As with most organs, differentiation of the kidney involves epithelial-mesenchymal interactions, which are under the control of multiple gene regulatory networks that act as inducers or inhibitors. Briefly, epithelium of the ureteric bud from the mesonephros interacts with mesenchyme of the metanephric blastema. The mesenchyme expresses WT-1, a transcription factor that makes this tissue competent to respond to induction by the ureteric bud. WT-1 also regulates production of glial-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF or scatter factor) by the mesenchyme, and these proteins stimulate branching and growth of the ureteric buds. The tyrosine kinase receptors RET, for GDNF, and MET, for HGF, are synthesized by the epithelium of the ureteric buds, establishing signaling pathways between the two tissues. In turn, the buds induce the mesenchyme via fibroblast growth factor 2 and bone morphogenetic protein 7. Both these growth factors block apoptosis and stimulate proliferation in the metanephric mesenchyme while maintaining production of WT1. Conversion of the mesenchyme to an epithelium for the nephron formation is also mediated by the ureteric buds, in part through modification of the extracellular matrix. Thus, fibronectin, collagen I, and collagen III are replaced with laminin and type IV collagen, characteristic of an epithelial basal lamina. In addition, the cell adhesion molecules, syndecan and E-cadherin, which are essential for condensation of the mesenchyme into an epithelium, are synthesized. Regulatory genes for conversion of the mesenchyme into an epithelium appear to involve PAX2 and WNT4 (4).

Permanent malposition of one or both kidneys is seen in 2% of pediatric autopsies (Table 17-1). The incidence is even higher in perinatal autopsies because renal ectopia is commonly associated with multiple other malformations; however, the incidence in screening studies is approximately 1 in 683 infants (14). The ectopic kidney(s) may be located in the pelvis (most common), on the other side (crossed renal ectopia) with or without fusion, or even in the thorax (rare) (15). Prenatal ultrasonographic diagnosis of the pelvic kidney is possible, usually after 24 weeks of gestation, although postnatal ultrasound or CT is more effective at diagnosing
anomalies of the urinary tract (14). While renal function is normal in the neonatal period in patients with renal ectopia without other associated malformations, vesicoureteral reflux and hydronephrosis have been reported in approximately 20% to 50%, particularly in crossed renal ectopia (16). Pseudocrossed renal ectopia occurs when an enlarging retroperitoneal mass displaces the kidney to the contralateral side of the abdomen.

Renal fusion, often with ectopia, was seen in 32 (1.2%) of 2684 pediatric autopsies (Table 17-1). The most common fusion anomaly is horseshoe kidney, in which both kidneys are normally lateralized but have fused lower poles (Figure 17-3) and are located in a lower than normal position. The incidence of horseshoe kidney is reported to be 1 in 600 to 700 in the general population (17). One-third of persons with this condition have associated congenital malformations of other organs, including Turner syndrome (18); two-third have a major urologic complication, most of which require surgery, although newer techniques such as laparoscopic roboticassisted management allow for minimally invasive procedures. Symptomatic hydronephrosis eventually develops in
more than half of patients with horseshoe kidney, secondary to ureteropelvic junction obstruction, reflux, or malrotation. Individuals with horseshoe kidney are at higher risk for the development of stones (19) and tumors (20). Rare cases of renal-adrenal fusion have been described, which may present as a renal mass in the upper pole (21).

Inadequate renal tissue can be considered as a continuum, ranging from renal agenesis to subtle congenital nephron deficits. Renal agenesis (i.e., the complete absence of one or both kidneys) is commonly accompanied by other malformations of the genitourinary tract and various lower body defects and is often the result of one or more genetic mutations that leads to molecular dysregulation of nephrogenesis. Homozygous null mice for c-Ret , Gdnf , and Gfra-1 all exhibit bilateral renal agenesis due to the inhibition of ureteric bud growth and branching morphogenesis; they are less frequently implicated in human renal agenesis (22). Pax2 plays an integral role in the initiation and maintenance of the Ret/Gdnf pathway by not only activating the ligand of the pathway but also enhancing the expression of the pathway receptor Ret (4). Since an exhaustive review is beyond the scope of this chapter, one can focus on Pax2, one of the earliest genes expressed widely during fetal kidney development in the nephric duct, the metanephric mesenchyme, the ureteric bud, and in the S-shaped body. Early failure in the first two developmental stages (e.g., homozygous inactivation of Pax2) precludes formation of metanephric kidneys and causes bilateral renal agenesis, incompatible with life. Interference with the later stages affects the extent of branching morphogenesis (e.g., heterozygous Pax2 mutations). Although the resulting nephron deficits are compatible with life, they may be moderately severe and account for up to 40% of the children in dialysis and transplant units around the world. Finally, the effect of Pax2 on apoptosis in the branching ureteric bud seems to imply a quantitative process that is finely tuned. Modest changes in this program could account for subtle nephron deficits in “normal” humans and increased risk of hypertension or susceptibility to acquired renal disease later in life (23).

Uniformly fatal, bilateral renal agenesis, although less common than unilateral renal agenesis (URA), is seen more frequently in pediatric autopsies (1.1% of total autopsies in Table 17-1). The incidence of bilateral renal agenesis varies from 0.1/1000 to 0.3/1000 births (8). It accounts for one-third of births with the oligohydramnios sequence (Table 17-2). The male to female ratio is 2.5:1. It is usually associated with severe oligohydramnios (Potter syndrome), intrauterine growth restriction, extrarenal anomalies, and malpresentation. The ureters and renal arteries are also absent, and the urinary bladder is hypoplastic or absent. The adrenals are disc shaped secondary to lack of molding from the kidneys (eFigure 17-3). Forty percent of affected infants are stillborn, and the remainder die in the immediate postnatal period, generally of pulmonary hypoplasia.

Bilateral renal agenesis is usually sporadic, although familial cases have been described (22). Hereditary renal adysplasia (agenesis/dysplasia syndrome) is defined as URA in association with dysplasia of the contralateral kidney. The term adysplasia is often used more broadly to include dysplasia, absent kidneys, and almost any associated structural or positional defect of the kidney or lower urinary tract. However, hereditary adysplasia should be considered as any combination of unilateral or bilateral agenesis, unilateral or bilateral renal dysplasia, or dysplasia of one kidney and agenesis of the other, in different members of the same family for which autosomal dominant inheritance with varying expression has been suggested (9,24). An increased prevalence of congenital renal anomalies was identified in the relatives of index patients with bilateral renal agenesis/adysplasia (14.7%) compared to controls (2.2%), with a recurrence risk of 6.2 for first-degree relatives (25). But the occasional cases of agenesis or dysplasia affecting siblings with normal parents suggest that there are other types of inheritance. Some patients with adysplasia have PAX2 mutations. The genetic link between renal agenesis and some types of renal dysplasia points to a common pathogenetic mechanism and may result from varying degrees of failure of induction of the metanephric blastema by the ureteric bud.

Other reported malformations associated with bilateral renal agenesis include congenital pulmonary airway malformation type 2 (cystic adenomatoid malformation), left heart hypoplasia (26), sirenomelia (27), and urorectal septum malformation sequence (28). Limb reduction defects and renal agenesis have been reported in fetuses born to mothers with cocaine addiction and insulin-dependent diabetes (29).

The genetic mechanisms leading to bilateral renal agenesis remain largely unresolved. The absence of kidney development in a large number of mouse knockout models suggests a role for recessive mutations in various genes. Indeed, homozygous mutations in FGF20 have been shown in fetuses from consanguineous families with bilateral renal agenesis (30). More recently, the same researchers have demonstrated recessive mutations in integrin alpha-8 (ITGA8) as being responsible for renal agenesis (31). Integrins are transmembrane receptors expressed in metanephric mesenchyme that mediate biologic processes during organogenesis. Interruption of signaling pathway can thus lead to severe kidney developmental defects.

URA is a common developmental defect in humans, occurring at a frequency of approximately 1 in 2000 (32). Although compatible with normal life, URA is still seen twice as often in pediatric autopsies (0.6%) than in the general population (0.3%) owing to its frequent association with other complex malformations (33). The male to female ratio is about 1:1.5.
Long-term follow-up of patients with URA has shown that these patients are at higher risk for the development of proteinuria, hypertension, and renal insufficiency.

Malformations of the genitalia are commonly associated with URA. These include ipsilateral absence of fallopian tube, unicornuate and bicornuate uterus, cysts of the epididymis and seminal vesicle, agenesis of the vas deferens, cystic dysplasia of the testis and rete testis, ectopia of the vas deferens, and urorectal septum malformation sequence (ambiguous genitalia with absence of perineal and anal openings) (28,32,34,35,36).

Cystic dysplasia of the testis appears to be associated consistently with renal malformations, most frequently ipsilateral renal agenesis; both conditions could be explained by failure of development of the ureteric bud (36).

Genetic factors seem to play a significant role in URA, especially when it is part of a syndrome. Mutations in genes such as HNF1-β, PAX2, SALL1, WT1, SIX1, and EYA1 have been shown to cause some of these rare syndromes; however, a genetic basis for the VATER association, in which URA is a common feature, has not yet been identified (32).

Renal hypoplasia, defined as histologically normal kidneys with a weight that is less than two standard deviations below the norm, is extremely rare. In the older literature, any small kidney was labeled hypoplastic, irrespective of the cause. Currently, small kidneys that are also dysplastic are considered with the dysplastic group, and those with scarring, inflammation, and hypertensive changes are end-stage kidneys with hypoplasia, or more correctly, atrophy, considered secondary to the underlying disease and thusly categorized. Segmental renal hypoplasia (so-called Ask-Upmark kidney), which may be unilateral or bilateral and is characterized by localized atrophic scarring, was originally regarded as a primary malformation is now known to be secondary to vesicoureteral reflux and considered a form of reflux nephropathy.

In true renal hypoplasia, the absolute number of nephrons is reduced, possibly as a consequence of inadequate branching of the ureteric ducts that may result in a decreased number (<5) of reniculi. Although the volume is reduced, the renal shape and differentiation are normal. Unilateral hypoplasia is a sporadic condition, only rarely associated with lower urinary tract anomalies; patients may present with hypertension and occasionally, when associated with malrotation, may be predisposed to reflux nephropathy. Bilateral hypoplasia results in renal insufficiency and early death in severe cases; less severe cases manifest growth retardation and chronic renal insufficiency likely a consequence of developing secondary focal segmental glomerulosclerosis (FSGS) and tubulointerstitial damage as a consequence of hyperfiltration (37).

Bilateral oligomeganephronic renal hypoplasia is a nonfamilial form of congenitally small kidneys characterized by slowly progressive renal insufficiency. The absolute number of nephrons is reduced. The characteristic feature is glomerulomegaly, unlike the normal glomerular size encountered in simple hypoplasia. Infection, dysplasia, and obstructive uropathy are absent, and patients present with polyuria, polydipsia, and salt wasting; proteinuria may develop. Although several causes, including toxic factors, renal infection, vascular insufficiency, and disseminated intravascular coagulation, have been mentioned, it is not known what factors arrest the development of the metanephric renal blastema, presumably between weeks 14 and 20 of fetal life. Mutations in hepatocyte nuclear factor-1beta (HNF-1β) and PAX2 have been reported in patients with oligomeganephronia (23,38). A nephron deficit has also been reported in premature and low-birth-weight infants and has been linked to the development of hypertension in adults (39).

Familial renal tubular dysgenesis (RTD) is a rare autosomal recessive congenital disorder of the renin-angiotensin system (RAS) that causes the absence or marked reduction in the number of differentiated proximal tubules. Mutations in AGT, encoding angiotensinogen; REN, encoding renin; ACE, encoding angiotensin-converting enzyme; or AGTR1, encoding angiotensin 2 receptor type 1 (AT1 receptor) affect the production or efficacy of angiotensin 2 and result in the absence of a functional RAS and abnormal renin expression (40). Oligohydramnios is detected as early as 20 weeks’ gestation and persists, resulting in the Potter sequence. Fetuses may die in utero, but more often, infants die shortly after birth as a consequence of anuria and respiratory failure secondary to lung hypoplasia. Kidneys are normal or slightly enlarged and lack significant ultrasound abnormalities. Intrauterine growth is normal in the genetic form (41). Associated skull ossification defects, attributed to bone hypoxia, spontaneously improve after birth. In most patients, no proximal tubules can be identified by anti-CD10 or anti-CD15 antibodies and glomeruli are closely packed. The medulla contains few loops of Henle, and collecting ducts are atrophic and collapsed and surrounded by abundant mesenchyme. Interlobular arteries and afferent arterioles show thick and disorganized muscular walls, but larger interlobular arteries are normal.

The lack of proximal tubules is not specific for autosomal recessive RTD and has been seen in animals and humans with reduced renal blood flow of various etiologies, confirming the importance of a functional RAS in the maintenance of fetal blood pressure and renal blood flow (41). Secondary RTD has been described in humans with major cardiac malformations, renal artery stenosis, and extensive ischemic necrosis of the placenta and in conjunction with twin-twin transfusion syndrome, neonatal hemochromatosis, and in utero exposure to RAS blockers and nonsteroidal antiinflammatory drugs (NSAIDs) (41,42). Despite the lack of normal proximal tubules, the major site of water resorption
in the kidney, the principal clinical manifestations are caused by fetal and neonatal oliguria.

The most common form of renal enlargement is compensatory hypertrophy, in which a single functioning kidney may reach twice the normal size and can be detected in utero. Bilateral renomegaly secondary to an increased number or size of normally developed nephrons is seen in growthrelated disorders such as Beckwith-Wiedemann syndrome, hemihypertrophy, Perlman syndrome, and congenital nephrosis of the Finnish type (43,44).

Duplex kidneys are the most common anomalies of the upper urinary tract in childhood with an estimated incidence of 0.8% (45). The term renal duplication denotes the presence of two separate pelves in the same kidney accompanied by complete or partial duplication of the ureter (45) (Figure 17-4). These kidneys usually have greater than normal number of reniculi. The anatomical and functional divisions between upper and lower moieties of duplex kidney are extremely variable. The underlying pathologic condition associated with a lower moiety is usually massive vesicoureteral reflux to the lower collecting system and only rarely, obstruction. The nonfunctioning upper moiety is usually associated with obstructive ectopic ureter (with or without ureterocele) and may show chronic tubulointerstitial injury and hypoplastic or dysplastic changes (46). In mice, a model of congenital kidney and urinary tract anomalies, severe early gestational hypoxia resulted in reduced β-catenin signaling and formation of duplex kidneys. This mirrors the defects caused by suppression of canonical Wnt/β-catenin signaling at that stage of development (47).

Supernumerary kidney is one of the rarest of renal malformations with fewer than 100 cases reported so far. In addition to the normal two kidneys, an additional, usually small, kidney is present within the renal fascia caudal to and completely separate from the ipsilateral kidney. Few cases of multiple supernumerary kidneys are described (48,49). Most cases are originally diagnosed as hydronephrosis, or pyelonephritis; thus, the true incidence may be higher than reported. The malformation is thought to result from greater than one ureteric bud divergently arising from different positions in the wolffian duct with induction of metanephric blastema and aberrant divisions resulting in at least two kidneys on one side.

Hydronephrosis may be congenital or acquired, unilateral or bilateral, and mild to severe. Renal dysplasia may or may not be present. Hydronephrosis is readily seen on antenatal ultrasonography but does not necessarily imply obstruction. Although most cases will resolve spontaneously, the probability of a significant pathology is related to the degree of pyelectasis, as seen on the third trimester ultrasound study. Criteria of obstruction are difficult to define with precision, but two that are well accepted are size of the renal pelvis (>15 mm) and relative renal function (50).

Hydronephrosis is the most common cause of an abdominal mass of genitourinary tract origin in neonates (51). It is most frequently caused by obstruction of the ureteropelvic junction, which leads to dilatation of the renal pelvis and calyceal system. Depending on the severity and timing of the obstruction, the appearance of the renal parenchyma varies from relatively normal to markedly atrophic, with fibrosis and a scant chronic inflammatory infiltrate (52). One hypothesis for ureteropelvic obstruction is impaired smooth muscle differentiation, aberrant smooth muscle arrangement, and abnormal pyeloureteral innervation, which results in impaired peristalsis and subsequent hydronephrosis (52,53). FOXF1 is the only gene so far associated with UPJ obstruction in humans (53).

The specimen most commonly seen in surgical pathology is a portion of the ureteropelvic junction that shows remarkably little pathology on microscopic examination. When end-stage nonfunctioning hydronephrotic kidneys are removed, marked dilatation of the pelvis and calyces with only microscopic foci of residual renal parenchyma can be
seen (Figures 17-5 and 17-6). Neonatal hydronephrotic kidneys seen at autopsies usually have a histologically normal, although grossly compressed, cortex and medulla.

Hydronephrosis is often associated with renal dysplasia, so that the definition of these two entities often overlaps. Also, because urinary tract obstruction is a common underlying condition, it is best to consider them as the opposite ends of a spectrum. When severe obstruction occurs early in fetal development, it results in renal dysplasia; when it occurs late, one sees hydronephrosis; when it develops in between, both hydronephrosis and dysplasia are apparent to varying degrees. Hydronephrosis associated with reflux disease is discussed later in this chapter in the section on tubulointerstitial diseases (52).

Although the vast majority of cases of hydronephrosis are sporadic, some syndromic associations have been reported (53,54,55). Hydronephrosis should also be distinguished from the rare disorder of megacalycosis (Puigvert disease), which is characterized by calyceal dilatation, an increased number of calyces, hypoplasia of the pyramids of Malpighi, a normal renal pelvis, and, most importantly, normal renal function (56).

Multicystic dysplastic kidneys are the most common type of malformed kidneys seen in pediatric autopsies (Table 17-1), with bilateral dysplasia accounting for 32% and unilateral dysplasia (with or without contralateral agenesis) for 7.1% of patients with renal malformations. It may involve one or both kidneys or a portion of one kidney, with or without enlargement of the affected kidney and with or without grossly visible cysts. Thus, the dysplastic kidney may be smaller or larger than normal and grossly misshapen or reniform. Renal dysplasia is one of the most common causes of an abdominal mass in children younger than 1 year; although often diagnosed antenatally, it may present in older children and adulthood (58).

The most common form of dysplasia is sporadic, although genetic causes are being increasingly identified (9,11,33). It is typically associated with obstruction of the ureteropelvic junction and enlarged distorted kidneys that are no longer reniform (Figure 17-7). Cysts of varying sizes can be
appreciated through the capsule and on sectioning are seen to be irregularly distributed throughout the parenchyma, with no residual identifiable cortex or medulla (Figure 17-8).

The microscopic hallmark is the presence of immature dysplastic-appearing tubules surrounded by collarettes of condensed mesenchyme (Figure 17-9). The tubules are lined by a single layer of primitive undifferentiated cuboidal to columnar epithelium that often appears to be excessive, so that it is folded and may fill the lumen (Figure 17-10). The cells tend to have a relatively high nuclear to cytoplasmic ratio, and the tubular basement membrane may be thick and eosinophilic. A myxoid, moderately cellular condensation of spindle cells encircles the tubules. Ducts and tubules are fewer in number than normal, and the remaining connective tissue is loose and contains many blood vessels, lymphatics, and peripheral nerves. Medullary pyramids often lack vasa recta and loops of Henle. The cortex is usually thin and may contain islands of immature-appearing hyaline cartilage, but their presence is not required for the diagnosis of dysplasia (Figure 17-11). Cysts of varying sizes are formed by the dilated, dysplastic tubules and lined by a markedly flattened, often inapparent, epithelium. Cysts can occur in any part of the nephron. Varying numbers of normal glomeruli and tubules can be identified between the dysplastic areas.

The terms renal adysplasia (aplastic dysplasia) and hypoplastic dysplasia are used to describe small kidneys with limited nephron development and extensive dysplasia (Figure 17-12) that are totally nonfunctioning or minimally functioning, respectively. The essential histologic features are the same regardless of the size of the kidney or the extent of involvement.

In patients who survive the immediate postnatal period, clinical complications include hypertension, febrile urinary tract infection (UTI), vesicoureteral reflux, progressive scarring, and renal failure. Approximately 50% to 60% of cases undergo involution by 10 years, the rate partly influenced by size on postnatal ultrasound and side (59,60). In 3% to 5% of cases of dysplastic kidney, nodular renal blastema is also present, and although Wilms tumor developing in dysplastic kidney has been reported, a systematic review showed no increased risk of development of WT (61).While the
majority of multicystic dysplastic kidneys (MCDK) can be an isolated finding and is uncommonly bilateral, it is often associated with other (contralateral) anomalies of the kidney and urinary tract. The vast majority of MCDK are associated with congenital urinary tract obstruction, which is often at the ureteropelvic junction but may occur at any level. Several animal models of renal dysplasia after gestational ureteral obstruction have been described (62).

Renal dysplasia is also seen as part of a syndrome in association with extrarenal manifestations. Also, it may be diagnosed sporadically or described with familial aggregation in up to 15% of the cases. When familial, the mode of inheritance is most often autosomal dominant with variable expressivity and reduced penetrance. Epigenetic modifications may explain some of the variability; factors as improbable as maternal diet have been shown to regulate embryonic renal gene expression (63).

Due to the central role of GDNF-RET signaling pathway in ureteric budding, it is not surprising that mutations in genes that regulate the pathway, including transcription factors PAX2, EYA1, and SALL1, have been implicated in dysplasia (9,12,24). Mutations in other genes including DSTYK CHD1L; SIX 1, SIX 2, or SIX 5; and HNF1-β have also been demonstrated in patients with dysplasia, and a recent large genetic screening study of 749 individuals with various nonsyndromic renal abnormalities identified SALL1, PAX2, and HNF1-β as the most prevalent disease-causing genes (24). An excellent and exhaustive tabulation of these can be found at the end of Chapter 27 in Potter Pathology of the Fetus, Infant, and Child (64). A brief summary is provided in Table 17-4.

Earlier work had shown that apoptosis is prominent in undifferentiated cells around dysplastic tubules, which perhaps explains the tendency of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia, thought to be ureteric bud malformations. A high rate of proliferation has been demonstrated postnatally in dysplastic tubules, and PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are down-regulated during normal maturation of human collecting ducts. Ectopic expression of BCL2, which encodes a protein that prevents apoptosis during renal mesenchymal to epithelial conversion, has been observed in dysplastic kidney epithelia. Thus, dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes that are tightly regulated in normal human nephrogenesis.

According to current concepts, the term polycystic kidneys should be used to describe only two forms of inherited disease, autosomal recessive (ARPKD) and autosomal dominant (ADPKD) polycystic kidney disease, and not for any other disease in which multiple renal cysts are present. Despite different patterns of inheritance, clinical presentation, and typical appearance of the kidneys, these two diseases have some similarities. Both diseases are caused by mutations in proteins located in primary cilia, resulting in renal concentrating defect, and both are characterized by increased rates of tubular epithelial proliferation, apoptosis, and secretion as well as elevated levels of tissue cAMP (65). Elucidation of the pathogenic mechanisms of PKDs has been aided by the availability of several animal models. Rodent models have arisen by spontaneous mutation, random mutagenesis, transgenic technologies, or gene-specific targeting. Many of the proteins encoded by these mutated genes are expressed in the primary cilium or the centrosome—indicating the importance of the ciliary-centrosomal axis to normal tubular epithelial cell differentiation—or at sites of cell-cell or cell-matrix adhesion. Cytogenesis is partly the result of loss-of-function mutations in these genes or from loss-of function or gainof-function mutations in genes that encode downstream signaling molecules and transcription factors in the cystogenic pathway (65,66).

Cysts in the medulla can occur as part of several cystic kidney diseases (e.g., multicystic dysplasia, ARPKD, and ADPKD). The term medullary cystic disease generally conjures three clinically and pathologically distinct entities.

While cystic dilatation of various parts of the nephron can involve the renal cortex (i.e., cystic change of the collecting ducts in ARPKD), cortical cysts primarily refer to glomerular cysts, characterized as cystic dilatation of Bowman space. The glomerulocystic kidney was recognized in the 1800s (84). The term disease is generally reserved for the familial autosomal dominant or sporadic GCK in which a cause is not identified. Bernstein delineated the diagnosis by defining the glomerular cyst as dilatation of Bowman space in the plane of section of two- to threefold that of normal (Figure 17-18) and considered that the presence of glomerular tufts within at least 5% of cysts as evidence to support the diagnosis of glomerulocystic kidney (98). The only evidence of a glomerular tuft may be a cluster of cells adherent to the cyst wall, but the presence of tubular cysts does not preclude the diagnosis. The cysts are usually round, ovoid, or polygonal, range from less than 0.1 cm to greater than 1.0 cm, and can be empty or filled with proteinaceous material or debris.

It is now recognized that GCK is not a single entity but can be categorized as primary or secondary. The former includes (a) autosomal dominant GCKD such as those due to UMOD, REN, or TCF2 mutations; (b) GCK associated with familial nonsyndromic cystic disease (ADPKD and ARPKD); (c) GCK associated with heritable syndromes such as tuberous sclerosis (TSC), NPH (NPHP3 mutations), Jeune syndrome, orofacialdigital syndrome type 1, glutaric aciduria type 2, Zellweger syndrome, among others; and (d) various genetic abnormalities including trisomies 21, 18, 13, and 9 and monosomy X. In the latter two categories, glomerular cysts are often a minor component, for example, Jeune syndrome and NPH, better known for chronic progressive tubulointerstitial disease, and Zellweger syndrome where glomerular cysts are scattered within the cortex but usually inconsequential and only occasionally serious enough to affect renal function. In all the syndrome and genetic abnormalities, the cysts are inconsistently expressed. Secondary and acquired causes relate to (a) ischemia (postthrombotic microangiopathy— hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), vasculitis, or renal artery stenosis); (b) drugs (lithium, corticosteroids); (c) renal dysplasia; and (d) obstruction (10,84,99).

Most GCKD cases are transmitted according to an autosomal dominant mode of inheritance (84). This disease is often discovered in infants within the context of a familial history of ADPKD. The most common cause in neonates and young children in one series of 20 patients (aged 30 weeks’ gestation age to 78 years) was dysplasia (84). Adult presentation has been described along with unilateral disease, both typically associated with secondary etiologies (84). Ultrasonographically, minute cysts, smaller than those occurring in the usual autosomal dominant polycystic kidney disease, are seen in the echogenic renal cortex. No cysts are observed in the renal medulla, in ADGCKD, but may been seen with other etiologies. Kidneys in ADGCKD and ADPKD presenting with a GCK phenotype are bilaterally enlarged and diffusely cystic, in which the main microscopic finding is represented by glomerular cysts, but an asymmetric onset of this disease has also been seen. Kidneys in sporadic GCKD of non-ADPKD phenotype can have either clustered or diffuse cysts and are either slightly larger or normal in size.

Finally, in familial hypoplastic GCKD, the kidneys are smaller than normal and often associated with medullocalyceal abnormalities (100). Familial hypoplastic GCKD
is associated with mutations in TCF2, which encodes HNF1-β, and is considered the main cause of fetal hyperechoic kidneys (100) and, in some families, is associated with maturity-onset diabetes of the young, type V (MODY5) (101,102).Glomerular cysts in all types of GCKD are less than 1 cm in size and located in the cortex from the subcapsular zone to the inner cortex (eFigure 17-5), and are histologically similar to glomerular cysts seen in other disease conditions.

Simple cortical cysts, or retention cysts, which are very common in adults, are rarely seen in children. They are typically asymptomatic and incidentally discovered. They are important because they may present as an abdominal mass, or their appearance ultrasonographic or radiologic images may raise the diagnostic consideration of cystic WT. The diagnosis is established on the basis of typical radiographic findings with surrounding normal renal parenchyma, normal renal function, and the absence of systemic illness or disorders. Simple cysts arise from the cortex, are unilocular, contain yellow clear fluid, and are lined by a single layer of cuboidal epithelium. The cysts may slowly increase in size, at a rate averaging 0.3 mm and 1.0% per year, but can also disappear (103). In addition to excluding malignancy, follow-up should be undertaken to exclude an early presentation of ADPKD, especially when there are bilateral or multiple unilateral cysts (104,105).

Cysts of the cortex (sometimes referred to as pluricystic kidney), are usually asymptomatic, and have been described as a minor component of multiple malformation syndromes, both inheritable and noninheritable, including tuberous sclerosis; von Hippel-Lindau (VHL) disease; MKS; orofaciodigital syndrome type I; trisomies 9, 13, 18, and 21; short rib-polydactyly syndrome; Jeune asphyxiating thoracic dystrophy syndrome; Zellweger cerebrohepatorenal syndrome; VATER association; lissencephaly; renal-hepatic-pancreatic dysplasia; glutaric aciduria type II; Ellis-van Creveld syndrome; Elejalde syndrome; Peutz-Jeghers syndrome; Robert syndrome; phocomelia syndrome or pseudothalidomide syndrome; and Bardet-Biedl syndrome (13). In the following diseases, the renal cysts are often a dominant feature of the disease and histologically distinct from dysplasia.

The incidence of idiopathic nephrotic syndrome is two to seven per 100,000 children, 95% of whom respond to steroid therapy, although 60% to 80% of these will experience one or more relapses (125). The distribution of lesions in multiple series of untreated children with nephrotic syndrome was minimal change disease (MCD), 34% to 53%; membranoproliferative glomerulonephritis (MPGN), 2% to 16%; FSGS,
9% to 40%; membranous glomerulonephritis (MGN), 1.5% to 9%; and chronic or unclassified glomerulonephritis, 6% to 17% (126). The incidence of MCD is higher in children under 6 years old at diagnosis (71% versus 24%), more frequent in males (male to female ratios of 60:40), and less often associated with hypertension or hematuria than other causes of nephrotic syndrome. A response to prednisone at 8 weeks was seen in 93% of patients with MCD, 75% with focal global glomerulosclerosis, 30% with FSGS, 56% with diffuse mesangial hypercellularity, 7% with MPGN, and none with MGN. MCD is underrepresented in more recent series, reflecting the current practice of not performing biopsies in children with nephrotic syndrome unless unresponsive or resistant to steroid therapy. However, even allowing for the changes in biopsy practice, the incidence of FSGS in children appears to be increasing in all ethnic groups, becomes more apparent in patients over 6 years of age at presentation, and appears to be more common and more aggressive in African American and possibly Japanese children (127). Familial FSGS has been attributed to mutations that alter slit-diaphragm proteins (nephrin [NPHS1], podocin [NPHS2], CD2-associated protein [CD2AP], short transient receptor potential channel 6 [TRPC6]), actin-regulating proteins (alpha-actinin-4 [ACTN4], inverted formin-2 [INF2], Rho GTPase-activating proteins 24 [ARHGAP24], Rho GDP-dissociation inhibitor 1 [ARHGDIA]), transcription factors (Wilms tumor protein [WT1], LIM homeobox transcription factor 1β [LMX1B], WSI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein [SMARCAL1]), glomerular basement membrane proteins (laminin subunit β2 [LAMB2], integrin β4 [ITGB4]), and various mitochondrial and lysosomal proteins. Many of these patients do not
present until adulthood, and there is considerable variability in the clinical severity and response to therapy, especially among heterozygotes, implying that other genes or nongenetic triggers may be involved (127,128). Altered expression or distribution of these and other podocyte proteins has been found in studies of nonfamilial FSGS suggesting that reorganization of podocyte proteins in response to injury is a key step in the pathogenesis of proteinuria (129). Gene expression profiling of isolated glomeruli from patients with FSGS, MCD, and normal controls demonstrated numerous significantly differentially regulated genes including some known to be part of the slit-diaphragm complex and previously described in dysregulated podocyte phenotype (130). FSGS, often with lesser (nonnephrotic) levels of proteinuria, is also the lesion seen in cyanotic congenital heart disease, sickle cell anemia, massive obesity, HIV, and other viral infections (parvovirus, SV40, and some cases of hepatitis C). Nephrotic syndrome in the first year of life may be associated with lesions that occur in older children but is more often caused by one of two lesions unique to this age group—congenital nephrotic syndrome (CNS) of the Finnish type (CNF) and diffuse mesangial sclerosis (DMS) that are discussed later. Medical complications of nephrotic syndrome include acute infections and thromboembolic disease related to the nephrotic state and long-term effects on bones, growth, and the cardiovascular system related to the disease and its treatment (125).