1.Effect of anti-tumor necrosis factor alpha treatment of rheumatoid arthritis and chronic kidney disease
Hyun Woo Kim · Chang-Keun Lee · Hoon-Suk Cha. Rheumatol Int (2015) 35:727–734
Therapies effective in slowing the decrease in kidney function mainly focus on the control of blood pressure, optimization of the renin–angiotensin–aldosterone system blockade, and glycemic control in diabetes mellitus. However, the current therapies cannot be regarded as best because they are only partially effective. Therefore, there have been a number of trials demonstrating the efficacy of novel therapeutic strategies for slowing or even preventing the progression of CKD, but large number of drugs failed to afford renoprotection. For example, treatment with bardoxolone methyl, an anti-oxidative and anti-inflammatory drug, which activates the nuclear factor-erythroid-2-related factor-Keap1 pathway, resulted in a significant increase and maintenance in eGFR in patients with type 2 diabetes and CKD stage 3 or 4. However, the BEACON trial, which was designed to assess whether bardoxolone methyl decreases the incidence of dialysis and can be safely used in patients with type 2 diabetes and CKD stage 4, showed that bardoxolone methyl did not reduce the risk of end-stage renal disease or death from cardiovascular causes and was early terminated because of excess mortality in the bardoxolone methyl treatment arm. On the other hand, growing evidence suggests that TNF-α plays a pathogenic role in CKD with a variety of etiologies, and pharmacological agents capable of suppressing this inflammatory mediator, such as mycophenolate mofetil and pentoxifylline have therapeutic potential.
2.Therapies on the Horizon for Diabetic Kidney Disease
Sadaf S. Khan & Susan E. Quaggin. Curr Diab Rep (2015) 15: 111
Bardoxolone methyl is a semisynthetic oleanane triterpenoid compound that possesses antioxidant properties through activation of nuclear factor erythroid derived 2 (Nrf-2) and inhibition of nuclear factor (NF)-kβ. Activation of NF-kβ promotes oxidative stress and is proinflammatory. The Nrf2 pathway is constitutively active and becomes upregulated in response to oxidative stress resulting in increased transcription of downstream gene targets. Synthetic triterpenoid bardoxolone methyl (CDDO-Methyl ester) is a potent inducer of the Nrf2/Keap1 pathway, which leads to Nrf2 translocation into the nucleus to upregulate antioxidant and cytoprotective genes. Bardoxolone methyl also has anti-inflammatory properties through its inhibition of the IKKβ/NF-kβ signaling pathway. Treatment with a bardoxolone methyl analog led to a reduction in glomerulosclerosis, interstitial fibrosis, and inflammation in rat models with CKD induced by 5/6 nephrectomy.
3.What Are New Avenues for Renal Protection, in Addition to RAAS Inhibition?
Shinji Hagiwara & Phillip Kantharidis & Mark E. Cooper. Curr Hypertens Rep (2012) 14:100–110
Bardoxolone methyl, an antioxidant inflammation modulator, activates the Keap1-Nrf2 pathway, which is involved in the downstream upregulation of multiple cytoprotective genes. In a phase 2, double-blind, randomized, placebo-controlled trial, 227 adults with CKD were assigned to receive placebo or bardoxolone methyl. Treatment with bardoxolone methyl for 52 weeks led to a sustained and significantly improved estimated glomerular filtration rate (GFR). The most frequent adverse events were muscle spasms, which were dose-related. Other adverse effects were hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects. Bardoxolone methyl therefore appears to be an attractive therapeutic candidate in patients with CKD; larger, longerterm clinical studies are warranted to better assess its clinical utility.
