Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

BACKGROUND: Thrombosis is a potentially life‐threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS‐associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS‐associated hypercoagulopathy. METHODS: Puromycin aminonucleoside‐induced rat NS was treated with sham, Low‐ or High‐dose MP, Pio, or combination (Pio + Low‐MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid‐sensitive NS (SSNS) and steroid‐resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively. RESULTS: In a rat model of NS, both High‐MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (p < .05). Proteinuria (p = .005) and hypoalbuminemia (p < .001) were correlated with ETP. In childhood NS, while ETP was not different at presentation, GC therapy improved proteinuria, hypoalbuminemia, and ETP in children with SSNS (p < .001) but not SRNS (p = .330). CONCLUSIONS: Both Pio and GC diminish proteinuria and significantly alleviate hypercoagulopathy. Both Pio and MP improved hypercoagulopathy in rats, and successful GC therapy (SSNS) also improved hypercoagulopathy in childhood NS. These data suggest that even a partial reduction in proteinuria may reduce NS‐associated thrombotic risk.