METHODS: It is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized trial of individuals with kidney biopsy-confirmed IgAN, proteinuria ≥1 g/day, and an estimated GFR of 20-120 mL/min/1.73 m2, following at least 3 months of standard of care including maximum labelled (or tolerated) dose of renin-angiotensin system blockade. The original study design randomized participants 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/day, maximum 48 mg/day) for 2 months, with subsequent weaning by 8 mg/day/month over 6-8 months, or matching placebo. The intervention was modified in 2016 (due to an excess of serious infection) to low-dose methylprednisolone (0.4 mg/kg/day, maximum 32 mg/day) for 2 months, followed by weaning by 4 mg/day/month over 6-9 months, or matching placebo. Participants recruited after 2016 also received prophylaxis against Pneumocystis jirovecii pneumonia during the first 12 weeks of treatment.

RESULTS: The study recruitment period extended from May 2012 to November 2019. By the time the excess of serious infections was observed, 262 participants had been randomized to the original full-dose treatment algorithm, and an interim analysis was reported in 2016. Subsequently, 241 additional participants were randomized to a revised low-dose protocol, for a total of 503 participants from China (373), India (78), Canada (24), Australia (18), and Malaysia (10). The mean age of randomized participants was 38, 39% were female, mean eGFR at randomization was 62.7 mL/min/1.73 m2, and mean 24-h urine protein 2.54 g. The primary endpoint is a composite of 40% eGFR decline from baseline or kidney failure (dialysis, transplantation, or death due to kidney disease), and participants will be followed until the primary outcome has been observed in at least 160 randomized participants. Analyses will also be made across predefined subgroups. Effects on eGFR slope and albuminuria will also be assessed overall, as well as by the steroid dosing regimen.

METHODS: Male Sprague Dawley rats weighing 200-250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR.

METHODS: Sprague Dawley rats were intravitreally injected with ET1. MgAT and TAU were administered as pre-, co-, or posttreatment. Subsequently, the expression of NOS isoforms was detected in retina by immunohistochemistry, retinal nitrotyrosine level was estimated using ELISA, and retinal cell apoptosis was detected by TUNEL staining.

RESULTS: Intravitreal ET1 caused a significant increase in the expressions of nNOS and iNOS while eNOS expression was significantly reduced compared to vehicle treated group. Administration of both MgAT and TAU restored the altered levels of NOS isoform expression, reduced retinal nitrosative stress and retinal cell apoptosis. The effect of MgAT, however, was greater than that of TAU alone.