Macrophages have been implicated in the pathogenesis of SLE, including classically activated inflammatory M1 macrophages and the alternately activated M2 macrophages M2a, M2b, and M2c, which demonstrate pro-fibrotic, immunity-regulatory, remodeling and anti-inflammatory effects, respectively. Initially, M1 macrophages were reported to be predominant in SLE, with M2a and M2c macrophage expression being reduced. (24) However, Gregor et al. detected more M2c than M2a macrophages, and few M1 macrophages, in all ISN/RPS classes of LN. (25) Several reports suggest that M2 macrophages play an important role in driving or regulating interstitial inflammation, cellular crescent formation, and fibrinoid necrosis. (9, 26, 27) These studies suggested that CD163 + M2c-like macrophages may be associated with the pathogenesis of SLE.
UsCD163 is a marker of the status of LN, and could also serve as a biomarker of SLE disease activity. Mejia-Vilet et al. reported an association between usCD163 and proteinuria. (9) Zhang et al. reported that the usCD163 level was correlated with the SLEDAI, rSLEDAI, and Physician Global Assessment scores in various ethnic groups. (28) Our results showed that the usCD163 level and urine usCD163/creatinine ratio were correlated with the UPCR, anti-dsDNA Ab level, and SLEDAI and rSLEDAI scores. A usCD163 level of 0.443 ng/mL and urine usCD163/creatinine ratio of 110.2 ng/mmol predicted high SLEDAI scores.
C3, C4, and anti-ds DNA Ab are traditional biomarkers of SLE disease activity; the SLEDAI-2K score is also based on these markers. We found that the usCD163 level and usCD163/creatinine ratio were also correlated with the SLEDAI-2K score and anti-ds DNA Ab level. Serum soluble CD163, monocyte chemoattractant protein-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), TNF-like weak inducer of apoptosis (TWEAK), and vascular cell adhesion molecule-1 (VCAM) are new biomarkers of SLE disease activity. (29)
Renal biopsy is the gold standard to diagnose LN. The identification of non-invasive biomarkers, such as usCD163, of active LN that are strongly correlated with renal biopsy results and underlying disease mechanisms has been a priority. Other non-invasive biomarkers of LN include anti-C1q antibody and urine MCP-1. (18, 30) The treatment goal should be an at least 25% and 50% reduction in the proteinuria level after 3 and 6 months, respectively, and a complete renal response (500–700 mg/day) at 12 months. (31) However, persistent proteinuria (lasting for 6 months) makes it difficult to titrate immunosuppressants. Mejia-Vilet et al. found that the level of usCD163 after treatment could be monitored to predict the renal response and kidney histology score. (9)
The in vivo expression of CD163 on macrophages is influenced by several medications including glucocorticoids, mycophenolate mofetil (MMF), tacrolimus, rituximab, and cyclophosphamide. (25, 32–35) However, the observed elevation in urine sCD163 in active and proliferative LN was not attributed to medications such as MMF and glucocorticoids in clinical studies. (4, 28)
As a biomarker, usCD163 can be evaluated noninvasively and directly reflects macrophage-mediated glomerular inflammation; it can also distinguish between class III/IV and V LN in patients showing proteinuria relapse during their clinical course. (4, 9, 28) The reason why usCD163 correlates with the proteinuria level and UPCR, but not with class V LN, needs further study.
The first limitation of our study was that renal biopsy was not performed, so the association of the ISN/RPS classification with renal histology was unknown. However, a previous study showed that usCD163 was associated with proliferative LN classes III and IV. Second, serial usCD163 measurements and long-term follow-up of renal were not performed, as this was a cross-sectional study. We will further analyte usCD163, anti-C1q antibody, and urine MCP-1 levels in LN in future studies.