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
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.5 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
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