Serum C3 Levels Are Diagnostically More Sensitive and Specific for Systemic Lupus Erythematosus Activity Than Are Serum C4 Levels

doi:10.1016/S0272-6386(12)80609-3

American Journal of Kidney Diseases

Volume 18, Issue 6, December 1991, Pages 678-685

https://doi.org/10.1016/S0272-6386(12)80609-3 Get rights and content

To determine whether serum C3 or C4 is more likely to be normal during systemic lupus erythematosus (SLE) remission and abnormal during SLE relapse we studied twelve SLE patients who presented with severe nephritis. The patients were followed long term (12 to 77 months) through multiple relapses (N = 41) and remissions (N =13) defined by protocol. A total of 471 serum samples were obtained at defined intervals during these relapses and remissions and were analyzed for C3 and C4 levels by two different methods: nephelometry (N) and radial immunodiffusion (R). During SLE remission (defined by protocol and without reference to serum complement levels), C3 measured by Nassay (CM) and by R-assay (C3R) tended to be normal (specificity of 93% and 71 %, respectively). By contrast, C4 measured by N-assay (C4N) and by R-assay (C4R) showed no such tendency (specificity of 50% for both C4N and C4R). During SLE relapse (defined by protocol and without reference to serum complement levels), C3N and C3R were more likely to be abnormal (sensitivity 95% and 85%, respectively) compared with C4N and C4R (sensitivity 56% and 54%, respectively, P < 0.001 compared with corresponding values for the C3 assay). Analysis by receiver-operator characteristic (ROC) curves demonstrated that the reduced diagnostic sensitivity of C4 versus C3 is not explained by use of an inappropriate lower limits of normal (LLN) for C4. Analysis of the regression curves of C4 on C3 in individual patients demonstrated that the reduced diagnostic sensitivity of C4 relative to that of C3 also is not explained by imprecision of the C4 assay, or by relatively smaller changes in C4 compared with C3 as SLE activity changes. Rather, the reduced diagnostic sensitivity of C4 (failure to be normal during SLE relapse) and reduced diagnostic specificity of C4 (failure to be normal during SLE remission) appears to be explained by the much broader range of normal of C4, relative to C3, and the increased prevalence of C4 null genes in the SLE population. Analysis of the slopes of the individual regressions of C4 on C3 also demonstrates that net molar consumption (moles consumed - moles produced) of C3 is approximately 6 times greater than that of C4, a value similar to that which can be predicted from previous in vitro studies of classical pathway activation. If serum complement levels (C3, C4) are used to monitor SLE activity in patients with a history of renal manifestations, it is sufficient to measure only C3 levels. This should simplify and reduce the cost of monitoring SLE patients.

References (19)

NC Hughes-Jones
The classical pathway
JP Atkinson
Complement deficiency
Predisposing factor to autoimmune syndromes. Am J Med
(1988)
CD West
The complement profile in clinical medicine
Complement Inflamm
(1989)
CB Carpenter et al.
Complement metabolism in man: Hypercatabolism of the fourth (C4) and third (C3) components in patients with renal allograft rejection and hereditary angioedema (HAE)
J Clin Invest
(1969)
S Ruddy et al.
Human complement metabolism: An analysis of 144 studies
Medicine
(1975)
FB Waldo et al.
A circulating inhibitor of fluid-phase amplification
C3 convertase formation in systemic lupus erythematosus. J Clin Invest
(1985)
WJW Morrow et al.
Useful laboratory measurements in the management of systemic lupus erythematosus
Q J Med
(1982)
RM Valentijn et al.
The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus
Arthritis Rheum
(1985)
AJG Swaak et al.
Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus
Ann Rheum Dis
(1986)

There are more references available in the full text version of this article.

Cited by (53)

Persistent Isolated C3 Hypocomplementemia as a Strong Predictor of End-Stage Kidney Disease in Lupus Nephritis
2022, Kidney International Reports
Proliferative lupus nephritis (LN) progresses to end-stage kidney disease (ESKD) in roughly 10% of the cases despite treatment. Other than achieving <0.8 g/24h proteinuria at 12 months after treatment, early biomarkers predicting ESKD or death are lacking. Recent studies encompassing not only LN have highlighted the central role of the alternative complement pathway (ACP), with or without histological evidence of thrombotic microangiopathy (TMA), as a key promotor of renal death.
We assessed whether persistent isolated C3 hypocomplementemia (PI-LowC3), that is not accompanied by C4 hypocomplementemia, 6 months after kidney biopsy, is associated with an increased risk of death or ESKD in proliferative LN.
We retrospectively followed-up 197 patients with proliferative LN (51 with PI-LowC3) for a median of 4.5 years (interquartile-range: 1.9−9.0), 11 of whom died and 22 reached ESKD. After adjusting for age, gender, ethnicity, hypertension, mycophenolate, or cyclophosphamide use, PI-LowC3 was associated with a hazard ratio [HR] of the composite outcome ESKD or death of 2.46 (95% confidence interval [CI]: 1.22−4.99, P = 0.012). These results were confirmed even after controlling for time-varying estimated glomerular filtration rate (eGFR) measurements in joint longitudinal-survival multiple regression models. After accounting for the competing risk of death, PI-LowC3 patients showed a strikingly increased risk of ESKD (adjusted HR 3.41, 95% CI: 1.31−8.88, P = 0.012).
Our findings support the use of PI-LowC3 as a low-cost readily available biomarker, allowing clinicians to modify treatment strategies early in the course of disease and offering a rationale for complement blockade trials in this particularly at-risk subgroup of LN patients.
Complement and SLE
2021, Lahita’s Systemic Lupus Erythematosus
The complement system has been intimately linked to systemic lupus erythematosus (SLE). Until recently, this association was viewed as inexplicably paradoxical. On the one hand, complement activation is thought to mediate tissue inflammation and contribute significantly to organ damage in patients with SLE. On the other hand, hereditary deficiencies of early components of the complement classical pathway impose a strikingly high risk for developing SLE. With an accelerated pace of advances over the past decade, the perplexing relationship of complement with SLE is being unraveled. This chapter will review the biology of the complement system in relation to SLE, focusing on the novel findings made in the past decade, revisit the utility of complement as biomarkers for SLE, and consider the potential of anticomplement therapeutics in SLE.
Utilization of Biomarkers in Lupus Nephritis
2019, Advances in Chronic Kidney Disease
Citation Excerpt :
Finally, anti-C1q led to enhanced complement activation in the setting of immune complex glomerulonephritis in mice.28 Although it is clear that complement activation is critical in the pathogenesis of LN, studies to determine how changes in complement levels can predict SLE or LN flare have yielded variable results.19,29-31 Esdaile and colleagues29 evaluated the sensitivity, specificity, and likelihood ratios of anti-dsDNA, C3, C4, and anti-C1q to predict future flares (renal and non-renal) in a cohort of 202 SLE patients.
Lupus nephritis (LN) occurs in up to 60% of SLE patients, and is a leading cause of disability and death. Current treatment of LN consists of a combination of high dose corticosteroids that non-specifically decrease inflammation and cytotoxic medications that reduce auto-antibody production. That combination of therapy is associated with significant side effects while remission rates remain inadequate. Since the introduction of biologics into the pharmacological armamentarium, there has been hope for less toxic and more effective therapies for LN. Unfortunately, after multiple clinical trials, no biologic has improved efficacy over standard of care therapies for LN. This is likely, in part, due to disease heterogeneity. The utilization of biomarkers in LN may provide a way to stratify patients and guide therapeutic options. In this review, we summarize traditional and novel LN biomarkers and discuss how they may be used to diagnose, stratify, and guide therapy in patients with LN, bringing precision medicine to the forefront of LN therapy.
Precision medicine in lupus nephritis: can biomarkers get us there?
2018, Translational Research
Citation Excerpt :
Studies to determine how changes in complement levels can serve as SLE or LN flare have yielded variable results.25,76-78 Reduced C3 levels are more predictive of active LN flare.77,79 A longitudinal study revealed that reduced C4 levels, 2 months prior to clinical manifestations of LN flare were predictive of future flare, whereas reduced levels of C3 were seen at time of the flare.79
Patients with systemic lupus erythematosus frequently develop lupus nephritis (LN), a condition that can lead to end-stage kidney disease. Multiple serum and urine biomarkers for LN have been proposed in recent years, yet none have become incorporated into clinical use. The majority of studies have been single center with significant variability in cohorts, assays, and sample storage, leading to inconclusive results. It has become clear that no single biomarker is likely to be sufficient to diagnose LN, identify flares, and define the response to therapy and prognosis. A more likely scenario is a panel of urine, serum, tissue, and genetic biomarkers. In this review, we summarize traditional and novel biomarkers and discuss how they may be utilized in order to bring precision medicine to clinical practice in LN.
C3 consumption as the only manifestation of lupus nephritis v/iii in male patient with nephrotic syndorme. Clinical case and short review
2015, Dialisis y Trasplante
El lupus eritematoso sistémico (LES) es una enfermedad crónica autoinmune que potencialmente causa inflamación y daño en cualquier órgano y/o sistema. Presentamos el caso de un paciente varón de 18 años de edad, que acude al servicio de nefrología por presentar en estudio de rutina elevación de creatinina sérica negando cualquier tipo de sintomatología; encontrando como hallazgo sérico indirecto únicamente C3 disminuido durante el estudio inicial. Se realiza una revisión de la literatura describiendo las características de esta enfermedad.
Systemic Lupus Erythematosus (SLE) is an autoimmune chronic disease that causes potentially systemic injury or/and inflammation. We report a case of a 18 year old Mexican man; presenting with serum creatinine elevation in a routine laboratories without any symptoms. We only found C3 alterations at the initial study. We provide a review of the literature describing Systemic lupus erythematosus characteristics.
The Complement System in Lupus Nephritis
2015, Seminars in Nephrology
Citation Excerpt :
Typically, the individual has four C4 genes, two from each parent. The clinical implications are that with active lupus, it is the serum C3 level that is more likely to be outside the normal range than the serum C4 level.44 This is the consequence of the relatively narrow range of normal for C3 (approximately two-fold) compared with C4 (approximately 3.5-fold).
The complement system is composed of a family of soluble and membrane-bound proteins that historically has been viewed as a key component of the innate immune system, with a primary role of providing a first-line defense against microorganisms. Although this role indeed is important, complement has many other physiological roles, including the following: (1) influencing appropriate immune responses, (2) disposing of waste in the circulation (immune complexes, cellular debris), and (3) contributing to damage of self-tissue through inflammatory pathways. These three roles are believed to be significant factors in the pathogenesis of systemic lupus erythematosus, particularly its renal manifestation (lupus nephritis), contributing both protective and damaging effects. In this review, we provide an overview of the human complement system and its functions, and discuss its intricate and seemingly contradictory roles in the pathogenesis of lupus nephritis.

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: Supported in part by National Institutes of Health Grants No. HL25404, AM27770, and RR00034.

^*: See Appendix for a list of members of The Lupus Collaborative Study Group.

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Serum C3 Levels Are Diagnostically More Sensitive and Specific for Systemic Lupus Erythematosus Activity Than Are Serum C4 Levels

Predisposing factor to autoimmune syndromes. Am J Med

The complement profile in clinical medicine

Complement Inflamm

Complement metabolism in man: Hypercatabolism of the fourth (C4) and third (C3) components in patients with renal allograft rejection and hereditary angioedema (HAE)

J Clin Invest

Human complement metabolism: An analysis of 144 studies

Medicine

A circulating inhibitor of fluid-phase amplification

C3 convertase formation in systemic lupus erythematosus. J Clin Invest

Useful laboratory measurements in the management of systemic lupus erythematosus

Q J Med

The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus

Arthritis Rheum

Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus

Ann Rheum Dis