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Resident Short Review
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Renal dysplasia
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ABSTRACT
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Renal dysplasia is an aberrant developmental disease usually diagnosed during the
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perinatal and childhood years. Prevalence is estimated at 0.1% of infants (via
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ultrasound screening) and 4% of fetuses and infants (via autopsy study). Occurrences
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may be combined with abnormalities in the collecting system or associated with
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complex syndromes. Histopathology shows primitive tubules surrounded by a
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fibromuscular collar. The differential diagnosis includes renal dysplasia, hypoplasia,
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and renal atrophy. The paired box genes 2 and 8 (PAX2/8) and Wilms tumor 1 (WT1)
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immunohistochemical expression are increased in the primitive ducts and
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fibromuscular collar, respectively. Renal dysplasia pathogenesis is not well
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understood, but may be caused by a nephron-inductive deficit due to ampullary
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inactivity or abnormal budding of the ureteric bud from the mesonephric duct. Either
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the PAX2 mutation only or cross-talk with the p53 pathway is involved in this deficit.
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Nephrectomy is the treatment of choice for symptomatic renal dysplasia.
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INTRODUCTION
Renal dysplasia is defined as abnormal metanephric differentiation diagnosed
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histopathologically, which can be diffuse, segmental, or focal.1 The diffuse type
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shows dysplastic area involving an entire kidney. The segmental type shows
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dysplastic area involving a portion of the kidney. The focal type is characterized by an
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admixture of normal nephrons and aberrantly formed nephros. Usually diagnosed
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around the time of birth or during childhood, it is rarely seen in adults. Ultrasound
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screening has indicated a 0.1% prevalence in infants2 and an autopsy study estimated
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a 4% prevalence in fetuses and infants.3 However, data on the prevalence of renal
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dysplasia in adults is unclear. While investigating the etiology of benign
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non-functioning kidneys removed by nephrectomy, Gupta et al4 discovered that renal
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dysplasia was one of the etiologies, accounting for 3.7%.
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Renal dysplasia with or without reflux is the most common cause of childhood
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end-stage renal disease and accounts for 34% of prevalent cases, with a
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male-to-female ratio of 2.0.5 Renal dysplasia is a developmental aberration
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characterized by cells undergoing active proliferation and programmed cell death in a
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deregulated manner, and this process involves the paired box gene 2 (PAX2), paired
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box gene 8 (PAX8), Wilms tumor 1 (WT1), and B-cell lymphoma 2 (BCL2) genes
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which have been reported.6,7
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We reviewed the clinical features, pathological features, pathogenesis,
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differential diagnosis, and treatments for renal dysplasia. Additionally, variable
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immunohistochemical expression of PAX2, PAX8, WT1, and BCL2 are discussed for
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their roles in the differential diagnosis of renal dysplasia, hypoplasia, and fetal kidney.
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CLINICAL FEATURES
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Renal dysplasia can be combined with abnormalities of the collecting system,
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including obstruction of the ureteropelvic junction, ureteral atresia, urethral
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obstruction, and vesicoureteric reflux. Therefore, patients’ symptoms and signs
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depend upon the extent and severity of the renal dysplasia and the associated
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anomalies. In the prenatal period, renal dysplasia is always found by ultrasound
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screening and manifests as multicystic kidney, pelvic cyst, renal agenesis, or genital
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mass.8 The presentations of maternal oligohydramnios and fetal hydronephrosis or
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hydroureteronephrosis are also reported. In the neonatal period, renal dysplasia with
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cysts is usually detected when a flank mass is palpable. In childhood and adulthood,
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conditions linked to renal dysplasia include voiding dysfunction, urinary incontinence,
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repeated urinary tract infections, flank or abdominal pain, vaginal discharge, genital
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masses, and chronic renal failure.8 Of them, urinary incontinence is more common in
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women than in men who have dysplastic kidneys with an ectopic ureter.9
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5
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Symptomatic renal dysplasia can be further investigated by renal ultrasound, magnetic
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resonance imaging, and magnetic resonance urography.10 Eventually, a definitive
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diagnosis of renal dysplasia can be made after the affected kidney is removed by
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nephrectomy or autopsy.
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The renal dysplasia-associated syndromes include Meckel syndrome, VATER
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association, renal-coloboma syndrome, Herlyn-Werner-Wunderlich syndrome, Prune
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bell syndrome, branchio-oto-renal dysplasia, renal-hepatic-pancreatic dysplasia, and
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multiple endocrine neoplasia type 2A.8,11–17 The VATER association is defined as
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vertebral defect, anal atresia, tracheo-esophageal fistula and renal dysplasia. The
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reported cases of Meckel syndrome and VATER association are more than those of the
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other syndromes. Most of these complex syndromes are derived from the
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developmental problems under genetic controls. Some syndromes are hereditary,
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including Meckel syndrome, renal-coloboma syndrome, branchio-oto-renal dysplasia,
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renal-hepatic-pancreatic dysplasia, and multiple endocrine neoplasia type 2A. The
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anomalous structures and genetic alterations of these syndromes are listed in Table 1.
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PATHOLOGIC FEATURES
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Macroscopic Features
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Gross features of renal dysplasia are variable and depend on their dysplastic
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extents and cystic components.1 Their gross morphologies show large irregular cystic
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masses or small rudimentary structures. Multicystic renal dysplasia exhibits dysplastic
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kidney with multiple irregular cysts. Aplastic dysplasia is characterized by small,
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barely recognizable rudimentary structures. Both multicystic and aplastic renal
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dysplasias are associated with pelvocaliceal occlusion, partial or total absence of the
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ureter, and ureteral atresia.1,3 Hypoplastic dysplastic kidneys have patent ureters, often
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have a reniform shape with corticomedullary differentiation, and may be partially
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functional (Figure 1).
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Microscopic Features
Renal dysplasia is characterized principally by primitive ducts with a
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fibromuscular collar and lobar disorganization.3 Primitive ducts, which may be cystic,
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are considered as altered collecting ducts lined by undifferentiated or
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columnar-to-cuboidal epithelium (Figure 2a). The fibromuscular collar is comprised
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of spindle cells arranged circumferentially around the primitive ducts. Incomplete and
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abnormal corticomedullary relationships and rudimentary medullary development
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constitute lobar disorganization (Figure 2b). The cysts derived from primitive ducts
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may be large or small, and numerous or scarce, and eventually lead to divergent
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macroscopic features of multicystic, hypoplastic or aplastic renal dysplasia. The other
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pathological findings include metaplastic cartilage, bone, basement membrane
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thickening of the primitive ducts, nodular renal blastema, and proliferating nerves.3
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Metaplastic cartilage is not essential for diagnosis of renal dysplasia; if present,
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metaplastic cartilage customarily appears within the cortex. Secondary to reflux or
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obstruction of the lower urinary tract, chronic pyelonephritis is occasionally detected
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in dysplastic kidneys.
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PATHOGENESIS
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In normal development, the kidney is derived from two components of the
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embryonic metanephros: the metanephric parenchyma, which undergoes an epithelial
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transformation to form nephrons, and the ureteric bud, an epithelium which branches
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to form collecting ducts.18 Based on the molecular basis, the conversion of
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metanephric parenchyma to nephron epithelia requires many transcriptional factors,
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including WT1, eyes absent homolog 1 (EYA1), forkhead box C1 (FOXC1), PAX2,
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PAX8, growth differentiation factor 11 (GDF11), sal-like 1 (SALL1), SIX homebox 1
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(SIX1),wingless-type MMTV integration site family, member 4 (WNT4), and GATA
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binding protein 3 (GATA3).6,7 These genes and their encoded proteins interact to form
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a network rather than a linear and hierarchical pathway. The reciprocal induction of
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WT1 and PAX2 expression has been demonstrated for the differentiation of
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8
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metanephric mesenchyma; furthermore, WT1 can down-regulate the expression of
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PAX2.19 Expression of WT1 involves the early induction of the renal mesenchyma and
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the production of growth factors, which can stimulate growth of the ureteric buds. The
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expression of PAX2/8 involves the late induction that drives the conversion of the
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metanephric mesenchyma to nephron epithelia. Both WT1 and PAX2 are
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down-regulated when the kidney becomes mature.7 BCL2 is a survival factor and
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protects the differentiating cells from cell apoptosis. Expression of BCL-2 is also
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detected in the metanephric mesenchyma when it undergoes epithelial transition.20
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Thus, the WT1, PAX2/8, and BCL2 gene expressions are the most important in normal
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nephrogenesis including branching morphogenesis and nephron differentiation.
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In comparison with normal nephrogenesis, dysplastic kidneys show abnormal
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differentiation of nephrons and renal tubules, and are comprised of abnormally
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developed metanephric elements with an abnormal structural organization. Jain et al21
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investigated the expression profile of human renal dysplasia in comparison with a
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normal kidney, and the results, as expected, showed that WT1 mRNA expression was
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decreased in renal dysplasia. Winyard et al22 demonstrated that PAX2 and BCL2
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immunoreactivities were shown in the dysplastic epithelia. They proposed that cyst
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formation in dysplastic kidneys was caused by the persistent expression of PAX2 and
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BCL2, which provided a continuous proliferation and decreased apoptosis of
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immature epithelia.
In animal studies, homozygous PAX2 null-mutant mice had no kidneys because
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the ureteric bud failed to branch from the mesonephric duct,23 and heterozygous PAX2
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mutant mice caused renal hypoplasia.24 However, urinary tract abnormalities are often
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combined with renal dysplasia. Recently, some studies have provided evidence that
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PAX2 and p53 gene alterations involve their connection.25-27 Mice with p53 deletion
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showed the development abnormalities of the kidney and urinary tracts such as duplex
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ureter formation, renal hypoplasia or dysplasia, and impaired terminal differentiation
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of renal epithelia because of excessive apoptosis and decreased proliferation of the
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ureteric epithelium.25,26 Furthermore, p53-null mice showed the down-regulation of
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PAX2, leading to nephron deficit.27 Collectively, PAX2 mutation only or combined
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with p53 deletion involves the pathogenesis of renal dysplasia.
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DIFFERENTIAL DIAGNOSIS
Histopathological examination is used to distinguish various etiologies among
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small kidneys, because this distinction is important for disease prognosis and genetic
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counseling. The diagnosis of renal dysplasia is not difficult; however, the diagnosis is
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sometimes confused with other conditions including polycystic kidney disease, fetal
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kidney, renal hypoplasia, and renal atrophy. The dysplastic kidney contains primitive
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ducts with or without dilated cysts.3 The kidney with concomitant multiple cysts and
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dysplasia is diagnosed as the multicystic renal dysplasia, although it grossly resembles
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polycystic kidney disease. Additionally, these cysts in multicystic renal dysplasia are
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usually smaller than those in polycystic kidney disease. The fetal kidney contains
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poorly differentiated tissues that are compatible with gestational development. The
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hypoplastic kidney has fewer nephrons than the normal kidney, but no dysplastic
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elements.1 The atrophic kidney exhibits segmental loss of parenchyma due to renal
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scarring, and compensatory hypertrophy in the remnant parenchyma.
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Immunophenotypic Features
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Based on a review of the literature, the protein expressions of PAX2, PAX8,
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WT1, and BCL-2 are variable in renal dysplasia, hypoplasia, the fetal kidney, and the
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adult kidney.22,28 These conditions are considered as differential diagnoses. Between
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2010 and 2012, two cases with renal dysplasia were diagnosed in our hospital. Both
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were female and aged 20 years and 4 years, respectively. They shared the same
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symptom—urinary incontinence due to an ectopic ureter in their right kidney.
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In renal dysplasia, the WT1 immunoreactivity exhibits nuclear staining in the
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spindle cells of the fibromuscular collar, but negativity in the columnar-to-cuboidal
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epithelial cells of the primitive ducts (Figure 3a).22,28 In the hypoplastic fetal and adult
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kidneys,WT1 immunoreactivity exhibits in the smooth muscle cells of vascular walls,
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in the podocytes and parietal epithelial cells of Bowman’s capsules, and in the
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endothelial cells of the vessels and glomeruli (Figure 3b). The intensity of WT1
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expression in the glomeruli or vessels is not different among the hypoplastic, fetal,
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and adult kidneys. In renal dysplasia, the PAX2 immunoreactivity, in contrast to WT1
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immunoreactivity, exhibits strong nuclear staining in the columnar-to-cuboidal
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epithelial cells of primitive ducts, but negativity in the spindle cells of the
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fibromuscular collar (Figure 4a). In the hypoplastic fetal and adult kidneys, the PAX2
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immunoreactivity exhibits less strong nuclear staining in the distal convoluted tubules
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and parietal epithelial cells of Bowman’s capsules. Relatively weak cytoplasmic
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staining of PAX2 in the podocytes of glomeruli and epithelial cells of proximal
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convoluted tubules is also detected (Figure 4b).22,28 The features of PAX8
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immunohistochemistry are similar to those of PAX2.
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Winyard et al22 found the BCL2immunoreactivity at mesenchymal condensates
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of fetal kidney, negative staining at ureteric bud braches, and ectopic staining at
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dysplastic primitive ducts, but negative staining at surrounding collar cells. In
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comparison with our cases, the immunostaining of BCL2, partially consistent with
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Winyard’s findings, exhibits cytoplasmic staining in the epithelial cells of primitive
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ducts and immature or mature renal tubules, in which the intensity and proportion of
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BCL2-positive cells are variable in these conditions. The mesenchymal condensates
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of the fetal kidney and fibromuscular collar surrounding dysplastic tubules also show
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no BCL2 staining. According to the immunophenotypic features, PAX2, PAX8, WT1,
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and BCL-2 immunohistochemical expressions cannot be useful to differentiate renal
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dysplasia from renal hypoplasia and fetal kidney.
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CURRENT TREATMENT AND PROGNOSIS
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Although a nephrectomy of the dysplastic kidney is the routine treatment, there
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is a trend toward conservative management with careful follow-up.29 If the condition
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is limited to one kidney and the patient has no symptoms, the patient is usually
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monitored with periodic ultrasounds to examine the affected kidney and contralateral
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kidney to determine whether they continue to be normal. Removal of the kidney
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should be considered only if the kidney causes bothersome symptoms for the patients.
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A nephrectomy can cure their symptoms. Neild et al30 investigated the effect of
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angiotension converting enzyme inhibitor (ACEI) in patients who had chronic renal
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failure due to renal dysplasia with or without reflux. This study suggests that there is a
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watershed glomerular filtration rate of 40–50 ml/min, at which ACEI treatment can be
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successful in improving renal function. Nonetheless, there is no evidence of malignant
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transformation in renal dysplasia.
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References
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9. MacDonald GR. The ectopic ureter in men. J Urol. 1986;135(6):1269–1271.
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12. Mori M, Matsubara K, Abe E, et al. Prenatal diagnosis of persistent cloaca
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associated with VATER (vertebral defects, anal atresia, tracheo-esophageal fistula,
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13. Oppezzo C, Barberis V, Edefonti A, Cusi D, Marra G. [Genetic basis for
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malformation-associated uropathy and renal dysplasia]. G Ital Nefrol.
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14. Melnick M, Hodes ME, Nance WE, Yune H, Sweeney A. Branchio-oto-renal
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dysplasia and branchio-oto dysplasia: two distinct autosomal dominant disorders. Clin
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15. Bergmann C, Fliegauf M, Brüchle NO, et al. Loss of nephrocystin-3 function
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renal-hepatic-pancreatic dysplasia. Am J Hum Genet. 2008;82(4):959–970.
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16. McIntyre E, Bond P, Douglas F, Lennard T, Peaston R, Perros P. Multiple
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endocrine neoplasia type 2A: an unusual clinical presentation and association with
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renal dysplasia. Cancer Genet Cytogenet. 2003;141(2):157–159.
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17. Li Y, Manaligod JM, Weeks DL. EYA1 mutations associated with the
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renal dysplasia reveal new insights into renal development and disease. Pediatr
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24. Torban E, Dziarmaga A, Iglesias D, et al. PAX2 activates WNT4 expression
during mammalian kidney development. J Biol Chem. 2006;281(18):12705–12712.
25. Saifudeen Z, Marks J, Du H, El-Dahr SS. Spatial repression of PCNA by p53
during kidney development. Am J Physiol Renal Physiol. 2002;283(4):F727–F733.
26. Saifudeen Z, Dipp S, Stefkova J, Yao X, Lookabaugh S, El-Dahr SS. p53
regulates metanephric development. J Am Soc Nephrol. 2009;20(11):2328–2337.
27. Saifudeen Z, Liu J, Dipp S, et al. A p53-Pax2 pathway in kidney
development: implications for nephrogenesis. PLoS One. 2012;7(9):e44869.
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28. Lozanoff S, Johnston J, Ma W, Jourdan-Le Saux C. Immunohistochemical
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29. Lennert T, Tetzner M, Er M, Jung F, Kaufmann HJ, Biewald W. Multicystic
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30. Neild GH, Thomson G, Nitsch D, Woolfson RG, Connolly JO, Woodhouse
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CR. Renal outcome in adults with renal insufficiency and irregular asymmetric
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kidneys. BMC Nephrol. 2004;5:12.
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Legends
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Figure 1. Gross image: Renal hypoplastic dysplasia in a 20-year-old girl with an
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ectopic ureter. The small kidney measures 5.5 × 3.5 × 1.5 cm and includes dysplastic
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(arrow) and hypoplastic (arrowhead) components.
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Figure 2. Photomicrographs of renal dysplasia. a, Primitive ducts lined by cuboidal
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epithelium (arrow) and surrounded by a fibromuscular collar (＊). b, Loss of normal
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renal structures showing lobar disorganization (hematoxylin-eosin, original
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magnification X200[a] and X20[b]).
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Figure 3. Photomicrographs of WT1 immunohistochemistry. a, Renal dysplasia
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showing WT1-positiveimmunoreactivity in fibromuscular collar, but negative in
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primitive ducts. b, Adult kidney showing WT1-positive immunoreactivity in
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endothelium and smooth muscle cells of vessels, as well as glomeruli
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(immunoperoxidase, original magnification X200).
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Figure 4. Photomicrographs of PAX2 immunohistochemistry. a, Renal dysplasia
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showing nuclear immunoreactivity only in epithelial cells of primitive ducts. b, Adult
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kidney showing nuclear staining only at distal renal tubules and parietal epithelial
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cells of Bowman’s capsules (immunoperoxidase, original magnification X200).
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Table 1. Renal dysplasia associated with syndromes and genetics
Associated syndromes
Characteristics
Incidence
Genetics
Meckel syndrome
Occipital encephalocele, renal cystic dysplasia, hepatic
developmental defects, pulmonary hypoplasia, and
polydactyly
0.02–1.1 per 10,000
live births
Autosomal recessive
trait; MKS3 mutation
VATER association
Vertebral defect, anal atresia, tracheo-esophageal fistula, and
renal dysplasia
Optic nerve coloboma, renal anomalies, and vesicoureteral
reflux
Uterovaginal duplication, and obstructed hemivagina
16 per 100,000 live
births
10% of patients with
renal dysplasia
15%–20% of
uterine/vaginal
anomalies

Deficient abdominal muscle, and genitourinary anomaly
including dysplastic kidneys
External ear malformations, cervical fistula, mixed hearing
loss, and renal anomalies
Cystic malformations of the kidneys, liver, and pancreas
1 per 40,000 live births

9 cases reported
Autosomal dominant
trait; EYA1 mutation
Autosomal recessive
trait; NPHP3
mutation
Medullary thyroid carcinoma,pheochromocytomas, and
parathyroid hyperplasia
One case reported
Renal-coloboma syndrome
Herlyn-Werner-Wunderlich
syndrome
Prune belly syndrome
Branchio-oto-renal dysplasia
Renal-hepatic-pancreatic
dysplasia
Multiple endocrine neoplasia
type 2A
Undetermined; fatal at
birth
Autosomal dominant
trait; PAX2 mutation

Autosomal dominant
trait; RET mutation
MKS3, Meckel syndrome type 3; PAX2, paired box gene 2; EYA1,eyes absent homolog 1; NPHP3,nephrocystin 3; RET, rearranged during
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transfection
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