Complement in Lupus Nephritis: New Perspectives

Bao, Lihua; Cunningham, Patrick N.; Quigg, Richard J.

doi:10.1159/000431278

Cited by 85 publications

(56 citation statements)

References 76 publications

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“…Robust consumption of complement, leading to low serum levels of complement C4 and C3, is initiated by the presence of high concentrations of ICs. Excess complement activation has been implicated in the pathogenesis of lupus nephritis (LN), a major cause of hypertension in SLE 23–25. The inverse relationship between SLE disease activity and serum complement levels makes C4 and C3 protein levels convenient clinical biomarkers of disease activity.…”

Section: Introductionmentioning

confidence: 99%

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

et al. 2019

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ObjectiveSystemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship between complement and CVD in cSLE.MethodsGene copy numbers (GCNs) for total C4, C4A and C4B were measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student’s t-test and χ2 analyses. Effects of total C4, C4A and C4B GCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses.ResultsAt baseline, C4 protein levels strongly correlated with GCNs of total C4 (p=1.8×10−6). Each copy of C4 gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10−25; C3: P=5.84×10−20). Individuals with ≥2 C4B genes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those with C4B deficiency. At the study end, subjects with ≥2 C4B and atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018).ConclusionscSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN of C4B; cSLE with ≥2 C4B genes would benefit from statins therapy to prevent atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

et al. 2019

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“…C4d levels correlated positively with LN in cross-sectional study LN is considered a severe manifestation in SLE, and it is strongly associated with complement activation caused by autoantibody deposition in the kidney [9]. In the higher disease activity group, 34 patients had LN.…”

Section: C4d Levels Correlate With Disease Activitymentioning

confidence: 85%

Plasma C4d as marker for lupus nephritis in Systemic Lupus Erythematosus

Martin

Smolag-Kłosowska

Björk

et al. 2017

Molecular Immunology

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Background: In the present study, we sought to evaluate the complement activation product C4d as a marker for lupus nephritis in systemic lupus erythematosus (SLE). Methods: C4d levels were determined by enzyme-linked immunosorbent assay in plasma samples of patients with established SLE using a novel approach based on detection of a short linear cleavage neoepitope. Cross-sectional associations were studied in 98 patients with SLE with samples taken at lower or higher respective disease activity. Temporal associations were investigated in 69 patients with SLE who were followed longitudinally for up to 5 years. Plasma samples from 77 healthy donors were included as controls. Results: C4d levels were negligible in healthy control subjects and significantly increased in patients with SLE in the cross-sectional study (p < 0.0001). C4d levels discriminated between higher and lower disease activity according to ROC curve analysis (p < 0.001), exhibiting a positive predictive value of 68%. At higher disease activity, C4d levels correlated with the modified Systemic Lupus Erythematosus Disease Activity Index (p = 0.011) and predominantly with lupus nephritis (p = 0.003), exhibiting a sensitivity of 79% to identify patients with nephritis. High C4d levels together with the presence of anti-dsDNA autoantibodies preceded and thus predicted future lupus nephritis in the longitudinal study (OR 5.4,3). When we considered only patients with renal involvement (19 of 69) during the longitudinal study, we found that high C4d levels alone could forecast recurrence of future lupus nephritis (OR 3.3, 95% CI 1.2-9.6).Conclusions: C4d appears to be a valuable marker for use in monitoring of patients with SLE, particularly for lupus nephritis. Importantly, C4d levels can predict impending flares of lupus nephritis and may thus be useful for informing treatment.

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“…The association of C4 and other immune-mediated renal diseases has been suggested in the previous studies. C4 was closely associated with lupus nephritis ( 22 ). The role of C4 has also been implicated in the outcome of IgAN ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Association of Glomerular Complement C4c Deposition With the Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes

et al. 2020

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Objectives: As accumulating data supporting the potential role of the complement system in the pathogenesis of diabetic kidney disease (DKD), the present study aimed to explore the association of glomerular complement C4c deposition with the baseline clinicopathological characteristics and the prognosis of DKD in type 2 diabetes (T2DM) patients. Methods: A total of 79 T2DM patients with biopsy-proven DKD were enrolled. Clinicopathological features and renal outcomes were compared between groups divided by the glomerular C4c deposition patterns and median values of serum C4. Renal outcomes were defined by doubling of serum creatinine level or progression to end-stage renal disease (ESRD). A Cox proportional hazards model was employed to identify the risk factors associated with renal events. Results: Patients with glomerular C4c deposition had worse renal insufficiency than those without C4c deposits, along with higher 24-h urinary protein, triglyceride, but lower serum albumin and higher interstitial inflammation score. Besides, serum C4 levels positively correlated with urinary protein and serum C3 levels. During 21.85 ± 16.32 months of follow-up, Kaplan-Meier curve analysis showed significantly faster deterioration of renal function for patients with positive glomerular C4c deposition as well as higher levels of serum C4. More specifically, more than 50% of the patients with glomerular C4c had co-deposition of C3c or C1q, and patients with glomerular complement complex of C4c and one or two of C3/C1q deposition had more severe proteinuria and a higher rate of DKD progression than those with negative C4c deposits. The univariate Cox regression indicated that factors of combined serum and glomerular C4, urinary protein, serum creatinine, serum C3, combined glomerular C4c and IgM and interstitial inflammation were associated with an increased risk of DKD, but only glomerular C4c intensity (HR 1.584, 95% CI [1.001, 2.508], p = 0.0497), as well as baseline age and diabetic neuropathy, were independent risk factors for renal survival by the multivariate Cox analysis. Conclusions: Glomerular C4c deposition was associated with deteriorated renal function and outcomes in patients with T2DKD. Glomerular C4c deposition was an independent risk factor for DKD progression.

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Complement in Lupus Nephritis: New Perspectives

Cited by 85 publications

References 76 publications

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Plasma C4d as marker for lupus nephritis in Systemic Lupus Erythematosus

Association of Glomerular Complement C4c Deposition With the Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes

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