CLINICAL CHARACTERISTICS

Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral kidney cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Kidney manifestations include early-onset hypertension, kidney pain, and kidney insufficiency. Approximately 50% of individuals with ADPKD have end-stage kidney disease (ESKD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD), most often in females. Overall, the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of kidney disease and other extra-kidney manifestations.

DIAGNOSIS/TESTING: The diagnosis of ADPKD is established in a proband with age-specific kidney imaging criteria and either an affected first-degree relative with ADPKD or a heterozygous pathogenic variant in , , or one of the less common associated genes (, , , , ) identified by molecular genetic testing.

MANAGEMENT

Treatment with vasopressin V2 receptor antagonists (e.g., tolvaptan) to slow disease progression is approved for individuals with rapidly progressive disease. Treatment for hypertension may include ACE inhibitors or angiotensin II receptor blockers and diet modification. Delayed onset of ESKD has been suggested with lipid control; low osmolar intake (e.g., moderate sodium and protein); increased hydration by moderate water intake; maintenance of sodium bicarbonate ≥22 mEq/L; moderation of dietary phosphorus intake; moderation of caloric intake; and low-impact exercise to maintain normal body mass index. Conservative treatment of flank pain includes nonopioid agents, tricyclic antidepressants, narcotic analgesics, and splanchnic nerve blockade. More aggressive treatments include cyst decompression with cyst aspiration and sclerosis, laparoscopic or surgical cyst fenestration, kidney denervation, and nephrectomy. Cyst hemorrhage and/or gross hematuria usually responds to bed rest, analgesics, and adequate hydration. Severe bleeding may require transfusion, segmental arterial embolization, or surgery. Treatment of nephrolithiasis is standard. Treatment of cyst infections is difficult, with a high failure rate. Therapeutic agents of choice include trimethoprim-sulfamethoxazole, fluoroquinolones, clindamycin, vancomycin, and metronidazole. ESKD is treated with dialysis and transplantation. Symptomatic liver cysts may improve with avoidance of estrogens and the use of H2 blockers or proton pump inhibitors. Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization. The mainstay of therapy for ruptured or symptomatic intracranial aneurysm is surgical clipping of the ruptured aneurysm at its neck; however, for some individuals, endovascular treatment with detachable platinum coils may be indicated. Thoracic aortic replacement is indicated when the aortic root diameter reaches 55-60 mm. CT or MRI examination of the abdomen with and without contrast enhancement every one to five years in adults depending on disease stage; blood pressure monitoring every three years beginning at age five years in those with normal blood pressure; urine studies for microalbuminuria or proteinuria every one to five years in adults depending on disease stage; echocardiography or chest MRI every two to three years in adults with a first-degree relative with thoracic aortic dissection; MRA examination for intracranial aneurysms in adults determined to be at high risk. Long-term administration of nephrotoxic agents, high levels of caffeine, high-salt diet, smoking, and obesity, and in individuals with severe PLD, use of estrogens and possibly progestogens. Testing of adult relatives at risk permits early diagnosis, initiation of treatment, and treatment of associated complications. Pregnant women with ADPKD should be monitored for the development of hypertension, urinary tract infections, oligohydramnios, and preeclampsia; the fetus should be monitored for intrauterine fetal growth restriction, oligohydramnios, and fetal kidney anomalies including cysts, enlarged size, and atypical echogenicity.

GENETIC COUNSELING

In most affected families, ADPKD is caused by a heterozygous or pathogenic variant and inherited in an autosomal dominant manner. More rarely, ADPKD is caused by a heterozygous pathogenic variant in , , , , or Complex inheritance (biallelic - or -related ADPKD or digenic ADPKD) may play a role in a minority of families and is important when considering the risk to other family members. Most individuals diagnosed with ADPKD have an affected parent; 10%-20% of affected individuals have the disorder as the result of a pathogenic variant. Each child of an individual who is heterozygous for an ADPKD-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the ADPKD-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.