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Autosomal dominant polycystic kidney disease
A rare, genetic, renal tubular disease characterized by progressive outgrowths of fluid-filled cysts from the renal epithelium, which can manifest with hematuria, urinary tract infections, hypertension, and abdominal or flank pain. The slowly progressive loss of kidney function may evolve to end stage kidney disease (ESKD).
ORPHA:730Classification level: Disorder
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, with estimated prevalence of 1/2,500 in Europe.
Symptoms typically manifests in adulthood; however, approximately 2-5% of cases present before 15 years of age. The renal phenotype ranges from patients in advanced age with preserved kidney function to rare cases of enlarged kidneys that are detected in utero. Clinical symptoms, including early-onset hypertension, abdominal fullness and pain, hematuria and urinary tract infections (UTIs), are usually observed decades before the onset of renal insufficiency. Renal insufficiency is slowly progressive leading to ESKD by 60 years of age in approximately half of patients. Up to a third of adult patients have nephrolithiasis. Extra-renal features often include polycystic liver disease, cardiovascular abnormalities (including left ventricular hypertrophy, aortic root dilatation, arterial aneurysms, heart valve abnormalities and intracranial aneurysms), bronchiectasis, seminal vesicle cysts, pancreatic cysts, and diverticulosis. Male infertility is also described.
Mutations in PKD1 (16p13.3) and PKD2 (4q22.1) account for approximately 78% and 15% of affected individuals, respectively. The remaining ~7% of cases are genetically unresolved or are due to mutations in other recently identified genes, such as GANAB (11q12.3), DNAJB11 and ALG9, involved in the maturation and trafficking of the polycystins.
Diagnosis is established by the presence of age-specific ultrasound criteria and an affected first-degree relative, or by genetic testing. Pre-symptomatic screening of ADPKD is not currently recommended for at-risk children. A positive family history is absent in 10-15% of patients. Where other causes of cystic disease have been excluded, a patient with bilaterally enlarged kidneys and innumerable cysts most likely has ADPKD.
The differential diagnosis for early onset ADPKD is autosomal recessive polycystic kidney disease, renal cysts and diabetes syndrome (HNF1B), tuberous sclerosis complex (TSC), the TSC2/PKD1 contiguous gene syndrome, von Hippel-Lindau syndrome, medullary sponge kidney, simple renal cysts and acquired cystic kidney disease.
Kidney cysts can be detected by prenatal ultrasound scans. Large hyperechogenic kidneys are also a possible early manifestation. Prenatal genetic testing may be possible in at risk families, where the mutation has been previously identified in a family member.
The pattern of inheritance is autosomal dominant. The risk of inheriting the disease from an affected individual is 50%. However, penetrance is incomplete and intra-familial phenotypes can vary in progression and severity. PKD1 mutations are associated with more severe disease, larger kidneys, earlier onset and earlier development of ESKD, than PKD2 mutations. GANAB mutations are associated with mild cystic disease, usually without decline in kidney function. Mutations arising de novo are possible.
Management and treatment
Early treatment and management of symptoms and complications, such as arterial hypertension is important. ACE inhibitors are the first choice for treatment of hypertension. For children with a family history of ADPKD, screening for hypertension from the age of 5 years onward is recommended. Tolvaptan, the vasopressin V2 receptor antagonist, has shown to reduce the rates of growth in total kidney volume and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. It is currently recommended for adult ADPKD with a rapid disease progression.
Prognosis depends on the age of disease onset and the disease severity. Approximately half of affected individuals develop ESKD by 60 years of age. Presence of proteinuria and arterial hypertension in affected children correlate with much more severe disease progression.