Background/Purpose: Early treatment is critical to prevent irreversible kidney damage in lupus nephritis (LN). Current guidelines recommend kidney biopsy when the urine protein-to-creatinine ratio (UPCR) reaches ≥0.5 g/g. However, one-third of patients with UPCR between 0.25–0.5 g/g already harbor ISN Class III or IV ± V LN. While urinary biomarkers can detect active LN in patients with UPCR >0.5, their utility at lower proteinuria thresholds remains unclear. We analyzed candidate urinary biomarkers in SLE patients undergoing kidney biopsy at the initial onset of UPCR 0.25–0.49 g/g to identify molecular signatures of clinically underestimated LN that could support earlier diagnosis and treatment.

Methods: SLE patients with no history of LN, UPCR 0.250–0.49 g/g, and at least one additional LN risk factor (non-White race, low C3, low C4, anti-dsDNA positivity, or active urine sediment) were prospectively enrolled (KP1; n=21). For comparison, we analyzed a cohort of SLE patients with UPCR >0.5 undergoing clinically indicated kidney biopsy (AMP; n=282), and healthy controls (HC; n=31). Urine samples were collected near the time of biopsy, and 5,416 proteins were quantified using the Olink Explore HT platform. We focused on eight candidate biomarkers previously associated with histological activity, fibrosis, and future kidney function loss: IL16, CD163, CD206 (MRC1), PR3 (PRTN3), Galectin-1 (LGALS1), Tenascin-C (TNC), BAFF (TNFSF13B), and C9.

Results: In this interim analysis, 13 of 21 low proteinuria patients (62%) had biopsy-confirmed LN, including 3 (14%) with Class III and 5 (24%) with Class V (Table 1).Compared to UPCR >0.5 SLE patients, low proteinuria patients had higher eGFR (but not statistically significant) and lower NIH activity and chronicity indices, suggesting earlier stages of inflammation and fibrosis.Although the sample size limited statistical power, patients with Class III LN showed elevated levels of multiple candidate biomarkers—including CD163, CD206, IL16, Galectin-1, BAFF, C9, and Tenascin-C—compared to those with no LN (Figure 1).All eight biomarkers were significantly enriched in low proteinuria Class III patients, mirroring the Class III profile in high proteinuria patients (Figure 2). This suggests that proliferative LN is already molecularly active at lower proteinuria levels, with signatures of M1/M2 macrophage activation (CD163, CD206), B cell stimulation (BAFF), complement activation (C9), and fibrotic remodeling (Tenascin C). Importantly, biomarker levels in KP1 Class III patients were comparable to those in AMP patients with UPCR >0.5, indicating that proteinuria alone underestimates the degree of renal inflammation. Notably, Class V patients in both KP1 and AMP cohorts showed elevated Tenascin-C, highlighting a pro-repair/fibrotic signature even in early membranous LN.

Conclusion: Urinary biomarkers may detect proliferative LN in SLE patients with subclinical proteinuria. These findings support the potential of biomarker-guided strategies to enable screening as well as earlier diagnosis and intervention in lupus nephritis. Ongoing analysis of the full 5,416-protein panel aims to elucidate early mechanisms of LN and identify novel targets for timely intervention.

Table 1. Patient Characteristics and Histopathologic Features at Time of Biopsy. # one patient had UPCR >0.5 at screening but 0.099 on repeat pre biopsy.

Figure 1. Urinary biomarkers of inflammation and fibrosis are elevated in early lupus nephritis across ISN classes.

Boxplots display expression levels of inflammation-associated markers (IL16, CD163, CD206 [MRC1], PR3 [PRTN3], Galectin-1 [LGALS1], BAFF [TNFSF13B], and C9) and the myofibroblast marker Tenascin C [TNC] in early LN biopsies. Among the eight KP1 patients without histologic LN, six (75%) exhibited 20–30% foot process effacement, two (25%) showed glomerulosclerosis, five had atherosclerosis, and one had IgA nephropathy. Proteins are expressed as normalized protein expression (NPX) and normalized by plate controls.

Figure 2. Urinary inflammatory and fibrotic protein expression is elevated in early and established proliferative and membranous lupus nephritis.

Boxplots show expression levels of eight candidate biomarkers—IL16, CD163, CD206 (MRC1), PR3 (PRTN3), Galectin-1 (LGALS1), BAFF (TNFSF13B), C9, and Tenascin-C (TNC)—in urine samples from patients with low proteinuria LN (UPCR < 0.5, KP1), high proteinuria LN (UPCR >= 0.5, AMP), and healthy controls (HC). KP1 Class III patients exhibited similar biomarker profiles to AMP Class III patients, suggesting early molecular activation despite subclinical proteinuria. Class V patients in both cohorts also showed enrichment of fibrotic markers (Tenascin-C). The blue shaded area represents the 5th to 95th percentile range of protein expression in HC. Statistical comparisons were performed using the Wilcoxon test. *p < 0.05; **p < 0.01; ***p < 0.001.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/urinary-biomarkers-detect-proliferative-lupus-nephritis-in-sle-patients-with-subclinical-proteinuria/