At a glance

  • Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of chronic kidney disease.
  • Patients may present with flank or abdominal pain, cystitis secondary to UTI, hematuria and headaches.
  • There is no proven treatment available that will prevent or delay the progression of ADPKD.
  • About 50% of ADPKD patients will require a dialysis or a renal transplant by the age of 60 years.

Autosomal dominant polycystic kidney disease (ADPKD), also referred to as adult PKD, is the most common genetic cause of chronic renal disease.1 Among all hereditary diseases, ADPKD is 20 times more common than Huntington’s chorea, 15 times more common than cystic fibrosis, and 10 times more common than sickle cell disease.2 As research continues, the understanding of the mechanisms of the disease has led to an increase in clinical trials available to patients. Many of these trials show promise in preventing cyst formation, which is the underlying cause of renal failure attributable to ADPKD.

A comprehensive understanding of the disease process will enable providers to accurately diagnose and manage patients with this condition. While there is currently no approved cure for the disease,3 it is crucial for clinicians to update their knowledge on the topic as new information is discovered and new treatments are made available. It is the role of the primary-care provider to manage patients’ overall health and offer prompt treatment of complications as well as referral to a nephrologist when appropriate.

Prevalence and epidemiology

ADPKD has an estimated prevalence of one case in every 500 people, affecting approximately 600,000 Americans and as many as four to six million people worldwide.4 As the most common inherited disorder of the kidneys in humans, ADPKD afflicts approximately 10% of the patient population with end stage renal disease (ESRD).2

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ADPKD is considered a systemic disorder and results from mutations in either the PKD1 or PKD2 gene.5 The PKD1 gene is found on the short arm of chromosome 16, while the PKD2 gene is found on chromosome 4. The prevalence is 85%-90% having the PKD1 mutation, with the remaining 10%-15% having the PKD2 mutation.6

The PKD1 gene encodes for polcystin-1, a large receptor-like molecule. The PKD2 gene encodes for polycytin-2, which acts like an ion channel protein. Both polcystin-1 and 2 are transmembrane proteins that are present in all segments of nephrin, a protein necessary for proper function of the renal filtration barrier, and are involved with the slit diaphragm. It is not certain whether the proteins act together or independently to carry out their functions. They are thought to regulate epithelial cell gene transcription, differentiation, apoptosis, and cell matrix interactions. Improper functioning of these proteins leads to epithelial differentiation, uncontrolled proliferation, apoptosis, altered cell polarity, disorganized surrounding extracellular fluid, increased fluid sections, and the abnormal expression of several genes. Cyclic adenosine monophosphate levels increase and are thought to be secondary to vasopressin stimulation. This may lead to cystogenesis by causing an increase in cell proliferation and fluid secretion into the cyst through aquaporin channels and chloride channels.5 When cysts enlarge, they begin to compress adjacent parenchyma, causing ischemia and occluding normal tubules. This leads to progressive impairment of renal function.7

Patient presentation and history

The initial workup of a patient presenting with ADPKD should include a full history and physical exam. On physical exam, large kidneys may be a palpable sign, but most patients will present with one or more of the following signs and symptoms:6,7

Pain—Flank or abdominal pain secondary to mass effect, infection, bleeding into the cyst, and nephrolithiasis is common.

Chills and fever may accompany an infection.

Hematuria—Cystic ruptures into the renal pelvis may result in gross hematuria. Kidney stones and urinary tract infections (UTIs) can also cause gross hematuria. Gross hematuria should be closely monitored and should last no longer than seven days.

Nephrolithiasis—Kidney stones, most of which are composed of calcium oxalate, are prevalent in up to 20% of patients with PKD.

Hypertension—Almost all patients will develop hypertension during the course of the disease, with nearly half being hypertensive at the time of presentation. Activation of the renin-angiotensin-aldosterone system (RAAS) due to cyst-induced ischemia seems to be the cause.

Cerebral aneurysms—Arterial aneurysms within the circle of Willis (circulus arteriosus cerebri) occur in about 10%-15% of patients with PKD and can be a source of headaches.

Blood-vessel abnormalities—Mitral valve prolapse, aortic aneurysms, and aortic valve abnormalities

Colonic diverticulitis with left-lower-quadrant pain

Ophthalmic exam may reveal arteriovenous nicking and papilledema (optic disc swelling secondary to elevated intracranial pressure).

ESRD signs and symptoms in late stage of disease—Malaise, cardiac arrhythmias, hypertension, anemia, fatigue, edema, and tetany.

ADPKD workup

In the initial workup of an individual with ADPKD, special attention should be given to the family history, social history, and medical history as well as to the genitourinary, GI, and cardiac/vascular portions of the physical exam. Pertinent family history findings include first-degree relatives with ADPKD or ESRD, stroke, intracranial aneurysms, heart-valve disorders, and colonic diverticulitis. The patient may present with flank or abdominal pain, hematuria, cystitis secondary to UTI, and headaches. Physical findings may include palpable kidneys and/or hepatomegaly. Hypertension is often the first detectable abnormality, but the patient may also have symptoms of renal insufficiency. Be alert for hernia-repair scars in the inguinal or umbilical regions. A cardiac murmur may also be noted during the cardiac exam.

Once family history or exam findings have raised suspicion of ADPKD, laboratory studies (comprehensive metabolic profile, urinalysis [UA], fasting lipid panel, complete blood count, and possibly a parathyroid hormone level) and imaging studies should follow.

Creatinine is used to calculate the glomerular filtration rate (GFR), which allows for staging of the disease. The staging of renal failure is as follows:

Stage 1 – GFR >90 mL/min/1.73 m2

Stage 2 – GFR 60-90

Stage 3 – GFR 30-60

Stage 4 – GFR 15-30

Stage 5 – GFR<15

Pertinent findings on UA include microalbuminuria and hematuria—both of which may indicate renal dysfunction—and leukocyturia, which may signify a UTI.

The most common initial imaging study for suspected PKD is an abdominal ultrasound, which is cost-effective and safe for the patient. The Ravine criteria are used as a standard when interpreting ultrasound results for the diagnosis of ADPKD.8 These criteria are based on the patient’s age, family history, and number of cysts (Table 1).

Sonographic diagnostic criteria for patients at 50% risk for ADPKD include at least two unilateral or bilateral cysts in people younger than age 30 years; two cysts in each kidney in patients aged 30-59 years; and four cysts in each kidney in patients older than age 60 years. Sensitivity of these criteria is nearly 100% for patients aged 30 years or older and for younger patients with PKD1 mutations but only 67% for patients younger than age 30 years with PKD2 mutations. Therefore, CT scan or MRI should be used in this group. In a child at 50% risk for ADPKD, large echogenic kidneys (without distinct macroscopic cysts) are diagnostic.9