The identification of intrarenal pathological processes is key to develop better diagnostic and treatment strategies in lupus nephritis (LN). The direct study of renal tissue can be limited by degradation, availability, and cell survival. We employed urine proteomics to define the molecular pathways involved in proliferative LN.
We quantified 1200 biomarkers (RayBiotech) in urine samples collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy in SLE patients with urine protein to creatinine ratio on random or 24 hr collection of > .5. Protein concentrations were normalized by urine creatinine.
A total of 195 patients were included: 138 (71%) had a proliferative histological class (III or IV +/- V), 57 (29%) pure membranous (V). There were 21 (FDR 1%) differentially abundant urinary proteins in proliferative compared to pure membranous LN (Figure 1A). These included several neutrophil granule proteins (Figure 1B) in addition to previously reported biomarkers such as IL-16 and CD163. Unsupervised clustering based on the proliferative LN signature identified 3 groups characterized by low, medium or high protein abundance (Figure 2). Higher proliferative signature abundance (right cluster) was associated with higher histological activity (NIH Activity Index). Immunofluorescence confirmed an abundant MPO+ neutrophil infiltrate in proliferative LN (Figure 3).
Proliferative LN was associated with a urinary neutrophil degranulation signature, especially in patients with higher histological activity. Neutrophil activity could be noninvasively monitored to assist with the diagnosis of proliferative LN. These findings implicate neutrophils in LN pathogenesis and support the study of treatment targeted to neutrophils.
To elucidate whether clinical features and the weighted genetic risk score (wGRS) were associated with the presence of lupus nephritis (LN).
We retrospectively divided patients with systemic lupus erythematosus (SLE, n = 1,078) into biopsy-proven LN (n = 507) and non-LN groups (non-LN, n = 571). Baseline clinical features, serologic markers, and the wGRS were collected. The wGRS was calculated from 112 non-HLA loci and HLA-DRβ1 amino acid haplotypes for SLE. Associations among clinical features, wGRS, and the presence of LN were identified.
In the multivariate analysis, patients with LN were younger at diagnosis (odds ratio (OR) = 0.97, p < 0.001), had more pleuritis (OR = 2.44, p < 0.001) and pericarditis (OR = 1.62, p = 0.029), had a higher detection rate of anti-double stranded deoxyribonucleic acid (anti-dsDNA antibodies, OR = 2.22, p < 0.001), anti-Smith antibodies (anti-Sm antibodies, OR = 1.70, p = 0.002), low level of complement (OR = 1.37, p = 0.043) and absence of antiphospholipid antibodies (aPL antibodies, OR = 1.60, p = 0.002), and had higher wGRS (OR = 1.16, p = 0.012). Mediation analysis suggested that anti-Sm antibodies and low complement could be mediators in the relationship between high wGRS and the presence of LN.
Onset age, pleuritis, pericarditis, several serologic markers, and wGRS were associated with the presence of LN. Anti-Sm antibodies and low complement appeared to mediate the indirect relationship between wGRS and the presence of LN.