Kidney Injury In Lupus Nephritis Research Articles

Knockdown of USF2 inhibits pyroptosis of podocytes and attenuates kidney injury in lupus nephritis.

As an essential factor in the prognosis of Systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to chronic kidney disease or even end-stage renal disease (ESRD). Proteinuria due to decreased glomerular filtration rate following podocyte injury is LN's most common clinical manifestation. Podocyte pyroptosis and related inflammatory factors in its process can promote lupus to involve kidney cells and worsen the occurrence and progression of LN, but its regulatory mechanism remains unknown. Accumulating evidence has shown that upstream stimulatory factor 2 (USF2) plays a vital role in the pathophysiology of kidney diseases. In this research, multiple experiments were performed to investigate the role of USF2 in the process of LN. USF2 was abnormally highly expressed in MRL/lpr mice kidney tissues. Renal function impairment and USF2 mRNA levels were positively correlated. Silencing of USF2 in MRL/lpr serum-stimulated cells significantly reduced serum-induced podocyte pyroptosis. USF2 enhanced NLRP3 expression at the transcriptional level. Silencing of USF2 in vivo attenuated kidney injury in MRL/lpr mice, which suggests that USF2 is important for LN development and occurrence.

Urinary ferritin creatinine ratio, a potential biomarker for lupus nephritis activity.

Ferritin has gained increasing attention in systemic lupus erythematosus (SLE).This study aimed to investigate the clinical significance of urinary ferritin/creatinine ratio in lupus nephritis (LN). Samples from 62 SLE patients (35 with LN and 27 without LN) and 62 healthy controls were evaluated. There were nine patients who underwent renal biopsy. The amount of urinary ferritin was measured by enzyme-linked immunosorbent assay (ELISA) and normalized by the amount of urinary creatinine to obtain the urinary ferritin/creatinine ratio (UFCR). The relationships between UFCR and inflammatory markers, laboratory indicators, as well as the activity index (AI), and chronicity index (CI) of KBs were also investigated by correlation analysis. UFCR level in severe active SLE patients was significantly higher than that in inactive SLE patients (P < 0.01) or healthy controls (P < 0.01). In addition, UFCR level was significantly increased in the patients with LN when compared with those without LN (P < 0.01).Correlation analysis showed that UFCR level is positively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (P < 0.01), 24h urine protein quantitation, serum creatinine, serum cystatin C, and GFR. The UFCR levels was significantly positively correlated with AI (P < 0.05) but not CI (P = 0.614) of KBs. UFCR level is a potential biomarker for the kidney injury in LN. Key Points • UFCR level is significantly increased in LN patients. • UFCR level is positively correlated with SLEDAI. • UFCR level is closely related to kidney injury indicators. • UFCR level is a potential biomarker for the kidney injury in LN.

OP0044 WHOLE KIDNEY TRANSCRIPTOMIC ANALYSIS OF FORMALIN-FIXED PARAFFIN-EMBEDDED LUPUS NEPHRITIS KIDNEY BIOPSY TISSUE USING THE NANOSTRING NCOUNTER PLATFORM

Background:There is an ongoing effort to elucidate the molecular pathways that are key to kidney injury in lupus nephritis (LN). One approach is to study the transcriptome utilising kidney tissue obtained during diagnostic renal biopsy [1]. In clinical practice the most common tissue that is surplus to diagnostic requirements is formalin-fixed paraffin-embedded (FFPE) tissue. However, due to RNA degradation, transcriptomic analysis has been sub-optimal and challenging using standard procedures. The NanoString technology platform has the advantage that reliable detection of transcripts can be achieved even with degraded RNA. In this study we explored the utility of NanoString technology in identifying transcripts in RNA isolated from archival FFPE kidney biopsy sections in a cohort of patients with LN.Objectives:To explore the utility of the NanoString platform in elucidating a renal transcriptomic signature in formalin-fixed paraffin-embedded Lupus Nephritis kidney biopsy tissue.Methods:We utilised well defined Class III (n=11); Class IV (n=22) and Class V (n=24) LN FFPE kidney biopsies from female patients attending the Imperial College Healthcare NHS Trust. We excluded biopsies with mixed lesions or chronic lesions (i.e. significant glomerular scarring). Kidney biopsies from patients with Thin Basement Membrane (TBM; n=14) disease were used as controls. Six 10 micron thick sections were obtained from each biopsy and RNA isolated using the Qiagen RNeasy FFPE Kit. 100 micrograms of RNA was used for the detection of transcripts. We used the NanoString PanCancer immune profiling panel (770 transcript probes) and an additional 30 custom designed probes, enabling us to detect 800 transcripts, including 40 reference genes. Transcript analysis was performed according to manufacturer’s instructions using the NanoString nSolver software. When analysing differential gene expression (DGE) we used Benjamini-Hochberg adjustment to account for multiple testing. The threshold for statistical significance was an adjusted P value of 0.05 (5% false discovery rate).Results:Transcriptomic data passing NanoString nSolver quality control metrics was obtained from all sections. Notably sections included biopsies up to 16 years old (range: 1-16 years). Our transcript panel contained several Type I interferon (IFN) responsive genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1). We detected a type I IFN signature using 8 IFN-responsive transcripts in 39 (68.4%) of the LN biopsies but in none of the TBM biopsies. This signature was present in Class III (n=9, 81.8%), Class IV (n=16, 72.7%) and Class V (n=14, 58.3%) LN samples. When we performed DGE analysis using TBM as the baseline we detected significantly increased expression across the classes (Class III = 202; Class IV = 357 and Class V = 237 differentially expressed transcripts, Figure 1).Conclusion:We have successfully identified transcriptomic signatures in RNA samples derived from a relatively large cohort of FFPE LN samples. Consistent with published reports we could detect a type I IFN signature in the LN kidney tissue [1]. Consistent with a recent study [1], we detected increased expression of OPN (osteopontin) and FN1 (fibronectin-1) in proliferative (Class III and IV) but not Class V LN. We are now performing clinical correlations to determine if the differentially expressed transcripts are clinically informative.

HIF1α blockade reduces kidney injury in lupus nephritis

HIF1α blockade reduces kidney injury in lupus nephritis

HIF1α blockade reduces kidney injury in lupus nephritis.

HIF1α blockade reduces kidney injury in lupus nephritis.

Low-Grade Proteinuria Does Not Exclude Significant Kidney Injury in Lupus Nephritis

Low-Grade Proteinuria Does Not Exclude Significant Kidney Injury in Lupus Nephritis

Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis

Complement plays an important role in the pathogenesis of lupus nephritis (LN). With the emergence of therapeutic complement inhibition, there is a need to identify patients in whom complement-driven inflammation is a major cause of kidney injury in LN. Clinical and histopathological data were obtained retrospectively from 57 biopsies with class III, IV, and V LN. Biopsies were stained for complement components C9, C5b-9, C3c, and C3d and for the macrophage marker CD68. C9 and C5b-9 staining were highly correlated (r = 0.92 in the capillary wall). C5b-9 staining was detected in the mesangium and/or capillary wall of both active and chronic proliferative LN in all but one biopsy and in the capillary wall of class V LN in all biopsies. C5b-9 staining intensity in the tubular basement membrane correlated with markers of tubulointerstitial damage, and more intense capillary wall C5b-9 staining was significantly associated with nonresponse to conventional treatment. Glomerular C5b-9 staining intensity did not differ between active and chronic disease; in contrast, C3c and CD68 staining were associated with active disease. Evaluation of serial biopsies and comparison of staining in active and chronic LN demonstrated that C5b-9 staining persisted for months to years. These results suggest that C5b-9 staining is almost always present in LN, resolves slowly, and is not a reliable marker of ongoing glomerular C5 activation. This limits the utility of C5b-9 staining to identify patients who are most likely to benefit from C5 inhibition.

Mechanisms of Kidney Injury in Lupus Nephritis - the Role of Anti-dsDNA Antibodies.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a breakdown of self-tolerance, production of auto-antibodies and immune-mediated injury, resulting in damage accrual in multiple organs. Kidney involvement, termed lupus nephritis, is a major cause of morbidity and mortality that affects over half of the SLE population during the course of disease. The etiology of lupus nephritis is multifactorial and remains to be fully elucidated. Accumulating evidence suggests that in addition to forming immune complexes and triggering complement activation, anti-dsDNA antibodies contribute to the pathogenesis of lupus nephritis through binding, either directly or indirectly, to cross-reactive antigens or chromatin materials, respectively, to resident renal cells and/or extracellular matrix components, thereby triggering downstream cellular activation and proliferation as well as inflammatory and fibrotic processes. Several cross-reactive antigens that mediate anti-dsDNA antibody binding have been identified, such as annexin II and alpha-actinin. This review discusses the mechanisms through which anti-dsDNA antibodies contribute to immunopathogenesis in lupus nephritis. Corticosteroids combined with either mycophenolic acid (MPA) or cyclophosphamide is the current standard of care immunosuppressive therapy for severe lupus nephritis. This review also discusses recent data showing distinct effects of MPA and cyclophosphamide on inflammatory and fibrotic processes in resident renal cells.

FRI0439 Urinary Collagen Fragments Are Reduced in Lupus Nephritis Subjects with Renal Dysfunction

BackgroundInterstitial fibrosis is a key component of chronic kidney injury in lupus nephritis (LN) and a critical determinant of the disease progression as it leads to the reduction of functioning...

MiR-150 Promotes Renal Fibrosis in Lupus Nephritis by Downregulating SOCS1

MicroRNAs (miRs) seem to mediate renal fibrosis in several renal diseases, with some miRs having profibrotic effects and others having opposing effects. Although differential expression of certain miRs has been described in lupus nephritis, it is unknown whether miRs contribute to fibrosis or could serve as biomarkers of specific histologic manifestations of lupus nephritis. Here, we compared miR expression in kidney biopsies from patients with lupus nephritis and identified miR-150 as the most differentially expressed miR in kidneys with high chronicity (chronicity index [CI] ≥ 4); miR-150 positively correlated with chronicity scores and the expression of profibrotic proteins. Overexpression of miR-150 significantly reduced expression of the antifibrotic protein suppressor of cytokine signaling 1 (SOCS1) and upregulated profibrotic proteins in both proximal tubular and mesangial cells. Directly targeting SOCS1 with a small interfering RNA produced similar results. Furthermore, TGF-β1 induced miR-150 expression, decreased SOCS1, and increased profibrotic proteins in proximal tubular cells and podocytes; a miR-150 inhibitor reversed these changes, suggesting that the profibrotic effects of TGF-β1 are, at least in part, mediated by miR-150. Consistent with these in vitro observations, biopsies with high miR-150 and high CI exhibited substantial expression of TGF-β1, reduced SOCS1, and an increase in profibrotic proteins. In summary, miR-150 is a promising quantitative renal biomarker of kidney injury in lupus nephritis. Our results suggest that miR-150 promotes renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1.