Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis

INTRODUCTION — Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder, occurring in approximately 1 in 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 78 percent of families with ADPKD have an abnormality on chromosome 16 (PKD1 locus) [4]. Most of the remaining families (14 percent) have a different defect that involves a gene on chromosome 4 (the PKD2 locus), while a minority of families have a defect in the GANAB gene, encoding the glucosidase II alpha subunit, the ALG9 gene or the DNAJB11 gene [5]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth".)

Patients with PKD2 have a less severe phenotype than those with PKD1, but neither disorder is benign [6]. Cysts occur later in PKD2 disease, as does end-stage kidney disease (ESKD; mean age 74.0 versus 54.3 years in PKD1) [7].

The epidemiology, clinical presentation, and diagnosis of ADPKD in adults will be reviewed here. The treatment of adults with this disease is discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)

The clinical presentation, diagnosis, and management of ADPKD in children is discussed elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD) in children".)

EPIDEMIOLOGY — ADPKD occurs in all races and has a reported prevalence of 1:1000 [8]. ADPKD is the underlying cause of kidney disease in approximately 5 percent of patients who initiate dialysis annually in the United States [9,10].

ADPKD is predominantly caused by mutations in one of two genes: PKD1 (which encodes polycystin-1) on chromosome 16 and PKD2 (which encodes polycystin-2) on chromosome 4 [9]. Among most patients, kidney function remains intact until the fourth decade of life. Once the glomerular filtration rate (GFR) starts to decline, the average reduction is 4.4 to 5.9 mL/min per year [8].

Risk factors that have been identified for progressive kidney disease in ADPKD include [6,11-23]:

●Genetic factors – The causative gene mutation is the major factor that determines the rate of progression among individual patients [24]. Patients with PKD2 develop fewer cysts and progress more slowly than those with PKD1 [24,25]. The median age of the onset of end-stage kidney disease (ESKD) was 54 and 74 years for PKD1 and PKD2, respectively, in two studies [7,25].

Less than 2 percent of patients have deletions involving both the PKD1 gene and the tuberous sclerosis complex-2 gene, resulting in a more severe cystic kidney disease called the contiguous gene syndrome [24]. Truncating mutations in PKD1 produce more severe disease than missense mutations [26].

Among patients with known PKD and a family history of PKD of unknown genotype, the careful attention to family history may allow the prediction of the mutation. This was shown in a study of 484 patients from 90 families with well-characterized ADPKD mutations. To predict PKD1 or 2, various age cutoffs for the onset of ESKD or for kidney survival without ESKD of affected family members were analyzed [27]. The following observations were made:

•The presence of at least one family member who developed ESKD before age 55 years predicted a PKD1 mutation with a positive predictive value of 100 percent and a sensitivity of 72 percent.

•The presence of at least one family member who reached 70 years of age without ESKD predicted a PKD2 mutation with a positive predictive value of 100 percent and a sensitivity of 74 percent.

Since neither criterion had a negative predictive value of 100 percent, the absence of an affected family member who satisfied these criteria did not allow for exclusion of either mutation.

In addition, extensive variability in disease severity is common within families. Intrafamilial variability may be explained by somatic mosaicism, in which the PKD1 mutation is not expressed in all cells [28,29], or by modifier genes that are inherited independently of the PKD mutation [9,11,30-32]. Candidate modifier genes include the angiotensin I converting enzyme gene [33], the cystic fibrosis transmembrane conductance regulator gene [34,35], the endothelial nitric oxide synthase gene [8], and the Dickkopf 3 (DKK3) gene.

The patients with GANAB or ALG9 mutations usually have mild PKD that rarely progresses to ESKD and variable polycystic liver disease [5,36].

The patients with DNAJB11 mutations have small bilateral kidney cysts without marked kidney enlargement and generally develop ESKD at an advanced age (60 to 90 years) [37,38]. Concomitant polycystic liver disease is rare [38]. DNAJB11 has features similar to autosomal dominant tubulointerstitial disease caused by UMOD or MUC1 mutations [37].

Mild PKD can also be observed with mutations more commonly associated with autosomal dominant polycystic liver disease (PRKCSH, SEC63, LRP5, ALG8, and SEC61B) [39,40]. In approximately 8 percent of families with mild ADPKD, no mutation is detected [4].

●Kidney size – The rate of kidney growth is quasi-exponential, unique to and variable among patients, and kidney growth precedes decline in GFR [17-19]. Height-adjusted total kidney volume (htTKV) in concert with age predicts future GFR decline.

The Mayo imaging classification is a simple tool that uses htTKV and age to identify patients at the highest risk for progression independent of kidney function [22,23]. Most patients with ADPKD (approximately 95 percent) have typical disease with diffuse cystic involvement (class 1). Patients with class 1 are further stratified into five subclasses (A to E) on the basis of growth rates (<1.5, 1.5 to <3, 3 to <4.5, 4.5 to <6, or ≥6 percent per year) estimated from patient age and a theoretical starting htTKV (150 mL/m) (figure 1) [41,42]. A model that uses this classification plus estimated GFR (eGFR) predicts future eGFR decline with reasonable accuracy.

In the approximately 5 percent of patients displaying atypical kidney imaging (class 2), htTKV does not predict eGFR decline. Most patients with htTKV class 2 have focal cystic disease, and a few are older individuals with atrophic kidneys with cysts. The Mayo imaging classification has been validated by an independent study [43] and shown to be informative in post-hoc analyses of several clinical trials [44,45]. It is now often used to identify patients with rapidly progressive disease who are most likely to be informative in clinical trials and to benefit from proven effective therapies as they become available.

●Hypertension – Patients with larger kidneys tend to develop hypertension earlier in life, even before a decline in GFR, and this is a risk factor for progressive disease [15,19,46]. Issues related to hypertension in ADPKD, including the goal blood pressure, are discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of hypertension".)

●Early onset of symptoms – Patients who present with symptoms at an early age are more likely to develop ESKD [13,14,23]. In one study, patients diagnosed before the age of 30 years had a mean kidney survival that was 10 years less than those diagnosed after the age of 30 years [13]. 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) [47].

●Male sex – Male sex is associated with more rapid progression of PKD1 in most [12,15,48], but not all [49], studies. The reasons for this are not known [50].

●Proteinuria – Patients who have dipstick-positive proteinuria and moderately increased albuminuria (formerly called "microalbuminuria") account for approximately one-fourth of those with ADPKD. Such patients are at greater risk for progression to ESKD. Proteinuria also associates with kidney size, hypertension, and reduced kidney function [15,51-53].

●High urinary sodium excretion – Higher urinary sodium excretion is associated with a more rapid decline in eGFR [20]. The underlying mechanism is unknown.

CLINICAL PRESENTATION — Virtually all individuals who inherit PKD1 or PKD2 mutations eventually develop kidney cysts that are visible by ultrasonographic imaging studies [54]. The age at which affected individuals have clinical manifestations, such as kidney function impairment or hypertension, is variable. As discussed above, patients with PKD1 present with symptoms at a younger age than those with PKD2 mutations. At any given age, patients with PKD1 typically have larger kidneys and more cysts than those with PKD2 [55]. In one study, the median age of patients who presented with end-stage kidney disease (ESKD) was 54 and 74 years for those with PKD1 and PKD2, respectively [7]. However, early-onset disease has been described with both mutations [26,56].

Patients with ADPKD can present with hypertension, hematuria, proteinuria, or kidney function impairment. Flank pain, due to kidney hemorrhage, obstructive calculi, or urinary tract infection, is the most common symptom reported by patients [9]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations".)

Hypertension is present in the majority of patients who have normal kidney function and have reached the fourth decade of life; the prevalence of hypertension increases to almost 100 percent among patients with ESKD [9].

Patients may also present with symptoms that are secondary to cysts in other organs, such as the liver, pancreas, spleen, or epididymis. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

Large kidney and hepatic cysts can compress the inferior vena cava (IVC) and, when the obstruction is severe, lead to hypotension, thromboembolism, and hepatic venous outflow obstruction [57-63]. In one study, approximately one-third of patients with ADPKD had ≥50 percent compression of their IVC compared with age- and sex-matched controls [64]. However, among patients who had IVC compression, complications were uncommon and typically occurred in the presence of additional risk factors (eg, pregnancy, hypercoagulability).

The diagnosis is most commonly made in the settings of routine evaluation in an asymptomatic patient with a positive family history of ADPKD, initial work-up for new-onset hypertension, as an incidental finding during an imaging study performed for an unrelated reason (pregnancy, trauma, spinal pain, etc), and during evaluation of ADPKD-specific symptoms (hematuria, cyst rupture, pyelonephritis, kidney stones, etc).

Most patients with ADPKD die from cardiac causes [65]. In one report of 129 patients with ADPKD, causes of death included heart disease (36 percent), infection (24 percent), and a neurologic event (12 percent) [66,67]. Cardiac hypertrophy was seen in 89 percent of autopsied patients and coronary disease in 81 percent. Neurologic deaths were primarily due to ruptured intracranial aneurysm (6 percent) and hypertensive intracerebral hemorrhage (5 percent). No patient died of kidney cancer.

DIAGNOSIS

When to suspect ADPKD — The diagnosis of ADPKD should be suspected in patients with clinical features mentioned above and in those with a family history of ADPKD. (See 'Clinical presentation' above.)

ADPKD is also sometimes discovered when large kidneys with extensive cysts are observed as an incidental finding in patients who undergo abdominal imaging for a different indication (image 1).

Establishing the diagnosis of ADPKD — The initial step toward diagnosis of ADPKD is to obtain a detailed family history from the patient. The diagnosis of ADPKD is confirmed primarily by imaging [9]. Genetic testing is generally reserved for atypical cases or to rule out ADPKD in a young potential kidney donor. However, prior to performing any imaging or genetic testing, patients should be counseled regarding risks and benefits of having an established diagnosis of ADPKD, especially if they are asymptomatic. (See 'Diagnostic counseling and screening of family members' below.)

Patients with a family history of ADPKD — Criteria for establishing the diagnosis of ADPKD (or excluding the diagnosis) in patients who have a positive family history depends upon the genetic type of ADPKD in their family, if known. Data important to elicit on family history include number and relationship of family members affected, their age at diagnosis, their age of developing end-stage kidney disease (ESKD; if applicable), and any known genetic mutations in the family. In addition to family history, we obtain an initial ultrasound, computed tomography (CT), or magnetic resonance image (MRI) for diagnosis.

The choice of imaging study for the initial evaluation depends upon family history and presenting features (including kidney function):

●In asymptomatic patients with normal kidney function who have a family history of ADPKD, an ultrasound is usually sufficient to diagnose or rule-out the presence of disease. In these individuals, MRI may be necessary if the results of the ultrasound are equivocal or to further evaluate incidentally detected complications (eg, kidney mass or complex cysts). Some experts perform genetic testing to confirm the diagnosis, if available, as an alternative to follow-up imaging with an MRI. (See 'Specific role of genetic testing' below.)

If the ultrasound confirms the diagnosis of ADPKD, a baseline CT or MRI, to calculate height-adjusted total kidney volume (htTKV), may be appropriate to evaluate risk for progression and need for disease-modifying treatment (eg, tolvaptan). (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment", section on 'Identification of high-risk patients'.)

●In patients with typical findings of ADPKD, such as those with palpable kidneys and decreased estimated glomerular filtration rate (eGFR), and patients with decreased eGFR who have a family history of ADPKD, we obtain a CT or MRI rather than an initial ultrasound. In addition to confirming the diagnosis, a CT or MRI can serve as a baseline image for future comparison, can help identify complications of ADPKD or disease in other organs (eg, pancreas), and can be used to calculate the htTKV for prognostication and planning of treatment. (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment", section on 'Identification of high-risk patients' and "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations".)

The choice between a CT or MRI depends upon the patient's kidney function, given the risk of contrast exposure with CT. In patients with an eGFR ≥60 mL/min/1.73 m², we obtain a CT without and with contrast. While an unenhanced CT allows calculation of TKV, contrast-enhancement permits differentiation between cystic and noncystic tissue, assessment of cyst burden, and identification of any stones in the collecting system. For patients with an eGFR <60 mL/min/1.73 m², we prefer MRI. MRI is also able to distinguish between cystic and noncystic tissue but is unable to reliably detect kidney stones or parenchymal calcifications.

Our imaging preference is based upon available literature and personal experience. Ultrasonography is inexpensive and safe, making it the most commonly used imaging modality for diagnosis.

Ultrasound-based criteria have been established for diagnosis or exclusion of ADPKD in patients with a positive family history (table 1). These criteria were derived from multiple studies in various populations using ultrasound and molecular genotyping [68-70]. These studies utilized an ultrasound machine capable of detecting cysts that were 1 cm or more in diameter. However, most contemporary ultrasound machines detect kidney cysts of 5 mm or more with certainty. Thus, there has been an overall increase in the sensitivity of cyst detection (from approximately 82 to 97 percent in one study), although it remains center- and operator-dependent [71]. Nevertheless, we continue to use these criteria for diagnosis in individuals with a family history of ADPKD. We use these same criteria for patients who obtain a CT or MRI as the initial diagnostic modality.

For patients with equivocal ultrasound results, we perform MRI because of its superior sensitivity. Generally, this is required in patients younger than 40 years of age. This is based upon a study of 73 affected (positive genetic testing) and 83 nonaffected (negative genetic testing) individuals, which found that fewer than five cysts by MRI is sufficient to exclude the diagnosis of ADPKD in potential living-related kidney donors [71]. However, they are more expensive, and diagnostic criteria using MRI are based upon only a small number of patients [71].

In patients with equivocal ultrasound and MRI findings, and a need to establish an accurate diagnosis (eg, for transplant candidacy or prenatal planning), we perform genetic testing (see 'Specific role of genetic testing' below). Alternatively, an asymptomatic patient may be followed clinically by monitoring blood pressure and kidney function.

Patient without a family history of ADPKD — There are no established imaging-based criteria for diagnosis of ADPKD in patients without a family history. We diagnose these individuals with ADPKD if they have 10 or more cysts (≥5 mm) in each kidney, particularly if the kidneys are enlarged or liver cysts are noted, and obvious features of a different cystic disorder are absent. Genetic testing should be performed, if possible, in patients with equivocal imaging results, or if there is a need to establish an accurate diagnosis (eg, for transplant candidacy or prenatal planning). (See 'Differential diagnosis' below.)

In up to 25 percent of individuals with ADPKD, the clinical presentation and imaging studies suggest a diagnosis of ADPKD, but no one else in the family is known to have the disease [2]. 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. Thus, review of medical information or imaging studies of parents or other family members may prove helpful in such patients. In approximately 5 percent of cases, the disease may be due to a new mutation or due to mosaicism [72].

Families with rare genotypes — Based upon the available data regarding risk of progression, we perform genetic testing for diagnosis among individuals who are from families carrying the DNAJB11 mutations [37]. For patients with GANAB or ALG9 mutations, excluding the diagnosis by imaging may be sufficient based upon their mild phenotype [36].

Specific role of genetic testing — We perform genetic testing in the following scenarios:

●Imaging results uncertain, and need for a definitive diagnosis (eg, for a transplant donor).

●Atypical presentations:

•Early and severe ADPKD

•Kidney failure without significant enlargement of the kidneys

•Marked discordant disease within family

•Marked asymmetry in disease severity between kidneys

Genetic testing in these cases can provide information that explains the atypical presentation, most commonly due to genetic complexity (eg, mutation of a cystic disease gene other than PKD1, PKD2 mosaicism, coinheritance of a second mutation in another cystic disease gene, modifier genes). This information may be important among those with atypical presentation who need diagnostic confirmation or information for genetic counseling.

●Sporadic ADPKD with no family history. (See 'Patient without a family history of ADPKD' above.)

●PKD with syndromic features. (See 'Differential diagnosis' below.)

●When required for reproductive counseling. (See 'Diagnostic counseling and screening of family members' below.)

We perform genetic testing by Sanger sequencing of the PKD1 and PKD2 genes followed by multiplex-dependent probe amplification in cases with negative sequencing results [73]. Next-generation sequencing technologies have a potential for high-throughput screening and lower cost. However, genetic testing remains cost prohibitive for most patients, with significant out-of-pocket costs (up to USD $3000). This cost is expected to decline over time.

Up to 8 percent of patients with suspected ADPKD do not have mutations in these genes despite a comprehensive screen [74]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth".)

Diagnostic counseling and screening of family members — Diagnostic counseling by experienced staff is essential for all patients with suspected ADPKD prior to diagnostic testing.

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 of testing include possible difficulties with employment and insurability (eg, due to creation of a "preexisting condition") and the psychologic impact of having a life-altering diagnosis.

Additional genetic counseling related to family planning should include discussing the risk of passing the disease to the offspring, reproductive options including preimplantation genetic testing, and risks associated with pregnancy. Some clinicians may choose to refer patients to a genetic counselor. Either way, all of these benefits and risks must be discussed prior to any diagnostic testing.

Differential diagnosis — Disorders other than ADPKD must be considered in the patient with kidney cysts who does not have 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.

Acquired disorders that should be considered in adults 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. (See "Simple and complex kidney cysts in adults", section on 'Simple kidney cysts'.)

●Localized kidney cystic disease – Localized cystic disease of the kidney is an uncommon, benign condition that can be confused with ADPKD [75-77]. 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 ADPKD [77]. Imaging studies revealed multiple cysts of various sizes separated by normal or atrophic parenchyma involving one kidney. In contrast to ADPKD, localized cystic disease is neither bilateral nor progressive [75].

●Acquired kidney cystic disease – Chronic kidney disease (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 several cm [78]. The diagnosis of acquired cystic disease in kidney disease is established by ultrasonography or CT, 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 in ADPKD [78]. Rarely, however, the kidneys in those with acquired kidney cystic disease may enlarge and resemble those of ADPKD. In such cases, acquired kidney cystic disease can be distinguished by the absence of the extrarenal features of ADPKD. (See "Acquired cystic disease of the kidney in adults" and "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

●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, although the kidney cortex is spared on CT or MRI. Autosomal dominant inheritance has been reported in some cases [79]. (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 [80]. The lack of cysts in the cortex distinguishes this disorder from ADPKD.

Genetic disorders that should be considered in adults 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 or macrocystic changes, frequently with nephrolithiasis, hypertension, or impairment of kidney 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. (See "Autosomal recessive polycystic kidney disease in children".)

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 [81].

●Autosomal dominant tuberous sclerosis complex – Patients with tuberous sclerosis can also present with multiple kidney cysts. The diagnosis of tuberous sclerosis is usually confirmed by noting the presence of other features of the disease, such as renal angiomyolipomas, facial angiofibromas, hypomelanotic macules, and retinal nodular hamartomas. (See "Tuberous sclerosis complex: Clinical features" and "Renal manifestations of tuberous sclerosis complex".)

●von Hippel-Lindau disease – In addition to kidney 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 kidney 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 tubulointerstitial kidney disease – Unlike those with ADPKD, patients with autosomal dominant tubulointerstitial kidney disease may have kidney cysts at the corticomedullary junction, small-to-normal-size kidneys, hyperuricemia, and gout. (See "Autosomal dominant tubulointerstitial kidney disease".)

●Autosomal dominant hepatocyte nuclear factor-1beta (HNF-1B) nephropathy – Autosomal dominant HNF1B-associated nephropathy is characterized by high phenotypic heterogeneity, including: renal structural characteristics (kidney cysts in 60 to 80 percent of patients, multicystic dysplasia, unilateral or bilateral agenesis); tubular transport abnormalities (hypomagnesemia, hypokalemia, hyperuricemia); chronic tubulointerstitial nephropathy; genital tract abnormalities; maturity-onset diabetes of the young; exocrine pancreatic failure; and fluctuating liver test abnormalities.

●Autosomal dominant polycystic liver disease (ADPLD) – ADPLD is distinct from ADPKD because such patients have little or no kidney cyst burden [82]. Nevertheless, in some cases, it is difficult to differentiate mild ADPKD with liver cysts from mild ADPLD with kidney cysts. 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 [83].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Polycystic kidney disease (The Basics)")

●Beyond the Basics topic (see "Patient education: Polycystic kidney disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder, occurring in approximately 1 in 1000 live births. Approximately 78 percent of families with ADPKD have an abnormality on chromosome 16 (PKD1 locus). Most of the remaining families (14 percent) have a different defect that involves a gene on chromosome 4 (the PKD2 locus), while a minority of families have a defect in the GANAB gene, encoding the glucosidase II alpha subunit, or the DNAJB11 gene. (See 'Introduction' above.)

●Risk factors for progression – Patients with PKD2 have a less severe phenotype than those with PKD1, but neither disorder is benign. Risk factors for progressive kidney disease in ADPKD include the causative gene mutation within the context of family history, male sex, onset of symptoms at an early age, kidney size, presence of hypertension, proteinuria, and high urinary sodium excretion. (See 'Epidemiology' above.)

●Clinical presentation – Patients with ADPKD may be asymptomatic or present with hypertension, hematuria, proteinuria, or kidney function impairment, detected by routine laboratory examination. Flank pain due to kidney hemorrhage, calculi, or urinary tract infection are the most common symptoms reported by patients. Patients may also present with symptoms that are secondary to cysts in other organs, such as the liver, pancreas, spleen, or epididymis. (See 'Clinical presentation' above.)

●Diagnosis

•When to suspect ADPKD – The diagnosis is most commonly made in the settings of routine evaluation in an asymptomatic patient with a positive family history of ADPKD, initial work-up for new-onset hypertension, as an incidental finding during an imaging study performed for an unrelated reason (eg, pregnancy, trauma, spinal pain), and during evaluation of ADPKD-specific symptoms (hematuria, cyst rupture, pyelonephritis, kidney stones, etc). (See 'When to suspect ADPKD' above.)

•Diagnostic counseling – Diagnostic counseling by experienced staff is essential for all patients with suspected ADPKD prior to diagnostic testing. The benefits and adverse consequences of diagnostic testing, as well as genetic counseling related to family planning, when relevant, should be discussed. (See 'Diagnostic counseling and screening of family members' above.)

•Establishing the diagnosis – Diagnostic confirmation of ADPKD is primarily by imaging. Genetic testing is generally reserved for atypical cases or to rule out ADPKD in a young potential kidney donor (see 'Specific role of genetic testing' above):

-Among patients with a family history of ADPKD, who are asymptomatic with normal kidney function, an ultrasound is usually sufficient to diagnose or rule-out the presence of disease (table 1). In these individuals, magnetic resonance imaging (MRI) may be necessary if the results of the ultrasound are equivocal or to further evaluate incidentally detected complications (eg, kidney mass or complex cysts). Some experts perform genetic testing to confirm the diagnosis, if available, as an alternative to follow-up imaging with an MRI. (See 'Patients with a family history of ADPKD' above.)

-Among patients with a family history and typical findings of ADPKD, such as those with palpable kidneys and decreased estimated glomerular filtration rate (eGFR), we obtain a computed tomography (CT) or MRI rather than an initial ultrasound. The choice between a CT or MRI depends upon the patient's kidney function, given the risk of contrast exposure with CT. In patients with an eGFR ≥60 mL/min/1.73 m², we obtain a CT without and with contrast. For patients with an eGFR <60 mL/min/1.73 m², we prefer MRI. (See 'Patients with a family history of ADPKD' above.)

-There are no established imaging-based criteria for diagnosis of ADPKD in patients without a family history. We diagnose these individuals with ADPKD if they have 10 or more cysts (≥5 mm) in each kidney, particularly if the kidneys are enlarged or liver cysts are noted, and obvious features of a different cystic disorder are absent. Genetic testing should be performed, if possible, in patients with equivocal imaging results or if there is a need to establish an accurate diagnosis (eg, for transplant candidacy or prenatal planning). (See 'Patient without a family history of ADPKD' above.)

-Based on the available data regarding risk of progression, we perform genetic testing for diagnosis among individuals who are from families carrying the DNAJB11 mutations. For patients with GANAB mutations, excluding the diagnosis by imaging may be sufficient based on their mild phenotype.

•Differential diagnosis – Disorders other than ADPKD must be considered in the patient with kidney cysts who does not have 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 differentiate between various conditions. (See 'Differential diagnosis' above.)