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Investigating the newborn kidney: update on imaging techniques
Seminars in Neonatology (2003) 8, 269–278
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Investigating the newborn kidney: update on imaging techniques Isky Gordon a*, Michael Riccabona b a b
Great Ormond Street Hospital for Children, London WC1N 3JH, UK Division of Pediatric Radiology, Department of Radiology, University Hospital, Graz, Austria
KEYWORDS Ultrasound; MAG3 renogram; DMSA; Magnetic resonance imaging; Functional imaging
Summary Advances in imaging have resulted in higher-quality resolution. Techniques formerly considered to give pure anatomic information are now providing functional data, but the functions provided are not those typically measured in pathophysiologic terms. Instead, the data provided demand that we incorporate this new information into the understanding of the pathologic processes that confront us in clinical practice. Ultrasound provides information about kidney volume, blood flow velocity and blood flow volume. Radioisotopes can show the ability of the proximal tubules to extract the tracer from the blood as well as the ability of the kidney to clear the tracer into the bladder. Magnetic resonance imaging provides information about water content of the kidney. © 2003 Elsevier Ltd. All rights reserved.
Introduction Imaging of the kidney and urinary tract in the newborn requires specific clinical indications. Broadly, these fit into two categories: the prenatal ultrasound (US) diagnosis of a nephro-urological abnormality1 and the ill neonate.
Techniques Ultrasound Modern US examination of the neonatal urinary tract demands high-resolution curved- and lineararray transducers (14–7 MHz). These transducers, with new technology allowing modern beam formation, and image compounding techniques, enable a detailed evaluation of the neonatal kidney (Figs. 1–3). This is in addition to assessment of dilatation and bladder structure. US is heavily operator dependent, and the more modern * Corresponding author. Tel.: +44-20-7829-8615; +44-20-7829-8665 E-mail address: [email protected] (I. Gordon).
fax:
equipment requires the most skilled and experienced operator.2 M-mode US enables a semiquantitative assessment and documentation of ureteral peristalsis.3 Harmonic imaging is a new US technique based on the first harmonic response generated by tissue resemblance or by the specific contrast media response. This improves border delineation, particularly in liquid-filled structures such as a dilated collecting system, or improves the depiction of US contrast material (e.g. in echo-enhanced urosonography). US contrast media instilled into the bladder enable a sonographic assessment of vesico-ureteric reflux (VUR).4 The various Doppler techniques allow a semiquantitative assessment of aspects of blood flow: color Doppler sonography (CDS) gives a quick and comprehensive overview of the anatomy, flow velocity and direction of flow in the major renal vessels (see Figs. 1 and 2). Duplex Doppler sonography (DDS) provides detailed information of flow profiles, with a physiologically higher resistive index and relatively lower diastolic flow velocity in preterms and the first days of neonatal life (see Fig. 2). DDS may be valuable for the depiction of
1084-2756/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1084-2756(03)00031-9
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Fig. 2 Normal Doppler US. (A) Physiologically high resistive index (RI) (78–90%, versus less than 70% in children and adults) of the central renal segmental artery (cross-section, with a huge gallbladder anterior to the kidney). (B) Transverse CDS image, with DDS trace below: Increased (RI), as seen in patent ductus arteriosus or any other ARF, e.g. renal vein thrombosis. Note the negative diastolic flow with an otherwise normal-looking systolic flow profile. (C) aCDS of a neonatal kidney demonstrating normal renal vasculature in a longitudinal section.
Fig. 1 Normal kidney on US. High-resolution US scan of a normal neonatal kidney (increased cortical echogenicity compared with the liver so that a neonatal normal kidney looks like a severely diseased adult kidney), with physiologically transient hyperechoic papillary/medullary appearance (A,B) believed to be caused by sedimentations in the medullary tubuli or proteinuria. On CDS this causes twinkling (arrow).
indirect signs of perfusion disturbance, for example in renal vein thrombosis or infarction with consecutively altered/high-resistive arterial flow patterns in the affected renal segment. Amplitude-coded CDS (aCDS, or ‘power Doppler’), based on the
totally integrated Doppler spectrum, is a newer CDS technology demonstrating blood flow volume rather than blood flow velocity.5 The higher sensitivity of aCDS for visualization of the peripheral renal vasculature improves the sonographic evaluation of diffusely impaired cortical perfusion (the ‘halo sign’) and focal perfusion defects (e.g. infarction, thrombosis and segmental pyelonephritis). An experienced operator is essential to apply the correct aCDS settings (e.g. filter, gain and sample size), and—particularly in neonates—aCDS requires an US device with high frame rates. Echo-enhanced US has to date only rare neonatal indications.
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Other aspects can only be extrapolated indirectly and are limited: for example, dilatation does not equal obstruction (a severely dilated kidney with parenchymal thinning can have a better function than some kidneys with only little distension due to reduced renal urine production by the severely dilated kidney).
Micturating cystourethrogram (MCUG) This classical examination requires that the neonate is brought down to the radiology department. A bladder catheter is placed, the urine is drained and contrast is instilled into the bladder. Detailed anatomy of the bladder and male urethra is obtained, lateral views of the male urethra being mandatory for evaluation of a posterior urethral valve (PUV; Fig. 4). If VUR is present, details of the ureter and pelvi-calyceal system are also seen.7
Isotopes
Fig. 3 US in the presence of a UTI (no anatomical abnormality). (A) A swollen kidney with hazy corticomedullary differentiation but an otherwise normal-appearing kidney (increased in volume, but of normal length). (B) Longitudinal image of a right neonatal kidney demonstrates a focal lesion in the upper pole on aCDS (arrow; i.e. regionally diminished color signals in the area of focal renal involvement) consistent with segmental renal involvement, with some diffuse vessel rarefaction in the rest of the kidney.
A completely new tool is three-dimensional (3D) US. Preliminary experiences have been reported for neonates and infants, mainly focusing on the neonatal brain. Three-dimensional US examination provides a multiaxial demonstration of the whole kidney and enables improved renal parenchymal volume calculations, particularly in irregularly shaped kidneys or in significant hydronephrosis, as the dilated collecting system can be deducted from the overall renal volume.6 This may have diagnostic implications, whereas the potential for creating rendered views (e.g. of the dilated collecting system) may serve as an excellent tool for the comprehensive demonstration of complex pathology comparable to intravenous urogram (IVU) or magnetic resonance urogram (MRU) images. This modality may be applicable to neonates as a bed side investigation. Functional evaluation is currently limited to aspects of perfusion and peristalsis assessment.
Functional imaging studies using a short-lived radiotracer (technetium-99m) are possible at any age. The child must come to the gamma camera as very few units have mobile cameras. A dynamic study uses a tracer that is taken up by the kidney and excreted into the urine, either diethylenetriaminepentaacetic acid (DTPA) or mercaptoacetyl triglycine (MAG3). The latter has high protein binding and thus remains mainly in the intravascular space compared with DTPA. The renal extraction of MAG3 is virtually double that of DTPA, making MAG3 the isotope of choice in the neonate and infant. The parameters that can be estimated include renal blood flow as a percentage of cardiac output, differential renal function (DRF) and transit/drainage, especially if dilatation exists. Renal blood flow is estimated during the period between 0 and 20 s after the intravenous bolus injection, whereas DRF is estimated during the period between 60 and 120 s (Fig. 4B). The results of all three parameters are expressed for each kidney. Background tracer activity during this period is high and so background subtraction is essential. The drainage function is evaluated when dilatation is present using a diuretic (furosemide). Quantification of drainage should take into account DRF as well as allow gravity to have its full effect, and the bladder should be empty. An empty bladder is usually achieved spontaneously when furosemide has been given intravenously. A static scan using dimercaptosuccinic acid (DMSA) will allow an estimation of DRF and focal parenchymal defects. DMSA is extracted by the
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Fig. 4 Obstruction due to posterior urethral valve (PUV). This male infant presented with urosepsis and in renal failure at 4 weeks of age. (A) The top two images are longitudinal images of each kidney showing marked hydronephrosis. Both kidneys were of equal size on US. The bottom left image shows a cross-section through the thick-walled bladder with the two dilated ureters behind (++). The MCUG shows contrast refluxing into the left ureter, dilated posterior urethra and the abrupt change in caliber of the urethra due to the valve. (B) The renal failure was not improving despite improvement of the urosepsis and treatment of the PUV. The technetium-99m MAG3 diuretic renogram images on the left showed reduced function of the right kidney with severely reduced function of the left kidney. The functional image in the top right shows the poorly functioning left kidney to better advantage. The kidney curves reveal poor drainage, which is what one would expect with renal immaturity, CRF and markedly dilated collecting systems.
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proximal tubules and fixed in these cells thus allowing imaging 2–4 h post-intravenous injection. The main advantage of this static DMSA scan over the dynamic scan is the lower background tracer activity, thus enabling a more reproducible DRF estimation (Figs. 5 and 6). In the older child, glomerular filtration rate (GFR) is used to measure overall renal function, whereas in the neonate and during the first few months of life, overall renal function is usually based on serum creatinine level. GFR is rarely estimated during the neonatal/infancy period except under research conditions. A direct isotope cystogram is carried in a similar fashion to micturating cystourethrogram (MCUG). Instead of using contrast, one uses tecnetium-99 m, so the radiation dose is much lower than with MCUG. The disadvantage is the loss of anatomical detail, especially of the urethra. There are no longer any indications for undertaking IVUs during the neonatal period, and only rare indications in the first 6–12 months of life. The anatomic and functional information from US or MRU, and DMSA or MAG3 scanning, will provide virtually all that an IVU can offer, plus a great deal more.
Maturation and growth The full complement of nephrons are present at 36 weeks gestation, so that all further development is by growth and maturation of the nephron. During the first 24–48 h of life, there are large changes in renal blood flow. Maturation of filtration is most rapid in the first few weeks of life, slowing somewhat during the subsequent months. If filtration is adjusted for surface area, GRF is virtually at an adult level by 2 years of age, and tubular maturity by 1 year of age. Growth continues, however, throughout childhood and adolescence.8 Low renal function will cause a reduced clearance of radiologic contrast media and the uptake of both DMSA and MAG3.9 This includes any cause of renal damage or renal insufficiency as well as lack of renal maturation so an IVU is never performed in these situations or during the first 4 weeks of life. DRF is unaffected by maturation. Values for GFR in the first year are available but rarely used. Most current common US examinations are independent of both filtration and drainage function. Renal size is an important indicator of kidney growth and disease; furthermore, renal maturation is marked by a normalization of the higher resistive index on DDS and the adaptation of renal
Fig. 5 Images from four different neonates. (A) The left-hand image is from a 5-day-old neonate with a prenatal diagnosis of both a multicystic kidney and a teratoma. US examination revealed a cystic structure behind the bladder and no left kidney (not shown). The DMSA scan here shows the normal right kidney with no evidence of renal function on the left or in the region of the bladder. The right-hand image was obtained from a 12-day-old neonate with a prenatal diagnosis of a duplex left kidney, which was confirmed on postnatal US. At 3 weeks of age, the DMSA scan shows bilateral duplex kidneys with reduced function in the left upper moiety (top arrow) resulting from an ectopic ureterocele. Reduced function in the right lower moiety is caused by dysplasia associated with VUR (bottom arrow). (B) A small, echogenic kidney with reduced parenchymal differentiation, consistent with renal dysplasia. (C) Diffuse renal vessel rarefaction, indicating poor perfusion and reduced function, in a child with renal failure arising from bilateral congenital renal dysplasia.
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Fig. 6 Autosomal recessive polycystic kidney disease. (A) Gray-scale US image showing a transverse section of the enlarged kidney with a non-specific increase in echogenicity of the parenchyma, with some microcystic anechoic spots. (B) DMSA scan where there are multiple areas of reduced or absent uptake of radiotracer. This is despite the relatively uniform appearance of the kidneys on US. (C,D) Images from a series of iminodiacetic acid (HIDA) liver scans. The early image (C) shows the enlarged left lobe, whereas the 30 min image (D) shows the dilated bile ducts and slow transit into the small bowel.
parenchymal echogenicity to the ‘adult’ appearance. Growth-related charts for normal values of kidney volume and bladder size (including those for neonates and preterm babies) are available for US. Renal length on US is, however, a suboptimal tool for evaluating renal size and growth.
Indications and timing of imaging Before imaging the kidneys and urinary tract, the clinician must be clear why the investigation is being requested, what results are possible and whether this potentially impacts on management. The timing of the investigations is important as some neonates are ill and others are well. It is especially important when the pathology has a short dynamic time course (e.g. renal venous thrombosis (RVT)). The first examination should always be a full US examination of the kidneys and urinary tract, if possible in a well-hydrated baby.
Antenatal hydronephrosis Antenatal diagnosis of bilateral hydronephrosis, especially with hydro-ureteronephrosis with or without a bladder abnormality, requires an US scan on the first day of life, especially in a boy, where a PUV may be present (see Fig. 4). With such findings in a girl, one should consider a neurogenic bladder, and a spinal US should be performed. If infravesical obstruction is diagnosed, adequate drainage is essential, and in boys a MCUG should be undertaken once drainage has been established. If the US is undertaken after drainage has been achieved, and the bladder is thus empty, saline should be instilled into the bladder so that adequate visualization of the lower ureters can be obtained and bladder wall thickness reliably measured. Functional imaging is not required in the neonatal period if overall renal function is maintained. A MAG3 diuretic renogram should be undertaken at about 3 months of age. With a raised serum creatinine level, a DMSA scan may be helpful (see Fig. 5).
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Fig. 7 Duplex right kidney with ectopic ureterocele. These MR images were taken following contrast (gadolinium) enhancement. (A) T1-weighted, early post-contrast image showing the dilated upper pole calyx (dark) of the left kidney. (B) Delayed 3D-MIP T1-weighted post-contrast image in which the collecting system of the upper moiety has also filled with gadolinium; the dilated ureter has not yet homogenously filled with contrast and is not seen properly. (C) Oblique view of the bladder showing contrast in the bladder, the ureterocele being seen as a filling defect at the bladder base.
In unilateral hydronephrosis (with or without a dilated ureter) and a normal opposite kidney, there is no urgency to undertake imaging. US for the evaluation of prenatally diagnosed unilateral hydronephrosis should be postponed to between the 5th and 7th day of life in order not to miss potential disease.10 If the first US is normal then, a repeat scan at 1–2 months of age is recommended. If that is normal, no further imaging is required. With significant unilateral renal pelvic dilatation, a dynamic diuretic MAG3 renogram is required at 4 weeks of age.11,12 If a dilated ureter is also detected, or other indirect signs suggestive of VUR (e.g. a thickened pelvic wall) are present on US, an MCUG should be undertaken at the time of the MAG3 renogram to exclude VUR as the cause of the ureteric dilatation. In complex urogenital anomalies, MRU may be helpful to complete the imaging. MR is independent of function (Fig. 7).
The sick neonate The neonate may be ill because of an acute insult (e.g. prolonged labor, septicaemia or asphyxia). Acute renal failure (ARF) in a neonate may be pre-renal, renal or post-renal. The differential diagnosis of intrinsic ARF includes toxic renal damage, RVT, acute tubular necrosis (ATN), cortical and/or medullary necrosis as well as pre-existing conditions such as hypoplasia or dysplasia. These conditions may co-exist and may be accompanied
by any degree of ARF. In all these conditions, an urgent US examination is required; this will usually allow differentiation of the three subtypes and may provide hints toward the specific disease entity. On the US scan, one looks for dilatation, assesses the renal parenchymal echomorphology and size, evaluates renal blood flow velocity by Doppler ultrasonography and documents kidney status. Further imaging, if indicated, and therapy depends on the laboratory and US findings, as described below. If severe bilateral hydronephrosis with or without pyonephrosis is seen on US examination, drainage must be facilitated as soon as possible. With bladder outflow obstruction, this is achieved by bladder drainage. With upper tract dilatation, an image-guided percutaneous nephrostomy is required, which may be even bilateral. Note that if the neonate is anuric or oliguric, the absence of dilatation does not exclude obstruction, including posterior urethral values. Further imaging will depend on the clinical course. If the renal failure persists in the presence of bilateral hydronephrosis, a DMSA scan will establish whether either kidney is non-functioning (see Figs. 3 and 4). The value of aCDS to assess function in the neonate should be evaluated in the clinician's institution. ARF secondary to an acute non-obstructive episode requires sequential US (including DDS and aCDS) in the neonatal period for initial assessment and follow-up. If the ARF resolves, a DMSA scan at
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3–6 months of age is suggested in addition to US follow-up in order to determine the long-term sequelae of the acute episode on individual kidney function. Protracted ARF or chronic renal failure (CRF) raises the clinically important issue of the potential for recovery of renal function. In this scenario, the combination of Doppler US and a DMSA scan help to establish prognosis. On DMSA, one will see a photon-deficient area in cases of cortical necrosis, whereas in prolonged ATN, the kidneys are visualized, even if not very well.
Neonatal chronic renal failure This may present in the first weeks of life in the absence of any acute episode. US scanning is required to estimate renal volume, evaluate parenchymal echogenicity, disturbance of renal parenchymal differentiation and cysts and assess for dilatation and bladder status. It is imperative that the neonate is well hydrated and has a full bladder at the time of the US examination. The most common finding is that of two small kidneys with little or no dilatation (see Fig. 5). The renal parenchyma may have a few small cysts, consistent with renal dysplasia. An MCUG should be undertaken in the neonatal period to ensure there is no PUV and to assess VUR and congenital reflux nephropathy. US follow-up and a DMSA scan at about 3–6 months of age are required. The child may eventually progress to end-stage renal failure although this may not occur until adolescence.
Urinary tract infection If the neonate has a symptomatic urinary tract infection (UTI) with fever, an US examination should be undertaken to assess the presence of obstructive uropathy and signs of renal involvement such as increased renal size, altered echogenicity and focal perfusion defects (see Fig. 3). If no dilatation is seen and there is a good response to treatment, further imaging can be delayed. An MCUG should be undertaken when the infection has been cleared, and a DMSA scan should be carried out at 6 months of age. If US shows an abnormal bladder, MCUG should be undertaken as soon as possible. If the infection is severe, an US is required immediately and should always include aCDS of the kidney.
Other conditions The kidneys may warrant investigation because of an abnormal prenatal US without hydronephrosis.
I. Gordon, M. Riccabona
The postnatal US may show a small bright kidney with or without cysts and—if unilateral—normal renal function. These small dysplastic kidneys usually have some function, even if it is rather poor. A kidney with ‘cysts’ of different sizes and no clear communication between them represents a multicystic non-functioning kidney (see Fig. 5). As long as the other kidney is normal on US scanning, the prognosis is good. The associated important abnormalities are dilatation of the opposite kidney due to pelvi-ureteric junction obstruction (PUJO) or (mid) ureteric stenosis/obstructive megaureter. This requires a dynamic MAG3 renogram. Bilateral multicystic kidney disease is incompatible with survival. If the kidneys have bilateral cysts of different sizes, yet the neonate has a normal creatinine and an otherwise sonographically normal renal parenchyma, the most probable diagnosis is autosomal dominant polycystic kidney disease (ADPKD), although this is relatively rare. The diagnosis of tuberous sclerosis must also be considered, especially since the gene defects for both these conditions are located in close proximity to each other. Tuberous sclerosis may present in the neonatal period with cardiac rhabdomyoma, so echocardiography should be suggested. The presence of bilateral large kidneys that are ‘solid’, with a ‘salt and pepper’ appearance, on US may result from autosomal recessive polycystic kidney disease (ARPKD; see Fig. 6). Furthermore in a clinical context, imaging can help to differentiate between neonatal nephritis and a kidney with ARF secondary to metabolic disease (e.g. hyperoxaluria), toxic damage or following an acute infective episode. When ARPKD is suspected then a liver US (liver fibrosis), a DMSA and iminodiacetic acid (HIDA) scans are essential in the first year of life.13 Rarely, neonatal renal tumors are discovered, the most common being a benign nephroblastic nephroma.
Associated congenital abnormalities In neonates with a congenital cardiac or gastrointestinal abnormality, a urinary tract US is required. If this is normal, no further imaging is required except in neonates with an anorectal malformation, who require an MCUG and a thorough systemic work-up. If the urinary tract US is abnormal, a radiotracer study (DMSA for an ectopic or single kidney, MAG3 with dilatation) and an MCUG
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are required. The ipsilateral genitalia are often involved in particularly complex congenital urinary tract malformations, especially in girls with a single kidney.
Practice points • There is a need for adequate training and research in the field of imaging. • Interdisciplinary interaction and communication/co-operation is necessary to adapt imaging protocols and to optimally exploit what modern imaging potentially offers. • This approach will facilitate research and help focus developments on clinical needs.
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• In nuclear medicine, modern advances will improve the detection and assessment of apoptosis and ischemia. High-quality images from radioisotope studies must become the norm. • The pathologic significance of the reactive cascade has been demonstrated by research into the tumor necrosis factor system and the enzymes directing angiogenesis. The assessment of new treatment strategies demands imaging techniques capable of evaluating responses to them. Image fusion plus a refinement of MR and isotope studies may allow non-invasive monitoring of these phenomena. New contrast media and radiotracers may open further avenues for imaging modalities.
References Research directions • The future of US examination holds promise in terms of combining contrast-enhanced US with harmonic imaging techniques, aCDS and real-time 3DUS scanning, allowing better morphologic and functional evaluation. US should become less operator dependent so that the full potential of the technological advances may be exploited • Magnetic resonance imaging (MRI) has been successfully applied to the neonatal and infant urinary tract. Fast sequences with strong gradients, improved gating and triggering techniques and improved spatial and temporal resolution provide excellent anatomic and functional (perfusion and drainage) imaging.14–16 The value of renal MRI in differentiating various parenchymal disease entities has not yet been evaluated, but the technique has vast potential for improving non-invasive diagnosis. Gadolinium-enhanced MR angiography using fast 3D gradient echo sequences allows a good depiction of the major vessels (e.g. an additional crossing renal artery in UPJO). To date, however, the restricted access, the need for sedation, the relatively high cost and the good results from US and scintigraphy limit the indications for MRU and MR angiography. MRI with the use of paramagnetic tracers promises to become capable of additional non-invasive and non-ionizing functional imaging.
1. de Bruyn R, Gordon I. Postnatal investigation of fetal renal disease. Prenat Diagn 2001;21(11):984–91. 2. Riccabona M. Potential of modern sonographic techniques in paediatric uroradiology. Eur J Radiol 2002;43:110–21. 3. Riccabona M, Sorrantin E, Fotter R. Application of functional m-mode sonography in pediatric patients. Eur Radiol 1998; 8:1457–61. 4. Bosio M. Cystosonography with echocontrast: a new imaging modality to detect vesicoureteric reflux in children. Pediatr Radiol 1998;28:250–5. 5. Riccabona M, Schwinger W, Ring E et al. Amplitude coded color Doppler sonography in pediatric renal disease. Eur Radiol 2001;11:861–6. 6. Riccabona M, Fritz G. Three-dimensional ultrasound (3DUS) in pediatric urological disease—preliminary experience, including volumetry. J Ultrasound Med 2002;21:S86. 7. Avni FE, Ayadi K, Rypens F et al. Can careful US examination of the urinary tract exclude vesicoureteral reflux in the neonate? Br J Radiol 1997;70:977–82. 8. Awad H, el-Safty I, el-Barbary M et al. Evaluation of renal glomerular and tubular functional and structural integrity in neonates. Am J Med Sci 2002;324(5):261–6. 9. Lythgoe MF, Gordon I, Anderson PJ. Effect of renal maturation on the clearance of Tc 99m MAG3. Eur J Nucl Med 1994; 21:1333–7. 10. Riccabona M, Ring E, Fueger G et al. Doppler sonography in congenital ureteropelvic junction obstrucion. Eur J Ultrasound 1996;3:205–9. 11. Gordon I. Diuretic renography in infants with prenatal unilateral hydronephrosis: an explanation for the controversy about poor drainage. BJU Int 2001;87(6):551–5. 12. Ozcan Z, Anderson PJ, Gordon I. Assessment of regional kidney function may provide new clinical understanding and assist in treatment of children with prenatal hydronephrosis. J Urol 2002;168(5):2153–7. 13. Zagar I, Anderson PJ, Gordon I. The value of radionuclide studies in children with autosomal recessive polycystic kidney disease. Clin Nucl Med 2002;27(5):339–44. 14. Avni F, Bali MA, Regnault M et al. MR urography in children. Eur J Radiol 2002;43:154–66.
278 15. Riccabona M, Simbrunner J, Ring E et al. Feasibility of MR-urography in neonates and infants with anomalies of the upper urinary tract. Eur Radiol 2002;12:1442–50.
I. Gordon, M. Riccabona 16. Borthne A, Nordshus T, Reiseter T et al. MR urography: the future gold standard in pediatric urogenital imaging? Pediatr Radiol 1999;29:694–701.
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Investigating the newborn kidney: update on imaging techniques Isky Gordon a*, Michael Riccabona b a b
Great Ormond Street Hospital for Children, London WC1N 3JH, UK Division of Pediatric Radiology, Department of Radiology, University Hospital, Graz, Austria
KEYWORDS Ultrasound; MAG3 renogram; DMSA; Magnetic resonance imaging; Functional imaging
Summary Advances in imaging have resulted in higher-quality resolution. Techniques formerly considered to give pure anatomic information are now providing functional data, but the functions provided are not those typically measured in pathophysiologic terms. Instead, the data provided demand that we incorporate this new information into the understanding of the pathologic processes that confront us in clinical practice. Ultrasound provides information about kidney volume, blood flow velocity and blood flow volume. Radioisotopes can show the ability of the proximal tubules to extract the tracer from the blood as well as the ability of the kidney to clear the tracer into the bladder. Magnetic resonance imaging provides information about water content of the kidney. © 2003 Elsevier Ltd. All rights reserved.
Introduction Imaging of the kidney and urinary tract in the newborn requires specific clinical indications. Broadly, these fit into two categories: the prenatal ultrasound (US) diagnosis of a nephro-urological abnormality1 and the ill neonate.
Techniques Ultrasound Modern US examination of the neonatal urinary tract demands high-resolution curved- and lineararray transducers (14–7 MHz). These transducers, with new technology allowing modern beam formation, and image compounding techniques, enable a detailed evaluation of the neonatal kidney (Figs. 1–3). This is in addition to assessment of dilatation and bladder structure. US is heavily operator dependent, and the more modern * Corresponding author. Tel.: +44-20-7829-8615; +44-20-7829-8665 E-mail address: [email protected] (I. Gordon).
fax:
equipment requires the most skilled and experienced operator.2 M-mode US enables a semiquantitative assessment and documentation of ureteral peristalsis.3 Harmonic imaging is a new US technique based on the first harmonic response generated by tissue resemblance or by the specific contrast media response. This improves border delineation, particularly in liquid-filled structures such as a dilated collecting system, or improves the depiction of US contrast material (e.g. in echo-enhanced urosonography). US contrast media instilled into the bladder enable a sonographic assessment of vesico-ureteric reflux (VUR).4 The various Doppler techniques allow a semiquantitative assessment of aspects of blood flow: color Doppler sonography (CDS) gives a quick and comprehensive overview of the anatomy, flow velocity and direction of flow in the major renal vessels (see Figs. 1 and 2). Duplex Doppler sonography (DDS) provides detailed information of flow profiles, with a physiologically higher resistive index and relatively lower diastolic flow velocity in preterms and the first days of neonatal life (see Fig. 2). DDS may be valuable for the depiction of
1084-2756/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1084-2756(03)00031-9
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Fig. 2 Normal Doppler US. (A) Physiologically high resistive index (RI) (78–90%, versus less than 70% in children and adults) of the central renal segmental artery (cross-section, with a huge gallbladder anterior to the kidney). (B) Transverse CDS image, with DDS trace below: Increased (RI), as seen in patent ductus arteriosus or any other ARF, e.g. renal vein thrombosis. Note the negative diastolic flow with an otherwise normal-looking systolic flow profile. (C) aCDS of a neonatal kidney demonstrating normal renal vasculature in a longitudinal section.
Fig. 1 Normal kidney on US. High-resolution US scan of a normal neonatal kidney (increased cortical echogenicity compared with the liver so that a neonatal normal kidney looks like a severely diseased adult kidney), with physiologically transient hyperechoic papillary/medullary appearance (A,B) believed to be caused by sedimentations in the medullary tubuli or proteinuria. On CDS this causes twinkling (arrow).
indirect signs of perfusion disturbance, for example in renal vein thrombosis or infarction with consecutively altered/high-resistive arterial flow patterns in the affected renal segment. Amplitude-coded CDS (aCDS, or ‘power Doppler’), based on the
totally integrated Doppler spectrum, is a newer CDS technology demonstrating blood flow volume rather than blood flow velocity.5 The higher sensitivity of aCDS for visualization of the peripheral renal vasculature improves the sonographic evaluation of diffusely impaired cortical perfusion (the ‘halo sign’) and focal perfusion defects (e.g. infarction, thrombosis and segmental pyelonephritis). An experienced operator is essential to apply the correct aCDS settings (e.g. filter, gain and sample size), and—particularly in neonates—aCDS requires an US device with high frame rates. Echo-enhanced US has to date only rare neonatal indications.
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Other aspects can only be extrapolated indirectly and are limited: for example, dilatation does not equal obstruction (a severely dilated kidney with parenchymal thinning can have a better function than some kidneys with only little distension due to reduced renal urine production by the severely dilated kidney).
Micturating cystourethrogram (MCUG) This classical examination requires that the neonate is brought down to the radiology department. A bladder catheter is placed, the urine is drained and contrast is instilled into the bladder. Detailed anatomy of the bladder and male urethra is obtained, lateral views of the male urethra being mandatory for evaluation of a posterior urethral valve (PUV; Fig. 4). If VUR is present, details of the ureter and pelvi-calyceal system are also seen.7
Isotopes
Fig. 3 US in the presence of a UTI (no anatomical abnormality). (A) A swollen kidney with hazy corticomedullary differentiation but an otherwise normal-appearing kidney (increased in volume, but of normal length). (B) Longitudinal image of a right neonatal kidney demonstrates a focal lesion in the upper pole on aCDS (arrow; i.e. regionally diminished color signals in the area of focal renal involvement) consistent with segmental renal involvement, with some diffuse vessel rarefaction in the rest of the kidney.
A completely new tool is three-dimensional (3D) US. Preliminary experiences have been reported for neonates and infants, mainly focusing on the neonatal brain. Three-dimensional US examination provides a multiaxial demonstration of the whole kidney and enables improved renal parenchymal volume calculations, particularly in irregularly shaped kidneys or in significant hydronephrosis, as the dilated collecting system can be deducted from the overall renal volume.6 This may have diagnostic implications, whereas the potential for creating rendered views (e.g. of the dilated collecting system) may serve as an excellent tool for the comprehensive demonstration of complex pathology comparable to intravenous urogram (IVU) or magnetic resonance urogram (MRU) images. This modality may be applicable to neonates as a bed side investigation. Functional evaluation is currently limited to aspects of perfusion and peristalsis assessment.
Functional imaging studies using a short-lived radiotracer (technetium-99m) are possible at any age. The child must come to the gamma camera as very few units have mobile cameras. A dynamic study uses a tracer that is taken up by the kidney and excreted into the urine, either diethylenetriaminepentaacetic acid (DTPA) or mercaptoacetyl triglycine (MAG3). The latter has high protein binding and thus remains mainly in the intravascular space compared with DTPA. The renal extraction of MAG3 is virtually double that of DTPA, making MAG3 the isotope of choice in the neonate and infant. The parameters that can be estimated include renal blood flow as a percentage of cardiac output, differential renal function (DRF) and transit/drainage, especially if dilatation exists. Renal blood flow is estimated during the period between 0 and 20 s after the intravenous bolus injection, whereas DRF is estimated during the period between 60 and 120 s (Fig. 4B). The results of all three parameters are expressed for each kidney. Background tracer activity during this period is high and so background subtraction is essential. The drainage function is evaluated when dilatation is present using a diuretic (furosemide). Quantification of drainage should take into account DRF as well as allow gravity to have its full effect, and the bladder should be empty. An empty bladder is usually achieved spontaneously when furosemide has been given intravenously. A static scan using dimercaptosuccinic acid (DMSA) will allow an estimation of DRF and focal parenchymal defects. DMSA is extracted by the
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Fig. 4 Obstruction due to posterior urethral valve (PUV). This male infant presented with urosepsis and in renal failure at 4 weeks of age. (A) The top two images are longitudinal images of each kidney showing marked hydronephrosis. Both kidneys were of equal size on US. The bottom left image shows a cross-section through the thick-walled bladder with the two dilated ureters behind (++). The MCUG shows contrast refluxing into the left ureter, dilated posterior urethra and the abrupt change in caliber of the urethra due to the valve. (B) The renal failure was not improving despite improvement of the urosepsis and treatment of the PUV. The technetium-99m MAG3 diuretic renogram images on the left showed reduced function of the right kidney with severely reduced function of the left kidney. The functional image in the top right shows the poorly functioning left kidney to better advantage. The kidney curves reveal poor drainage, which is what one would expect with renal immaturity, CRF and markedly dilated collecting systems.
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proximal tubules and fixed in these cells thus allowing imaging 2–4 h post-intravenous injection. The main advantage of this static DMSA scan over the dynamic scan is the lower background tracer activity, thus enabling a more reproducible DRF estimation (Figs. 5 and 6). In the older child, glomerular filtration rate (GFR) is used to measure overall renal function, whereas in the neonate and during the first few months of life, overall renal function is usually based on serum creatinine level. GFR is rarely estimated during the neonatal/infancy period except under research conditions. A direct isotope cystogram is carried in a similar fashion to micturating cystourethrogram (MCUG). Instead of using contrast, one uses tecnetium-99 m, so the radiation dose is much lower than with MCUG. The disadvantage is the loss of anatomical detail, especially of the urethra. There are no longer any indications for undertaking IVUs during the neonatal period, and only rare indications in the first 6–12 months of life. The anatomic and functional information from US or MRU, and DMSA or MAG3 scanning, will provide virtually all that an IVU can offer, plus a great deal more.
Maturation and growth The full complement of nephrons are present at 36 weeks gestation, so that all further development is by growth and maturation of the nephron. During the first 24–48 h of life, there are large changes in renal blood flow. Maturation of filtration is most rapid in the first few weeks of life, slowing somewhat during the subsequent months. If filtration is adjusted for surface area, GRF is virtually at an adult level by 2 years of age, and tubular maturity by 1 year of age. Growth continues, however, throughout childhood and adolescence.8 Low renal function will cause a reduced clearance of radiologic contrast media and the uptake of both DMSA and MAG3.9 This includes any cause of renal damage or renal insufficiency as well as lack of renal maturation so an IVU is never performed in these situations or during the first 4 weeks of life. DRF is unaffected by maturation. Values for GFR in the first year are available but rarely used. Most current common US examinations are independent of both filtration and drainage function. Renal size is an important indicator of kidney growth and disease; furthermore, renal maturation is marked by a normalization of the higher resistive index on DDS and the adaptation of renal
Fig. 5 Images from four different neonates. (A) The left-hand image is from a 5-day-old neonate with a prenatal diagnosis of both a multicystic kidney and a teratoma. US examination revealed a cystic structure behind the bladder and no left kidney (not shown). The DMSA scan here shows the normal right kidney with no evidence of renal function on the left or in the region of the bladder. The right-hand image was obtained from a 12-day-old neonate with a prenatal diagnosis of a duplex left kidney, which was confirmed on postnatal US. At 3 weeks of age, the DMSA scan shows bilateral duplex kidneys with reduced function in the left upper moiety (top arrow) resulting from an ectopic ureterocele. Reduced function in the right lower moiety is caused by dysplasia associated with VUR (bottom arrow). (B) A small, echogenic kidney with reduced parenchymal differentiation, consistent with renal dysplasia. (C) Diffuse renal vessel rarefaction, indicating poor perfusion and reduced function, in a child with renal failure arising from bilateral congenital renal dysplasia.
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Fig. 6 Autosomal recessive polycystic kidney disease. (A) Gray-scale US image showing a transverse section of the enlarged kidney with a non-specific increase in echogenicity of the parenchyma, with some microcystic anechoic spots. (B) DMSA scan where there are multiple areas of reduced or absent uptake of radiotracer. This is despite the relatively uniform appearance of the kidneys on US. (C,D) Images from a series of iminodiacetic acid (HIDA) liver scans. The early image (C) shows the enlarged left lobe, whereas the 30 min image (D) shows the dilated bile ducts and slow transit into the small bowel.
parenchymal echogenicity to the ‘adult’ appearance. Growth-related charts for normal values of kidney volume and bladder size (including those for neonates and preterm babies) are available for US. Renal length on US is, however, a suboptimal tool for evaluating renal size and growth.
Indications and timing of imaging Before imaging the kidneys and urinary tract, the clinician must be clear why the investigation is being requested, what results are possible and whether this potentially impacts on management. The timing of the investigations is important as some neonates are ill and others are well. It is especially important when the pathology has a short dynamic time course (e.g. renal venous thrombosis (RVT)). The first examination should always be a full US examination of the kidneys and urinary tract, if possible in a well-hydrated baby.
Antenatal hydronephrosis Antenatal diagnosis of bilateral hydronephrosis, especially with hydro-ureteronephrosis with or without a bladder abnormality, requires an US scan on the first day of life, especially in a boy, where a PUV may be present (see Fig. 4). With such findings in a girl, one should consider a neurogenic bladder, and a spinal US should be performed. If infravesical obstruction is diagnosed, adequate drainage is essential, and in boys a MCUG should be undertaken once drainage has been established. If the US is undertaken after drainage has been achieved, and the bladder is thus empty, saline should be instilled into the bladder so that adequate visualization of the lower ureters can be obtained and bladder wall thickness reliably measured. Functional imaging is not required in the neonatal period if overall renal function is maintained. A MAG3 diuretic renogram should be undertaken at about 3 months of age. With a raised serum creatinine level, a DMSA scan may be helpful (see Fig. 5).
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Fig. 7 Duplex right kidney with ectopic ureterocele. These MR images were taken following contrast (gadolinium) enhancement. (A) T1-weighted, early post-contrast image showing the dilated upper pole calyx (dark) of the left kidney. (B) Delayed 3D-MIP T1-weighted post-contrast image in which the collecting system of the upper moiety has also filled with gadolinium; the dilated ureter has not yet homogenously filled with contrast and is not seen properly. (C) Oblique view of the bladder showing contrast in the bladder, the ureterocele being seen as a filling defect at the bladder base.
In unilateral hydronephrosis (with or without a dilated ureter) and a normal opposite kidney, there is no urgency to undertake imaging. US for the evaluation of prenatally diagnosed unilateral hydronephrosis should be postponed to between the 5th and 7th day of life in order not to miss potential disease.10 If the first US is normal then, a repeat scan at 1–2 months of age is recommended. If that is normal, no further imaging is required. With significant unilateral renal pelvic dilatation, a dynamic diuretic MAG3 renogram is required at 4 weeks of age.11,12 If a dilated ureter is also detected, or other indirect signs suggestive of VUR (e.g. a thickened pelvic wall) are present on US, an MCUG should be undertaken at the time of the MAG3 renogram to exclude VUR as the cause of the ureteric dilatation. In complex urogenital anomalies, MRU may be helpful to complete the imaging. MR is independent of function (Fig. 7).
The sick neonate The neonate may be ill because of an acute insult (e.g. prolonged labor, septicaemia or asphyxia). Acute renal failure (ARF) in a neonate may be pre-renal, renal or post-renal. The differential diagnosis of intrinsic ARF includes toxic renal damage, RVT, acute tubular necrosis (ATN), cortical and/or medullary necrosis as well as pre-existing conditions such as hypoplasia or dysplasia. These conditions may co-exist and may be accompanied
by any degree of ARF. In all these conditions, an urgent US examination is required; this will usually allow differentiation of the three subtypes and may provide hints toward the specific disease entity. On the US scan, one looks for dilatation, assesses the renal parenchymal echomorphology and size, evaluates renal blood flow velocity by Doppler ultrasonography and documents kidney status. Further imaging, if indicated, and therapy depends on the laboratory and US findings, as described below. If severe bilateral hydronephrosis with or without pyonephrosis is seen on US examination, drainage must be facilitated as soon as possible. With bladder outflow obstruction, this is achieved by bladder drainage. With upper tract dilatation, an image-guided percutaneous nephrostomy is required, which may be even bilateral. Note that if the neonate is anuric or oliguric, the absence of dilatation does not exclude obstruction, including posterior urethral values. Further imaging will depend on the clinical course. If the renal failure persists in the presence of bilateral hydronephrosis, a DMSA scan will establish whether either kidney is non-functioning (see Figs. 3 and 4). The value of aCDS to assess function in the neonate should be evaluated in the clinician's institution. ARF secondary to an acute non-obstructive episode requires sequential US (including DDS and aCDS) in the neonatal period for initial assessment and follow-up. If the ARF resolves, a DMSA scan at
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3–6 months of age is suggested in addition to US follow-up in order to determine the long-term sequelae of the acute episode on individual kidney function. Protracted ARF or chronic renal failure (CRF) raises the clinically important issue of the potential for recovery of renal function. In this scenario, the combination of Doppler US and a DMSA scan help to establish prognosis. On DMSA, one will see a photon-deficient area in cases of cortical necrosis, whereas in prolonged ATN, the kidneys are visualized, even if not very well.
Neonatal chronic renal failure This may present in the first weeks of life in the absence of any acute episode. US scanning is required to estimate renal volume, evaluate parenchymal echogenicity, disturbance of renal parenchymal differentiation and cysts and assess for dilatation and bladder status. It is imperative that the neonate is well hydrated and has a full bladder at the time of the US examination. The most common finding is that of two small kidneys with little or no dilatation (see Fig. 5). The renal parenchyma may have a few small cysts, consistent with renal dysplasia. An MCUG should be undertaken in the neonatal period to ensure there is no PUV and to assess VUR and congenital reflux nephropathy. US follow-up and a DMSA scan at about 3–6 months of age are required. The child may eventually progress to end-stage renal failure although this may not occur until adolescence.
Urinary tract infection If the neonate has a symptomatic urinary tract infection (UTI) with fever, an US examination should be undertaken to assess the presence of obstructive uropathy and signs of renal involvement such as increased renal size, altered echogenicity and focal perfusion defects (see Fig. 3). If no dilatation is seen and there is a good response to treatment, further imaging can be delayed. An MCUG should be undertaken when the infection has been cleared, and a DMSA scan should be carried out at 6 months of age. If US shows an abnormal bladder, MCUG should be undertaken as soon as possible. If the infection is severe, an US is required immediately and should always include aCDS of the kidney.
Other conditions The kidneys may warrant investigation because of an abnormal prenatal US without hydronephrosis.
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The postnatal US may show a small bright kidney with or without cysts and—if unilateral—normal renal function. These small dysplastic kidneys usually have some function, even if it is rather poor. A kidney with ‘cysts’ of different sizes and no clear communication between them represents a multicystic non-functioning kidney (see Fig. 5). As long as the other kidney is normal on US scanning, the prognosis is good. The associated important abnormalities are dilatation of the opposite kidney due to pelvi-ureteric junction obstruction (PUJO) or (mid) ureteric stenosis/obstructive megaureter. This requires a dynamic MAG3 renogram. Bilateral multicystic kidney disease is incompatible with survival. If the kidneys have bilateral cysts of different sizes, yet the neonate has a normal creatinine and an otherwise sonographically normal renal parenchyma, the most probable diagnosis is autosomal dominant polycystic kidney disease (ADPKD), although this is relatively rare. The diagnosis of tuberous sclerosis must also be considered, especially since the gene defects for both these conditions are located in close proximity to each other. Tuberous sclerosis may present in the neonatal period with cardiac rhabdomyoma, so echocardiography should be suggested. The presence of bilateral large kidneys that are ‘solid’, with a ‘salt and pepper’ appearance, on US may result from autosomal recessive polycystic kidney disease (ARPKD; see Fig. 6). Furthermore in a clinical context, imaging can help to differentiate between neonatal nephritis and a kidney with ARF secondary to metabolic disease (e.g. hyperoxaluria), toxic damage or following an acute infective episode. When ARPKD is suspected then a liver US (liver fibrosis), a DMSA and iminodiacetic acid (HIDA) scans are essential in the first year of life.13 Rarely, neonatal renal tumors are discovered, the most common being a benign nephroblastic nephroma.
Associated congenital abnormalities In neonates with a congenital cardiac or gastrointestinal abnormality, a urinary tract US is required. If this is normal, no further imaging is required except in neonates with an anorectal malformation, who require an MCUG and a thorough systemic work-up. If the urinary tract US is abnormal, a radiotracer study (DMSA for an ectopic or single kidney, MAG3 with dilatation) and an MCUG
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are required. The ipsilateral genitalia are often involved in particularly complex congenital urinary tract malformations, especially in girls with a single kidney.
Practice points • There is a need for adequate training and research in the field of imaging. • Interdisciplinary interaction and communication/co-operation is necessary to adapt imaging protocols and to optimally exploit what modern imaging potentially offers. • This approach will facilitate research and help focus developments on clinical needs.
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• In nuclear medicine, modern advances will improve the detection and assessment of apoptosis and ischemia. High-quality images from radioisotope studies must become the norm. • The pathologic significance of the reactive cascade has been demonstrated by research into the tumor necrosis factor system and the enzymes directing angiogenesis. The assessment of new treatment strategies demands imaging techniques capable of evaluating responses to them. Image fusion plus a refinement of MR and isotope studies may allow non-invasive monitoring of these phenomena. New contrast media and radiotracers may open further avenues for imaging modalities.
References Research directions • The future of US examination holds promise in terms of combining contrast-enhanced US with harmonic imaging techniques, aCDS and real-time 3DUS scanning, allowing better morphologic and functional evaluation. US should become less operator dependent so that the full potential of the technological advances may be exploited • Magnetic resonance imaging (MRI) has been successfully applied to the neonatal and infant urinary tract. Fast sequences with strong gradients, improved gating and triggering techniques and improved spatial and temporal resolution provide excellent anatomic and functional (perfusion and drainage) imaging.14–16 The value of renal MRI in differentiating various parenchymal disease entities has not yet been evaluated, but the technique has vast potential for improving non-invasive diagnosis. Gadolinium-enhanced MR angiography using fast 3D gradient echo sequences allows a good depiction of the major vessels (e.g. an additional crossing renal artery in UPJO). To date, however, the restricted access, the need for sedation, the relatively high cost and the good results from US and scintigraphy limit the indications for MRU and MR angiography. MRI with the use of paramagnetic tracers promises to become capable of additional non-invasive and non-ionizing functional imaging.
1. de Bruyn R, Gordon I. Postnatal investigation of fetal renal disease. Prenat Diagn 2001;21(11):984–91. 2. Riccabona M. Potential of modern sonographic techniques in paediatric uroradiology. Eur J Radiol 2002;43:110–21. 3. Riccabona M, Sorrantin E, Fotter R. Application of functional m-mode sonography in pediatric patients. Eur Radiol 1998; 8:1457–61. 4. Bosio M. Cystosonography with echocontrast: a new imaging modality to detect vesicoureteric reflux in children. Pediatr Radiol 1998;28:250–5. 5. Riccabona M, Schwinger W, Ring E et al. Amplitude coded color Doppler sonography in pediatric renal disease. Eur Radiol 2001;11:861–6. 6. Riccabona M, Fritz G. Three-dimensional ultrasound (3DUS) in pediatric urological disease—preliminary experience, including volumetry. J Ultrasound Med 2002;21:S86. 7. Avni FE, Ayadi K, Rypens F et al. Can careful US examination of the urinary tract exclude vesicoureteral reflux in the neonate? Br J Radiol 1997;70:977–82. 8. Awad H, el-Safty I, el-Barbary M et al. Evaluation of renal glomerular and tubular functional and structural integrity in neonates. Am J Med Sci 2002;324(5):261–6. 9. Lythgoe MF, Gordon I, Anderson PJ. Effect of renal maturation on the clearance of Tc 99m MAG3. Eur J Nucl Med 1994; 21:1333–7. 10. Riccabona M, Ring E, Fueger G et al. Doppler sonography in congenital ureteropelvic junction obstrucion. Eur J Ultrasound 1996;3:205–9. 11. Gordon I. Diuretic renography in infants with prenatal unilateral hydronephrosis: an explanation for the controversy about poor drainage. BJU Int 2001;87(6):551–5. 12. Ozcan Z, Anderson PJ, Gordon I. Assessment of regional kidney function may provide new clinical understanding and assist in treatment of children with prenatal hydronephrosis. J Urol 2002;168(5):2153–7. 13. Zagar I, Anderson PJ, Gordon I. The value of radionuclide studies in children with autosomal recessive polycystic kidney disease. Clin Nucl Med 2002;27(5):339–44. 14. Avni F, Bali MA, Regnault M et al. MR urography in children. Eur J Radiol 2002;43:154–66.
278 15. Riccabona M, Simbrunner J, Ring E et al. Feasibility of MR-urography in neonates and infants with anomalies of the upper urinary tract. Eur Radiol 2002;12:1442–50.
I. Gordon, M. Riccabona 16. Borthne A, Nordshus T, Reiseter T et al. MR urography: the future gold standard in pediatric urogenital imaging? Pediatr Radiol 1999;29:694–701.