epidermal-growth-factor and Lupus-Nephritis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease where the body's immune system targets cells and tissue in numerous organs, including the kidneys. Lupus nephritis (LN) is a highly heterogeneous disease, and diagnosis is difficult because clinical manifestations vary widely among patients. Comprehensive proteomic studies reported recently in LN have identified several urinary proteins which are also cell-surface receptors. If indeed these receptor proteins are also hyper-expressed within the kidneys, ligands to these receptors may be useful for drug targeting.. scRNA sequence data analysis and immunohistochemistry were performed on LN kidneys for expression of four implicated receptors, EGFR, FOL2R2, PDGF-RB, and TFRC.. In reported scRNA sequencing studies from 21 LN patients and 3 healthy control renal biopsies or renal-infiltrating immune cells from 24 LN biopsies, EGFR, FOLR2, PDGF-Rb, and TFRC were all hyper expressed within LN kidneys in comparison to healthy kidneys, either within resident renal cells or infiltrating leukocytes. Immunohistochemistry staining of murine lupus renal biopsies from lupus mice revealed EGFR, FOLR2, TFRC and PDGF-RB were elevated in LN kidneys. Immunohistochemistry staining of human Class II, Class III, and Class IV kidney tissue sections revealed EGFR, TFRC, and PDGF-RB were significantly elevated in proliferative LN kidneys.. These findings underscore the potential of EGFR, TFRC, FOLR2, and PDGF-RB as promising receptors for potential drug-targeting in LN.

Topics: Animals; Biomarkers; Epidermal Growth Factor; ErbB Receptors; Folate Receptor 2; Folic Acid; Humans; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Proteomics; Transferrin

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.. 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.. 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, renal SLEDAI, classes III/IV/V, and high activity index.) By contrast, EGF correlated with eGFR, but not with proteinuria, activity index, or class III/IV/V. MCP-1 was higher, and EGF was lower in high chronicity index. EGF/MCP-1 decreased with greater clinicopathological severity. In a subgroup with proliferative LN who completed six months of induction therapy (n = 41), EGF at baseline was lower in non-responders compared to responders, whereas MCP-1 was similar. By multivariable analysis, baseline EGF was independently associated with subsequent treatment response. Area under the curve for EGF to predict response was 0.80 (0.66-0.95). EGF ≥ 65.6 ng/ mgCr demonstrated 85% sensitivity and 71% specificity for response. EGF/MCP-1 did not improve the prediction for response compared to EGF alone.. MCP-1 increased with disease activity, whereas EGF decreased with low GFR and chronic damage. Urine EGF may be a promising biomarker to predict therapeutic response in LN. EGF/MCP-1 did not improve the prediction of response.

Topics: Biomarkers; Chemokine CCL2; Cross-Sectional Studies; Epidermal Growth Factor; Female; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Proteinuria

To evaluate the role of urinary epidermal growth factor (EGF) as a biomarker of chronic kidney damage in lupus nephritis (LN).. A proteomics approach was used to identify urinary EGF as a biomarker of interest in a discovery cohort of patients with LN. The expression of urinary EGF was characterized in 2 large multiethnic LN cohorts, and the association between urinary EGF levels at the time of flare and kidney outcomes was evaluated in a subset of 120 patients with long-term follow-up data. For longitudinal studies, the expression of urinary EGF over time was determined in 2 longitudinal cohorts of patients with LN from whom serial urine samples were collected.. Discovery analysis showed the urinary EGF levels as being low in patients with active LN (median peptide count 8.4, interquartile range [IQR] 2.8-12.3 in patients with active LN versus median 48.0, IQR 45.3-64.6 in healthy controls). The peptide sequence was consistent with that of proEGF, and this was confirmed by immunoblotting. The discovery findings were verified by enzyme-linked immunosorbent assay. Patients with active LN had a significantly lower level of urinary EGF compared to that in patients with active nonrenal systemic lupus erythematosus (SLE), patients with inactive SLE, and healthy kidney donors (each P < 0.05). The urinary EGF level was inversely correlated with the chronicity index of histologic features assessed in kidney biopsy tissue (Spearman's r = -0.67, P < 0.001). Multivariate survival analysis showed that the urinary EGF level was associated with time to doubling of the serum creatinine level (DSCr), a marker of future end-stage kidney disease (ESKD) (hazard ratio 0.88, 95% confidence interval 0.77-0.99, P = 0.045). Patients whose LN symptoms progressed to DSCr and those who experienced progression to ESKD had a lower urinary EGF level at the time of flare, and urinary EGF levels decreased over the 12 months following flare. All patients who experienced progression to ESKD were identified based on a urinary EGF cutoff level of <5.3 ng/mg.. Urinary EGF levels are correlated with histologic kidney damage in patients with LN. Low urinary EGF levels at the time of flare and decreasing urinary EGF levels over time are associated with adverse long-term kidney outcomes.

Topics: Adult; Blotting, Western; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Disease Progression; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Longitudinal Studies; Lupus Nephritis; Male; Middle Aged; Prognosis; Proteomics; Renal Insufficiency, Chronic; Symptom Flare Up

Prediction of prognosis in patients who have lupus nephritis is inadequate, limiting individualization of potentially toxic therapy. Advances in tissue molecular 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 mRNAs 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.

Topics: Biomarkers; Biopsy; Collagen Type I; Collagen Type I, alpha 1 Chain; Epidermal Growth Factor; Humans; Kidney; Lupus Nephritis; Matrix Metalloproteinase 7; Polymerase Chain Reaction; Prognosis; RNA, Messenger