Response In Lupus Nephritis Research Articles

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.

Lupus Nephritis: Role of Serum Complement Levels as Prognostic Marker

Background: Lupus Nephritis (LN) is one of the most common and serious manifestations in Systemic Lupus Erythematosus (SLE) patients that causes significant morbidity and mortality. Certain biomarkers for LN are sometimes able to assess treatment response of lupus nephritis. Objective: To compare serum complement levels (C3 &amp; C4) as markers of treatment response of LN and their relation to the LN class in renal biopsy. Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with lupus nephritis after kidney biopsy were included in this study. Serum complement levels (C3 &amp; C4), 24 hours urinary total protein (24-hr UTP) and anti-double-stranded DNA (anti-ds DNA) were measured in all patients at baseline, 3 months and 6 months after treatment. These biomarker values before and after treatment were compared between the treatment response and non response groups. Results: Serum C3 levels were significantly different in patients of proliferative lupus nephritis (Class III &amp; Class IV) than non proliferative lupus nephritis (Class V) at baseline (0.47 ± 0.32 vs0.89 ± 0.43g/l, p = 0.009) and levels changed significantly 6 months after treatment (p &lt;0.001) and likewise for Serum C4 levels (0.10 ± 0.06 vs0.24 ± 0.26g/l, p = 0.040). Serum C3 levels were also found to correlate significantly with SLEDAI and renal SLEDAI. No significant difference was observed for 24-hr UTP levels at baseline between remission and non-remission groups. Conclusion: Serum C3 &amp; C4 levels may be utilized as serological biomarkers to predict and monitor the treatment response of lupus nephritis.

Variable selection methods for identifying predictor interactions in data with repeatedly measured binary outcomes.

Identifying predictors of patient outcomes evaluated over time may require modeling interactions among variables while addressing within-subject correlation. Generalized linear mixed models (GLMMs) and generalized estimating equations (GEEs) address within-subject correlation, but identifying interactions can be difficult if not hypothesized a priori. We evaluate the performance of several variable selection approaches for clustered binary outcomes to provide guidance for choosing between the methods. We conducted simulations comparing stepwise selection, penalized GLMM, boosted GLMM, and boosted GEE for variable selection considering main effects and two-way interactions in data with repeatedly measured binary outcomes and evaluate a two-stage approach to reduce bias and error in parameter estimates. We compared these approaches in real data applications: hypothermia during surgery and treatment response in lupus nephritis. Penalized and boosted approaches recovered correct predictors and interactions more frequently than stepwise selection. Penalized GLMM recovered correct predictors more often than boosting, but included many spurious predictors. Boosted GLMM yielded parsimonious models and identified correct predictors well at large sample and effect sizes, but required excessive computation time. Boosted GEE was computationally efficient and selected relatively parsimonious models, offering a compromise between computation and parsimony. The two-stage approach reduced the bias and error in regression parameters in all approaches. Penalized and boosted approaches are effective for variable selection in data with clustered binary outcomes. The two-stage approach reduces bias and error and should be applied regardless of method. We provide guidance for choosing the most appropriate method in real applications.

The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis.

Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (n = 7) and non-response (n = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNFα, IFNα and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, p < 0.0001). HIF1A was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. HIF1A inhibition reduced mesangial proliferation and IL-8, CCL2, CCL3, and CXCL1 mesangial cell production and IL-6/VCAM-1 in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by HIF1A inhibition.

Non-albumin proteinuria as a parameter of tubulointerstitial inflammation in lupus nephritis.

Tubulointerstitial inflammation (TI) has prognostic significance in the renal outcomes of lupus nephritis. Here, we aimed to determine whether non-albumin proteinuria is associated with TI severity and with the renal response in lupus nephritis. We included patients with biopsy-confirmed lupus nephritis at a tertiary medical center in Korea from January 2011 to April 2017. Patients in whom the urine protein/creatinine ratio (uPCR) and the urine albumin/creatinine ratio (uACR) were measured simultaneously were included. Laboratory data and renal pathology were reviewed. Non-albumin proteinuria was calculated by subtracting uACR from uPCR. The renal response was assessed by the amount of proteinuria present at 6months after treatment with immunosuppressants. Logistic regression analyses were performed to identify factors associated with TI severity and renal response. Out of 45 patients, 36 (80%) had no-to-mild TI, whereas 9 (20%) had moderate-to-severe TI. Proliferative (class III ± V/IV ± V) and nonproliferative (class II/V) glomerulonephritis (GN) were present in 38 (84.4%) and 7 (15.6%) patients, respectively. In the logistic regression analyses, non-albumin proteinuria (uPCR - uACR) was associated with moderate-to-severe TI (odds ratio [OR] 3.166, 95% confidence interval [95% CI] 1.145-8.757, p = 0.026) and was inversely associated with complete renal response (adjusted OR 0.180, 95% CI 0.045-0.718, p= 0.015). In lupus nephritis, non-albumin proteinuria was associated with TI severity and with poor renal response after immunosuppressive treatment. Thus, the determination of non-albumin proteinuria can provide clinically valuable information on lupus nephritis.

Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis.

Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78. A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.

DC-SIGN expression on podocytes and its role in inflammatory immune response of lupus nephritis.

Podocytes, the main target of immune complex, participate actively in the development of glomerular injury as immune cells. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is an innate immune molecular that has an immune recognition function, and is involved in mediation of cell adhesion and immunoregulation. Here we explored the expression of DC-SIGN on podocytes and its role in immune and inflammatory responses in lupus nephritis (LN). Expression of DC-SIGN and immunoglobulin (Ig)G1 was observed in glomeruli of LN patients. DC-SIGN was co-expressed with nephrin on podocytes. Accompanied by increased proteinuria of LN mice, DC-SIGN and IgG1 expressions were observed in the glomeruli from 20 weeks, and the renal function deteriorated up to 24 weeks. Mice with anti-DC-SIGN antibody showed reduced proteinuria and remission of renal function. After the podocytes were stimulated by serum of LN mice in vitro, the expression of DC-SIGN, major histocompatibility complex (MHC) class II and CD80 was up-regulated, stimulation of T cell proliferation was enhanced and the interferon (IFN)-γ/interleukin (IL)-4 ratio increased. However, anti-DC-SIGN antibody treatment reversed these events. These results suggested that podocytes in LN can exert DC-like function through their expression of DC-SIGN, which may be involved in immune and inflammatory responses of renal tissues. However, blockage of DC-SIGN can inhibit immune functions of podocytes, which may have preventive and therapeutic effects.

THU0171 Therapeutic response of lupus nephritis based on pathological findings in yokohama city university hospital

BackgroundISN/RPS classification of lupus nephritis was popular and reliable classification because of its semi-quantitativity of glomerular changes. However, tubulointerstitial involvement and the grade of glomerular sclerosis and of hyaline thrombi...

Elevated interleukin-18 and skewed Th1:Th2 immune response in lupus nephritis

There is evidence that interleukin-18 plays a role in lupus nephritis (LN). Since interleukin -18 (IL-18) promotes polarization of the immune response toward Th1, we investigated level of IL-18 and assessed the phenotypic distribution of Th1 and Th2 type cells in LN. A predominance of Th1 type (IFN-γ+) cells and significant correlations with serum IL-18 was seen in the patients with LN compared to healthy controls. Although most patients were treated with high dosage of glucocorticoid and other immunosuppressive agents, higher level of IL-18 was found in both serum and glomeruli. However, there was no paralleled upregulation of its gene expression in peripheral blood mononuclear cells. Our findings indicate that the elevated IL-18 should be a symbol of disease activity and play a major role in the pathogenesis of LN by promoting cytokine imbalance towards Th1 type immune response. We conclude that patients with LN would benefit from it while the bioactivity of this cytokine was effectively counteracted.

Toll-like Receptors and Lupus Nephritis

A variety of immune mechanisms, both humoral and cellular, are involved in the onset and amplification of the inflammatory response in lupus nephritis (LN). Accumulating evidence substantiates the view that innate immunity pathways may also amplify inflammatory reactions within the kidneys. Toll-like receptors (TLRs) are essential modulators of the innate immune response thanks to their ability to rocognize conserved molecular patterns that are microbe specific and other danger signals. Their recognition of endogenous molecules released from injured cells may also contribute to renal inflammation. Studies conducted in vivo and in vitro provide experimental evidence for the functional role of TLRs in LN. Intriguingly, these data suggest that pharmacological TLR signal suppression could be a useful approach to the treatment of systemic lupus erythematosus.

Expression of endothelial protein C receptor in cortical peritubular capillaries associates with a poor clinical response in lupus nephritis

To study the membrane expression of endothelial protein C receptor (mEPCR) in the renal microvasculature in lupus nephritis (LN) as a potential marker of injury and/or prognostic indicator for response to therapy. mEPCR expression was analysed by immunohistochemistry in normal kidney and in 59 biopsies from 49 patients with LN. Clinical parameters were assessed at baseline, 6 months and 1 year. mEPCR was expressed in the medulla, arterial endothelium and cortical peritubular capillaries (PTCs) in all biopsies with LN but not in the cortical PTCs of normal kidney. Positive mEPCR staining in >25% of the PTCs was observed in 16/59 biopsies and associated with poor response to therapy. Eleven (84.6%) of 13 patients with positive staining for mEPCR in >25% of the PTCs and follow-up at 6 months did not respond to therapy, compared with 8/28 (28.6%) with mEPCR staining in < or =25% PTCs, P = 0.0018. At 1 year, 10 (83.3%) of 12 patients with positive mEPCR staining in >25% of the PTCs did not respond to therapy (with two progressing to end-stage renal disease) compared with 8/24 (33.3%) with positive staining in < or =25% of the PTCs, P = 0.0116. Although tubulo-interstitial damage (TID) was always accompanied by mEPCR, this endothelial marker was extensively expressed in the absence of TID suggesting that poor response could not be attributed solely to increased TID. mEPCR expression was independent of International Society of Nephrology/Renal Pathology Society class, activity and chronicity indices. Increased mEPCR expression in PTCs may represent a novel marker of poor response to therapy for LN.

Inhibition of mesangial cell nitric oxide in MRL/lpr mice by prostaglandin J2 and proliferator activation receptor-gamma agonists.

MRL/Mp-lpr/lpr (MRL/lpr) mice develop immune complex glomerulonephritis similar to human lupus. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. PGJ2, a product of cyclooxygenase, is a potent in vitro inhibitor of macrophage inflammatory functions and is postulated to function as an in vivo inhibitor of macrophage-mediated inflammatory responses. We hypothesized that in lupus, a defect in PGJ2 production allows the inflammatory response to continue unchecked. To test this hypothesis, mesangial cells were isolated from MRL/lpr and BALB/c mice and stimulated with IL-1beta or LPS plus IFN-gamma. In contrast to the 2- to 3-fold increase in PGJ2 production by stimulated BALB/c mesangial cells, supernatant PGJ2 did not increase in MRL/lpr mesangial cell cultures. NO production in stimulated MRL/lpr and BALB/c mesangial cells, was blocked by PGJ2 and pioglitazone. These studies suggest that abnormalities in PGJ2 production are present in MRL/lpr mice and may be linked to the heightened activation state of mesangial cells in these mice.

Cellular interactions in the pathogenesis of lupus nephritis: the role of T cells and macrophages in the amplification of the inflammatory process in the kidney.

A significant number of T cells and macrophages infiltrate the kidneys of patients with lupus nephritis. Chemotactic factors, especially monocyte chemoattractant factor-1 (MCP-1) and adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), cooperatively facilitate recruitment of mononuclear cells into inflamed tissue. Increased expression of class II MHC molecules and CD40 on renal tubular epithelial cells coupled with upregulation of CD40 ligand (CD40L) and interleukin-2 receptor on infiltrating T cells suggest ongoing cellular immune responses. Recent studies employing knockout mice suggest that the T(H)-1 cytokine interferon-gamma is an important cytokine in amplifying the local immune response of lupus nephritis. Infiltrating mononuclear cells exert their effects on resident renal cells through secretion of soluble factors and/or direct cell to cell contact. These interactions, among others, involve molecules such as CD40/CD40L and adhesion molecules. Studies to better define these molecules are in progress and may provide additional targets for therapeutic intervention. Thus, while autoantibody production and complement activation are the major players in initiating the inflammatory response in lupus nephritis, cellular immune mechanisms mediated through infiltrating mononuclear cells have an important role in its amplification and the progression of renal injury.