Non-proliferative Lupus Nephritis Research Articles

Clinico-serological associations of urinary activated leukocyte cell adhesion molecule in systemic lupus erythematosus and lupus nephritis

BackgroundLupus nephritis (LN) is one of the major complications associated with Systemic Lupus Erythematosus (SLE). Activated leukocyte cell adhesion molecule (ALCAM or CD166) is a promising urine biomarker that binds to CD6, a receptor found on lymphocytes. This binding results in T-cell activation, proliferation, and recruitment, which causes tissue inflammation and may explain the pathophysiology of LN.Aim of workInvestigate the urinary ALCAM level in SLE, study its relationship to disease activity, and clarify the association with LN activity and histopathology.Patients and methodsA case–control study was performed on 60 patients with SLE and 20 matched controls. The SLE disease activity index (SLEDAI) and the activity of renal disease (rSLEDAI) were evaluated. Renal biopsy and uALCAM levels were also investigated.ResultsUrinary ALCAM levels were higher significantly in active LN patients than inactive LN patients, active and inactive non-LN SLE, and the control group (p < 0.001). The cut-off value for identifying active and inactive LN was above 270 ng/mg (p < 0.001). ALCAM levels were greater in proliferative (class III, IV, and IV/V) than in non-proliferative (class II and V) LN (p < 0.001). ALCAM exhibited high positive correlations with SLEDAI and rSLEDAI (p < 0.001 each) and negative significant correlations with C3 (p < 0.001) and C4 (p = 0.005).ConclusionUrinary ALCAM is a sensitive biomarker evaluating LN in SLE patients. Levels above 270 ng/mg can help distinguish between active and inactive LN. ALCAM levels are correlated positively with SLEDAI and rSLEDAI but have a negative correlation with C3 and C4.Key Points• Urinary ALCAM shows promise as a biomarker for evaluating kidney dysfunction in SLE patients.• It is a non-invasive marker that can differentiate between proliferative and non-proliferative LN.• A urinary ALCAM level above 270 ng/mg can indicate active LN, while lower levels indicate inactive LN.• Urinary ALCAM levels are correlated positively with SLEDAI and rSLEDAI scores but correlated negatively with C3 and C4.

Clinical profiles in pediatric systemic lupus erythematosus: a retrospective study

Aims: This study aimed to analyse clinical and laboratory findings, prognosis, and survival of systemic lupus erythematosus (SLE) patients, differentiating according to gender, pubertal status, and renal involvement. Methods: Ninety-six pediatric SLE patients, diagnosed using ACR criteria, were retrospectively analyzed. Inclusion criteria comprised age under 18, meeting at least four ACR criteria, and six months of monitoring. Data encompassed demographics, symptoms, diagnosis, organ involvement, autoantibodies, treatment, prognosis, and survival. Categorization was based on gender and pubertal status. Renal biopsies followed WHO-ISN classification, with asymptomatic findings termed “silent lupus nephritis.” Biopsied patients were divided into proliferative and non-proliferative lupus nephritis categories, excluding irreversible damage cases. Outcomes studied included remission, relapse, end-stage renal failure, and mortality. Results: Among 96 participants, females constituted 82.3%, males 17.7%, resulting in a female-to-male ratio of 4.6:1. Mean age at diagnosis was 11.9 years, with 37 prepubertal (38.5%) and 59 pubertal (61.5%) cases. Oral-nasal ulcers (p=0.01) were more prevalent in males related to system involvement. Nephrotic syndrome prevalence increased from 21.6% in prepubertal to 44.1% in pubertal cases (p=0.025). Positive Anticardiolipin IgM antibodies decreased from 56.2% in prepubertal to 25.9% in pubertal cases (p=0.047). Type IV lupus nephritis was predominant, followed by Type II, in prepubertal and pubertal groups and both genders. Proliferative lupus nephritis showed higher rates of renal involvement (95.7% vs. 65.6%), nephrotic syndrome (46.8% vs. 21.9%), proteinuria (89.4% vs. 62.5%), hematuria (57.4% vs. 28.1%), elevated creatinine (43.5% vs. 9.7%), and low albumin (67.4% vs. 23.3%). Cases with proliferative lupus nephritis had higher neuropsychiatric involvement (36.2% vs. 12.5%), seizures (25.5% vs. 3.1%, p=0.008), and increased hemolytic anemia rates (78.7% vs. 56.2%, p=0.033). Thirteen had silent lupus nephritis, revealing various types through biopsy. All reported deaths occurred within the first five years, resulting in stable 91% survival rates at 5, 10, and 15 years. Conclusion: This study provides insights into the clinical, prognostic, and survival characteristics of pediatric systemic lupus erythematosus (SLE), revealing notable patterns related to gender, pubertal development, and renal involvement. There is an association between proliferative lupus nephritis and renal involvement, nephrotic syndrome, and neuropsychiatric symptoms. Significantly, silent lupus nephritis highlights the complex renal implications, necessitating diligent surveillance for prompt intervention.

Circulating neutrophil extracellular trap remnants as a biomarker to predict outcomes in lupus nephritis

ObjectiveTo determine if the serum levels of neutrophil extracellular trap (NET) remnants (Elastase-DNA and HMGB1-DNA complexes) at the time of a lupus nephritis (LN) flare predict renal outcomes in the...

Characterization of Serum Cytokine Profiles of Patients with Active Lupus Nephritis.

Cytokines contribute to the pathogenesis of lupus nephritis (LN), yet their value as prognostic biomarkers is still debated. We aimed to describe the serum cytokines' profiles and prospectively assess correlations with disease features and renal response in a multicentric cohort of consecutive adult patients with biopsy-proven active LN. Cytokine associations with clinical and serological data were performed at LN diagnosis (T0), and at 3 (T3) and 6 months (T6) of follow up. Renal response according to EULAR definition was assessed at T3, T6 and T12. BAFF and interleukin (IL)-37 were measured by ELISA; IL-2, IL-10, IL-17A and IL-18 by a bead-based multiplex cytokine assay (Luminex). Thirty-nine patients with active LN (age 40.5 ± 15.6 years; F 71.8%; 84.6% proliferative LN) were enrolled, of whom twenty-nine displayed complete longitudinal records. At T0, we observed higher levels of IL-37 and IL-17 in proliferative vs. non-proliferative LN (IL-37: 0.0510 (0.0110-0.2300) vs. 0.0000 (0.0000-0.0397) ng/mL, p = 0.0441; IL-17: 2.0920 (0.5125-17.9400) vs. 0.0000 (0.0000-0.6025) pg/mL, p = 0.0026, respectively), and positive correlations between IL-10 and 24 h proteinuria (r = 0.416, p = 0.0249) and anti-dsDNA levels (r = 0.639, p = 0.0003). BAFF was higher in patients with low complement (p < 0.0001). We observed a sustained correlation between BAFF and IL-10 throughout T6 (r = 0.654, p = 0.0210). Higher baseline IL-37 and BAFF levels were associated with renal response at T3 and T6, respectively, while baseline IL-18 levels were higher in patients achieving response at T12. Our study highlights the complexity of the cytokine network and its potential value as a marker of active LN and renal response.

Serum S100P and C4d proteins as markers for active proliferative lupus nephritis in Egyptian patients with systemic lupus erythematosus

Lupus nephritis (LN), occurring in approximately 50% of individuals with systemic lupus erythematosus (SLE), significantly influences therapy and prognosis. Proliferative LN, more prevalent than non-proliferative LN, is associated with a poorer prognosis. This study aimed to investigate the potential correlation between serum levels of the pro-inflammatory proteins human calcium-binding S100P (S100P) and Human complement Fragment 4 (C4d) and confirmed proliferative LN through biopsy. The objective was to evaluate their reliability as biomarkers for disease activity in proliferative LN.&#x0D; Methods. Serum S100P and C4d were measured using enzyme-linked immunosorbent assay in 100 female patients with established SLE. Among these, 50 had confirmed proliferative LN through biopsy, and 50 did not. A control group of 50 healthy female donors' plasma samples was included.&#x0D; Results. SLE patients with proliferative LN exhibited significantly higher serum levels of S100P (P &lt; 0.001) and C4d (P &lt; 0.001) compared to SLE patients without LN and controls. Serum S100P demonstrated a significantly higher positive correlation with the activity index in renal biopsies (r = 0.784) compared to serum C4d (r = 0.416). Additionally, serum S100P had a significantly higher positive correlation with SLEDAI-R than serum C4d (r = 0.651 vs. r = 0.257). Both serum S100P and C4d showed promise as reliable biomarkers for the diagnosis of active proliferative LN, as indicated by the ROC curve and AUC assessments.&#x0D; Conclusion. Serum concentrations of S100P and C4d emerge as useful indicators for identifying SLE patients with active proliferative LN.

Long-term renal outcomes of patients with non-proliferative lupus nephritis.

Although non-proliferative lupus nephritis (LN) (class I, II or V) has been considered as a less severe type of LN, data on long-term renal prognosis are limited. We investigated the long-term outcomes and prognostic factors in non-proliferative LN. We retrospectively reviewed patients with systemic lupus erythematosus who were diagnosed with LN class I, II, V, or II + V by kidney biopsy from 1997 to 2021. A poor renal outcome was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2. We included 71 patients with non-proliferative LN (class I = 4; class II = 17; class V = 48; class II+V = 2), and the overall rate of poor renal outcomes was 29.6% (21/71). The univariate analysis indicated that older age, low eGFR at 6 or 12 months, failure to reach complete remission at 6 months, and LN chronicity score > 4 or activity score > 6 were significantly associated with poor renal outcomes. The multivariate analysis revealed that low eGFR at 6 months (HR 0.971, 95% CI 0.949-0.991; p = 0.014) was significantly associated with poor renal outcomes. Poor renal outcomes occurred in approximately 30% of patients with non-proliferative LN after long-term follow-up. More active management may be needed for non-proliferative LN, especially for patients with eGFR < 60 mL/ min/1.73 m2 at 6 months follow-up after LN diagnosis.

Potential role of circulating miRNA-146a and serum kallikrein 1 as biomarkers of renal disease in biopsy-proven lupus nephritis patients

Aim of the workTo evaluate the performance of circulating miR-146a and serum kallikrein1 (KLK1) as biomarkers for detecting disease activity and distinguishing histopathological changes associated with lupus nephritis (LN). Patients and methods90 systemic lupus erythematosus (SLE) patients (44 with active non-renal disease and 46 with LN) were examined for relative expression levels of circulating miR-146a, assessed by reverse transcription quantitative real-time PCR (RT-qPCR) and serum KLK1 levels, measured by ELISA. SLE disease activity was assessed using SLEDAI-2 k. Receiver operating characteristic curve was employed to examine the diagnostic performance of both biomarkers and established conventional laboratory parameters of renal function with specific renal histologic features seen in LN. As well, 40 apparently healthy control subjects were enrolled. ResultsCirculating miR-146a levels were significantly lower (p < 0.01), while serum KLK1 levels were significantly higher (p < 0.01) in active LN patients compared to active non-renal and controls. miR-146a levels negatively correlated with serum creatinine, Albumin/Creatinine and SLEDAI-2 k (p ≤ 0.01), while serum KLK1 significantly correlated with serum creatinine, Albumin/Creatinine and C3 (p ≤ 0.05) and inversely with miR-146a (p = 0.002). Both circulating miR-146a and KLK1 revealed an outstanding performance in predicting renal activity among SLE patients with an AUC of 0.949 and 0.947 respectively. In active LN patients, KLK1 and miR-146a exhibited good ability in differentiating proliferative from non-proliferative LN (AUC 0.73, 0.65 respectively), and in predicting biopsy activity index ≥7, surpassing conventional disease measures. ConclusionCirculating miR-146a and serum KLK1 are potential biomarkers for LN that could compete with invasive renal biopsy. Independent validation is warranted.

Serum Soluble Interleukin 2 Receptor Alpha vs. Urinary Parameter and Serum Immunological Markers as a Monitoring Tool of Treatment Response of Lupus Nephritis and their Relation to Lupus Nephritis Class on Renal Biopsy

Background: Lupus Nephritis (LN) is one of the most common and serious manifestations in SLE patients that causes significant morbidity and mortality. Current conventional biomarkers for LN are sometimes unable to predict treatment response of lupus nephritis. Recently serum soluble interleukin-2 receptor alpha (sIL-2 R alpha) is shown to be a good marker to predict treatment response of LN. Objective: To compare serum sIL-2R alpha with other commonly used markers as a marker of treatment response of LN and their relation to the LN class in renal biopsy. Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with lupus nephritis after kidney biopsy were included in this study. Serum soluble interleukin-2 receptor alpha, 24 hrs UTP, anti-dsDNA, complements level (C3 &amp; C4) were measured in all patient at baseline, 3-months and 6- months after treatment. Serum soluble interleukin-2 receptor alpha level was measured by ELISA and is expressed as pg/mg. Serum sIL-2R alpha as well as conventional biomarker value were compared before and after treatment and in between treatment response and non-response group. Results: Serum sIL-2R alpha levels were significantly higher in patients of proliferative lupus nephritis (Class III &amp; Class IV) than non-proliferative lupus nephritis (Class V) at baseline (3934.3 ± 1095.2, 3934.3 ± 1095.2 &amp; 1801.98 ± 205.8 pg/L respectively) and levels were decreased significantly 6 months after treatment (p &lt;0.001). Serum sIL-2R alpha levels were also significantly higher in non-remission proliferative group then remission proliferative group (4071.60 ± 769.91 vs 5169.20 ± 394.76) with p value 0.008 at baseline. In contrast no significant difference were observed for 24 hrs UTP levels at baseline between this group which suggest that serum sIL-2R alpha are more sensitive marker than 24 hrs UTP in predicting treatment response of lupus nephritis. Conclusions: Serum sIL-2R alpha might be a valuable serological biomarker to diagnose and to predict and monitor the treatment response of lupus nephritis.

Differences and similarities of proliferative and non-proliferative forms of biopsy-proven lupus nephritis: Single centre, cross-disciplinary experience.

ObjectiveWe aimed to compare clinical features, outcomes, treatments, and to define the predictive factors of complete renal response (CRR) in patients with proliferative and non-proliferative lupus nephritis (LN).MethodsPatients with systemic lupus erythematosus (SLE) followed between 2014 and 2020 at Hacettepe University Hospitals and who had a kidney biopsy were the subject of the study. One hundered and sixteen patients’ kidney biopsies reported as LN were evaluated retrospectively. Clinical characteristics and laboratory values at the time of kidney biopsy, histopathological forms of LN, and renal response (complete or partial) were recorded. We analyzed the association between CRR rates during the 2-year follow-up after induction therapy and the predictive factors for CRR.ResultsOf 116 (93 females, 23 males) patients, 95 (81.9%) were in the proliferative group (class III and IV) and 21 (18.1%) were in the non-proliferative group (class II and V). In the proliferative group, the percentage of the patients with elevated basal creatinine levels, median daily proteinuria, anti-double-stranded DNA (dsDNA) positivity, low C3 and C4 levels, the presence of active urinary sediment, and median renal SLE Disease Activity Index (SLEDAI) scores at the time of kidney biopsy were significantly higher than the non-proliferative group. Renal response status during the 2-year follow-up after induction therapy was available for 99 patients. During this time, 70 (70.7%) patients had achieved CRR and time-to-CRR was similar between the proliferative and non-proliferative groups (p = 0.64, log-rank test). The Cox proportional hazards model showed that achievement of CRR was associated with female gender [HR: 2.15 (1.19–3.89 95% CI), p = 0.011], newly diagnosed SLE with renal biopsy [HR: 2.15 (1.26–3.67 95% CI), p = 0.005], hypertension [HR: 0.40 (0.27–0.94 95% CI), p = 0.032], eGFR increase [HR: 1.01 (1.00–1.01 95% CI), p = 0.046], and the presence of active urinary sediment [HR: 0.46 (0.22–0.96 95% CI), p = 0.039].ConclusionsAchieving CRR was similar in proliferative and non-proliferative LN patients, although certain laboratory parameters differed at the onset. Our results indicated the importance of kidney biopsy in the decision-making of treatment of SLE patients with renal involvement and that the defined factors associated with CRR achievement help to predict good renal response.

Diffusion tensor imaging of renal cortex in lupus nephritis.

To evaluate the diagnostic value of diffusion tensor imaging (DTI) of renal cortex in assessment of lupus nephritis (LN) and prediction of its pathological subtypes. Prospective study was performed upon 39 female patients with pathologically proven LN and 16 sex- and age-matched healthy controls. Patients and controls underwent DTI of kidney.Mean diffusivity (MD) and fractional anisotropy (FA) of renal cortex were calculated by two radiologists. LN patients were pathologically classified into either non-proliferative (n = 15) or proliferative (n = 24). Mean MD of renal cortex in LN was significantly lower (p = 0.001) than that of controls with cut-off (2.16 and 2.2 X10-3mm2/s), area under curve (AUC) of (0.92, 0.94) and accuracy of (91%, 89%) for both observers. Mean FA of renal cortex in LN was significantly higher (p = 0.001) than that of controlswith cut-off (0.20, 0.21), AUC of (0.86, 0.82) and accuracy of (86%, 84%) for both observers. Renal cortex MD and FA in non-proliferative LN were significantly different (p = 0.001) from that of proliferative LN for both observers. There was excellent inter-observer agreement of MD and FA (ICC = 0.96 and 0.81). MD and FA of renal cortex may help to assess renal affection in LN patients and predict its pathological subtypes.

Serum complement levels as prognostic marker for monitoring treatment response in lupus nephritis

Background: Lupus nephritis (LN) is one of the most common and serious manifestations of systemic lupus erythematosus (SLE) that causes significant morbidity and mortality. Certain biomarkers for LN are sometimes able to assess treatment response in lupus nephritis. This study aimed to compare serum complement levels (C3 and C4) as markers of treatment response of LN and their relation to the LN class in renal biopsy.&#x0D; Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with LN after kidney biopsy were included in this study. Serum complement levels (C3 and C4), 24 hours urinary total protein (24-hr UTP) and anti-double-stranded DNA (anti-ds DNA) were measured in all patients at baseline, 3 months and 6 months after treatment initiation. These biomarker values before and after treatment were compared between the proliferative and non-proliferative LN patients.&#x0D; Results: Serum C3 levels were significantly different between patients with proliferative LN (Class III and Class IV) and non-proliferative LN (Class V) at baseline (0.47 ± 0.32 g/l versus 0.89 ± 0.43 g/l, p=0.009) and levels changed significantly 6 months after treatment initiation (p&lt;0.001) and likewise for serum C4 levels (0.10 ± 0.06 g/l versus 0.24 ± 0.26 g/l, p=0.040). The values of 24-hr UTP and anti-ds-DNA were significantly different 6 months after treatment with p value &lt;0.05 in both groups but C3 (p&lt;0.001) and renal Systemic Lupus Erythematosus Disease Activity Index (rSLEDAI) (p&lt;0.001) were only significant in the proliferative group. On the other hand, after 6 months treatment, C4 levels became relatively higher but that was not significant in both groups (p&gt;0.05).&#x0D; Conclusion: After 6 months of treatment, serum C3 and C4 levels increased towards normal in both LN groups. Serum C3 and C4 levels in patients with LN correlate with disease activity. Therefore, serum complement (C3 and C4) levels may be utilized as serological biomarkers for treatment response of LN.&#x0D; Birdem Med J 2021; 11(2): 97-102

Correlation between the clinical remission and histological remission in repeat biopsy findings of quiescent proliferative lupus nephritis.

The optimal duration of maintenance therapy is controversial in proliferative lupus nephritis (LN). Discordance between clinical parameters of renal remission and histological findings has made repeat biopsy a compulsory tool to confirm the histological remission (HR), but the timing is debatable. Aim of this study was to find the correlation of sustained complete clinical remission (CR) in sever lupus nephritis with histological findings on repeat kidney biopsy and appropriate duration of treatment in maintenance phase after achieving complete clinical remission. Repeated kidney biopsy (biopsy 2) was performed on patients of biopsy proven (biopsy 1) proliferative LN who had been in CR for at least 2-years. The clinical and histologic findings of these groups (biopsy 1 and biopsy 2) were compared. Total 29 patients were included for the final analysis. Group 2 was further divided as per the duration of sustained CR (>48 months & <48 months). Regression analysis were used to find predictors of the HR. Average time taken to achieve CR was 9(range 2-24) months. Average duration of follow up and maintenance therapy was 68 ± 17.8 and 62.5 ± 14.2 months respectively. In the repeat kidney biopsy, HR was observed in 93.1% patients. Immunofluorescence study (IF) was normal in 72% of the patients. Normal light microscopy (LM) findings were observed in 58% patients. Transformation from proliferative to nonproliferative LN was noted in 82% cases. Other than the duration of CR on maintenance therapy and blood pressure, rest of the variables failed to predict HR. In sustained remission for more than 48-months group, 100% patients achieved HR whereas only 84% in 24-48-months group. Sustained CR on maintenance immunosuppressive therapy for more than 48-months duration predicts HR in repeat kidney biopsy findings in quiescent proliferative LN. Hence the minimum duration of maintenance therapy in proliferative LN should be at least for another 48 months after achieving CR.

Simple And Cost-Effective Classics Are Back- Revisiting The Role Of Urine Microscopic Analysis For Assessing Severity Of Renal Involvement In Lupus Nephritis

Abstract Casestudy Urinalysis is important to assess disease activity in Lupus nephritis (LN). Hematuria, pyuria, cellular/granular casts and proteinuria are scored separately for assessing renal activity in SLEDAI. However, pyuria is not specific, and could indicate infection. We studied the correlation of microscopic urinalysis and degree of lymphocyturia with histological ISN/RPS 2018 class of LN. Methods Pre-biopsy urine was collected in 76 LN patients. The urine sediment was analyzed using light and phase- contrast microscope. Smear stained with supravital stain Sternheimer Malbin, was assessed semi-quantitatively for lymphocytes (per HPF). Renal biopsy was classified into proliferative (Class III/IV ± V)[N=64] and non-proliferative LN (Class I, II, V, VI) [N=12]. Results 48 patients had active urinary sediment. Cellular and/or granular casts were identified only in proliferativeLN (n=15/64; 23.4%). Hematuria (Range 0-65/HPF) was seen in 45 patients. Dysmorphic RBCs were identified in proliferative (n=17/41; mean 9.9 RBCs/HPF) and were absent in non-proliferative LN (mean 1.4 RBCs/HPF). 20 of the 34 patients with pyuria showed predominant lymphocytes. Lymphocyturia (Range 0-20/HPF) was significantly higher in proliferative LN (Mean 4.6/HPF) as compared to non-proliferative LN (Mean 1.5/HPF). Degree of pyuria or proteinuria had no correlation with biopsy class or activity. Lymphocyturia and hematuria showed correlation with biopsy activity index (r=0.30 and 0.39; p&amp;lt;0.05 and &amp;lt;0.001 respectively). A cut-off of average 6 RBCs/HPF or 5 lymphocytes/HPF could correctly identify proliferative LN with 100% specificity (p&amp;lt;0.001; AUC 0.72 and 0.74 respectively, combined AUC 0.81) and sensitivity of 0.42 and 0.36 respectively. Conclusion Although renal biopsy is the gold standard for assessment of renal lesions in LN, urine lymphocytes ≥5 and RBCs ≥6/HPF have a high specificity to differentiate proliferative and non-proliferative LN. This may be especially important in patients having comorbidities contraindicating a renal biopsy. Defining urine sediments using lymphocytes can increase the specificity of clinical activity indices.

Clinical and histological significance of urinary CD11c+ macrophages in lupus nephritis

BackgroundInfiltration of immune cells into the kidney is one of the key features of lupus nephritis (LN). The presence of immune cells in the urine may be used as a non-invasive biomarker of LN. Here, we aimed to analyze the clinicopathologic significance of urinary CD11c+ macrophages in patients with LN.MethodsThe numbers and proportions of CD11c+ macrophages in the urine samples of patients with LN at the time of kidney biopsy were examined using flow cytometry. We also examined the association between the levels of urinary CD11c+ macrophages and the clinical and pathologic features of patients with LN.ResultsCompared with patients without LN or those with non-proliferative LN, patients with proliferative LN had significantly higher numbers and proportions of urinary CD11c+ macrophages, which were strongly correlated with the serum anti-dsDNA antibody titer. The numbers and proportions of urinary CD11c+ macrophages were significantly associated with the values of chronicity indices such as tubular atrophy and interstitial fibrosis. No significant relationships were found between the levels of urinary CD11c+ macrophages and the activity scores, degree of proteinuria, or lupus disease activity. Urinary CD11c+ macrophages were more abundant in patients who did not achieve renal response to induction treatment with immunosuppressants than in those who achieved complete or partial response. The receiver operating characteristic (ROC) curve analysis showed that the number of urinary CD11c+ macrophages was the most powerful predictor of renal response at 6 months (ROC-AUC = 1.00, p = 0.0004).ConclusionThe urinary levels of CD11c+ macrophages were closely associated with the chronic pathologic changes of LN and renal response and may thus be used as a novel biomarker in LN.

Immunological characteristics and clinical significance of urinary CD11c+ macrophages in lupus nephritis

Abstract Kidney-infiltrating immune cells may be involved in the pathogenesis of lupus nephritis (LN). We aimed to analyse the immunological characteristics and clinicopathologic relevance of urinary CD11c+ macrophages in patients with LN. Compared with patients with no LN or non-proliferative LN, those with proliferative LN had significantly higher urinary levels of CD11c+ macrophages, which were strongly correlated with their anti-dsDNA antibody titer. Urinary CD11c+ macrophages expressed pro-inflammatory cytokines, such as interleukin (IL)-6 and IL-1β, and resembled infiltrated monocytes rather than tissue-resident macrophages in terms of surface marker expression. They showed high expression of the chemokine receptor CXCR3, whose cognate chemokine IP-10 was expressed by urinary tubular epithelial cells (TECs). When treated with sera from systemic lupus erythematosus patients, peripheral monocytes acquired the morphological and functional properties of urinary CD11c+ macrophages, which was blocked by DNase treatment. Finally, SLE sera treated monocytes induced fibronectin expression, apoptosis, and cell detachment in HK-2 cells via IL-6 production. Importantly, the number of urinary CD11c+ macrophages was significantly associated with chronicity indices, including tubular atrophy and interstitial fibrosis, and renal response in LN patients. CD11c+ macrophages may be involved in the pathogenesis of tubulointerstitial damage in LN.

Association of Urine sCD163 With Proliferative Lupus Nephritis, Fibrinoid Necrosis, Cellular Crescents and Intrarenal M2 Macrophages.

CD163 is a marker for alternatively activated macrophages, which have been implicated in the pathogenesis of lupus nephritis (LN). In our preliminary screening of urine proteins in LN, urine soluble CD163 (sCD163) was significantly elevated in patients with active LN. To evaluate the potential of sCD163 as a biomarker in LN, urine sCD163 was assayed in patients with active LN, active non-renal lupus patients (ANR), inactive SLE and healthy controls (HC), using ELISA and normalized to urine creatinine. The correlation of urine sCD163 with clinical parameters and renal pathological attributes was further investigated in LN patients with concurrent renal biopsies. A total of 228 SLE patients and 56 HC were included from three cohorts. Results demonstrated that urine sCD163 was significantly elevated in active LN when compared with HC, inactive SLE, or ANR in African-American, Caucasian and Asian subjects (all P < 0.001). In LN patients with concurrent renal biopsies, urine sCD163 was significantly increased in patients with proliferative LN when compared with non-proliferative LN (P < 0.001). Urine sCD163 strongly correlated with SLEDAI, rSLEDAI, activity index (AI) of renal pathology, fibrinoid necrosis, cellular crescents, and interstitial inflammation on biopsies (all P < 0.01). Macrophages, particularly M2 macrophages, the predominant cells expressing CD163 within LN kidneys, represented a potential source of elevated urine sCD163, based on single-cell RNA sequencing analysis. To conclude, urine sCD163 discriminated patients with active LN from other SLE patients and was significantly elevated in proliferative LN. It strongly correlated with concurrent AI and several specific pathological attributes, demonstrating its potential in predicting renal pathology.

Serum GlycA Level is Elevated in Active Systemic Lupus Erythematosus and Correlates to Disease Activity and Lupus Nephritis Severity.

Objective: Reliable non-invasive biomarkers are needed to assess disease activity and prognosis in patients with systemic lupus erythematosus (SLE). Glycoprotein acetylation (GlycA), a novel biomarker for chronic inflammation, has been reported to be increased in several inflammatory diseases. We investigated the relevance of serum GlycA in SLE patients exhibiting various levels of activity and severity, especially with regards to renal involvement. Methods: Serum GlycA was measured by nuclear magnetic resonance spectroscopy in samples from well characterized SLE patients and from both healthy controls and patients with other kidney diseases (KD). Disease activity was evaluated using the Systemic Lupus Erythematosus Activity Index 2000 (SLEDAI-2K). Renal severity was assessed by kidney biopsy. Results: Serum GlycA was elevated in active (n = 105) compared to quiescent SLE patients (n = 39, p < 10−6), healthy controls (n = 20, p = 0.009) and KD controls (n = 21, p = 0.04), despite a more severely altered renal function in the latter. GlycA level was correlated to disease activity (SLEDAI-2K, ρ = 0.37, p < 10−4), C-reactive protein, neutrophil count, triglyceride levels, proteinuria and inversely to serum albumin. In patients with biopsy-proven lupus nephritis (LN), GlycA levels were higher in proliferative (n = 26) than non-proliferative LN (n = 10) in univariate analysis (p = 0.04), and was shown to predict proliferative LN independently of renal parameters, immunological activity, neutrophil count and daily corticosteroid dosage by multivariate analysis (p < 5 × 10−3 for all models). In LN patients with repeated longitudinal GlycA measurement (n = 11), GlycA varied over time and seemed to peak at the time of the flare. Conclusions: GlycA, as a summary measure for different inflammatory processes, could be a valuable biomarker of disease activity in patients with SLE, and a non-invasive biomarker of pathological severity in the context of LN.

Role of tubulointerstitial lesions in predicting renal outcome among pediatric onset lupus nephritis - A retrospective cohort study.

Raising evidence suggested a prognostic utility of tubulointerstitial lesions in lupus nephritis (LN). The exact prevalence of tubulointerstitial abnormalities and its predictive value among pediatric onset systemic lupus erythematous (pSLE) cases, however, remained unknown. Sixty-seven pSLE subjects diagnosed with LN with initial renal samples available were enrolled and followed for an average of 6.49±3.06 years. Renal histology was evaluated according to the International Society of Nephrology/Renal Pathology Society classification, National Institute of Health classification and tubulointerstitial activity index (TIAI). Tubulointerstitial injuries were observed in 38.81% of all LN cases, including 13.33% with non-proliferative lupus nephritis (nPLN) and 46.15% of with proliferative lupus nephritis (PLN). Tubulointerstitial injuries occurred solitarily in cases with nPLN(13.33%), but always associated glomerular changes and significantly impacted renal survival (p=0.032) among those with PLN. TIAI associated glomerular abnormalities (p=0.031) but did not correlate renal performance or subsequent outcome (p=0.445). Among the chronicity index, it was the chronic tubulointerstitial lesions that provided prognostic information (p=0.012). None of the individual tubulointerstitial factors, however, reached statistical significance in end-stage renal disease prediction. Finally, considering tubulointerstitial injuries in PLN further discriminated subsequent renal outcome (p=0.006). Tubulointerstitial abnormalities were found in nearly one-third of all pediatric LN cases. With its importance in early identifying those at risk of renal failure, histologic classification considering tubulointerstitial lesions may potentially assist outcome prediction.

The value of repeat biopsy in lupus nephritis flares.

Whether a repeat renal biopsy is helpful during lupus nephritis (LN) flares remains debatable. In order to analyze the clinical utility of repeat renal biopsy in this complex situation, we retrospectively reviewed our series of 54 LN patients who had one or more repeat biopsies performed only on clinical indications. Additionally, we reviewed 686 well-documented similar cases previously reported (PubMed 1990–2015).The analysis of all patients reviewed showed that histological transformations are common during a LN flare, ranging from 40% to 76% of cases. However, the prevalence of transformations and the clinical value of repeat biopsy vary when they are analyzed according to proliferative or nonproliferative lesions.The great majority of patients with class II (78% in our series and 77.5% in the literature review) progressed to a higher grade of nephritis (classes III, IV, or V), resulting in worse renal prognosis. The frequency of pathological conversion in class V is lower (33% and 43%, respectively) but equally clinically relevant, since almost all cases switched to a proliferative class. Therefore, repeat biopsy is highly advisable in patients with nonproliferative LN at baseline biopsy, because these patients have a reasonable likelihood of switch to a proliferative LN that may require more aggressive immunosuppression.In contrast, the majority of patients (82% and 73%) with proliferative classes in the reference biopsy (III, IV or mixed III/IV + V), remained into proliferative classes on repeat biopsy. Although rebiopsy in this group does not seem as necessary, it is still advisable since it will allow us to identify the 18% to 20% of patients that switch to a nonproliferative class. In addition, consistent with the reported clinical experience, repeat biopsy might also be helpful to identify selected cases with clear progression of proliferative lesions despite the initial treatment, for whom it is advisable to intensify inmunosuppression. Thus, our experience and the literature data support that repeat biopsy also brings more advantges than threats in this group.The results of the repeat biopsy led to a change in the immunosuppresive treatment in more than half of the patients on average, intensifying it in the majority of the cases, but also reducing it in 5% to 30%.

Is renal biopsy always necessary to start immunosuppressive therapy in lupus nephritis?

Objective: Most of the patients with proliferative lupus nephritis (LN) have high titer of anti-dsDNA antibody and low complement levels. In this study, we tried to predict proliferative LN with serological profile. Methods: This prospective study was conducted in fifty pateints with known systemic lupus erythematosus (SLE) with laboratory evidence of LN (proteinuria, microscopic hematuria, or increased serum creatinine). Serological profile (anti-dsDNA, C3, and C4) and renal biopsy were done in all patients. Results: Of 50 patients, 35 had Class IV (70%), 7 Class II (14%), 4 Class V (8%), and 4 had Class IV and V (8%) on renal biopsy. Totally, 39 (78%) patients had proliferative LN (Class IV and Class IV and V). The prevalence of anti-dsDNA, low C3, and low C4 was 97.1%, 68%, and 74% with LN and 97.4%, 84.6%, and 87.2% with proliferative LN (P < 0.001), respectively. About 72% (28 of 39 patients) with proliferative LN had the combination of anti-dsDNA positivity, low C3, and low C4 levels. However, whoever had the combination of anti-dsDNA positivity, low C3, and low C4 showed only proliferative LN on biopsy. Positive predictive value was 100% (P < 0.05). None of the patients with Class II or Class V (nonproliferative LN) had this combination of serology. Conclusion: In this study, it was found that proliferative LN can be predicted by serological profile alone. Thus it might be argued that immunosuppressive therapy (steroids and mycophenolate mofetil) may be started without renal biopsy in a known SLE patient with laboratory evidence of LN and positive serology; however, robust studies are required.