Even with the same germline mutation in a family with this inherited disease, the severity of ADPKD among family members is quite variable; this is true even in the case of twins.9,10,20 Since the age and symptoms at presentation can vary so greatly, a uniform method of identifying patients with ADPKD, along with staging, was needed. Most patients do not undergo genetic testing (ie, DNA linkage or gene-based direct sequencing9) for a diagnosis of ADPKD or to differentiate between the PKD 1 and PKD 2 disease forms unless they are participating in a research study. Diagnostic criteria were needed that were applicable for any type of ADPKD.
In 2009, the University of Toronto’s Division of Nephrology convened experts in the fields of nephrology and radiology to reach a consensus on standardized ultrasonographic diagnostic criteria.21 They formulated definitions based on a study of 948 individuals who were at risk for either PKD 1 or PKD 2 (see Table 221). The specificity and sensitivity of the resulting criteria range from 82% to 100%, making it possible to standardize the care and classification of renal patients worldwide.
Since family members with the same genotypes can experience very divergent disease manifestations, the two-hit hypothesis has been developed.22 In simple terms, it proposes that after the germline mutation (PKD1 or PKD2), there is a second somatic mutation that leads to progressive cyst formation; when the number and size of cysts increase, the patient starts to experience symptoms of ADPKD.22
Age at presentation can be quite variable, as can the presenting symptoms. Most patients with PKD 1 present in their 50s, with 54 being the average age in US patients.14 The most common presenting symptom is flank or back pain.2,5 The pain is due to the massive enlargement of the kidneys, causing a stretching of the kidney capsule and leading to a chronic, dull and persistent pain in the low back. Severe pain, sharp and cutting, occurs when one of the cysts hemorrhages; to some patients, the pain resembles a quick, powerful “kick in the back.” Hematuria can occur following cyst hemorrhage; depending on the location of the cyst that burst within the kidney (ie, how close it is to the collecting system) and how large it is, the amount and color of the hematuria can be impressive.
ADPKD is more common in men than women, and cyst rupture can be precipitated by trauma or lifting heavy objects. Cyst hemorrhage can turn the urine bright red, which is especially frightening to the male patient. Hematuria is often the key presenting symptom in patients who will be diagnosed with ADPKD-induced hypertension.
Besides hematuria, other common manifestations of ADPKD include:
• Hypertension (60% of affected patients, which increases to 100% by the time ESRD develops)
• Extrarenal cysts (100% of affected patients)
• Urinary tract infections
• Nephrolithiasis (20% of affected patients)
• Proteinuria, occasionally (18% of affected patients).2,5,23
Among these manifestations, those most commonly attributed to a diagnosis of ADPKD are hypertension, kidney stones, and urinary tract or kidney infections. Since isolated proteinuria is unusual in patients with ADPKD, it is recommended that another cause of kidney disease be explored in patients with this presentation.24
Extrarenal manifestations of cyst development are common, eventually occurring in all patients as they age. Hepatic cysts are universal in patients with ADPKD by age 30, although hepatic function is preserved. There may be a mild elevation in the alkaline phosphatase level in patients with ADPKD, resulting from the presence of hepatic cysts. Cysts may also be found in the pancreas, spleen, thyroid, and epididymis.5,25 Some patients may complain of dyspnea, pain, early satiety, or lower extremity edema as a result of enlarged cyst.
The Case Patient
Because you recently attended a lecture about ADPKD, you are aware that flank pain in men with hypertension is indicative of ADPKD until proven otherwise. Believing that this patient’s hypertension is renal in origin, you order an abdominal ultrasound. You also order a comprehensive metabolic panel and a complete blood count. The patient’s GFR is measured at 89 mL/min (indicative of stage 2 kidney disease). Other results are shown in Table 3.
The very broad differential includes essential hypertension, hypertension resulting from intake of “power drinks” or salt in an athlete, illicit use of medications (including steroids), herniated disc leading to transient hypertension, and urinary tract infection or sexually transmitted disease. All of this is moot when the ultrasound shows both kidneys measuring greater than 15 cm, with four distinct cysts on the right kidney and three distinct cysts on the left.