Lupus Nephritis in the Era of Biomarkers.

Renal biopsy remains the standard of care for the evaluation of suspected flares in lupus nephritis (1) and is generally indicated when proteinuria, active urine sediment, or elevated serum creatinine is present. By the time that a patient presents with these features, injury induced by the lupus disease activity may already be present, including acute and more concerning, chronic changes. Renal biopsy carries a small but significant risk, primarily of bleeding resulting in perirenal hematoma, blood transfusion, and in patients with severe (although rare) cases, need for angiogram (2). In light of difficulty in predicting kidney damage clinically or using current laboratory parameters (plus the inherent risk of kidney biopsy), the search for useful biomarkers continues; the goal of the ideal biomarker is to warn of impending disease, allow for more accurate prediction of lupus–related renal histopathology, and allow for monitoring of changes in disease activity. For a biomarker to be reliable and useful in clinical practice, it should have the following characteristics: it should have biologic and pathophysiologic relevance, it must be easy to use for routine practice, and it must accurately reflect disease state and track changes in disease activity (3). Although there have been several biomarkers identified in lupus nephritis, none have sufficiently fulfilled these criteria. Although anti-doublestranded DNA antibodies and complement levels have long been recognized as pathophysiologic contributors and predictors of disease activity, their ability to accurately predict flares or histopathology is limited. Anti-C1q antibodies have been associated with lupus nephritis, but the ability of this antibody to track disease or predict histopathology has not been shown (4). Other biomarkers, such as uMCP-1 and uIL-8, have also shown insufficient predictive ability (5). However, some have shown improvement in the diagnostic accuracy through the use of a combination of biomarkers (6). Although it is likely that, in the future, a scoring system using combined markers will become useful, it currently remains elusive. In this context, the discovery of new biomarkers is a high priority. The nephrology world has witnessed a fast-growing interest in biomarkers associated with renal disease. New biomarkers with potential clinical utility have been identified in bothAKI andCKD(7).Moreover, the Food and Drug Administration has recently approved the use of a bedside urine test identifying the presence of two cell cycle arrest proteins (IGF binding protein 7 and tissue inhibitor ofmetalloproteinases), the product of which correlates with risk of developing AKI (8). Although the clinical utility of these biomarkers remains ill defined at this time, it does suggest a coming of age of biomarkers in AKI that will likely spread to other areas of nephrology, including lupus nephritis. In this issue of the Clinical Journal of the American Society of Nephrology, Birmingham et al. (9) describe a subset of patients with lupus and a very specific antibody (anti-C3b IgG) for lupus nephritis. The studywas carried out among 114 patients with SLE followed bimonthly in the prospective Ohio SLE Study cohort: 73 with lupus nephritis and 41 without history of nephritis. Patients without lupus were also available to serve as normal controls. Searching for a biologically and pathophysiologically relevant biomarker, Birmingham et al. (9) measured antibodies against several complement proteins, including those to C1s, C4b, C2, C3b, C1INH, FH, C4BP, and FI in this observational cohort. Birmingham et al. (9) then performed two analyses; one was a cross-sectional analysis at the time of enrollment to assess association with disease, and one was a longitudinal analysis to assess ability of antibodies topredict a lupus flare. To screen for disease-associated antibodies, the profiles of the aforementioned antibodies in eight patients with lupus nephritis were compared with those in five control patients without lupus. Only anti-C3b IgG antibody showed a significant difference between lupus nephritis and normal samples. This antibody in addition toanti-C1q, analreadyestablishedbiomarker (although not previously studied through serial measurements), were, therefore, chosen for additional study as a potential biomarker of lupus nephritis and a predictor of flares. Cross-sectional analysis was carried out comparing antibody profiles (at time of cohort entry) of 114 cohort patients with those of 40 nonlupus controls. The analysis showed that both anti-C3b and anti-C1q were associated with SLE (compared with normal controls) and lupus nephritis in those with SLE. Of note, 26 of 27 patients with anti-C3b IgG were also positive for antiC1q IgG. Anti-C3b was less (and poorly) sensitive for lupus nephritis compared with anti-C1q (36% versus 63%) but highly specific for its presence (98% versus 71%)comparedwithanti-C1q.Furthermore,anti-doublestranded DNA antibodies were similarly sensitive to those of anti-C3b but less specific for lupus nephritis. Finally, those developing a flare were more likely (P,0.01) to have anti-C3b antibodies (51%) than those Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland