Abstract:
:IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA+, IgM+, and IgG+ B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Myette JR,Kano T,Suzuki H,Sloan SE,Szretter KJ,Ramakrishnan B,Adari H,Deotale KD,Engler F,Shriver Z,Wollacott AM,Suzuki Y,Pereira BJGdoi
10.1016/j.kint.2019.01.031subject
Has Abstractpub_date
2019-07-01 00:00:00pages
104-116issue
1eissn
0085-2538issn
1523-1755pii
S0085-2538(19)30174-7journal_volume
96pub_type
杂志文章abstract:BACKGROUND:1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D3, is a potent immunomodulatory agent on several cell types such as monocytes and mesangial cells. Recruitment of inflammatory cells, as well as stimulation of resident cells and mesangial matrix accumulation are key features of various expe...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.00775.x
更新日期:2001-07-01 00:00:00
abstract:BACKGROUND:Guidelines for treating anemia in dialysis patients accept, as high-end range of serum ferritin useful to optimize erythropoietin therapy, values high as 500 to 900 microg/L, on the hypothesis that ferritin might be not representative of iron overload. METHODS:A superconducting quantum interference device (...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.00480.x
更新日期:2004-03-01 00:00:00
abstract::In April 2006, Japan's health insurance system instituted a bundling policy that included recombinant human erythropoietin (rHuEPO) in outpatient hemodialysis therapy. To evaluate outcomes of this, we analyzed a prospective cohort of hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study, in ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2010.382
更新日期:2011-02-01 00:00:00
abstract::Cultures of human proximal tubule cells were exposed to elevated concentrations of glucose and dome formation was assessed over a 22 day period of growth. Cultures grown on 5.5 mM glucose formed five domes per microscopic field while those exposed to elevated glucose concentrations (11.0 mM to 27.5 mM) formed only two...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1989.5
更新日期:1989-01-01 00:00:00
abstract::Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducibl...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2017.06.015
更新日期:2017-12-01 00:00:00
abstract::The treatment of hyperphosphatemia remains challenging in patients receiving hemodialysis. This Phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport (NaPi-2b, PiT-1, PiT-2) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cro...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2020.09.035
更新日期:2020-10-30 00:00:00
abstract::Problems with vascular access are an important cause of morbidity and mortality in hemodialysis patients. We established a rodent model of arteriovenous fistula by anastomosing the end of a lateral vein to the side of the ventral artery of the rat tail. All operations were technically successful and in all animals the...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2008.207
更新日期:2008-08-01 00:00:00
abstract::In the present study we assessed the prevalence of thin glomerular basement membrane (TGBM) in a large group of native kidney biopsies done for evaluation of renal disease. TGBM was present in 54 of 1078 biopsies (5%). In 12 of 54 biopsies (24%), TGBM was the only abnormality present. In the remaining biopsies TGBM wa...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1994.296
更新日期:1994-08-01 00:00:00
abstract::The purpose of these studies was to clarify the basis of the relationship between the urine bicarbonate concentration and the urine minus blood PCO2 difference in alkaline urine (U-B PCO2) and hence shed light on factors that influence hydrogen ion secretion in the collecting duct in vivo. The U-B PCO2 was used to mon...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1981.187
更新日期:1981-11-01 00:00:00
abstract::Starting from observations in intact cells and extending to studies in native membranes and solubilized membrane proteins, a significant body of evidence has been accumulated to indicate that some of the short-term regulatory influences on the Na+-H+ exchanger in the apical membrane of the proximal convoluted tubule a...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.1989.226
更新日期:1989-10-01 00:00:00
abstract::Crim1 is a cell-surface, transmembrane protein that binds to a variety of cystine knot-containing growth factors, including vascular endothelial growth factor A. In the developing renal glomerulus, Crim1 acts to tether vascular endothelial growth factor A to the podocyte cell surface, thus regulating its release to gl...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2009.345
更新日期:2009-12-01 00:00:00
abstract::This very brief summary of the various possible contributions of PG to normal and abnormal renal function should highlight the problem of assigning a specific role to PG in overall renal physiology and pathophysiology. PG produced in specific segments of the nephron will affect specific functions occurring in this seg...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.1986.13
更新日期:1986-01-01 00:00:00
abstract::How much dialysis is required for optimal well-being and long-term survival? The Frequent Hemodialysis Network completed two prospective trials examining the effect of more frequent, short hours and, now, of nocturnal hemodialysis compared with standard thrice-weekly treatments. Whereas the short-hours trial reported ...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2011.267
更新日期:2011-11-01 00:00:00
abstract::EDTA (calcium disodium edetate) lead mobilization and x-ray fluorescence (XRF) finger bone lead tests were done in 42 patients with chronic renal failure and without persisting lead intoxication. Nineteen of 23 patients with gout and 8 of 19 without gout had positive EDTA lead mobilization tests. Those patients with g...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1984.175
更新日期:1984-09-01 00:00:00
abstract::Angiotensinase A (aminopeptidase A; ATA) is an angiotensin II splitting exopeptidase, which is localized in endothelial and epithelial cells of the glomerular tuft. In order to investigate the influence of a reduction in renal mass on enzyme activity, ATA activity was measured in isolated rat glomeruli five and 14 wee...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1990.283
更新日期:1990-11-01 00:00:00
abstract::Eight patients with chronic renal failure (GFR 18.8 +/- 2.7 ml/min) were randomized to a crossover comparison of a very low protein diet (VLPD) containing 0.28 g protein and 35 kcal per kg per day, plus an isosmolar mixture of either ketoacids (KA) or essential amino acids (EAA). Subjects initiated the diets 14 days b...
journal_title:Kidney international
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1038/ki.1994.157
更新日期:1994-04-01 00:00:00
abstract::In his hypothesis of the evolution of renal functions Homer Smith proposed that the formation of glomerular nephron and body armor had been adequate for the appearance of primitive vertebrates in fresh water and that the adaptation of homoiotherms to terrestrial life was accompanied by the appearance of the loop of He...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.1996.220
更新日期:1996-06-01 00:00:00
abstract:BACKGROUND:To study the molecular mechanism responsible for cadmium-induced Fanconi syndrome, an in vitro mouse model has been used. We have previously shown that exposure of primary cultures of kidney cortical cells to micromolar concentrations of cadmium inhibited uptake of the glucose analog, [14C] methyl alpha-d-gl...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00201.x
更新日期:2003-10-01 00:00:00
abstract::In this study, we have evaluated 50 children (30 girls and 20 boys; mean age, 10.1 years) with a variety of renal diseases in whom renal biopsy specimens showed crescents in greater than or equal to 50% of glomeruli. Initial clinical features included edema in 61%; hypertension in 51%; gross hematuria in 73%; 3 to 4+ ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1985.30
更新日期:1985-02-01 00:00:00
abstract::Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1016/j.kint.2019.02.009
更新日期:2019-08-01 00:00:00
abstract:BACKGROUND:The induction of stress response (heat shock) proteins (HSPs) is a highly conserved response that protects many cell types from diverse physiological and environmental stressors. We tested the hypothesis that the induction of HSPs is protective in experimental renal ischemia/reperfusion injury. METHODS:The ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.0590051798.x
更新日期:2001-05-01 00:00:00
abstract::We used the perfused hemicorpus preparation to measure individual rates of protein synthesis and degradation. Using fed animals, perfused either with or without insulin, muscle protein synthesis and hemicorpus protein degradation rates were similar, but myofibrillar protein degradation was clearly increased in the ure...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1986.119
更新日期:1986-06-01 00:00:00
abstract:BACKGROUND:The development of strategies to enhance the survival of transplanted organs and to potentially lower or even discontinue immunosuppressive therapy would represent a significant advancement in post-transplant patient care. METHODS:We studied the effect of pretransplant infusion of donor leukocytes alone or ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00631.x
更新日期:1999-09-01 00:00:00
abstract::We have described a simple technique for the measurement of picomoles or nanomoles of ammonium. Samples can be easily processed on the day of an experiment. analysis of 14C-glutamate can be done at a later date by an accurate sensitive and reliable method. We can readily process 50 samples per day. The sensitivity can...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1981.10
更新日期:1981-01-01 00:00:00
abstract:BACKGROUND:An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. As a defense mechanism, cells express ER stress inducible chaperons, such as oxygen-regulated proteins 150 (ORP150) and glucose-regulated proteins (GRPs). While ER stress is important in various diseas...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2005.00736.x
更新日期:2005-12-01 00:00:00
abstract::Monoclonal antibodies (mAb) reactive against complement components involved in the classical activation pathway were applied in an indirect immunoperoxidase technique for the histological study of normal and diseased human renal tissues. Prominent staining with antibodies against the C4d fragment was seen in all glome...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1989.302
更新日期:1989-12-01 00:00:00
abstract::Urinary exosomes have received considerable attention as a potential biomarker source for the diagnosis of renal diseases. Notwithstanding, their use in protein biomarker research is hampered by the lack of efficient methods for vesicle isolation, lysis, and protein quantification. Here we report an improved ultracent...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2012.25
更新日期:2012-06-01 00:00:00
abstract:BACKGROUND:Carriers of autosomal-recessive and X-linked Alport syndrome often have a thinned glomerular basement membrane (GBM) and have mutations in the COL4A3/COL4A4 and COL4A5 genes respectively. Recently, we have shown that many individuals with thin basement membrane disease (TBMD) are also from families where hem...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.060002480.x
更新日期:2001-08-01 00:00:00
abstract:BACKGROUND:Transforming growth factor-beta (TGF-beta) is known to play an important role in the pathophysiology of renal tubular disease. Researchers have recently identified a novel mitogen-activated protein kinase kinase kinase (MAPKKK), TAK (TGF-beta activated kinase)1, which stimulates the MKK3/6-p38K pathway. The ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00665.x
更新日期:1999-10-01 00:00:00
abstract:BACKGROUND:Disorders that manifest hypokalemic metabolic alkalosis, such as Bartter's syndrome and Gitelman's syndrome, are caused by the malfunction of renal tubular electrolyte transporters. Bartter's syndrome may be linked to dysfunction of Na-K-2Cl cotransporter (NKCC2), renal outer medullary K channel (ROMK), or C...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00163.x
更新日期:2003-09-01 00:00:00