Renoprotection and the Bardoxolone Methyl Story - Is This the Right Way Forward A Novel View of Renoprotection in CKD Trials: A New Classification Scheme for Renoprotective Agents

Abstract

In the June 2011 issue of the New England Journal of Medicine, the BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial investigators rekindled new interest and also some controversy regarding the concept of renoprotection and the role of renoprotective agents, when they reported significant increases in the mean estimated glomerular filtration rate (eGFR) in diabetic chronic kidney disease (CKD) patients with an eGFR of 20-45 ml/min/1.73 m² of body surface area at enrollment who received the trial drug bardoxolone methyl versus placebo. Unfortunately, subsequent phase IIIb trials failed to show that the drug is a safe alternative renoprotective agent. Current renoprotection paradigms depend wholly and entirely on angiotensin blockade; however, these agents [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)] have proved to be imperfect renoprotective agents. In this review, we examine the mechanistic limitations of the various previous randomized controlled trials on CKD renoprotection, including the paucity of veritable, elaborate and systematic assessment methods for the documentation and reporting of individual patient-level, drug-related adverse events. We review the evidence base for the presence of putative, multiple independent and unrelated pathogenetic mechanisms that drive (diabetic and non-diabetic) CKD progression. Furthermore, we examine the validity, or lack thereof, of the hyped notion that the blockade of a single molecule (angiotensin II), which can only antagonize the angiotensin cascade, would veritably successfully, consistently and unfailingly deliver adequate and qualitative renoprotection results in (diabetic and non-diabetic) CKD patients. We clearly posit that there is this overarching impetus to arrive at the inference that multiple, disparately diverse and independent pathways, including any veritable combination of the mechanisms that we examine in this review, and many more others yet to be identified, do concurrently and asymmetrically contribute to CKD initiation and propagation to end-stage renal disease (ESRD) in our CKD patients. We conclude that current knowledge of CKD initiation and progression to ESRD, the natural history of CKD and the impacts of acute kidney injury on this continuum remain in their infancy and call for more research. Finally, we suggest a new classification scheme for renoprotective agents: (1) the single-pathway blockers that block a single putative pathogenetic pathway involved in CKD progression, as typified by ACE inhibitors and/or ARBs, and (2) the multiple-pathway blockers that are able to block or antagonize the effects of multiple pathogenetic pathways through their ability to simultaneously block, downstream, the effects of several pathways or mechanisms of CKD to ESRD progression and could therefore concurrently interfere with several unrelated upstream pathways or mechanisms. We surmise that maybe the ideal and truly renoprotective agent, clearly a multiple-pathway block...

Bardoxolone methyl prevents fat deposition and inflammation in the visceral fat of mice fed a high-fat diet

“…Both preclinical and clinical studies have shown that BARD has antioxidant and anti-inflammatory effects in treating chronic kidney disease and cancer [42][43][44]. A treatment study has also shown an anti-diabetic effect of BARD in type 2 diabetes mouse models [35].…”

Four-Year Report on Renal Outcomes Following Elective Withdrawal of Long-Term RAAS Blockade in a Cohort of Patients with Otherwise Inexplicable New-Onset and Progressive Acute Kidney Injury

“…The original Vermont cohort consisted of 71 patients, 69 Caucasians, 1 African American and 1 Hispanic, 42:29 (M:F), mean age 69.4 (37-95) years [24,25]. Medical co-morbidities included diabetes mellitus (37) and hypertension (66). At the time of initial entry into this cohort study, they were mostly asymptomatic.…”

“…In 2013, in a comprehensive review of the RAAS blockade reno-protection RCTs and the evidence-base resulting therefrom, we had perceived and speculated that current reno-protection strategies with RAAS blockers, alone, were not the "magic bullet" nor were they perfect solutions to the problem [37]. We had highlighted the limitations of the RAAS blockade RCTs vis a viz reno-protection.…”

“…We had highlighted the limitations of the RAAS blockade RCTs vis a viz reno-protection. There was the absence of elaborate and systematic assessment methods of the reporting of individual patient-level adverse drug events in the RCTs [37]. Furthermore, we had emphasized the preponderance of the literature that supported the existence of other multiple and independent putative pathogenetic mechanisms that drive both diabetic and no-diabetic CKD progression [37].…”

“…There was the absence of elaborate and systematic assessment methods of the reporting of individual patient-level adverse drug events in the RCTs [37]. Furthermore, we had emphasized the preponderance of the literature that supported the existence of other multiple and independent putative pathogenetic mechanisms that drive both diabetic and no-diabetic CKD progression [37]. Our conclusion therefore was that the notion that the blockage of a single molecule, angiotensin II, would represent the cure all magic bullet for reno-protection, was most likely untenable, and that indeed such a claim represented an overreach [37].…”