Adult polycystic kidney disease management
Cysts (yellow) have replacd the majority of kidney tissue in this patient with PKD.
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.
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
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.
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
Extrarenal findings may include hepatic and pancreatic cysts. If the results of the ultrasound are inconclusive, CT or MRI may be beneficial, as these imaging studies are more sensitive than ultrasound for detecting cysts. MRI may also be used to diagnose intracranial aneurysms if patients have headaches or a family history of stroke. Optional procedures include barium enema to diagnose diverticuli and an echocardiography to evaluate for valvular abnormalities.10,11
Genetic testing can be with a 95% accuracy of diagnosis: (1) when imaging results are equivocal or inconclusive; (2) to confirm a presumed diagnosis in the absence of family history of ADPKD (conclusive diagnosis in these patients relies on mutation analysis); and (3) when a definite diagnosis is required in a younger patient (e.g., a potential living related kidney donor).11
No proven treatment available will prevent or delay the progression of ADPKD. Treatment options are mostly supportive and preventive with the goal of slowing the progression of renal failure, managing complications, and prolonging life.11 Some promising trials are under way for new medications that may slow the rate of cyst formation, but the results will not be known for several years.
The targeted complications to be considered include:
Lifestyle changes. Diet modification should include protein restriction, lowered salt intake, decreased caffeine intake, and increased daily water intake. One study in progress is designed to determine the effects of increased water intake in amounts greater than three liters per day.12 The increased water intake is suspected to suppress vasopressin, which is thought to play a role in cyst formation. Patients who consume such large volumes of water are at heightened risk for hyponatremia, so sodium levels should be monitored regularly.10,13
Hypertension. Tight control of BP is thought to delay or prevent progression of the disease. Increased BP is considered attributable to an activation of the RAAS, so blockage of this system is the focus of treatment. Although no guidelines have been set for ADPKD, most clinicians agree to follow the recommendation from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure of a BP <130/90 mm Hg. Studies are under way to determine whether even lower BP levels are beneficial. ACE inhibitors are considered first-line treatment followed by angiotensin II receptor blockers (ARBs) and direct renin inhibitors. Patients taking ACE inhibitors must have their creatinine and potassium monitored routinely for increased levels. Alternate treatment options include calcium channel blockers, beta blockers, and/or diuretics.8,11,13
UTIs. Increased frequency of UTIs is correlated with poorer outcomes in patients with PKD. Patient education and prompt treatment is crucial. Complications of UTI include obstruction and migration of infection to include the kidney, which can be devastating. Treatment can be started empirically with an antibiotic, but a specimen should be sent for culture and sensitivity so that proper therapy can be provided.8,11,13
Hyperlipidemia. Because elevated lipid levels have a coronary heart disease risk equivalent in patients with PKD, aggressive treatment should be implemented as needed. Statins are the first treatment option for lowering LDL and raising HDL. Statins may help preserve renal function, but this has not been proven.8,11,13
Pain. Pain can be caused by compression associated with enlarged kidneys, renal infections, cyst rupture, kidney stones, and even renal tumors. Most sources are self-limiting and can be controlled with rest and either acetaminophen, nonsteroidal anti-inflammatory drugs, or opioid analgesics. Treatment options for enlarged cysts include aspiration, sclerotic injections, or laparoscopic/surgical cyst fenestration.8,11,13
Nephrolithiasis. There are several ways to manage renal stones. For small stones, pain management with conservative observation may be indicated. Potassium citrate is indicated for three types of stones seen in ADPKD: (1) uric acid stones; (2) hypocitraturic calcium oxalate nephrolithiasis; and (3) distal acidification defects.11 For stones that do not spontaneously pass, urology referral is indicated. At this point, lithotripsy, percutaneous nephrolithotomy, and retrograde retrieval of stones are viable treatment options.8,11,13
Extrarenal complications. Intracranial aneurysms should be managed by a neurologist. Clipping or coiling are options for aneurysms >8 mm. Monitor heart-valve disorders with echocardiography, which can be used to assess the severity of need for valve-replacement surgery.8,11,13
Renal failure. A patient progressing into Stage 4 of renal failure should prepare for kidney replacement. Renal transplant is the treatment of choice. Look within the family for possible donors, and place the patient on the donor waiting list. Dialysis is a second-line option for a patient on the donor waiting list or a candidate suitable for replacement. Access for dialysis may be through a vascular site, including a catheter, graft, or fistula. Another viable option is peritoneal dialysis.8,11,13
Medications under trial. Several trials are examining treatments for ADPKD. The more promising include the vasopressin receptor antagonist tolvaptan, the somatostatin inhibitor octreotide, the kinase inhibitor everolimus, epidermal growth factor receptor inhibitors, tyrosine kinase, Src kinase, roscovitine, and ACE inhibitor/ARB antagonist combinations.8,11,13 For more information of ongoing clinical trials, visit ClinicalTrials.gov.
Approximately 50% of ADPKD patients will develop ESRD and require either a renal transplant or dialysis by age 60 years. The major factor for prognosis is the form of gene mutation present in the patient. Although the two forms of ADPKD (ADPKD1 and 2) share similar clinical features, renal prognosis is vastly different. Studies show that ADPKD2 is a milder disease, based on the age of onset of ESRD. The median age of renal survival for those with this form of ADPKD is 68 years. For those with ADPKD1, the median age of renal survival is 53 years.6
Other factors that can improve outcomes are tight control of BP, adherence to dietary recommendations, and prevention/prompt treatment of UTIs.5,6
The understanding of ADPKD has improved over the past decade. A comprehensive approach to caring for people with this disease that includes early detection, management of symptoms, and referral to a nephrologist when appropriate is imperative.
Mr. Moon is a second-year student in the physician assistant program at the Medical College of Georgia in Augusta, where Dr. Gunder is assistant professor and director of research and faculty development, and Ms. Steele is assistant professor.
2. Ross JE. Diseases of the kidney. In: AK David, DM Phillips, JE Scherger, TA Johnson, eds. Family Medicine: Principles and Practice, 6th ed. New York: Springer-Verlag New York, Inc.; 2003:838.
3. Patel V, Chowdhury R, Igarashi P. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens. 2009;18:99-106.
4. Gunder LM, Martin SA. Essentials of Medical Genetics for Health Professionals. Sudbury, Mass.: Jones & Bartlett Learning; 2011:155.
5. Salant DJ, Patel PS. Polycystic kidney disease and other inherited tubular disorders. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison's Principles of Internal Medicine. 17th ed. New York, N.Y.: The McGraw-Hill Companies; 2008:1797-1805.
6. Watnick S, Morrison G. Cystic diseases of the kidney. In: McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York, N.Y.: McGraw-Hill; 2010:846-848.
7. Mcaninch JW. Adult polycystic kidney disease. In: Tanagho EA, McAninch JW, eds. Smith's GeneralUrology. 17th ed. Columbus, Ohio: McGraw-Hill;2008:507-512.
9. Ravine D, Gibson RN, Walker RG, et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. 1994;343:824-827.
All electronic documents accessed May 15, 2011.