Diagnostic value of TWEAK for predicting active lupus nephritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis

Purpose Accumulative studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was up-regulated in the blood and urine from patients diagnosed with lupus nephritis (LN) and that it might be used as a novel biomarker for active LN. This meta-analysis aimed to determine the diagnostic value of TWEAK in active LN.Methods We searched the Cochrane Library, Embase, PubMed, Springer, Wanfang and CNKI databases for articles published up to 20 August 2020. The diagnostic capacity of TWEAK for active LN was assessed using pooled sensitivity and specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC). Quality assessment and publication bias were also evaluated. STATA 11.0 and Meta-Disc 1.4 were used to perform these analyses.Results Nine cross-sectional studies were included in this meta-analysis. The overall pooled sensitivity of TWEAK for the diagnosis of active LN was 0.69 (95% CI, 0.63–0.75), and specificity was 0.77 (95% CI, 0.71–0.82). The overall pooled PLR and NLR were 3.31 (95% CI, 2.05–5.35) and 0.38 (95% CI, 0.26–0.55), respectively, with a DOR of 10.89 (95% CI, 6.73–17.63) and AUC (SE) of 0.8276 (0.0289). Deeks’ funnel plot revealed that the publication bias was insignificant in the study (p = .32).Conclusions Our results suggest that TWEAK might be a potential biomarker for patients with active LN. Future cross-sectional and longitudinal studies are needed to confirm its diagnostic value, as well as to establish more definite cutoff for active LN.     

Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

TNF ligand superfamily member 12, also known as TNF-related weak inducer of apoptosis (TWEAK), acts through its receptor, fibroblast growth factor-inducible 14 (Fn14), to mediate several key pathologic processes involved in tissue injury relating to lupus nephritis. To explore the potential for renal protection in lupus nephritis by targeting this pathway, we introduced the Fn14 null allele into the MRL-lpr/lpr lupus mouse strain. At 26–38 weeks of age, female Fn14-knockout MRL-lpr/lpr mice had significantly lower levels of proteinuria compared with female wild-type MRL-lpr/lpr mice. Furthermore, Fn14-knockout mice had significantly improved renal histopathology accompanied by attenuated glomerular and tubulointerstitial inflammation. There was a significant reduction in glomerular Ig deposition in Fn14-knockout mice, despite no detectable differences in either serum levels of antibodies or splenic immune cell subsets. Notably, we found that the Fn14-knockout mice displayed substantial preservation of podocytes in glomeruli and that TWEAK signaling directly damaged barrier function and increased filtration through podocyte and glomerular endothelial cell monolayers. Our results show that deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model through prevention of the direct injurious effects of TWEAK on the filtration barrier and/or modulation of cytokine production by resident kidney cells. Thus, blocking the TWEAK/Fn14 axis may be a novel therapeutic intervention in immune-mediated proliferative GN.     

Dyslipidaemia in patients with lupus nephritis

Aim: There is little data on the prevalence and severity of dyslipidaemia in Asian patients with lupus nephritis (LN). Whether the dyslipidaemia in LN patients differs from subjects with comparable levels of renal impairment also remains undefined. Methods: Lipid profiles of 100 Chinese patients with quiescent LN (age 46.3 ± 9.3 years, 83% female, maintenance prednisolone dose 5.80 ± 2.43 mg/day) were studied and compared with 100 controls who had non‐lupus non‐diabetic chronic kidney diseases (CKD), matched for sex, age and renal function. Results: LN patients and CKD controls had similar renal function and proteinuria, while blood pressure was higher in controls. Twenty‐five percent of LN patients and 17% of controls were receiving statin treatment. Despite this, 59% of LN patients and 46% CKD controls showed abnormal lipid parameters (P = 0.066). LN patients showed higher levels of total cholesterol (TC) and triglycerides (TG) than controls (5.28 ± 0.12 vs 4.86 ± 0.08 mmol/L, P = 0.004; and 1.62 ± 0.12 vs 1.20 ± 0.07 mmol/L, P = 0.002, respectively). More LN patients had abnormal TC, TG or low‐density lipoprotein cholesterol (LDL‐C) (54%, 16% and 38%; P = 0.016, = 0.005 and = 0.021, respectively). Hydroxychloroquine (HCQ) treatment was associated with lower TC, LDL‐C and HDL‐cholesterol. Conclusion: Dyslipidaemia is prevalent in LN patients and is more severe than controls with a similar degree of CKD despite disease quiescence, low steroid dose and low level of proteinuria. Concomitant corticosteroid and renal impairment are likely contributing factors. HCQ treatment is associated with reduced severity of dyslipidaemia in LN patients.     

Efficacy of enteric-coated mycophenolate sodium in patients with active lupus nephritis

Background: The ideal treatment of lupus nephritis has yet to be defined. Both cyclophosphamide and mycophenolate mofetil have been used with encouraging results, but adverse events are frequently seen. There are no data on the use of enteric‐coated mycophenolate sodium. Methods: We retrospectively reviewed 12 patients with active forms of lupus nephritis (1 class III, 7 class IV and 4 class V) treated with enteric‐coated mycophenolate sodium combined with corticosteroids. Results: The mean age of the patients was 32.3 ± 11.2 years and the average length of follow up was 25.9 ± 8.9 months. The mean serum creatinine clearance was 93 ± 30.1 mL/min per 1.73 m² and the mean proteinuria level was 4.5 ± 3.6 g/day. All had features that warranted aggressive treatment. Mycophenolate sodium was given for 12.9 ± 9.7 months with an averaged starting dose of 1350 ± 163 mg/day. Six patients attained complete remission and six attained partial remission with treatment. The mean interval to attain first remission (complete or partial) was 8.3 ± 5.7 weeks. At last follow up, all patients were in complete or partial remission. Apart from herpes zoster that developed in one patient, no other significant side‐effects were encountered. Conclusion: Enteric‐coated mycophenolate sodium was effective and well‐tolerated in the treatment of active lupus nephritis.     

Role of intravenous cyclophosphamide in lupus nephritis patients with renal impairment

Summary: Twenty-three patients with lupus nephritis (21 diffuse proliferative glomerulonephritis and two with focal proliferative glomerulonephritis) with impaired renal functions were evaluated for their response to pulse cyclophosphamide. Diagnosis of lupus nephritis was based on American rheumatism association criteria or on the basis of renal manifestations with high anti dsDNA antibody titres. Cyclophosphamide was given in dosage of 900mg/m² as infusion in 500 mL of 5% dextrose (reduced by 25% if serum creatinine was more than 6 mg/dL) once every month for 6 months then 3 monthly for a minimum of 3 years. Response was defined by 24h protein excretion less than 500mg and serum creatinine less than 1.4mg/dL. Nine patients (group I) had normal function (serum creatinine 1.16 ± 0.21mg/dL) and 14 patients (group II) had impaired renal function at presentation (serum creatinine 3.72 ± 4.06 mg/dL). Both groups were compared for response to therapy. All patients in group I were in complete remission at last follow up of 44.6 ± 8.3 months (serum creatinine 1.14 ± 0.2mg/dL, 24h proteinuria 0.3 ± 0.3g). While in group 2, 13 patients showed improvement. Two patients were in complete remission, seven in partial remission, one patient died and four patients had mild renal failure at last follow up of 40.2 ± 10.4 months (serum creatinine 1.81 ± 0.74, 24h proteinuria 2.19 ± 2.54g). the side effects of therapy included infection, transient leucopenia and vomiting. We conclude that intravenous (I.V) cyclophosphamide is an effective therapy in severe lupus nephntis with renal impairment.     

Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up.

BACKGROUND: Whether corticosteroid and immunosuppressive therapy may be safely withdrawn in patients with proliferative lupus nephritis is still unclear. METHODS: In 32 patients with biopsy-proven proliferative lupus nephritis previously put into remission, therapy was gradually tapered off. RESULTS: When immunosuppressive therapy was stopped (median: 38 months; 25th-75th percentile: 24-81 months, after biopsy), 24 patients were in complete remission and eight had a median proteinuria of 1.05 g/24 h (25th-75th percentile: 0.91-1.1 g/24 h) with normal renal function. After stopping therapy, patients were followed for a median of 203 months (25th-75th percentile: 116-230 months). Fifteen patients (Group 1) never developed lupus activity. The other 17 patients (Group 2) developed lupus exacerbations in a median of 34 months (25th-75th percentile: 29-52 months) after stopping therapy and were re-treated. The only significant differences between the two groups were the longer median durations of treatment, 57 months (25th-75th percentile: 41.5-113.5 months) vs 30 months (25th-75th percentile: 18-41 months; P<0.009), and remission, 24 months (25th-75th percentile: 18-41) vs 12 months (25th-75th percentile: 7-20 months; P<0.02), before stopping therapy in Group 1 than in Group 2. At last follow-up, 12 patients of Group 1 were in complete remission, two had mild proteinuria and one had died. In Group 2, one patient died, 14 were in complete remission, one had mild proteinuria and in another patient serum creatinine doubled. CONCLUSIONS: Some patients with severe lupus nephritis who enter stable remission can be maintained without any specific treatment for many years. Those patients who have new flares can again go into remission with an appropriate treatment. The longer the treatment and remission before withdrawal, the lower the risk of relapse.     

152例V型狼疮肾炎的临床病理研究

目的 研究V型狼疮肾炎（LN）两种病理亚型的临床特点及其转归。方法 152例经肾穿刺活检确诊的V型LN，根据是否伴有肾小球系膜增生性病变。分为Va(61例），Vb(91例）两种亚型，分析其临床病理特点，并与同期的488例Ⅳ型LN作比较。结果 Vb型高血压，贫血，肾功能减退的发生率及低补体血症，抗dsDNA抗体阳性率明显高于Va型，与Ⅳ型接近。肾活检病理Vb型肾小球节段襻坏死，微血栓比例高于Va型，免疫复合物沉积强于Va 型。在行重复肾活检的11例Va型，13例Vb型中分别有2例（18．2％）和8例（61．5％）转为Ⅳ型LN(P＜0．05）。随访1年以上的47例Va型，66例Vb型中分别有3例（6．4％）和10例（15．2％）出现血肌酐倍培。结论 Va型患者不仅肾组织损害轻，而且肾外表现较少。与之相比，Vb型临床特征更接近于Ⅳ型，部分患者可以转化为Ⅳ型，预后比Va型差。     

Predictors of poor renal outcome in patients with biopsy‐proven lupus nephritis

Aim: The development of lupus nephritis (LN) is associated with increased morbidity and mortality. In view of scarce data from South Africa on factors affecting renal outcome in LN, the authors' experience was reviewed to identify predictors of poor renal outcome. Methods: This is a retrospective review of 105 patients with biopsy‐proven LN under our care from January 1995 to December 2007. Results: Forty‐three (41.0%) patients reached the composite end‐point of persistent doubling of the serum creatinine over the baseline value, development of end‐stage renal disease (ESRD) or death during a mean follow‐up period of 51.1 months (range 1–137 months). Baseline factors associated with the composite end‐point included presence of systemic hypertension (P = 0.016), mean systolic blood pressure (SBP) (P = 0.004), mean diastolic blood pressure (DBP) (P = 0.001), mean serum creatinine (P = 0.001), estimated glomerular filtration rate (eGFR) (P = 0.003) and diffuse proliferative glomerulonephritis (World Health Organization class IV) (P = 0.024). Interstitial inflammation (P = 0.049), failure of remission in the first year following therapy (P < 0.001), the mean SBP on follow up (P < 0.001) and mean DBP on follow up (P < 0.001) were also associated with composite end‐point. On multivariate analysis, baseline serum creatinine, non‐remission following therapy (P = 0.038) and mean SBP on follow up (P = 0.016) were predictors of poor renal outcome. Conclusion: Baseline serum creatinine, failure of remission in the first year and mean SBP were predictors of poor renal outcome.     

狼疮肾炎患者循环miRNA表达谱研究及循环miR-130b-3p的临床意义

目的分析处于不同进展阶段的狼疮肾炎(LN)患者循环miRNA的表达变化并探讨其可能存在的临床意义。 方法本研究共94份血清标本,包括58例LN患者和36名健康体检者(作为对照组)。挑选出其中性别、年龄匹配的12份血清标本用于循环miRNA表达谱筛选,包括早期LN组4份(CKD 1～3期),晚期LN组4份(CKD分期4～5期)及对照组4份作为芯片组,使用miRNA PCR芯片检测血清miRNA变化;剩余50例LN患者(40例早期LN患者、10例晚期LN患者)及32名对照者血清样本作为验证组,用于验证miRNA表达谱筛选结果;以Nanodrop 2000检测血清总RNA抽提浓度;选择miR-130b-3p和miR-1233-3p作为验证对象;进行Spearman相关性分析。 结果芯片组结果显示,与对照组相比,早期LN组中7个表达上升的miRNA差异具有统计学意义,分别是：miR-1233-3p (P＝0.019)、miR-130b-3p (P＝0.021)、miR-18a-3p (P＝0.021)、miR-628-3p (P＝0.023)、miR-1260b (P＝0.030)、miR-1539 (P＝0.041)和miR-378e (P＝0.047);晚期LN组分别与对照组及早期LN组比较,未发现表达上调大于2倍或者上调差异具有统计学意义的miRNA。验证组结果显示：晚期LN组患者分别与对照组、早期LN组比较,血清总RNA浓度下降(U＝4.5,P<0.001;U＝18.0,P<0.001);早期LN组与对照组比较,血清中miR-130b-3p表达升高[IQR 16.2(8.7,42.7)与9.6(4.8,17.4), U＝405.5,P＝0.008];晚期LN组分别与对照组及早期LN组比较,MiR-130b-3p和miR-1233-3p表达均下降(U＝69.0、P＝0.008,U＝46.0、P<0.001;U＝80.0、P＝0.019,U＝70.0、P＝0.002);相关性分析显示循环miR-130b-3p的相对表达量与24 h尿蛋白(r＝0.404,P＝0.010)、肾脏慢性活动指数(r＝0.389,P＝0.013)、甘油三酯(r＝0.376,P＝0.017)呈正相关。 结论严重肾功能衰竭患者可能存在循环miRNA广泛表达下调,循环miRNA-130b-3p在早期LN患者中表达升高并与肾脏损伤和血脂调节异常相关,在LN发生发展中可能起作用。     

Comparison between males and females with lupus nephritis

Summary: In this study 17 male and 100 female cases with lupus nephritis were divided into four groups according to their clinical features at presentation. Each case was compared in order to identify sex-linked differences in their disease manifestations as well as underlying histopathological features and ultimate prognosis. the World Health Organization (WHO) histologic criteria were used for classification purposes. In all patients, age, chronicity index, duration of clinical activity of the disease before kidney biopsy and follow-up periods were statistically similar in the two groups of males and females. However, males had a significantly higher activity index in comparison to females at the time of initial kidney biopsy. In addition, diffuse proliferative histopathology was more common in males compared to females ( P = 0.002). Moreover, the renal and patient survival was significantly shorter in males as compared to female cases ( P = 0.0024, P = 0.0165, respectively). the proportions of males with severe lupus nephritis presenting with hypertension, reduced creatinine clearance, massive proteinuria and reduced levels of complement leading to end-stage renal disease was significantly higher compared to the females among the four clinical groups of the patients. In conclusion, our data indicates that lupus nephritis in males is a more progressive and severe disease in comparison to female cases. In addition its underlying histopathology is almost always diffuse proliferative lesions, leading to a poorer renal and patient survival in them.     

狼疮性肾炎94例的治疗总结

目的:探讨中西医结合治疗狼疮性肾炎(IN)的疗效。方法:随机设置中西医组和西医组,分别为94例、84例,两组进行有效率、复发率、副作用的比较。结果:西医组总有效率80.9％,复发率21.4％,副作用发生率77.1％;中西医组总有效率94.6％,复发率4.2％,副作用发生率38.0％,中西医组总有效率高于西医组(P<0.05)。结论:中西医结合治疗在提高疗效,减少复发及减轻副作用均显著优于西医组。     

Effects of mycophenolate mofetil for patients with crescentic lupus nephritis

Objective: To compare the effects, relapse ratio and outcomes between mycophenolate mofetil (MMF) and pulse intravenous cyclophosphamide (CTX) for the induction therapy in patients with crescentic lupus nephritis. Methodology: This is a retrospective, controlled study. Twenty-seven MMF therapeutic and twenty-five CTX therapeutic lupus patients with ≥50% crescent formation were enrolled in this study. The general conditions, clinicopathological findings, remission and relapse ratio, and outcomes of them were compared. Results: There was no significant difference of general condition and clinicopathological findings between MMF and CTX group. At 12 months, the total remission ratio in MMF and CTX group were 73.1% and 69.6%, while the complete remission ratio in MMF group (53.8%) was significantly higher than that in CTX group (26.1%). The relapse ratio in MMF group (10.5%) was significantly lower than in CTX group (43.8%). Forty per cent of PR patients in CTX group suffered from relapse. Until June 2005, the patients in CTX group received a follow time with 38.5 ± 21.2 (range 10∼80) months, and in MMF group the follow time was 41.1 ± 27.0 (range 12∼90) months. Two patients in MMF group and two in CTX group entered into end stage renal failure. The side effect of infection was more significant in CTX group. Conclusion: Higher complete remission ratio and lower relapse ratio were observed in MMF group than in CTX group. The side effect of infection was more infrequent in MMF group, which showed preferable security of MMF.     

Methylprednisolone pulse therapy in Japanese children with severe lupus nephritis

Six Japanese children with severe lupus nephritis received prompt initiation of methylprednisolone pulse therapy (MPT). After three courses of MPT, oral prednisolone combined with a 12-week course of oral cyclophosphamide was given and prednisolone was tapered. At presentation, urine protein excretion and histological indices of the mean activity index and the mean chronicity index in the patients were 2.2±1.5 g/day, 10.3±2.0, and 2.8±1.2, respectively. Urine protein excretion and the activity index decreased significantly at the second renal biopsies obtained at a mean interval of 8 months after the first [0.1±0.1 g/day and 3.5±1.4 (P<0.05), respectively], while the chronicity index did not change. At the latest observation (mean interval 53 months), all showed clinical and serological improvement. Complete remission was achieved in two patients, and no patient showed renal impairment. Although this case series is without controls, our treatment protocol may be of benefit to Japanese children with severe lupus nephritis. Received: 21 March 2000 / Revised: 1 December 2000 / Accepted: 19 April 2001     

Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis

In most cases of systemic lupus erythematosus (SLE), glomerular lesions are the main renal complication. Although tubulointerstitial lesions are often associated with severe glomerular lesions, predominant or isolated tubulointerstitial injury in the presence of minimal glomerular abnormalities with SLE, so-called predominant tubulointerstitial lupus nephritis, is rare. Only ten cases are reported in the English literature. Herein, we describe the case of a 64-year-old man with SLE who presented with acute renal deterioration attributable to acute tubulointerstitial nephritis. Renal biopsy showed diffuse infiltration of inflammatory mononuclear cells in the interstitium and tubulitis without significant glomerular lesions. Immunofluorescence study revealed positive staining for IgG, C3, and C1q along the renal tubular basement membrane (TBM). Electron microscopy also showed electron-dense deposits in the TBM. Other causes of tubulointerstitial injury, such as drug use and infection, were ruled out. Taking these findings together with the presence of antitubular basement membrane antibody, predominant tubulointerstitial lupus nephritis was diagnosed. Treatment with oral corticosteroids for 6 weeks improved renal function. Even after tapering of the corticosteroid, renal function and serological markers of SLE activity have remained stable in this patient for more than 12 months.     

Glomerular and tubulointerstitial miR-638, miR-198 and miR-146a expression in lupus nephritis

Aim: MicroRNAs (miRNAs) play important roles in the pathogenesis of autoimmune diseases. We studied the intra‐renal expression of miRNA targets that were reported to be differentially expressed in peripheral blood or urine between lupus nephritis (LN) patients and normal controls. Methods: We quantified the expression of in glomerulus and tubulointerstitium of miR‐146a, miR‐155, miR‐198 miR‐638 and miR‐663 in 42 patients with LN and 10 healthy controls. Results: As compared with controls, LN patients had lower glomerular expression of miR‐638 (P < 0.001) but higher tubulointerstitial expression of this target (P = 0.001). Both glomerular and tubulointerstitial expression of miR‐198 were higher in LN patients than controls (P < 0.001). For miR‐146a, LN patients only had higher expression in glomerulus (P = 0.005) but not in tubulointerstitium. Tubulointerstitial miR‐638 expression was significantly correlated with proteinuria (r = 0.404; P = 0.022) and disease activity score (r = 0.454; P = 0.008), while glomerular miR‐146a expressions were correlated with estimated GFR (r = 0.453; P = 0.028) and histological activity index (r = 0.494; P = 0.027). Conclusion: We found that intra‐renal expression of miR‐638, miR‐198 and miR‐146a are differentially expressed between LN patients and normal controls. Furthermore, the degree of change in glomerular miR‐146a and tubulointerstitial miR‐638 expression correlated with clinical disease severity. The results suggested that these miRNA targets may play a role in the pathogenesis of lupus nephritis.     

Outcome in African-American children of neuropsychiatric lupus and lupus nephritis

The present study reviews the course of lupus nephritis (LN) with the added complication of neuropsychiatric systemic lupus erythematosus (NPSLE) in a predominantly African-American population in order to identify the risk factors accounting for the increased morbidity and mortality in African-American children. Previous studies, including those at our center, have demonstrated the poor prognosis for African-American children with LN. A possible factor is the involvement of the central nervous system (CNS), resulting in a heightened risk of morbidity, although to date there are no reports suggesting an association between NPSLE and patient and renal survival in children with lupus nephritis. To this end, we retrospectively analyzed charts of 72 children with lupus nephritis seen at our center from 1965 to 1999. These 72 patients formed two groups, with group 1 consisting of patients with lupus nephritis and NP manifestations and group 2 only lupus nephritis. We then examined various demographic factors such as age, sex and race along with the histopathologic class of lupus nephritis, occurrence of hypertension, incidence of end stage renal disease (ESRD), time to ESRD and mortality in both groups with the aid of Fisher’s exact t-test and the chi-square test. Briefly, the results revealed significantly higher class III or IV histopathologic lesions on biopsy, incidence of hypertension, progression to ESRD and mortality in children with NPSLE and LN (group 1) compared to LN alone (group 2) in spite of aggressive immunosuppressive therapy. In conclusion, we report that NPSLE with LN is associated with an increased rate of ESRD and mortality in our predominantly African-American children. Received: 26 March 2001 / Revised: 13 August 2001 / Accepted: 13 August 2001