Renal Involvement In Systemic Lupus Erythematosus Research Articles

Serum ferritin level correlates with SLEDAI scores and renal involvement in SLE.

Ferritin is an acute-phase reactant that is elevated in various autoimmune disorders. Serum ferritin levels have been positively correlated with disease activity scores of rheumatoid arthritis and systemic lupus erythematosus (SLE). Further, enhanced levels of ferritin have also been reported in lupus nephritis. However, there are no reports from the Indian subcontinent. Seventy-six female SLE patients, diagnosed on the basis of revised ACR criteria, and 50 healthy females, age matched from similar geographical areas, were enrolled in the present study. Serum levels of ferritin, IFN-α and IL-6 were quantified by enzyme-linked immunosorbent assay (ELISA). Clinical, biochemical, serological and other markers of disease activity (C3, C4 and anti-dsDNA) were measured by standard laboratory procedure. Serum ferritin levels were significantly higher in SLE patients compared to healthy controls (p < 0.0001). Ferritin levels positively correlated with SLE Disease Activity Index (SLEDAI) (p = 0.001, r = 0.35), anti-dsDNA (p = 0.001, r = 0.35), IFN-α (p < 0.0001, r = 0.51) and IL-6 (p < 0.0001, r = 0.65) and negatively correlated with C3 (p = 0.0006, r = -0.38) and C4 (p = 0.01, r = -0.28). Interestingly, serum levels of ferritin were positively associated with proteinuria (p = 0.001, r = 0.36), serum urea (p = 0.0004, r = 0.39) and serum creatinine (p = 0.0006, r = 0.38). Serum ferritin is an excellent marker of disease activity and renal dysfunction in SLE.

Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

Association between -1486 T&gt;C and +1174 G&gt;A single nucleotide polymorphisms in TLR9 gene and severity of lupus nephritis

Signaling through Toll-like receptor-9 (TLR9), a mediator of innate immune responses, could have a role in the pathogenesis of systemic lupus erythematosus (SLE). Some studies have shown an association between polymorphisms in the TLR9 gene and disease manifestations. We investigated whether two single nucleotide polymorphisms (-1486 T>C and +1174 G>A) in the TLR9 gene are associated with the risk of renal involvement in SLE. DNA samples from 112 SLE patients (62 with lupus nephritis) and 100 healthy controls were obtained. TLR9 polymorphisms (-1486 T>C and +1174 G>A) were analyzed by polymerase chain reaction–restriction fragment length polymorphism. Genotype and allelic frequencies were compared between lupus patients and healthy controls. Clinical and laboratory manifestations and activity scores on renal biopsy of patients with lupus nephritis were compared between various genotypes. There was no difference in the frequency of genotype or allele distribution at either of the two loci between lupus patients and controls and in lupus patients with or without nephritis. Patients with CC/CT genotype at the -1486 position had higher serum creatinine (P = 0.03) and Austin activity scores (P = 0.015). Patients with AA/AG genotype at +1174 position showed higher serum creatinine (P = 0.04), proteinuria (P = 0.011), anti-dsDNA titers (P < 0.001) and Austin activity scores (P = 0.003) than the GG genotype. Variations at the -1486 and +1174 positions of TLR9 gene are not associated with increased risk of SLE or that of kidney involvement in North Indians. CC/CT genotypes at -1486 and AA/AG at +1174 positions are associated with more severe kidney disease at presentation.

Recent advances in the treatment of lupus nephritis

Lupus nephritis is a common complication of systemic lupus erythematosus (SLE) which is associated with significant morbidity and mortality. The concept of two phases of therapy for lupus nephritis, such as an induction phase and a maintenance phase, is widely accepted. Since the renal involvement in SLE is heterogeneous, the treatment of lupus nephritis is governed by its pathological type and ranges from nonspecific measures, such as maintenance of adequate blood pressure control and blockade of the renin-angiotensin-aldosterone system, to the use of immunosuppressive agents. Cyclophosphamide (CYC) in combination with prednisone has been the standard method of treatment of the proliferative forms of lupus nephritis. However, the high rates of progression to end-stage renal disease coupled with the adverse effects of CYC and prednisone have led to an intensive search for more effective and less toxic therapies for lupus nephritis. We review the options available for the treatment of proliferative and membranous lupus nephritis and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE.

Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus

IntroductionThere is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE. The aim of this study was to investigate the distribution and phenotypical characteristics of IL-17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134.MethodsThirty-four patients (3 male, 31 female, mean age 41 ± 15 years) fulfilling at least four of the American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE and 24 healthy controls were enrolled. T-cells from the peripheral blood were analysed by fluorescence activated cell sorting (FACS) for their expression levels of CD80, CD134 and CCR6. In vitro stimulated CD3+IL17+ cells were also investigated for the expression of these costimulatory markers. Finally, renal biopsies from SLE patients were evaluated for the presence of CD134 expressing T-cells.ResultsPercentages of IL-17 expressing T-cells were significantly increased in patients with active disease as compared to healthy controls (1.46 ± 0.58% versus 0.93 ± 0.30%, P = 0.007). The percentage of IL-17 producing T-cells was correlated with disease activity as assessed by systemic lupus erythematosus disease activity index (SLEDAI) (r = 0.53, P = 0.003). In patients, most of the IL-17 producing T-cells were confined to the CCR6+ T-cell subset (80 ± 13%). Expression of CD80 and CD134 on the IL-17 producing T-cell subset was higher in SLE than in healthy controls (HC) (CD134: 71.78 ± 14.51% versus 51.45 ± 16.58%, P = 0.002; CD80: 25.5 ± 14.99% versus 14.99 ± 5.74%, P = 0.02). Also, patients with lupus nephritis expressed higher levels of CD134+ on CD3+IL-17+ cells as compared to HC (72.69 ± 11.54% versus 51.45 ± 16.58%, P = 0.006). Furthermore, renal biopsies of lupus nephritis patients showed infiltration of CD134+ T cells.ConclusionsPercentages of IL-17 expressing T-cells correlate with disease activity. Further, these cells show increased expression of costimulatory markers such as CD134 and CD80. The presence of CD134+ T-cells in renal biopsies of lupus nephritis patients suggest that these cells migrate to the kidney and might contribute to inflammatory processes through IL-17 secretion.

New Strategies in the Management of Children and Adolescents with Proliferative Lupus Nephritis

Systemic lupus erythematosus (SLE) is a serious medical illness with frequent renal involvement at disease onset. Although predominantly affecting young women, SLE often first presents during childhood. Previous studies have suggested that patients with disease onset in childhood have a worse prognosis. Renal involvement in SLE is the major determinant of long-term outcome; the ten-year survival in children with lupus nephritis was only around 20% in late 60s, but outcomes have improved dramatically in recent years to around 94%. This article will review recent data on new approaches in the treatment of pediatric lupus nephritis by referencing the major studies over the last few years. We will also examine the validity of various factors that have been suggested by previous studies to have prognostic value in determining outcomes.

Peripheral Circulating Activated B‐cell Populations are Associated with Nephritis and Disease Activity in Patients with Systemic Lupus Erythematosus

B-cell-dependent autoantibody production is a hallmark of systemic lupus erythematosus (SLE) which requires costimulatory molecules. The aim of the study was to analyse the expression of costimulatory molecules on B cells in patients with SLE. Twenty-six patients with SLE (four male, 22 female, mean age 46 +/- 15 years) as defined by the American College of Rheumatology criteria and 13 healthy controls (three male, 10 female, mean age 43 +/- 15 years) were included in the study. In a subgroup analysis, SLE patients were divided according to renal involvement due to SLE (10 with and 16 patients without renal involvement). Clinical disease activity was assessed according to the systemic lupus erythematosus disease activity index (SLEDAI). Blood B-cell populations were analysed by FACS for the cell surface marker expression of CD27, CD38, CD71, CD80, CD86 and CD137 ligand. The expression levels of CD71, CD80 and CD86 on B cells were significantly enhanced in SLE patients when compared with healthy controls (27 +/- 3% versus 11 +/- 2%, P = 0.0003, 55 +/- 2% versus 28 +/- 4%, P < 0.0001, 34 +/- 3% versus 12 +/- 2%, P < 0.0001). CD86 expression was significantly elevated in patients with renal involvement when compared with patients without renal disease (43 +/- 6% versus 28 +/- 3%, P < 0.05). There was a significant correlation between the expression levels of CD80 and CD86 on CD19(+) B cells and disease activity. Moreover, prednisone dose significantly correlated with SLEDAI (r = 0.5, P = 0.02) and with the expression levels of CD86 (r = 0.47, P = 0.02). A pathological B-cell population is associated with disease activity and renal involvement in SLE which are obviously resistant to therapy with medium doses of prednisone.

New Therapies for Lupus Nephritis

Renal involvement is frequent in patients with systemic lupus erythematosus (SLE) and may strongly influence their expectancy and quality of life. Until recently, the treatment of lupus nephritis mainly rested on three drugs: corticosteroids, cyclophosphamide, and azathioprine. However, newer agents have been introduced in the last few years. In this paper, the available treatments for lupus nephritis are reviewed, with special emphasis on diffuse proliferative glomerulonephritis, which represents the most severe form of renal involvement in SLE. After the seminal paper of Pollak et al. (1), who showed the better efficacy of high-dose prednisone over small doses, the treatment of diffuse proliferative SLE nephritis has been based for some years on high doses of corticosteroids. Such an approach, however, was often unable to control the progression of nephritis and was complicated by severe morbidity and elevated mortality. Therefore, a number of clinicians decided to add either cyclophosphamide or azathioprine to corticosteroids both to reduce the doses and side effects of corticosteroids and to slow the progression of renal disease. A meta-analysis of the available trials showed that the risk of renal insufficiency and dialysis was lowered by the addition of immunosuppressive drugs but mortality rate was not (2). In 1986, the group of the National Institutes of Health (NIH) reported the long-term results of a randomized trial, in which 107 patients with SLE nephritis were assigned to receive prednisone alone or moderate doses of prednisone in combination with intravenous (IV) pulses of cyclophosphamide, oral cyclophosphamide, azathioprine, or a combination of oral cyclophosphamide and azathioprine (3). The administration of IV pulses of cyclophosphamide was associated with a 10-yr renal survival significantly better than that observed with prednisone. However, there was not any significant difference in renal survival between IV cyclophosphamide and the other three immunosuppressive regimens. After this report, most centers …

Cytochrome P450 and manganese superoxide dismutase genes polymorphisms in systemic lupus erythematosus

Objectives: To investigate the role of cytochrome P450 1A1 (CYP1A1) and manganese superoxide dismutase (Mn SOD) genes polymorphisms in the pathogenesis of systemic lupus erythematosus (SLE) in Taiwan. Methods: CYP1A1 and Mn SOD genes polymorphisms were determined by the polymerase chain reaction/restriction fragment length polymorphism (RFLP) method in 90 patients with SLE and 94 healthy controls. Results: The genotype frequency of CYP1A1 4887C/A was significantly higher in patients with SLE than in controls. The allele and phenotype frequencies of CYP1A1 4887A were also significantly increased in SLE patients. In contrast, there were no significant differences in the genotype, allele and phenotype frequencies of Mn SOD C1183T polymorphisms between patients with SLE and controls. We also found that SLE patients with CYP1A1 4887A had a trend of increasing prevalence of renal involvement, while Mn SOD C1183T polymorphisms were not associated with the renal involvement in SLE. Conclusions: CYP1A1 4887A may be a precipitating factor for the development of SLE. It also tended to be associated with the occurrence of renal involvement in SLE patients. A synergistic effect was found between CYP1A1 4887C/A and Mn SOD 1183T/T on the susceptibility to SLE.

Inflammatory cytokine gene expression in the urinary sediment of patients with lupus nephritis.

Lupus nephritis is characterized by intrarenal inflammation and lymphocyte activation. In the present study, the expression of cytokine genes in the urinary sediment of patients with systemic lupus erythematosus (SLE) was examined. We studied 3 SLE patient groups (25 with active lupus nephritis [active group], 25 with inactive SLE and previous renal involvement [remission group], 20 with inactive SLE and no history of renal involvement [nonrenal SLE group]) and 2 control groups (10 patients with noninflammatory renal diseases [non-SLE group] and 10 healthy volunteers [healthy group]). Cytokine gene expression in the urinary sediment was studied by real-time quantitative polymerase chain reaction. Expression of interferon-gamma (IFNgamma) in urinary sediment was significantly higher in the active group than in all other groups (P < 0.001 by Kruskal-Wallis test). Among the SLE patient groups, there was a close correlation between IFNgamma expression and the overall SLE Disease Activity Index (SLEDAI) score (Spearman's r = 0.590, P < 0.001) and the SLEDAI renal score (r = 0.642, P < 0.001). Urinary expression of interleukin-2 (IL-2) in the active group was significantly higher than that in the healthy group (P = 0.046) but not in the remission or nonrenal SLE groups. There was no difference in the levels of IL-4 expression among the SLE groups. We found a predominance of Th1 cytokine in the urinary sediment of patients with active lupus nephritis. Measurement of cytokine gene expression in urinary sediment may be a useful noninvasive tool for assessing the severity of renal involvement in SLE.

Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents.

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) can be associated with significant morbidity in children and adolescents. Renal involvement in SLE appears to be more severe and more frequent in the pediatric age group, with the major predictors for poor outcome being the severity of histopathologic lesions, severity of renal impairment at diagnosis, and hypertension. In addition to currently recognized cardiovascular and pulmonary involvement, accelerated atherosclerosis is of increasing concern in young individuals with SLE, because of both disease effects and medication usage. Neuropsychiatric SLE seen in childhood ranges from subtle cognitive dysfunction to severe central nervous system involvement; however, there is controversy over the value of different diagnostic studies. APS in children may be associated with SLE, idiopathic, or associated with viral infections. Systemic anticoagulation is recommended for patients with thrombotic events, but long-term management has not been well studied in children.

Changes in antibodies to C1q predict renal relapses in systemic lupus erythematosus

The presence of elevated plasma levels of autoantibodies against C1q, a subcomponent of the first component of complement in sera of patients with systemic lupus erythematosus (SLE) has been found to be associated with renal involvement. The purpose of this study was to determine whether increases in anti-C1q antibodies (anti-C1q) precede renal involvement in SLE. Forty-three SLE patients were studied longitudinally to determine the relationship between manifestations of the disease and levels of anti-C1q as well as to identify antibodies against double-stranded DNA (anti-dsDNA). Increased levels of anti-C1q were detected in all 14 of the patients who developed proliferative lupus nephritis out of 17 patients with renal relapses, which was significantly more frequent ( P < 0.005) than in patients with nonrenal relapses (six of 16 patients) or with inactive disease (two of 10 patients). Increased anti-dsDNA levels were observed in 14 of 17 patients with renal relapses compared with 15 of 16 patients with nonrenal relapses and five of 10 patients with inactive disease. Significant increases in anti-C1q levels prior to the relapse occurred in 10 of 14 patients who developed proliferative nephritis and in three of 16 patients with nonrenal relapses. Significant increases in anti-dsDNA levels occurred in 11 patients of the former group and in nine patients of the latter group. No significant increases in anti-C1q or anti-dsDNA levels were observed in the patients with inactive disease. The mean time period between the occurrence of a significant increase in anti-C1q or anti-dsDNA level and the moment of renal relapse for both antibodies was 2.3 months. These results suggest that an increase in anti-C1q level has a predictive value for an ensuing renal relapse of proliferative lupus nephritis, and that serial measurements of anti-C1q levels might be useful in the management of SLE patients.

Clinical Significance of Antineutrophil Cytoplasmic Autoantibodies With Specificity for Lactoferrin in Renal Diseases

The prevalence and clinical significance of antineutrophil cytoplasmic antibodies with specificity for lactoferrin was determined in patients with renal diseases. Antilactoferrin antibodies were found in only 12 of 920 patients (1.3%). These patients had either "pauci-immune" necrotizing crescentic glomerulonephritis (three cases) or lupus nephritis (nine cases). To verify whether antilactoferrin antibodies were specific for patients with systemic lupus erythematosus (SLE) and renal involvement, we studied 61 additional lupus patients, 40 with active lupus nephritis and 21 with active SLE and no renal involvement. Antilactoferrin antibodies were found in approximately 15% to 20% of patients with SLE, irrespective of the presence of renal involvement. We conclude that antineutrophil cytoplasmic antibodies with specificity for lactoferrin are only sporadically found in patients with renal diseases; these patients have either necrotizing crescentic glomerulonephritis or lupus nephritis. However, antilactoferrin antibodies are not a marker for renal involvement in SLE.