Polycystic Kidney Disease, Autosomal Dominant

Clinical characteristics Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal 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. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). 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 renal disease and other extrarenal manifestations even within the same family. Diagnosis/testing The diagnosis of ADPKD is established in a proband with age-specific renal imaging criteria and an affected first-degree relative with ADPKD or identification of a heterozygous pathogenic variant in PKD1, PKD2, GANAB, or DNAJB11. Management Treatment of manifestations: Vasopressin V2 receptor antagonists (e.g., tolvaptan) to slow disease progression. Treatment for hypertension may include ACE inhibitors or angiotensin II receptor blockers and diet modification. 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, renal denervation, and nephrectomy. Cyst hemorrhage and/or gross hematuria is usually self-limiting. Treatment of nephrolithiasis is standard. Treatment of cyst infections is difficult, with a high failure rate. Therapeutic agents of choice may include trimethoprim-sulfamethoxazole, fluoroquinolones, clindamycin, vancomycin, and metronidazole. The diagnosis of malignancy requires a high index of suspicion. Therapeutic interventions aimed at slowing the progression of ESRD in ADPKD include control of hypertension and hyperlipidemia, dietary protein restriction, control of acidosis, and prevention of hyperphosphatemia. Most individuals with PLD have no symptoms and require no treatment, but rare severe cases may require surgical resection or even liver transplantation. 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 exceeds established size. Prevention of secondary manifestations (lifestyle and therapeutic factors that may modulate disease): Maintain appropriate blood pressure and urine osmolarity; low osmolar intake (e.g., moderate sodium and protein); increase hydration by moderate water intake; maintain sodium bicarbonate ≥22 mEq/L; moderate dietary phosphorus intake; moderate caloric intake to maintain normal BMI; low-impact exercise; lipid control; tolvaptan therapy. Surveillance: Early blood pressure monitoring starting in childhood; MRI screening for intracranial aneurysms in those determined to be at high risk; screening echocardiography in those with a heart murmur and those with a family history of a first-degree relative with a thoracic aortic dissection. Agents/circumstances to avoid: Long-term administration of nephrotoxic agents, high levels of caffeine, use of estrogens and possibly progestogens by individuals with severe PLD, smoking, and obesity. Evaluation of relatives at risk: Testing of adult relatives at risk permits early detection and treatment of complications and associated disorders. Pregnancy management: 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 ADPKD is inherited in an autosomal dominant manner. About 95% of individuals with ADPKD have an affected parent, but at least 10% of families can be traced to a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ADPKD are possible.