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1.  Identification of urinary metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal segmental glomerulosclerosis 
Arthritis Research & Therapy  2011;13(6):R199.
Introduction
Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS).
Methods
Metabolic profiling was conducted using urine samples of patients with proliferative LN without membranous features (Class III/IV; n = 7) or pure membranous LN (Class V; n = 7). Patients with primary FSGS and proteinuria (n = 10) served as disease controls. For each patient, demographic information and clinical data was obtained and a random urine sample collected to measure NMR spectra. Data and sample collection for patients with LN occurred around the time of kidney biopsy. Metabolic profiling analysis was done by visual inspection and principal component analysis.
Results
Urinary citrate levels were 8-fold lower in Class V LN compared to Class III/IV patients, who had normal levels of urinary citrate (P < 0.05). Class III/IV LN patients had > 10-fold lower levels of urinary taurine compared to Class V patients, who had mostly normal levels (P < 0.01). Class V LN patients had normal urinary hippurate levels compared to FSGS patients, who completely lacked urinary hippurate (P < 0.001).
Conclusions
This pilot study indicated differences in urinary metabolites between proliferative LN and pure membranous LN patients, and between LN and FSGS patients. If confirmed in larger studies, these urine metabolites may serve as biomarkers to help discriminate between different classes of LN, and between LN and FSGS.
doi:10.1186/ar3530
PMCID: PMC3334650  PMID: 22152586
2.  Urine VCAM-1 as a marker of renal pathology activity index in lupus nephritis 
Arthritis Research & Therapy  2012;14(4):R164.
Introduction
Although renal pathology is highly predictive of the disease course in lupus nephritis, it cannot be performed serially because of its invasive nature and associated morbidity. The goal of this study is to investigate whether urinary levels of CXC ligand 16 (CXCL16), monocyte chemotactic protein-1 (MCP-1) or vascular cell adhesion molecule-1 (VCAM-1) in patients with lupus nephritis are predictive of particular features of renal pathology in renal biopsies obtained on the day of urine procurement.
Methods
CXCL16, MCP-1, and VCAM-1 levels were measured in urine samples from 74 lupus nephritis patients and 13 healthy volunteers. Of the patients enrolled, 24 patients had a concomitant kidney biopsy performed at the time of urine collection. In addition, patients with other renal diatheses were also included as controls.
Results
All three molecules were elevated in the urine of systemic lupus erythematosus patients, although VCAM-1 (area under curve = 0.92) and MCP-1 (area under curve = 0.87) were best at distinguishing the systemic lupus erythematosus samples from the healthy controls, and were also most strongly associated with clinical disease severity and active renal disease. For patients in whom concurrent renal biopsies had also been performed, urine VCAM-1 exhibited the strongest association with the renal pathology activity index and glomerulonephritis class IV, although it correlated negatively with the chronicity index. Interestingly, urinary VCAM-1 was also elevated in anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis, focal segmental glomerulosclerosis and membranous nephropathy but not in minimal-change disease.
Conclusion
Urinary VCAM-1 emerges as a reliable indicator of the activity:chronicity ratios that mark the underlying renal pathology in lupus nephritis. Since VCAM-1 is involved in the acute phase of inflammation when leukocytic infiltration is ongoing, longitudinal studies are warranted to establish whether tracking urine VCAM-1 levels may help monitor clinical and pathological disease activity over time.
doi:10.1186/ar3912
PMCID: PMC3580557  PMID: 22788914
3.  Usefulness of ISN/RPS Classification of Lupus Nephritis 
Journal of Korean Medical Science  2009;24(Suppl 1):S7-S10.
About 50-80% of patients with lupus suffer from lupus nephritis which is one of major causes of morbidity and mortality. Renal pathologists and nephrologists should evaluate the degree of histological damages to establish therapeutic plans for lupus nephritis. In order to standardize definitions, to emphasize clinically relevant lesions, and to improve interobserver reproducibility, the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed. Recently, several retrospective validation studies concerning the utility of the ISN/RPS classification, especially among class IV, were performed. In these reports, reproducibility is improved by the definition of diagnostic term, but the outcome related with classification, especially in class IV, is controversial. We performed retrospective analysis of 99 biopsy-proven subjects with lupus nephritis in our facility using the ISN/RPS classification. The class IV-G group tended to exhibit a worse renal outcome, but the difference compared with IV-S was not significant. In a Cox proportional hazards models, Independent histological predictors of poor renal outcome were extracapillary proliferation, glomerular sclerosis and fibrous crescents, while hyaline thrombi and fibrous adhesions were of favorable renal outcome. Both were similarly observed in IV-G and IV-S. The more qualitative categorization by the response to standard treatment may be needed to emphasize clinically relevant lesion related to renal outcome.
doi:10.3346/jkms.2009.24.S1.S7
PMCID: PMC2633180  PMID: 19194566
ISN/RPS Classification; Lupus; Lupus Nephritis; Outcome
4.  The spectrum of renal thrombotic microangiopathy in lupus nephritis 
Introduction
Among various lupus renal vascular changes, thrombotic microangiopathy (TMA) presented with the most severe clinical manifestations and high mortality. The pathogenesis of TMA in systemic lupus erythematosus (SLE) was complicated. The aim of this study was to assess clinical manifestations, laboratory characteristics, pathological features and risk factors for clinical outcomes of lupus nephritis patients co-existing with renal TMA in a large cohort in China.
Methods
Clinical and renal histopathological data of 148 patients with biopsy-proven lupus nephritis were retrospectively analyzed. Serum complement factor H, A Disintegrin and Metalloprotease with Thrombospondin type I repeats 13 (ADAMTS-13) activity, antiphospholipid antibodies and C4d deposition on renal vessels were further detected and analyzed.
Results
In the 148 patients with lupus nephritis, 36 patients were diagnosed as co-existing with renal TMA based on pathological diagnosis. Among the 36 TMA patients, their clinical diagnoses of renal TMA were as followings: 2 patients combining with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 2 patients combining with anti-phospholipid syndrome, 2 patients with malignant hypertension, 1 patient with scleroderma and the other 29 patients presenting with isolated renal TMA. Compared with the non-renal TMA group, patients with renal TMA had significantly higher urine protein (7.09 ± 4.64 vs. 4.75 ± 3.13 g/24h, P = 0.007) and serum creatinine (159, 86 to 215 vs. 81, 68 to 112 μmol/l, P <0.001), higher scores of total activity indices (AI) (P <0.001), endocapillary hypercellularity (P <0.001), subendothelial hyaline deposits (P = 0.003), interstitial inflammation (P = 0.005), glomerular leukocyte infiltration (P = 0.006), total chronicity indices (CI) (P = 0.033), tubular atrophy (P = 0.004) and interstitial fibrosis (P = 0.018). Patients with renal TMA presented with poorer renal outcome (P = 0.005) compared with the non-TMA group. Renal TMA (hazard ratio (HR): 2.772, 95% confidence interval: 1.009 to 7.617, P = 0.048) was an independent risk factor for renal outcome in patients with lupus nephritis. The renal outcome was poorer for those with both C4d deposition and decreased serum complement factor H in the TMA group (P = 0.007).
Conclusions
There were various causes of renal TMA in lupus nephritis. Complement over-activation via both classical and alternative pathways might play an important role in the pathogenesis of renal TMA in lupus nephritis.
doi:10.1186/ar4142
PMCID: PMC3672792  PMID: 23320601
5.  Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis 
Arthritis Research & Therapy  2009;11(6):R188.
Introduction
Serum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients.
Methods
Thirty-eight patients with lupus nephritis were included. Treatment with corticosteroids combined with cyclophosphamide, mycophenolate mofetil or rituximab was started after baseline kidney biopsy. A second biopsy was taken after ≥ 6 months. Serum creatinine, cystatin C, complement, anti-dsDNA, anti-CRP and urinalysis were done on both occasions. Biopsies were evaluated regarding World Health Organisation (WHO) class and indices of activity and chronicity. Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index.
Results
At baseline, 34/38 patients had renal BILAG-A; 4/38 had BILAG-B. Baseline biopsies showed WHO class III (n = 8), IV (n = 19), III to IV/V (n = 3) or V (n = 8) nephritis. Seventeen out of 38 patients were anti-CRP-positive at baseline, and six at follow-up. Overall, anti-CRP levels had dropped at follow-up (P < 0.0001) and anti-CRP levels correlated with renal BILAG (r = 0.29, P = 0.012). A positive anti-CRP test at baseline was superior to anti-dsDNA and C1q in predicting poor response to therapy as judged by renal BILAG. Baseline anti-CRP levels correlated with renal biopsy activity (r = 0.33, P = 0.045), but not with chronicity index. Anti-CRP levels were positively correlated with anti-dsDNA (fluorescence-enhanced immunoassay: r = 0.63, P = 0.0003; Crithidia luciliae immunofluorescence microscopy test: r = 0.44, P < 0.0001), and inversely with C3 (r = 0.35, P = 0.007) and C4 (r = 0.29, P = 0.02), but not with C1q (r = 0.14, P = 0.24). No associations with urinary components, creatinine, cystatin C or the glomerular filtration rate were found.
Conclusions
In the present study, we demonstrate a statistically significant correlation between anti-CRP levels and histopathological activity in lupus nephritis, whereas a baseline positive anti-CRP test predicted poor response to therapy. Our data also confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis.
doi:10.1186/ar2880
PMCID: PMC3003497  PMID: 20003354
6.  Urinary monocyte chemotactic protein-1 and transforming growth factor-β in systemic lupus erythematosus 
Indian Journal of Nephrology  2012;22(1):5-12.
The purpose of this investigation was to assess the correlation of two biomarkers with the occurrence of renal flares in systemic lupus erythematosus (SLE). Urine levels of monocyte chemotactic protein-1 (MCP-1) and transforming growth factor beta (TGF-β) were measured at baseline, and at two and four months in five groups of patients: 25 lupus nephritis patients with active disease (active LN), 10 lupus nephritis patients with SLE in remission (remission LN), 25 patients with clinical active SLE and without nephritis (active NLN), 10 patients without nephritis with SLE in remission (remission NLN) and 10 healthy controls. We used repeated measurement and ANOVA with Duncan's post hoc to analyze the data; the urine level of the two proteins could distinguish the groups based on the existence of lupus nephritis and/or activity of SLE disease. Furthermore we performed receiver operating curve analysis to identify a cutoff point with a good sensitivity and specificity to diagnose lupus nephritis with either one of the urine proteins. Finally the samples from active LN were grouped according to whether they were Class IV or other classes. Baseline urinary MCP-1, but not TGF-β, was significantly different between the classes. Further investigation into the use of these cytokines in a prospective study is needed to determine their capacity as diagnostic tools for renal flares.
doi:10.4103/0971-4065.91179
PMCID: PMC3263065  PMID: 22279336
Lupus nephritis; monocyte chemotactic protein-1; systemic lupus erythematosus; transforming growth factor beta
7.  Anti-C1q antibodies antedate patent active glomerulonephritis in patients with systemic lupus erythematosus 
Introduction
Autoantibodies against C1q correlate with lupus nephritis. We compared titers of anti-C1q and anti-dsDNA in 70 systemic lupus erythematosus patients with (n = 15) or without (n = 55) subsequent biopsy-proven lupus nephritis.
Methods
The 15 patients with subsequent lupus nephritis had anti-C1q assays during clinical flares (mean Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), 10.0 ± 4.7; range, 3 to 22) before the diagnosis of lupus nephritis (median, 24 months; range 3 to 192). Among the 55 others, 33 patients had active lupus (mean SLEDAI, 10.3 ± 6.2; range, 4 to 30) without renal disease during follow-up (median 13 years; range 2 to 17 years) and 22 had inactive lupus (mean SLEDAI, 0; range, 0 to 3).
Results
Anti-C1q titers were elevated in 15/15 (100%) patients who subsequently developed nephritis (class IV, n = 14; class V, n = 1) and in 15/33 (45%) patients without renal disease (P < 0.001). The median anti-C1q titer differed significantly between the groups (P = 0.003). Anti-C1q titers were persistently positive at the time of glomerulonephritis diagnosis in 70% (7/10) of patients, with no difference in titers compared with pre-nephritis values (median, 147 U/ml; interquartile range (IQR), 69 to 213 versus 116 U/ml; 50 to 284, respectively). Titers decreased after 6 months' treatment with immunosuppressive drugs and corticosteroids (median, 76 U/ml; IQR, 33 to 106) but remained above normal in 6/8 (75%) patients. Anti-dsDNA antibodies were increased in 14/15 (93.3%) patients with subsequent nephritis and 24/33 (72.7%) patients without nephritis (P = ns). Anti-C1q did not correlate with anti-dsDNA or the SLEDAI in either group.
Conclusions
Anti-C1q elevation had 50% positive predictive value (15/30) and 100% (18/18) negative predictive value for subsequent class IV or V lupus nephritis.
doi:10.1186/ar2725
PMCID: PMC2714141  PMID: 19515233
8.  Intrarenal cytokine gene expression in lupus nephritis 
Annals of the Rheumatic Diseases  2007;66(7):886-892.
Background
Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation.
Aim
To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis.
Methods
36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon γ (IFN)γ, T‐bet (the Th1 transcription factor), GATA‐3 (the Th2 transcription factor), transforming growth factorβ and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real‐time quantitative PCR.
Results
There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti‐double strand DNA antibody level with glomerular expression of T‐bet, IFNγ and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNγ, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA‐3.
Conclusions
Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.
doi:10.1136/ard.2006.063123
PMCID: PMC1955122  PMID: 17324967
9.  Juvenile systemic lupus erythematosus onset patterns in Vietnamese children: a descriptive study of 45 children 
Background
Incidence and disease pattern of childhood-onset SLE is reported to differ among ethnic groups.
Methods
To describe disease pattern and 6 month follow-up in a referral based cohort of 45 Vietnamese children with SLE. Forty-five children who were subsequently diagnosed to have systemic lupus erythematosus (f/m = 4/1) were referred to the Ho Chi Minh City Children’s Hospital No.1 during a 12-month period in 2009.
Results
The mean age at diagnosis was 12.8 years (SD = 2.5). Thirty-seven (82%) fulfilled criteria for lupus nephritis (LN). At diagnosis, impressively high SLEDAI and ECLAM scores were recorded (mean and SD), 23.8 (11.6) and 6 (2.3), respectively. The mean renal SLEDAI score was 8.2. The mean haemoglobin (g/dL, SD) was 8.5 (2.1). The Coombs test was positive in 30 of 36 children (83%). The mean plasma creatinine was 0.98 (SD 1.2) and mean Westergren sedimentation rate was 83.6 (SD 37.4). The patient age at diagnosis was positively correlated to the SLEDAI (p = 0.034) and ECLAM (p = 0.022). At 6 month follow-up of the 45 children, 15 patients were in complete remission, 5 were in partial remission, 6 had stable disease, 3 had relapsed, 3 had evolving disease, 2 had ongoing resistant disease and 4 had died. Seven patients were lost to follow-up. A second renal biopsy showed an improved ISN class in 13 of 15; in 2 cases the ISN class remained unchanged.
Conclusions
Forty-five Vietnamese children with SLE were referred to Ho Chi Minh Children’s Hospital No. 1 during a16 month period from 2008–2009. These patients had a strikingly high prevalence of Coombs positive anaemia, a high prevalence of lupus nephritis, and very high SLEDAI and ECLAM scores at the time of diagnosis. While there may be referral biases, our Vietnamese SLE patients appear to have severe disease upon presentation but do reasonably well in the short-term.
doi:10.1186/1546-0096-10-38
PMCID: PMC3551686  PMID: 23164451
10.  Expression of endothelial protein C receptor in cortical peritubular capillaries associates with a poor clinical response in lupus nephritis 
Rheumatology (Oxford, England)  2009;48(5):513-519.
Objective. To study the membrane expression of endothelial protein C receptor (mEPCR) in the renal microvasculature in lupus nephritis (LN) as a potential marker of injury and/or prognostic indicator for response to therapy.
Methods. mEPCR expression was analysed by immunohistochemistry in normal kidney and in 59 biopsies from 49 patients with LN. Clinical parameters were assessed at baseline, 6 months and 1 year.
Results. mEPCR was expressed in the medulla, arterial endothelium and cortical peritubular capillaries (PTCs) in all biopsies with LN but not in the cortical PTCs of normal kidney. Positive mEPCR staining in >25% of the PTCs was observed in 16/59 biopsies and associated with poor response to therapy. Eleven (84.6%) of 13 patients with positive staining for mEPCR in >25% of the PTCs and follow-up at 6 months did not respond to therapy, compared with 8/28 (28.6%) with mEPCR staining in ⩽25% PTCs, P = 0.0018. At 1 year, 10 (83.3%) of 12 patients with positive mEPCR staining in >25% of the PTCs did not respond to therapy (with two progressing to end-stage renal disease) compared with 8/24 (33.3%) with positive staining in ⩽25% of the PTCs, P = 0.0116. Although tubulo-interstitial damage (TID) was always accompanied by mEPCR, this endothelial marker was extensively expressed in the absence of TID suggesting that poor response could not be attributed solely to increased TID. mEPCR expression was independent of International Society of Nephrology/Renal Pathology Society class, activity and chronicity indices.
Conclusion. Increased mEPCR expression in PTCs may represent a novel marker of poor response to therapy for LN.
doi:10.1093/rheumatology/kep034
PMCID: PMC2722802  PMID: 19286697
Endothelial protein C receptor; Lupus nephritis; Lupus nephritis pathological biomarker; Renal microvasculature in lupus nephritis
11.  Renal biopsy pathology in a cohort of patients from southwest Sydney with clinically diagnosed systemic lupus erythematosus 
Purpose
The pathological manifestations in the kidneys in systemic lupus erythematosus (SLE) are commonly known as lupus nephritis. We have studied the pathological changes in renal biopsies from 59 cases of clinically diagnosed SLE obtained over a 15-year period from a racially diverse population in the Sydney metropolitan area. Our aim was to see if there was any regional variation in the morphological changes.
Methods
Renal biopsy changes were assessed by routine light, immunofluorescence, and electron microscopy. We used the modified 1974 World Health Organization classification of lupus nephritis to classify cases into six classes. Disease severity was assessed by age, sex, and across racial groups, including Caucasian, Asian, Middle Eastern, Mediterranean, Indian subcontinental, South American, and Pacific Islander.
Results
Our analysis showed that cases of lupus nephritis contributed 5.4% of our total renal biopsies examined over a 15-year period. The overall incidence of biopsy-proven cases was 0.49 per 100,000 per year. The ages of our patients ranged from 10 to 79 years, with most below 50 years of age. A female to male ratio was determined to be 4.4:1. There was no relationship to ethnicity, nor was there a relationship between any of these parameters and the class or severity of disease.
Conclusion
Renal biopsy with multimodal morphological and immunohistochemical analysis remains the gold standard for diagnosis and determination of the level of disease in lupus nephritis. Based on this approach we have identified an incidence rate for southwest Sydney that is slightly higher but comparable to that found in a similar study from the United Kingdom. We also found that there was no relationship between sex, race, or age and severity of disease.
doi:10.2147/IJNRD.S34357
PMCID: PMC3575160  PMID: 23431084
systemic lupus erythematosus; SLE; lupus nephritis; histology; immunohistochem-istry; electron microscopy
12.  Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis 
Rheumatology (Oxford, England)  2010;49(5):960-971.
Objectives. Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis.
Methods. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit’s uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort.
Results. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort.
Conclusions. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.
doi:10.1093/rheumatology/kep468
PMCID: PMC2853702  PMID: 20144927
Systemic lupus erythematosus; Lupus nephritis; Neutrophil gelatinase-associated lipocalin; Systemic Lupus Erythematosus Disease Activity Index; British Isles Lupus Assessment Group; Biomarkers
13.  Renal Dnase1 Enzyme Activity and Protein Expression Is Selectively Shut Down in Murine and Human Membranoproliferative Lupus Nephritis 
PLoS ONE  2010;5(8):e12096.
Background
Deposition of chromatin-IgG complexes within glomerular membranes is a key event in the pathogenesis of lupus nephritis. We recently reported an acquired loss of renal Dnase1 expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase1 expression in lupus nephritis were analyzed.
Methodology/Principal Findings
Total nuclease activity and Dnase1 expression and activity was evaluated using in situ and in vitro analyses of kidneys and sera from (NZBxNZW)F1 mice of different ages, and from age-matched healthy controls. Immunofluorescence staining for Dnase1 was performed on kidney biopsies from (NZBxNZW)F1 mice as well as from human SLE patients and controls. Reduced serum Dnase1 activity was observed in both mesangial and end-stage lupus nephritis. A selective reduction in renal Dnase1 activity was seen in mice with massive deposition of chromatin-containing immune complexes in glomerular capillary walls. Mice with mild mesangial nephritis showed normal renal Dnase1 activity. Similar differences were seen when comparing human kidneys with severe and mild lupus nephritis. Dnase1 was diffusely expressed within the kidney in normal and mildly affected kidneys, whereas upon progression towards end-stage renal disease, Dnase1 was down-regulated in all renal compartments. This demonstrates that the changes associated with development of severe nephritis in the murine model are also relevant to human lupus nephritis.
Conclusions/Significance
Reduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. Reduced Dnase1 activity reflects loss in the expression of the protein and not inhibition of enzyme activity.
doi:10.1371/journal.pone.0012096
PMCID: PMC2938370  PMID: 20856893
14.  Biomarker Discovery for Lupus Nephritis Through Longitudinal Urine Proteomics 
Kidney international  2008;74(6):799-807.
Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE). Treatment often requires the use of immunosuppression, and may be associated with severe side effects. The ability to predict relapse, relapse severity, and recovery could be used to more effectively implement therapy and reduce toxicity. We postulated that a proteomic analysis of the low-molecular weight urine proteome using serial urine samples obtained before, during, and after SLE nephritis flares would demonstrate potential biomarkers of SLE renal flare. This study was undertaken to test our hypothesis.
Urine from 25 flare cycles of 19 WHO Class III, IV, and V SLE nephritis patients was used. Urine samples included a baseline, and pre-flare, flare, and post-flare specimens. The urines were fractionated to remove proteins larger than 30 kDa, and spotted onto weak cation exchanger (CM10) protein chips for analysis by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS).
SELDI-TOF MS screening showed 176 protein ions between 2-20 kDa of which 27 were found to be differentially-expressed between specific flare intervals. On-chip peptide sequencing by integrated tandem mass spectrometry was used to positively identify selected differentially-expressed protein ions. The identified proteins included the 20 and 25 amino acid isoforms of hepcidin, a fragment of α1-antitrypsin, and an albumin fragment. Hepcidin 20 increased 4 months pre-flare and returned to baseline at renal flare, whereas hepcidin 25 decreased at renal flare and returned to baseline 4 months post-flare.
Using SELDI-TOF urine protein profiling in lupus nephritis, several candidate biomarkers of renal flare were found. To verify these candidates as true biomarkers, further identification and validation are needed in an independent SLE cohort.
doi:10.1038/ki.2008.316
PMCID: PMC2614389  PMID: 18596723
lupus nephritis; biomarker; SELDI
15.  Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2004;64(3):444-448.
Objective: To investigate antibodies to complement 1q (anti-C1q) and investigate the correlation between anti-C1q titres and renal disease in systemic lupus erythematosus (SLE).
Methods: 151 SLE patients were studied. In patients with biopsy proven lupus nephritis (n = 77), activity of renal disease was categorised according to the BILAG renal score. Sera were tested for anti-C1q by enzyme immunoassay. Serum samples were randomly selected from 83 SLE patients who had no history of renal disease, and the positive and negative predictive value of the antibodies was studied.
Results: Patients with active lupus nephritis (BILAG A or B) had a higher prevalence of anti-C1q than those with no renal disease (74% v 32%; relative risk (RR) = 2.3 (95% confidence interval, 1.6 to 3.3)) (p<0.0001). There was no significant difference in anti-C1q prevalence between SLE without nephritis and SLE with non-active nephritis (BILAG C or D) (32% v 53%, p = 0.06) or between active and non-active nephritis (74% v 53%, p = 0.06). Patients with nephritis had higher anti-C1q levels than those without nephritis (36.0 U/ml (range 4.9 to 401.0) v 7.3 U/ml (4.9 to 401.0)) (p<0.001). Anti-C1q were found in 33 of 83 patients (39%) without history of renal disease. Nine of the 33 patients with anti-C1q developed lupus nephritis. The median renal disease-free interval was nine months. One patient with positive anti-C1q was diagnosed as having hypocomplementaemic urticarial vasculitis syndrome during follow up.
Conclusions: Anti-C1q in SLE are associated with renal involvement. Monitoring anti-C1q and their titres in SLE patients could be important for predicting renal flares.
doi:10.1136/ard.2004.024943
PMCID: PMC1755385  PMID: 15286009
16.  Role of serum anti-C1q antibodies as a biomarker for nephritis activity in pediatric and adolescent Egyptian female patients with SLE 
Objective
To evaluate serum anti-C1q antibodies as a biomarker of systemic lupus erythematosus (SLE) flare and as a proposed noninvasive alternative to renal biopsy which is still the “gold standard” to determine renal activity in SLE.
Methods
Serum anti-C1q antibodies were measured in our patients (all were females), they were followed at the nephrology and pediatric nephrology units at the Faculties of Medicine of Cairo University and Misr University for science and technology (MUST). Our study included 120 patients in the pediatric and adolescent age group and they were categorized into three groups with (mean ± SD of 16.7 ± 3, 16.1 ± 2, 15.9 ± 3) respectively: Group 1 including 40 patients with SLE and active lupus nephritis; Group 2 including 40 patients with SLE and without active lupus nephritis, but with some extra renal activity mainly arthritis; and Group 3 including 40 healthy subjects.
Results
Anti-C1q antibodies were found to be significantly higher in patients with active lupus nephritis than those without active nephritis than control individuals with a median (range) of [27.5 (14 – 83), 9 (2.5 – 30), 7 (2 – 13)] respectively. In those with active lupus nephritis, anti-C1q was found to correlate significantly with other parameters assessing lupus nephritis activity like C3 (r = -0.33, p < 0.04), C4 (r = -0.32, p < 0.044), daily urinary protein excretion (r = 0.32, p < 0.036), renal SLEDAI (r = 0.64, p < 0.001), and activity index (r = 0.71, p < 0.001).
Conclusions
Anti-C1q antibodies can be used as a considerable marker for LN activity in that age group with 97.5% sensitivity and 65% specificity with the cutoff level 12 U/l. These levels are clearly higher than those for traditional markers of disease activity such as C3/C4 consumption and anti-dsDNA.
doi:10.1517/17530059.2012.715632
PMCID: PMC3581052  PMID: 23480832
anti-C1q antibodies; anti-dsDNA; C3; C4; ELISA; juvenile systemic lupus erythematosus; lupus nephritis; renal SLEDAI; urinary proteins
17.  Serum levels and renal deposition of C1q complement component and its antibodies reflect disease activity of lupus nephritis 
BMC Nephrology  2013;14:63.
Background
Lupus nephritis is considered to be a principal cause of morbidity and mortality in SLE. Few studies focus on the association between anti-C1q antibodies in circulation and renal C1q deposition in human lupus nephritis. In this study, we detected the serum levels of C1q, presence of anti-C1q antibodies in circulation, renal C1q deposition and further analyzed their associations with clinical and pathological activity in a large cohort of Chinese lupus nephritis patients.
Methods
Sera and renal biopsies from 218 consecutive patients with lupus nephritis with long-term follow up data were studied. Sera were tested for levels of C1q and anti-C1q autoantibodies. Associations of levels of C1q, anti-C1q autoantibodies with renal deposition of C1q, clinical and histopathological data and renal outcome were further investigated.
Results
The levels of serum C1q were significantly lower in lupus nephritis than that in normal controls [33.81 ± 20.36 v.s. 61.97 ± 10.50 μg/ml (P < 0.001)]. The prevalence of anti-C1q antibodies, ratios of glomerular and vascular deposition of C1q in patients with lupus nephritis were 42.7% (93/218), 71.6% (156/218) and 86.2% (188/218), respectively. The serum C1q levels and anti-C1q antibodies were associated with SLEDAI scores (P < 0.001, P = 0.012, respectively), renal total activity indices scores (P < 0.001, P < 0.001, respectively). Granular positive staining of C1q and IgG by immunofluorescence was co-localized almost completely along the glomerular capillary wall and mesangial areas. Patients with anti-C1q antibodies presented with significantly lower serum C1q levels than those without it (23.82 [0.60, 69.62] μg/ml v.s. 37.36 [0.64, 82.83] μg/ml, P < 0.001). The presence of anti-C1q antibodies was associated with the presence of glomerular C1q deposition (P < 0.001), but not with the presence of renal vascular C1q deposition (P = 0.203).
Conclusion
Anti-C1q autoantibodies were closely associated with serum levels of C1q and glomerular deposition of C1q. Kidney is at least one of the target organs of anti-C1q autoantibodies.
doi:10.1186/1471-2369-14-63
PMCID: PMC3616847  PMID: 23510032
Lupus nephritis; Anti-C1q autoantibodies; Serum levels of C1q; C1q depostion
18.  Association of Intrarenal B-Cell Infiltrates with Clinical Outcome in Lupus Nephritis: A Study of 192 Cases 
Background. Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined. Methods. Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies. Results. Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (all P < 0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (all P < 0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies. Conclusion. It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.
doi:10.1155/2012/967584
PMCID: PMC3389683  PMID: 22792121
19.  Association of Serum Nitrate and Nitrite Levels With Longitudinal Assessments of Disease Activity and Damage in Systemic Lupus Erythematosus and Lupus Nephritis 
Arthritis and rheumatism  2008;58(1):263-272.
Objective
Reactive intermediate production is an essential component of the innate immune response that is induced during disease activity in murine lupus. This study was undertaken to determine whether a marker of systemic nitric oxide (NO) production correlates with prospectively studied disease activity in human systemic lupus erythematosus (SLE) and lupus nephritis patients.
Methods
Eighty-three SLE patients and 40 control subjects were studied longitudinally. The SLE group included 23 patients with lupus nephritis documented by renal biopsy and 26 with a history of lupus nephritis. During each visit, following a 24-hour low-nitrate diet, traditional markers of disease activity and damage were determined. Serum nitrate plus nitrite (NOx) levels were determined by chemiluminescence detection.
Results
NOx levels were higher in SLE patients than in controls during the first visit. In univariate longitudinal analyses, NOx levels were associated with SLE Disease Activity Index scores. In multivariate analyses, NOx levels were associated with serum levels of C3 and creatinine and the urinary protein:creatinine ratio. Among patients with lupus nephritis, those with proliferative lesions had higher NOx levels, and higher NOx levels were associated with accumulation of renal damage and lack of response to therapy.
Conclusion
This is the first study to prospectively demonstrate longitudinal associations between serum NOx levels and markers of SLE and lupus nephritis disease activity. The more pronounced association with proliferative lupus nephritis and with longitudinal response to lupus nephritis therapy provides a rationale for the study of reactive intermediates as biomarkers of disease activity and therapeutic targets in proliferative lupus nephritis.
doi:10.1002/art.23153
PMCID: PMC2733831  PMID: 18163495
20.  Urine Biomarkers Predict the Cause of Glomerular Disease 
Diagnosis of the type of glomerular disease that causes the nephrotic syndrome is necessary for appropriate treatment and typically requires a renal biopsy. The goal of this study was to identify candidate protein biomarkers to diagnose glomerular diseases. Proteomic methods and informatic analysis were used to identify patterns of urine proteins that are characteristic of the diseases. Urine proteins were separated by two-dimensional electrophoresis in 32 patients with FSGS, lupus nephritis, membranous nephropathy, or diabetic nephropathy. Protein abundances from 16 patients were used to train an artificial neural network to create a prediction algorithm. The remaining 16 patients were used as an external validation set to test the accuracy of the prediction algorithm. In the validation set, the model predicted the presence of the diseases with sensitivities between 75 and 86% and specificities from 92 to 67%. The probability of obtaining these results in the novel set by chance is 5 × 10−8. Twenty-one gel spots were most important for the differentiation of the diseases. The spots were cut from the gel, and 20 were identified by mass spectrometry as charge forms of 11 plasma proteins: Orosomucoid, transferrin, α-1 microglobulin, zinc α-2 glycoprotein, α-1 antitrypsin, complement factor B, haptoglobin, transthyretin, plasma retinol binding protein, albumin, and hemopexin. These data show that diseases that cause nephrotic syndrome change glomerular protein permeability in characteristic patterns. The fingerprint of urine protein charge forms identifies the glomerular disease. The identified proteins are candidate biomarkers that can be tested in assays that are more amenable to clinical testing.
doi:10.1681/ASN.2006070767
PMCID: PMC2733832  PMID: 17301191
21.  Aberrant Activation of the WNT/β-Catenin Signaling Pathway in Lupus Nephritis 
PLoS ONE  2014;9(1):e84852.
Objective
The canonical WNT pathway has been implicated as playing important roles in the pathogenesis of a variety of kidney diseases. Recently, WNT pathway activity was reported to be elevated in the renal tissue of a lupus mouse model. This study aimed to evaluate the potential role of the WNT pathway in the pathogenesis of human lupus nephritis.
Methods
The expression of β-catenin was evaluated in renal biopsy specimens from lupus nephritis patients and control kidney tissues by immunohistochemistry and western blotting. Real-time polymerase chain reaction (RT-PCR) was used to detect RNA expression of β-catenin, Dkk-1 and Axin2. Plasma concentrations of Dkk-1 were measured by ELISA.
Results
Immunohistochemistry and western blotting revealed increased expression of β-catenin in the kidneys of patients with lupus nephritis compared with control kidney tissues (p<0.05), accompanied by an increase in mRNA expression of β-catenin (p<0.01) and axin2 (p<0.05).
β-catenin was significantly greater in LN patients without renal interstitial fibrosis compared with those with renal interstitial fibrosis (p<0.01) at the mRNA expression level; the increase in β-catenin mRNA positively correlated with the creatinine clearance rate (Ccr) and negatively correlated with chronicity indices of renal tissue injury. Greater plasma Dkk-1 concentrations were found in LN patients compared with controls (p<0.05). Plasma Dkk-1 concentrations also correlated negatively with anti-dsDNA antibody levels and positively with serum C3 levels.
Conclusions
The canonical WNT/β-catenin signaling pathway was activated in lupus nephritis patients, accompanied by an increase in plasma levels of Dkk-1. Altered WNT/β-catenin signaling was related to the pathogenesis of lupus nephritis and might play a role in renal fibrosis.
doi:10.1371/journal.pone.0084852
PMCID: PMC3897389  PMID: 24465439
22.  Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis 
Introduction
High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a pro-inflammatory mediator following extracellular release. HMGB1 has been increasingly recognized as a pathogenic mediator in several inflammatory diseases. Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE). However, the local expression of HMGB1 in active lupus nephritis (LN) is not known. Here we aimed to study both tissue expression and serum levels of HMGB1 in LN patients with active disease and after induction therapy.
Methods
Thirty-five patients with active LN were included. Renal biopsies were performed at baseline and after standard induction therapy; corticosteroids combined with immunosuppressive drugs. The biopsies were evaluated according to the World Health Organization (WHO) classification and renal disease activity was estimated using the British Isles lupus assessment group (BILAG) index. Serum levels of HMGB1 were analysed by western blot. HMGB1 expression in renal tissue was assessed by immunohistochemistry at baseline and follow-up biopsies in 25 patients.
Results
Baseline biopsies showed WHO class III, IV or V and all patients had high renal disease activity (BILAG A/B). Follow-up biopsies showed WHO I to II (n = 14), III (n = 6), IV (n = 3) or V (n = 12), and 15/35 patients were regarded as renal responders (BILAG C/D).
At baseline HMGB1 was significantly elevated in serum compared to healthy controls (P < 0.0001). In all patients, serum levels decreased only slightly; however, in patients with baseline WHO class IV a significant decrease was observed (P = 0.03). Immunostaining revealed a pronounced extranuclear HMGB1 expression predominantly outlining the glomerular endothelium and in the mesangium. There was no clear difference in HMGB1 expression comparing baseline and follow-up biopsies or any apparent association to histopathological classification or clinical outcome.
Conclusions
Renal tissue expression and serum levels of HMGB1 were increased in LN. The lack of decrease of HMGB1 in serum and tissue after immunosuppressive therapy in the current study may reflect persistent inflammatory activity. This study clearly indicates a role for HMGB1 in LN.
doi:10.1186/ar3747
PMCID: PMC3392835  PMID: 22348591
23.  Geographical distribution, a risk factor for the incidence of lupus nephritis in China 
BMC Nephrology  2014;15:67.
Background
Geographical variation in lupus nephritis epidemiology may indicate important environmental factors contributions to the etiology of lupus nephritis. This paper first describes the epidemiology of biopsy-proven lupus nephritis in China by performing a systematic literature review and the possible social-environmental influential factors.
Methods
The keywords “lupus nephritis”, “renal biopsy” and “systemic lupus erythematous” were searched in the three largest Chinese electronic databases and Medline/PubMed. The data of the patients with biopsy-proven lupus nephritis were extracted. The possible environmental influential factors including the population density, ethnic group populations, the ratio of females to males, the average sunshine per year, annual average temperature and annual relative humidity, in different regions of China were analyzed.
Results
Forty-one study centers with 34574 renal disease patients, and 3699 lupus nephritis patients met the inclusion criteria. Lupus nephritis accounts for 2.37% to 25% of all renal disease and 27.2% to 80.65% of renal disease associated with secondary glomerular diseases. The male-to-female ratio is approximately 1:5 in lupus nephritis patients. The included period is predominantly from 1995 to 2010. The proportion ratio of biopsy-proven lupus nephritis in all renal disease or in secondary glomerular disease significantly increased with decreasing latitude from the north to the south part of China. The population is predominantly Han Chinese.
Conclusions
Geographical distribution appears to be a risk factor for the incidence of biopsy-proven LN in China.
doi:10.1186/1471-2369-15-67
PMCID: PMC4013059  PMID: 24885458
Biopsy; Lupus nephritis; Geographical distribution; China
24.  Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis 
Annals of the Rheumatic Diseases  2012;71(11):1771-1782.
Objectives
To develop recommendations for the management of adult and paediatric lupus nephritis (LN).
Methods
The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.
Results
Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IVA or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.
Conclusions
Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.
doi:10.1136/annrheumdis-2012-201940
PMCID: PMC3465859  PMID: 22851469
25.  Features and outcomes of lupus nephritis in Morocco: analysis of 114 patients 
Background
There is wide variation in clinical presentation and outcome of lupus nephritis (LN) among different ethnic groups. Few data for LN exist on North Africans, especially those from Morocco. The aim of our study was to review retrospectively the features and outcome of LN in Moroccan patients.
Patients and methods
We performed a single-center retrospective study. A total of 114 patients with LN were included. All patients met American Rheumatism Association criteria. LN was classified according to the International Society of Nephrology/Renal Pathology Society classification. We adopted previously defined outcome criteria for LN.
Results
There were 101 females and 13 males, with a mean age of 29.9 years. At first presentation, we noted hypertension in 33%, hematuria in 76%, nephrotic syndrome in 53%, and renal failure in 60% of cases. Renal biopsy revealed predominant proliferative classes in more than 80% of patients. Patients received different regimens mainly based on intravenous cyclophosphamide. After a mean follow-up of 22 months, remission occurred in 45.5%, relapses in 82%, end-stage renal failure in 21%, and death in 16% of cases. Infection and neurological and cardiovascular diseases were the most frequent causes of death.
Conclusion
LN seems to be severe in our study, with a predominance of proliferative forms, severe renal manifestations, and poor renal and overall survival.
doi:10.2147/IJNRD.S34299
PMCID: PMC3839844  PMID: 24294005
lupus nephritis; systemic lupus erythematosus; nephritis

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