhesion molecule-1 blockade.

Background: Parenteral nutrition (PN) decreases gut-associated lymphoid tissue (GALT), the intestinal IgA stimulating cytokines IL-4 and IL-10 in gut homogenates, intestinal IgA levels and the expression of Peyer patch (PP) mucosal cellular adhesion molecule-1 (MAdCAM-1), an adhesion molecule found on the high endothelial venules of PP and other tissues. IL-4 in PP stimulates MAdCAM expression in vitro. MAdCAM-1 blockade with MECA-367 reduces GALT cell populations to PN levels but maintains intestinal IgA levels if the animals are chow fed.

Epithelial-to-mesenchymal transition and oxidative stress in chronic allograft nephropathy.

Epithelial-to-mesenchymal transition (EMT) and oxidative stress contribute to kidney tissue fibrosis in various forms of native kidney disease. However, their role in chronic allograft nephropathy (CAN) remains somewhat uncertain. To address this question, kidney transplants were performed in 3-month-old rats, using the Fisher 344 --> Lewis model of CAN.

l-selectin and alpha4beta7 integrin, but not ICAM-1, regulate lymphocyte distribution in gut-associated lymphoid tissue of mice.

Background: Adhesion molecules on lymphocytes ( l -selectin and alpha4beta7) and endothelium (MAdCAM-1 and ICAM-1) direct lymphocytes into the gut-associated lymphoid tissue (GALT) of mice. Parenteral nutrition and MAdCAM-1 blockade reduce GALT cell mass. This study examined the effects on GALT cell mass of blockade of l -selectin, alpha4beta7, and ICAM-1 with saturating doses of monoclonal antibodies.