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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.
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).
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.
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).
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.
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.
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.
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.
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.
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.
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.
PMCID: PMC2633180  PMID: 19194566
ISN/RPS Classification; Lupus; Lupus Nephritis; Outcome
4.  CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis 
The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters.
Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II–V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test.
The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.
M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.
PMCID: PMC4835936  PMID: 27091114
Lupus nephritis; Macrophages; T-reg-cells; Macrophage subtypes
5.  The spectrum of renal thrombotic microangiopathy in lupus nephritis 
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.
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.
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).
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.
PMCID: PMC3672792  PMID: 23320601
6.  NADPH oxidase and nitric oxide synthase dependent superoxide production is increased in proliferative lupus nephritis 
Lupus  2013;22(13):1361-1370.
Lupus nephritis (LN) is an immune complex-mediated glomerulonephritis. Proliferative LN (PLN, International Society of Nephrology and Renal Pathology Society (ISN/RPS) classes III and IV)) often leads to renal injury or failure despite traditional induction and maintenance therapy. Successful targeted therapeutic development requires insight into mediators of inflammation in PLN. Superoxide (SO) and its metabolites are mediators of the innate immune response through their ability to mediate reduction-oxidation signaling. Endothelial nitric oxide synthase (eNOS) modulates inflammatory responses in endothelial cells. We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex.
Patients with systemic lupus erythematosus were enrolled at the time of renal biopsy for active LN of all classes. Serum collected at baseline was analyzed by HPLC with electrochemical detection for markers of SO production (durable modifications of serum protein Tyr ultimately requiring SO as a substrate). Renal cortex from MRL/MpJ-FASlpr (MRL/lpr) mice with and without functional eNOS was analyzed during active disease for superoxide (SO) production with and without inhibitors of SO producing enzymes.
Serum protein modifications indicative of total SO production were significantly higher in patients with PLN. These markers were increased in association with more active, inflammatory PLN. Mice lacking functional eNOS had 80% higher levels of renal cortical SO during active disease, and inhibitors of nitric oxide synthase and NADPH oxidase reduced these levels by 60% and 77%, respectively.
These studies demonstrate that SO production is unique to active PLN in a NOS and NADPH oxidase-dependent fashion. These findings suggest the emulating or augmenting eNOS activity or inhibiting NADPH oxidase SO production may be targets of therapy in patients with PLN. The markers of SO production used in this study could rationally be used to select SO-modulating therapies and serve as pharmacodynamic indicators for dose titration.
PMCID: PMC3839955  PMID: 24106214
Lupus nephritis; Systemic lupus erythematosus; Nitric oxide; Endothelial nitric oxide synthase; NADPH Oxidase; Proliferative lupus nephritis; Superoxide; Oxidation-reduction; Inflammation
7.  Renal Biopsy: A much needed tool in patients with Systemic Lupus Erythematosis (SLE) 
Background and Objective:
Systemic lupus erythematosis (SLE) is an inflammatory disorder associated with significant morbidity and mortality. Kidneys are frequently affected in SLE and various stages of lupus nephritis have been identified based on severity of the disease. Treatment varies with the staging and correct diagnosis is essential for timely intervention as it can have significant impact on morbidity and mortality. The objective of the study was to determine whether laboratory parameters of lupus nephritis (LN); including urinalysis, serum creatinine (S. Cr) and 24 hours urine protein can accurately predict histologic staging of the disease.
This retrospective study was conducted in department of Nephrology, Liaquat National Hospital Karachi from January 2012 to December 2014. Fifty one patients of SLE who underwent renal biopsy were selected. Patients, urinalysis at the time of renal biopsy, serum creatinine and 24 hours urine collection for protein were noted. All patients renal biopsy was read by the same pathologist. Patients were clinically staged based on these parameters and their histologic staging based on biopsy findings were compared, to see their correlation. Data was analyzed using SPSS version 17. Chi-square test was used to analyze categorical data and p<0.05 was considered significant. Cohen’s kappa (κ) analysis was used to examine the agreement by comparing lupus nephritis staging done by laboratory and histological ground. P value <0.05 indicates that agreement was unlikely due to chance alone.
Among 51 patients analyzed, 37 patients were females (72.5%) and 14 patients were males (27.5%) with mean age of 32.51 + 16.91 years. In stage II, kappa (κ) of 0.304 represented fair strength of agreement and a p value of 0.012 (p<0.05)which was statistically significant. In stage III, kappa was 0.209 indicating none to slight agreement and a p value of 0.131 (p>0.05). In stage IV, kappa (κ) was 0.141 (slight agreement)and p value 0.301 (p>0.05) in stage V; kappa (κ) of 0.030 represented poor agreement and a p value of 0.828 (p>0.05).
Staging of lupus nephritis done on basis of laboratory findings did not correlate well with underlying histological staging. Therefore, renal biopsy is an essential tool in approach to lupus nephritis in order to provide timely and appropriate treatment to patients.
PMCID: PMC4795892  PMID: 27022348
Lupus Nephritis; Renal Biopsy; SLE; Proteinuria; Urinalysis
8.  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.
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.
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.
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.
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.
PMCID: PMC3003497  PMID: 20003354
9.  Biomarkers for Refractory Lupus Nephritis: A Microarray Study of Kidney Tissue 
The prognosis of severe lupus nephritis (LN) is very different among individual patients. None of the current biomarkers can be used to predict the development of refractory LN. Because kidney histology is the gold standard for diagnosing LN, the authors hypothesize that molecular signatures detected in kidney biopsy tissue may have predictive value in determining the therapeutic response. Sixty-seven patients with biopsy-proven severely active LN by International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification III/IV were recruited. Twenty-three kidney tissue samples were used for RNA microarray analysis, while the remaining 44 samples were used for validation by real-time polymerase chain reaction (PCR) gene expression analysis. From hundreds of differential gene expressions in refractory LN, 12 candidates were selected for validation based on gene expression levels as well as relevant functions. The candidate biomarkers were members of the innate immune response molecules, adhesion molecules, calcium-binding receptors, and paracellular tight junction proteins. S100A8, ANXA13, CLDN19 and FAM46B were identified as the best kidney biomarkers for refractory LN, and COL8A1 was identified as the best marker for early loss of kidney function. These new molecular markers can be used to predict refractory LN and may eventually lead to novel molecular targets for therapy.
PMCID: PMC4490552  PMID: 26110394
lupus nephritis; biomarker; microarrays; gene expression; chronic kidney disease
10.  Monocyte Chemotactic Protein-1, Fractalkine, and Receptor for Advanced Glycation End Products in Different Pathological Types of Lupus Nephritis and Their Value in Different Treatment Prognoses 
PLoS ONE  2016;11(7):e0159964.
Early diagnosis is important for the outcome of lupus nephritis (LN). However, the pathological type of lupus nephritis closely related to the clinical manifestations; therefore, the treatment of lupus nephritis depends on the different pathological types.
To assess the level of monocyte chemotactic protein (MCP-1), fractalkine (Fkn), and receptor for advanced glycation end product (RAGE) in different pathological types of lupus nephritis and to explore the value of these biomarkers for predicting the prognosis of lupus nephritis.
Patients included in this study were assessed using renal biopsy. Class III and class IV were defined as the proliferative group, class V as non-proliferative group, and class V+III and class V+IV as the mixed group. During the follow-up, 40 of 178 enrolled patients had a poor response to the standard immunosuppressant therapy. The level of markers in the different response groups was tested.
The levels of urine and serum MCP-1, urine and serum fractalkine, and serum RAGE were higher in the proliferative group, and lower in the non-proliferative group, and this difference was significant. The levels of urine and serum MCP-1 and serum RAGE were lower in the poor response group, and these differences were also significant. The relationship between urine MCP-1 and urine and serum fractalkine with the systemic lupus erythematosus disease activity index was evaluated.
The concentration of cytokines MCP-1, fractalkine, and RAGE may be correlated with different pathology type of lupus nephtitis. Urine and serum MCP-1 and serum RAGE may help in predicting the prognosis prior to standard immunosuppressant therapy.
PMCID: PMC4961285  PMID: 27458981
11.  Successful Treatment with Mycophenolate Mofetil and Tacrolimus in Juvenile Severe Lupus Nephritis 
Case Reports in Pediatrics  2015;2015:651803.
Lupus nephritis (LN) of juvenile onset often has severe disease presentation. Despite aggressive induction therapy, up to 20% of patients with LN are resistant to initial therapy and up to 44% suffer a renal relapse. However, there is no consensus on an appropriate therapeutic regimen for refractory LN. We report a 13-year-old girl with recurrent LN who was not taking her medications. At age of 11 years, she was diagnosed with LN classified as International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV G (A) + V. She was treated with prednisolone and MMF after nine methylprednisolone pulses. Nineteen months later, she was admitted to the hospital with generalized edema. Her symptoms were nephrotic syndrome and acute renal dysfunction. She received three methylprednisolone pulses for 3 days, followed by oral prednisolone and MMF. Twenty-seven days after the three methylprednisolone pulses, her acute renal dysfunction was improved, but the nephrotic syndrome was not improved. A second biopsy showed diffuse lupus nephritis classified as the predominant finding of ISN/RPS class V. We added tacrolimus to the MMF. Four months after adding tacrolimus, the nephrotic syndrome improved. We conclude that adding tacrolimus to the treatment regimen for LN resistant to MMF is effective.
PMCID: PMC4346693  PMID: 25785217
12.  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.
PMCID: PMC3263065  PMID: 22279336
Lupus nephritis; monocyte chemotactic protein-1; systemic lupus erythematosus; transforming growth factor beta
13.  Anti-C1q antibodies antedate patent active glomerulonephritis in patients with systemic lupus erythematosus 
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.
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).
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.
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.
PMCID: PMC2714141  PMID: 19515233
14.  Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells 
Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level.
We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies.
Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature.
Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0588-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4389585  PMID: 25889472
15.  Role of early repeated renal biopsies in lupus nephritis 
Lupus Science & Medicine  2014;1(1):e000018.
A renal biopsy is generally recommended for diagnosis and is necessary for classification of lupus nephritis (LN), but second biopsies after immunosuppressive therapy are seldom a routine procedure. We investigated how repeat biopsies contribute to the evaluation of treatment response and long-term outcome in LN.
Sixty-seven patients with active LN were included. Renal biopsies were performed at diagnosis and after standard induction immunosuppressive therapy in all patients (median 8 months), regardless of clinical outcome. Biopsies were evaluated according to the International Society of Nephrology/Renal Pathology Society classification. Clinical response was defined as complete (CR), partial (PR) or non-response (NR) according to recent definitions. Histological response (HR) was defined as Class I, II or III/IV-C on repeat biopsies. Long-term renal outcome was determined in 55 patients after a median of 10 years.
CR was demonstrated in 25%, PR in 27% and NR in 48% of patients. HR was shown in 42% and histopathological non-response (HNR) in 58% of patients. Twenty-nine per cent of CR and 61% of patients with PR had active lesions on repeat biopsies, that is, were HNR. Poor long-term renal outcome was associated with high chronicity index at repeated biopsies, but not with clinical or histological response.
Despite apparent clinical response to immunosuppressive therapy, repeated biopsies revealed persisting active nephritis in almost half of the patients, thus providing additional information to clinical response criteria. Repeated renal biopsies may be a tool to improve the evaluation of treatment response in LN.
PMCID: PMC4213828  PMID: 25379188
Systemic Lupus Erythematosus; Lupus Nephritis; Autoimmune Diseases
16.  Serum and Urinary Interleukin-6 in Assessment of Renal Activity in Egyptian Patients with Systemic Lupus Erythematosus 
This study investigates whether serum and urinary interleukin-6 (IL-6) represent an early marker of kidney involvement and assesses the difference between them and renal biopsy in lupus nephritis (LN).
A total of 60 systemic lupus erythematosus (SLE) patients were compared to 20 healthy controls. Urinary and serum IL-6 were measured in both patients and controls. In addition, renal biopsy was done prior or shortly after urine and blood sampling; the results were classified according to the International Society of Nephrology/Renal Pathology Society classification of LN by recording the activity score and chronicity score for each sample.
There was a significant higher level of urinary IL-6 in the SLE patients with biopsy-proven LN than in those without LN and those of the control group. However, no significant difference was reported between the three groups as regards serum IL-6. A strong positive correlation was found between urinary IL-6 and renal disease activity based on the renal SLE disease activity index (SLEDAI) score with no significant correlation regarding the extra renal SLEDAI. Urinary IL-6 was positively correlated with renal biopsy results and with its activity scores but weakly correlated with the chronicity scores.
Urinary IL-6 may provide a simple noninvasive potential marker of disease activity of renal involvement in adult patients with SLE.
PMCID: PMC4782971  PMID: 26966395
lupus nephritis; SLE; urinary interleukin-6; biopsy in lupus nephritis
17.  Pentraxin 3 Is Closely Associated With Tubulointerstitial Injury in Lupus Nephritis 
Medicine  2016;95(3):e2520.
Lupus nephritis always elicits immune inflammatory tissue damages in kidney. Pentraxin 3 (PTX3), mainly produced at inflammatory sites, is known to be involved in the regulation of the innate immunity system. The aim of this study was to investigate the serum and urine levels of PTX3, and the expression of PTX3 in renal tissues in lupus nephritis patients from a large Chinese cohort.
The study used cross-sectional survey and 288 active lupus nephritis patients, including discovery cohort and validation cohort, 115 systemic lupus erythematosus (SLE) patients without clinical renal involvement and 46 healthy controls were enrolled. Serum and urine PTX3 were screened by enzyme-linked immunosorbent assay (ELISA). The renal deposition of PTX3 was detected by immunohistochemistry and immunofluorescence.
The average level of serum PTX3 in the discovery cohort of lupus nephritis was significantly higher than that in nonrenal involvement SLE group and normal controls (P < 0.001, P < 0.001, respectively), which was confirmed by the validation cohort. Serum PTX3 levels of 15 lupus nephritis patients in remission decreased significantly compared with that in active phase. Serum PTX3 levels were significantly higher in patients with hematuria (P = 0.014), leucocyturia (P = 0.002), acute renal failure (P = 0.001), and nephrotic syndrome (P = 0.036). There were significant correlations between serum PTX3 levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, serum creatinine value, renal pathological activity indices, and serum complement 3 (C3) in active lupus nephritis patients. The urinary PTX3 levels were significantly higher in active lupus nephritis patients compared with patients in remission and normal controls (P = 0.011, P = 0.008, respectively). There were significant associations between urinary PTX3 levels and multiple indices of tubulointerstitial lesions, including urinary KIM-1 (r = 0.368, P = 0.016), neutrophil gelatinase-associated lipocalin (NGAL) (r = 0.320, P = 0.039), microalbumin (r = 0.621, P = 0.003), transferring (r = 0.451, P = 0.040) levels and renal pathological indices scores, especially interstitial inflammation (r = 0.349, P = 0.025) in active lupus nephritis patients. A significant correlation was found between serum and urine PTX3 levels (r = 0.431, P = 0.006). PTX3 staining was mainly observed in tubulointerstitial areas of patients with lupus nephritis, and immunofluorescence study showed that PTX3 could colocalize with fibroblast in interstitium.
Circulating and local PTX3 levels were significantly increased in patients with active lupus nephritis and might be a biomarker for the disease progression, especially of tubulointerstitial injury.
PMCID: PMC4998266  PMID: 26817892
18.  The Impact of Baseline Serum Creatinine on Complete Remission Rate and Long-Term Outcome in Patients with Severe Lupus Nephritis 
Nephron Extra  2016;6(2):12-21.
We assess the impact of serum creatinine at baseline on complete remission rate and long-term outcome in severe lupus nephritis (SLN).
A total of 86 adult patients with SLN [International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV lesions] were evaluated based on baseline serum creatinine levels (≤1.0, 1.01-1.5, 1.51-2.0, 2.01-3.0, and >3.0 mg/dl; n = 22, 23, 16, 12, and 13, respectively). The complete remission rates (serum creatinine level of ≤1.4 mg/dl and proteinuria of ≤0.33 g/day) and long-term outcomes (stable renal function, dialysis, and death) were compared. The patients were followed for 121 ± 64 months.
The baseline clinical features were similar, but the chronicity index was significantly higher with increasing levels of serum creatinine. Complete remission rates were significantly higher in patients with lower levels of serum creatinine (86 vs. 52 vs. 19 vs. 25 vs. 0%, p < 0.0001). Patients with a baseline serum creatinine level of ≤1.0 mg/dl were >16 times as likely (OR 16.2; 95% CI: 4.2-61.5) to attain a complete remission and >6 times as likely (OR 6.1; 95% CI: 1.9-18.6) to have stable renal function at the last follow-up as compared to patients with a serum creatinine level of >1.0 mg/dl. The 15-year renal survival rate was greatest among those patients with a baseline serum creatinine level of ≤1.0 mg/dl (76 vs. 57 vs. 48 vs. 25 vs. 10%, p < 0.0001).
The prognosis of SLN is significantly affected by the serum creatinine level at baseline. The complete remission rate is highest, and the long-term prognosis most favorable, in patients with a baseline serum creatinine level of ≤1.0 mg/dl. This emphasizes the importance of early diagnosis and treatment.
PMCID: PMC5040929  PMID: 27721821
Lupus nephritis; Remission; Serum creatinine; Proteinuria
19.  Treatment Results of Patients With Lupus Nephritis: A Single Center’s Experience 
The Eurasian Journal of Medicine  2010;42(3):132-136.
Lupus nephritis (LN) is a type of organ involvement of systemic lupus erythematosus (SLE) that leads to disease-related morbidity and mortality. Lack of good treatments for LN continues to be problematic. Many different treatment protocols are applied in treatment centers. Not every treatment protocol is successful. Moreover, patients who reached remission may present with exacerbations. In this study, we aimed to evaluate the treatment results of our patients and investigate their remission rates as well as factors that affect remissions.
Materials and Methods:
We retrospectively investigated the results of 41 patients who were diagnosed with lupus nephritis after kidney biopsy in the Nephrology and Immunology-Rheumatology departments of Atatürk University Medical Faculty Training Hospital between January 2000 and December 2008. Demographic information, clinical history and laboratory results were collected from each patient’s records. The relationships among clinical, laboratory, demographic parameters and remissions were investigated. The patients were grouped in terms of urine protein levels; patients with urine protein < 330 mg/day were regarded as in remission and patients with urine protein ≥ 330 mg/day were were regarded as uncontrolled.
At the end of a 12-month period of therapy, 24 (58.5 %) of the patients were in remission. There were no statistically significant relationships among age, sex, anti-ds-DNA, C3, C4, activity indexes, chronicity indexes, serum level of creatinine, urine protein levels and remission (p>0.05). We compared class 3 LN patients at the 6th and 12th months according to treatment protocols. Azathioprin or mycophenolate mophetil were significantly better at placing urine protein levels in remission as compared to cyclophosphamide (p<0.05).
According to our study, no relationship was found between basal clinical and laboratory parameters and patient remission. Response rates of our LN patients were similar to those in the literature. However, complete remission is still a problem in LN. The results of the protocols used in the treatment of LN show similarities. Although there are some data suggesting that MMF used in recent years is effective, it should be supported by prospective multicenter studies. It is important to note that it is difficult to achieve complete remission in LN patients.
PMCID: PMC4261255  PMID: 25610143
Lupus nephritis; Treatment; Remission
20.  Autoantigen microarrays reveal autoantibodies associated with proliferative nephritis and active disease in pediatric systemic lupus erythematosus 
Pediatric systemic lupus erythematosus (pSLE) patients often initially present with more active and severe disease than adults, including a higher frequency of lupus nephritis. Specific autoantibodies, including anti-C1q, anti-DNA and anti-alpha-actinin, have been associated with kidney involvement in SLE, and DNA antibodies are capable of initiating early-stage lupus nephritis in severe combined immunodeficiency (SCID) mice. Over 100 different autoantibodies have been described in SLE patients, highlighting the need for comprehensive autoantibody profiling. Knowledge of the antibodies associated with pSLE and proliferative nephritis will increase the understanding of SLE pathogenesis, and may aid in monitoring patients for renal flare.
We used autoantigen microarrays composed of 140 recombinant or purified antigens to compare the serum autoantibody profiles of new-onset pSLE patients (n = 45) to healthy controls (n = 17). We also compared pSLE patients with biopsy-confirmed class III or IV proliferative nephritis (n = 23) and without significant renal involvement (n = 18). We performed ELISA with selected autoantigens to validate the microarray findings. We created a multiple logistic regression model, based on the ELISA and clinical information, to predict whether a patient had proliferative nephritis, and used a validation cohort (n = 23) and longitudinal samples (88 patient visits) to test its accuracy.
Fifty autoantibodies were at significantly higher levels in the sera of pSLE patients compared to healthy controls, including anti-B cell-activating factor (BAFF). High levels of anti-BAFF were associated with active disease. Thirteen serum autoantibodies were present at significantly higher levels in pSLE patients with proliferative nephritis than those without, and we confirmed five autoantigens (dsDNA, C1q, collagens IV and X and aggrecan) by ELISA. Our model, based on ELISA measurements and clinical variables, correctly identified patients with proliferative nephritis with 91 % accuracy.
Autoantigen microarrays are an ideal platform for identifying autoantibodies associated with both pSLE and specific clinical manifestations of pSLE. Using multiple regression analysis to integrate autoantibody and clinical data permits accurate prediction of clinical manifestations with complex etiologies in pSLE.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0682-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4493823  PMID: 26081107
21.  Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy 
Lupus Science & Medicine  2015;2(1):e000061.
Lupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response.
Sixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index.
Baseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment (p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5 ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline.
BLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.
PMCID: PMC4305068  PMID: 25632350
Systemic Lupus Erythematosus; Lupus Nephritis; B cells
22.  Relation of peritubular capillary features to class of lupus nephritis 
BMC Nephrology  2016;17:169.
Experimental studies have linked peritubular capillary (PTC) loss with progression of chronic kidney disease. Minimal information on PTC in lupus nephritis (LN) has been reported. We therefore evaluated the PTC area in different classes of LN and determined if specific clinical characteristics correlated with PTC changes.
Renal biopsies of 253 subjects with LN (categorized using the ISN/RPS 2003 classification) and 13 normal renal donors (the controls) were retrospectively evaluated for PTC morphology by staining for CD31 with immunohistochemistry method. The percent positive area of PTC (% PTC) was correlated with serum and urinary measures of renal function and renal pathology.
Significant PTC loss was observed in all classes of LN compared to controls. The % PTC area was highest in controls (7.64±1.48 %) with levels of 1.95±1.50, 4.16±3.85, 4.19±4.45, 5.02±1.79, and 4.45±3.75 in classes II, III, IV, IV combined with V and V, respectively (all p values < 0.05). The lowest PTC density was observed in class II LN, but this may be because some cases with worse classes of LN showed increased PTC density due to abnormally dilated capillaries associated with acute inflammation and angiogenesis. %PTC was increased in those with hematuria (5.8±5.2 vs. 3.6±3.4 %, red blood cells 3-10 vs. < 3 cells/high power field, p < 0.05) and was reduced in those with a moderately declined renal function (3.29±3.40 vs. 4.42±4.12, eGFR 15-59 vs. ≥ 60 ml/min/1.73 m2, p < 0.05). Nephrotic-range proteinuria also trended to be associated with lower PTC density although it did not reach statistical significance (3.1±2.6 vs. 4.9±4.5, p= 0.067).
LN is associated with PTC loss and the severity correlates with reduced renal function. Further studies are needed to investigate whether a loss of PTC can predict long term renal outcomes in LN.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-016-0388-2) contains supplementary material, which is available to authorized users.
PMCID: PMC5103390  PMID: 27829387
Peritubular capillary; Lupus nephritis
23.  Intrarenal cytokine gene expression in lupus nephritis 
Annals of the Rheumatic Diseases  2007;66(7):886-892.
Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation.
To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis.
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.
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.
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.
PMCID: PMC1955122  PMID: 17324967
24.  Lupus nephritis in children – 10 years’ experience 
Systemic lupus erythematosus (SLE) in children is usually more severe than it is in adults and there is a higher incidence of renal involvement. We described 18 children (16 girls, 2 boys) with lupus nephritis (LN), whose average age was 14.4 ±1.81 years. Disease activity was assessed according to SLEDAI (SLE Disease Activity Index). Renal biopsy was classified according to the INS/RPS (International Society of Nephrology/Renal Pathology Society). The patients were treated with steroids (100%) and pulses of cyclophosphamide (88.9%) or mycophenolate mofetil (11.1%), next azathioprine or mycophenolate mofetil with prednisone in reduced doses. In children with renal/multi-organ insufficiency and/or septicaemia, renal replacement therapy (27.8%), and plasmapheresis (22.2%) were used in the initial treatment. The SLEDAI initial activity was high in 44.4% and moderate in 55.6% of children. LN manifested as: nephrotic syndrome (83.3%), microhaematuria (100%), leukocyturia (60%), hypertension (72.2%), and acute renal injury (83.3%); mean GFR was 54.55 ±33.09 ml/min/1.73 m2. In the renal biopsy, class IV LN according to INS/RPS was mainly diagnosed (82%). At the end of follow-up, mean observation time 32.1±23.36 months: mean GFR was 90.87 ±12.13 ml/min/1.73 m2, proteinuria disappeared in 66.7% and decreased in 33.3% of children to the average of 1.7 g/day (range: 0.5-4.0 g/day), hypertension was observed in 83.4% of children. Intensive immunosuppressive treatment with pulses of cyclophosphamide in early stage of LN in children is very effective.
PMCID: PMC5099380  PMID: 27833441
acute kidney injury; cyclophosphamide; lupus nephritis; children
25.  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.
PMCID: PMC2722802  PMID: 19286697
Endothelial protein C receptor; Lupus nephritis; Lupus nephritis pathological biomarker; Renal microvasculature in lupus nephritis

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