Lupus Nephritis In Systemic Lupus Erythematosus Patients Research Articles

Clinico-serological associations of urinary activated leukocyte cell adhesion molecule in systemic lupus erythematosus and lupus nephritis

BackgroundLupus nephritis (LN) is one of the major complications associated with Systemic Lupus Erythematosus (SLE). Activated leukocyte cell adhesion molecule (ALCAM or CD166) is a promising urine biomarker that binds to CD6, a receptor found on lymphocytes. This binding results in T-cell activation, proliferation, and recruitment, which causes tissue inflammation and may explain the pathophysiology of LN.Aim of workInvestigate the urinary ALCAM level in SLE, study its relationship to disease activity, and clarify the association with LN activity and histopathology.Patients and methodsA case–control study was performed on 60 patients with SLE and 20 matched controls. The SLE disease activity index (SLEDAI) and the activity of renal disease (rSLEDAI) were evaluated. Renal biopsy and uALCAM levels were also investigated.ResultsUrinary ALCAM levels were higher significantly in active LN patients than inactive LN patients, active and inactive non-LN SLE, and the control group (p < 0.001). The cut-off value for identifying active and inactive LN was above 270 ng/mg (p < 0.001). ALCAM levels were greater in proliferative (class III, IV, and IV/V) than in non-proliferative (class II and V) LN (p < 0.001). ALCAM exhibited high positive correlations with SLEDAI and rSLEDAI (p < 0.001 each) and negative significant correlations with C3 (p < 0.001) and C4 (p = 0.005).ConclusionUrinary ALCAM is a sensitive biomarker evaluating LN in SLE patients. Levels above 270 ng/mg can help distinguish between active and inactive LN. ALCAM levels are correlated positively with SLEDAI and rSLEDAI but have a negative correlation with C3 and C4.Key Points• Urinary ALCAM shows promise as a biomarker for evaluating kidney dysfunction in SLE patients.• It is a non-invasive marker that can differentiate between proliferative and non-proliferative LN.• A urinary ALCAM level above 270 ng/mg can indicate active LN, while lower levels indicate inactive LN.• Urinary ALCAM levels are correlated positively with SLEDAI and rSLEDAI scores but correlated negatively with C3 and C4.

Circulating exosomal microRNAs as biomarkers of lupus nephritis.

Disruption in the delicate symphony of genes, microRNA (miRNA), or protein expression can result in the dysregulation of the immune system, leading to the devastating consequences such as lupus nephritis (LN). The capacity of exosomes to transport miRNAs between cells and modify the phenotype of recipient cells implies their involvement in persistent kidney inflammation. This study unveils identifying two previously undiscovered exosomal miRNAs in the serum of LN patients, offering potential solutions to the current challenges in LN diagnosis and management. Initially, we used a reagent-based kit to isolate serum exosomes from patients with Systemic lupus erythematosus (SLE) and used Trizol method for total RNA extraction. Subsequently, we employed small RNA sequencing to screen for differential expression profiles of exosomal small RNAs. The RT-qPCR method was used to individually validate samples in both the screening and validation cohorts, enabling the identification of candidate small RNAs; specific to LN. We assessed the diagnostic potency using receiver operating characteristic (ROC) curve, and explored the biological roles of miRNAs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Compared to SLE patients without LN, SLE patients accompanied by LN exhibited significantly spiked levels of exosomal hsa-miR-4796-5p and hsa-miR-7974. The duo of miRNAs, hsa-miR-4796-5p and hsa-miR-7974, exhibited promising potential as biomarkers for diagnosing LN, with an AUC exceeding 0.8. Correlation analysis revealed a strong positive association between these miRNAs and proteinuria, as well as the SLE Disease Activity Index (SLEDAI) score. Moreover, the levels of two miRNAs in LN patients were significantly elevated in comparison to other autoimmune nephritis conditions, such as immunoglobulin A nephropathy (IgAN) and diabetic nephropathy (DN). Furthermore, the bioinformatics analysis indicated that this miRNAs duo can play a pivotal role in the regulation of immune processes by modulating signal pathways, such as the mTOR and PI3K-Akt signaling pathway. This study provides a new ground that serum exosomal miRNAs can effectively identify and predict LN in SLE patients.

Analysis of risk factors and development of a nomogram prediction model for lupus nephritis in systemic lupus erythematosus patients

Background This study aimed to explore risk factors for lupus nephritis (LN) in systemic lupus erythematosus (SLE) patients and establish a Nomogram prediction model based on LASSO-logistic regression. Methods The clinical and laboratory data of SLE patients in Meishan People’s Hospital from July 2012 to December 2021 were analyzed retrospectively. All SLE patients were divided into two groups with or without LN. Risk factors were screened based on LASSO-logistic regression analysis, and a Nomogram prediction model was established. The receiver operating characteristic curve, calibration curves, and decision curve analysis were adopted to evaluate the performance of the Nomogram model. Results A total of 555 SLE patients were enrolled, including 303 SLE patients with LN and 252 SLE patients without LN. LASSO regression and multivariate logistic regression analyses showed that ESR, mucosal ulcer, proteinuria, and hematuria were independent risk factors for LN in SLE patients. The four clinical features were incorporated into the Nomogram prediction model. Results showed that calibration curve was basically close to the diagonal dotted line with slope 1 (ideal prediction case), which proved that the prediction ability of the model was acceptable. In addition, the decision curve analysis showed that the Nomogram prediction model could bring net clinical benefits to patients when the threshold probability was 0.12–0.54. Conclusion Four clinical indicators of ESR, mucosal ulcer, proteinuria, and hematuria were independent risk factors for LN in SLE patients. The predictive power of the Nomogram model based on LASSO-logistic regression was acceptable and could be used to guide clinical work.

Serum beta-2 microglobulin as a predictor of nephritis, disease activity, and damage score in systemic lupus erythematosus: a cross-sectional study

A strong correlation between lupus nephritis (LN), disease activity, and serum beta 2-microglobulin (b2MG) was observed. The current study examines the correlation between serum b2MG and renal involvement, damage score, and disease activity in systemic lupus erythematosus (SLE) patients. One hundred SLE patients from Ain Shams University Hospital were enrolled and categorized into two groups. Group I had 40 patients with negative b2MG, while Group II had 60 patients with positive b2MG levels. Medical history, clinical examination, and assessing disease activity based on SLE disease activity index (SLEDAI-2 K), and damage score were recorded for all patients. Laboratory examinations, such as serum b2MG, complete blood count, blood urea nitrogen (BUN), serum creatinine, glomerular filtration rate (GFR), urine analysis, 24 h urinary protein excretion, Antinuclear antibodies (ANA), anti-dsDNA antibody, and serum complement (C3, C4). BUN, 24 h urinary protein, serum creatinine, active urinary sediment, SLEDAI score, and damage score were all elevated in group II compared to group I (p < 0.001). There is a positive correlation between serum b2MG and 24 h urinary protein, BUN, serum creatinine, disease activity, and damage score (p < 0.001), while it was negatively correlated with GFR, C3, and C4 (p < 0.001). Serum b2MG has proven to be a predictor of LN in SLE patients (Sensitivity 92.45%, Specificity 74.47%), also being a predictor of the activity of the disease as well as damage index (Sensitivity 96.67%, Specificity 85%) (Sensitivity 92.45%, Specificity 74.47%), respectively. Serum b2MG level can be used as a valuable predictor for LN, clinical disease activity, and damage score.

Toll-like receptor 5 and Toll-like receptor 9 single nucleotide polymorphisms and risk of systemic lupus erythematosus and nephritis in Egyptian patients

BackgroundToll-like (TLRs) play a crucial role in both adaptive and innate immunity. The aim of the present study was to assess the association of TLR5-rs5744168, TLR9-rs187084, and TLR9-rs352140 single nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Egyptian patients.ResultsThe C allele and homozygous CC genotype of the TLR9-rs352140 in co-dominant and recessive models were more prevalent in SLE patients than controls (P = 0.047, P = 0.017, and P = 0.005 respectively). In contrast, allelic and genotyping distribution of TLR5-rs5744168 and TLR9-rs187084 SNPs showed no association with the risk of SLE. The T allele of the TLR5-rs5744168 was more prevalent in LN patients than controls (P = 0.021). The homozygous TT genotype of TLR5-rs5744168 SNP was more prevalent in LN patients in the co-dominant and the recessive models than controls (P = 0.036 and P = 0.011 respectively). The C allele of the TLR9-rs352140 was more prevalent in LN patients than controls (P = 0.015). The homozygous CC genotype of the TLR9-rs352140 SNP was more prevalent in LN than controls in co-dominant and recessive models (P = 0.002 and P < 0.001). In the recessive model of the TLR5-rs5744168 SNP, the TT genotype was found in 3.2% of the SLE patients while none of the SLE patients without LN or controls had TT genotype (P = 0.036). Also, in the recessive model of the TLR9-rs352140 SNP, the CC genotype was significantly more frequent in SLE patients with LN than without LN (44.4% vs 29.9%, P = 0.045).ConclusionOur results support the potential role of TLR5-rs5744168 SNP and TLR9-rs3532140 SNP not only in increasing the risk for development of SLE, but also in increasing the risk of LN in SLE patients among the Egyptian population.

Thrombotic microangiopathy versus class IV lupus nephritis in systemic lupus erythematosus.

Kidney involvement is common in patients with systemic lupus erythematosus (SLE). This study investigates the clinical and prognostic characteristics of thrombotic microangiopathy (TMA) compared to class IV lupus nephritis in SLE patients. A retrospective review of patients who underwent kidney biopsy, with a primary diagnosis of SLE and TMA between June 2006 and September 2018 was conducted. Those patients were subsequently compared to patients with class IV lupus nephritis between January 2018 and December 2018. Demographics, laboratory, and serological data at the time of biopsy were abstracted. Among 214 SLE patients records screened, 27 were included in the final analysis. Eight patients had lupus-related TMA without evidence of active lupus nephritis, while 19 patients had class IV lupus nephritis without evidence of TMA. TMA patients had significantly higher lactate dehydrogenase levels (718 ± 499 vs. 264 ± 107.7 U/L, p = 0.009), serum C3 (100.6 ± 39.3 vs. 65.8 ± 27mg/dL, p = 0.049), white blood cell count (14743.8 ± 7933.3 vs. 5807.9 ± 2053.2 × 10E3/uL, p < 0.001), and total bilirubin (0.8 ± 0.5 vs. 0.3 ± 0.1mg/dL, p = 0.007) in addition to significantly lower platelet counts (158.4 ± 88.6 vs. 240.3 ± 100.3 × 10E3/uL, p = 0.03), and haptoglobin (68.8 ± 116.1 vs. 166.8 ± 95.4mg/dL, p = 0.03). After a median follow-up time of 53 weeks, 3 patients with TMA were dialysis-dependent (37.5%), compared with none in class IV lupus nephritis patients (p = 0.002). TMA-associated SLE has worse prognosis compared to class IV lupus nephritis. An array of laboratory and pathological findings may be of value in discriminating between those two entities.

Value of sTNF-R1 and linc0597 as indicators for disease activity and diagnosis of lupus nephritis.

To explore whether Soluble tumor necrosis factor-receptor 1 (sTNF-R1) and linc0597 can be used as indicators for disease activity and diagnosis of lupus nephritis (LN). Eighty LN patients treated in our hospital were enrolled as the LN group, while 60 Systemic Lupus Erythematosus (SLE) patients without nephritis were included in the SLE group, and 50 healthy subjects who conducted physical examination during the same period as the control group. After admission, 5 mL of venous blood was taken from all the study subjects to measure sTNF-R1 level and linc0597 expression by enzyme-linked immunosorbent assay (ELISA) and RT-qPCR respectively. In addition, the receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic value of serum sTNF-R1 and linc0597 for LN, and Spearman correlation coefficient was adopted for the correlation between sTNF-R1, linc0597, and LN clinical disease Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Moreover, the logistic multiple regression analysis was applied to analyze the independent risk factors affecting the complication of LN in SLE patients. The LN group presented significantly higher serum sTNF-R1 and linc0597 levels than the control group and the SLE group. Besides, ROC curve analysis revealed that sTNF-R1 and linc0597 had good clinical diagnostic value in LN and SLE. Furthermore, Spearman correlation coefficient indicated that serum sTNF-R1 and linc0597 were positively correlated with disease activity index SLEDAI (r=0.551, p<0.001; R =0.604, p<0.001). Moreover, multivariate Logistic regression analysis demonstrated that age (p=0.001), fever (p=0.004), arthralgia (p=0.034), serum uric acid (p=0.019), decreased complement C3 (p=0.023), ANA peripheral type (p=0.007), anti-ds-DNA antibody (p=0.003), ANCA (p=0.002), sTNF-R1 (p=0.001), and linc0597 (p<0.001) were all independent risk factors affecting the complication of LN in SLE patients. STNF-R1 and linc0597 can be used as the indicators for disease activity and diagnosis of LN.

Plasma immunoglobulin binding protein 1 as a predictor of development of lupus nephritis.

Urine levels of immunoglobulin binding protein 1 (IGBP1) are increased in patients with lupus nephritis (LN) compared with systemic lupus erythematosus (SLE) patients without nephritis. However, the clinical significance of IGBP1 level in plasma is unclear. We aimed to evaluate whether the plasma level of IGBP1 can predict future development of LN in SLE patients without nephritis. Forty-three SLE patients without nephritis were followed for 5 years. Plasma IGBP1 levels were measured using ELISA, and clinical and laboratory data were obtained at study entry. Development of LN was confirmed by renal biopsy. Cox regression analysis was performed to identify factors associated with development of LN, and receiver operating characteristic curve analysis was used to determine the predictive value of each factor. Of the total 43 patients, eight (18.6%) developed LN during the follow-up period. Compared with patients who did not develop LN, those who developed LN had higher levels of plasma IGBP1 (6.3 ng/ml (range 4.3–9.6 ng/mL) vs. 13.3 ng/ml (range 7.2–31.3 ng/ml); p=0.023). In the Cox regression analysis, higher CRP (hazard ratio (HR)=1.325, 95% confidence interval (CI) 1.073–1.637, p=0.009), anti-dsDNA antibody (Ab; HR=1.066, 95% CI 1.012–1.124, p=0.017) and plasma IGBP1 (HR=1.091, 95% CI 1.034–1.152, p=0.002) were associated with future development of LN. Among these factors, anti-dsDNA Ab (area under the curve (AUC)=0.893) had the highest predictive value followed by plasma IGBP1 (AUC=0.761) and CRP (AUC=0.634). A combination of anti-dsDNA Ab and plasma IGBP1 as a composite predictor was highly specific (97%) for predicting the development of LN. Plasma IGBP1 can be used complementarily with anti-dsDNA Ab for detecting SLE patients at a higher risk of developing LN.

SAT-411 Anti nuclear Antibody negative Lupus like Nephritis. A 5 case series report

Systemic lupus erythematosus (SLE) is a disease due to an autoantibody response to nuclear and cytoplasmic antigen which is associated with the inflammatory cascades and end-organ damage in multiple organs like kidney, skin, brain, etc. In the kidney, immune-complex deposits leads to the deterioration of renal function leading to a condition called lupus nephritis. Lupus nephritis is a common but serious complication in SLE patients. Previously, American College of Rheumatology (ACR) required at least 4 of 11 clinical or laboratory criteria to diagnose SLE which included malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, pleuritis or pericarditis, kidney disorder, neurological disorder, hematologic disorder and positive antinuclear antibody. In 2019, there has been an update in this criteria, where positive antinuclear antibody is given as entry level criterion. If negative, cases cannot be classified as Systemic lupus erythematosus. If positive, further accumulation of 10 points is required for diagnosis of SLE. Lupus-like glomerulonephritis is defined as immune complex kidney disease with full house pattern in glomeruli where immunofluorescence staining for immunoglobulin G (IgG), IgA, IgM, complement (C3), and C1q are positive in an ANA negative patients. This findings is otherwise described as diagnostic criteria for lupus nephritis in SLE patients. Extraglomerular immune deposits within tubular basement membranes and tubuloreticular inclusions are other characteristic features that can be found in lupus nephritis. A total of 5 cases of ANA negative lupus like nephritis were reported in the department of renal pathology in University of Alberta between 1st January 2019 to 30th September, 2019. All of our cases were positive (IgG, IgA, IgM, C3, C1q) in immunofluorescence and were described as full house pattern. In light microscopy, 2 of the cases correlated with stage IV lupus nephritis, 2 correlated with stage V lupus nephritis and 1 case correlated with stage I lupus nephritis. Tubuloreticular inclusions were present in the one of the case. All patients responded to prednisolone as suggested by follow up laboratory datas.Table 1Variations in parameters among five cases.Case 1Case 2Case 3Case 4Case 5Age/sex62y/f56y/f24y/m42y/m7y/fANANegativeNegativeNegativeNegativeNegativedsDNANegative (positive after 2 month borderline 127 <120MFU)NegativeNegativeNegativeNegativeProtein creatinine ratio (PCR)306.3553.9(Normal <13.0 mg/mmol)238.57439.33975.52Urine Hemoglobin2+1+3+1+1+Serum. Creatinine121 (40-100 µmol/L)84 (40-100 µmol/L)106 (50-120 µmol/L)146 (50-120 µmol/L)29 (20-75 µmol/L)HematologyNormalNormalNormalNormalNormalLupus Nephritis gradeIVIIVVV Open table in a new tab In ANA negative patients, immune complex mediated glomerulonephritis with full house immunofluorescence pattern may be considered as lupus like glomerulonephritis. Other features like tubuloreticular inclusions, DsDNA might be positive in these patients. These patients present and response to treatment like renal limited lupus nephritis. They may develop full blown SLE in long term; hence close follow up is required. However, other causes of immune complex mediated glomerulonephritis must be ruled out before considering this diagnosis.

Urinary neutrophil gelatinase-associated lipocalin and monocyte chemoattractant protein 1 as biomarkers for lupus nephritis in Colombian SLE patients.

Background Information regarding urinary biomarkers in Mestizo and Afro-Latin-American patients is very limited. We investigated whether levels of urinary neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein 1 (MCP-1) are good biomarkers to differentiate patients with lupus nephritis among Latin-American systemic lupus erythematosus (SLE) patients. Methods SLE patients meeting the revised American College of Rheumatology classification criteria for SLE were recruited. Urinary levels of NGAL and MCP-1 were measured using a commercial ELISA kit. Serum anti-C1q antibodies were measured by ELISA. SLE activity was measured with the systemic lupus erythematosus disease activity index (SLEDAI). Mann-Whitney tests were used to compare data and Spearman's rank correlations were used to examine associations between continuous variables. In addition, receiver operating characteristic curves were performed. Results One hundred and twenty SLE patients were recruited (87% women) with a median age of 32.8 ± 12.1 years and median disease duration of 7.3 ± 6.9 years. Afro-Latin-Americans had a significantly higher prevalence of lupus nephritis and higher SLEDAI scores than Mestizos. The three biomarkers were significantly higher in patients with lupus nephritis than in patients without lupus nephritis. In addition, urinary NGAL and MCP-1 were significantly higher in patients with active lupus nephritis than in inactive lupus nephritis. Urinary NGAL levels were significantly higher in Afro-Latin-American patients. A receiver operating characteristic curve for urinary biomarkers for lupus nephritis in all SLE patients showed a good level of sensitivity and specificity. Conclusion In our cohort of SLE patients, we found that urinary NGAL and MCP-1 in addition to anti-C1q antibodies were useful biomarkers for the identification of renal involvement and discrimination of active lupus nephritis among patients with renal disease.

Dickkopf-1 Is a Biomarker for Systemic Lupus Erythematosus and Active Lupus Nephritis.

An early diagnosis of lupus nephritis (LN) has an important clinical implication in guiding treatments of systemic lupus erythematosus (SLE) in clinical settings. In this study, the concentrations of Wnt-3A, Frizzled-8 (FZD-8), and Dickkopf-1 (DKK-1) of Wnt signaling, as well as their diagnostic values for accessing LN, were evaluated by ELISA in sera and urine of 111 SLE patients (31 with LN and 80 without LN) and 70 healthy cohorts. Significantly more abundances of DKK-1 protein were determined in both of sera and urine of SLE patients compared to healthy cohorts (p < 0.0001); in particular the serum DKK-1 concentration was even higher in LN-SLE patients relative to non-LN SLE subjects (p < 0.0001). Intriguingly, concentrations of above examined proteins in SLE patients showed no correlation between serum and urine. Moreover, a combination of DKK-1 with anti-dsDNA and/or levels of complement C3 and C4 could not increase the specificity and/or sensitivity for identification of patients with LN diseases, but both ROC curve and multiple-factor nonconditional logistic regression analysis showed that serum DKK-1 was considered better positive biomarker for identification of LN in SLE patients. These results imply that serum and/or urine DKK-1 may be a valuable and independent biomarker for identification of SLE patients with LN.

Associations between eNOS polymorphisms and susceptibility to systemic lupus erythematosus and rheumatoid arthritis: ameta-analysis.

The aim of this study was to determine whether endothelial nitric oxide synthase (eNOS) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Ameta-analysis was conducted on associations between the 4b/a, T786C, and G894T polymorphisms of eNOS and SLE or RA using the following methods: (1)allele contrast, (2)recessive model, (3)dominant model, and (4)homozygous contrast. Nineteen studies were included in this meta-analysis, comprising eleven studies on SLE (1561 patients and 1565 controls) and eight on RA (1624 patients and 2118 controls). Meta-analysis showed asignificant association between SLE and the 4b/a polymorphism using the recessive model and the homozygous contrast (odds ratio [OR]= 1.836, 95 % confidence interval [CI]= 1.171-2.878, p= 0.008; OR= 2.055, 95 % CI= 1.302-3.243, p= 0.002). Ethnicity-specific meta-analysis showed asignificant association between the aa vs. bb of the 4b/a polymorphism and SLE in European populations (OR= 2.096, 95 % CI= 1.288-4.0, p= 0.027), but not in Arab populations. Stratification by presence of lupus nephritis (LN) indicated asignificant association between the aallele and the aa+ ab genotype of the 4b/a polymorphism and LN in SLE patients (OR= 2.125, 95 % CI= 1.289-3.054, p= 0.003; OR= 2.655, 95 % CI= 1.509-4.671, p= 0.001). Meta-analysis indicated no association between SLE and the T786C and G894T polymorphisms. No association was found between the eNOS 4b/a, T786C, and G894T polymorphisms and RA CONCLUSIONS: This meta-analysis of published studies shows that the eNOS 4b/a polymorphism may be associated with the development of SLE, but the 4b/a, T786C, and G894T polymorphisms may be not associated with RA susceptibility.

Antiphospholipid Antibodies in Lupus Nephritis

Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). It remains unclear whether antiphospholipid antibodies (aPL) alter the course of LN. We thus investigated the impact of aPL on short-term and long-term renal outcomes in patients with LN. We assessed levels of aPL cross-sectionally in SLE patients diagnosed with (n = 204) or without (n = 294) LN, and prospectively in 64 patients with active biopsy-proven LN (52 proliferative, 12 membranous), before and after induction treatment (short-term outcomes). Long-term renal outcome in the prospective LN cohort was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease (CKD) stage, after a median follow-up of 11.3 years (range: 3.3–18.8). Cross-sectional analysis revealed no association between LN and IgG/IgM anticardiolipin or anti-β2-glycoprotein I antibodies, or lupus anticoagulant. Both aPL positivity and levels were similar in patients with active LN and non-renal SLE. Following induction treatment for LN, serum IgG/IgM aPL levels decreased in responders (p<0.005 for all), but not in non-responders. Both at active LN and post-treatment, patients with IgG, but not IgM, aPL had higher creatinine levels compared with patients without IgG aPL. Neither aPL positivity nor levels were associated with changes in eGFR from either baseline or post-treatment through long-term follow-up. Moreover, aPL positivity and levels both at baseline and post-treatment were similar in patients with a CKD stage ≥3 versus 1–2 at the last follow-up. In conclusion, neither aPL positivity nor levels were found to be associated with the occurrence of LN in SLE patients. However, IgG aPL positivity in LN patients was associated with a short-term impairment of the renal function while no effect on long-term renal outcome was observed. Furthermore, IgG and IgM aPL levels decreased following induction treatment only in responders, indicating that aPL levels are affected by immunosuppressive drugs in a response-dependent manner.

Correlation of Serum Soluble Interleukin-7 Receptor and Anti-C1q Antibody in Patients with Systemic Lupus Erythematosus.

Background. Serum concentrations of soluble interleukin-7 receptor (sIL-7R) and anti-C1q antibody have recently been identified as unique serological markers for lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE). In this study, we evaluated the correlation of serum sIL-7R and anti-C1q in SLE patients. Methods. Sera from 134 patients with SLE and 84 healthy cohorts were tested for levels of sIL-7R and anti-C1q antibodies in terms of ELISA. Correlations of the sIL-7R and anti-C1q autoantibodies were evaluated. Results. The serum concentrations of sIL-7R and anti-C1q antibodies were significantly higher in SLE patients and LN patients in comparison with healthy individuals/controls and SLE patients with non-LN, respectively. In addition, both sIL-7R and anti-C1q concentrations were found to significantly correlate with the SLE disease activity as evaluated by SLEDAI scores. Interestingly, the serum sIL-7R concentration was strongly correlated with the level of anti-C1q antibodies (r = 0.2871, p = 0.0008) but not statistically correlated with other serological markers, including the anti-dsDNA and complements C3 and C4 concentrations in SLE patients. Conclusion. Both serum sIL-7R and anti-C1q antibodies were strongly associated with disease activity and LN in SLE patients, suggesting that they may be reliable serological markers for identification of SLE patients with active diseases and LN.

Function of the Th17/interleukin-17A immune response in murine lupus nephritis.

The CD4+ T cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of the Th17/interleukin-17 (IL-17) immune pathway to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. The aim of this study was to characterize the function of the Th17/IL-17A immune response in 2 murine models of lupus nephritis. IL-17A-deficient MRL/MPJ-Fas(lpr) /2J (MRL/lpr) mice were generated, and the clinical course of nephritis was monitored by assessing the levels of albuminuria, extent of renal tissue injury, and functional parameters. In addition, lupus-prone (NZB × NZW)F1 (NZB/NZW) mice were treated with anti-IL-17A and anti-interferon-γ (anti-IFNγ) antibodies, and their effects on the clinical course of lupus nephritis were assessed. Characterization of renal IL-17A-producing and IFNγ-producing T cells in MRL/lpr and NZB/NZW mice revealed low numbers of infiltrating CD3+IL-17A+ cells. Renal IL-17A was mainly produced by CD4/CD8 double-negative CD3+ T cells and CD4+ Th17 cells. In contrast, the number of renal CD3+IFNγ+ cells continuously increased over time and largely consisted of typical CD4+ Th1 cells. IL-17A deficiency did not affect the morphologic or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of nephritis in NZB/NZW mice, but anti-IFNγ treatment attenuated the severity of the disease. The Th17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. Thus, the results of this study do not support the hypothesis that IL-17A targeting could be an intriguing new therapeutic approach for the management of proliferative lupus nephritis in SLE patients.

4G/5G plasminogen activator inhibitor-1 and −308 A/G tumor necrosis factor-α promoter gene polymorphisms in Argentinean lupus patients: focus on lupus nephritis

We investigated the relationship between the 4G/5G plasminogen activator inhibitor (PAI-1) and -308 A/G tumor necrosis factor-α (TNF-α) polymorphisms and the clinical and biochemical features of systemic lupus erythematosus (SLE) in an Argentinean patient cohort. A total of 402 patients were studied, including 179 SLE patients and 223 healthy individuals. PCR-RLFP was used to determine the genotypes of the 4G/5G PAI-1 and -308 A/G TNF-α polymorphisms. SLE patients with lupus nephritis (LN) (n = 86) were compared with patients without LN (n = 93). Additionally, LN patients were divided into proliferative LN and non-proliferative LN groups according to the results of the renal biopsies. No significant differences were noted in the genotype distributions or allele frequencies of these TNF-α and PAI-1 polymorphisms between SLE patients and controls. There were higher numbers of criteria for SLE, more lupus flares and higher damage scores in LN patients, but there were similar frequencies of anti-phospholipid antibody (APA) positivity and anti-phospholipid syndrome. No significant difference was noted for any studied variable between the proliferative LN and non-proliferative LN groups except for the presence of APA. We found no significant differences in the TNF-α and PAI-1 genotype distributions or allele frequencies between groups. We found that the -308 A/G TNF-α and 4G/5G PAI-1 polymorphisms are not associated with susceptibility to SLE in an Argentinean population. We also did not find any association between the presence of any specific allele or genotype and the development of LN in SLE patients. Finally, no association was noted between either of the two polymorphisms and the severity of renal disease.

Associations between eNOS polymorphisms and susceptibility to systemic lupus erythematosus: a meta-analysis

To determine whether endothelial nitric oxide synthase (eNOS) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE). A meta-analysis was conducted on the associations between the 4b/a, G894T, and C786T polymorphisms of eNOS and SLE and lupus nephritis (LN) (when available) using (1) the allele contrast, (2) the recessive, (3) the dominant, and (4) the additive models. A total of eight studies, which included 1,297 cases and 1,214 controls, were included in the meta-analysis. Meta-analysis showed no association between SLE and the 4b/a polymorphism in any study subjects. Stratification by presence of LN indicated a significant association between the a allele and the aa+ab genotype of the 4b/a polymorphism and LN in SLE patients [odds ratio (OR)=2.125, 95% confidence interval (CI)=1.289-3.054, p=0.003; OR=2.655, 95% CI=1.509-4.671, p=0.001]. No association was found between SLE and the G894T polymorphism using the allelic, recessive, or dominant, or additive models. Meta-analysis of the T786C polymorphism showed a tendency to an association between the TT genotype and SLE (OR=1.220, 95% CI=1.000-1.489, p=0.050), and meta-analysis of the TT versus CC genotype of the C786T polymorphism in group in Hardy-Weinberg equilibrium revealed a significant association between the TT genotype and SLE (OR=1.643, 95% CI=1.021-2.644, p=0.041). This meta-analysis of published studies shows that the 4b/a polymorphism may be associated with the development of LN, and the C786T polymorphism may be associated with SLE susceptibility.

Association of serum uric acid with lupus nephritis in systemic lupus erythematosus

The aim of the present study is to assess the association of elevated serum uric acid (UA) with lupus nephritis (LN) in systemic lupus erythematosus (SLE) patients. A total of 130 SLE patients were recruited, of whom 73 patients developed LN. Blood samples were obtained for determination of uric acid, complement 3 (C3), C-reactive protein (CRP) and some autoantibodies including anti-double-stranded DNA, -Smith, -SSA, -SSB, -U1RNP, SCL-70, and -Jo-1 antibodies. Correlations of UA with LN were assessed. UA was an independent risk factor for LN [odds ratio (95% CI): 1.01 (1.005-1.014); P=0.0000]. The best cut-off value for UA using the ROC curve was 330 μmol/L (sensitivity 78.1% and specificity 75.4%) and the area under the ROC curve was 0.803±0.039 (95% CI: 0.727-0.878, P=0.000). Spearman's correlation coefficient analysis showed negative association of UA with C3 in SLE patients with LN (r=-0.356, P=0.002), but no association in those without LN. No correlations were found between UA and age, SLEDAI, CRP, IgG, IgM or IgA. Furthermore, analysis of covariance demonstrated that anti-Sm (β=-0.218, P=0.004) and -U1RNP (β=0.177, P=0.008) autoantibodies were independent determinants of serum UA. The UA level is independently associated with the development of LN in SLE patients.

Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study

IntroductionTNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-κB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity.MethodsMulticenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4.ResultsuTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed-effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity.ConclusionsHigh uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN.

Urinary lipocalin‐2 is associated with renal disease activity in human lupus nephritis

Pathogenic monoclonal anti-double-stranded DNA (anti-dsDNA) antibodies up-regulate the expression of lipocalin-2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal anti-dsDNA antibodies promote the local secretion of lipocalin-2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin-2 represents a marker of kidney involvement in SLE. Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross-sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin-2 were assessed. Among SLE patients, urinary lipocalin-2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3-45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1-20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0-11.1; n = 14), urinary levels of lipocalin-2 in SLE patients were significantly higher (non-normalized median 19.3 ng/ml, IQR 8-34.2) (P = 0.004). The presence of lipocalin-2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity. The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin-2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE.