Autosomal dominant polycystic kidney disease is one of the most commonly inherited diseases in the United States. It affects nearly 500,000 Americans and accounts for 5 to 10 percent of patients with end-stage renal disease. Diagnosis is usually made in middle age, when complications such as hypertension, pain and hematuria develop. Renal complications include hypertension, cyst infection and hemorrhage, hematuria and flank pain. Other manifestations and related conditions include polycystic liver disease, cerebral aneurysm, cardiac valve abnormalities and diverticulosis. The severity and course of the disease vary in individual patients. Management involves the control of hypertension and treatment of complications. Genetic counseling is important. Dialysis and renal transplantation often are successful treatments in patients who develop renal failure.
Autosomal dominant polycystic kidney disease (ADPKD) affects nearly 500,000 Americans,(1) making it the most common monogenic inherited disease in the United States.(2) It occurs in approximately one in 500 to 1,000 individuals.(3) It 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.(1) ADPKD accounts for 5 to 10 percent of patients with end-stage renal disease.(3)
The definition of ADPKD depends on the age of the individual being screened.(4), (5) In adults, diagnosis requires documentation of three or more renal cysts, with bilateral involvement of renal parenchyma.(3) In children who are at risk, the presence of at least two unilateral or bilateral renal cysts is indicative of the disease.(5) Although the initial defect is in the kidneys, involvement of the liver, colon, heart and cerebral vasculature is common. Other organs, such as the pancreas and spleen, occasionally may be involved.
The autosomal dominant inhertitance of PKD was identified in 1957, but it was not until 1985 that a causative gene was identified.(1) Approximately 95 percent of all cases in whites are linked to ADPKD1 on the short arm of chromosome 16. A second gene has recently been identified on chromosome 4. Offspring of affected persons have a 50 percent chance of acquiring the disease, making reproductive counseling an important issue.(6) Prenatal diagnosis is possible by DNA analysis of tissue obtained by amniocentesis or chorionic villus sampling.(1) Cases of ADPKD detected in utero have been reported.(4)
The severity of the disease varies among affected individuals.(1) Symptoms generally occur in the fourth or fifth decade.(6) Pain in the flank or abdomen is a frequent presenting complaint, occurring in about 60 percent of patients.(1) The pain is believed to be due to the large size of the kidneys and cysts. The pain may be chronic or acute. Pain of sudden onset may be secondary to hemorrhage of a cyst, infection or calculus.
In 35 percent of patients, hematuria is the presenting complaint. Either gross or microscopic hematuria eventually occurs in 50 percent of patients.(1) Many patients simply present with hypertension.
Cysts begin to develop in the kidneys during fetal life, although they are usually undetectable at birth.(7) The cysts may develop at any site along the nephron and collecting duct.(8) Cysts may vary in size from a few millimeters to several centimeters in diameter.(1) Figure 1 shows renal cysts demonstrated by sonogram.
Although unproved, compression and displacement of renal parenchyma by cysts may contribute to the loss of renal function, which occurs in 50 percent of patients.(9) Renal concentrating ability may be mildly impaired at an early age, particularly in children with many renal cysts bilaterally. This mechanism is believed to reflect the cystic disruption of the tubules.(10)
Complications and Management
Hypertension. Hypertension is the most frequent renal complication of ADPKD.(1) It affects 30 percent of children, 60 percent of adults with normal renal function and 80 percent of patients with end-stage renal disease.(1) The etiology of hypertension in patients with ADPKD is currently unknown. Activation of the renin-angiotensin-aldosterone system may be related to larger kidneys and larger cysts.(1)
Hypertension appears to be the major factor in the acceleration of renal failure(1). Control of hypertension may alter the outcome of the disease.(2) A reasonable treatment choice for hypertension in patients with ADPKD is an angiotensin-converting enzyme (ACE) inhibitor.(7) These agents effectively block the enhanced reninangiotensin-aldosterone system that occurs in patients with ADPKD.(3) ACE inhibitors dilate the efferent arterioles, reducing glomerular capillary pressure and injury. Careful monitoring of renal function is important with use of these drugs, especially if they are used in combination with diuretics, since acute renal failure may occur in certain patients with renal impairment. Diuretics may be effective in control of blood pressure, especially when combined with a low-salt diet but may predispose to the development of gout and have an unfavorable metabolic profile.(11) Calcium channel blockers may be equally effective alone or in combination with ACE inhibitors. These agents dilate afferent arterioles.(7)
Hematuria. Gross or microscopic hematuria is a common symptom of ADPKD and is related to kidney size and hypertension.(6) Gross hematuria is due to rupture of renal cysts.(11) Frequent episodes of gross hematuria may have a negative effect on renal function.(6) The hematuria generally resolves with hydration, bed rest and correction of coagulopathies, if present. Persistent hematuria needs further evaluation.(3)
Proteinuria. Mild proteinuria is common, occurring in about one-third of patients with ADPKD. It is not, however, indicative of the degree of cystic involvement and is not necessarily an early finding. Excretion of more than 1 g of protein a day may indicate underlying glomerular disease.(1)
Flank Pain and Abdominal Pain. The pain of ADPKD can be difficult to manage. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution in patients with impaired renal function. Most episodes of acute pain can be managed conservatively with several days of bed rest and use of analgesics.(6) Investigation of a urinary tract infection or calculus is appropriate.(1)
If chronic debilitating pain is present, the cysts may be decompressed with percutaneous needle aspiration and drainage. Alcohol sclerosis will generally prevent the reaccumulation of fluid. If fluid reaccumulates, open cyst-reduction surgery may be indicated. Renal function is not impaired following either procedure.(12)
Urinary Tract Infections. Infections of the urinary system occur with with increased frequency in patients with ADPKD. Such infections generally are the result of ascending gram-negative organisms and can be treated with conventional antibiotics based on sensitivity.(6) Infection often follows lower tract instrumentation performed without prophylactic antibiotics.(2) Urinary tract infection in men appear to worsen the course of renal disease.(1)
Infection of the parenchymal renal cysts can be difficult to diagnose, since bacteriuria may not be present.(2) Treatment of cyst infection requires a lipid-soluble antimicrobial, such as trimethoprim-sulfamethoxazole (Bactrim, Septra, Trimpex), chloramphenicol (Chloromycetin) or ciprofloxacin (Cipro), which penetrate the cyst wall.(6) If the infected renal cysts can be identified by imaging, aspiration and drainage of the cysts should be considered in patients who remain febrile despite receiving a lipophilic agent.(3)
End-Stage Renal Disease. End-stage renal disease occurs by the age of 60 years in approximately 45 percent of patients with ADPKD.(1) Patients with the ADPKD1 gene develop renal failure at an earlier age than patients with the ADPKD2 gene. Table 1 lists risk factors for end-stage renal disease in patients with ADPKD. Blacks develop end-stage renal disease nearly 10 years earlier than whites, and those with sickle cell trait have an even earlier onset.
The disease tends to have a more aggressive course in men than in women.(1) The median age when renal failure occurs in men is approximately 52.5 years, compared with approximately 58.0 years in women.(13) Renal transplantation often is successful in patients with ADPKD.(2)
Renal Calculi. Kidney stones, usually calcium oxalate or uric acid, occur in approximately 20 percent of patients with ADPKD. Stone disease is a significant cause of morbidity in these patients. Due to the distorted anatomy of the polycystic kidney, diagnosis of renal calculi may be difficult. Computed tomographic (CT) scanning is most sensitive in detecting small stones as well as differentiating stones from other conditions such as tumors or calcifications of the cyst wall.
Risk Factors for End-Stage Renal
Disease in Patients with ADPKD
Early age at diagnosis
Increased left ventricular mass
Large renal volume
Three or more pregnancies
Urinary tract infections in men
Sickle cell trait
ADPKD = autosomal dominant polycystic kidney disease. Derived from reference 4.
The majority of stones are located in the papillary tips and calices. Both metabolic factors and urinary stasis play a role in the formation of renal calculi. The frequencies of hyperuricosuria, hyperoxaluria and hypercalciuria in patients with ADPKD are no different from those found in other patients with nephrolithiasis in the general population. Low levels of urinary citrate, a substance protective against formation of renal stones, are observed more frequently. The treatment of renal stones in patients with ADPKD is the same as that for any patient with nephrolithiasis, although the use of lithotripsy and nephrostolithotomy carries even more safety concerns in patients with ADPKD.(14)
Renal Cell Carcinoma. Some evidence shows an increased rate of renal cell carcinoma in patients with chronic renal failure.(3) However, there is no evidence to support an increased rate of renal cell carcinoma in patients with ADPKD.(10)
The pathogenesis of intracranial aneurysm in patients with ADPKD is unknown but is most likely congenital or developmental. Although hypertension may be a related factor, not all patients with cerebral aneurysms are hypertensive.(15) The frequency of aneurysm in patients with ADPKD is generally reported to be between 5 and 10 percent. Most aneurysms occur in the middle cerebral artery, with fewer in the internal carotid artery than occur in the general population.(15)
Although the frequency of aneurysm rupture in patients with ADPKD appears to be equal to that of patients without the disease,(16) rupture tends to occur at an earlier age in patients with ADPKD.(17)
Most patients with intracranial aneurysms do not have a family history of aneurysm, but those with a family history are at increased risk. Since the development of aneurysm is familial, a family history is the major criterion for screening for intracranial aneurysms in patients with ADPKD. Patients with neurologic symptoms are also considered at high risk and should be screened. High-resolution CT and magnetic resonance imaging (MRI) are adequate screening procedures for larger intracranial aneurysms.(16) Magnetic resonance angiography, where available, has become the procedure of choice to detect smaller aneurysms.(18) High-risk patients should be screened at five-year intervals if no aneurysm is found. Surgical guidelines are the same as for the general population.
Both cerebral infarction and hypertensive hemorrhage also occur in patients with ADPKD, perhaps with greater frequency than ruptured intracranial aneurysm.(17)
Adult polycystic liver disease occurs in 34 to 78 percent of patients with ADPKD. It consists of gradual cyst development in both lobes of the liver, as shown in Figure 2. Cysts may range in size from microscopic to those containing liters of fluid causing enlargement of the liver. Despite massive cyst formation, hepatic parenchymal volume is preserved.(19)
Hepatic cysts generally develop with increasing age and declining renal function. Although uncommon in patients younger than 16 years of age, cysts are found in 30 percent of 40-year-old patients and in 77 percent of patients over age 60.(6)
Some studies cite the development of hepatic cysts to be two to four times more common in women than in men(19); other studies report an equal prevalence in men and women.(6) Women tend to have more extensive polycystic liver disease.(6) The prevalence and severity of liver disease also correlates with the number of pregnancies and the use of exogenous hormones.(16)
Liver function studies remain normal in most patients regardless of age, but symptoms of liver dysfunction occur most commonly between 40 and 60 years of age. Hepatic complications occur in 5 to 10 percent of patients. This number is believed to be increasing due to the large number of patients surviving renal disease due to dialysis or renal transplantation. Common symptoms include abdominal swelling, pain (particularly with stooping) and dyspnea. Major complications are hemorrhage into a cyst and cyst infection. Carcinoma is rare. Diagnosis is made by ultrasonography or CT scan of the liver.(19)
Treatment of symptomatic cyst disease with simple cyst aspiration nearly always results in recurrence. Sclerosis of cysts with alcohol has shown some promise in preventing recurrence and infection, but long-term results are not available. For severe disease, combined hepatic resection and cyst fenestration may be considered when there is relative preservation of two or more adjacent liver segments.(19)
Cardiac valvular abnormalities are more prevalent in patients with ADPKD than in the general population. Mitral valve prolapse occurs in 26 percent of patients, compared with 2 percent of the general population. The aortic valve may also be involved. Nonexertional chest pain and palpitations are common symptoms.(1)
Colonic diverticuli are not only more common in patients with ADPKD than in the general population, but patients are more likely to have a serious complication such as colonic perforation.(1) This is especially true in patients who require renal dialysis.(6)
Polycythemia has been reported in patients with ADPKD, although it is rare. Patients generally maintain higher hematocrit levels than other patients with endstage renal disease,(10) which is probably due to higher levels of erythropoietin.(1)
Cysts may develop in other organs, including the pancreas, spleen, ovary and central nervous system.(1)
All types of dialysis treatment generally are successful in patients with ADPKD. Factors such as lifestyle, age, concomitant illness and family support help determine whether hemodialysis or peritoneal dialysis is appropriate.(20) Patients who undergo dialysis show increasing renal cystic changes, while those who undergo transplantation actually show stabilization or regression of renal cysts.(3)
Renal transplantation is successful in most patients with ADPKD. A variety of factors influence the success of transplantation. Depending on the quality of the match between the donor and recipient, there is an 80 to 90 percent chance that the transplanted kidney will continue to function normally one year after transplantation. Renal function may remain normal for 10 years or more after transplantation.(21)
Patients must be screened for suitability based on the presence of other system abnormalities, such as severe cardiac dysfunction. Screening for diverticular disease, with resection of involved segments, has also been recommended but is not widely accepted. Generally, the polycystic kidneys are left in place with transplantation. Indications for removal include a history of recurrent infections, significant hematuria, pain or massively obstructing kidney size.(11)
A number of research efforts are being directed for the treatment of ADPKD. Three factors appear important in the cystogenesis of this disorder: epithelial cell proliferation, altered secretion and abnormal extracellular matrix.(1) Preliminary studies on autosomal-recessive mice show slowed progression of renal disease with administration of either epithelial growth factor or paclitaxel (Taxol), an agent used for the treatment of some types of malignant neoplasms. Methylprednisolone (Medrol) also has shown preliminary success in reducing the severity of the disease in animals by reducing inflammation and interstitial fibrosis.(8) Further studies may one day produce effective methods to alter the course of ADPKD.
Implications for Patients and Family
Screening family members of affected patients could be advantageous in finding a kidney donor if the relative does not have ADPKD. If ADPKD is found, early diagnosis may enhance control of blood pressure and early screening for other complications of the disease, such as cerebral aneurysm.(2) As clinical advances are made regarding ADPKD, early diagnosis may become more beneficial.
Knowledge of the disease may, however, increase worry about its outcome.(2) Some patients have difficulty coping with an incurable illness. Many patients report adverse social and psychologic changes after diagnosis, particularly after presymptomatic testing.(22) The issues of pain and possible early disability or death may be especially difficult for patients and their family members.(13) Insurance and financial concerns must also be considered. Patients with the diagnosis are at risk for loss of employment, increased insurance premiums or uninsurability.(22) A few lifestyle considerations are appropriate, such as avoidance of strenuous exercise and contact sports, which increase the chance of kidney damage.
Family planning is a vital issue for patients with ADPKD. The issue is complicated by the fact that the variance in the severity of the disease among affected persons is unknown.(2) Gene penetrance is believed to be 100 percent, with all carriers (on average, 50 percent of offspring) developing some degree of symptoms of the disease. The type, number and degree of symptoms, as well as the age at which they develop, are highly variable.(22)
Among affected patients and persons who are at risk, the possibility of passing the gene on to children is a primary concern. Concern for health problems is secondary in both groups. Affected individuals note concern about emotional, family and work stress related to the disease, as well as financial obligations. Despite these concerns, few patients would alter reproductive plans as a result of the disease.(23) Additionally, few patients utilizing prenatal diagnosis would definitely terminate a pregnancy because of ADPKD. The individual's experience with the disease and the severity of ADPKD in the family have not been shown to influence the choice of prenatal determination or pregnancy termination.(23)
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(2) Lieske JC, Toback FG. Autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1993;3:1442-50.
(3) Anderson GA, Degroot D, Lawson RK. Polycystic renal disease. Urology 1993;42:358-64.
(4) Fick GM, Duley IT, Johnson AM, Strain JD, Manco-Johnson ML, Gabow PA. The spectrum of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 1994;4:1654-60.
(5) Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P. Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease. Lancet 1994;343:824-7.
(6) Fick GM, Gabow PA. Natural history of autosomal dominant polycystic kidney disease. Ann Rev Med 1994;45:23-9.
(7) Florijn KW, van Saase JL, Breuning MH, Chang PC. Autosomal-dominant polycystic kidney disease and hypertension: a review. Contrib Nephrol 1992;97:71-92.
(8) Grantham JJ. Pathogenesis of renal cyst expansion: opportunities for therapy. Am J Kidney Dis 1994;23:210-8.
(9) Grantham JJ. Polycystic kidney disease: hereditary and acquired. Adv Intern Med 1993;38:409-20.
(10) Gabow PA, Bennett WM. Renal manifestations: complication management and long-term outcome of autosomal dominant polycystic kidney disease. Semin Nephrol 1991;11:643-52.
(11) Bennett WM, Elzinga LW. Clinical management of autosomal dominant polycystic kidney disease. Kidney Int Suppl 1993;42:74-9.
(12) Elzinga LW, Barry JM, Bennett WM. Surgical management of painful polycystic kidneys. Am J Kidney Dis 1993;22:532-7.
(13) Zerres K. polycystic kidney disease: thoughts on the meaning of prevention. Contrib Nephrol 1992;97:7-14.
(14) Torres VE, Wilson DM, Hattery RR, Segura JW. Renal stone disease in autosomal dominant polycystic kidney disease. Am J Kidney Dis 1993;22:513-9.
(15) Lozano AM, Leblanc R. Cerebral aneurysms and polycystic kidney disease: a critical review. Can J Neurol Sci 1992;19:222-7.
(16) Chapman AB, Johnson AM, Gabow PA. Intracranial aneurysms in patients with autosomal dominant polycystic kidney disease: how to diagnose and who to screen. Am J Kidney Dis 1993;22: 526-31.
(17) Kaehny WD, Everson GT. Extrarenal manifestations of autosomal dominant polycystic kidney disease. Semin Nephrol 1991;11:661-70.
(18) Huston J 3d, Torres VE, Sulivan PP, Offord KP, Wiebers DO. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1993;3:1871-7.
(19) Que F, Nagerney DM, Gross JB Jr, Torres VE. Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroenterology 1995;108:487-94.
(20) Schoenfeld P. Dialysis: choice of therapy. Kidney Health 1994:14-5.
(21) Kidney transplant: a new lease on life. New York: National Kidney Foundation, 1991.
(22) Hodgkinson KA, Kerzin-Storrar L, Watters EA, Harris R. Adult polycystic kidney disease: knowledge, experience, and attitudes to prenatal diagnosis. J Med Genet 1990;27:552-8.
(23) Sujansky E. Kreutzer SB, Johnson AM, Lezotte DC, Schrier RW, Gabow PA. Attitudes of at-risk and affected individuals regarding presymptomatic testing for autosomal dominant polycystic kidney disease. Am J Med Genet 1990;35:510-5.
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