Test code: 34303

Clinical use

• Monitor proliferative lupus nephritis (LN) disease activity
• Help assess the likelihood of LN flares in individuals with systemic lupus erythematosus (SLE)

Clinical background

About 20% to 40% of patients with SLE have biopsy-proven LN, which can be a severe complication leading to chronic kidney disease, end-stage renal disease, and death.1 In most cases, renal injury starts with deposition of immune complexes (eg, IgG and complement) in the glomerulus, which can elicit a variety of immune, inflammatory, metabolic, or hypoxic responses.2 Glomerular injury can lead to renal fibrosis, chronic kidney disease, and poor prognosis. In many cases, disease management with immunosuppressive treatments can lead to better outcomes.1

LN can be classified into 5 histologic subtypes based on microscopic examination: nonproliferative (classes I and II), focal (class IIl) or diffuse (class IV) proliferative, or membranous (class V).2,3 Differentiation has implications for therapy, as classes III, IV, and V have more potential for long-term consequences.2

Although renal biopsy remains the gold standard for diagnosis of LN, autoantibodies have proven to be useful, less-invasive markers. Antibodies against C1q—a subcomponent of C1, the first component in the complement cascade—are markers of proliferative LN. The antibodies impede the ability of C1q to bind, solubilize, and remove immune complexes deposited on kidney and other tissues.4

C1q antibodies can be useful for distinguishing active from inactive proliferative LN in SLE patients; a meta-analyses has demonstrated fair pooled sensitivity (74%; 95% CI, 68% to 79%) and specificity (77%; 95% CI, 71% to 82%) estimates.5 However, because C1q antibodies are associated with many disorders, they are not very specific for LN.6 Lower pooled sensitivity (58%; 95% CI, 56% to 61%) and specificity (75%; 95% CI, 72% to 77%) estimates for C1q antibody-based assays limit their clinical utility as stand-alone tests for diagnosis of LN.5

For active LN, C1q antibody titers have been shown to correlate with both renal and global (eg, general symptoms of SLE) disease activity in multiple diverse populations. Most recent studies suggest that, among SLE patients, C1q antibody titers are significantly higher in those with active proliferative LN than in those with inactive nonproliferative LN.7-11 Global SLE disease activity also strongly correlates with C1q antibody levels for patients with LN, but not for those without.12 Absence of C1q antibodies suggests that LN is currently inactive.6

C1q antibody-based assays are also useful for identifying individuals with SLE who are unlikely to have future flares in LN activity.13 For example, an 18-month follow-up of a cohort of 69 adults with SLE demonstrated that absence of C1q-antibody had a high negative predictive value (93%) for absence of flares (positive predictive value 35%).14 A smaller study following 28 children with SLE (median follow up 55.5 months) yielded a negative predictive value of 98% (positive predictive value 50%).15 Thus, absence of C1q antibodies may inform decisions for biopsy or changes in treatment.

Increasing C1q antibody levels over time have been suggested to predict future LN flares,16 although consensus is yet to be reached on this interpretation.4,12,13

Based in part on these findings, the European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) suggest that C1q antibody tests, along with tests for other markers of SLE disease activity (double stranded DNA [dsDNA], complement C3 and C4), be considered for patients with suspected LN and for monitoring disease activity in confirmed LN.16