Background/Purpose: Lupus nephritis (LN) is a severe manifestation of Systemic Lupus Erythematosus (SLE). Renal biopsy is gold standard for evaluation of renal activity and damage in LN. Evaluation of new biomarkers for non-invasive assessment of renal pathology is warranted. Ferritin is considered an acute phase protein and studies have reported elevated serum concentrations in patients with active SLE, as compared to patients with inactive disease, and also correlations with LN. Insulin-like Growth Factor-Binding Protein 2 (IGFBP2) has been found to be a robust diagnostic and prognostic biomarker in malignancies. In animal models, IGFBP2 expression was increased in anti-glomerular basement membrane (anti-GBM) glomerulonephritis and MRL/lpr lupus mice. The role of these molecules in LN has yet to be clarified.

Methods: Serum levels of Ferritin and IGFBP2 were assessed by ELISA (Raybiotech Inc. and R&D Systems, respectively) in 64 patients with biopsy-ascertained active LN before and after completion of induction treatment. Follow-up renal biopsies were performed after a mean time of 8.1 months. Reduced proteinuria by ≥50%, normal or improved estimated Glomerular Filtration Rate (eGFR) by ≥25%, and inactive urinary sediment signified clinical responders (CR). Improvement of Activity Index in the follow-up biopsies by ≥50% signified histopathological responders (HR). Long-term renal outcome after a mean time of 10.9 years was determined by the last eGFR.

Results: Serum Ferritin and IGFBP2 levels declined following induction therapy for LN in both CR and HR (p<0.001). In clinical non-responders (CNR), IGFBP2 levels remained unchanged (p=0.438) while Ferritin levels declined (p=0.030). In histopathological non-responders (HNR), both Ferritin (p=0.056) and IGFBP2 (p=0.158) levels remained stable.

In patients with proliferative LN (PLN; n=52), Ferritin and IGFBP2 levels declined following therapy in both CR and HR (p<0.001). Ferritin and IGFB2 levels declined in CNR (p<0.05). In HNR, IGFBP2 levels remained stable (p=0.086) while Ferritin levels declined (p=0.011).

In patients with membranous LN (MLN; n=12), Ferritin and IGFBP2 levels declined in CR (p<0.05), but not in CNR. Ferritin levels declined in HR (p=0.046), but not in HNR while IGFBP2 levels remained stable in both HR and HNR.

Follow-up IGFBP2 levels were higher in CNR compared to CR (p=0.004). There was no correlation between Ferritin or IGFBP2 concentrations and long-term renal outcome. We noted a correlation between IGFBP2 levels and Chronicity Index at follow-up (p=0.009, r=0.324).

Conclusion: The decreases in Ferritin and IGFBP2 levels following induction therapy suggest an association of these molecules with renal disease activity. The data also suggest higher follow-up IGFBP2 levels as a biomarker of unfavorable treatment outcome in LN and point to IGFBP2 being a candidate biomarker of histopathological outcome following induction treatment for PLN. Moreover, our results indicate an important role and a potential utilization of both Ferritin and IGFBP2 as biomarkers of treatment response in MLN. The correlation between Chronicity Index and IGFBP2 levels at follow-up suggests IGFBP2 as a biomarker of renal damage in LN patients after induction therapy.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-ferritin-and-insulin-like-growth-factor-binding-protein-2-as-biomarkers-of-clinical-and-histopathological-treatment-response-in-lupus-nephritis/