Acute Lupus Nephritis Research Articles

#6547 ON104, A NOVEL BIOENGINEERED ANTIBODY TARGETING OXIDIZED MACROPHAGE MIGRATION INHIBITORY FACTOR (OXMIF) AMELIORATES EXPERIMENTAL GLOMERULONEPHRITIS

Abstract Background and Aims Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine and a primary counter-regulator of glucocorticoids (GCs) that emerged as a pivotal regulator of immune-mediated disorders including glomerulonephritis (GN). MIF occurs in two immunologically distinct, conformational isoforms: reduced MIF, ubiquitously present in various tissues and the circulation of healthy subjects, and oxidized MIF (oxMIF), described as the pathogenic and druggable isoform of MIF [1]. We previously reported a positive correlation between disease severity and urinary oxMIF levels in patients with acute lupus nephritis, suggesting oxMIF contribution to kidney damage [2]. In this study we evaluated the anti-inflammatory effects of oxMIF neutralization using ON104 antibody during crescentic GN. Method By advanced antibody engineering we generated the fully human antibody ON104 that is specific and highly affine for human oxMIF and its orthologs. ON104 was tested for its therapeutic potential in a rodent model of GN. Nephritis was induced in male WKY rats by a single intravenous (i.v.) injection of rabbit anti-rat GBM (glomerular basement membrane) serum. On day 4 and day 6 after GN induction, ON104 was administrated intraperitoneally (i.p.). Body weight, proteinuria, and hematuria were assessed to evaluate GN severity. On day 8, kidneys were harvested for immuno-histological examinations by HE, PAS-staining and IHC staining. Results Treatment with ON104 substantially attenuated clinical signs of GN by preserving kidney function demonstrated by reduced proteinuria, and reduced hematuria. Furthermore, ON104 significantly reduced tissue injury, reduced crescentic glomerulus formation, and increased the percentage of normal glomeruli. On the cellular level, oxMIF neutralization by ON104 reduced CD68+ macrophage accumulation within the inflamed kidneys compared to untreated and isotype Ig-treated rats. Conclusion Our findings substantiate the role of oxMIF in the pathogenesis of experimental GN. Thus, targeting oxMIF may represent a new and promising treatment option for kidney diseases.

Predictors of treatment outcomes in lupus nephritis with severe acute kidney injury and requirement of dialytic support.

Acute kidney injury (AKI) with the requirement of kidney replacement therapy (KRT) portends a poor prognosis for kidney function in lupus nephritis (LN). This study evaluated the kidney function recovery rates, the rates of reinitiation of KRT, and factors associated with these outcomes in LN. All consecutive patients hospitalized for LN with KRT requirement between 2000 and 2020 were included. Their clinical and histopathologic characteristics were retrospectively registered. The outcomes and associated factors were evaluated by multivariable Cox regression analysis. Among 140 patients, 75 (54%) recovered kidney function, with recovery rates of 50.9% and 54.2% by 6 and 12months of therapy. The factors associated with a lower probability of recovery included a previous history of LN flares, worse eGFR and higher proteinuria at presentation, immunosuppression with azathioprine, and hospitalizations within 6months of therapy initiation. There was no difference in the kidney function recovery rates between mycophenolate and cyclophosphamide treatment schemes. Out of 75 patients who recovered kidney function, 37 (49%) reinitiated KRT, with KRT reinitiation rates of 27.2% and 46.5% by 3 and 5years. Seventy-three (52%) patients had at least one hospitalization within 6months of initial therapy, 52 (72%) of them secondary to infectious events. Approximately 50% of patients with LN and KRT requirement recover kidney function within 6months. The risk-to-benefit ratio decisions may be aided by clinical and histological factors. These patients require close follow-up as ≈50% of those who recover kidney function will reinitiate dialysis in the long term. Key Points • Approximately 50% of patients with severe acute lupus nephritis with the need for kidney replacement therapy requirement recover their kidney function. • The factors associated with a lower probability of recovery of kidney function include a previous history of LN flares, worse eGFR and higher proteinuria at presentation, immunosuppression with azathioprine, and hospitalizations within 6 months of therapy initiation. • Patients who recover kidney function will require close follow-up as around 50% of them will eventually reinitiate kidney replacement therapy.

POS-461 A LUPUS NEPHROLOGIST'S NIGHTMARE- MANAGEMENT OF A YOUNG PATIENT WITH SEVERE COMBINED CLASS IV AND V LUPUS NEPHRITIS,STEROID INTOLERANCE AND COMCOMITANT HEPATITIS B VIRAL LOAD

Lupus nephritis (LN) is an increasing and prevalent complication of patients with lupus disease, occurring in up to 45% of this population. Significant gradual podocyte loss and nephron loss accompanied each episode of an acute lupus nephritis flare. Early diagnosis and treatment initiation is paramount to preserving kidney function in patients with LN. In patient with advanced and combined class IV and V lupus, management is often tortuous and produces a poor outcome. Patients with poor steroid tolerance are particularly at risk of limited therapy. Moreover, in the presence of associated viral infection such as hepatitis B, the risk of progression to liver failure with start of immunosuppressant agents for lupus nephritis management may limit use of aggressive immune suppression therapy. In this paper, we present a 37 year old Asian-American female with no significant past medical history presented with clinical features of nephrotic syndrome with a 35 lbs weight gain , body swelling , uncontrolled blood pressure, 14 g/g proteinuria. She underwent a renal biopsy with findings of combined class IV and V lupus, pre- immunosuppression workup reveals a positive hepatitis B viral infection with viral load of > 25 million copies. Patient was unable to tolerate greater than 20 mg /day prednisone dosage due to several side effects. Treatment with concurrent therapy for Hepatitis B as well as substituting Tacrolimus doses for steroids in addition to Mycophenolate induction therapy was able to able clearance of the viral load as well as > 30% reduction in proteinuria in 3 months. Discounting a description of providing a steroid free approach to LN management, this abstract is unique in that it revisits the common approach of treating viral hepatitis first before commencing therapy for LN as nephron loss during this interim of delay could be detrimental to the risk of ESRD in the long term.

LB001EFFICACY AND SAFETY OF BELIMUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS: A PHASE 3, RANDOMISED, PLACEBO-CONTROLLED TRIAL

Abstract Background and Aims Belimumab (BEL), an anti-B-cell-activating factor (BAFF) monoclonal antibody, is approved in patients (pts) ≥5 years of age with active systemic lupus erythematosus (SLE). Post hoc analyses of pooled renal outcomes data from two Phase 3 SLE studies showed favourable trends of greater reduction in proteinuria, haematuria, pyuria and lower renal flare rates in BEL-treated pts vs placebo (PBO).1 This is the largest study in acute lupus nephritis (LN) to date that evaluated efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in pts with active LN. Method BLISS-LN is a Phase 3, randomised, double-blind, placebo-controlled, 104-week study (GSK study BEL114054, NCT01639339); eligible pts (≥18 years) with autoantibody-positive SLE and active, biopsy-proven LN (classes III, IV and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomisation was stratified by induction regimen: high dose corticosteroids [HDCS] plus either cyclophosphamide (CyC), followed by azathioprine + low dose corticosteroids (LDCS), or mycophenolate mofetil (MMF), followed by MMF + LDCS. Primary endpoint: primary efficacy renal response (PERR; defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] no more than 20% below pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: complete renal response (CRR; defined as uPCR <0.5; eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73m2; no rescue therapy) at Wk 104; PERR at Wk 52; risk of renal-related event (defined as end-stage renal disease/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death at any time up to Wk 104. Other endpoints: PERR and CRR at Wk 104 by induction regimen; proportions of pts with baseline uPCR ≥0.5 with uPCR shift to <0.5 while on study. Results Overall, 448 pts were randomised (efficacy: 223/treatment group; safety: 224/treatment group); 118 pts received CyC induction and 328 MMF induction; 278 (62.3%) completed the treatment. At Wk 104, 43.0% BEL and 32.3% PBO pts achieved PERR (OR [95% CI] vs PBO 1.55 [1.04, 2.32], p=0.0311); 30.0% BEL and 19.7% PBO pts achieved CRR (OR [95% CI] vs PBO 1.74 [1.11, 2.74], p=0.0167). Over 104 weeks, more BEL than PBO pts achieved CRR at each visit (Figure 1A). PERR at Wk 52 was achieved by 46.6% BEL and 35.4% PBO pts (OR [95% CI] vs PBO 1.59 [1.06, 2.38], p=0.0245). The risk of a renal-related event or death was 49% lower with BEL than PBO (HR [95%CI] 0.51 [0.34, 0.77]; p=0.0014) at any time point during the study. Overall, 15.7% of BEL and 28.3% of PBO pts experienced a renal-related event or death. When analysed by induction regimen, PERR at Wk 104 was achieved by 33.9% BEL and 27.1% PBO CyC-induced pts (OR [95% CI] vs PBO 1.52 [0.66, 3.49], p=0.3272), and by 46.3% BEL and 34.1% PBO MMF-induced pts (OR [95% CI] vs PBO 1.58 [1.00, 2.51], p=0.0501). CRR at Wk 104 was achieved by 18.6% BEL and 18.6% PBO CyC-induced pts (OR [95% CI] vs PBO 1.07 [0.41, 2.78], p=0.8843), and by 34.1% BEL and 20.1% PBO MMF-induced pts (OR [95% CI] vs PBO 2.01 [1.19, 3.38], p=0.0085). Proportions of pts with uPCR shift from ≥0.5 at baseline to <0.5 while on study (calculated post hoc) are presented in the Figure 1B. Overall, 95.5% BEL and 94.2% PBO pts had ≥1 adverse event (AE); 25.9% BEL and 29.9% PBO pts had ≥1 serious AE; 13.8% BEL and 17.0% PBO pts had serious infections; 12.9% pts in each group had ≥1 AE resulting in study treatment discontinuation; on-treatment fatal AEs were reported in 1.8% BEL and 1.3% PBO pts. Conclusion BEL demonstrated improved renal responses vs PBO in pts with active LN, with a safety profile consistent with previous BEL trials.

Relationship between The Level Of Anti-Double Strand DNA Antibody And Lupus Renal Diseases In Patients With Systemic Lupus Erythematosus

Objective: The goal of this study was to investigate the development of acute lupus nephritis or end stage renal disease in patients who had persistently high or variant levels of anti-dsDNA. Methods: Patients who fulfilled the diagnostic criteria for SLE were placed into one of three groups: persistent high levels, variant levels, and persistent normal levels of anti-dsDNA. Clinical renal diseases were based on the present of acute lupus nephritis, and the development of end stage renal disease (ESRD). Results: A total of 257 patients were enrolled in the study. Among them, 86 patients never have an elevation of anti-dsDNA during the follow-up period, 46 patients had variant levels of anti-dsDNA, and 125 patients had persistently high levels of anti-dsDNA. We compared the lupus nephritis flares and ESRD between normal anti-dsDNA group with high anti-dsDNA group or variant anti-dsDNA group, and the results showed significantly statistics different in acute lupus nephritis between the comparisons (p＜ 0.001, p＜0.001 respectively). However, there were no statistics different in ESRD (p=0.539, p=0.061 respectively). Conclusion: Patients who consistently showed a high anti-dsDNA level would have higher rate of acute lupus nephritis. Besides, if their serum elevated level of anti-dsDNA could not back and consistently within normal range, these patients also have less favorable renal outcome. Therefore, more intensive follow up and aggressive medical treatments are needed for these patients.

An antibody profile of systemic lupus erythematosus detected by antigen microarray

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states--SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein-Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

Nephrogenic Fibrosing Dermopathy in a Patient with Systemic Lupus Erythematosus and Acute Lupus Nephritis

Nephrogenic fibrosing dermopathy is a recently recognized skin disorder similar in appearance to scleromyxedema but without the systemic involvement. We describe a 14-year-old girl with new-onset systemic lupus erythematosus and acute lupus nephritis who developed on the lower extremities confluent hyperpigmented, woody, indurated plaques that contained groups of coalescing erythematous papules. Nephrogenic fibrosing dermopathy was diagnosed histologically. Possible etiologies are discussed.

Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) reduces proteinuria and the rate of renal function deterioration in diabetic nephropathy and other glomerular diseases, but its role in quiescent lupus nephritis has not been established. We conducted a retrospective study to investigate the effects of ACEI/ARB on proteinuria and renal function in patients with persistent proteinuria (>1 g/day) despite resolution of acute lupus nephritis following immunosuppressive treatment. Fourteen out of 92 patients were included. The duration of treatment with ACEI/ARB was 52.1 +/- 35.7 months. The levels of proteinuria, serum albumin, serum creatinine, systolic and diastolic blood pressure were 1.10 to 6.90 g/day, 35.8 +/- 3.6 g/L, 102.54 +/- 34.48 micromol/L, 137.6 +/- 10.9 and 81.9 +/- 9.2 mmHg at baseline. Proteinuria and serum albumin showed significant sustained improvements after 6 and 24 months of treatment. Comparison of slopes for serial proteinuria, albumin and reciprocal of serum creatinine before and after treatment showed significant improvements in six (43%), eight (57%) and two patients, respectively. At last follow-up proteinuria remained significantly lower (0.36 g/day, P = 0.043) and albumin higher (41.3 +/- 2.2 g/L, P = 0.023). Eleven (78.6%) patients had proteinuria improved by >50%, and five had insignificant proteinuria at last follow-up. Systolic blood pressure was significantly reduced from 6 months onwards, but this did not correlate with proteinuria reduction. Diastolic blood pressure, serum creatinine, creatinine clearance, anti-dsDNA, C3 and haemoglobin were not altered. We conclude that ACEI/ARB effectively reduces proteinuria and improves serum albumin in patients with persistent proteinuria despite quiescent lupus nephritis.

Sequential evaluation of clinical and laboratory changes amongst children suffering from lupus nephritis during intermittent intravenous cyclophosphamide therapy

We prospectively evaluated the efficacy and safety of a 24-month course of intermittent intravenous cyclophosphamide (IC) therapy for children suffering from lupus nephritis soon after the diagnosis of systemic lupus erythematosus (SLE) was made. Eight children with severe lupus nephritis were treated with IC monthly for 6 months and then every 3 months, totaling 24 months. The repeated measurements of sequential serological parameters of lupus nephritis, monitored over the course of the study, were analyzed statistically. The urine creatinine clearance rate (Ccr), the 24-h urine protein excretion, and the serum creatinine level significantly improved (p<0.05) after 6, 9 and 12 months of treatment, respectively. The serum C3, C4, albumin, and triglyceride level, the hemoglobin level, and the erythrocyte sedimentation rate significantly improved (p<0.05) 1 month after treatment. The IC appeared to elicit a significant effect (p<0.05) upon the mean leukocyte and neutrophil counts but had no effect (p>0.05) on the platelet count. The lymphocyte count decreased (p<0.05) during the first six monthly IC, whereas the lymphocyte count returned to the baseline level during the quarterly IC events. From a total of 96 IC doses given to those SLE patients, severe myelotoxicity occurred in one patient when lymphocyte count declined to 98 mm(-3); however, no sign of clinical infection was observed. The daily steroid dosage can be tapered rapidly, and the SLE-associated hyperlipidemia resolved parallel to the resolution of the acute lupus nephritis. We concluded that the efficacy of a 24-month IC course for a child suffering from lupus nephritis is significant.

Growth arrest specific protein 6/Axl signaling in human inflammatory renal diseases

Background: Growth arrest-specific gene 6 (Gas6) and its binding partner, the receptor tyrosine kinase Axl, are important mediators in experimental nephritis. The authors tested whether the Gas6/Axl signaling pathway participates in human renal diseases. Methods: The authors compared 26 human renal specimens from patients with IgA nephritis, acute diffuse immune complex glomerulonephritis, acute lupus nephritis, antineutrophil cytoplasmic antibody—associated glomerulonephritis, acute transplant rejection, and normal renal tissue. Because reactive oxygen species are pivotal in inflammation, the authors tested whether the Axl/Gas6 expression is influenced by NADPH oxidase in vitro. Results: Gas6 and Axl immunofluorescence was barely detectable in normal kidney. However, in disease Axl was copiously expressed in the small vessel media, glomeruli, distal tubules, and collecting ducts. Similarly, Gas6 was upregulated in the small vessel intima and media, all segments of the renal tubules, the brush border, and glomeruli. Gas6 and Axl upregulation was a prominent but nonspecific finding in these renal diseases. Cultured rat vascular smooth muscle cells and immortalized human mesangial cells were stimulated with angiotensin (Ang) II (1 × 10−7 mol/L) for 6 or 18 hours. Confocal microscopy and Western blot showed Ang II-dependent Gas6 and Axl expression. An antisense probe against the p22 phox unit of NADPH-oxidase suppressed Ang II-induced Gas6 and Axl expression. In addition, in p47 phox knockout cells Ang II-induced Gas6 and Axl expression were blocked. Conclusion: GAS6/Axl signaling is involved in human renal disease. The Ang II-induced Gas6 and Axl expression may be dependent on NADPH-oxidase. Gas6 and Axl are important signaling molecules in human renal disease and may be potential therapeutic targets.

Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity

To determine if measurement of serum complement split products (C4d, Bb, C5b-9) is better than conventional C3 and C4 measurements in distinguishing patients with varying degrees of lupus disease activity, and to determine if the presence of C3d in urine is helpful in distinguishing lupus patients with from those without early lupus nephritis. Lupus disease activity was prospectively determined at 3 consecutive visits an average of 4 months apart, using the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and physician global assessment (PGA). Blood samples were evaluated for the presence of C4d, Bb, and C5b-9 by quantitative microassay plate enzyme immunoassay at each patient visit. We characterized urinary excretion of C3 fragments (with attention to C3d) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western blotting. Thirty-one SLE patients were enrolled in the study. The mean SLAM score and the mean SLEDAI score each correlated well with the PGA at all 3 visits. A SLAM score of 6 and a SLEDAI score of 4 had the best overall sensitivity and specificity for predicting moderate-to-severe disease activity by PGA (100% and 73%, respectively, for the SLAM and 86% and 94%, respectively, for the SLEDAI). Serum C4d and Bb were more sensitive indicators of current moderate-to-severe lupus disease activity at all 3 visits than were serum C5b-9, C3, and C4. C3 and C4 were more specific indicators of moderate-to-severe disease activity. Serum C4d and Bb were more sensitive at predicting moderate-to-severe disease activity at subsequent visits than were C5b-9, C3, and C4. Urine C3d was better than C3, plasma C4d, Bb, C5b-9 and anti-double-stranded DNA antibody in distinguishing patients with from those without acute lupus nephritis (P = 0.02). C4d and Bb are sensitive indicators of moderate-to-severe lupus disease activity and may be most helpful in situations where conventional measurements are not, such as in lupus patients whose C3 and C4 levels remain normal despite evidence of clinical disease activity. It appears from this study that detection of urine C3d may be a simple way of measuring complement activation in the setting of lupus renal disease. The availability of instruments for clinical disease activity measurement such as the SLAM and the SLEDAI may enable more consistent definition of lupus disease activity and may thus provide a means for better examining the role of complement activation products in predicting lupus disease activity in larger patient populations.

Antiendothelial cell antibodies in lupus: correlations with renal injury and circulating markers of endothelial damage

Systemic lupus erythematosus is characterized by the production of a broad spectrum of autoantibodies. Autoantibodies directed against endothelial cells (AECA) have been particularly well documented. We investigated associations between such antibodies, double-stranded DNA (dsDNAb), phospholipid (cardiolipin, ACA), and indices of activity and chronicity scored on renal biopsy specimens from 22 patients with acute lupus. AECA were present in 73% of these patients, and both the percentage of patients with AECA and the mean antibody titre fell significantly as patients entered remission. When patients already on immunosuppressive therapy were excluded from analysis (n = 7), only levels of AECA and DNAb (p = 0.02) correlated with histological evidence of active lesions and the presence of glomerular epithelial cell crescents; no correlation was found with chronic changes in the renal biopsies. Serum von Willebrand factor (vWf) and serum total protein S levels, two parameters reflecting endothelial cell function, were also measured during acute disease and remission. vWf concentrations were elevated during acute disease (m = 1.9 IU/ml, p = 0.02), but the values did not correlate with AECA titres. In contrast, total protein S levels were reduced (0.81 IU/ml vs. 0.97 IU/ml, p = 0.01) during active disease, but remained within the normal range (0.56-1.16 IU/ml). Furthermore, protein S levels were inversely related to levels of AECA (r = -0.4, p = 0.01). AECA were therefore present in most patients with acute lupus nephritis and were associated with histological evidence of active renal injury and serological evidence of endothelial cell dysfunction. These data provide indirect support for a pathogenic role for AECA in lupus nephritis.

Immunoadsorbent plasmaperfusion in acute lupus nephritis

Immunoadsorbent plasmaperfusion in acute lupus nephritis