Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis

Abstract

Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Invasive renal biopsy remains the gold standard for the diagnosis and management of LN. The objective of this study is to validate serum insulin-like growth factor binding protein-2 (IGFBP-2) as a novel biomarker for clinical disease and renal pathology in LN. Eighty-five biopsy-proven lupus nephritis patients, 18 chronic kidney disease (CKD) patients and 20 healthy controls were recruited for enzyme-linked immunosorbent assay (ELISA) testing of serum IGFBP-2 levels. Compared to CKD patients of origins other than lupus or healthy controls, serum IGFBP-2 levels were elevated significantly in LN patients. Serum IGFBP-2 was able to discriminate LN patients from the other two groups of patients [area under the curve (AUC) = 0·65, 95% confidence interval (CI) = 0·52-0·78; P = 0·043 for LN versus CKD; 0·97, 95% CI = 0·93-1·00; P < 0·0001 for LN versus healthy controls]. Serum IGFBP-2 was a potential indicator of both global disease activity and renal disease activity in LN patients, correlated with serum creatinine levels (r = 0·658, P < 0·001, n = 85) and urine protein-to-creatinine levels (r = 0·397, P < 0·001, n = 85). More importantly, in 19 concurrent patient samples, serum IGFBP-2 correlated with the chronicity index of renal pathology (r = 0·576, P = 0·01, n = 19) but not renal pathological classification. In conclusion, serum IGFBP-2 is a promising biomarker for lupus nephritis, reflective of disease activity and chronicity changes in renal pathology.

Keywords: IGFBP2; biomarkers; lupus nephritis; pathology.

© 2016 British Society for Immunology.

Figures

Figure 1

Serum insulin‐like growth factor binding protein‐2 (IGFBP‐2) levels were elevated in patients with lupus nephritis (LN). (a) Serum IGFBP‐2 levels in LN patients (380·8 ± 37·4 ng/ml) were increased significantly when compared to those of chronic kidney disease (CKD) controls (213·6 ± 43·9 ng/ml, P = 0·013) and healthy controls (HC) (42·1 ± 6·8 ng/ml, P < 0·0001); (b) receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) value was 0·65 [95% confidence interval (CI) = 0·52–0·78; P = 0·043] for LN versus CKD and 0·97 (95% CI = 0·93–1·00; P < 0·0001) for LN versus HC.

Figure 2

Correlation between serum insulin‐like growth factor binding protein‐2 (IGFBP‐2) with disease activity. (a) Serum IGFBP‐2 levels were elevated significantly in the high global disease activity group (448·1 ± 51·9 ng/ml) compared to the low global disease activity group (263·7 ± 41·7 ng/ml). Both were increased significantly when compared to healthy controls (HC). (b) Serum IGFBP‐2 levels were increased significantly in active lupus nephritis (LN) patients compared to inactive LN patients (429·1 ± 44·5 ng/ml versus 213·3 ± 49·1 ng/ml; P = 0·007). However, there was no significant difference in IGFBP‐2 levels between inactive LN patients and chronic kidney disease (CKD) controls (P = 0·81). (c) Correlation analysis showed a significant correlation between serum IGFBP‐2 levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (r = 0·379, P < 0·0001, n = 85); (d) correlation analysis showed a significant correlation between serum IGFBP‐2 levels and rSLEDAI score (r = 0·409, P < 0·0001, n = 85).

Figure 3

Correlation between serum insulin‐like growth factor binding protein‐2 (IGFBP‐2) with clinical parameters. (a) A significant increase in serum IGFBP‐2 levels was observed between anti‐double‐stranded DNA (dsDNA)‐positive and anti‐dsDNA‐negative patients (526·7 ± 76·7 ng/ml versus 262·6 ± 38·4 ng/ml; P = 0·012); (b) significant difference in serum IGFBP‐2 levels between patients with low and normal complement levels (465·1 ± 61·0 ng/ml versus 215·1 ± 32·8 ng/ml; P = 0·027); (c) no significant difference in serum IGFBP‐2 levels in patients with different anti‐nuclear antibodies (ANA) status. (c–e) Serum IGFBP‐2 levels were correlated positively with serum creatinine levels (r = 0·658, P < 0·001, n = 85), urine protein‐to‐creatinine levels (r = 0·397, P < 0·001, n = 85).

Figure 4

Correlation between serum insulin‐like growth factor binding protein‐2 (IGFBP‐2) levels with renal pathology in patients with lupus nephritis. (a) Serum IGFBP‐2 levels did not correlate with renal pathology activity index (r = 0·273, P = 0·25, n = 19); (b) Serum IGFBP‐2 levels correlated with renal pathology chronicity index (r = 0·576, P = 0·01, n = 19). For this analysis, the serum was obtained concurrent to the renal biopsy.