Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis

Abstract

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 LN patients (573 samples) in the longitudinal Accelerating Medicines Partnership (AMP) in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PRTN3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.92, EGFR 0.9, CD163 0.89, proteinuria 0.8, p<0.01). Candidate biomarkers were validated and provide new potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN, guide treatment, and as surrogate endpoints for clinical trials. These findings provide new insights into the processes involved in LN activity. This dataset (matching other AMP omics) is a public resource to generate and test hypotheses and validate biomarkers.

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis

“…After adjusting for FDR < 0.10, we observed significant differences between groups ( Figure 5E ). The group G2 was enriched in granzyme A and with proteins previously associated with increased NIH activity and proliferative LN class, such as Catalase and CD163(35, 70) ( Figure 5E ). Compared to the group G1, G2 had increased secretion of several proteins, including TGFβ1, which had been reported to be enriched in kidney tissue during proliferative LN flares and was predictive of complete renal response(7) ( Figure 5E ).…”

“…5e). The group G2 was enriched in granzyme A and with proteins previously associated with increased NIH activity and proliferative LN class, such as Catalase and CD163 35,70 (Fig. 5e).…”

“…To further extend the association between blood immune profiles and kidney injury, we compared the urine proteomic profiles obtained from paired samples (n=115), previously generated using the Raybiotech kiloplex technology and published separately(35). After adjusting for FDR < 0.10, we observed significant differences between groups ( Figure 5E ).…”

“…Patients were treated during the study at the discretion of their physicians based on standard of care. Renal response to treatment was determined clinically at week 52 as complete, partial, or none, adapted from the ACCESS trial definitions(87), and as reported(35), in patients with a baseline UPCR ratio > 1. Briefly, complete response (CR) was defined by UPCR <0.5, normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, <125% of baseline, and prednisone < 10mg/day.…”

“…Patients were treated following standard of care according to the judgment of their physician (16,17). Clinical renal response was defined as previously reported in patients with a UPCR > 1 at baseline (35,36). At 52 weeks, 28% achieved complete response, 24% a partial response and 48% no response.…”