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PubMed1977

Lupus nephritis. Clinical course as related to morphologic forms and their transitions.

An intensive study of the course of lupus nephritis has been undertaken in 88 patients in whom strict morphologic criteria were utilized in classification. All were treated with steroid, and 17 received cytotoxic drugs in addition. Focal proliferative lupus nephritis generally follows a benign course except in the occasional instances when transition to the diffuse proliferative or membranous forms occurs. Membranous lupus nephritis, when characterized by persistent nephrotic syndrome, leads slowly to renal failure, but this progression is aborted in the one-third in whom remission of the nephrotic syndrome can be achieved. A fatal outcome occurs within five years in the majority of those with diffuse proliferative lupus nephritis and the nephrotic syndrome, often in association with necrotizing renal vasculitis, severe hypertension and accelerated renal failure. A small number with the diffuse proliferative form have a remission and then show only mesangial abnormalities, usually, however, with the appearance of glomerular sclerosis. Progressive glomerular sclerosis is observed in some patients and may be a sequel of the remission of the diffuse or focal proliferative lesions, or it may represent still another form of lupus nephritis. Mesangial immune deposits with or without proliferation, at times in the absence of clinical renal disease, are observed early in the course of systemic lupus erythematosus (SLE) and may proceed to the diffuse proliferative or membranous forms. The present observations serve to emphasize the importance of strict morphologic classification in the comparison of different treatment regimens for lupus nephritis. In view of the grave prognosis of established diffuse proliferative lupus nephritis, which probably evolves from a mesangial involvement common to all patients with SLE from its onset, early therapy may be the key to the management of lupus nephritis.

Adolescent↗

PubMed1976

Beneficial effects of methylprednisolone "pulse" therapy in diffuse proliferative lupus nephritis.

Seven patients with diffuse proliferative lupus nephritis were subjected to highdose intravenous methylprednisolone (pulse) therapy. Following the pulse, five patients with rapidly deteriorating ranal function improved within three days and their serum-creatinine levels returned to baseline by one month. All seven patients demonstrated reversal of severe immunological abnormalities including increased serum D.N.A binding, decreased serum C3 levels, and reduced number of T lymphocytes in the peripheral blood. This form of therapy may make it possible to maintain patients with lupus nephritis on lower doses of steroids than is normally feasible.

Adolescent↗

PubMed1978

Acute renal failure secondary to interstitial lupus nephritis.

A patient with systemic lupus erythematosus (SLE), followed up over a six-month period, exhibited numerous immunologic abnormalities and varied renal pathologic features. Initial findings included minimal glomerular lesions, serum antibodies directed solely against nuclear RNA protein, and lupus band test showing pure IgM deposition. These findings suggested a good prognosis. Subsequently, the patient developed acute renal failure secondary to an interstitial lupus nephritis, without progression of the glomerular abnormality. Serum antibodies to the nuclear non-nucleic acid macromolecule and single stranded and native DNA were demonstrated concurrently. New skin deposits of IgG and IgA in addition to IgM also were observed. This patient demonstrates the potential progression of lupus renal disease despite the initial favorable prognostic indicators.

Acute Kidney Injury↗

PubMed1979

The significance of serial measurements of serum complement C3 and C4 components and DNA binding capacity in patients with lupus nephritis.

Eighteen patients with systemic lupus erythematosus (SLE) and proliferative glomerulonephritis, underwent serial serum determinations of C3, C4, and native DNA binding capacity, as well as repeat renal biopsy 7 to 48 months (median 25 months) following initial biopsy. Highly significant correlations were found between serum C3 levels and renal histologic changes (P less than 0.0001), and between serum C3 levels and DNA binding capacity (P less than 0.03). Histologic deterioration correlated with depressed C3 levels, while improvement was associated with normalization of C3 levels. No correlation between renal histologic changes and either serum C4 levels or DNA binding capacity was found. The data suggest that the serum level of C3 is the best index of activity of lupus nephritis.

Adolescent↗

PubMed1979

Comparison of chlorambucil, azathioprine or cyclophosphamide combined with corticosteroids in the treatment of lupus nephritis.

163 patients with diffuse lupus glomerulonephritis, proven by renal biopsy, were divided into four therapeutic trial groups: 67 were put on corticosteroids alone, 11 on corticosteroids and azathioprine, 32 on corticosteroids and cyclophosphamide, and 53 on corticosteroids and chlorambucil and were followed up for several years. The addition of azathioprine to corticosteroids did not increase the survival rate, improve the renal function or alter the grim prognosis of the patients. Cyclophosphamide appeared to influence favourably the pathological lesion and the renal function when added to corticosteroids, and the disease progressed at a slower rate. The fatal side effects nearly balanced the therapeutic value of cyclophosphamide. Patients on corticosteroids and chlorambucil had an excellent course. This therapeutic regimen resulted in resolution or regression of the renal pathology, marked improvement of the renal function and marked improvement of the survival rate. The authors believe that this therapeutic regimen holds the best chance of becoming the standard treatment for lupus nephritis, particularly since the side effects of chlorambucil were minimal.

Adolescent↗

PubMed1978

Immunologic findings, thrombocytopenia and disease activity in lupus nephritis.

Twenty patients with nephritis due to systemic lupus erythematosus were followed up for a mean of 34 months after renal biopsy with serial determinations of total serum complement and C3 and C4 concentrations, binding of deoxyribonucleic acid (DNA), antinuclear antibody pattern and platelet count. There were 25 episodes of nonhematologic observed disease activity in 16 of the 20 patients; elevated DNA binding and thrombocytopenia correlated well with these episodes. The mean platelet count during episodes of observed disease activity was 96 +/- 42 X 10(9)/L, which was significantly different from the mean count of 248 +/- 90 X 10(9)/L during disease quiescence. The proportion of false-positive results with the immunologic tests varied from 25% to 67% and with platelet counts it was 11%. It is suggested that thrombocytopenia may be a simple and accurate index of disease activity in lupus nephritis.

Antibodies, Antinuclear↗

PubMed1976

Urinary fibrin split products in lupus nephritis.

Antigen-antibody interaction and fibrin deposition at the glomerular basement membrane can release activators that ultimately convert fibrin into degradation products of varying molecular size. Thus, increased urinary fibrinogen/fibrin split products (FSP) might be expected in active lupus nephritis. A longitudinal study was done on 27 patients with biopsy-proven lupus nephritis. Those patients who were persistent FSP excretors were found to be at a significantly greater risk of progressive nephritis and renal death than those who were FSP negative. It is suggested that FSP excretion in lupus nephritis, particularly on a continued basis and despite normalization of other renal disease parameters, is a grave prognostic sign.

Antigen-Antibody Complex↗

PubMed2026

Anifrolumab Treatment Leads to Rapid Reduction in Urinary Biomarkers of Intrarenal Inflammation in Lupus Nephritis: Results From the Phase 2 Randomized Trial.

OBJECTIVE: Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE) and is partially driven by type I interferon signaling. Anifrolumab, an approved treatment for patients with SLE, has been investigated in a phase 2 trial in patients with LN receiving standard therapy (TULIP-LN, ClinicalTrials.gov identifier NCT02547922). We studied the impact of anifrolumab treatment on urinary biomarker expression in patients with LN through proteomic analysis of samples from TULIP-LN. METHODS: Urine samples were collected at weeks 0, 12, and 48 from patients treated with the anifrolumab basic regimen (n = 35), intensified regimen (n = 42), or placebo (n = 35), in addition to standard therapy, and analyzed for the presence of 197 proteins. The impact of anifrolumab relative to placebo on prespecified biomarkers linked to histologic activity was assessed, and a comparison of responders versus nonresponders was conducted on proteins detected in ≥75% of samples. RESULTS: Anifrolumab treatment significantly reduced urinary CD163 and monocyte chemoattractant protein 1 expression at week 12 versus placebo, including in patients classified as proteinuric nonresponders across all regimens. By week 48, biomarker levels declined in all groups, indicating that standard therapy alone can eventually suppress intrarenal inflammation but with slower kinetics. Proteomic analyses further revealed that anifrolumab was superior to placebo in reducing the proteomic inflammatory signature, regardless of responder status. CONCLUSION: Compared with placebo, anifrolumab treatment significantly reduced urinary biomarkers of renal histologic activity in patients with LN, which may accelerate the resolution of intrarenal inflammation, potentially preventing damage accrual.

Humans↗

PubMed1978

Class of immunoglobulin deposition and prognosis in lupus nephritis.

In the three major morphologic groups of lupus nephritis--diffuse, focal proliferative, and membranous--glomerular deposition of immunoglobulins is usually a combination of IgG, IgM, and IgA and is not a good indicator of initial renal severity or outcome. In this study of 60 patients with systemic lupus erythematosus and nephritis, patients with exclusive or predominant glomerular deposition of IgG did not have more severe renal disease or a worse prognosis than those with combined IgG-IgM deposition.

Adolescent↗

PubMed1978

Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide.

To evaluate the effectiveness of cyclophosphamide in the treatment of lupus nephritis, we designed a prospective study of patients with diffuse proliferative lupus nephritis. Twenty-six patients received prednisone (average dose, 40 mg per day) and 24 combined prednisone (average dose, 29 mg per day) and cyclophosphamide (average dose, 107 mg per day) for six months. Thereafter, all patients received maintenance doses of prednisone. Most of the patients improved (84 per cent) after six months of initial treatment with either program. Early progression of disease, ending mainly in end-stage renal disease, was equally frequent in the two treatment groups in patients with already advanced disease. In a four-year follow-up study there was a higher incidence (P approximately 0.04) and average rate (P approximately 0.02) of clinical recurrence of nephritis in the group initially given only steroid than in the group initially given both drugs. However, the proportion of patients alive after four years with stable or improved renal function was similar in the two treatment groups.

Adolescent↗

PubMed1978

The effect of normalization of serum complement and anti-DNA antibody on the course of lupus nephritis: a two year prospective study.

A prospective study was carried out in 25 patients with systemic lupus erythematosis (SLE) on the effect of normalizing serum complement (CH50) and anti-DNA antibodies on the course of lupus nephritis. In 16 of the 25 patients, CH50 was maintained within the normal range for two years. Urinary protein excretion increased or remained low in all 16. Repeat renal biopsies were performed in 10 of these 16, and disclosed either stabilization of glomerular disease or diminution. In the nine patients in whom CH50 could not be normalized with tolerated doses of drugs, urinary protein excretion increased or remained increased. Repeat renal biopsies in six of these nine patients were carried out and showed worsening of glomerular disease in five. No clear-cut correlation was found between urinary protein excretion or renal disease and the serum levels of anti-DNA antibody. We conclude from these observations that continuous normalization of CH50 by drug therapy in patients with SLE is associated with stabilization or diminution of lupus nephritis.

Antibodies↗

PubMed2026

DIA proteomics of FFPE renal biopsies reveals two molecular subtypes of lupus nephritis and identifies APOL1 as candidate biomarker for stratification.

INTRODUCTION: Lupus nephritis (LN) exhibits substantial clinical and pathological heterogeneity. We aimed to define proteomics-based molecular subtypes of LN and identify candidate biomarkers for subtype discrimination. METHODS: We analysed formalin-fixed paraffin-embedded (FFPE) renal biopsy specimens from 292 patients with biopsy-proven LN from four tertiary hospitals using data-independent acquisition (DIA)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics. Molecular subtypes were identified by non-negative matrix factorisation. Differential proteins, functional enrichment, immune pathway activity, protein-protein interaction networks and subtype-associated clinical/pathological features were evaluated. Extreme Gradient Boosting (XGBoost) with SHapley Additive exPlanations (SHAP) and Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression were used to identify key subtype-related features and derive a protein panel distinguishing proliferative (class III/IV) from membranous (class V) LN. RESULTS: Two stable molecular subtypes were identified, with 1002 differential proteins between them. Subtype_2 was enriched for interferon-related innate immunity, complement activation, phagocytosis-endocytosis-lysosome pathways and ribosome biogenesis/RNA metabolism, whereas Subtype_1 was characterised by keratinisation and epithelial structural remodelling. Subtype_2 was associated with higher serum creatinine, lower estimated glomerular filtration rate and higher chronicity index. APOL1 showed discriminatory value between subtypes, and serum ELISA demonstrated a consistent pattern with FFPE proteomic findings. A five-protein LASSO panel achieved an area under the curve of approximately 0.76 for distinguishing class III/IV from class V LN. CONCLUSION: DIA-based proteomic profiling of FFPE renal biopsies identifies biologically and clinically relevant LN molecular subtypes and may support tissue-informed classification and risk stratification.

Humans↗

PubMed2025

Uncovering potential biomarkers and metabolic pathways in systemic lupus erythematosus and lupus nephritis through integrated microbiome and metabolome analysis.

OBJECTIVE: This study aims to explore the relationship between gut microbiota and fecal metabolomic profiles in patients with systemic lupus erythematosus (SLE), with and without lupus nephritis (LN), in order to identify potentially relevant biomarkers and better understand their association with disease progression. METHODS: Fecal samples from 15 healthy controls (HC) and 36 SLE patients (18 SLE-nonLN and 18 SLE-LN) were analyzed using 16S rRNA gene sequencing and untargeted metabolomics. Differential microbial taxa and metabolites were identified using Linear Discriminant Analysis Effect Size (LEfSe) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Receiver Operating Characteristic (ROC) curve analyses were used to assess the potential clinical relevance of selected metabolites. RESULTS: Beta diversity analysis demonstrated distinct microbial clustering between groups (p < 0.05). SLE-LN samples showed an increased relative abundance of Proteobacteria and decreased Firmicutes compared to SLE-nonLN. Metabolomic profiling identified multiple differentially abundant metabolites, with notable enrichment in primary bile acid biosynthesis pathways (e.g., Glycocholic acid, AUC = 0.951). In the SLE-nonLN group, increased Glycoursodeoxycholic acid levels (AUC = 0.922) were observed in pathways related to taurine and hypotaurine metabolism. Correlation analysis indicated a negative association between Escherichia-Shigella and bile acid levels (p < 0.01). CONCLUSION: This integrative analysis suggests that patients with SLE and LN harbor distinct gut microbiota and metabolomic profiles. The identified microbial taxa and metabolites may have potential as non-invasive biomarkers and could contribute to a better understanding of SLE pathogenesis and progression.

Humans↗

PubMed2025

Proteomics uncovers ICAM2 (CD102) as a novel serum biomarker of proliferative lupus nephritis.

OBJECTIVES: This study aimed to identify novel, non-invasive biomarkers for lupus nephritis (LN) through serum proteomics. METHODS: Serum proteins were detected in patients with LN and healthy control (HC) groups through liquid chromatography-tandem mass spectrometry. The key networks associated with LN were screened out using Cytoscape software, followed by pathway enrichment analysis. The best candidate biomarkers were selected by machine learning models, further validated in a larger independent cohort. Finally, the expression of these candidate markers was verified in kidney tissue samples, and the mechanism was explored by knocking down the expression of intercellular adhesion molecule 2 (ICAM2) through in vitro cell transfection with siRNA. RESULTS: Following the serum proteomic screening of LN, a key network of 20 proteins was identified. Machine learning models were used to select ICAM2 (CD102), metalloproteinase inhibitor 1 (TIMP1) and thrombospondin 1 (THSB1) for validation in independent cohorts. ICAM2 exhibited the highest area under the curve (AUC) value in distinguishing LN from HC (AUC=0.92) and was significantly correlated with activity index, proteinuria, albumin and anti-dsDNA antibody levels. Particularly, ICAM2 was significantly elevated in proliferative LN and was associated with specific pathological attributes, outperforming conventional parameters in distinguishing proliferative LN from non-proliferative LN. ICAM2 expression was also elevated in renal tissue samples from patients with proliferative LN. In vitro, knockdown of ICAM2 expression can inhibit the activation of the PI3K/Akt pathway and alleviate the injury of glomerular endothelial cells. CONCLUSION: ICAM2 (CD102) may serve as a potential serum biomarker for proliferative LN that reflects renal pathology activity, potentially contributing to the progression of LN through the PI3K/Akt pathway.

Humans↗

PubMed1978

Aggravating factor in lupus nephritis; electron microscopic observation.

47 renal biopsies from 36 patients with SLE were examined in detail to compare with clinical courses and ultrastructural findings. Of 36 patients, 8 cases were free from renal involvement. The severity of electron dense deposits in glomeruli with lupus nephritis were generally well correlated with each clinical feature obtained. Moreover, mesangiocapillary cell proliferation was considered to be the main morphological promoting factor in poor prognosis of the lupus nephritis. Prominent circumferential subendothelial dense deposits were suggested to enhance to enhance the proliferation of mesangial cells, mostly with a mode of circumferential interposition. In each deposit with lapse of time and/or treatments, subepithelial deposits were gradually degraded to granular material but not lucent, though most subendothelial deposits rapidly disappeared without any remnant structure or with only a few flocculent materials. Mesangial deposits were mostly stabilized and rarely turned membranous.

Adolescent↗

PubMed1978

Three genes for lupus nephritis in NZB x NZW mice.

The occurrence of early severe lupus nephritis in (NZB x NZW)F1 mice must depend on the action of at least two dominant or codominant genes (at least one gene from each parent) as neither of the inbred parental strains shows the disorder. Identifying affected animals by antemortem determinations of renal function, we have studied the incidence of the renal disease in 230 (NZB x NZW) x NZW backcross mice (an earlier study) and, in this study, in 150 (NZB x NZW) x NZB backcross mice. The data indicate that the NZB strain contributes only one gene and the NZW strain contributes two genes, or clusters of closely linked genes, to the renal disorder of the F1 hybrid. One of the NZW genes was found to be linked to the H-2 complex. All three genes must be dominant or codominant, as their effect is expressed in the heterozygous state.

Animals↗

PubMed2026

Crotonylome profiling identifies MLKL crotonylation in lupus nephritis associated with RAB1A-mTOR signalling and autophagy changes in tubular epithelial cells.

OBJECTIVE: To investigate whether MLKL crotonylation is associated with tubular autophagy-lysosome pathway homeostasis in lupus nephritis (LN) and to explore its relationship with RAB1A-mechanistic target of rapamycin (mTOR) signalling. METHODS: Crotonylome proteomics was performed in peripheral blood mononuclear cells from patients with LN, patients with systemic lupus erythematosus without nephritis and healthy controls. Renal biopsy tissues were evaluated for tubulointerstitial fibrosis and autophagy-lysosome pathway-related markers. Mechanistic studies were conducted in lipopolysaccharide-stimulated HK-2 cells. Autophagic flux was assessed using bafilomycin A1. The dependency of mTOR/autophagy changes on RAB1A was tested by siRNA-mediated knockdown. RESULTS: MLKL was identified as a differentially crotonylated protein in LN, with increased crotonylation at K95 and K219. Kidney tissues from patients with LN showed increased fibronectin and collagen III deposition compared with controls, whereas no significant difference was observed between class IV and class V LN. LC3 signal did not differ significantly between groups, whereas LAMP1 expression and LC3-LAMP1 co-localisation were reduced in LN. In HK-2 cells, crotonylation-deficient MLKL mutants were associated with increased LC3-II and reduced p62, whereas K219Q showed the opposite pattern. Autophagic flux assays using bafilomycin A1 showed that K219R-expressing cells had higher LC3-II levels than WT cells both before and after lysosomal inhibition, with comparable BafA1-induced LC3-II accumulation, consistent with increased autophagosome formation rather than impaired lysosomal degradation. HDAC1 knockdown increased MLKL crotonylation and was accompanied by mTOR activation. MLKL crotonylation enhanced RAB1A guanriphosphat osphate (GTP) binding without altering total RAB1A abundance. RAB1A knockdown in MLKL WT-expressing cells attenuated mTOR phosphorylation and partly reversed the autophagy-suppressive marker profile. Sodium crotonate induced an autophagy-suppressive marker profile that was partly reversed by rapamycin. CONCLUSION: MLKL crotonylation is associated with activation of the RAB1A-mTOR axis and altered tubular autophagy-lysosome pathway homeostasis in LN. These findings suggest that tubular injury-related changes in LN may not be fully reflected by glomerulus-based classification alone.

Humans↗

PubMed2026

Maternal high-fat diet modulates lupus nephritis through fetal Wnt-steroid hormone and epigenetic reprogramming in MRL/lpr mouse offspring.

We previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/β-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/β-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.

Axin2↗