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Objectives Growth-Differentiation Factor-15 (GDF-15) is a mitochondrial-stress responsive cytokine implicated in cardiovascular and kidney diseases, also linked to nephritis in Systemic Lupus Erythematosus (SLE). This study aimed to define the association of GDF-15 to SLE disease activity, organ damage, and renal function, assessing its role as a marker of activity versus organ damage.Methods Plasma GDF-15 levels were measured (ELISA) in 530 SLE patients and 320 matched controls. Chronicity Index (CI) and Activity index (AI) were retrieved from first-time renal biopsies (n=98). Cross-sectional differences in GDF-15 (log-transformed) according to SLE-Disease Activity Index (SLEDAI-2K), SLICC/ACR-Damage Index (SDI), and renal British-Isles Lupus Assessment Group (BILAG) were compared via Mann-Whitney and Kruskal-Wallis tests. Multivariate logistic regression explored GDF-15 in relation to myocardial infarction, stroke and heart failure. Multivariate linear regression explored associations of biopsy AI and CI to GDF15 accounting for biopsy time-lag and assessed the relationship of GDF-15 to NT-proBNP adjusting for age, sex, eGFR, antihypertensives.Results GDF-15 levels were higher in SLE versus controls (p<0.001). Within SLE, GDF-15 was associated with organ damage ( figure 1B). A robust association was observed with renal dysfunction: GDF-15 increased according to renal SDI scores (figure 1D) and lower eGFR (figure 1A). While associated with SLEDAI proteinuria/hematuria (p<0.001), GDF-15 did not differ by renal BILAG (A/B vs C/D figure 1C) and showed no correlation with anti-dsDNA/complement. Of 98 biopsies, 59 reported CI and AI (median time-lag 3 years, IQR 1-7). CI, but not AI, remained associated with GDF-15 adjusted for age, sex, biopsy time-lag and eGFR (19% increase in GDF-15 per 1-unit increase in CI, p=0.029).GDF-15 was elevated in patients with prior ischemic stroke, myocardial infarction and heart failure (p<0.01). These associations did not withstand adjustment for traditional risk factors, although GDF-15 remained associated with markers of cardiac dysfunction (NT-proBNP, p<0.001).Abstract PO:02:055 Figure 1Conclusions GDF-15 represents an organ damage biomarker in SLE, particularly in the renal and possibly in the cardiovascular domain. GDF-15 may reflect tissue damage partly captured by measures like CI, rather than immunological activity. These findings position GDF-15 as a damage severity indicator in SLE, especially in nephritis, warranting prospective studies to explore its prognostic value for damage accrual and adverse outcomes.