Background Human Epidermal Growth Factor Receptor 2 (HER2) expression is increased in the kidneys of patients with proliferative lupus nephritis (LN) as well as the kidneys of the mouse model NZM2410, though it is not increased in other glomerulonephritides. Preliminary data indicated that urinary HER2 (uHER2) may be elevated in adult patients with proliferative LN (class III and class IV). This study sought to establish whether uHER2 can serve as a biomarker to predict flare of proliferative lupus nephritis in patients with systemic lupus erythematosus (SLE).
Methods We performed a multicenter prospective study of children with LN as well as a single center prospective study of adults from Johns Hopkins; children and adults without lupus were enrolled as controls. Urine samples were collected at scheduled visits over the course of 4 years. uHER2 was measured by a commercially available ELISA and compared to two other commercially assayable prospective urinary markers of LN, TNF-like weak inducer of apoptosis (TWEAK) and vascular cell adhesion molecule-1 (VCAM-1). Active lupus nephritis was defined as the presence of one or more of the following findings: granular or red blood cell casts,>5 red blood cells/high power field with the exclusion of other causes, or proteinuria of >0.5 grams/24 hours or recent increase of >0.5 grams/24 hours.
Results One hundred children with LN were enrolled from five academic centers across the United States alongside 91 age-matched controls (mean age 15 years). Children with LN had significantly higher levels of uHER2 compared with controls (p<0.01); the difference was greater for children with active LN (p<0.005). uHER2/creatinine correlated with uTWEAK/creatinine (p<0.0001) and with uVCAM-1/Creatinine (p<0.05); uHER2 was more sensitive for flare than TWEAK and more specific for flare than VCAM-1. The adult cohort consisted of 142 SLE patients and 23 healthy controls. uHER2/creatinine levels were increased in adult SLE patients when compared to controls (p<0.05) with the difference also greatest in patients with active LN (p<0.005).
Conclusion This multicenter prospective study establishes uHER2 as a promising new biomarker for determination of lupus nephritis flare in both children and adults. Combined with implications for HER2 as a driver of mesangial cell proliferation through microRNA downregulation, these results provide further impetus to explore already-available HER2-inhibiting drugs, including tyrosine kinases and certain monoclonal antibodies, for the treatment of LN, such as lapatinib (Tyverb) or trastuzumab (Herceptin).
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