1 Imaging Diagnosis Center (Ultrasound Unit), 2 Departments of Nephrology and 3 Genetics, Hospital Clínic, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona and 4 Department of Nephrology, Hospital Juan XXIII, Tarragona, Spain
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Abstract |
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Methods. An abdominal ultrasound was performed on four ARPKD subjects (with a mean age of 20.2) and on 33 ADPKD subjects in early adulthood (29 without renal failure with a mean age of 20.5, and four with renal failure with a mean age of 26.5). Linkage studies with ADPKD and ARPKD markers were compatible with the clinical diagnosis in all cases.
Results. The renal sonographic features in ARPKD subjects included multiple small cysts in a normal-sized kidney, increased cortical echogenicity and loss of corticomedullary differentiation. In ADPKD subjects without renal failure, sonographic features included few or multiple cysts of different sizes, in normal-sized kidneys in 22 out of 29 patients (75.8%), normal cortical echogenicity and conserved corticomedullary differentiation, except in patients with nephromegaly. All ADPKD subjects with renal failure had nephromegaly and loss of corticomedullary differentiation. The hepatic sonographic features in ARPKD patients included portal fibrosis and in some cases Caroli's disease, while in ADPKD patients a normal hepatic echostructure was detected in all but one case, in addition to simple hepatic cysts in a few cases.
Conclusions. The evaluation of the sonographic features of the kidneys and those of the liver may help in the differential diagnosis between ARPKD and ADPKD in early adulthood.
Keywords: ADPKD; ARPKD; Caroli's disease; hepatic fibrosis; sonography; ultrasound
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Introduction |
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Subjects and methods |
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Methods
A complete medical history, physical examination, measurement of arterial blood pressure and serum creatinine and a complete abdominal ultrasound study were performed on these patients. Using ultrasound, the kidneys (kidney size, number of cysts per kidney (<6, 615, >15), cysts size, cortical echogenicity, corticomedullary differentiation), liver (echostructure, signs of hepatic fibrosis, presence of cysts) and biliary tree (dilatation) were specifically studied. All studies were performed and evaluated by a single consultant radiologist, with a Toshiba SSA 140 (Toshiba, Japan) equipped with a 3.7 MHz transducer. The diagnosis of ARPKD and ADPKD was confirmed by linkage genetic studies in each case. Linkage analysis was performed by using microsatellite markers flanking the PKHD1 (D6S269, 272, 436, 427, 465, 423, 466, 295, 294, 257), PKD1 (AC2.5-D16S291, KG8-PKD1 and CW2-D16S663) and PKD2 (D4S423, D4S1534 and D4S1542) genes as previously described [7,8]. We obtained informed consent from all subjects who participated in the study. The study was approved by the Ethical Committee of the Hospital.
Clinical data
Group 1. ARPKD patients All subjects were products of non-consanguineous marriages.
Case 1. A 20-year-old man was admitted to our hospital because of biochemical features of advanced renal failure. His medical history included palpable masses in both flanks and hepatomegaly at birth. At that time, an exploratory laparotomy had showed enlarged kidneys with multiple cysts. His growth and development were apparently normal. There was no family history of renal disease. The patient had been apparently well until 3 months earlier, when he began to experience fatigue, anorexia, weight loss, and muscle cramps. On admission he presented with end-stage renal disease (ESRD) and non palpable kidneys, and he underwent haemodialysis. Due to the sonographic findings and the presence of pancytopenia, an endoscopy was indicated. Endoscopy excluded oesophageal varices, and the patient refused a haemodynamic study to evaluate portal hypertension. The patient underwent a liver biopsy that showed periportal fibrosis. After the procedure the patient presented with severe hepatic bleeding that required surgery. Results from abdominal ultrasound examinations in both parents and two sisters were normal.
Case 2. A 19-year-old woman underwent a blood test due to asthenia and amenorrhoea during the previous 3 months. The blood analysis showed clear signs of ESRD and the patient underwent haemodialysis. There were no clinical signs of portal hypertension. The patient's younger brother had died at 2 months of age from ARPKD. Results of abdominal ultrasound examinations of both parents and another brother were normal.
Case 3. This 20-year-old woman had been diagnosed of ARPKD at birth. She was known to have severe portal hypertension and renal failure in her teens. At 18 years of age she had gone to the emergency room because of upper digestive bleeding due the rupture of oesophageal varices. The intensity of haemorrhage precluded treatment with sclerosis, so she underwent a portocaval shunt that prevented any subsequent variceal bleeding. The patient's renal function is severely impaired (serum creatinine of 6 mg/dl) but she still does not need renal replacement therapy. Results of abdominal ultrasound examinations of both parents, two sisters, and one brother were strictly normal.
Case 4. A 22-year-old woman was diagnosed of ARPKD at birth. At 5 years of age she had upper digestive bleeding caused by rupture of oesophageal varices. After various bleeding episodes she underwent a splenorenal shunt. On admission, her renal function was impaired and serum creatinine levels were of 2.8 mg/dl. Her brother and parents showed normal abdominal sonography scans.
Group 2. ADPKD young adults None of the 29 ADPKD patients in this group had renal failure. Five of them had hypertension. None of them had a history of haematuria or renal calculi. They were initially examined in our department because of family history of ADPKD.
Group 3. ADPKD patients <30 years old with renal failure All four of these patients had hypertension. Two of them entered ESRD at 28 and 26 years of age. The other two, who were 24 and 25 years old, had serum creatinine levels of 6 and 4 mg/dl respectively.
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Results |
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Group 2. ADPKD patients without renal failure
Linkage analysis of all the families was consistent with ADPKD linked to the PKD1 gene. Nephromegaly was only seen in seven patients (24.1%) while kidney size was normal in 22 (75.9%) (Figure 4). Loss of corticomedullary differentiation was detected in only five patients (all of them having nephromegaly). No increase of cortical echogenicity was detected in any patient in whom it was possible to evaluate this (not evaluated in seven patients because the kidneys were almost completely full of cysts). Simple hepatic cysts were found in six subjects (20.6%) (Figure 5
). No signs of hepatic fibrosis, portal hypertension or bile ducts ectasia were seen in any patient.
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Group 3. ADPKD patients with renal failure
Linkage analysis was consistent with ADPKD linked to the PKD1 gene in each patient. Moderate or severe nephromegaly (at least >15 cm) was seen in all subjects. The parenchyma was almost completely replaced by innumerable cysts of different sizes, distributed throughout all the renal parenchyma with loss of corticomedullary differentiation, not allowing the examination of the cortical echogenicity. There were simple hepatic cysts in all cases. In one case we also detected multiple intrahepatic duct ectasia compatible with Caroli's syndrome as well as signs of hepatic fibrosis, with cavernous transformation of the portal vein.
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Discussion |
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The differentiation of ARPKD from ADPKD is important for genetic counseling and prognosis. A patient with ARPKD is not going to pass the disease to the following generation while the children of an ADPKD patient have a 50% chance of suffering from the disease. A positive family history is the most important information in establishing the diagnosis of ADPKD, and in most cases, ultrasonography of both parents is a reliable way to distinguish between ADPKD and ARPKD. However, when paternity is in doubt, or in cases of spontaneous mutations (accounting for up to 10% of ADPKD cases) parental sonograms are irrelevant. The linkage technique is also useful in diagnosing both entities. However, it is an expensive technique not available in most hospitals, not useful in sporadic cases, and frequently not informative in small families. When mutational detection in the PKD genes becomes available the differential diagnosis of these diseases will become easier. Until then, in these rare cases, a classification problem arises, and the diagnosis must be performed using radiological methods or biopsy of the involved organs [13,14]. Computed tomography (CT) and magnetic resonance imaging (MRI) have been used with success in the evaluation of ARPKD patients [1416], especially in older children who are able to co-operate during the performance of the test. These techniques can delineate fine details of the renal architecture and may add useful information to the ultrasound data. However, the intravenous contrast used in CT scans can be dangerous for patients with renal failure. Thus, for these patients, ultrasound is the most useful non-invasive diagnostic tool.
The sonographic findings in children with ARPKD are well known. Sonography reveals diffusely increased cortical echogenicity when compared with the hepatic parenchyma as well as loss of the corticomedullary differentiation [17]. Kidney size in ARPKD patients peaks at 12 years of age, gradually becoming smaller and stabilizing by 45 years of age, while echogenicity tends to normalize over time [17]. Furthermore, secondary cortical cyst formation can be found in older children and young adults with ARPKD, producing a pattern that has been described as being similar to that seen in sonograms of ADPKD patients [9,17]. Nevertheless, our study suggests that these sonographic findings may be different enough in comparison with those found in ADPKD patients to allow a correct diagnosis.
The loss of the corticomedullary differentiation, increase of cortical echogenicity, and presence of multiple cyst smaller than 1.5 cm throughout the normal-sized kidney are common findings in young adults with ARPKD. The basic pathological lesion in ARPKD is at the level of the collecting ducts. The increased echogenicity is due to the interfaces produced by the walls of ectatic tubules that are too small to be resolved by sonography [18]. Jain et al. [19] explained that the peripheral layer of cortex remains free of cysts because the peripheral cortex does not have any collecting or connecting ducts. Nevertheless our study does not corroborate this finding in any ARPKD patient because the peripheral cortex also had cysts, probably due to secondary cortical cyst formation in older children and young adults.
In ADPKD patients multiple or discrete cysts of varying sizes may be seen scattered throughout the cortex, including the subcapsular location, because cysts in ADPKD can arise from anywhere in the nephron or collecting system. The natural history of ADPKD kidneys is well established, with a correlation between the sonographic findings (number and size of cysts and size of the kidney) and the age and/or severity of the disease [20]. As the diseases progresses, the size and number of cysts and the renal volume increases. Nevertheless, we have found a high incidence of normal-sized kidneys (75.9%) in young adults with ADPKD (without the marked increase in kidney size described in other reports) [17,18] and less than 15 cysts per kidney (65.4%), probably because they were asymptomatic subjects. In this age group, the renal cortex is almost always conserved, unlike with ARPKD, except in patients with more advanced forms of ADPKD in which there is moderate or severe nephromegaly and the cortex is barely visible. Detecting nephromegaly can help in differentiating ADPKD from ARPKD, as in the four ADPKD subjects with renal failure in our study. Moreover, in general, ADPKD patients with renal failure present with larger cysts than those in ARPKD patients.
Our results also indicate that the sonographic evaluation of the liver is very useful in differentiating between ADPKD and ARPKD. In patients with ARPKD whose disease becomes manifest in later childhood, hepatic disease is more severe than in early onset [5,18,19]. ARPKD is always associated with hepatic fibrosis and may occasionally be associated with Caroli's disease. Liver histopathology reveals biliary dysgenesis or ductal plate malformation, characterized by the fibrous enlargement of the portal tracts or by portalportal bands of fibrous tissue containing abnormal bile ducts. In addition, various segments of the intrahepatic bile ducts may be dilated, producing bile stasis and cholangitis. The sonographic findings observed in the four patients with ARPKD in our study represent the spectrum of hepatic involvement of the disease. The sonographic appearance of hepatic fibrosis can show increase of the echogenicity and diffuse heterogeneous structure, but the visualization of multiple diffuse echogenic areas that represent the thickened fibrosed portal tracts encompassing portal tributaries is characteristic. This finding is non-specific because it has been described in other diseases such as schistosomiasis, hepatitis, etc. [21]. In ARPKD patients thickened fibrosed portal tracts reveal abnormal development of the biliary tree. The sonographic appearance of Caroli's disease is characteristic: saccular dilatations of bile ducts, which may contain intraluminal bulbar protrusions and cross-bridges, as the result of an encasement of portal radicles by areas of ductal ectasia [22]. Colour Doppler discloses hepatic arterial and portal venous flow within the fibrovascular projections in the bile ducts [23]. Demonstration of communication between sacculi and bile ducts is important in distinguishing Caroli's disease from polycystic liver disease [24]. Our results indicate that the presence of a polycystic kidney in a young adult with hepatic fibrosis or Caroli's disease is highly suggestive of ARPKD. In rare cases without any clear clinical signs of hepatic fibrosis, or without typical findings in the ultrasound study, a liver biopsy can be useful [13] in demonstrating congenital fibrosis. Only one of the patients presented in this study underwent a liver biopsy. We did not perform this procedure in the other patients, because liver biopsy is an invasive procedure with a risk of complications (two patients had multiple and large intrahepatic duct ectasia), and linkage analysis was consistent with ARPKD in all cases. However, ADPKD cannot be completely excluded in patients with polycystic kidneys and hepatic fibrosis because this association has been reported in ADPKD patients [25,26]. Of the 400 ADPKD subjects studied in our department in the last 3 years, we have found this association in only one case (a subject of the group of ADPKD with renal failure), thus confirming that it is a rare association. On the other hand, the presence of a normal liver or simple hepatic cysts in a young adult with polycystic kidneys is highly suggestive of ADPKD [3]. Simple hepatic cysts are a common feature in ADPKD adults and in 20% of ADPKD patients younger than 30, but are extremely rare in ARPKD patients.
In conclusion, the evaluation of the sonographic features of the kidneys and those of the liver may help in the differential diagnosis between ARPKD and ADPKD in early adulthood.
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Notes |
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References |
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