At the time of a nephritis flare in patients with systemic lupus erythematosus (SLE), elevated levels of two neutrophil extracellular trap (NET) protein complexes, elastase-DNA and HMGB1-DNA, predict declining renal function, poor response to therapy, and adverse renal outcomes, according to work presented at the annual meeting of the Canadian Rheumatology Association.
“These proteins are not only predominantly elevated in patients with proliferative lupus nephritis, but they correlate with adverse renal outcomes when patients are followed over 24 months,” reported Laura P. Whittall-Garcia, MD, a clinical fellow in rheumatology at the University of Toronto.
Lupus nephritis is common in SLE, developing in about 50% of patients, according to Dr. Whittall-Garcia. Of these, up to 20% will not respond to standard therapies, typically resulting in end-stage renal disease. Up until now, there has been no reliable method of predicting this adverse clinical course.
Proteins identified in NETs
The series of studies conducted by Dr. Whittall-Garcia and coinvestigators were focused on NETs, a network of strings of DNA that typically bind pathogenic microbes to prevent infection but can participate in the pathology of immune-mediated conditions. As Dr. Whittall-Garcia explained, DNA extruded from NETs has been a source of autoantigens.
Based on earlier work, they pursued the hypothesis that high mobility group box 1 (HMGB1) and elastase, which are both NET components, mediate NETosis, the immune response that protects against microbes in healthy individuals but contributes to tissue damage in patients with immune-related disorders. The first aim of this work was to confirm that elevations of elastase-DNA and HMGB1-DNA correlate with active lupus nephritis. The second aim was to determine if levels of these proteins at the time of lupus nephritis flare predicted renal outcomes at 12 and 24 months.
To pursue the first hypothesis, 49 patients with active SLE (18 of whom had active lupus nephritis) were evaluated along with 23 patients with inactive SLE and 20 healthy controls.
Highest levels seen in proliferative nephritis
Relative to healthy controls, patients with active SLE have highly significantly increased levels of both proteins (P < .0001). And relative to those with inactive SLE, the levels of active patients were higher but fell short of statistical significance. However, when the researchers compared those with active lupus nephritis with those who had active SLE but no nephritis, both proteins were significantly higher (P < .04), and the levels in patients with proliferative relative to nonproliferative lupus nephritis were higher still (P < .009).
To pursue the second aim of the study, the researchers retrospectively evaluated 109 patients with SLE. All had active lupus nephritis, a baseline estimated glomerular filtration rate (eGFR) greater than 30 mL/min prior to the flare, and at least 2 years of follow-up. They evaluated complete response at 12 and 24 months, percent decline in eGFR, and severe renal impairment (eGFR ≤ 30 mL/min) in the context of levels of elastase and HMGB1.
With elevations in either NET remnant, the odds ratio of failing to achieve a complete response at 24 months were approximately doubled for elastase-DNA (OR, 1.96; P = .01) and for HMGB1 (OR, 2.61; P = .02). For the endpoint of severe renal impairment 24 months after a lupus nephritis flare, there was also a positive association with both elastase-DNA (OR, 1.55; P = .005) and HMBG1-DNA (OR, 1.91; P = .01).
“For every 100-unit increase in elastase-DNA complexes, there is a 4.8% decrease in eGFR,” reported Dr. Whittall-Garcia, who noted this relationship was highly statistically significant (P < .0001). For HMGB1-DNA, each 100-unit increase was associated with a 5.3% decrease in eGFR (P = .0006).