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2.
Adv Chronic Kidney Dis ; 26(5): 338-350, 2019 09.
Article in English | MEDLINE | ID: mdl-31733718

ABSTRACT

The majority of patients with systemic lupus erythematosus develop lupus nephritis (LN) which significantly contributes to increased risks of hospitalizations, ESRD, and death. Unfortunately, treatments for LN have not changed over the past 15 years. Despite continued efforts to elucidate the pathogenesis of LN, no new drugs have yet replaced the standard-of-care regimens of cyclophosphamide or mycophenolate mofetil plus high-dose corticosteroids. The significant limitations of standard-of-care are low complete response rates, risk of flares, and ongoing inflammation in the kidney leading to progressive renal dysfunction. Repeat and prolonged treatments are often needed to control disease, leading to a high level of severe side effects. The development of targeted drugs with better efficacy and safety are desperately needed. The rationale for targeting key immunologic pathways in LN continues to be strongly supported by basic and translational research and has generated the hope and excitement of testing these therapies in human LN. This review provides an overview of biologics studied to date in clinical trials of LN, discusses the potential reasons for their failure, and addresses the challenges moving forward.


Subject(s)
Biological Products , Lupus Nephritis , Biological Products/immunology , Biological Products/pharmacology , Clinical Trials as Topic , Humans , Lupus Nephritis/immunology , Lupus Nephritis/physiopathology , Lupus Nephritis/therapy , Medication Therapy Management , Therapies, Investigational/methods , Treatment Outcome
3.
J Autoimmun ; 93: 37-44, 2018 09.
Article in English | MEDLINE | ID: mdl-29895432

ABSTRACT

Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally. GN was induced with anti-GBM sera. Renal disease development was followed by serial blood urine nitrogen (BUN) determinations and by evaluation of kidney histology at the time of sacrifice. Axl-associated signaling proteins were analyzed by Western blotting and inflammatory cytokine secretion was analyzed by Proteome array. SiRNA data revealed the transcription factor Sp1 to be an important regulator of mesangial Axl expression. Anti-GBM serum induced severe nephritis with azotemia, protein casts and necrotic cell death. R428 treatment diminished renal Axl expression and improved kidney function, with significantly decreased BUN and glomerular proliferation. R428 treatment inhibited Axl and significantly decreased Akt phosphorylation and renal inflammatory cytokine and chemokine expression; similar effects were observed in anti-GBM antiserum-treated Axl-KO mice. These studies support a role for Axl inhibition in glomerulonephritis.


Subject(s)
Benzocycloheptenes/pharmacology , Immunologic Factors/pharmacology , Lupus Nephritis/drug therapy , Mesangial Cells/drug effects , Molecular Targeted Therapy/methods , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Triazoles/pharmacology , Administration, Oral , Animals , Antibodies/administration & dosage , Cell Line, Transformed , Drug Administration Schedule , Gene Expression Regulation , Glomerular Basement Membrane/drug effects , Glomerular Basement Membrane/immunology , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/immunology , Lupus Nephritis/chemically induced , Lupus Nephritis/genetics , Lupus Nephritis/immunology , Mesangial Cells/immunology , Mesangial Cells/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/immunology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/immunology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/immunology , Signal Transduction , Sp1 Transcription Factor/antagonists & inhibitors , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/immunology , Sp3 Transcription Factor/antagonists & inhibitors , Sp3 Transcription Factor/genetics , Sp3 Transcription Factor/immunology , Axl Receptor Tyrosine Kinase
4.
Clin Immunol ; 158(2): 231-41, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25814173

ABSTRACT

Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell-bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD.


Subject(s)
Gene Expression Regulation/physiology , Intercellular Signaling Peptides and Proteins/metabolism , Protein S/metabolism , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Renal Insufficiency, Chronic/metabolism , Humans , Inflammation , Intercellular Signaling Peptides and Proteins/genetics , Monocytes/metabolism , Protein S/genetics , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Renal Insufficiency, Chronic/immunology , c-Mer Tyrosine Kinase , Axl Receptor Tyrosine Kinase
5.
Front Biosci (Landmark Ed) ; 20(4): 784-95, 2015 01 01.
Article in English | MEDLINE | ID: mdl-25553479

ABSTRACT

Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes to the morbidity and mortality of chronic kidney disease (CKD) patients receiving hemodialysis. We hypothesized that the uremic conditions associated with CKD promote a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to neointimal hyperplasia. We analyzed the effect of culturing human VSMC with uremic serum. Expression of VSMC contractile marker genes was reduced 50-80% in cells exposed to uremic serum and the decreased expression was accompanied by changes in histone marks. There was an increase in proliferation in cells exposed to uremic conditions, with no change in the levels of apoptosis. Interestingly, we found that uremic serum inhibited PDGF-induced migration of VSMC. Histomorphometric analysis revealed venous neointimal hyperplasia in veins from chronic kidney disease (CKD) patients prior to any surgical manipulation as compared to veins from patients with no kidney disease. We conclude that uremia associated with CKD alters VSMC phenotype in vitro and contributes to neointimal hyperplasia formation in vivo contributing to the pathogenesis of vascular access dysfunction in CKD patients.


Subject(s)
Kidney Failure, Chronic/pathology , Muscle, Smooth, Vascular/pathology , Apoptosis/drug effects , Biomarkers , Cell Movement , Cell Proliferation , Cells, Cultured , Humans , Real-Time Polymerase Chain Reaction , Staurosporine/pharmacology , Uremia/blood , Vascular Access Devices
6.
Clin Transpl ; : 143-51, 2014.
Article in English | MEDLINE | ID: mdl-26281139

ABSTRACT

Kidney transplantation (KT) recipients with donor specific HLA antibodies (DSA) encounter higher rates of acute rejection and inferior allograft survival. We report our single center experience with prospective DSA monitoring and provide details of treatments utilized to overcome the potential impact of DSA in a cohort of predominantly African American adult KT recipients. Seventy-five flow crossmatch negative KT recipients underwent periodic screening for DSA utilizing the single antigen bead assay at 3, 6, 9, and 12 months post-transplant. Allograft biopsies were performed in the presence of DSA and/or evidence of graft dysfunction. The incidence of DSA was 23%, with a predominance of Class II antibodies. The rate of rejection was 6 times higher in DSA positive KT recipients compared to DSA negative patients (41% versus 7%, p = 0.004). In the DSA positive group, rejections occurred exclusively in the presence of de novo DSA and were predominantly antibody-mediated or mixed rejections. Despite a higher incidence of rejection in KT recipients with DSA, there were no significant differences in serum creatinine, graft survival, and patient survival between DSA positive and negative recipients at median follow-up of 18 months. DSA positive patients had significantly higher proteinuria compared to DSA negative recipients at 6 months, 1 year, and 3 years of follow-up. In conclusion, the detrimental effects of DSA on allograft function could be mitigated by serial DSA surveillance, protocol biopsies, and alterations in immunosuppression. With these measures, the improvement in graft survival in DSA positive KT recipients, at least at short-term, is encouraging.


Subject(s)
HLA Antigens/immunology , Histocompatibility , Isoantibodies/blood , Kidney Transplantation , Monitoring, Immunologic , Adult , Black or African American , Aged , Biomarkers/blood , Biopsy , Female , Graft Rejection/drug therapy , Graft Rejection/ethnology , Graft Rejection/immunology , Graft Survival/drug effects , Histocompatibility Testing , Humans , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/adverse effects , Kidney Transplantation/mortality , Male , Middle Aged , Philadelphia , Predictive Value of Tests , Retrospective Studies , Risk Factors , Survival Analysis , Time Factors , Treatment Outcome
7.
Nephrol Dial Transplant ; 27(11): 4166-72, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22907951

ABSTRACT

BACKGROUND: The TAM receptors (tyro3, axl and mer) and their ligands (vitamin K-dependent proteins-Gas6 and Protein S) are crucial modulators of inflammation, which may be relevant in chronic kidney disease (CKD). Gas6 and axl have multiple roles in mediating vascular atherosclerosis and injury, thrombosis and inflammation, yet nothing is known about the Gas6-axl pathway in humans with CKD. Given the prevalence of chronic inflammation and vascular disease in this population, we measured TAM ligands in patients with various levels of renal function. METHODS: Gas6 and protein S were quantified in the plasma by ELISA in three patient groups: end-stage renal disease on chronic hemodialysis (HD), CKD and normal controls. RESULTS: Significantly increased levels of Gas6 and protein S were found in CKD patients compared with normal controls (P < 0.01 and <0.001, respectively). In HD patients, Gas6 levels were elevated compared with controls (P < 0.001) and positively associated with low albumin (r = 0.33; P = 0.01), dialysis vintage (r = 0.36; P = 0.008) and IV iron administration (r = 0.33; P = 0.01). The levels of Gas6 rose with CKD stage and were inversely associated with estimated GFR (P < 0.0001). CONCLUSIONS: Dysregulation of circulating Gas6 is associated with renal disease and inversely proportional to renal function. Low albumin and higher IV iron administration were associated with higher Gas6 levels, suggesting a possible connection between inflammation and oxidative stress mediated by iron. Protein S levels were also elevated in CKD patients, but the relevance of this finding needs to be further investigated.


Subject(s)
Intercellular Signaling Peptides and Proteins/blood , Kidney Failure, Chronic/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Protein Precursors/blood , Protein S/analysis , Prothrombin , Renal Dialysis
8.
Biomark Med ; 2(6): 603-12, 2008 Dec.
Article in English | MEDLINE | ID: mdl-20477449

ABSTRACT

Identifying surrogate markers of renal allograft outcome and biomarkers of acute and chronic graft injury is a critical issue for the transplant community. Measurement of serum creatinine and biopsy remain the current gold standards for the evaluation of renal allografts. These tests have significant limitations in predicting which patients are destined for immune tolerance or immune-mediated graft loss, and aiding in the management of long-term immunosuppression. The goal of biomarkers is to diagnose rejection early, determine prognosis and tailor immunosuppressive therapy in a noninvasive, cost-effective manner. Biomarker research has focused on primary areas of kidney injury, the tubules and the cells that infiltrate them. This article reviews biomarkers currently under investigation in the setting of renal allograft transplantation.

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