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Lupus nephritis: the evolving role of novel therapeutics.

ABSTRACT: Immune complex accumulation in the kidney is the hallmark of lupus nephritis and triggers a series of events that result in kidney inflammation and injury. Cytotoxic agents and corticosteroids are standard of care for lupus nephritis treatment, but are associated with considerable morbidity and suboptimal outcomes. Recently, there has been interest in using novel biologic agents and small molecules to treat lupus nephritis. These therapies can be broadly categorized as anti-inflammatory (laquinamod, anti-tumor necrosis factor-like weak inducer of apotosis, anti-C5, and retinoids), antiautoimmunity (anti-CD20, anti-interferon ?, and costimulatory blockers), or both (anti-interleukin 6 and proteasome inhibitors). Recent lupus nephritis clinical trials applied biologics or small molecules of any category to induction treatment, seeking short-term end points of complete renal response. These trials in general have not succeeded. When lupus nephritis comes to clinical attention during the inflammatory stage of the disease, the autoimmune stage leading to kidney inflammation will have been active for some time. The optimal approach for using novel therapies may be to initially target kidney inflammation to preserve renal parenchyma, followed by suppression of autoimmunity. In this review, we discuss novel lupus nephritis therapies and how they fit into a combinatorial treatment strategy based on the pathogenic stage.

SUBMITTER: Rovin BH

PROVIDER: S-EPMC4159074 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Lupus nephritis: the evolving role of novel therapeutics.

Rovin Brad H BH Parikh Samir V SV

American journal of kidney diseases : the official journal of the National Kidney Foundation 20140107 4

Immune complex accumulation in the kidney is the hallmark of lupus nephritis and triggers a series of events that result in kidney inflammation and injury. Cytotoxic agents and corticosteroids are standard of care for lupus nephritis treatment, but are associated with considerable morbidity and suboptimal outcomes. Recently, there has been interest in using novel biologic agents and small molecules to treat lupus nephritis. These therapies can be broadly categorized as anti-inflammatory (laquina ...[more]

PMID: 24411715

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Project description:Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.

Project description:BackgroundThe purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x NZW) F1 murine lupus model.MethodsFemale NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes.ResultsTreatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 microg/ml versus 1,036 microg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 microg/ml versus 614 microg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-gamma, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand.ConclusionAldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis.

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Lupus nephritis: the evolving role of novel therapeutics.

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Lupus nephritis: the evolving role of novel therapeutics.

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