狼疮肾炎患者肾组织白细胞介素-18表达的研究

目的　初步探讨白细胞介素 18(IL 18)在人类狼疮肾炎 (LN)肾组织炎症损伤中的作用。方法　应用免疫组织化学和原位杂交技术观察 6例正常肾组织和 18例LN患者肾组织IL 18的蛋白和基因表达量 ,并用酶联免疫吸附测定 (ELISA)法对该组患者尿IL 18水平进行检测。结果　正常肾组织有弱的IL 18mRNA及蛋白表达 ;LN患者肾组织IL 18mRNA及蛋白表达量均较正常肾组织显著增高 (IL 18mRNA :8 9± 3 4比 2 2± 0 6 ;IL 18蛋白 :8 8± 3 7比 1 4± 0 4 ) ,而且WHOⅣ型LN患者肾组织IL 18表达量显著高于非WHOⅣ型LN患者 (IL 18mRNA :10 8± 3 2比6 6± 1 7;IL 18蛋白 :11 2± 2 7比 5 6± 2 0 ) ;Spearman相关分析提示肾组织IL 18蛋白表达量与狼疮肾炎肾组织活动指数 (AI)、尿IL 18水平及肾组织损伤程度均呈正相关 (P均 <0 0 5 )。结论　肾内IL 18表达上调参与LN肾组织炎症损伤过程 ,尿IL 18水平可能作为衡量LN肾组织炎症活动程度的评估指标。     

Serum interleukin-18 levels in patients with systemic lupus erythematosus: Relation with disease activity and lupus nephritis

Aim of the workTo further investigate the possible role of IL-18 in the pathogenesis of systemic lupus erythematosus (SLE) and development of lupus nephritis (LN), and to explore its relationship with pathological classes of LN, degree of acute renal activity and chronic damage.Patients and methodsForty-one SLE patients with LN, thirty-one lupus non-nephritis patients and fifteen age and sex matched healthy controls were enrolled in this study. SLE patients were subjected to disease activity assessment by SLEDAI, renal disease activity assessment by the Systemic Lupus International Collaborating Clinics (SLICC) Renal Activity Score, laboratory investigations including measurement of serum interleukin-18 using Enzyme Linked Immunosorbent Assay. Renal biopsy was obtained from LN patients and pathological classification was made according to World Health Organization (WHO) criteria. Analysis of activity and chronicity indices was done on these biopsy specimens.ResultsSerum levels of IL-18 were significantly higher in patients with LN than lupus non-nephritis patients and healthy controls (p < 0.001). There were significant correlations between IL-18 and SLEDAI (p = 0.002), proteinuria (p = 0.027), renal activity score (p = 0.003) and activity index (p = 0.039) in patients with LN. There was no significant difference in the serum levels of IL-18 between WHO classes of LN.ConclusionIL-18 appears to have a pathogenic role in the development of SLE and plays a crucial role in triggering inflammation in LN. Serum IL-18 levels could be a useful biomarker to assess the activity of renal disease in SLE.     

Occurrence of renal tubular dysfunction in lupus nephritis

We prospectively evaluated 30 patients who presented with active systemic lupus erythematosus (SLE) for the presence of tubular abnormalities. All patients fulfilled the American Rheumatology Association criteria for SLE. When appropriate, a renal biopsy was performed. Of the 30 patients studied, 12 had no abnormal tubular study results, whereas 18 patients had some form of defect in the handling of potassium, sodium, or hydrogen ions. Eight patients had distal renal tubular acidosis (dRTA) due to an isolated proton secretory defect. Five had dRTA of the gradient or acid back-leak type. Two had an unresponsive voltage-dependent form of dRTA; one had a responsive voltage-dependent form of dRTA. One individual had hyporeninemic hypoaldosteronism and one had dRTA plus hypoaldosteronism. Clinically, patients with the abnormal tubular study results more often presented with nephritis or nephrotic sediment, peripheral edema, or anemia. Renal biopsies failed to demonstrate any difference in glomerular histologic findings and calculated activity, chronicity, or interstitial indexes. We conclude that SLE may be associated with a variety of tubular defects.     

Glomerular deposition of renal tubular epithelial antigen in patients with systemic lupus erythematosus: its possible role in lupus nephritis

Fifty-three renal specimens from 48 patients with SLE were examined for the presence of RTE in the glomeruli. Glomerular RTE, presumably in immune complex form was detected in 60% of the tissues. The deposition of these complexes was related to the severity of histologic changes and activity of SLE. In addition, glomerular localization of RTE was associated with decreased renal function and increased proteinuria. The association between the presence of glomerular RTE antigen, the severity of renal histologic changes and the decreased renal function suggested a possible role for this antigen in the pathogenesis of lupus nephritis.     

Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis

Objective

To ascertain whether engineered expression of kallikreins within the kidneys, using an inducible Cre/loxP system, can ameliorate murine lupus nephritis.

Methods

In mice with a lupus‐prone genetic background, we engineered the expression of tamoxifen‐inducible Cre recombinase under the control of a kidney‐specific promoter whose activation initiates murine kallikrein‐1 expression within the kidneys. These transgenic mice were injected with either tamoxifen or vehicle at age 2 months and then were monitored for 8 months for kallikrein expression and disease.

Results

Elevated expression of kallikrein was detected in the kidney and urine of tamoxifen‐injected mice but not in controls. At age 10 months, all vehicle‐injected mice developed severe lupus nephritis, as evidenced by increased proteinuria (mean ± SD 13.43 ± 5.65 mg/24 hours), increased blood urea nitrogen (BUN) and serum creatinine levels (39.86 ± 13.45 mg/dl and 15.23 ± 6.89 mg/dl, respectively), and severe renal pathology. In contrast, the tamoxifen‐injected mice showed significantly reduced proteinuria (6.6 ± 4.12 mg/24 hours), decreased BUN and serum creatinine levels (15.71 ± 8.17 mg/dl and 6.64 ± 3.39 mg/dl, respectively), and milder renal pathology. Tamoxifen‐induced up‐regulation of renal kallikrein expression increased nitric oxide production and dampened renal superoxide production and inflammatory cell infiltration, alluding to some of the pathways through which kallikreins may be operating within the kidneys.

Conclusion

Local expression of kallikreins within the kidney has the capacity to dampen lupus nephritis, possibly by modulating inflammation and oxidative stress.

     

Evaluation of visfatin in patients with systemic lupus erythematosus: Correlation with disease activity and lupus nephritis

IntroductionRenal involvement affects about 50% of SLE patients accounting for significant morbidity and mortality in these patients. The adipokine “visfatin” acting as a growth factor for B-lymphocyte-precursors, exerts several proinflammatory functions. It was demonstrated as a marker of endothelial dysfunction (ED) in chronic kidney disease (CKD) thus could be a factor linking inflammation in SLE and kidney disease.Aim of the workTo assess serum visfatin level in SLE patients and its correlation to disease activity and lupus nephritis (LN) in these patients.Patients and methodsSerum level of visfatin using enzyme-linked immunosorbent assay (ELISA), chemical and immunological markers of SLE and LN were measured in 40 SLE patients and 40 age and sex matched healthy controls. Disease activity and renal involvement were assessed using SLE Disease Activity Index (SLEDAI) and Renal SLEDAI respectively further dividing patients into active versus inactive and LN versus non-LN respectively. Renal biopsies were taken from LN subgroup and were classified according to the modified WHO classification.ResultsA significantly higher serum visfatin level was found on comparing SLE patients (mean 109 ± 180 ng/ml, median18) with controls (mean 9.4 ± 11 ng/ml, median2.5) with statistically highly significant difference (z = 5.2, P < 0.001). Also there was a statistically significant difference as regards serum visfatin level between active SLE patients (mean 173 ± 111 ng/ml, median 14) and inactive patients (mean 139 ± 88 ng/ml, median 5) (z = 2.1, P < 0.05) as well as between patients with LN (mean 226 ± 180 ng/ml, median18) and patients with no LN (mean 101 ± 140 ng/ml, median 8(2-229)) (z = 2.1, P < 0.05). Visfatin had a highly significant positive correlation with disease duration (r = 0.48, P < 0.001), SLEDAI (r = 0.62, P < 0.001) as well as ESR, CRP and, renal score (r = 0.45, 0.35, and 0.65, respectively) while inverse correlation with estimated GFR (r = ?0.614) and C3 and C4 titre (r = ?0.26, r = ?0.35, respectively) was recorded. Visfatin showed high sensitivity in detecting active SLE and LN 83% and 85%, respectively.ConclusionSerum visfatin is strongly associated with LN in SLE patients and is a promising biomarker for prediction of renal involvement in these patients. It reflects SLE activity specially LN activity namely renal score and GFR decline. Further prospective studies are required to confirm visfatin as a destructive mediator of predictive and prognostic value in active lupus nephritis.     

Elevated interleukin-18 levels correlated with disease activity in systemic lupus erythematosus

The aim of this study was to determine the serum interleukin-18 (IL-18) levels in patients with systemic lupus erythematosus (SLE) and to assess their relationship with disease activity. Thirty-five patients with SLE and 35 age- and sex-matched controls were enrolled in this study. Paired serum samples were collected from all the patients with SLE, both at active stage before treatment and at the stable stage after treatment. The serum IL-18 levels were determined using ELISA and their correlations with the disease activity, measured using the SLE Disease Activity Index (SLEDAI) and laboratory parameters such as anti-dsDNA antibody, CH50, C3, C4, and circulating immune complex levels, were analyzed. The serum IL-18 levels in patients with SLE were significantly higher than those in the controls, particularly when the disease status was active (mean±SD: active stage, 721.23±360.15 pg/ml; inactive stage, 343.68±317.78 pg/ml; controls, 113.98±13.22 pg/ml, p<0.05). The IL-18 levels measured at the active stage before treatment correlated well with SLEDAI (r=0.41, p<0.05) and anti-dsDNA antibody titer (r=0.35, p<0.05). When we compared the changes of the IL-18 level and those of parameters reflecting the disease activity between the active stage and the stable stage of the disease, it was found that the changes in IL-18 level correlated well with the changes of SLEDAI score during the patients disease course (r=0.39, p<0.05). In conclusion, the serum IL-18 levels were elevated in patients with SLE, and these increased levels correlated well with SLE disease activity.Abbreviations CIC Circulating immune complex - IFN Interferon - IL Interleukin - SLE Systemic lupus erythematosus - TNF Tumor necrosis factor     

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

狼疮肾炎终末期肾病患者尸体肾移植的临床观察

目的　探讨狼疮肾炎终末期肾病 (LN ESRD)患者行尸体肾移植手术的可行性及预后和狼疮活动的情况。方法　回顾性分析我院自 1972年开展肾移植手术以来 6例LN ESRD患者在透析时、术前及术后狼疮活动性指数 (SLEDAI)以及移植的时机、移植后免疫抑制剂的使用和人 /肾存活情况。结果　 6例皆为女性患者 ,皆因LN而出现ESRD。移植前皆接受慢性透析治疗 ,其中透析距移植的时间最短为 3个月 ,最长为 9年。移植后 3例用强的松、环孢素A和霉酚酸酯三联免疫抑制治疗 ,另 3例用泼尼松、环孢素A和硫唑嘌呤治疗。 6例患者有 5例存活至今 ,平均存活 (44± 34 )个月 ,最长为 85个月 ,最短为 4个月。 1例在移植后 4个月因高血压脑出血而死亡 ,死前肾功能正常 ,且无狼疮活动。移植术后 1周内移植肾功能皆恢复正常 ,无 1例因狼疮复发而致移植肾功能减退或丧失 ,其中带肾存活最长且肾功能的保持正常者已达 77个月。在慢性透析期间及移植术后无狼疮活动 (SLEDAI<9分 )。结论　肾移植是治疗LN ESRD成功而有效的手段 ,肾移植后狼疮复发率低。     

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

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

     

Association of serum renalase with disease activity in lupus nephritis

<正>Objective To investigate the relationship between serum renalase and disease activity in lupus nephritis(LN).Methods Total of 70 patients with LN and 35healthy volunteers admitted in Renji Hospital of Shanghai Jiao Tong University from March 2012 to March 2013were enrolled in the study.LN patients were classified     

Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus

BACKGROUND: Previous studies have indicated that the autoimmune phenomenon might be caused by an imbalance of T-helper cell (Th) cytokines. METHODS: We investigated the plasma concentrations of a novel pro-inflammatory Th1 cytokine, interleukin (IL)-18, and its inducer, IL-12, in patients with systemic lupus erythematosus (SLE) and correlated them with the SLE disease activity index (SLEDAI). Plasma IL-18 and IL-12 concentrations of 40 SLE patients and 18 sex- and age-matched control subjects were measured by enzyme-linked immunosorbent assay. RESULTS: Plasma IL-18 and IL-12 concentrations were significantly higher in SLE patients than in control subjects [median (interquartile range): IL-18, 320.0 pg/ml (164.4-475.6 pg/ml) vs 130.1 pg/ml (57.8-202.4 pg/ml), P<0.001; IL-12, 143.3 pg/ml (39.4-247.2 pg/ml) vs. 84.7 pg/ml (29.3-140.1 pg/ml), P<0.001]. Increases in IL-18 concentration correlated positively and significantly with SLEDAI score (r = 0.449, P = 0.004). CONCLUSION: The novel cytokine IL-18 might play a crucial role in triggering the inflammatory processes in SLE.     

Lck在狼疮肾炎肾小管上皮细胞中表达的研究

目的 观察狼疮肾炎病理过程中淋巴细胞特异性蛋白酪氨酸激酶（Lck）在肾小管上皮细胞内的表达及白细胞介素-2（IL-2）对其表达的影响。方法 体外培养6周龄BXSB狼疮小鼠的近端肾小管上皮细胞，给予IL-2刺激，采用反转录聚合酶链反应（RT—PCR）方法及免疫印迹法检测肾小管上皮细胞中Lck mRNA和蛋白的表达，观察IL-2对Lck表达水平的影响。同时用免疫组织化学方法观察Lck蛋白在狼疮肾炎小鼠和人类肾脏组织标本肾小管上皮细胞内的表达情况。结果 体外培养的6周龄BXSB狼疮小鼠近端肾小管上皮细胞中仅有微量LckmRNA及蛋白的表达，IL-2刺激后表达水平显著增加（P〈0．05）。免疫组织化学方法显示：正常BALB／C小鼠、未发病的狼疮小鼠和人类微小病变性肾病肾脏组织的肾小管上皮细胞内均未发现明显的Lck蛋白表达，而已发病的16周龄狼疮肾炎小鼠和人类Ⅳ型狼疮肾炎肾脏组织标本的肾小管上皮细胞内则有明显的Lck蛋白表达。结论 IL-2可活化肾小管上皮细胞并诱导Lck表达，Lck可能作为细胞因子或炎症因子的重要信号分子，在小管-间质性炎症及狼疮肾炎病理过程中发挥着重要作用。     

狼疮肾炎患者外周血白细胞和肾组织白细胞介素-18及其结合蛋白的表达

目的 研究狼疮肾炎(LN)患者外周血白细胞及.肾组织局部白细胞介素-18(IL-18)及其内源性抑制蛋白IL-18结合蛋白(IL-18BP)的表达水平,进一步探讨IL-18及IL-18BP在LN发病中的作用.方法 SYBR green dye Ⅰ实时定量聚合酶链反应(PCR)方法检测外周血白细胞IL-18 mRNA及IL-18BPmRNA的表达;酶联免疫吸附试验(ELISA)方法检测血清IL-18的表达;免疫组织化学方法检测肾组织局部IL-18和IL-18BP的表达.结果 LN组IL-18BP mRNA的2-△△CT值(6±9)显著低于对照组(13±9,P=O.006);IL-18 mRNA的2-△△CT值(1.1±1.0)与对照组(1.1±0.7)之间差异无统计学意义(P=0.929),而血清IL-18的水平(146±101)pg/ml比对照组(48±45)pg/ml明显升高(P=0.000);激素联合应用环磷酰胺(CTX)冲击治疗的患者血清IL-18的水平明显低于单用激素或激素联合应用其他免疫抑制剂的患者(P=0.042);LN患者肾小球内IL-18呈高表达,IL-18BP在肾小管内高表达,而肾小球内表达相对较弱.结论 LN患者外周血白细胞IL-18BP基因的表达降低,而血清IL-18的水平显著升高.作为IL-18的内源性抑制蛋白,较低的IL-18BP的表达可能不能完全中和IL-18的作用而导致TLN疾病的活动与反复发作.LN患者肾小球高表达IL-18,IL-18可能参与了肾组织局部的炎症反应.     

Correlation between hemoglobin and progression of renal function in patients with proliferative lupus nephritis

<正>Objective To explore the correlation between hemoglobin( Hb) and progression of renal function in patients with proliferative lupus nephritis( PLN).Methods Data of biopsy-proven PLN patients from January 2010 to February 2019 in Department of Nephrology,     

狼疮肾病终末期患者肾移植的临床分析

目的：对6例系统性红斑狼疮（SLE）终末期肾病患者的肾移植情况进行总结。方法：对6例终末期狼疮肾病肾移植患者的临床、实验室资料和手术后随访情况进行分析。结果：6例患者均为女性，平均病程4.4年，进行移植手术时全身病情稳定；术前均使用激素和/或免疫抑制剂控制SLE病情，手术后免疫抑制剂使用情况差异无显著性，术后平均随诊时间为24.2个月，无1例发生急、慢性排异反应及狼疮肾病复发，移植肾功能良好。结论：终末期狼疮肾病患者的移植肾存活及功能状况良好，无狼疮肾病复发，肾移植是治疗终末期狼疮肾病的有效方法之一。