Decreased renal expression of vascular endothelial growth factor in lupus nephritis is associated with worse prognosis (original) (raw)

Urinary epidermal growth factor as a marker for lupus nephritis: clinical, laboratory, and histopathological study

Egyptian Rheumatology and Rehabilitation

Background Lupus nephritis can be seen in up to 60% of all SLE patients with 10–15% of nephritis patients progressing to end-stage renal disease; late diagnosis of lupus nephritis is correlated with a higher frequency of renal insufficiency. The study aim is determination of the value of urinary human epidermal growth factor (urinary EGF) as an early biomarker of lupus nephritis in SLE patients and its relevance to disease activity and renal histopathology. Results The study included 58 SLE patients and 30 healthy controls; a significant difference was noticed between SLE and controls in urinary protein, creatinine, protein/creatinine ratio, and urinary EGF. The mean level of urinary EGF was less in classes IV and V renal nephritis than in classes I, II, and III. There is a significant difference in urinary EGF (33±29, 27±16, P = 0.04) between class II and class III lupus nephritis, with no significant differences in urinary protein, creatinine, protein/creatinine ratio, and SLEDAI....

Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus and lupus nephritis

Lupus, 2019

Background: Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy. Methods: A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1a (MIP-1a) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas' Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay. Results: The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups (p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF (p ¼ 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores (p < 0.001), while serum VEGF correlated weakly with SLEDAI (p ¼ 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio. Conclusion: These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN. Lupus (2019) 0, 1-9.

Glomerular Expression of Some Profibrotic Factors in Progressive Childhood Lupus Nephritis

JCR: Journal of Clinical Rheumatology, 2019

Background Lupus nephritis (LN) is a major cause of mortality and morbidity in both adult and pediatric patients. However, studies regarding pathogenesis and predictors of renal outcomes in childhood LN are limited. Transforming growth factor-β1 (TGF-β1) and Connective tissue growth factor (CTGF) have an important role in proliferative and fibrotic changes in many renal diseases. We aim to evaluate the role of such two profibrotic factors in the progression of childhood onset LN and to detect if their glomerular expression could represent an early predictor of future deterioration of renal function. Methods 34 children with new onset of LN were included. Glomerular expressions of TGF-β1 and CTGF were evaluated by immunohistochemical analysis in the renal tissue of such patients and in control tissue. GFR was estimated at time of renal biopsy at the onset of LN and after 2 years of follow-up. Rate of GFR change (ΔGFR) was calculated and used as indicative of degree of renal disease p...

Relationship of Intrarenal Gene Expression and the Histological Class of Lupus Nephritis -- A Study on Repeat Renal Biopsy

The Journal of Rheumatology, 2012

Objective.To study the role of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/Fn14 and the interferon-inducible protein (IP-10)/CXCR3 axis in lupus nephritis (LN).Methods.We studied 113 patients with LN who had had repeat renal biopsies. Glomerular and tubulointerstitial messenger RNA expression of TWEAK, Fn14, IP-10, and CXCR3 were quantified.Results.Glomerular Fn14 expression decreased when changed from proliferative or mixed nephritis to membranous nephropathy (p = 0.016), and increased when changed from membranous to proliferative or mixed nephritis (p = 0.0006). On the other hand, tubulointerstitial TWEAK expression decreased when changed from proliferative or mixed nephritis to membranous nephropathy (p = 0.004), and increased when changed from membranous nephropathy to proliferative nephritis (p = 0.010). Tubulointerstitial IP-10 expression decreased when changed from proliferative or mixed nephritis to membranous nephropathy (p < 0.0001). Histological ...

Analysis of urinary TGF-β1, MCP-1, NGAL, and IL-17 as biomarkers for lupus nephritis

Pathophysiology, 2015

This study was aimed to determine the diagnostic performance of transforming growth factor beta 1 (uTGF-␤1), monocyte chemoattractant protein-1 (uMCP-1), neutrophil gelatinase-associated lipocalin (uNGAL) and interleukin 17 (uIL-17) in LN. Seventy participants were studied, categorized into three groups: 38 severe LN (class III-IV LN patients); 12 mild LN (class I-II LN patients); and 20 control (healthy volunteers). Diagnosis of SLE was based on the 1997 ARA criteria. Class NL classified according to ISN/RPS 2004. uTGF-␤1, uMCP-1, uNGAL, uIL-17 levels were determined by ELISA, using spot urine. The level of uMCP-1 and uNGAL was significantly greater in severe or mild LN compared with control group (P < 0.05). The level of uTGF-␤1 and uIL-17 was significantly higher in severe LN than that controls group (P < 0.05). The AUC of uTGF-␤1, uMCP-1, uNGAL, uIL-17 was 66.50%; 86.90%; 87.50%; 71.70%, with the cutoff value of 27.13 pg/ml; 1.54 pg/ml; 446.30 pg/ml; 36.62 pg/ml. Only uNGAL showed a significant correlation with the activity (P = 0.016; r = 0.389) and chronicity indices (P = 0.018; r = 0.381). This study showed that uTGF-␤1, uMCP-1, uNGAL, uIL-17 levels were increased in LN. The AUC values for each biomarker are indicating a good diagnostic value. Urinary NGAL had the best sensitivity and specificity followed by uMCP-1, uIL-17 and uTGF-␤1. For combinations of two biomarkers, the best sensitivity and specificity were displayed by the combination of uTGF-␤1 & u-NGAL, followed by uMCP-1 & uNGAL.

Predicting treatment response and clinicopathological findings in lupus nephritis with urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratios

PLOS ONE, 2022

Introduction There is a need for sensitive and specific biomarkers to predict kidney damage and therapeutic response in lupus nephritis (LN). Monocyte chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF) are cytokines with divergent roles. EGF or EGF/MCP1 ratio have been shown to correlate with prognosis in primary glomerulonephritis, but there is limited information in lupus nephritis (LN). This study evaluated the roles of MCP-1, EGF or their ratio as biomarkers of histopathology and response to treatment in LN. Methods This was a cross-sectional and observational study. Baseline urine MCP-1 and EGF levels in systemic lupus erythematosus (SLE) patients and controls (total n = 101) were compared, and levels were correlated with clinicopathological findings and subsequent response to treatment. Results MCP-1 was higher in active LN (n = 69) compared to other SLE groups and controls, whereas EGF was not different. MCP-1 correlated with disease activity (proteinuria, re...

Molecular Markers of Injury in Kidney Biopsy Specimens of Patients with Lupus Nephritis

The Journal of Molecular Diagnostics, 2011

techniques offer new approaches to study mechanisms underlying kidney injury, and add to prognostic information gleaned from biopsy specimens. Analysis of mRNA expression in formalin-fixed, paraffin-embedded renal biopsy specimens is limited by both quantity and quality of RNA, requiring RNA pre-amplification, which can introduce bias. Accordingly, we developed a new technique for RNA extraction from human kidney formalin fixed paraffin embedded biopsy specimens, and used Taqman low-density arrays Applied Biosystems, Carlsbad, CA to simultaneously measure 48 mR-NAs in duplicate, in a single biopsy. We extracted mRNA from more than 150 blocks to determine the quantity and vintage of biopsy tissue suitable for analysis using this protocol. We then used Taqman low-density arrays to identify suitable housekeeping genes in lupus nephritis. Finally, we measured expression of 48 mRNA transcripts in archived lupus biopsy specimens (n ‫؍‬ 54). We identified that the mRNA levels of three transcripts (MMP7, EGF, COL1A1) relate to pathological indices of kidney injury and kidney function at the time of biopsy; these were associated with parallel changes in expression of these proteins. This new method for measurement of kidney biopsy mRNA expression has enabled us to identify tissue biomarkers of kidney damage and function, and potentially can increase the information yielded from diagnostic kidney biopsy specimens to improve tailoring of therapy.

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices

Kidney international, 2018

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific desc...

Biomarkers for Refractory Lupus Nephritis: A Microarray Study of Kidney Tissue

International Journal of Molecular Sciences, 2015

The prognosis of severe lupus nephritis (LN) is very different among individual patients. None of the current biomarkers can be used to predict the development of refractory LN. Because kidney histology is the gold standard for diagnosing LN, the authors hypothesize that molecular signatures detected in kidney biopsy tissue may have predictive value in determining the therapeutic response. Sixty-seven patients with biopsy-proven severely active LN by International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification III/IV were recruited. Twenty-three kidney tissue samples were used for RNA microarray analysis, while the remaining 44 samples were used for validation by real-time polymerase chain reaction (PCR) gene expression analysis. From hundreds of differential gene expressions in refractory LN, 12 candidates were selected for validation based on gene expression levels as well as relevant functions. The candidate biomarkers were members of the innate immune response molecules, adhesion molecules, calcium-binding receptors, and paracellular tight junction proteins. S100A8, ANXA13, CLDN19 and FAM46B were identified as the best kidney biomarkers for refractory LN, and COL8A1 was identified as the best marker for early loss of kidney function. These new molecular markers can be used to predict refractory LN and may eventually lead to novel molecular targets for therapy.