ATTAINMENT OF ULTRA-LOW LEVELS OF UPCR IN THE AURORA 1 STUDY ASSOCIATED WITH ALTERATIONS IN THE CIRCULATING LIPIDOME

PV122 / #252 Poster Topic: AS15 - Lupus Nephritis-Clinical Background/Purpose Lupus nephritis (LN) is an independent risk factor for cardiovascular disease (CVD) and is associated with a nearly 5-fold greater risk of cardiovascular mortality compared to non-renal systemic lupus erythematosus. In the Phase 3 AURORA 1 study of adult patients with active LN, the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose glucocorticoids resulted in significantly greater and earlier urine protein-creatinine ratio (UPCR) reduction as well as significant reductions in many classes of lipids within the circulating lipidome.[1,2] We hypothesized that patients who achieved an ultra-low UPCR (≤0.2 g/g) would have distinct changes in their lipidomes over time compared to patients achieving a partial renal response (PRR). Methods Patients enrolled in the 52-week AURORA 1 study were randomized to either voclosporin 23.7 mg twice daily or placebo (control), in combination with MMF (target 2 g/day) and low-dose glucocorticoids (starting dose 20-25 mg/day, tapered to ≤2.5 mg/day by Week 16). Serum samples were collected from each patient prior to treatment (baseline) and at the end of treatment (Week 52). A lipidomic analysis assessing 19 classes of lipids (935 individual lipids) was performed on a subset of 58 patients. Lipids were extracted from biofluid and quantified as previously described.[1] Changes in mean lipid levels from baseline to Week 52 were compared in patients who achieved a UPCR ≤0.2 g/g at Week 52 with patients who achieved a PRR (≥50% reduction in UPCR from baseline) at Week 52 but maintained UPCR levels >0.2 g/g. Results Overall, 115 (31.9%) patients (voclosporin, 72; control, 42) achieved a UPCR ≤0.2 g/g at any point during the 52-week study. Of the subset of patients with available lipidomic data, 7 (voclosporin, 4; control, 3) achieved a UPCR ≤0.2 g/g at Week 52; 22 patients achieved a PRR with UPCR >0.2 g/g. In patients achieving UPCR ≤0.2 g/g, mean levels of the following lipids decreased from baseline to Week 52 and were statistically different from corresponding levels in patients who achieved PRR: triacylglycerol (TAG; p=<0.0001), diacylglycerol (DAG; p<0.0001), phosphatidylcholine (PC; p<0.0001), phosphatidylethanolamine (PE; p<0.0001), phosphatidylinositol (PI; p=0.0122), lyso-PC (LPC; p=0.0170), and lyso-PE (LPE; p=0.0026; Figure 1). Mean levels of PE-O (p<0.0001), acylcarnitine (AC; p=0.0006), and PE-P (p=0.0011) were increased from baseline to Week 52 in patients achieving UPCR ≤0.2 and statistically different from corresponding mean levels in patients achieving PRR. Figure 1. Change in lipid level by UPCR Level Conclusions Proteinuria confers CVD risk due to alterations in the lipidome. This analysis has revealed a distinct lipidomic profile in patients who achieved ultra-low UPCR compared to patients who achieved a PRR. ACs transport long chain fatty acid into mitochondria for β-oxidation, and the AC profiles change dynamically according to the completeness of β-oxidation.[3] In our previous work, AC levels decreased in patients with UPCR ≤0.5 g/g.[1] In the current analysis, the increase in AC levels in those who achieved UPCR ≤0.2 g/g suggests a possible restoration of fatty acid metabolism homeostasis with deeper UPCR reductions.[3] Taken together, our data suggest that differential modification of CVD risk in LN can be further modified with attainment of ultra-low UPCR targets. References: [1.] Afshinnia F. Kidney Int Rep 2024;9(8):2559-62. [2.] Rovin BH. Lancet 2021;397(10289):2070-80. [3.] Makrecka-Kuka M. Sci Rep 2017;7(1):17528.

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