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(Radiology. 1999;213:273-276.)
© RSNA, 1999

Genitourinary Imaging

Autosomal Dominant Polycystic Kidney Disease Types 1 and 2: Assessment of US Sensitivity for Diagnosis1

Carlos Nicolau, MD, Roser Torra, MD, PhD, Cèlia Badenas, PhD, Ramón Vilana, MD, PhD, Luis Bianchi, MD, PhD, Rosa Gilabert, MD, PhD, Alejandro Darnell, MD, PhD and Concepció Brú, MD, PhD

1 From the Ultrasound Unit, Department of Radiology (C.N., R.V., L.B., R.G., C. Brú), and the Departments of Nephrology (R.T., C. Badenas, A.D.) and Genetics (C. Badenas), Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. Received December 1, 1998; revision requested January 26, 1999; revision received February 18; accepted April 15. From the 1998 RSNA scientific assembly. Supported in part by a grant of the Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS 97/2047). Address reprint requests to C.N. (e-mail: nicolau@medicina.ub.es).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To estimate the sensitivity and specificity of ultrasonography (US) in the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) types 1 and 2, as compared with those of genetic linkage analysis.

MATERIALS AND METHODS: A renal US and DNA analysis for ADPKD was performed in 319 patients who were at risk, 161 of whom were younger than 30 years, from 54 families with ADPKD. The sensitivity of US for diagnosis was estimated by comparing the US results with genotypes inferred from linkage studies.

RESULTS: The sensitivity of US in individuals younger than 30 years who were at risk was 95% for ADPKD type 1 but only 67% for ADPKD type 2. The sensitivity of US for either ADPKD type 1 or ADPKD type 2 in individuals aged 30 years or older who were at risk was 100%. The overall sensitivity in individuals younger than 30 years was 93%. For both ADPKD types 1 and 2 in all patients, US demonstrated a sensitivity of 97%, a specificity of 100%, and an accuracy of 98%.

CONCLUSION: US is the first-line imaging technique that should be used in the diagnosis of ADPKD. The sensitivity in individuals aged 30 years or older is 100%, but if there is a clinical suspicion of ADPKD type 2 in individuals younger than 30 years, linkage analysis should also be considered.

Index terms: Genes and genetics • Kidney, cysts, 81.3121 • Kidney, diseases, 81.3121 • Kidney, US, 81.1298 • Ultrasound (US), comparative studies, 81.1298


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Autosomal dominant polycystic kidney disease (ADPKD) is responsible for 6%–10% of cases of end-stage renal disease in North America and Europe (1). ADPKD is a multisystemic disorder characterized mainly by the progressive formation and enlargement of renal cysts in the kidney and frequently in other organs such as the liver, pancreas, and spleen. The major cause of morbidity in ADPKD is progressive renal disease, which results in grossly enlarged kidneys and end-stage renal disease. The clinical features usually begin in the 3rd to 4th decade of life, but cysts may be detectable in childhood (2,3).

The gene for ADPKD was found on the tip of the short arm of chromosome 16 (4). Genetic linkage to the PKD1 locus accounts for 85%–90% of the population with ADPKD, but in a small proportion (10%–15%) of families with ADPKD, this locus has been demonstrated to be linked to another locus for PKD2 on the long arm of chromosome 4 (5,6). In some other families, no linkage to either PKD1 or PKD2 has been reported (7).

Although the different forms of ADPKD share the same principal features, some clinical differences may distinguish them. The main difference is the overall younger age of onset of end-stage renal disease with ADPKD type 1 than with ADPKD type 2 (8–11).

Ultrasonography (US) is useful for diagnosing ADPKD since it does not involve the use of radiation or contrast material, and it is widely available and inexpensive. On the other hand, molecular analysis of ADPKD is the most accurate diagnostic tool, but it is expensive and cannot be performed everywhere. In these circumstances, US is likely to remain a widely applied method for the diagnosis of ADPKD. The purpose of this study was to assess the sensitivity and specificity of US for the diagnosis of ADPKD by comparing US results to those obtained at genetic linkage analysis. To our knowledge, this study represents the first and largest clinical study to date to include patients with ADPKD type 2.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
A renal US and linkage analysis was performed in 319 patients at risk for ADPKD, 161 of whom were younger than 30 years, from 54 families with ADPKD. The group included 151 male and 168 female patients between 9 months to 72 years of age (mean age, 32.5 years). A patient was considered to be at risk for inheriting the PKD gene if a parent was known to have the disease. Informed consent was obtained from each patient examined. This study was approved by the ethical committee of Hospital Clínic, Barcelona, Spain.

We used US to determine the presence of renal cysts to diagnose the disease. Diagnostic criteria were based on those established by Ravine et al (3) and included the presence of at least two cysts in one kidney or one cyst in each kidney in a person younger than 30 years who was at risk, two cysts in each kidney in a person aged 30–59 years who was at risk, or four cysts in each kidney for a person aged 60 years or older who was at risk.

Findings suggestive of ADPKD (finding of any cyst in patients younger than 30 years) that did not meet these criteria were designated as indeterminate. Thus, US findings were classified as positive, negative, or indeterminate. Patients with negative results were included in the same group with patients who had indeterminate results for the purpose of determining the accuracy of the technique.

All US images were obtained and interpreted by a single consultant radiologist (C.N.), who used an SSA 140 unit (Toshiba Medical Systems, Tokyo, Japan) with a 3.7- or 5-MHz transducer. The number of renal cysts per kidney was coded as 0, 1, 2–5, 6–15, or more than 15. Diagnoses based on US findings were compared (by C.N., R.V., R.T.) with polycystic kidney disease genotypes inferred from genetic linkage studies in the patients' families, which were considered the standard. In all cases, the US study was performed before the linkage analysis; thus, the radiologist was not aware of the genetic diagnosis of any disease in any individual before examining him or her.

Fifteen milliliters of peripheral blood was obtained from each family member and was anticoagulated with ethylenediaminetetraacetic acid. DNA was extracted according to the salting out method (12). Genotypes for families with ADPKD were obtained by using three dinucleotide repeat (CA)n microsatellites for PKD1 (AC2.5–D16S291, KG8–PKD1, and CW2-D16S663) and PKD2 (D4S423, D4S1534, and D4S1542). Amplification was performed by means of the polymerase chain reaction, as described previously (13). The silver staining technique was used to develop the ADPKD microsatellites (14).

We (R.T., C. Badenas) performed linkage analysis by using the lod score method (15) to estimate the recombination fraction q between the disease locus PKD1 and the markers AC2.5, KG8, and CW2 in a two-point analysis. We also performed q estimations for PKD2 and for markers D4S423, D4S1534, and D4S1542. To calculate the different q values and their respective lod scores Z(q), we used the computer programs MLINK and ILINK (LINKAGE software package, PC DOS version 5.2; Columbia University, NY)

The sensitivity and specificity of US and the exact 95% binomial CI were calculated (by R.T.) for each age group.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Results from DNA linkage studies allowed us to correctly diagnose the disease in all families. Forty-nine families had ADPKD type 1, whereas five had ADPKD type 2; this represents 182 individuals who had ADPKD type 1 and 20 who had ADPKD type 2. Findings from US examinations of 319 individuals with a 50% risk of having ADPKD (161 individuals younger than 30 years) were compared with genotypes inferred from linkage studies, which disclosed the high sensitivity and specificity of this technique. The results are expressed in the Table. Discordance between negative US findings and genotypes was age dependent.


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  		US Sensitivity and Specifity for All ADPKD Age Groups
 
There was concordance between findings at US and DNA linkage analysis in 178 of the 182 (97.8%) individuals with ADPKD type 1 who were assessed (Fig 1). In four individuals, there were discordant or equivocal results: Two individuals (2 and 5 years old) did not have renal cysts, and two individuals (3 and 26 years old) had indeterminate US results (Fig 2). In individuals aged 0–29 years, the sensitivity of US was 95% (80 of 84 individuals who inherited the PKD1 mutation had positive findings; 95% CI: 88%, 99%). In individuals aged 30 years or older, the sensitivity of US was 100% (98 of 98 individuals with a >95% probability of having ADPKD type 1 had positive findings; 95% CI: 95%, 100%). Negative findings were recorded for all patients with a linkage probability less than 0.05%.



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  		Figure 1. Longitudinal US images of the right kidney in a 28-year-old man with ADPKD type 1 show nephromegaly with multiple anechoic cysts. This is the most typical presentation of ADPKD in advanced stages.

 


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  		Figure 2. Longitudinal US image of the left kidney in a 26-year-old woman with ADPKD type 1 shows only one small cortical cyst (arrow). There were no cysts on the US image of the right kidney. The study was designated as indeterminate on the basis of the diagnostic criteria.

 
There was concordance between findings at US and DNA linkage analysis in 18 of the 20 (90%) individuals with ADPKD type 2 who were assessed. In two individuals (5 and 10 years old), no cysts were depicted at US. In individuals aged 0–29 years, the sensitivity of US was 67% (four of six individuals who inherited the PKD2 mutation had positive findings; 95% CI: 22%, 96%). In individuals aged 30 years or older, the sensitivity of US was 100% (14 of 14 individuals with a >95% probability of having ADPKD type 2 had positive findings; 95% CI: 77%, 100%).

The overall sensitivity of US in patients younger than 30 years who were at risk was 93% (84 of 90). Negative findings were recorded for all patients with a linkage probability less than 0.05%. In individuals with ADPKD types 1 or 2 in all age groups, US demonstrated a global sensitivity of 97% (196 of 202), a specificity of 100% (117 of 117), and an accuracy of 98% (313 of 319).

Among the nonaffected family members who were at risk, we found a prevalence of 7.7% (nine of 117) of simple renal cysts; all cysts were found in patients older than 30 years.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
For families with ADPKD, it is frequently essential to know if their family members who are at risk are affected by the disease. In the past, they could be informed only that they had a 50% risk. When nephrotomography and intravenous urography became available, a more accurate diagnosis could be made (16,17). But the problem with these techniques was that only moderately advanced ADPKD could be diagnosed. With the widespread availability of US, this modality was established as the main radiologic tool for the diagnosis of ADPKD (16–18). Ever since PKD1 and PKD2 were localized, DNA linkage analysis has been the standard in the diagnosis of ADPKD. But linkage analysis is expensive and is not available in most hospitals.

In this study, findings from DNA linkage analysis showed that US had good sensitivity for depicting ADPKD, especially in people older than 30 years and in patients with ADPKD type 1. Our data demonstrate that US offers the same sensitivity as DNA linkage analysis in patients older than 30 years. Elles et al (19) obtained similar results in a retrospective study performed in 1994. In patients younger than 30 years, US is more accurate in patients with ADPKD type 1 than in patients with ADPKD type 2.

We had a low rate of false-negative findings in patients with ADPKD type 1 who were younger than 30 years, whereas this rate was substantially higher in patients with ADPKD type 2. To our knowledge, there are no reports in the literature about the sensitivity of US in patients with ADPKD type 2, but several articles (9,19–22) show different rates of false-negative findings in patients with ADPKD type 1, which range from 3.4% (one of 29) in the study conducted by Elles et al (19) to 25% (14 of 56) in the study conducted by Gabow et al (22).

Our study findings show one of the lowest rates of false-negative results: 4.9% (six of 123). This may be due to the fact that we used more accurate criteria and that all images were obtained by the same consultant radiologist; it may also be due to an improved version of the US equipment. The only false-negative finding of ADPKD in a patient older than 10 years occurred in a 26-year-old woman with ADPKD type 1 (Fig 2), who did not fulfill the diagnostic criteria because of the presence of only one simple cyst in one kidney and the absence of cysts in the other. This patient had a sister who was affected and two cousins in their 20s who were affected and who had very few cysts, which suggested a mild involvement of the disease in that family group.

From our experience (with 37 patients younger than 16 years who were at risk), the finding of a cyst in a child who is at risk is highly diagnostic of ADPKD. Thus, we support the advice of Gabow et al (22) for families: When a child has any cyst, he or she may go on to have ADPKD, but a definitive clinical diagnosis cannot be given.

Reports in the literature show a very low prevalence of simple renal cysts in children. McHugh et al (23) reported a prevalence of 0.2% (35 of 16,102 patients) of simple renal cysts in children. Although renal cysts in children are very rare, if we consider only the presence of one cyst when diagnosing ADPKD, there is the risk of obtaining some false-positive diagnoses. These are much less acceptable than are false-negative diagnoses because of the anxiety usually generated with the diagnosis of this disease.

We did not have any false-positive findings, but in some children, ADPKD had been misdiagnosed at other centers (because of enlarged medullary pyramids), with a false-positive rate of 2% (one of 50) (22). This normal physiologic variation is frequent in children and can be misdiagnosed as a cyst when US is performed by an inexperienced radiologist. On the other hand, the high prevalence of simple renal cyst in adults (>50% in individuals older than 50 years) could suggest that false-positive diagnoses of ADPKD are frequent, but this is not the case. The criteria from Ravine et al (3) are very stringent in these patients and require the presence of more than four cysts in each kidney to diagnose ADPKD. Also, from our experience, the kidney in adult patients with ADPKD does not have only a few cysts; it is full of cysts and usually is enlarged. Moreover, adult patients with ADPKD have renal cysts and usually also hepatic or pancreatic cysts. Thus, an equivocal US finding in an adult patient who is at risk is the exception rather than the rule.

When considering individuals younger than 30 years, findings from this study showed a high sensitivity for US in patients with ADPKD type 1 (95%, 80 of 84), but sensitivity was much lower in patients with ADPKD type 2 (67%, four of six). Although the number of patients with ADPKD type 2 who were examined was low, these differences may be partially explained by the fact that ADPKD type 2 is much less severe than ADPKD type 1.

In our patients with ADPKD, we found striking clinical differences between both types of the disease, which agreed with our previous findings. In patients with ADPKD type 1, end-stage renal disease develops almost 20 years before it develops in patients with ADPKD type 2 (mean age of patient at onset, 53.4 vs 72.7 years), and patients with ADPKD type 1 have a lesser prevalence of hypertension in all age groups (11). This supports the finding that false-negative US results are more frequent in patients with ADPKD type 2 than in patients with ADPKD type 1. Although this could suggest that kidneys affected by ADPKD type 1 are larger than those affected by ADPKD type 2, our data do not support this hypothesis and show no substantial US differences between ADPKD types 1 and 2, when cysts are fully developed in ADPKD type 2 (11).

Because ADPKD type 2 is much less prevalent than ADPKD type 1, further studies are necessary to establish the US criteria for patients with ADPKD type 2 during childhood. Although the US criteria may become less stringent, which would mean any cyst in a young patients who is at risk, US would still have an unacceptably low level of sensitivity in these patients. For this reason, in young patients who are at risk of ADPKD type 2, we recommend that linkage or mutational analysis of PKD2 be considered if US discloses a negative result.

In normal practice, a radiologist will not know if the individual being examined belongs to a family with ADPKD type 1 or 2. For this reason, we also analyzed the overall sensitivity of the technique in all individuals younger than 30 years who are at risk. This sensitivity was 93% (84 of 90), which was only slightly lower than that for ADPKD type 1 (because of the higher prevalence of ADPKD type 1 compared with ADPKD type 2).

In conclusion, these results indicate that US is the first-line imaging technique that should be performed when diagnosing ADPKD in individuals who are at risk. The sensitivity was very high for ADPKD type 1, but if there is a reasonable clinical suspicion for ADPKD type 2, linkage analysis should also be considered in individuals younger 30 years.


   Acknowledgments
 
This study would not have been possible without the generous cooperation of the patients and their families.


   Footnotes
 
Abbreviation: ADPKD = autosomal dominant polycystic kidney disease

Author contributions: Guarantor of integrity of entire study, C.N.; study concepts, C.N., R.T., A.D., C. Brú; study design, R.T., C.N.; definition of intellectual content, C.N., R.T., A.D., C. Brú; literature research, R.T., C.N.; clinical studies, C.N., R.T., R.V., L.B., R.G., C. Badenas; data acquisition, C.N., R.T.; data analysis, C.N., R.V., R.T.; statistical analysis, R.T.; manuscript preparation, C.N., R.T., A.D., C. Brú; manuscript editing, C.N., R.T.; manuscript review, C. Brú, R.G., A.D.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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