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

Abstract

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, Lowor 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. How to cite this article: Waller AP, Agrawal S, Wolfgang KJ, et al. Nephrotic syndrome-associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors.

Selective Modulator of Nuclear Receptor PPARγ with Reduced Adipogenic Potential Ameliorates Experimental Nephrotic Syndrome

“…5B. ETP is a consistently elevated thrombin generation parameter in NS 39, 40 , and we found it to be significantly increased in nephrotic rats (PAN, 3646 ± 199 nM*min vs. Control, 2445 ± 402 nM*min; p = 0.014) (Fig. 5B and C).…”

“…Our previous observations have found increased ETP to be very well-correlated with increased proteinuria during NS and its decrease with standard treatment in both human studies and in animal models 39,40 . In the current study, we find a good correlation of ETP with proteinuria, significant increase with injury, and a decrease with GQ-16 treatment.…”

“…We have previously shown a significant correlation between hypercoagulopathy and proteinuria during NS, and correction of hypercoagulopathy with glucocorticoid treatment, which is a standard treatment for NS 39, 40 . We thus measured thrombin generation parameters in our model of NS, their alteration with treatment with Pio and GQ-16, and correlation with proteinuria.…”

“…Serum and urine chemistries were performed, and kidneys, glomeruli, liver, and white adipose tissue (WAT) were harvested for histology, RNA, and protein extraction. Blood was collected through the inferior vena cava, then processed to Platelet Poor Plasma (PPP) as described previously for determination of thrombin generation parameters 39, 40 . Detailed methods are provided in Supplementary.…”

“…Spot urine and serum were collected, and body weights were recorded throughout the study. The rats were anesthetized with 3% isoflurane and sacrificed on Day 11, at which time blood was collected through the inferior vena cava with a 23-G needle into the 0.32% sodium citrate and 1.45μM corn trypsin inhibitor, then processed to Platelet Poor Plasma (PPP) as described previously 4, 5 . Kidneys were harvested, and the glomeruli were isolated from 1 and ½ kidneys using the sequential sieving method 3 .…”