Polycystic Kidney Disease
GENERAL PRINCIPLES
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder resulting in cystic enlargement of the kidneys. The incidence is estimated to be 1 in 500 to 1000 live births.
Approximately 20% of patients with ADPKD do not have a positive family history. ADPKD currently accounts for up to 10% of patients with ESRD. There are two well-described mutations in the polycystin genes, PKD1 and PKD2 which encode for polycystin (PC) 1 and 2, respectively. PKD1 is more common, accounting for approximately 85% of ADPKD. PKD2 is associated with later progression of disease.
The mechanism by which cysts form is unclear; a proposed two-hit hypothesis implicates a second somatic mutation that inactivates the wild-type allele in individual cells. The polycystin gene products localize to the primary cilium of the apical membrane of tubular cells. Disordered cell division and aberrant planar cell polarity may lead to overgrowth of the tubular segment, eventually pinching off from the rest of the collecting system and forming discrete cysts. In abnormal cells, cyclic AMP imparts a proliferative phenotype as well as inducing chloride extrusion into the cyst lumen.
DIAGNOSIS
Clinical Presentation
Hypertension is an early feature of ADPKD and occurs even prior to a reduction in the GFR in approximately 60% of patients. As the affected tubules enlarge, they impinge on the blood flow to neighboring glomeruli, rendering them ischemic. This in turn leads to RAAS activation and systemic hypertension. Onset of kidney failure is highly variable, with half of patients reaching ESRD by the age of 60.
Kidney stones develop in approximately 25% of patients with ADPKD, with a higher proportion of uric acid composition as compared to the general population.
Cerebral aneurysms, hepatic cysts, mitral valve prolapse, and colonic diverticula are found in association with ADPKD.
As cysts enlarge, they may result in a palpable flank mass. Gross hematuria and pain may indicate cyst hemorrhage into the collecting system. Flank pain may also be caused by cyst infection or stretching of the renal capsule.Diagnostic Testing
Differentiation from other renal cystic diseases (acquired cystic kidney diseases, medullary sponge kidney, medullary cystic kidney disease, glomerulocystic kidney disease) can be made by the presence of enlarged cystic kidneys rather than shrunken or normal-sized cystic kidneys.
Ultrasonography reveals multiple cysts. In the setting of a positive family history, a diagnosis of ADPKD can be made from ultrasound findings, with criteria differing according to age. Three or more cysts (unilateral or bilateral) are required for diagnosis in patients between the ages of 15 and 39. From ages 40 to 59, two or more cysts in each kidney are required. From age 60 and older, more than four cysts in each kidney are required to make the diagnosis.
Patients with a family history of cerebral aneurysms or with symptoms attributable to a cerebral aneurysm should undergo evaluation with brain MRI/MRA; imaging can be performed without the use of gadolinium contrast.
Genetic testing may be considered if patients have equivocal imaging results or a definitive diagnosis is required.
TREATMENT
Treatment of hypertension consists of reduction in sodium intake and pharmacologic therapy when indicated. A large randomized controlled trial of patients with ADPKD suggested improved preservation of renal function at blood pressure targets of 95-110/60-75, but tolerability was limited by symptomatic hypotension.40 Thus, guidelines for blood pressure control in patients with ADPKD are similar to those in other patients with CKD, targeting a systolic pressure of 65 who were enrolled in the clinical trial did not show a benefit beyond that of placebo. Polyuria and polydipsia are frequently experienced by patients on this medication, and it may limit dose escalation to the goal of 90 mg in the morning and 30 mg in the afternoon.
Close monitoring of hepatic enzymes is mandatory, with measurements at baseline, at 2 weeks, 4 weeks, monthly through the first 18 months, then every 3 months afterward. Gross hematuria from cyst hemorrhage can usually be managed with bed rest, hydration, and analgesia. Resolution may take 5-7 days.
Cyst infections are generally treated with antibiotics that achieve good penetration into the cysts. Sulfamethoxazole-trimethoprim and ciprofloxacin are the antibiotics of choice. The absence of bacterial growth in the urine does not rule out infection as the cystic fluid does not necessarily communicate with the rest of the collecting system.
Pain that persists without an obvious hemorrhagic or infectious cause may respond to targeted cyst drainage or cyst reduction surgery. Drained cysts do tend to recur, limiting the long-term efficacy of this procedure.