Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease, affecting approximately 1 in 1000 individuals worldwide. This accounts for up to 10% of all cases of end-stage renal disease (ESRD). “Autosomal dominant” means that both males and females are affected equally, and that a person only needs to inherit one non-working copy of an ADPKD gene to develop symptoms. However, the age of onset, rate of progression and other symptoms can vary, even within a family. While the diagnosis can often be made by ultrasound, genetic testing provides additional useful information for providers and patients. Genetic testing for ADPKD has made significant improvements over the past decade, resulting in less expense testing options, and better detection rates.
Classic ADPKD is typically caused by variants, or mutations, in one of two genes: PKD1 or PKD2. The PKD1 gene, located on chromosome 16, is the most common cause of ADPKD, accounting for roughly three-quarters of cases. Most of the remaining cases are caused by changes in the PKD2 gene, located on chromosome 4. Certain PKD1 variants tend to be associated with more severe disease, with an average age of progression to ESRD of 58 years. In contrast, the PKD2 gene is associated with comparatively milder disease and an average age of ESRD of 79 years. Up to 11% of cases with clinical symptoms of ADPKD do not have identifiable changes in either of these genes, meaning that there are additional genes and/or mechanisms causing this disease in a significant proportion of patients with cystic kidneys.
Other Cystic Kidney Genes
Other, much less common, genes have been identified that may present with clinical symptoms similar to PKD1/2-related ADPKD. For example, the GANAB and DNAJB11 genes together account for less than 1% of ADPKD. However, both genes are associated with milder disease, and less risk of ESRD. Autosomal dominant polycystic liver disease (ADPLD) can result from changes in several different genes, and the kidney cysts may be minimal and non-progressive. Despite the discovery of these genes, and better understanding of their mechanisms, at least 7% of people with ADPKD have no identifiable genetic cause for their condition. It is evident that there is still much to uncover about the genetics of this disease, and how this information could impact management.
Utility of Genetic Diagnosis
Understanding which gene is causing cystic kidney disease has several benefits. It can confirm the clinical diagnosis and provide specific genetic information as to the cause. Especially in cases where there is no family history (~10-25% of ADPKD), it is important to understand the underlying genetic cause to confirm the correct diagnosis and genes. This helps the healthcare provider and the patient understand the typical disease course and allows for identification of other at-risk relatives. This is also critical in cases where living related organ donation is being considered. A young relative may not show clinical symptoms yet or have unspecific features. Genetic testing can definitively determine if the genetic cause for ADPKD was inherited in a prospective donor, regardless of their current health status.
Genetic testing also allows for other family members who are at risk to decide if they would like to have testing performed prior to any symptoms developing. While there is no cure for ADPKD, lifestyle changes to promote overall kidney health are important. If an individual is of reproductive age and they know the variant that caused their ADPKD, they have the option of undergoing pre-implantation genetic testing (PGT) to avoid having a child with this condition. PGT involves testing embryos from a couple where one member has ADPKD for the disease-causing variant. Only embryos that did not inherit this variant are used for subsequent in-vitro fertilization (IVF). While this option is not for everyone, uptake of PGT has increased over time for a number of genetic conditions, including ADPKD.
ADPKD may be associated with non-kidney issues, including brain and abdominal aneurysms, heart valve defects, hernias and urinary tract infections. Knowledge of the underlying genetic cause for cystic kidney disease can provide guidance on the necessity of referrals to other specialists.
Genetic testing may also be useful, or even required, for some clinical trial enrollment. Many clinical trials aim to improve the management of ADPKD to slow disease progression, or even ultimately find a cure.
Genetic testing to confirm or diagnose ADPKD has many benefits to both the healthcare provider and the patient. As we continue to learn more about the genetics of cystic kidney disease, new opportunities for personalized medicine and therapeutics will arise.