Polycystic kidney disease

Polycystic kidney disease

How common is polycystic kidney disease?

Polycystic kidney disease (PKD) is a genetic disorder inherited as an autosomal dominant or recessive trait¹. Autosomal dominant PKD is one of the most common genetic disorders and the fourth leading cause of end-stage kidney disease (ESKD) in children and adults^2,3. The prevalence of autosomal dominant PKD has been reported to be between 1 in 400 and 1 in 1000 and it is predicted to affect more than 10 million people worldwide³. Autosomal recessive PKD is less common but more severe, and has an estimated prevalence of 1 in 20,000⁴.

What is the clinical course of polycystic kidney disease?

Autosomal dominant PKD is caused by mutations in the PKD1 or PKD2 genes, which encode the proteins polycystin (PC) 1 and PC2, respectively. It is generally thought to manifest in adulthood, but there is increasing awareness that the clinical course can also begin in childhood⁵. There is wide variation in the phenotype of ADPKD, ranging from asymptomatic to severely ill⁵. Autosomal recessive PKD is caused primarily by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene. It is typically identified in the late stages of pregnancy or at birth; 30–50% of affected neonates die soon after birth⁴. Both forms of PKD cause renal and extrarenal manifestations^3,5. In the kidneys, parenchymal destruction leads to ESKD, requiring dialysis or kidney transplantation in more than half of patients by the age of 60 years⁶.

What are unmet needs in polycystic kidney disease?

The disease process for autosomal dominant PKD is known to start in utero, but symptoms do not always manifest until later in life and, often, only when substantial kidney damage has occurred. Early diagnosis and treatment, while potentially beneficial, can also have adverse consequences, including psychological distress in asymptomatic children^5,7. There is an urgent unmet need for data on the natural history of both types of PKD and, for children at risk of autosomal dominant PKD, whether early diagnosis and treatment can alter the disease course⁷. There is also a need for disease-modifying treatments; at present, there is only one such agent available for treatment of autosomal dominant PKD, but this has not been approved for use in patients under the age of 18 years^5,7,8. There are no disease-modifying treatments for autosomal recessive PKD³.

How is polycystic kidney disease treated?

Treatment of polycystic kidney disease consists of lifestyle modifications to enhance hydration and limit sodium intake, pharmacological therapy to manage complications, and general supportive measures, such as counselling³. Antihypertensive agents have been the mainstay of treatment^3,7 as hypertension is one of the most common complications of PKD; 50–70% of people with autosomal dominant PKD⁹ and up to 80% of children with autosomal recessive PKD develop hypertension³. Blood pressure control improves cardiovascular outcomes but has little effect in slowing disease progression¹⁰.

What are the targeted treatments for polycystic kidney disease?

Identification of vasopressin as a key agent in the pathogenesis of PKD, through activation of vasopressin 2 receptors (V2R), has enabled the development of disease-modifying drugs that target cyst-forming pathways^3,10. Tolvaptan, a V2R antagonist, is the first disease-modifying drug to have been developed for the treatment of PKD. A phase 3 clinical trial showed that tolvaptan slowed the increase in total kidney volume (TKV) and the decline in kidney function in patients with autosomal dominant PKD over a period of three years¹¹. Tolvaptan has now been approved in several countries for treatment of autosomal dominant PKD in patients with rapidly progressing disease³.

References

1. Paul BM, Vanden Heuvel GB. Kidney – Polycystic Kidney Disease. Wiley Interdiscip Rev Dev Biol. 2014;3(6):465.
2. Suwabe T, Shukoor S, Chamberlain AM, Killian JM, King BF, Edwards M, et al. Epidemiology of autosomal dominant polycystic kidney disease in Olmsted county. Clin J Am Soc Nephrol. 2020;15(1):69–79.
3. Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE. Polycystic kidney disease. Nat Rev Dis Prim. 2018;4(1):1–58.
4. Bergmann C. Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses. Front Pediatr. 2018;5(February):1–13.
5. De Rechter S, Bammens B, Schaefer F, Liebau MC, Mekahli D. Unmet needs and challenges for follow-up and treatment of autosomal dominant polycystic kidney disease: the paediatric perspective. Clin Kidney J. 2018;11(Suppl 1):i14.
6. Chebib FT, Torres VE. Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am J Kidney Dis. 2016;67(5):792.
7. Janssens P, Jouret F, Bammens B, Liebau MC, Schaefer F, Dandurand A, et al. implications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial. doi:10.1038/s41598-020-61303-9.
8. Liebau MC, Mekahli D. Translational research approaches to study pediatric polycystic kidney disease. Mol Cell Pediatr. 2021;8(1). doi:10.1186/s40348-021-00131-x.
9. Nobakht N, Hanna RM, Al-Baghdadi M, Ameen KM, Arman F, Nobahkt E, et al. Advances in Autosomal Dominant Polycystic Kidney Disease: A Clinical Review. Kidney Med. 2020;2(2):196.
10. Torres VE. Pro: Tolvaptan delays the progression of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2019;34(1):30.
11. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2012;367:2407–2425.