ADPKD Overview

  • Autosomal dominant polycystic kidney disease (ADPKD) is an inherited condition that causes fluid-filled cysts to develop in the kidneys and other organs.1
  • ADPKD is a progressive disease that leads to kidney failure, in 50 percent of patients by the age of 50, and up to 75% of patients reach kidney failure by the age of 70.2,3
  • ADPKD is the most common inherited cause of kidney failure and the fourth leading cause of kidney failure in the US.1,4 ADPKD affects over 400,000 people in the US1, with an estimated 140,000 patients diagnosed with ADPKD.5
  • ADPKD is caused by mutations in either the PKD1 or PKD2 genes, which encode for proteins called polycystin-1 and polycystin-2, respectively.3
  • As in other forms of CKD, chronic inflammation and mitochondrial dysfunction play important roles in the pathophysiology and progression of ADPKD.3,6,7
  • Reata is conducting FALCON, a pivotal Phase 3 study of bardoxolone methyl for the treatment of ADPKD.


Polycystic kidney disease affects people of all races and genders, and is the fourth leading cause of kidney failure, accounting for 5% of all cases of kidney failure.1

ADPKD is caused by mutations in the PKD1 and PKD2 genes in 85% and 15% of patients, respectively.  Both types of ADPKD can lead to kidney failure, but patients with mutations in PKD1 generally progress to kidney failureKIDNEY FAILURE at an earlier age.8  While PKD1 and PKD2 mutations are recognized as the primary underlying genetic drivers of ADPKD, downstream drivers such as inflammation, mitochondrial dysfunction, impaired fatty acid oxidation, and increased oxidative stress are all critical to the pathogenesis of the disease.3,6,7

Current approaches to treating ADPKD include monitoring, use of blood pressure-lowering therapies, and JYNARQUE™ (tolvaptan), a selective vasopressin V2-receptor antagonist.9  Despite these treatment options, ADPKD patients generally continue to lose kidney function and progress towards KIDNEY FAILUREkidney failure while on standard of care therapy, highlighting the significant unmet need for additional therapies in ADPKD.10

Diagnosis and Prognosis

The National Kidney Foundation reports that more than 400,000 patients are affected with ADPKD in the US1. A recent publication reports that an estimated 140,000 of these patients are currently diagnosed with the disease.Early and accurate diagnosis is critical since timely management has the potential to improve life expectancy.3

ADPKD is typically diagnosed by identifying cysts on the kidneys by ultrasound, CT, or MRI, as well as by the appearance of hepatic cysts, hypertension, urologic symptoms, and cardiovascular disease.11  Genetic testing can also be used to diagnose patients or to confirm the diagnosis in patients or families with suspected complex genetic underpinning, or to diagnose de novo onset cases.8

The clinical course of ADPKD is highly variable, and in most cases progression to  kidney failure occurs between the 4th and 6th decades, although severe disease may occur in children.12

In adults with ADPKD, several risk factors for faster progression have been identified, including PKD1 gene mutation, male gender, young age at diagnosis, presence of hypertension, hematuria, proteinuria, and young age at onset of hypertension.12

Once kidney insufficiency has begun, the average yearly rate of decline in glomerular filtration rate for patients with ADPKD is ~3-4 mL/min/1.73 m2.10,14  Approximately 50% of patients with ADPKD reach  kidney failure and kidney failure by the age of 50, and up to 75% of patients reach  kidney failure by the age of 70.2,3

What Causes ADPKD?

ADPKD is a multi-organ disorder resulting primarily from mutations in PKD1 and PKD2 genes that affects the liver, as well as the kidneys. Clusters of fluid-filled cysts in the kidneys and other organs cause progressive enlargement and loss of organ function.  As cysts grow and expand, healthy renal tissue is remodeled through increased oxidative stress, recruitment of inflammatory cells, and accumulation of extracellular matrix.3,15

Growth of the cysts in the kidney lead to chronic kidney inflammation as well as changes in cellular metabolism that resemble pathways found in cancer, such as increased glucose consumption (a Warburg-like effect) and decreased oxidative phosphorylation and fatty acid oxidation.  Additionally there is evidence of mitochondrial dysfunction, including swollen mitochondria, deformed cristae, reduced mitochondrial DNA (mtDNA) copy number, increased mtDNA mutation rate, and impaired mitochondrial biogenesis.3,6

  1. National Kidney Foundation. Polycystic Kidney Disease Accessed 20/5/2020.
  2. What is ADPKD? Polycystic Kidney Disease Foundation. Accessed 27/5/2020.
  3. Bergmann C, Guay-Woodford LM, Harris PC, et al. Polycystic kidney disease. Nat Rev Dis Primers. 4:50. 2018.
  4. United States Renal Data System. 2018 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2018.
  5. Willey C, Kamat S, Stellhorn R, Blais J. Analysis of Nationwide Data to Determine the Incidence and Diagnosed Prevalence of Autosomal Dominant Polycystic Kidney Disease in the USA: 2013–2015. Kidney Dis (Basel). 5(2):107‐117. 2019.
  6. Podrini C, Cassina L, Boletta A. Metabolic Reprogramming and the Role of Mitochondria in Polycystic Kidney Disease. Cell Signal. 68:109495. 2020.
  7. Kahveci AS, Barnatan TT, Kahveci A, et al. Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease. Int J Mol Sci. 21(6):1994. 2020.
  8. Song X, Haghighi A, Iliuta IA, Pei Y. Molecular diagnosis of autosomal dominant polycystic kidney disease. Expert Rev Mol Diagn. 17(10):885-895. 2017.
  9. Testa F, Magistroni R. ADPKD Current Management and Ongoing Trials. J Nephrol. 33(2):223-237. 2020.
  10. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 377:1930-1942. 2017.
  11. Alves M, Fonseca T, de Almeida E.A.F. Differential Diagnosis of Autosomal Dominant Polycystic Kidney Disease. Chapter 1 in Polycystic Kidney Disease. Codon Publications. Brisbane, QLD 4122, Australia. 2015.
  12. Helal I, Reed B, Schrier RW. Emergent Early Markers of Renal Progression in Autosomal-Dominant Polycystic Kidney Disease Patients: Implications for Prevention and Treatment. Am J Nephrol. 36(2):162-7. 2012.
  13. Rastogi A, Ameen KM, Al-Baghdadi M, et al. Autosomal Dominant Polycystic Kidney Disease: Updated Perspectives. Ther Clin Risk Manag. 15:1041-1052. 2019.
  14. Klawitter J, Reed-Gitomer BY, McFann K, et al. Endothelial dysfunction and oxidative stress in polycystic kidney disease. Am J Physiol Renal Physiol. 307(11):F1198-206. 2014.
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