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Diagnosis of and screening for autosomal dominant polycystic kidney disease
Authors
Vicente E Torres, MD
William M Bennett, MD
Section Editor
Ronald D Perrone, MD
Deputy Editor
Alice M Sheridan, MD
Disclosures: Vicente E Torres, MD Grant/Research/Clinical Trial Support: Otsuka [ADPKD (Tolvaptan)]. William M Bennett, MD Nothing to disclose. Ronald D Perrone, MD Grant/Research/Clinical Trial Support: Otsuka [polycystic kidney disease (tolvaptan)]. Consultant/Advisory Boards: Vertex [polycystic kidney disease]; Sanofi-Genzyme [polycystic kidney disease]. Alice M Sheridan, MD Employee of UpToDate, Inc. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2014. | This topic last updated: Jan 11, 2013.
INTRODUCTION — Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder, occurring in approximately 1 in every 400 to 1000 live births [1-3]. It is estimated that less than one-half of these cases will be diagnosed during the patient's lifetime as the disease is often clinically silent [1].
Approximately 85 percent of families with ADPKD have an abnormality on chromosome 16 (PKD1 locus) that is tightly linked to the alpha-globin gene locus [4]. The remaining patients have a different defect that involves a gene on chromosome 4 (the PKD2 locus). (See "Genetics of autosomal dominant polycystic kidney disease and mechanisms of cyst growth".)
Patients with PKD2 have a less severe phenotype than those with PKD1, but neither disorder is benign [5]. Cysts occur later in PKD2 disease, as does end-stage renal disease (ESRD; mean age 74.0 versus 54.3 years in PKD1) [6]. As a result, false-negative results are more likely when screening young subjects with PKD2 disease. (See "Course and treatment of autosomal dominant polycystic kidney disease".)
The diagnosis of and screening for ADPKD will be reviewed here. The course and treatment of this disorder are discussed separately. (See "Course and treatment of autosomal dominant polycystic kidney disease".)
OVERVIEW — The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) relies principally upon imaging of the kidney [7]. Typical findings include large kidneys and extensive cysts scattered throughout both kidneys. Because of cost and safety, ultrasonography is most commonly used as the imaging modality. In certain settings, genetic testing is required for a definitive diagnosis.
Important issues related to the diagnosis of ADPKD include the presence or absence of a family history of the disease, the number and types of renal cysts, and the age of the patient.
POSITIVE FAMILY HISTORY
Screening and diagnosis of asymptomatic individuals — Screening for the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) in an asymptomatic individual at risk because of a positive family history usually relies upon imaging of the kidney. Among at-risk individuals, ultrasonography of the kidneys is usually the initial modality used for screening and diagnosis. Since this technique is less reliable in younger individuals, genetic diagnosis using linkage or DNA analysis and/or an alternative imaging modality can be performed when a definitive diagnosis is required. (See 'Genetic testing' below and 'Other imaging modalities' below.)
In children (less than 18 years of age), we recommend NOT screening. This is principally because the adverse consequences associated with a positive diagnosis prior to symptoms in young individuals (such as career, educational, emotional, and insurability issues) far outweigh any benefits since effective therapies are not yet available. Nevertheless, children at risk for ADPKD should be monitored for early disease presentations that require treatment. Among these, hypertension is underrecognized.
In adults (greater than 18 years of age), we recommend screening in potential living related kidney donors, given the adverse medical consequences of transplanting a kidney from a donor with ADPKD. It is important to realize, however, that all potential kidney donors undergo imaging of the kidneys. In other at-risk adults, the decision to screen for the disease should be based upon the patient's preferences and values after the benefits and adverse consequences of certainty concerning the diagnosis are fully understood.
Prior to testing, counseling by experienced staff must be performed. The benefits derived from testing include knowledge concerning the diagnosis, appropriate family planning, the ability to detect and treat complications associated with the disease, reassurance of unaffected individuals, and appropriate selection of unaffected relatives as possible donors for kidney transplantation. Adverse consequences with testing, including possible difficulties with insurability and employment due to a positive diagnosis, must be discussed.
There has been a trend for earlier diagnosis of ADPKD in patients at risk for the disease. In one cohort of patients, for example, the age at diagnosis was significantly lower among those born between 1951 and 1974 compared with those born before 1951 (27 versus 39 years, respectively) [8].
Ultrasonographic criteria for adults — Renal ultrasonography is usually used for screening because it is safe, effective, and inexpensive. There have been no studies that adequately compared ultrasonography with other imaging modalities for the screening and diagnosis of ADPKD.
The criteria for diagnosis varies based upon whether the familial genotype is known. In the vast majority of cases, the individual at risk for ADPKD is from a family with an unknown genotype.
At risk but unknown familial genotype — We use the following ultrasonographic criteria for the diagnosis of ADPKD for at-risk individuals from families of unknown genotype:
●Among individuals between 15 and 39 years of age, at least three unilateral or bilateral kidney cysts. The specificity and positive predictive value of this criterion for individuals of this age is 100 percent. By comparison, this criterion is associated with a sensitivity of 82 and 96 percent for individuals between 15 and 29 years, and between 30 to 39 years of age, respectively.
●Among individuals 40 to 59 years of age, at least two cysts in each kidney. This finding is associated with a sensitivity, specificity, and positive predictive value of 90, 100, and 100 percent, respectively.
●Among individuals 60 years or older, at least four cysts in each kidney. This is associated with 100 percent sensitivity and specificity.
These criteria are based upon a well-designed study of 948 individuals at risk for either PKD1 or PKD2 in which the performance of different ultrasound criteria was evaluated among at-risk individuals who subsequently underwent molecular genotyping [9]. A statistical resampling method termed "bootstrapping" was used to obtain the best estimate for the accuracy of different ultrasonographic diagnostic criteria for various age groups and also to ensure that the analysis involved a constant ratio of 85:15 of patients with PKD1 to those with PKD2. This latter feature was performed to simulate the case mix observed in a general clinic assessing at-risk individuals of all age groups.
This study also provided some guidance concerning the ability of specific ultrasonographic findings to exclude the diagnosis of ADPKD among at-risk individuals from families of unknown genotype:
●Among individuals 40 years of age or older, ultrasonographic evidence of zero or only one renal cyst excludes the disease since these findings are associated with a negative predictive value of 100 percent.
●Among those 30 to 39 years of age, the disease is essentially excluded if ultrasonography reveals the absence of any renal cysts, which is associated with a false-negative rate of 2 percent. The finding of no renal cysts with more sensitive modalities, such as computed tomography (CT) scanning or magnetic resonance imaging (MRI), would provide further support that the disease is not present. (See 'Other imaging modalities' below.)
●Among patients less than 30 years of age, ultrasonographic imaging is limited in its ability to help exclude the disease. The approach to such patients is discussed in other sections in this topic review. (See 'Other imaging modalities' below and 'Approach after equivocal ultrasound results' below and 'Infant/child' below.)
At risk for type 1 ADPKD — Some asymptomatic patients at risk for ADPKD are from families with known and well-characterized pathogenic mutations in the PKD1 locus. In this setting, testing for the known mutation is more definitive and may be more cost effective than ultrasonography.
However, if genetic testing is not available or less desirable, ultrasonographic imaging may be used for individuals who are known to be at risk for type 1 ADPKD. Among such patients, the following age-dependent ultrasonographic criteria have been used for the diagnosis:
●Among individuals between 15 and 30 years of age, at least two unilateral or bilateral cysts
●Among individuals 30 to 59 years of age, two cysts in each kidney
●Among individuals 60 years or older, four cysts in each kidney
These criteria were derived from an ultrasonographic study of 128 individuals at risk for PKD1 that compared imaging findings with genotype [10]. The specificity of these criteria was found to be 100 percent for all patients at risk for type 1 ADPKD [9,11]. By comparison, the sensitivity of these findings varies by patient age [9,11]. Among patients between 15 and 30 years of age at risk for type 1 disease, the sensitivity of these criteria is 95 percent. The sensitivity increases to 97 to 100 percent for those older than 30 years of age. Thus, a negative ultrasound can definitely exclude type 1 disease when the patient is older than 30 years, although the false-negative rate at age 20 is only approximately 4 percent [10,11].
At risk for type 2 ADPKD — Some asymptomatic patients at risk for ADPKD are from families with known and well-characterized pathogenic mutations in the PKD2 locus. In this setting, testing for the known mutation is more definitive and may be more cost effective than ultrasonography.
If genetic testing is not available or less desirable, established ultrasonographic criteria are less sensitive for patients who are known to be at risk for type 2 ADPKD. In this setting, some clinicians would use the ultrasonographic criteria created for those at risk for ADPKD but of unknown familial genotype, as noted above.
Other imaging modalities — Because CT and MRI are more sensitive than ultrasonography, the sonographic criteria listed above are not applicable to these modalities. Contrast-enhanced CT scanning or MRI or heavy-weighted unenhanced T2 MR images can reliably detect small cysts of 2 to 3 mm diameter [12].
Although not formally evaluated and only studied in small case series and reports, we believe that a negative test (no cysts in either the kidneys or the liver) found with these techniques by 20 years of age virtually excludes the presence of PKD, at least for type 1 disease.
Conversely, among patients with equivocal ultrasonographic studies, these techniques may demonstrate numerous small cysts, thereby possibly precluding the need for genetic testing.
Approach after equivocal ultrasound results — No formal studies have compared CT or MRI techniques, or genetic testing among at-risk adult patients with equivocal ultrasonographic results. In the setting of an equivocal ultrasound, some clinicians prefer genetic testing, while others choose either a CT scan or MR study, with genetic testing performed if the diagnosis remains uncertain after additional radiologic evaluation. (See 'Genetic testing' below.)
Infant/child — In an infant/child at 50 percent risk for ADPKD, ultrasonography of the kidney is less useful than in adults, with inconclusive results being noted in one-half of those at risk (particularly children less than five years of age) [13]. As previously mentioned, we recommend NOT screening in children. However, if desired, we use renal ultrasonography for initial evaluation because it is safe and inexpensive.
The finding of large echogenic kidneys without distinct macroscopic cysts in infants is highly suggestive of the disease. The presence of one cyst is adequate for the diagnosis in an at-risk child (0 to 15 years of age) [13].
Genetic testing can be used when the imaging results are equivocal and/or when a definite diagnosis is required (see "Autosomal recessive polycystic kidney disease in children" and 'Genetic testing' below). Prenatal screening in the fetus at risk for ADPKD is discussed separately. (See 'Prenatal and preimplantation genetic testing' below.)
Diagnosis of symptomatic individuals — The diagnosis is easy to establish in patients with symptomatic disease who have a family history of ADPKD. In such patients, the diagnosis is certain with the finding of large kidneys with multiple bilateral cysts on ultrasonography or CT scanning (image 1). The specific number of cysts per kidney detected by ultrasonography that will definitively establish the diagnosis of ADPKD depends upon patient age and is the same as the criteria used in patients with asymptomatic disease. (See 'Ultrasonographic criteria for adults' above.)
Affected patients may present with flank pain or renal insufficiency and hypertension [2]. Cysts may also be seen in the liver and pancreas. Hepatic cysts, for example, can be detected in over half of cases and are more commonly seen in women and in patients over the age of 40 years [14]. Additional manifestations may include intracranial aneurysms, decreased urinary-concentrating ability, and abdominal wall hernias [15]. (See "Renal manifestations of autosomal dominant polycystic kidney disease" and "Extrarenal manifestations of autosomal dominant polycystic kidney disease".)
NEGATIVE FAMILY HISTORY — In up to 25 percent of cases, the clinical presentation and imaging studies suggest a diagnosis of autosomal dominant polycystic kidney disease (ADPKD) [2]; however, no one else in the family is known to have the disease.
In most such cases, the disease is inherited, but the affected parent has died without a diagnosis or is alive with a mild form of the disease that has gone undetected. In this case, reviewing medical information or obtaining imaging studies on the parents or other family members may prove helpful. In up to 5 percent of cases, the disease may be due to a new mutation.
In the absence of a family history, there is no definitive number of cysts and/or cyst location that provides an unequivocal diagnosis of ADPKD. The diagnosis should be strongly suspected in the presence of multiple and bilateral cysts (arbitrarily defined as 10 or more cysts in each kidney) in the absence of findings suggestive of a different renal cystic disease, particularly if renal enlargement or liver cysts are also present.
Differential diagnosis — Disorders other than ADPKD must be considered in the patient without a family history of the disease. The age of the patient, a family history of other genetic disorders, and the presence of associated manifestations help in the differential diagnosis.
Adults and older children — Acquired disorders that should be considered in adults and older children (greater than 10 years of age) in the absence of a family history of ADPKD include:
●Multiple benign simple cysts – Multiple benign simple cysts are relatively common in the general adult population and increase in number with age. Since they may be difficult to differentiate from a mild form of ADPKD, knowledge concerning the relative prevalence of simple cysts in the general population can help distinguish ADPKD from benign simple cysts. The prevalence of such cysts was evaluated in a study in which renal ultrasonography was performed in 729 individuals with normal renal function who were referred for the investigation of symptoms unrelated to the urinary tract [16]. Ultrasonography detected at least one cyst in 0, 1.7, 11.5, and 22.1 percent of individuals aged 15 to 29, 30 to 49, 50 to 70, and ≥70 years, respectively. Bilateral renal cysts (at least one cyst in each kidney) were detected in 1, 4, and 9 percent of those aged 30 to 49, 50 to 70, and >70 years, respectively.
Computed tomography (CT) and magnetic resonance imaging (MRI) are more sensitive than ultrasonography. Spiral CT detects renal cysts in approximately 50 percent of men (mean age, 66 years) and 35 percent of women (mean age, 63 years), with a total number of cysts ranging from 1 to 10 per patient [17].
Thus, since the diagnosis of ADPKD is a possibility in some patients of the appropriate age with multiple cysts detected via abdominal ultrasonographic imaging, but without a family history of ADPKD, the number and location of cysts may favor one diagnosis over the other:
•Simple renal cysts are uncommon in patients younger than 30 years and are rarely multiple or bilateral.
•It is uncommon for patients aged 30 to 59 years to have at least two cysts in each kidney.
•In patients over the age of 60 years, the finding of four or more cysts in each kidney is rarely due to multiple simple cysts [18,19].
In problem cases, further evaluation with more sensitive imaging techniques (such as contrast-enhanced CT scanning or MRI or heavy-weighted unenhanced T2 MRI), and the presence of extrarenal manifestations and/or enlarged kidneys can further help establish the diagnosis of ADPKD.
Renal ultrasonography in parents and family members can also help detect asymptomatic ADPKD, if present [15].
●Localized renal cystic disease – Localized cystic disease of the kidney is an uncommon benign condition that can be confused with PKD [20-22]. In one series of 18 patients, the age at diagnosis ranged from 24 to 83 years (average, 54 years), and none had a family history of PKD [22]. Imaging studies revealed multiple cysts of various sizes separated by normal or atrophic parenchyma involving one kidney. In contrast to PKD, localized cystic disease is neither bilateral nor progressive [20].
●Acquired renal cystic disease – Chronic renal failure (particularly patients on maintenance hemodialysis or peritoneal dialysis) is frequently associated with the development of multiple and bilateral small cysts; these cysts are usually <0.5 cm in diameter, but can be as large as 2 to 3 cm [23]. The diagnosis of acquired cystic disease in renal failure is established by ultrasonography and/or CT scanning, although each procedure can have false-negative results. A positive test requires involvement of both kidneys, with four or more cysts being present.
Acquired cystic disease is usually easily distinguished from ADPKD since there is no family history of ADPKD and the kidneys are small to normal in size, with a smooth contour, as opposed to usually extreme renal enlargement, with a cystic contour [23]. Rarely, however, the kidneys in those with acquired renal cystic disease may enlarge and resemble those of ADPKD. In such cases, acquired renal cystic disease can be distinguished by the absence of the extrarenal features of ADPKD. (See "Acquired cystic disease of the kidney in adults" and "Extrarenal manifestations of autosomal dominant polycystic kidney disease".)
●Medullary sponge kidney – Medullary sponge kidney is characterized by tubular dilatation of the collecting ducts confined to the medullary pyramids. The urographic appearance of the kidneys in this disorder can mimic those in ADPKD, but the renal cortex is spared on CT or MRI. Autosomal dominant inheritance has been reported in some cases [24]. (See "Medullary sponge kidney".)
●Bilateral parapelvic cysts – Bilateral parapelvic cysts (eg, cystic disease of the renal sinus) may distort the renal pelvis, infundibula, and calyces, and can be confused with ADPKD on excretory urography [25]. The lack of cysts in the cortex/medulla distinguishes this disorder from ADPKD.
Genetic disorders that should be considered in adults and older children (over the age of 10 years) in the absence of a family history of ADPKD include the following:
●Autosomal recessive polycystic kidney disease (ARPKD) – In older children or young adults, ARPKD is associated with collecting duct ectasia and/or macrocystic changes, frequently with nephrolithiasis, hypertension, and/or impairment of renal function. Patients also often present with symptoms and signs of hepatic fibrosis and portal hypertension or ascending cholangitis, while neonates may present with enlarged echogenic kidneys and pulmonary hypoplasia.
The ultrasonographic appearance of the kidney may not distinguish ARPKD from autosomal dominant disease. Extrarenal (hepatic, pancreatic) cysts also favor the presence of autosomal dominant disease, while portal fibrosis or signs of portal hypertension, cholangitis, or biliary dysgenesis favor the diagnosis of autosomal recessive disease.
A careful family history and analysis of the parents is often helpful. Ultrasonography of parents of children with ARPKD will not show cysts, while autosomal dominant disease is often first discovered in a parent at the time of diagnosis in the child. However, affected parents with ADPKD under the age of 25 to 30 years may not yet have cysts detectable on ultrasonography, and establishing the diagnosis may require evaluation of the grandparents.
Genetic testing may also be helpful in some cases [26]. (See 'Genetic testing' below.)
●Autosomal dominant tuberous sclerosis complex – Patients with tuberous sclerosis can also present with multiple renal cysts. The diagnosis of tuberous sclerosis is usually confirmed by noting the presence of other features of the disease.
The diagnosis requires two major features (renal angiomyolipoma, facial angiofibromas or forehead plaques, nontraumatic ungual or periungual fibroma, three or more hypomelanotic macules, shagreen patch, multiple retinal nodular hamartomas, cortical tuber, subependymal nodule, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis) or one major plus two minor features (multiple renal cysts, nonrenal hamartoma, hamartomatous rectal polyps, retinal achromic patch, cerebral white matter radial migration tracts, bone cysts, gingival fibromas, "confetti" skin lesions, multiple enamel pits). (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis" and "Renal manifestations of tuberous sclerosis complex".)
●Autosomal dominant von Hippel-Lindau disease – In addition to renal cysts, patients with von Hippel-Lindau disease may have retinal hemangiomas, clear cell carcinomas of the kidney, cerebellar and spinal hemangioblastomas, pheochromocytoma, endocrine pancreatic tumors, and/or epididymal cystadenoma.
Infrequently, patients with renal cysts, but without the other manifestations of the disorder, may be misdiagnosed with ADPKD. The correct diagnosis is eventually uncovered with the development of a manifestation that is unique to von Hippel-Lindau disease, such as a hemangioblastoma. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)
●Autosomal dominant medullary cystic disease – Unlike those with ADPKD, patients with medullary cystic disease have renal cysts at the corticomedullary junction, small-to-normal-size kidneys, and, particularly in type 2 disease, hyperuricemia and gout. (See "Autosomal dominant interstitial kidney disease (medullary cystic kidney disease)", section on 'Uromodulin-associated kidney disease (UAKD)'.)
●Autosomal dominant polycystic liver disease – Autosomal dominant polycystic liver disease is distinct from PKD since it is not associated with kidney involvement. However, it may be difficult to distinguish the patient with autosomal dominant polycystic liver disease plus simple renal cysts from the patient with ADPKD. Although family history may be helpful, genetic testing may be required to make a definitive diagnosis. (See "Diagnosis and management of cystic lesions of the liver".)
●X-linked dominant orofaciodigital syndrome type I (OFD1) – Affected females with X-linked dominant OFD1 (prenatal lethality in males) may have kidneys that are indistinguishable from autosomal dominant polycystic kidneys. Distinguishing features are extrarenal manifestations that include oral (hyperplastic frenula, cleft tongue, cleft palate or lip, and malposed teeth); facial (broad nasal root with hypoplasia of nasal alae and malar bone); and digital (brachy, syn, clino, campto, polydactyly) anomalies [27].
Young children and infants — In the absence of a family history of ADPKD, the differential diagnosis of severe presentations in infants or young children (up to 10 years of age) include the following (see "Renal cystic diseases in children"):
●Autosomal recessive polycystic kidney disease – As previously mentioned, imaging of the kidneys cannot definitively distinguish ARPKD from a severe early presentation of ADPKD. Genetic testing by direct mutational analysis of the culprit genes will clarify the diagnosis [26]. (See above and (see "Autosomal recessive polycystic kidney disease in children")).
●Contiguous PKD1-TSC2 contiguous syndrome – Deletions that inactivate both the TSC2 and PKD1 genes are associated with severe PKD [28-30]. This disorder is usually diagnosed in the first year of life and leads to end-stage renal disease (ESRD) at an earlier age than ADPKD alone. The presence of manifestations unique to tuberous sclerosis helps clarify the diagnosis. Multiplex ligation-dependent probe amplification (MLPA), which detects large gene rearrangements, may allow for definitive diagnosis of this syndrome [31]. (See 'Genetic testing' below.)
●Meckel-Gruber syndrome – Meckel-Gruber syndrome includes occipital encephalocele, polycystic kidneys, biliary dysgenesis and polydactyly. By comparison, patients with ADPKD do not have encephalocele or polydactyly.
●Other multiple malformation syndromes.
GENETIC TESTING — Among patients with equivocal imaging results and/or when a definite diagnosis is required (such as a potential living related donor, only with informed consent), genetic testing should be considered [32]. (See 'Differential diagnosis' above.)
Methods used to perform genetic testing are linkage or sequence analysis of DNA:
●Linkage analysis uses microsatellite markers that flank the PKD1 and PKD2 genes. The technique requires the accurate diagnosis in an adequate number of known family members (at least four) who are willing to be tested. Linkage analysis is therefore suitable in less than one-half of families.
●Direct DNA analysis of the PKD1 and PKD2 genes is hampered by their immense size, complexity, and allelic heterogeneity. With both genes, mutation detection rates of approximately 65 to 70 percent have been reported with denaturing high-performance liquid chromatography (DHPLC) [33,34]. Direct sequencing is associated with rates of approximately 85 to 90 percent [35,36]. High-throughput next generation sequencing may allow for the genetic characterization of large populations of patients with autosomal dominant polycystic kidney disease (ADPKD) [37].
Whether a mutation is associated with pathogenicity is unclear since most changes are unique and missense changes in PKD1 constitute nearly one-third of all mutations. Sequence analysis of the PKD1 and PKD2 genes is currently clinically available.
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