Chronic Kidney Disease

kidney

Chronic Kidney Disease (CKD)

CKD is characterized by a progressive worsening in the rate at which the kidney filters waste products from the blood, called the glomerular filtration rate (GFR). Fibrosis arising from chronic inflammation and resulting loss of kidney function eventually leads to end-stage kidney disease (ESKD) requiring dialysis or transplantation.

Declining kidney function leads to the buildup of high levels of waste products in the blood that cause the patient to suffer symptoms, such as nausea and fatigue, and to develop complications including high blood pressure, anemia, weak bones, poor nutritional health, and nerve damage.

We believe that by promoting the Nrf2-dependent resolution of inflammation and rescue of mitochondrial dysfunction, bardoxolone methyl addresses a final common pathway of kidney function loss triggered by a variety of insults and improves kidney function by increasing the effective glomerular filtration surface area, reducing inflammation, and preventing fibrosis.

In a recent study of CKD, Nrf2 was identified as a central link between metabolic and inflammatory pathways that affect estimated GFR (eGFR) (1). This study included biopsies from 157 patients representing nine different types of CKD, including thin basement membrane nephropathy, IgA nephropathy, diabetes, focal segmental glomerulosclerosis, hypertension, lupus, and others. Most patients with thin basement membrane nephropathy are now considered to have Alport syndrome. These data highlight the importance of Nrf2 across diverse CKD etiologies.

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Alport Syndrome

Alport syndrome is a rare, genetic form of CKD caused by mutations in the genes encoding type IV collagen, which is a major structural component of the glomerular basement membrane in the kidney. The kidneys of patients with Alport syndrome progressively lose the capacity to filter waste products out of the blood, which can lead to ESKD and the need for chronic dialysis treatment or a kidney transplant. Strategies are needed to target pathogenesis earlier before conversion to ESKD.

The Alport Syndrome Foundation estimates that Alport syndrome affects approximately 30,000 to 60,000 people in the United States. Alport syndrome affects both children and adults and can manifest as early as the first decade of life and causes average annual declines in eGFR of approximately -5.1 mL/min/1.73 m2. In patients with the most severe forms of the disease, approximately 50% progress to dialysis by age 25, 90% by age 40, and nearly 100% by age 60.

There are currently no approved therapies to treat CKD caused by Alport syndrome.

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is a rare and serious hereditary form of CKD caused by a genetic defect in PKD1 or PKD2 genes leading to the formation of fluid-filled cysts in the kidneys and other organs (2). Cyst growth can cause the kidneys to expand up to five to seven times their normal volume, leading to pain and progressive loss of kidney function. Inflammation appears to play a role in cyst growth and is associated with disease progression in ADPKD (3-5).

ADPKD affects both men and women of all racial and ethnic groups and is the leading inheritable cause of kidney failure with an estimated diagnosed population of 140,000 patients and an estimated prevalent population of 400,000 patients in the United States. Despite current standard-of-care treatment, an estimated 50% of ADPKD patients progress to ESKD and require dialysis or a kidney transplant by 60 years of age (6-9).

In ADPKD, inflammation and mitochondrial dysfunction, processes known to be suppressed by Nrf2 activation, drive cyst growth in the kidney tubules (3-5, 10, 11). We have shown in preclinical cellular models that in primary and immortalized ADPKD cyst-derived cells, bardoxolone methyl induces expression of Nrf2 target genes, reduces levels of MCP-1 (marker of inflammation), increases total cellular glutathione levels, reduces ROS levels, and improves mitochondrial function. Bardoxolone methyl also reduces cyst formation in a cell-based cystogenesis model. These results suggest that activation of Nrf2 by bardoxolone methyl may have the potential to improve the molecular features that are hallmarks of ADPKD.

References

  1. Martini, S., Nair, V., Keller, B. J., Eichinger, F., Hawkins, J. J., Randolph, A., Böger, C. A., Gadegbeku, C. A., Fox, C. S., Cohen, C. D., and Kretzler, M. (2014) Integrative biology identifies shared transcriptional networks in CKD. J Am Soc Nephrol 25, 2559-2572
  2. Bergmann, C., Guay-Woodford, L. M., Harris, P. C., Horie, S., Peters, D. J. M., and Torres, V. E. (2018) Polycystic kidney disease. Nat Rev Dis Primers 4, 50
  3. Karihaloo, A. (2015) Role of Inflammation in Polycystic Kidney Disease. In Polycystic Kidney Disease (Li, X., ed), Codon Publications. Copyright: The Authors., Brisbane (AU)
  4. Song, C. J., Zimmerman, K. A., Henke, S. J., and Yoder, B. K. (2017) Inflammation and Fibrosis in Polycystic Kidney Disease. Results Probl Cell Differ 60, 323-344
  5. Ta, M. H., Harris, D. C., and Rangan, G. K. (2013) Role of interstitial inflammation in the pathogenesis of polycystic kidney disease. Nephrology (Carlton) 18, 317-330
  6. Spithoven, E. M., Kramer, A., Meijer, E., Orskov, B., Wanner, C., Caskey, F., Collart, F., Finne, P., Fogarty, D. G., Groothoff, J. W., Hoitsma, A., Nogier, M. B., Postorino, M., Ravani, P., Zurriaga, O., Jager, K. J., and Gansevoort, R. T. (2014) Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease. Kidney Int 86, 1244-1252
  7. Shaw, C., Simms, R. J., Pitcher, D., and Sandford, R. (2014) Epidemiology of patients in England and Wales with autosomal dominant polycystic kidney disease and end-stage renal failure. Nephrol Dial Transplant 29, 1910-1918
  8. Reule, S., Sexton, D. J., Solid, C. A., Chen, S. C., Collins, A. J., and Foley, R. N. (2014) ESRD from autosomal dominant polycystic kidney disease in the United States, 2001-2010. Am J Kidney Dis 64, 592-599
  9. Budhram, B., Akbari, A., Brown, P., Biyani, M., Knoll, G., Zimmerman, D., Edwards, C., McCormick, B., Bugeja, A., and Sood, M. M. (2018) End-Stage Kidney Disease in Patients With Autosomal Dominant Polycystic Kidney Disease: A 12-Year Study Based on the Canadian Organ Replacement Registry. Can J Kidney Health Dis 5, 2054358118778568
  10. Podrini, C., Cassina, L., and Boletta, A. (2020) Metabolic reprogramming and the role of mitochondria in polycystic kidney disease. Cell Signal 67, 109495
  11. Nowak, K. L., and Hopp, K. (2020) Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease. Clinical Journal of the American Society of Nephrology 15, 577

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