Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening genetic disorder.1 It affects 1 in 500 people, yet less than half of cases are diagnosed.2,3
The majority of patients with ADPKD eventually develop renal failure.4 ADPKD is the cause of end-stage renal disease (ESRD) in approximately 5% of patients who start dialysis each year.1 Given the prevalence and prognosis of ADPKD, primary care providers must be well informed about it.
"Mr. R" is a 51-year-old man from Mexico with a history of type 2 diabetes and hypertension. He presents to his primary care provider to investigate an onset of gross hematuria. Mr. R reports no flank pain, dysuria, nausea, vomiting or fever. Family history is negative for hypertension, cancer and renal/hepatic disease. The patient reports that his mother died suddenly before age 70 of "old age." His father is 80 years old and has no known medical problems. The patient has no siblings and is not in close contact with his extended family.
Mr. R's medications are lisinopril 10 mg daily, hydrochlorothiazide 12.5 mg daily and metformin 500 mg twice a day.
The physical examination reveals no costovertebral angle tenderness. Vital signs are within normal limits. The patient is afebrile. A dipstick urinalysis reveals microscopic hematuria and trace protein, but it is otherwise unremarkable.
The provider orders a urine culture and prescribes trimethroprim-sulfamethoxazole twice a day for 10 days to treat the presumed urinary tract infection (UTI). The urine culture is negative, the hematuria resolves, and the patient doesn't seek further follow-up.
Two years later, the patient is seen in an emergency department for evaluation of abdominal pain. An abdominal ultrasound study reveals bilateral spherical polycystic kidneys: four cysts on the left kidney and five on the right kidney.
The initial signs and of symptoms of ADPKD predate a notable rise in serum creatinine by many years. Patients with ADPKD who develop renal failure usually initiate dialysis between the fifth and seventh decade of life.5 Cysts are generally apparent on ultrasound by the time a patient is in the third decade of life. This means that 2 decades or more may lapse between the time diagnosis could be made and the time when fulminant renal failure develops. For the majority of this time, most patients are solely under the care of a primary care provider. Because early diagnosis and treatment can improve outcomes, it is imperative that primary care providers be alert to signs and symptoms of ADPKD, and that they screen appropriately and refer promptly.
The most commonly reported symptoms of ADPKD are flank pain, abdominal pain and gross hematuria.1 These symptoms are most often due to renal calculi, enlarged renal size, UTI or renal hemorrhage. Renal calculi and UTI are more common in patients with ADPKD than in the general population.6 Early signs include hypertension, microhematuria and renal concentrating defect. At later stages of the disease, enlarged cystic kidneys may be palpable on physical exam and serum creatinine will begin to rise.
Diagnosis of ADPKD is based on the presence of renal cysts identified through diagnostic imaging. Ultrasound is the standard firstline study. Diagnostic criteria based on ultrasound findings are well established and have high levels of sensitivity and specificity (see table).
To facilitate early diagnosis, the primary care provider must be astute in patient assessment and alert for harbingers of ADPKD. The case study illustrates that although a family history always exists due to the familial nature of the disease, the patient may not be aware of the presence of ADPKD in the family. Therefore, a family history of ADPKD but cannot be relied upon to cue the provider to include ADPKD in the differential diagnosis list. Patients presenting with any of the constellation of symptoms associated with ADPKD should prompt a provider to consider screening for the disease.
Current treatments for polycystic kidney disease focus on preventing or slowing the progression of comorbid illness. No specific treatment targets the underlying disease pathology,7 but benefits are derived from controlling blood pressure, moderating sodium intake, quitting smoking and reducing cardiovascular risk profile. The majority of patients with ADPKD die as a result of cardiovascular disease, underscoring the vital importance of tight blood pressure control, regular exercise, healthy diet, smoking cessation and healthy weight.
Angiotensin-converting enzyme (ACE) inhibitors should be used preferentially for blood pressure control because patients with ADPKD have increased activity of the renin-angiotensin system and therefore generally respond well to this class of medications. Patients with ADPKD are at risk for cerebral hemorrhage and diverticulitis, so they should be advised to monitor for and report symptoms.
ADPKD is classified in two distinct genetic mutations, PKD 1 and PDK 2. PKD 1 is responsible for 85% of ADPKD cases and is associated with a more rapid progression of cyst development and earlier onset of ESRD.8 Genetic testing may be used in rare cases for early diagnosis or to differentiate between the phenotypes.
As noted, the majority of patients diagnosed with ADPKD eventually develop kidney failure. Some studies suggest that the use of MRI at periodic intervals to assess rapidity of cyst growth has predictive value in terms of rapidity of disease progression.
This finding has not had a significant impact because MRI is costly and accurate prediction of disease progression has no impact on treatment.
A number of factors have been identified as predictors of more rapid disease progression: poorly controlled hypertension, younger age at time of diagnosis, male gender, hepatic cysts in women, proteinuria and recurrent gross hematuria. Generally, renal function is preserved until the fourth decade of life, after which the average rate of decline in epidermal growth factor receptor is 4.4 mL/min to 5.9 mL/min per year.9
The development of cysts in patients with ADPKD occurs through physiologic pathways that are not well defined. In vitro studies suggest that dysregulation of cyclic adenosine monophosphate (cAMP), anti-diuretic hormone (ADH), the renin-angiotensin system (RAS) and the mammalian target of rapamycin signaling pathway (mTOR) all play a role.
Therapies for ADPKD have focused primarily on disrupting the physiologic pathways thought to be responsible for pathologic cell proliferation: increased water consumption (for ADH suppression), vasopressin receptor antagonists, sirolimus (mTOR inhibitor) and ACE inhibitor/angiotensin receptor blocker therapy for RAS suppression. Somatostatin has been trialed with the intent of reducing fluid accumulation in renal and hepatic cysts.
Many of these therapies appear promising, but none has demonstrated the standard of evidence required to recommend it for clinical use.7
Back to Mr. R
Mr. R's blood pressure was slightly elevated in the emergency department, at 142/84 mm Hg. Blood testing included a renal panel, which determined a calculated glomerular filtration rate of 80 mL/min/1.73 m2. The provider explained to Mr. R the importance of adhering to ACE inhibitor therapy and provided introductory education about ADPKD. The provider instructed Mr. R to make an appointment with his primary care provider to further discuss treatment of ADPKD. The provider also told Mr. R to avoid nonsteroidal anti-inflammatory and sulfa-based medications because they could affect his renal function.
Click to view larger graphic.
According to the National Institute for Health and Care Excellence, patients with chronic kidney disease (i.e., ADPKD) must meet specific criteria to necessitate referral. These criteria include stage of disease process, proteinuria levels, declining GFR, uncontrolled hypertension, genetic causes, and possible renal artery stenosis. In Mr. R's case, further diagnostic testing is needed to determine referral status.10
1. Torres VE, et al. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287-1301.
2. PCKD Foundation. Learn about ARPKD. http://www.pkdcure.org/learn/arpkd
3. Davies F, et al. Polycystic kidney disease re-evaluated: a population-based study. Q J Med. 1991;79(290):477-485.
4. Patel V, et al. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens. 2009;18(2):99-106.
5. Hateboer N, et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 study group. Lancet. 1999;353(9147):103-107.
6. Gabow PA, et al. Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int. 1992;41(5):1311-1319.
7. Chapman AB, et al. Course and treatment of autosomal polycystic kidney disease. Available with subscription at uptodate.com
8. Pei Y. Diagnostic approach to autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2006;1(5):1108-1114.
9. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76(2):149-168.
10. National Collaborating Centre for Chronic Conditions. Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care. London: Royal College of Physicians, September 2008.
Alexis Chettiar is a nurse practitioner at East Bay Nephrology Medical Group in Oakland, Calif. Laura Jennings is a student in the Drexel University-Hahnemann physician assistant program in Philadelphia, Pa., and is scheduled to graduate in December 2014. They have completed disclosure statements and report no relationships related to this article.