Association of Urine sCD163 With Proliferative Lupus Nephritis, Fibrinoid Necrosis, Cellular Crescents and Intrarenal M2 Macrophages

Abstract

CD163 is a marker for alternatively activated macrophages, which have been implicated in the pathogenesis of lupus nephritis (LN). In our preliminary screening of urine proteins in LN, urine soluble CD163 (sCD163) was significantly elevated in patients with active LN. To evaluate the potential of sCD163 as a biomarker in LN, urine sCD163 was assayed in patients with active LN, active non-renal lupus patients (ANR), inactive SLE and healthy controls (HC), using ELISA and normalized to urine creatinine. The correlation of urine sCD163 with clinical parameters and renal pathological attributes was further investigated in LN patients with concurrent renal biopsies. A total of 228 SLE patients and 56 HC were included from three cohorts. Results demonstrated that urine sCD163 was significantly elevated in active LN when compared with HC, inactive SLE, or ANR in African-American, Caucasian and Asian subjects (all P < 0.001). In LN patients with concurrent renal biopsies, urine sCD163 was significantly increased in patients with proliferative LN when compared with non-proliferative LN (P < 0.001). Urine sCD163 strongly correlated with SLEDAI, rSLEDAI, activity index (AI) of renal pathology, fibrinoid necrosis, cellular crescents, and interstitial inflammation on biopsies (all P < 0.01). Macrophages, particularly M2 macrophages, the predominant cells expressing CD163 within LN kidneys, represented a potential source of elevated urine sCD163, based on single-cell RNA sequencing analysis. To conclude, urine sCD163 discriminated patients with active LN from other SLE patients and was significantly elevated in proliferative LN. It strongly correlated with concurrent AI and several specific pathological attributes, demonstrating its potential in predicting renal pathology.

Role of Macrophages and Related Cytokines in Kidney Disease

“…By ectodomain shedding, the extracellular portion of CD163 can be released from the cell surface into circulation, in a process regulated by ADAM17/TACE (tumor necrosis factor α-converting enzyme) ( 116 ). Soluble CD163 (sCD163) is stable and measured easily in serum, and has been investigated as potential biomarker of macrophage activation in various disease contexts ( 117 – 119 ).…”

“…Indeed, urinary sCD163 is a marker of human glomerulonephritis ( 118 , 134 ) and active renal vasculitis ( 135 , 136 ). On the other hand in LN ( 119 ), sCD163 in the urine is considered as a marker of disease activity and treatment response ( 137 , 138 ). Interestingly, CD163 + cells in crescents of ANCA glomerulonephritis patients colocalized with CCL18 ( 95 ) and Gremlin ( 107 ).…”

Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

“…For instance, in rheumatoid arthritis and spondyloarthropathy the sCD163 level is elevated in the synovial fluid, where it is associated with disease activity and progression [93,94]. Furthermore, elevated sCD163 levels in sputum, urine, cerebrospinal fluid and vitreous fluid have been shown to be associated with disease activity and treatment in asthma [95,96], lupus nephritis [97,98], multiple sclerosis [99] and proliferative diabetic retinopathy [89,90], respectively. Generally, CD163 has been used to identify TAMs in malignant diseases and the level of CD163 expressing TAMs has been linked to poor prognosis, overall survival and metastasis of a range of malignancies, as listed in Table 2.…”

Circulating Soluble CD163: A Potential Predictor for the Functional Outcome of Acute Ischemic Stroke

“…CD163 could shed from cell membranes to release soluble CD163 (sCD163) upon stimulation by inflammatory stimuli ( 4 ). sCD163 has been suggested to be biomarkers of many diseases, such as infectious diseases ( 5 ), tumors ( 6 ), and autoimmune diseases ( 7 ). sCD163 is increased in patients with intracranial hemorrhage and is associated with the improvement of neurological functions by promoting hematoma absorption ( 8 ).…”