Tubulointerstitial Injury In Lupus Nephritis Research Articles

Iguratimod alleviates tubulo-interstitial injury in mice with lupus

Introduction Tubulo-interstitial injury is a poor prognostic factor for lupus nephritis (LN). Here, we tested whether iguratimod could inhibit tubulo-interstitial injury in LN. Methods MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney were evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor β1 (TGF-β1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3, and p-p38 MAPK, β-catenin and TGF-β type II receptor (TGFβRII) in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence. Results Iguratimod reduced immune deposition along the tubular basement membrane, inhibited the tubulo-interstitial infiltration of inflammatory cells, and alleviated tubular injury in MRL/lpr mice. Moreover, Iguratimod eased the tubulo-interstitial deposition of collagen fibers, which was confirmed by decreased expression of COL-I. Furthermore, iguratimod suppressed the expression of FSP-1 and increased that of E-cadherin in renal tubular epithelial cells. In HK2 cells cultured with TGF-β1, iguratimod treatment not only reversed cellular morphological changes, but also prevented E-cadherin downregulation and fibronectin upregulation. In addition, iguratimod inhibited phosphorylation of TGFβRII, Smad2/3 and p38 MAPK in HK2 cells treated with TGF-β1, and also blocked nuclear translocation of β-catenin. Conclusion Iguratimod eased tubulo-interstitial lesions in LN, especially tubulo-interstitial fibrosis, and might have potential as a drug for inhibiting the progression of tubulo-interstitial fibrosis in LN.

Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis.

Nephritis is a common manifestation of systemic lupus erythematosus, a condition associated with inflammation and iron imbalance. Renal tubules are the work horse of the nephron. They contain a large number of mitochondria that require iron for oxidative phosphorylation, and a tight control of intracellular iron prevents excessive generation of reactive oxygen species. Iron supply to the kidney is dependent on systemic iron availability, which is regulated by the hepcidin-ferroportin axis. Most of the filtered plasma iron is reabsorbed in proximal tubules, a process that is controlled in part by iron regulatory proteins. This review summarizes tubulointerstitial injury in lupus nephritis and current understanding of how renal tubular cells regulate intracellular iron levels, highlighting the role of iron imbalance in the proximal tubules as a driver of tubulointerstitial injury in lupus nephritis. We propose a model based on the dynamic ability of iron to catalyze reactive oxygen species, which can lead to an accumulation of lipid hydroperoxides in proximal tubular epithelial cells. These iron-catalyzed oxidative species can also accentuate protein and autoantibody-induced inflammatory transcription factors leading to matrix, cytokine/chemokine production and immune cell infiltration. This could potentially explain the interplay between increased glomerular permeability and the ensuing tubular injury, tubulointerstitial inflammation and progression to renal failure in LN, and open new avenues of research to develop novel therapies targeting iron metabolism.

Urinary soluble VCAM-1 is a useful biomarker of disease activity and treatment response in lupus nephritis

IntroductionVascular cell adhesion molecule-1 (VCAM-1) is involved in the progression of glomerular and tubulointerstitial injury in lupus nephritis (LN) and can be easily assessed in urine. The aim of this study was to assess urinary soluble VCAM-1 (uVCAM-1) as a biomarker of disease activity and treatment response in LN.MethodsThis prospective study enrolled 62 patients with class III, IV or V LN diagnosed within the last 3 years and divided them in two groups: with and without active nephritis at the inclusion, each group with 31 patients. At each visit, a urine sample was collected for uVCAM-1 evaluation and the nephritis status was assessed.ResultsMedian uVCAM-1 level was elevated in patients with active compared to inactive LN (P < 0.001). The ROC curve of uVCAM-1 demonstrated an AUC of 0.84 and a cutoff of 47.2 ng/mgCr yielded a good sensitivity (74.2%) and specificity (74.2%) for the diagnosis of active LN. A significant correlation was found between uVCAM-1 level and renal activity scores and traditional biomarkers of LN. The level of uVCAM-1 dropped in patients with active LN who went into remission (P < 0.001), increased in patients who went into activity (P = 0.002) and did not change in patients who remained inactive (P = 0.797). The level of uVCAM-1 peaked during the flare of LN (P < 0.05).ConclusionThe uVCAM-1 is a reliable biomarker that reflects renal disease activity and is useful for monitoring individual patients with lupus nephritis over time.

AB0412 URINARY SOLUBLE VCAM-1 IS A USEFUL BIOMARKER OF DISEASE ACTIVITY AND TREATMENT RESPONSE IN LUPUS NEPHRITIS

Background:The traditional lupus nephritis (LN) biomarkers are not sensitive nor specific enough for detecting ongoing disease activity and early relapse of nephritis and they do not reflect kidney damage nor have prognostic value1. Urinary biomarkers are directly excreted by the kidney and are easily obtained. They can also differentiate the renal activity of the disease from other organic manifestations more accurately than the serum biomarkers2. Vascular cell adhesion molecule-1 (VCAM-1) is involved in the progression of glomerular and tubulointerstitial injury in LN and its soluble form can be easily assessed in urine (uVCAM-1)3. Several studies correlated the uVCAM-1 levels with urine protein-creatinine ratio (UPC), with general disease activity and with active LN3.Objectives:To assess uVCAM-1 as a biomarker of disease activity and treatment response in LN.Methods:This prospective study enrolled patients with class III, IV or V LN diagnosed within the last three years and divided them in two groups: with and without active nephritis at the inclusion. The patients with active nephritis were included before they started a new immunosuppressive treatment. Active LN was defined as proteinuria (UPC≥0.5) plus active urinary sediment (hematuria, leukocyturia or cellular hematic/granular casts). At each visit, a urine sample was collected for uVCAM-1 evaluation and the nephritis status was accessed.Results:Median uVCAM-1 level was elevated in patients with active compared to inactive LN (p&lt;0.001). The ROC curve of uVCAM-1 demonstrated an AUC of 0.84 and a cutoff of 47.2 ng/mgCr yielded a good sensitivity (74.2%) and specificity (74.2%) for the diagnosis of active LN. A significant correlation was found between uVCAM-1 level and renal activity scores and traditional biomarkers of LN (table 1). The level of uVCAM-1 dropped in patients with active LN who went into remission (p&lt;0.001), increased in patients who went into activity (p=0.002) and did not change in patients who remained inactive (p=0.797) (figure 1). The level of uVCAM-1 peaked during the flare of LN (p&lt;0.05) (figure 2).Table 1.Correlations between urinary soluble VCAM-1 and other LN biomarkers/disease scoresLN biomarkers/disease scoresVCAM-1SLEDAI-2k0.597***Renal SLEDAI0.569***Renal SLAM-R0.470***Renal SLICC0.620***Anti-dsDNA0.342**C3-0.344**C4-0.382**UPC0.654***Spearman’s correlation coefficients*pvalue &lt;0.05; **pvalue &lt;0.01; ***pvalue &lt;0.001C, complement; LN, lupus nephritis; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; renal SLAM-R, The renal Systemic Lupus Activity Measure revised; renal SLICC, The Systemic Lupus International Collaborating Clinics renal activity/response exercise; UPC, urine protein-creatinine ratio.Conclusion:The uVCAM-1 is a reliable biomarker that reflects renal disease activity and is useful for monitoring individual patients with lupus nephritis over time.

Immunological characteristics and possible pathogenic role of urinary CD11c+ macrophages in lupus nephritis.

Kidney-infiltrating immune cells can contribute to the pathogenesis of lupus nephritis (LN). We investigated the immunological characteristics of CD11c+ macrophages and their functions associated with the pathogenesis of LN. CD11c+ macrophages were examined in the urine samples of patients with LN. Phenotypic markers and pro-inflammatory cytokine expression levels were analysed by flow cytometry. To determine the origin of urinary macrophages, peripheral monocytes were treated with sera from patients with systemic lupus erythematosus (SLE). The pathogenic role of CD11c+ macrophages in tubulointerstitial damage was investigated using SLE sera-treated monocytes and HK-2 cells. Urinary CD11c+ macrophages expressed pro-inflammatory cytokines, such as IL-6 and IL-1β, and resembled infiltrated monocytes rather than tissue-resident macrophages with respect to surface marker expression. CD11c+ macrophages had high expression levels of the chemokine receptor CXCR3, which were correlated with cognate chemokine IP-10 expression in urinary tubular epithelial cells. When treated with sera from SLE patients, peripheral monocytes acquired the morphological and functional characteristics of urinary CD11c+ macrophages, which was blocked by DNase treatment. Finally, SLE sera-treated monocytes induced fibronectin expression, apoptosis and cell detachment in HK-2 cells via production of IL-6. CD11c+ macrophages may be involved in the pathogenesis of tubulointerstitial injury in LN.

SAT-404 Clinicopathological factors associated with tubulointerstitial injury in lupus nephritis

SAT-404 Clinicopathological factors associated with tubulointerstitial injury in lupus nephritis

Clinicopathological factors for tubulointerstitial injury in lupus nephritis

To investigate the incidence of tubulointerstitial injury in lupus nephritis (LN) and to examine clinicopathological factors that could indicate the presence of tubulointerstitial injury. This study included 98 patients with LN. Clinical data and the pathological results of the initial renal biopsy were collected. The frequency of each tubulointerstitial injury parameter was over 50%, except for the interstitial edema, in the 98 patients investigated in this study. The most frequently detected tubulointerstitial injury parameter was tubular atrophy in this study. Neutrophil infiltration/karyorrhexis, wire loop lesion, and arteriosclerosis were observed frequently in patients with tubulointerstitial injuries. High serum creatinine and blood urea nitrogen (BUN) were observed more frequently in patients with tubulointerstitial injuries except tubular degeneration. The multivariable regression analysis showed a relationship between neutrophil infiltration/karyorrhexis and interstitial fibrosis/tubular degeneration, a relationship between wire loop lesion and tubulointerstitial inflammation/edema, and a relationship between arteriosclerosis and tubulointerstitial injuries (except interstitial edema). Patients with tubular degeneration had lower D-Dimer levels compared with those without. Patients with interstitial fibrosis had higher blood leukocyte counts than those without. The rate of low response to therapy was 13% among those without tubulointerstitial inflammation, but 35% in those with interstitial inflammation (P = 0.03). Acute and chronic renal tubulointerstitial lesions are often found along with glomerular and vascular lesions. Immune and vascular factors are probably involved in tubulointerstitial injuries. Tubulointerstitial inflammation may be the initiator of chronic renal injury and may predict response to therapy.Key Points•To provide a theoretical basis for tubulointerstitial injury in LN.

Molecular and Immunological Basis of Tubulo-Interstitial Injury in Lupus Nephritis: a Comprehensive Review

Lupus nephritis is an important cause of kidney failure in patients of Asian, African, or Hispanic descent. Its etiology and pathogenesis are multifactorial and remain to be elucidated. Accumulating evidence suggests that anti-double-stranded DNA (dsDNA) antibodies play a critical role in the pathogenesis, through its direct binding to cross-reactive antigens on resident renal cells or indirect binding through chromatin material to extracellular matrix components, resulting in complement activation, cell activation and proliferation, and induction of inflammatory and fibrotic processes. While tubulo-interstitial damage portends poor long-term renal prognosis, the mechanisms leading to tubulo-interstitial injury in lupus nephritis has received relatively less attention to date. Immune deposition along the tubular basement membrane is often observed in lupus nephritis and correlates with tubulo-interstitial infiltration of immune cells and interstitial fibrosis. Anti-dsDNA antibodies bind to resident renal cells, including proximal renal tubular epithelial cells, and contribute to renal inflammation and fibrosis. There is emerging evidence that epigenetic influence such as DNA methylation, histone modification, and microRNAs (miRs) also contribute to kidney fibrosis. Overexpression of miR-150 is observed in renal biopsies from patients with lupus nephritis and correlates with kidney fibrosis and chronicity score. Mycophenolate mofetil (MMF) is an established and effective standard-of-care therapy for patients with lupus nephritis. Accumulating data suggest that in addition to its immunosuppressive actions on lymphocyte proliferation, mycophenolic acid (MPA), the active metabolite of MMF, can exert a direct effect on nonimmune cells. Mediators of inflammation and fibrosis induced by anti-dsDNA antibodies in cultured proximal renal tubular epithelial cells are ameliorated by the addition of MPA, suggesting that in addition to its immunosuppressive actions, MPA may also have a beneficial effect in improving tubulo-interstitial inflammation and fibrosis through its direct action on proximal renal tubular epithelial cells.

Pentraxin 3 Is Closely Associated With Tubulointerstitial Injury in Lupus Nephritis

Lupus nephritis always elicits immune inflammatory tissue damages in kidney. Pentraxin 3 (PTX3), mainly produced at inflammatory sites, is known to be involved in the regulation of the innate immunity system. The aim of this study was to investigate the serum and urine levels of PTX3, and the expression of PTX3 in renal tissues in lupus nephritis patients from a large Chinese cohort.The study used cross-sectional survey and 288 active lupus nephritis patients, including discovery cohort and validation cohort, 115 systemic lupus erythematosus (SLE) patients without clinical renal involvement and 46 healthy controls were enrolled. Serum and urine PTX3 were screened by enzyme-linked immunosorbent assay (ELISA). The renal deposition of PTX3 was detected by immunohistochemistry and immunofluorescence.The average level of serum PTX3 in the discovery cohort of lupus nephritis was significantly higher than that in nonrenal involvement SLE group and normal controls (P < 0.001, P < 0.001, respectively), which was confirmed by the validation cohort. Serum PTX3 levels of 15 lupus nephritis patients in remission decreased significantly compared with that in active phase. Serum PTX3 levels were significantly higher in patients with hematuria (P = 0.014), leucocyturia (P = 0.002), acute renal failure (P = 0.001), and nephrotic syndrome (P = 0.036). There were significant correlations between serum PTX3 levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, serum creatinine value, renal pathological activity indices, and serum complement 3 (C3) in active lupus nephritis patients. The urinary PTX3 levels were significantly higher in active lupus nephritis patients compared with patients in remission and normal controls (P = 0.011, P = 0.008, respectively). There were significant associations between urinary PTX3 levels and multiple indices of tubulointerstitial lesions, including urinary KIM-1 (r = 0.368, P = 0.016), neutrophil gelatinase-associated lipocalin (NGAL) (r = 0.320, P = 0.039), microalbumin (r = 0.621, P = 0.003), transferring (r = 0.451, P = 0.040) levels and renal pathological indices scores, especially interstitial inflammation (r = 0.349, P = 0.025) in active lupus nephritis patients. A significant correlation was found between serum and urine PTX3 levels (r = 0.431, P = 0.006). PTX3 staining was mainly observed in tubulointerstitial areas of patients with lupus nephritis, and immunofluorescence study showed that PTX3 could colocalize with fibroblast in interstitium.Circulating and local PTX3 levels were significantly increased in patients with active lupus nephritis and might be a biomarker for the disease progression, especially of tubulointerstitial injury.