Abstract
OBJECTIVES: To study neutrophil gelatinase-associated lipocalin (NGAL) levels in peripheral blood in SLE, and to propose a mechanism by which neutrophils secrete NGAL on stimulation with immune complexes (IC). METHODS: NGAL was measured by ELISA in two independent Swedish SLE cohorts acting as exploratory and validation cohort (n=124 and n=308, respectively), disease controls (n=38) and healthy controls (n=77). NGAL levels were measured in supernatant from IC-stimulated neutrophils in the presence or absence of a toll-like receptor 8 inhibitor (TLR8i). RESULTS: In the exploratory cohort, serum levels of NGAL were increased in patients with SLE as compared with healthy controls (p=0.021), and associated with histological-proven membranoproliferative lupus nephritis (LN) (p=0.018). In the validation cohort, plasma levels of NGAL were elevated in patients with a history of LN (p=0.0048), as well as in patients with SLE with secondary antiphospholipid syndrome (APS) compared with those without (p=0.0022). In both cohorts, NGAL was able to discriminate patients with a creatinine clearance <60 mL/min (chronic kidney disease stage 3 or more) with high accuracy, with an area under the curve of 0.92 (p<0.0001) and 0.94 (p=0.0088), respectively. Neutrophils stimulated with IC secrete more NGAL, when compared with baseline, and this process was blocked by adding a TLR8i. CONCLUSION: Blood levels of NGAL are increased in patients with SLE with decreased kidney function, and in those with secondary APS. The mechanism behind NGAL increase in SLE may be related to TLR8 pathway activation by circulating RNA-containing IC.