Targeting Fibrosis Pathways in Alport Syndrome—Is it Too Late?

Alport syndrome is an inherited kidney disease that leads to dysfunction of the glomerular basement membrane (GBM) due to absence or malformation of the normal type IV collagen network. This leads to failure of the glomerular filtration barrier that manifests as microscopic hematuria followed by progressive proteinuria and CKD with kidney failure in many affected patients. There are currently no approved therapies for Alport syndrome, and the standard of care is treatment with nonspecific renin angiotensin aldosterone system (RAAS) blockade.¹ In animal models and retrospective registry studies of affected patients with Alport syndrome, treatment with RAAS blockade has significant benefits on kidney lifespan. However, most patients have progressive kidney disease despite RAAS blockade, and additional treatments are particularly needed.

In the March issue of Kidney360, Omachi and colleagues present a novel approach to slowing the progression of kidney disease in a mouse model of Alport syndrome using treatment with a peroxisome proliferator-activated receptor (PPAR) δ agonist.² Activation of PPAR δ is known to improve lipid metabolism and insulin sensitivity in mice.³ What is the rationale for using PPAR δ agonists to treat patients with a genetic defect in the basement membrane? Recently, the same group showed that treatment of a mouse model of Alport syndrome with metformin, which similarly affects metabolic dysregulation, improves proteinuria, kidney inflammation, and fibrosis.⁴ Targeting the inflammation and fibrosis signaling that occurs during progressive CKD is a reasonable approach to slowing progression in Alport syndrome and has been successful in animal models. In the newest study, the authors show that Col4a3^−/− mice treated with a PPAR δ agonist had less proteinuria and lower BUN at late stages of the disease compared with untreated mice with reduced fibrosis on pathologic evaluation and reductions in biomarkers associated with inflammation and fibrosis.² Unfortunately, a comparison with animals treated with RAAS inhibition was not reported, so it is unclear whether this treatment offers any benefit above the current standard of care.

There have been a number of attempts over the years to suppress inflammation and fibrosis in animal models and patients with Alport syndrome with mixed results. MicroRNA-21 is upregulated in Alport kidneys and contributes to stimulating fibrosis and inflammation pathways. Treatment with an anti–microRNA-21 agent slows the progression of CKD in mouse models of Alport syndrome with longer survival and improved clinical and pathologic features in treated animals.^5,6 Unfortunately, a clinical trial assessing the use of anti–microRNA-21 agents in humans with Alport syndrome (NCT02855268) was stopped early due to lack of efficacy. Despite the strong promise of this antifibrotic agent in animal models, it did not pan out in human disease. Discoidin domain receptor 1 inhibitors and osteopontin blocking agents are additional anti-inflammatory or antifibrotic drugs that show benefit in Alport mice but have not yet been trialed in humans. Animal models of Alport syndrome have turned out to be a robust model of progressive CKD in general in the laboratory and a convenient first animal model for testing novel agents for treatment of CKD.⁷ Whether the benefits of suppression of fibrosis and inflammation in animal models of Alport syndrome can be translated directly to humans with Alport syndrome remains to be seen.

Rather than focusing on suppressing the final common pathway in CKD of kidney fibrosis, the field of Alport syndrome research needs to pivot to focusing on the primary defect in the GBM and address those earliest signals that trigger dysfunction. In even the most severely affected boys with X-linked Alport syndrome due to nonsense mutations in COL4A5, the function of the GBM at birth and for the first few years of life is very normal despite complete absence of the alpha345 collagen IV network. They may leak a few red blood cells across the GBM, but the overall glomerular filtration rate is normal, and there is not any proteinuria. The key questions are as follows: How can we maintain this early state? What are the initial signals induced by the abnormal GBM early in the disease course and how can we block them so that fibrosis and inflammation are never triggered to begin with. In this study, looking at treatment of Col4a3^−/− mice with PPAR δ agonists, a benefit on proteinuria was not seen at the earliest stages examined (12 and 15 weeks) but was observed at later stages (17 weeks).² Treatment was started at age 6 weeks in the mice corresponding to roughly adolescence in humans. Why was the effect only seen late in the disease course? One could hypothesize that the fibrosis pathways targeted by the PPAR δ agonists were not active early in the Alport kidney disease time course and that the benefit was only at the late stages of disease. When thinking about how to apply antifibrotic agents to treatment of patients with Alport syndrome, we need to determine at which stage of disease a medication would be most beneficial. Treatment of children with antifibrotic agents for life, for example, with attendant risk of adverse effects, may not be the optimal approach. Perhaps these agents should be added later in the disease course. Well-designed clinical trials examining timing of initiation of antifibrotic agents are necessary before they can be considered as add-on therapy for all with Alport syndrome.

Until the Alport basement membrane can be directly repaired through gene editing or biochemical techniques, we will need to continue to work to find additional therapies for patients with this disease to add to RAAS inhibition. Omachi et al. provide solid evidence for one such approach of blocking fibrosis and inflammation; however, a number of questions remain about optimal timing of this approach for patients.

Disclosures

M.N. Rheault reports the following—consultancy: Otsuka; ownership interest: Microsoft and Protolabs; research funding: Chinook, Kaneka, Reata, River 3 Renal, Sanofi, and Travere; patents or royalties: Wolters Kluwer-Royalties for Textbook of Glomerulonephritis as editor; and advisory or leadership role: Alport Syndrome Foundation Medical Advisory Board, NephJC (501c3) Board of Directors, Peds Nephrology Research Consortium (501c3) Steering Committee, and Women In Nephrology (501c3), all unpaid.

Funding

None.

Author Contributions

Conceptualization: Michelle N. Rheault.

Writing – original draft: Michelle N. Rheault.