Lupus Nephritis Patients Research Articles

FAR in systemic lupus erythematosus: a potential biomarker of disease activity and lupus nephritis.

The fibrinogen-to-albumin ratio (FAR), a novel inflammatory marker, has been studied in various diseases. However, the significance of FAR in systemic lupus erythematosus (SLE) has not been fully elucidated. This study was to investigate the connection between FAR and SLE. A retrospective analysis of 154 SLE patients and 77 healthy individuals was performed. The clinical and laboratory data were reviewed. Receiver operating characteristic (ROC) curves were conducted for FAR at baseline to predict disease activity and lupus nephritis (LN) in SLE patients. Pearson correlation was also applied. FAR in the SLE group was found to be significantly higher than that of the healthy control group (83.71mg/g vs. 53.14mg/g, P < 0.001). It was also significantly higher in patients with LN than that in patients without (107.64mg/g vs. 67.75mg/g, P < 0.001). The ROC curve for predicting LN showed that the area under the curve (AUC) of FAR (0.859, 95% CI 0.803-0.914) was the largest when compared to albumin (0.852, 95% CI 0.789-0.916) or fibrinogen (0.736, 95% CI 0.659-0.814) alone. In addition, FAR was a good predictor of severe disease activity in SLE (AUC = 0.721, 95% CI 0.612-0.830) and LN patients (AUC = 0.789, 95% CI 0.680-0.898). Pearson correlation analysis indicated that FAR demonstrated a strong correlation with SLE disease activity index 2000 (r = 0.4288, P < 0.001). FAR was significantly increased in SLE patients. It is a possible biomarker for disease activity and renal involvement in SLE.

Panax notoginseng saponins reverse steroid resistance in lupus nephritis: Involvement of the suppression of exosomal P-gp levels from lymphocytes to glomerular endothelial cells

Microangiopathy is the most basic pathological manifestation of lupus nephritis (LN), and glomerular endothelial cells (GECs) injury is an important pathological mechanism. LN patients with microangiopathy are prone to steroid resistance (SR). Our previous studies confirmed that Panax notoginseng saponins (PNS) could reverse SR by downregulating the expression of P-gp in SR lymphocytes of LN mice (SLCsL/S). However, the mechanism of how circulating lymphocytes transmit SR information to GECs and thus affect the efficacy of kidney treatment is not clear. Recent studies have found that exosomes (exos) are an important carrier for intercellular bioactive substance communication. But whether exosomes derived from SLCsL/S mediate SR in GECs and PNS interventions. To solve this problem, Exosomes isolated from SLCsL/S were characterized, and in vitro cell coculture was further conducted to investigate the effect of SLCsL/S-derived exosomes in the SR of GECs and PNS intervention. Sequencing was used to define the exosomal miRNA expression profiling of SR GECs. Moreover, the in vivo experiments were performed through the injection of exosomes extracted from SLCsL/S into the tail vein of mice.Our research results indicate that exosomes derived from SLCsL/S could transmit SR information to GECs and lead to the aggravation of inflammatory injury through conferring P-gp, which were negated by a P-gp inhibitor. Further, we identified higher levels of exosomal miR-125b-5p from SR GECs were associated with SR in LN and could serve as biomarker for the risk of developing SR. PNS could reverse the SR of GECs and alleviate inflammatory injury by suppressing exosomal P-gp levels from lymphocytes to GECs in vitro and in vivo. However, the specific molecular mechanism by which PNS regulates exosomes has not yet been elucidated, and we need to conduct more in-depth research in the future. Overall, Our findings suggest that exosomal transfer of SLCsL/S derived P-gp confer SR to GECs, and PNS can target exosome communication to reverse SR in LN, which provides new ideas and a scientific basis for improving the clinical efficacy of traditional Chinese medicine in the treatment of refractory LN.

Successful glucocorticoid withdrawal in Chinese lupus nephritis patients: A single centre experience

ObjectiveTo evaluate the proportion of patients successfully withdrawn from glucocorticoids (GC) in a longitudinal cohort of patients with lupus nephritis over a period of 20 years, clinical and pathological predictors of patients with GC withdrawal and renal outcomes after GC withdrawal were further explored. MethodsPatients with successful GC withdrawal were identified for the cohort, and the following data were collected: demographic characteristics, clinical manifestations, pathological findings at disease onset, flares, and renal outcomes subsequent to GC withdrawal. ResultsThere were 365 patients with lupus nephritis included with a median follow-up of 109.5 (83.5,165.3) months in our cohort. A total of 21 patients (5.8 %) achieved successful GC discontinuation, with a median duration of 7.5 (3,10) years necessary for GC withdrawal. The average duration of GC reduction from 7.5 mg/d to complete withdrawal lasted for approximately 25 months (18,30). Patients in the GC-withdrawal group had a lower prevalence of nephrotic syndrome (NS) at onset (28.5 % vs. 47.3 %, P = 0.035), a higher prevalence of positive anti–double-stranded DNA (anti-dsDNA) antibody (85.7 % vs. 61.6 %, P = 0.028) and more severe endocapillary hypercellularity in the renal histopathology evaluations (3(2.5,3) vs. 3(2,3), P = 0.022). NS at disease onset was an independent risk factor to predict unachievable GC withdrawal (OR 0.296, 95 % CI (0.104,0.842), P = 0.022) by multivariate analysis. With a median follow-up of 34 (20,42) months, none of these patients had flares after GC withdrawal. ConclusionsThe discontinuation of GC therapy in LN patients with complete remission and a stable treatment regimen for at least 5 years was feasible without an increased risk of flares, ESKD or death. Low-dose GC withdrawal necessitates a prolonged duration of time and meticulous monitoring.

Caracterización de los pacientes menores de 18 años con nefritis lúpica en el Hospital Pablo Tobón Uribe y en el Hospital San Vicente Fundación de la ciudad de Medellín, entre 2008 y 2017

IntroductionThe kidney is one of the organs frequently affected in systemic lupus erythematosus (40-60%); the manifestations are variable, from a silent pattern to the irreversible impairment of renal function. Objetives•To characterize patients under 18 years of age with a diagnosis of lupus nephritis treated at the Pablo Tobón Uribe Hospital and San Vicente Fundación Hospital during the years 2006 to 2017.•Establish the frequency of lupus nephritis in patients diagnosed with childhood systemic lupus erythematosus.•Describe the general, sociodemographic, clinical and paraclinical characteristics, as well as histopathological characteristics, immunosuppressive treatment and complications such as chronic kidney disease, high blood pressure, need for renal replacement therapy and death in patients diagnosed with lupus nephritis.•Explore the association between lupus nephritis with a histological pattern defined as moderate or severe and chronic kidney disease, arterial hypertension, need for renal replacement therapy and death. Materials and methodsDescriptive study with retrospective information in a group of patients under 18years of age with a diagnosis of lupus nephritis, attended in two referral centres of the city of Medellin between 2008 and 2017. Clinical records of patients who met the inclusion criteria were reviewed. ResultsThe median age was 13 years, with predominance in females. The majority had renal involvement at the time of diagnosis of lupus. Histological classIV was the most frequent (48%). Age under 10years, absence of response to induction therapy, and histological classIV, were related to the development of chronic kidney disease (>60ml/min/1.73m2). ConclusionsRenal involvement was higher in this study. Age, classIV, and non-response to induction were associated with impaired renal function.

Factors Predictive of Infections over Time in Lupus Nephritis Patients: Data from a Single-Center Retrospective Cohort

Factors Predictive of Infections over Time in Lupus Nephritis Patients: Data from a Single-Center Retrospective Cohort

Abstract 15 — Lupus Low Disease Activity State: An Underutilised Clinical Target that is Attainable and Protective against Lupus Nephritis Relapse

Background Lupus nephritis (LN) is a significant comorbidity affecting approximately 50-60% of patients with systemic lupus erythematosus (SLE). Complete and partial renal response (CRR/PRR) have been recommended as treatment targets in LN. Lupus low disease activity state (LLDAS) is also associated with favourable clinical outcomes. This study aims to investigate the LLDAS attainment rate and outcomes in patients with LN. Methods Patients with biopsy-proven LN during 2010-2020 in Queen Mary Hospital were included. Baseline demographics, blood parameters and urinalysis results were documented. Renal response and LLDAS attainment were assessed at 12 months after LN diagnosis. CRR was defined as proteinuria [Formula: see text]0.5g/day with a normal estimated glomerular filtration rate (eGFR); PRR was defined as a reduction in proteinuria by [Formula: see text]50% with near normal eGFR. A relapse was defined as a biopsy-proven active LN on histology after an initial treatment response of proteinuria reduction of [Formula: see text]50% or to sub-nephrotic range. Time-to-relapse survival analysis was performed to compare the significance of CRR/PRR and LLDAS attainment. Results 143 LN patients were included, with a median follow-up duration of 10.4 years. At 12 months, 57 (40%), 14 (10%) and 69 (48%) patients achieved CRR, PRR and LLDAS, respectively. Although 39 (27%) patients attained both CRR/PRR and LLDAS, a significant number of 30 (21%) patients reached LLDAS without meeting CRR/PRR (Figure 1). Among 136 patients who achieved the pre-defined treatment response, 30 (22%) patients developed LN relapse after a median of 2.98 years. Patients reaching either CRR/PRR or LLDAS had a significantly lower risk of relapse (CRR/PRR: HR = 0.34, p = 0.02; LLDAS: HR = 0.28, p = 0.003). The attainment of both CRR/PRR and LLDAS was associated with the lowest risk of relapse (Figure 2). Conclusion We advocate LLDAS as a target for LN patients as attaining LLDAS reduces future LN relapse risks.

Symposium 1

Proteomics has been a very informative tool in uncovering several biomarkers that may have clinical utility in managing patients with lupus nephritis (LN). Both non-targeted (mass spectrometry-based) and targeted (ligand-based) proteomics point to promising biomarkers in the urine of LN patients. Aptamer-based interrogation of 1129 proteins using the Somascan platform, followed by ELISA-validation in two independent cohorts has indicated that the urine proteins that best distinguish active LN from controls were ALCAM, PF-4, properdin, and VCAM-1 among African Americans, E-selectin, VCAM-1, BFL-1 and Hemopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians (PMID: 32366845). Most of these urine proteins correlate significantly with disease activity indices and surpass conventional metrics in identifying active LN. Several elevated urinary molecules are also expressed within LN kidneys, based on single-cell RNA-seq analysis. Of these, ALCAM has been validated in a large multi-ethnic, multi-national cohort of LN subjects, and has also been shown to be a pathogenic driver and therapeutic target in LN (PMID: 34981775). Antibody array based screening of 1000 proteins using the Raybiotech Kiloplex platform has identified urine L-selectin, Angptl4, TGF[Formula: see text] 1, TPP1, TSP-1, FOLR2, PDGFR[Formula: see text], and PRX2, as markers of active renal lupus, outperforming conventional metrics, with L-selectin, Angptl4 and TGF[Formula: see text] 1 tracking well with concurrent or pending disease flares in LN (PMID: 32651195). Of these, urine L-selectin has been validated in large multi-ethnic/national cohorts of LN subjects (under review). Proteomic screens of LN urine using an electrochemiluminescence platform (Mesoscale/MSD) has identified IL-7, IL-12p40, IL-15, IP-10, and TARC as markers of active renal lupus that correlated significantly with disease activity (PMID: 30618193). Very recent global proteomic screens of LN urine using a proximity ligation assay platform from Olink has added several additional biomarker candidates that have been successfully ELISA-validated (under review). Given the plethora of urine biomarkers that have been identified using proteomics, it now becomes important to validate the clinical utility of these urine proteins, using multiple well-annotated patient cohorts, across ethnicities. Among the completed studies, we now know that some urine proteins are diagnostic of concurrent renal pathology LN Class or Activity Index or Chronicity index (e.g. CD163: PMID: 32351512; VCAM-1: PMID: 29076253; Angiostatin: PMID: 29076253; Hemopexin, Kim-1 and Lipoxcalin-2/NGAL; Renin and SAP; PMID: 20065116), while others exhibit prognostic value (e.g., ALCAM and VCAM-1; PMID: 31722419). Ongoing studies also show that most of the urine proteins interrogated in LN are not elevated in circulation (PMID: 36091001), but are expressed within LN kidneys, as ascertained by immunohistochemistry (Clinical Immunology, 2022) and Imaging Mass Cytometry (Tissue CyTOF). To facilitate monitoring of urinary biomarkers in outpatient clinics or to enable self-monitoring of disease status by the patient from the comfort of one’s home, we have recently engineered a smartphone-readable nanophosphor-based lateral flow assay for point of care monitoring of urine ALCAM (Frontiers in Immunology, 2022). The long-term goal is to decipher the clinical utility of different urine biomarkers in managing lupus and LN in the clinics, to empower LN patients with easy-to-use tools to monitor their own disease status, and to understand the mechanistic significance of the uncovered molecules in renal disease pathogenesis. Ongoing research on this front is summarized at: https://mohanlab.bme.uh.edu/ .

MAIT cells altered phenotype and cytotoxicity in lupus patients are linked to renal disease severity and outcome.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which circulating immune complexes can cause different types of glomerulonephritis, according to immune deposits and to the type of glomerular cell injury. Proliferative lesions represent the most severe form of lupus nephritis (LN) and often lead to kidney failure and death. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial-derived ligands from the riboflavin synthesis pathway. Although abundant in peripheral blood, MAIT cells are enriched in mucosal and inflamed tissues. While previous studies have reported concordant results concerning lower MAIT cell frequencies in the blood of SLE patients, no information is known about MAIT cell function and LN severity and outcome. In the current study, we analyzed the baseline phenotype and function of peripheral blood MAIT cells by flow cytometry in 26 patients with LN and in a control group of 16 healthy individuals. We observe that MAIT cell frequencies are markedly reduced in blood of LN patients. MAIT cells from patients have an altered phenotype in terms of migration, proliferation and differentiation markers, notably in most severe forms of LN. Frequencies of PMA/ionomycin stimulated MAIT cells secreting effector molecules, such as proinflammatory IL-17 and cytotoxic protein granzyme B, are higher in LN patients. Patients undergoing a complete renal remission after immunosuppressive therapy had higher MAIT cell frequency, lower expression of proliferation marker Ki-67 and granzyme B (GzB) at inclusion. Remarkably, GzB production defines a predictive model for complete remission. We report here that blood MAIT cells display proinflammatory and cytotoxic function in severe lupus nephritis which may play a pathogenesis role, but without association with systemic lupus activity. Finally, low cytotoxic profile of MAIT cells may represent a promising prognostic factor of lupus nephritis remission one year after induction therapy.

Tumor necrosis factor-α, its related immunoregulatory long non-coding RNA (THRIL) and micro-RNA 145 as potential biomarkers in lupus nephritis patients

Tumor necrosis factor-α, its related immunoregulatory long non-coding RNA (THRIL) and micro-RNA 145 as potential biomarkers in lupus nephritis patients

Development and validation of a prognostic nomogram for the renal relapse of lupus nephritis

ObjectivesThis study aims to assess the risk of relapse after complete remission (CR) and partial remission (PR), and to develop a prognostic nomogram predicting the probability in lupus nephritis (LN) patients. MethodsData from patients with LN who had been in remission were collected as a training cohort. The prognostic factors were analyzed using the univariable and multivariable Cox model for the training group. A nomogram was then developed using significant predictors in multivariable analysis. Both discrimination and calibration were assessed by bootstrapping with 100 resamples. ResultsA total of 247 participants were enrolled, including 108 in the relapse group and 139 in the no relapse group. In multivariate Cox analysis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), erythrocyte sedimentation rate (ESR), complement 1q (C1q), and antiphospholipid (aPL), anti-Sm antibody were found to be significant for predicting relapse rates. The prognostic nomogram including the aforementioned factors effectively predicted 1- and 3-year probability of flare-free. Moreover, a favorable consistency between the predicted and actual survival probabilities was demonstrated using calibration curves. ConclusionsHigh SLEDAI, ESR, and positive aPL, anti-Sm antibody are potential risk factors for LN flare, while high C1q can reduce its recurrence. The visualized model we established can help predict the relapse risk of LN and aid clinical decision-making for individual patients.

Urine Proteomics Link Complement Activation with Interstitial Fibrosis/Tubular Atrophy in Lupus Nephritis Patients

BackgroundIntrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRβ), platelet-derived growth factor beta (PDGFβ) and platelet-derived growth factor receptor beta (PDGFRβ). MethodsWe included urine samples from 46 adults and pediatric biopsy-proven lupus nephritis patients who underwent clinically indicated kidney biopsies between 2010 and 2019. We compared individual urinary complement components and the urinary C9-to-CD59 ratio between LN patients with moderate/severe IFTA and none/mild IFTA. IFTA was defined as none/mild (<25% of interstitium affected) versus moderate/severe (≥ 25% of interstitium affected). Proteomics analysis was performed using mass spectrometry (Orbitrap Fusion Lumos, Thermo Scientific) and processed by the Proteome Discoverer. Urinary complement proteins enriched in LN patients with moderate/severe IFTA were correlated with serum creatinine, TGFβR1, TGFβR2, PDGFβ, and PDGFRβ. ResultsOf the 46 LN patients included in the study, 41 (89.1%) were women, 20 (43.5%) self-identified as Hispanic or Latino, and 26 (56.5%) self-identified as Black or African American. Ten of the 46 (21.7%) LN patients had moderate/severe IFTA on kidney biopsy. LN patients with moderate/severe IFTA had an increased urinary C9-to-CD59 ratio [median 0.91 (0.83-1.05) vs 0.81 (0.76-0.91), p=0.01]. Urinary C3 and CFI levels in LN patients with moderate/severe IFTA were higher compared to those with none/mild IFTA [C3 median (IQR) 24.4(23.5-25.5) vs. 20.2 (18.5–22.2), p= 0.02], [CFI medium (IQR) 28.8 (21.8-30.6) vs. 20.4 (18.5-22.9), p=0.01]. Complement C9, CD59, C3 and CFI correlated with TGFβR1, PDGFβ, and PDGFRβ, while C9, CD59 and C3 correlated with TGFβR2. ConclusionThis study is one of the first to compare the urinary complement profile in LN patients with moderate/severe IFTA and none/mild IFTA in human tissues. This study identified C3, CFI, and C9-to-CD59 ratio as potential markers of tubulointerstitial fibrosis in LN.

Repeat kidney biopsy findings of lupus nephritis patients in clinical remission treated with Mycophenolate associated with Belimumab or Mycophenolate plus standard of care therapy. A "post-hoc" analysis of participants in the BLISS-LN and open label extension study belonging to a single center.

Background: Lupus nephritis affects 40 to 70% of Systemic Lupus Erythematous(SLE) patients increasing their morbi-mortality; therefore, successful treatments are required to improve outcomes. Research Design and Study Sample: In this paper 20 patients who participated in the BLISS LN trial at a single center (OMI) in Argentina were studied. All the patients continued Mycophenolate (MMF) treatment when the trial was finished and until a second biopsy was performed to determine the withdrawal of the immunosuppression according to the achieved clinical and histological response. Ten patients treated with MMF + Placebo versus 10 receiving MMF + Belimumab, were compared evaluating the complete clinical (CCR) and complete histological response (CHR) and the flares in each group. Results: All the patients in the Belimumab group showed a CCR and 7 in the Placebo one; CHR was found in 9 and 5 patients of the Belimumab and Placebo group, respectively. None of the patients in the Belimumab group flared meanwhile two of the Placebo one did it. Conclusions: Although the number of patients is insufficient to be able to draw unquestionable conclusions, adding Belimumab to the standard of care treatment with MMF would seem to increase the possibility of achieving a CCR, CHR, and a lower rate of relapses during treatment and long follow-up.

Association between immunoglobulin G N-glycosylation and lupus nephritis in female patients with systemic lupus erythematosus: a case-control study.

Lupus nephritis (LN) is a crucial complication of systemic lupus erythematosus (SLE) and has important clinical implications in guiding treatment. N-glycosylation of immunoglobulin G (IgG) plays a key role in the development of SLE by affecting the balance of anti-inflammatory and proinflammatory responses. This study aimed to evaluate the performance of IgG N-glycosylation for diagnosing LN in a sample of female SLE patients. This case-control study recruited 188 women with SLE, including 94 patients with LN and 94 age-matched patients without LN. The profiles of plasma IgG N-glycans were detected by hydrophilic interaction chromatography with ultra-performance liquid chromatography (HILIC-UPLC). A multivariate logistic regression model was used to explore the associations between IgG N-glycans and LN. A diagnostic model was developed using the significant glycans as well as demographic factors. The performance of IgG N-glycans in the diagnosis of LN was evaluated by receiver operating characteristic (ROC) curve analysis, and the area under the curve (AUC) and its 95% confidence interval (CI) were calculated. There were significant differences in 9 initial glycans (GP2, GP4, GP6, GP8, GP10, GP14, GP16, GP18 and GP23) between women with SLE with and without LN (P < 0.05). The levels of sialylated, galactosylated and fucosylated glycans were significantly lower in the LN patients than in the control group, while bisected N-acetylglucosamine (GlcNAc) glycans were increased in LN patients (P < 0.05). GP8, GP10, GP18, and anemia were included in our diagnostic model, which performed well in differentiating female SLE patients with LN from those without LN (AUC = 0.792, 95% CI: 0.727 to 0.858). Our findings indicate that decreased sialylation, galactosylation, and core fucosylation and increased bisecting GlcNAc might play a role in the development of LN by upregulating the proinflammatory response of IgG. IgG N-glycans can serve as potential biomarkers to differentiate individuals with LN among SLE patients.

Clinicopathological Characteristics and Prognosis of Lupus Nephritis Patients with Acute Kidney Injury

Introduction: Acute kidney injury (AKI) is common in lupus nephritis (LN) and a risk factor for chronic kidney failure. Here, we aimed to assess the characteristics and prognosis of LN patients with AKI. Methods: AKI and AKI severity stages in LN patients were defined by the Kidney Disease Improving Global Outcomes (KDIGO) classification. Long-term renal outcomes and patient mortality between different stages of AKI were compared by Cox regression analysis. Results: Of 1272 LN patients, 225 (17.69%) had AKI and 72 (5.66%) were AKI stage 3. Compared with the non-AKI group, the proportion of male patients was significantly higher in the AKI group (p = 0.002). In addition, there were markedly higher proportions of hematologic system damage, more severe renal manifestations, and higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores in the AKI group than in the non-AKI group. The active and chronic lesions in renal biopsy were significantly higher in LN patients with AKI than those without AKI. During a median follow-up of 53 months, Kaplan-Meier curve showed that LN patients with AKI stage 3 had significantly poorer long-term renal outcomes (p = 0.002) and patient survival (p < 0.001) than those without AKI. Furthermore, AKI stage 3, but not stage 1 or 2 was significantly associated with adverse renal outcomes (hazard ratio [HR] = 2.52, 95% confidence interval [CI] 1.01–6.28, p = 0.048) and all-cause mortality (HR = 2.80, 95% CI: 1.18–6.61, p = 0.019) in LN patients. In patients with AKI, increased baseline serum creatinine and severe glomerular sclerosis were independent risk factors for worse renal outcomes, while higher blood pressure, increased baseline serum creatinine, and anti-Sjogren’s syndrome A positivity could indicate poor survival. Discussion: LN patients with AKI stage 3, but not stages 1 and 2, have poorer long-term renal outcomes and patient survival. Our study demonstrates the importance of early identification and management of AKI in LN patients.

Long noncoding RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus

BackgroundDysregulated long noncoding RNA (lncRNA) expression with increased apoptosis has been demonstrated in systemic lupus erythematosus (SLE) patients with alveolar hemorrhage (AH). SNHG16, a lncRNA, can enhance pulmonary inflammation by sponging microRNAs, and upregulate toll-like receptor 4 (TLR4) expression via stabilizing its mRNAs. TRAF6, a TLR4 downstream signal transducer, can induce autophagy and NETosis formation. In this study, we investigated whether SNHG16 could regulate TLR4-mediated autophagy and NETosis formation in SLE-associated AH.MethodsExpression of SNHG16, TLR4 and TRAF6 and cell death processes were examined in lung tissues and peripheral blood (PB) leukocytes from AH patients associated with SLE and other autoimmune diseases, and in the lungs and spleen from a pristane-induced C57BL/6 mouse AH model. SNHG16-overexpressed or -silenced alveolar and myelocytic cells were stimulated with lipopolysaccharide (LPS), a TLR4 agonist, for analyzing autophagy and NETosis, respectively. Pristane-injected mice received the intra-pulmonary delivery of lentivirus (LV)-SNHG16 for overexpression and prophylactic/therapeutic infusion of short hairpin RNA (shRNA) targeting SNHG16 to evaluate the effects on AH. Renal SNHG16 expression was also examined in lupus nephritis (LN) patients and a pristane-induced BALB/c mouse LN model.ResultsUp-regulated SNHG16, TLR4 and TRAF6 expression with increased autophagy and NETosis was demonstrated in the SLE-AH lungs. In such patients, up-regulated SNHG16, TLR4 and TRAF6 expression was found in PB mononuclear cells with increased autophagy and in PB neutrophils with increased NETosis. There were up-regulated TLR4 expression and increased LPS-induced autophagy and NETosis in SNHG16-overexpressed cells, while down-regulated TLR4 expression and decreased LPS-induced autophagy and NETosis in SNHG16-silenced cells. Pristane-injected lung tissues had up-regulated SNHG16, TLR4/TRAF6 levels and increased in situ autophagy and NETosis formation. Intra-pulmonary LV-SNHG16 delivery enhanced AH through up-regulating TLR4/TRAF6 expression with increased cell death processes, while intra-pulmonary prophylactic and early therapeutic sh-SNHG16 delivery suppressed AH by down-regulating TLR4/TRAF6 expression with reduced such processes. In addition, there was decreased renal SNHG16 expression in LN patients and mice.ConclusionsOur results demonstrate that lncRNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in the human and mouse AH lungs, and provide a therapeutic potential of intra-pulmonary delivery of shRNA targeting SNHG16 in this SLE-related lethal manifestation.

Role of [68Ga]-pentixafor positron emission tomography/computed tomography imaging in assessing disease activity in patients with lupus nephritis: A pilot study.

The primary objective of our study was to evaluate renal uptake of 68Ga-pentixafor in patients with lupus nephritis. Eighteen patients who satisfied the inclusion criteria were included in our study. The study participants were patients with histopathologically confirmed lupus nephritis who were referred to our department for 68Ga-pentixafor PET/CT scan. We studied the renal images in these patients for uptake patterns based on purely visual as well as semi-quantitative parameters. The visual parameters included uptake relative to the spleen and liver. Semi-quantitative analysis involved the uptake as given by SUVmax. These parameters were correlated with the patients' biochemical as well as histological parameters. Kendall's tau-b test was used to look for an association between renal uptake by visual assessment and histopathological findings. Mean SUVmax values were compared by using the Mann-Whitney U test and a p value < .05 was considered to be statistically significant. No significant association between the mean renal SUVmax of the bilateral kidneys in pentixafor PET and histopathological class was observed. We did not observe any heterogeneity in uptake patterns that could be attributed to the disease process in our patients. 68Ga-pentixafor PET is not a suitable imaging modality for assessment of disease activity in lupus nephritis patients. There is a void in non-invasive testing for patients with this chronic and often disabling condition which calls for further research in this area.

Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

There is an urgent need for novel biomarkers in lupus nephritis (LN). We report a non-invasive urinary biomarker, L-selectin, in two independent multi-ethnic cohorts. uL-selectin was tested cross-sectionally in a Chinese cohort (n=255) and a US cohort (n=219) of SLE patients and controls using ELISA. A longitudinal cohort includes 20 active Chinese LN patients. uL-selectin was significantly increased in active LN patients compared to active non-renal SLE, inactive LN, inactive non-renal SLE, chronic kidney disease patients, and healthy controls. uL-selectin positively correlated with global and renal disease activities as well as histological activity index and chronicity index (CI). Low uL-selectin was an independent predictor for high CI. During follow-up, uL-selectin levels decreased significantly in the complete renal remission group. uL-selectin is a novel biomarker of disease activity and renal histopathology in LN across multiple ethnicities. It also reflects treatment response in LN patients during follow up.

Experience with abatacept in refractory lupus nephritis.

Lupus nephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Responsiveness to treatment is crucial to avoid chronic kidney disease. New molecules have been developed in recent years to improve renal survival rates. Biological therapies as coadjutant to conventional induction treatment have been tested in randomized clinical trials with heterogeneous results. Like many others biologic therapies, Abatacept has not shown a clear benefit in the context of clinical trials. We present two cases of lupus nephritis patients in whom addition of abatacept resulted in complete remission of the renal disease. The first case described a 49-year-old male with class IV lupus nephritis with nephrotic range proteinuria and high immunological activity refractory to conventional treatment with cyclophosphamide and corticosteroids and multitarget therapy with tacrolimus, mycophenolate mofetil and prednisone. Several biological therapies (rituximab, belimumab and tocilizumab) were unsuccessfully tried, so that abatacept was added to his background multitarget therapy showing complete clinical response. The second case described a 52-year-old female with class IV lupus nephritis treated initially with conventional treatment with partial response. In successive renal flares with nephrotic proteinuria, she showed intolerance to rituximab and refractoriness to voclosporin. Finally, abatacept was added to her background therapy with MMF and PDN showing complete and maintained remission of the disease. In no case the use of abatacept was associated with serious adverse events. Based on our experience, abatacept should be considered as a safe rescue therapy in patients with refractory lupus nephritis and proteinuria with nephrotic range. In addition to this case, we reviewed the use of abatacept in lupus nephritis in the literature.

Anti-Ficolin-2 Antibody: Could It Be a Predictor of Proliferative Lupus Nephritis in Lupus Patients?

Abstract Background Nephritis is a challenging domain of systemic lupus erythematosus (SLE). There is a growing need for identification of a non-invasive marker for diagnosing and monitoring nephritis. Objective To explore the relevance of using anti-ficolin-2 antibody (Anti-FCN2) as a biomarker for detecting lupus nephritis (LN), and its relation to renal biopsy histopathology and disease activity. Patients and Methods Sixty SLE patients were compared to 30 apparently healthy individuals. Thirty of the patients were LN patients (documented by a recent renal biopsy). Full history, examination and laboratory investigations were done. Activity was assessed by SLE disease activity index (SLEDAI) score, and Anti-FCN2 titer was measured by enzyme-linked immunosorbent assay technique (ELISA). Results Forty-four of our SLE patients were in disease activity by SLEDAI score. Anti-FCN2 titer was significantly higher among SLE patients compared to control group (p value &amp;lt;0.001). It was also higher among patients with high disease activity compared to those with low disease activity and cutoff value was at 37 ng/ml (p value is &amp;lt; 0.001). AntiFCN2 titer was significantly higher among patients with LN compared to those without LN (p value is &amp;lt; 0.001) with best cutoff value at 72.50 ng/ml. Regarding LN patients, it was significantly higher among patients with proliferative changes than LN patients with non-proliferative changes (p value is 0.05) with best cutoff value at 155 ng/ml. Conclusion Anti-FCN2 shows promising results as a biomarker for lupus disease activity, especially regarding LN and proliferative changes. Further longitudinal studies on larger samples are needed to confirm.

Platelet to Lymphocyte Ratio and Neutrophils to Lymphocyte Ratio as Potential Markers for Lupus Nephritis Flares

Abstract Background Systemic lupus erythematosus is chronic autoimmune disorder with variable clinical presentations and multi-organ involvement. The disease has female predominance and unpredictable course. The aim of this study was to measure platelet to lymphocyte, neutrophil to lymphocyte ratios in patients with lupus nephritis. Subjects and Methods This study was conducted on patients of lupus nephritis either in Nephrology clinic&amp; Dialysis unit or admitted as inpatient in Ain Shams university Hospitals. For 60 Patients as two groups; the first group includes 30 SLE patients with ESRD. The second group includes of 30 lupus, and 3rd group 30 control healthy group. Results A highly significant difference was observed between lupus nephritis patients and healthy controls regarding neutrophil to lymphocyte ratio (p &amp;lt; 0.001) Conclusion In conclusion, NLR appear to be potentially useful biomarkers in lupus nephritis patients for disease activity and damage-compared with the other inflammatory cytokines as IL-6. Being easily obtained and cheap, they can be applied as predictors of not only disease activity and damage but also relapse and remission in lupus nephritis patients before applying other expensive and invasive measures. Dangerous disease activity and flares in SLE are unpredictable and represent a challenge in clinical practice.