Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood

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1 Pediatr Radiol (2002) 32: DOI /s ORIGINAL ARTICLE Fred E. Avni Gretel Guissard Michelle Hall Franc oise Janssen Viviane DeMaertelaer Franc oise Rypens Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood Received: 15 May 2001 Accepted: 20 September 2001 Published online: 11 January 2002 Ó Springer-Verlag 2002 F. E. Avni (&) Æ G. Guissard Æ F. Rypens Department of Paediatric Imaging, Children University Hospital Queen Fabiola ULB, Avenue J.J. Crocq 15, 1020 Brussels, Belgium Tel.: Fax: M. Hall Æ F. Janssen Department of Nephrology, Children University Hospital Queen Fabiola ULB, Brussels, Belgium V. DeMaertelaer Department of Medical Statistics (IRIBHN), Faculty of Medicine Research, Brussels, Belgium Abstract Objective: To determine which US changes occur with time in children affected by autosomal recessive (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) and whether any of these changes correlate with the onset of renal failure. Materials and methods: We reviewed the US features of 29 patients (16 ARPKD, 13 ADPK) imaged by at least two US examinations. We analysed the size and echogenicity of the kidneys, corticomedullary differentiation (CMD), the presence, location and size of cysts and any other anomaly that developed with time. In order to determine whether a relationship could be found between any of the US changes and the onset of the renal failure (based on a glomerular filtration rate <50 ml/min per 1.73 m 2 ), a Pearson exact chi-square test was calculated. Results: For ARPKD, renal size was above 4 standard deviations (SD) in 10 of 16 patients, but it remained stable during evolution (10/16). The kidneys appeared hyperechoic (16/16), without CMDin the majority (11/16) of patients. Changes in the appearance of CMDover time were observed in five patients. Small cysts (<1 cm) were present at the time of diagnosis in seven patients, larger cysts (>1 cm) in three. A diffuse microcystic pattern was observed in three patients. Diffuse hyperechoic foci developed in 14 patients 13 of whom had developed renal failure at the time of the examination or rapidly thereafter (statistical correlation P=0.0125). For ADPKD, renal size was between 0 2 SDin 7 of 13 patients and above 2 SDin the other 6. Renal echogenicity was normal in five, difficult to assess in five and the kidneys appeared hyperechoic without CMDin three patients. Cysts larger than 1 cm were present in 8 of 12 patients (>3 cm in 5). In four patients, the cysts measured less than 1 cm. In the last child, the diagnosis had been made antenatally and the first cysts appeared at the age of 6 months. The size of the kidneys (13/13) and of the cysts (11/13) remained stable. No renal failure occurred. Conclusions: AR- PKDmay manifest with various US patterns and there may be evolution in the appearances over time. Our study confirms a significant relationship between the development of diffuse hyperechoic foci and the onset of renal failure. In older children, ARPKDand ADPKDmay closely resemble each other. Large (>3 cm) cysts are the US hallmark for the diagnosis of ADPKD; furthermore, fewer US changes occur with time during childhood in ADPKD. Keywords Ultrasound Æ Children Æ Kidneys Æ Cysts Æ Polycystic disease

2 170 Introduction Polycystic kidney diseases include two types of hereditary diseases that are characterised by their mode of transmission and by specific pathological findings autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) [1, 2, 3, 4]. During recent years, as a result of improvements in US, more cases have been detected during fetal life or during the neonatal period [5, 6, 7, 8, 9, 10, 11, 12]. Although patients may die rapidly after birth (due to pulmonary hypoplasia rather than renal failure), the prognosis of ARPKDis less bleak than it used to be. Many patients survive the neonatal period and progress satisfactorily through childhood as a consequence of better management and renal replacement therapy if required [2, 4, 5]. On the other hand, ADPKD tends to be detected earlier than it used to be in the past, secondary to obstetrical US or because of screening of relatives in affected families [13]. Most children remain asymptomatic up to adulthood; nevertheless, they should be monitored clinically and sonographically in order to prevent complications [14, 15, 16]. Very few studies have evaluated the evolution of the US appearances through childhood [17, 18]. The aims of the present study were to determine whether US changes occur during childhood and whether these changes correlate with worsening of renal function. Materials and methods We reviewed the US examinations of 29 patients with ARPKD (n=16) or ADPKD (n=13) who were followed up in our institution from 1985 to 2000 and who underwent at least two US examinations. The diagnosis of ARPKDwas based on pathological findings in 4 patients and clinical and radiological evaluation after multidisciplinary discussion in 16 others. The diagnosis of ADPKD was based on family history. Various US criteria were analysed by two observers (F.E.A. and G.G.) when reviewing the hard copies of the examinations performed at diagnosis and during follow-up: renal size [expressed in standard deviations (SD) from the mean] [19], parenchymal echogenicity (relative to the liver or spleen), status of corticomedullary differentiation (CMD; present, absent or reversed), number, location and size of cysts, and development of any particular new US pattern. The type of US pattern was determined after agreement between the two observers. The US examinations were performed with different equipment through time (ATL; Toshiba; Aloka; Acuson) using MHz curvilinear, sector and linear transducers. The US settings were optimised to the size of the patients. Renal function was assessed by calculation of the glomerular filtration rate (GFR). Impaired renal function was defined as a GFR of ml/min per 1.73 m 2 and renal failure when GFR was less than 50 ml/min per 1.73 m 2. The possible relationship between renal function (normal or abnormal) and the different US features evaluated were tested using a Pearson chi-square test (exact test when required) [20]. Values of P<0.05 were considered significant. Results During the review period, 20 patients presented the clinical and imaging features [21] of ARPKD. Four died rapidly after birth and the diagnosis was confirmed by pathological examination. The other 16 survived the neonatal period and are still alive. Among these 16 patients, 2 had an antenatal diagnosis at 19 and 30 weeks respectively, 5 were diagnosed during the neonatal period and 9 between 4 and 12 years of age. These patients have been followed up for a mean of 5 years 4 months (3 months 15 years). Renal size at the time of the diagnosis was normal (0 2 SD) in one child, more than 2 SD in five and more than 4 SDin ten. The size, as measured during the last examination on follow-up was stable in ten, increased in one and reduced in five patients. At the time of diagnosis, all kidneys in the 16 patients appeared hyperechoic. The CMDwas abnormal in all the patients (Figs. 1a, 2a, 3a): increased in 2, absent in 11 and reversed in 3. During follow-up examinations, evolution of the CMDwas observed in five patients: from hypoechoic to heterogeneous in one, from hypo- to hyperechoic in two, and from hyper- to hypoechoic in two. Two patients showed multiple changes with time (Fig. 2). In 14 patients, the entire renal parenchyma evolved towards a heterogeneous, ill-defined pattern that included the development of diffuse hyperechoic foci without acoustic shadowing (Figs. 1b, 3a). In one patient, pathological evaluation of a surgically removed kidney was possible; the hyperechoic foci corresponded to parenchymal deposits of calcium oxalate. Cysts were present at the time of diagnosis in ten ARPKDpatients. Their size was smaller than 1 cm in seven and greater than 1 cm in three patients. A diffusely microcystic pattern, defined as a globally hyperechoic kidney with diffuse tiny cysts, was encountered in three patients, two at the time of diagnosis and one during follow-up studies (Fig. 3b). The size of the cysts increased in one patient, new cysts appeared in two others (Fig. 2c). Among the 16 patients, 14 (13 with the pattern of diffuse hyperechoic foci) developed renal failure. Two have undergone transplantation, five have severe renal failure with systemic hypertension and seven have moderate renal failure. The mean age of onset of renal failure was 4 years 6 months (range 1 day 7 years 10 months). A statistically significant relationship was observed between the development of hyperechoic foci and renal failure (P=0.025) (Table 1). This correlation was not demonstrated for any other parameter that was studied (for instance, P=0.215 for the evolution of renal size or P=0.307 for the development of renal cysts).

3 171 Only 4 of the 16 patients presented US signs of hepatic involvement. In one, portal hypertension was present at the time of diagnosis; in two, periportal fibrosis was demonstrated on US; and in the fourth patient, there was evidence of cystic biliary duct dysgenesis. The patient with portal hypertension was shunted; no evolution was observed in the others. Thirteen patients from ten families had ADPKD. In one patient, an antenatal diagnosis was made on the basis of hyperechoic kidneys in the fetus of an affected mother. In another, the diagnosis was made incidentally at the age of 4 years. In ten patients, the diagnosis was made between 4 and 12 years and in the last patient at age 14 years. In all the patients but two, a positive family history of ADPKD was known at the time of diagnosis. Mean follow-up time was 11 years 2 months (range 3 months 17 years). At time of diagnosis, the renal size was within 0 2 SDin seven patients, more than 2 SDin two and more than 4 SDin four. No major size change in terms of SDwas observed during follow-up. The cortex of the kidneys appeared hyperechoic with increased CMDin three children. The echogenicity of the cortex and of the medulla was normal in five and difficult to assess due to large cysts in five patients. Cysts were present in all but one patient at the time of diagnosis. In the patient with an antenatal diagnosis of echogenic kidneys, the first cysts appeared after birth at the age of 6 months (Fig. 4). Among the 12 patients with cysts, the size of the cysts was greater than 3 cm in five, 1 3 cm in four and smaller than 1 cm in two. On followup, the size of the cysts was stable in 11 patients and increased in 2 (Fig. 5). None of the patients had evidence of hepatic or other visceral involvement. None of the patients with ADPKD developed renal failure during childhood. Mild decreasing renal function was observed in two patients at the age of 17 years and 25 years. Discussion Fig. 1a, b US evolution of a patient with ARPKDover a 5-year period. a At age 3 months. Transverse scan of the right kidney (4.5 cm between crosses) shows thin echogenic cortex and wide cystic-appearing medulla. b At age 5 years. Transverse scan of the right kidney shows heterogeneous renal parenchyma, without CMD, presenting small cysts and diffuse hyperechoic dots (arrowheads). At that time renal failure was present. The arrows point to the anterior limits of the kidney The discovery of renal cystic disease on US examination represents a difficult challenge. Among the many entities to be considered, ARPKDand ADPKDare the most commonly encountered. The diagnosis of ADPKD is facilitated by a positive family history of the disease. The diagnosis of ARPKDmay be difficult when a pathological specimen is not available, and in such cases the probable diagnosis can only be made after multidisciplinary discussion [1, 2, 3, 4]. ARPKDand ADPKDare characterised by genetic transmission and by their pathological characteristics. On pathological examination, ARPKDshows extremely dilated medullary tubules while in ADPKD the cysts and cystic dilatation involve the glomeruli and cortical tubules.

4 172 Fig. 2a c Long-term follow-up of ARPKD. Sagittal scans of the right kidney. a At birth the cortex is hyperechoic and the medulla hypoechoic with cystic components. b At age 3 years, CMDis now reversed. c At age 15 years, renal size has diminished, the renal parenchyma has become heterogeneous without CMDand there are small cysts and hyperechoic spots (arrowheads) Fig. 3a, b Evolution towards the microcystic pattern in ARPKD. Sagittal scans of the left kidney. a At age 7 years there is a heterogeneous pattern with hyperechoic dots and few cysts. b At age 11 years there is a diffuse microcystic pattern Due to the more widespread use of US, more cases are detected in utero or during childhood. Patients are thus treated and followed up for a longer time [14, 15, 16, 17, 18]. The perinatal mortality remains high among patients affected by the severe form of ARPKD(4/20 patients in our series). The survival rate has improved in milder forms thanks to early nephrological management. Recent series report a survival rate of 82% at age 3 years and 79% at age 15 years; all the patients in our series survived during the period of our study. Yet, many ARPKDpatients have or will develop renal failure (at a mean age of 4 years 6 months in our series) and therefore close clinical, biochemical and US follow-up is mandatory [14, 15]. Little is known of the evolution of the US patterns in these diseases. Our series reveals that the US appearances change with time. Only one other study has addressed this potential US evolution through time and the correlation with the onset of renal failure [17]. Compared to that study, much more variation of the US patterns occurred with time in our series. In our series, at diagnosis, the kidneys were enlarged (+2 to +4 SD) in most (15/16) patients surviving the neonatal period. The size was mainly stable (10/16) or decreased (5/16) during follow-up. The parenchyma appeared hyperechoic (16/16) and in most cases without CMD(11/16). Other patterns were observed: hypo- or hyperechoic medulla (three and two patients, respectively) or a diffuse microcystic pattern in three patients. Furthermore, an evolution from one pattern to another was observed in five patients. The appearance of the medulla depends upon the degree of tubular dilatation and on the presence of tubular precipitates at the time of the examination. This is better demonstrated with newer US equipment [21, 22, 23]. Another striking evolution in our series was the development of hyperechoic foci in 14 patients (13 of whom had developed renal failure). These spots range from 1 to 3 mm in size, are uniformly hyperechoic, do not display any acoustic shadowing and have been also described by Lucaya et al. [23] They found this feature in six

5 173 Table 1 Relationship between renal failure and hyperechoic dots (v 2 =100%, P=0.025; + present, absent) Hyperechoic dots + Hyperechoic dots Renal failure Renal failure 1 2 Fig. 5a, b Evolution of ADPKD. Sagittal scan of the right kidney. a At age 8 years there is no visible CMD; large cysts are present in the upper and lower poles of the kidney and small ones in the middle part. b At age 12 years, the size of cysts in the upper pole are stable while those in the middle segment have enlarged slightly Fig. 4a, b Perinatal evaluation of ADPKD. a In utero (28 weeks gestation) sagittal scan of the right fetal kidney (k). The cortex is hyperechoic increasing the CMD. b At age 6 months, sagittal scan of the right kidney. The first cyst has appeared (arrow). L liver of nine patients in their series, all of whom had renal failure. These authors believed the deposits to be calcium citrate in the renal parenchyma and the calcium content was confirmed in several of their patients on CT. Correlation with CT was not available in our series; yet, in one of our patients calcium oxalate crystals were found at pathology. Whatever their nature, they seem closely associated with the development of renal failure (see below) and Lucaya et al. hypothesised a defect in excretion of citrate due to renal failure. Our series confirms that cysts may be part of the US appearance of ARPKDeither at diagnosis or during follow-up. The cysts tend to be smaller than in ADPKD and tend to be localised within the medulla. Yet, in older children, ARPKDmay be difficult to differentiate from ADPKD. In such cases, the differential diagnosis must be based on the familial history, on hepatic involvement, which would be exceptional in children with ADPKD (although in a small number, it occurred in our series only in patients with ARPKD), on the size of the renal cysts that are larger in ADPKD, and on the presence of

6 174 hyperechoic foci (which developed only in patients with ARPKDin our series). When looking for a possible relationship between various US features and worsening of renal function or the development of renal failure, only the presence of hyperechoic foci was statistically significant (P=0.025); this confirms the findings in a smaller study [23]. All cases with ADPKD in our series survived into adulthood without significant morbidity [16]. A decrease in renal function occurred in two patients of our series, but at age 17 years and 25 years, respectively. Sonographically, the evolution was slow with a very slow increase in the size of the cysts rather than in the size of the kidneys. This slow evolution confirms the results of another series [18]. An interesting feature in our series was the in utero detection of presumed disease in one patient with hyperechoic kidneys in whom the cysts of ADPKD only developed after birth. This type of evolution must be differentiated from the lethal variant of ADPKD that resembles, on obstetrical US, the severe form of ARPKD[24]. In conclusion, ARPKDcan have various US patterns with possible evolution with time. The development of small hyperechoic foci may be predictive of the onset of renal failure. In older children and adolescents, ARPKDand ADPKDmay resemble each other. The differential diagnosis must be based on familial history, hepatic involvement, the size of the cysts, renal function and the presence or absence of hyperechoic foci. The presence of renal cysts, usually large, is the hallmark of ADPKD; little evolution of the US appearance occurs during childhood in ADPKD. Knowledge of these different patterns and possible evolutions over time should help in determining a correct diagnosis, especially when the disease is detected late in childhood. References 1. Kimberling WJ, Pieke-Dahi SA, Kumar S (1991) The genetics of cystic diseases of the kidney. Semin Nephrol 11: Ogborn MR (1994) Polycystic kidney disease a truly paediatric problem. Pediatr Nephrol 8: Reuss A, Wladimoroff JW, Niermeijer MF (1991) Sonographic, clinical and genetics aspects of prenatal diagnosis of cystic kidney disease. Ultrasound Med Biol 17: Kaplan BS, Kaplan P, Rosenberg HK, et al (1989) Polycystic kidney diseases in childhood. J Pediatr 115: Zerres K, Mu cher G, Becker J, et al (1998) Prenatal diagnosis of ARPKD: molecular, genetics, clinical experience, and fetal morphology. Am J Med Genet 76: Reuss A, Wladimoroff JW, Stewart PA, et al (1990) Prenatal diagnosis by ultrasound in pregnancies at risk for ARPKD. Ultrasound Med Biol 16: Wisser J, Hebisch G, Froster U, et al (1995) Prenatal sonographic diagnosis of ARPKDduring the early second trimester. Prenat Diagn 15: Macdermot KD, Saggar-Malik AK, Economides DS, et al (1998) Prenatal diagnosis of ADPKD (PKD 1) presenting in utero and prognosis for very early onset disease. J Med Genet 35: Zerres K, Rudnik-Scho neborn S, Deget F (1993) Childhood onset ADPKD in sibs: clinical picture and recurrence risk. J Med Genet 30: Michaud J, Russo P, Grignon A, et al (1994) ADPKD in the fetus. Am J Med Genet 51: Journel H, Guyot C, Barc RM, et al (1989) Unexpected ultrasonographic prenatal diagnosis of ADPKD. Prenatal Diagn 9: Edwards OP, Baldinger S (1989) Prenatal onset of ADPKD. Urology 34: Nicolau C, Tora R, Badenas C, et al (1999) ADPKD types 1 and 2: assessment of US sensitivity for diagnosis. Radiology 213: Jamil B, McMahon LP, Savige JA, et al (1999) A study of long-term morbidity associated with ARPKD. Nephrol Dial Transplant 14: Zerres K, Rudnik-Scho neborn S, Deget F, et al (1996) ARPKDin 115 children: clinical presentation, course and influence of gender. Acta Paediatr 85: Demetriou K, Tziakouri C, Anninou K, et al (2000) ADPKD type 2. Ultrasound, genetic and clinical correlation. Nephrol Dial Transplant 15: Blickman JG, Bramson RT, Herrin JT (1995) ARPKD: long-term sonographic findings in patients surviving the neonatal period. AJR 164: Fick GM, Duley IT, Johnson AM, et al (1994) The spectrum of ADPKD in children. J Am Soc Nephrol 4: Konus OL, Ozdemir A, Akkaya A, et al (1998) Normal liver spleen, and kidney dimensions in neonates, infants and children: evaluation with US. AJR 171: Mehta C, Patel N (1995) StatXact 3. Cytel Software Corporation, Cambridge 21. Lonergan GJ, Rice RR, Suarez ES (2000) Autosomal recessive polycystic disease: radiologic pathologic correlation. RadioGraphics 20: Jain M, LeQuesne GW, Bourne AJ, et al (1997) High-resolution ultrasonography in the differential diagnosis of cystic diseases of the kidney in infancy and childhood: preliminary experience. J Ultrasound Med 16: Lucaya J, Entiquez G, Nieto J, et al (1993) Renal calcifications in patients with ARPKD: prevalence and cause. AJR 160: Ceccherini I, Lituania M, Cordone MS, et al (1989) ADPKD: prenatal diagnosis by DNA analysis and sonography at 14 weeks. Prenat Diagn 9: