Bardoxolone Methyl for Alport Syndrome: Opportunities and Challenges

Alport syndrome, one of the most common genetic causes of kidney failure, is characterized by abnormalities in type IV collagen secondary to pathogenic variants in COL4A3, COL4A4, or COL4A5. Inheritance can be dominant (COL4A3 and COL4A4), with a 20% lifetime risk of kidney failure; recessive (COL4A3 and COL4A4), with a median age of kidney failure in teenage years; or X-linked (COL4A5), where XX females have a 25% lifetime risk of kidney failure and XY males have a median age at kidney failure of 25 years (1).

In fetal life, the collagen $\alpha 1\alpha 1\alpha 2\left(IV\right)$ heterotrimer is predominant in the developing glomerular basement membrane (GBM) until the capillary loop stage, when it is primarily replaced by the $\alpha 3\alpha 4\alpha 5\left(IV\right)$ collagen network. Without this $\alpha 3\alpha 4\alpha 5\left(IV\right)$ network, the $\alpha 1\alpha 1\alpha 2(IV$) collagen network persists, and children with Alport syndrome are born with normal kidney function. However, the GBM with a predominance of $\alpha 1\alpha 1\alpha 2\left(IV\right)$ collagen is less cross-linked, and thus more susceptible to proteolysis by matrix metalloproteases. Furthermore, the $\alpha 1\alpha 1\alpha 2\left(IV\right)$ GBM is more distensible, resulting in biomechanical strain, affecting adjacent endothelial cells and podocytes, inducing endothelin-1 expression in endothelial cells, and resulting in mesangial filopodial invasion of the GBM with deposition of aberrant laminins (2). Thus, children with pathogenic variants in COL4A3, COL4A4, or COL4A5 are born with normal kidney function and fragile GBMs, leading to the inexorable development of microscopic hematuria, and depending on the severity of the genotype, this is followed by proteinuria and finally progressive kidney failure. Alongside this, they may also exhibit high-frequency sensorineural hearing loss due to the dysfunction of the collagen IV heterotrimer in the cochlea and ocular findings, including perimacular flecks and anterior lenticonus (2).

The current mainstay of treatment for Alport syndrome is limited to pharmacological renin-angiotensin-aldosterone (RAAS) blockade with angiotensin-converting enzyme inhibitors, such as ramipril, and/or angiotensin II receptor antagonists, such as losartan, which current management recommendations advise be initiated at diagnosis for recessive disease, or for XY males with X-linked disease, and at the onset of proteinuria for all other groups (3). RAAS blockade has been demonstrated to be safe and effective in delaying progression of disease, and its efficacy is inversely related to the age at which it is started, that is, younger is better. However, for most patients with Alport syndrome, the lifetime risk of kidney failure is high, and those with recessive disease and X-linked males still face kidney failure in early adulthood (3).

Hard outcome studies are difficult in Alport syndrome because of the slow nature of progression; it takes a long time to reach end points of kidney failure or doubling of creatinine. Registry studies have been enormously helpful in demonstrating the effect of early initiation of RAAS inhibition, showing that in sibling pairs where the elder sibling started therapy later, the median age of kidney failure was 27 years in the elder and 40 years in the younger (1,2). Early recognition, accurate diagnosis, and prompt initiation of RAAS inhibition by pediatric nephrologists with control of proteinuria is key to slowing the progression of kidney disease. The EARLY PROTECT trial demonstrated that ramipril was safe in children with Alport syndrome from 2 years of age, and it appears to be effective in slowing progression of albuminuria (4).

Sparsentan, a dual-acting antagonist of endothelin type A and angiotensin II subtype 1, has been shown to reduce proteinuria in patients with FSGS and prolong lifespan in mice with Alport syndrome (5). Sodium-glucose cotransporter-2 inhibitors, which block glucose absorption in the proximal tubule and reduce glomerular pressure through glucose-induced osmotic diuresis and natriuresis, also hold promise. Small cohort studies have already demonstrated efficacy in children with Alport syndrome (6,7).

Following on from studies that showed patients with type 2 diabetes mellitus and CKD treated with bardoxolone methyl had a sustained reduction in serum creatinine (8), de Zeeuw et al. examined whether bardoxolone methyl decreased the risk of kidney failure or death from cardiovascular disease in patients with type 2 diabetes mellitus and stage 4 CKD (9). This trial showed no reduction in the risk of kidney failure, and a higher rate of cardiovascular events in the treatment arm led to early termination of the trial. Because the progression of Alport syndrome is accompanied by inflammatory changes in glomeruli and tubules, the use of an anti-inflammatory agent to prevent kidney disease progression seems logical. Bardoxolone methyl exerts its anti-inflammatory effect through suppression of NF-kB, activating transcription of antioxidant and anti-inflammatory genes. Bardoxolone methyl has also been shown to improve kidney function in multiple clinical studies with various kidney disease groups, including autosomal dominant polycystic kidney disease, without the same safety signal regarding heart failure as it did in the Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: The Occurrence of Renal Events trial, which led to the early termination (9).

In this randomized, double-blind, placebo-controlled trial, published in this issue of CJASN, Warady et al. (10) recruited 157 patients, aged between 12 and 70 years, whose Alport syndrome was defined by histopathology or genetic sequencing. Most patients had X-linked disease. The treatment group received bardoxolone methyl with the dose titrated for 8 weeks, followed by maintenance for 40 weeks, then 4 weeks washout, with a further 48 weeks of maintenance dose and a final 4 weeks of washout. The primary end point was a change from baseline in eGFR. This trial structure, including the washout periods, is important when interpreting the results of this trial.

CARDINAL showed a statistically significant preservation in mean eGFR in patients randomized to bardoxolone methyl, compared with placebo at 48 weeks. This statistical difference was also observed at 52 and 104 weeks, after the 4-week washout period. However, a post hoc analysis of the difference between treatment groups at week 104, using all available eGFR data, did not achieve statistical significance.

Serious adverse events occurred less frequently in the bardoxolone methyl group than in the placebo group; however, more patients discontinued treatment early due to an adverse event in the bardoxolone group compared with placebo (13% versus 5%), and a signal toward hepatotoxicity in the bardoxolone group, with almost all patients in the bardoxolone methyl group having alanine transaminase increases above normal range during the trial, which requires further evaluation.

Ultimately, the Food and Drug Administration has concluded that bardoxolone methyl does not have a favorable benefit-risk profile when evaluated for the treatment of patients with Alport syndrome, largely due to the number of patients who discontinued therapy due to increases in liver enzymes in the absence of overt liver injury (alanine transaminase 36/77, aspartate transaminase 19/77). Crucially, there were no differences in the incidence of kidney failure between treatment and placebo groups, with three patients in each group.

However, more interesting from a nephrology perspective is an examination of the serum creatinine during treatment in comparison with the urine albumin-creatinine ratio, because a decrease in serum creatinine was certainly seen in the bardoxolone methyl arm accompanied by an increase in the urine albumin-creatinine ratio during treatment, which reduced during the washout periods. This suggests that a decrease in serum creatinine may have been achieved through hyperfiltration at the glomerulus, which would be expected to increase the biomechanical strain on the fragile Alport GBM and exacerbate the decline in kidney function. An excellent perspective on this trial (11) was published by Lennon and Baigent before it started, which warned about this exact concern: “the possibility remains that some or all of the increase in eGFR and albuminuria results from raised intraglomerular pressure. If this is so, then bardoxolone may ultimately accelerate the decline in renal function.”

What can the practicing nephrologist gain from this trial? First, that bardoxolone is not a new therapy for Alport syndrome, and before this agent is assessed in a further population, its effect on glomerular hyperfiltration and hemodynamics should be examined. Second, that it is imperative that pediatricians and pediatric nephrologists consider Alport syndrome for all children with microscopic hematuria, because an early, accurate diagnosis with prompt initiation of ramipril where indicated remains the best chance these patients have to delay kidney failure well into adulthood.

Disclosures

C. Quinlan reports serving as a previous faculty member of NephSim, as an executive member of Nephrology Social Media Collective, and serving on the Blue Ribbon Panel of Nephmadness, the Education and Training committee of ANZSN, and the ASN Kidney Week scientific committee. She has received research funding from the Royal Children's Hospital Foundation and Melbourne Genomics. C. Quinlan’s partner reports employment with MYOB (Australian software company). K. Jayasinghe reports receiving research funding from Royal Australian College of Physicians Jacquot award, PhD Scholarship stipend, Melbourne Genomics, and Monash University PhD Scholarship stipend.

Funding

None.

Author Contributions

C. Quinlan conceptualized the study; K. Jayasinghe and C. Quinlan were responsible for the methodology; C. Quinlan was responsible for the resources; K. Jayasinghe and C. Quinlan wrote the original draft; and K. Jayasinghe and C. Quinlan reviewed and edited the manuscript.