Renal hypodysplasia

INTRODUCTION — Disruption of normal renal development can lead to congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypodysplasia, which is characterized by congenitally small kidneys with a reduced number of nephrons and dysplastic features.

Renal hypodysplasia, including its pathogenesis, etiologies, presentation, diagnosis, and management will be discussed here. Other CAKUT are discussed separately. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

RENAL MALFORMATIONS — Normal renal development is dependent upon the interaction between the ureteric bud and metanephric mesenchyme, which induces organogenesis. The average of number of nephrons is approximately 900,000 to 1 million per kidney, but there is a wide range, extending from 200,000 to >2.5 million nephrons per kidney (figure 1) [1]. Nephrogenesis, which starts at 10 weeks of human gestation, can be disturbed by mutations in genes that are involved in this process or by environmental factors, such as nutritional deficiencies during pregnancy. Nephron formation is completed at 36 weeks gestation. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Embryology'.)

Renal parenchymal malformations include the following (see "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Kidney parenchymal malformations' and 'Pathogenesis' below):

●Renal aplasia (agenesis) – Congenital absence of kidney(s). (See "Renal agenesis: Prenatal diagnosis".)

●Renal hypoplasia – Congenitally small kidneys with a reduced number of nephrons but normal architecture.

●Renal dysplasia – The presence of malformed renal tissue elements, including primitive tubules, interstitial fibrosis, and/or the presence of cartilage in the renal parenchyma. Dysplastic kidneys often contain cysts. (See "Kidney cystic diseases in children".)

●Renal hypodysplasia – Congenitally small kidney (reduced number of nephrons) with dysplastic features. Renal hypoplasia is more commonly associated with dysplasia than without.

These malformations, along with lower urinary tract abnormalities, constitute a spectrum of disorders referred to as congenital anomalies of the kidney and urinary tract (CAKUT). CAKUT occur in 1 to 3 in 500 live births and account for 40 to 50 percent of chronic renal disease cases in children [2]. Approximately 30 percent of CAKUT cases are either syndromic or occur within a familial aggregation. However, in most cases, anomalies are restricted to only the renal tract and are sporadic in nature. Renal malformations may be unilateral or bilateral and may occur in association with urinary tract anomalies, such as vesicoureteral reflux (VUR). (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)" and "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Etiology'.)

Pathology — The pathology of renal dysplasia and hypoplasia are as follows. Most patients with renal hypoplasia have dysplastic features (renal hypodysplasia) and will have pathologic features of both renal dysplasia and hypoplasia.

●Kidney dysplasia is characterized by the presence in the renal parenchyma of dysplastic elements such as primitive tubules surrounded by undifferentiated stroma, metaplastic cartilage, and smooth muscle, often with cystic tubule dilatations (picture 1). Dysplasia may affect a segment of the kidney, for example, in the upper part of a duplex kidney, or the entire kidney.

Kidney dysplasia is a histologic definition, although histologic confirmation is typically not needed for diagnosis.

●Kidney hypoplasia without dysplasia (oligomeganephronic renal hypoplasia) [3] is characterized by the following histopathologic features [4]:

•Smaller kidneys – Kidney weight that is less than 50 percent of age-matched normal controls.

•Low number of nephrons – The kidneys of patients with renal hypoplasia have only 20 to 25 percent of the normal total number of nephrons.

•Hypertrophic glomeruli – The diameter of glomeruli is twice the normal glomerular size (250 to 325 microns versus 100 to 150 microns).

•Hypertrophic tubules – Affected tubules are both longer (four times the normal length) and larger (15 times the normal volume for age) than normal.

•Other findings – Thickening of Bowman's capsule and variable abnormalities of the glomerular basement membrane (GBM) are seen. Electron microscopy also reveals irregular thickening and fusion of epithelial cell foot processes [5].

•Over time, these patients develop end-stage renal disease (ESRD) with histologic changes that include interstitial fibrosis and tubular atrophy (picture 2).

PATHOGENESIS — Renal hypodysplasia is believed to result from developmental arrest of the metanephric renal blastema during the first trimester of fetal life [6]. Although it remains unknown what causes renal hypodysplasia, two possible mechanisms include in utero vascular abnormalities and genetic developmental disorders.

Support for a major defect in the development of the renal blastema as a contributing cause of renal hypodysplasia in humans was provided by histological examination of two cases of oligomeganephronia with contralateral renal agenesis [7]. In both cases (an 18-week-old fetus and a preterm infant), the development of the metanephric blastema was deficient, resulting in a reduced blastema compared with normal controls [7]. Additional findings included a reduction in the number of glomeruli per gram of parenchyma, and severe hypertrophy combined with a decreased number of nephron generations.

Renal hypodysplasia may be an isolated finding or a component of a genetic syndrome (eg, renal-coloboma and branchio-oto-renal [BOR] syndromes) associated with urinary tract malformations.

ETIOLOGY

Vascular abnormalities — Support for in utero vascular abnormalities includes several cases of renal hypoplasia affecting only one of two homozygous twins [8,9]. In these cases, a placenta vascular shunt at a critical developmental period appears to have impaired kidney development. Other types of vascular accidents also might be involved, including disseminated intravascular coagulation or embolization of necrotic pieces, following the death in utero of a twin fetus [10].

Renal hypodysplasia and urinary tract abnormalities — Renal hypodysplasia may be observed in patients with urinary tract disorders, such as posterior urethral valves (PUV), vesicoureteral reflux (VUR), and ureteropelvic junction obstruction (UPJO) [11]. Proposed mechanisms for both renal and urinary tract disorders include either a common developmental insult or back pressure from urinary tract obstruction resulting in disrupted renal development and renal hypodysplasia. (See "Clinical presentation and diagnosis of posterior urethral valves", section on 'Chronic kidney disease' and "Congenital ureteropelvic junction obstruction", section on 'Pathophysiology' and "Clinical presentation, diagnosis, and course of primary vesicoureteral reflux", section on 'Congenital renal hypodysplasia'.)

Genetic disorders — Renal hypodysplasia is observed in over 200 syndromic disorders where anomalies involving other organs are present. In several of these syndromic disorders, mutations of genes involved in renal tract development have been identified (table 1) [12,13]. These genes encode transcriptional factors or other factors, which regulate early renal development and have extrarenal functions, and which explain the extrarenal phenotypes. A large case series reported that a genetic defect was identified in 6 percent of patients with CAKUT, and the most prevalent disease-causing genes included SALL1, HNF1B, and PAX2 [14]. Other gene mutations such as SIX2 and BMP4 [15], UPIIIa [16], or DSTYK [17] also have been associated with isolated or sporadic non-syndromic cases of CAKUT. In addition, whole exome sequencing performed in 202 patients identified GREB1L and SLIT3 as genes implicated in the pathogenesis of renal hypodysplasia [18]. Copy gene variants with deletions or duplications of regions such as 1q21, 4p16.1-6.3, 16p11.2, 16p13.11, 17q12, or 22q11.2 have been identified in patients with syndromic or nonsyndromic forms of renal hypodysplasia [19]. Several of these genetic syndromic disorders are discussed.

●Renal tubular dysgenesis – Autosomal recessive renal tubular dysgenesis (RTD; OMIM #267430) is a disorder of renal tubular development secondary to the hypoperfusion of the embryonic kidney [20,21]. Clinical manifestations consist of persistent fetal anuria resulting in oligohydramnios and pulmonary hypoplasia, persistent anuria, and arterial hypotension [22]. Most patients die in the perinatal period due to pulmonary hypoplasia and 10 to 15 percent survive with intensive care [23]. Renal histology shows an absence or paucity of differentiated proximal tubules. It is associated with skull ossification defects. Homozygous or compound heterozygous mutations of the genes encoding for the renin-angiotensin system have been identified as the underling etiology. These include renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II receptor type 1 (AGTR1) [24,25].

Renal tubular dysgenesis can also be caused by renal hypoperfusion in the first trimester due to twin-twin syndrome or prenatal exposure to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).

●Branchio-oto-renal syndrome – Branchio-oto-renal (BOR) syndrome (OMIM #113650, #610896), is an autosomal dominant disorder characterized by branchial defects with lateral cervical fistulas or cysts, ear pits, hearing loss, and renal anomalies, including renal aplasia and hypoplasia [26-28]. The incidence of BOR syndrome is 1 in 40,000 infants. In this syndrome, penetrance is incomplete, and patients may have only one or two features of the syndrome [29]. Renal anomalies are not observed in all patients and may differ in individuals of the same family. Renal findings include renal agenesis or hypoplasia (which may be unilateral or bilateral), VUR, UPJO, or ureteral duplication [26,27]. If renal hypoplasia is present, it may vary in severity and may progress to end-stage renal disease (ESRD). Ear abnormalities include periauricular pits, anomalies of the middle and external ear, and hypoplasia of the cochlea, resulting in hearing loss. (See "Congenital anomalies of the ear", section on 'Preauricular pits'.)

More than 80 mutations in the EYA1 gene on chromosome 8q13.3 have been identified in patients with BOR syndrome [27,30,31]. The EYA1 gene encodes for a transcription cofactor that is expressed in the metanephric mesenchyme during kidney development [32]. The EYA1 gene interacts with members of the SIX gene family, which encodes transcription factors that control expression of the PAX2 and GDNF protein products in the metanephric mesenchyme. Mutations in SIX1 (chromosome 14q23.1) and SIX5 genes have also been reported in families with the BOR syndrome [33-35].

●Renal-coloboma syndrome – Renal-coloboma syndrome (OMIM #120330), also known as the papillorenal syndrome, is an autosomal dominant disorder characterized by renal hypoplasia and optic nerve coloboma [36]. Renal malformations include renal hypodysplasia, VUR, and less often, multicystic dysplasia and UPJO [37]. Ophthalmologic examination shows an optic disc split and vascular anomalies associated with variable visual impairment [38]. Some patients have a large coloboma of the optic nerve while other patients present with optic nerve dysplasia without visual impairment. Other features include sensorineural hearing loss (SNHL), Arnold-Chiari malformation, seizures, and joint laxity [39]. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Optic disc coloboma'.)

More than 50 heterozygous mutations in the PAX2 gene have been described in patients with the renal-coloboma syndrome [40,41]. Identified mutations have mostly been located in the second and third exons of the PAX2 gene, which is located on chromosome 10q24-25 [40]. The PAX2 gene encodes a transcription factor involved in the development of the kidneys and eyes. PAX2 mutations have been identified in a few patients with renal hypodysplasia and limited or no optic nerve anomalies [42,43].

●HNF1b-related disease (renal cysts and diabetes syndrome) – Heterozygous mutations of HNF1b gene are responsible for an autosomal dominant disease referred to as renal cysts and diabetes (RCAD) syndrome (OMIM #137920). Antenatal ultrasound examination may detect this disorder based on characteristic findings, which include enlarged hyperechogenic kidneys, renal cysts, renal dysplasia, unilateral or bilateral multicystic kidney disease (MCKD), or unilateral renal agenesis [44]. During childhood, kidney size decreases while renal cysts increase in size. Progression to renal failure is observed during childhood in half of the patients [45]. Renal histology shows glomerular cysts or cysts developed in any part of the nephron and often renal dysplasia. Renal cell carcinoma may develop later in life [46].

Extrarenal manifestations include [47]:

•Diabetes mellitus typically presents in adolescence but may have occur in affected neonates [48,49]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Hepatocyte nuclear factor-1-beta'.)

•Increased risk of autism and schizophrenia [50,51].

•In adults, exocrine pancreas deficiency and asymptomatic cholestasis with increased levels of gamma-glutamyl transpeptidase (GGT) but without liver histologic anomalies may develop.

•Other abnormalities include hypomagnesemia, hyperuricemia, and urogenital tract anomalies.

The HNF1b gene is located on chromosome 17q12 and encodes for a transcription factor, which controls the expression of several genes involved in development in the liver, the kidneys, the intestine, and the pancreas. A deletion of the whole gene is observed in 50 to 60 percent of patients while other patients show small mutations. De novo mutations occur in more than 50 percent of cases. The severity of the renal disease associated with HNF1b mutations is extremely variable and is not correlated with the genotype [52].

●DiGeorge syndrome – DiGeorge syndrome (OMIM #188400) is a microdeletion syndrome, most often sporadic due to a de novo deletion of chromosome 22 (22q11.2). It is characterized by cardiac malformations, hypoparathyroidism, immune deficiency, and developmental delay. CAKUT are observed in 30 percent of patients with DiGeorge syndrome. A recurrent 370-kb deletion at the 22q11.2 locus that contains nine genes has been identified as the genetic driver of kidney defects in the DiGeorge syndrome and in sporadic CAKUT [53].

●Townes-Brocks syndrome – Townes-Brocks syndrome (TBS; OMIM #107480), also referred to as anus-hand-ear syndrome, is an autosomal dominant disorder characterized by the association of imperforate anus, preaxial polydactyly and triphalangeal thumbs, external ear anomalies, SNHL, and renal and cardiac anomalies [54]. Renal malformations consist of unilateral or bilateral hypoplastic and/or dysplastic kidneys, renal agenesis, multicystic kidney, horseshoe kidney, VUR, and PUV. These malformations may be responsible for renal failure, including ESRD. Most patients have normal intelligence.

TBS occurs in 1 in 200,000 live births. More than 60 mutations have been identified in SALL1 gene on chromosome 16q12.1, which codes for a zinc finger transcription factor involved in kidney development [55,56]. SALL1 is essential for ureteric bud invasion, the first step of metanephros development [57]. De novo mutations are observed in 50 percent of cases. Approximately 65 percent of patients have point mutations, and 5 percent deletions [58]. Severity of the disease varies and is not correlated with the genotype.

●Kallmann syndrome – Kallmann syndrome (OMIM #308700) is defined by the association of hypogonadotrophic hypogonadism and anosmia or hyposmia. Some patients also present with cleft lip, heart defects, obesity, and cognitive impairment [59]. Renal malformations include unilateral renal agenesis and, less frequently, hydronephrosis or VUR.

The association of hypogonadotrophic hypogonadism and anosmia is explained by the embryologic origin of gonadotrophin-releasing hormone (GnRH)-producing neurons and olfactory sensory neurons whose precursors migrate together during development from the nasal placode to the telencephalon. This migration is regulated by neurotransmitters, extracellular matrix proteins, and growth factors. Kallmann syndrome is genetically heterogeneous. Anomalies have been found in six different genes (KAL1, FGFR1, FGF8, CHD7, PROK2, PROKR2), explaining one-third of cases [60,61]. KAL1 gene is located on the X chromosome and encodes anosmin-1, an extracellular matrix protein which is involved in neuronal development, migration, and organogenesis. Anosmin-1 was detected in the basement membranes of mesonephric tubules and duct as well as branches of the ureteric bud [62]. Forty percent of patients with KAL1 gene mutations show renal anomalies, most often unilateral renal agenesis [63]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics'.)

●Simpson-Golabi-Behmel syndrome – Simpson-Golabi-Behmel syndrome (SGBS; OMIM #312870) is a rare X-linked congenital syndrome characterized by pre- and postnatal overgrowth, craniofacial anomalies, organomegaly, increased risk of tumors, moderate intellectual deficiency, and variable congenital malformations [64]. Two types of the disorder have been described, a less severe form (SGBS type I) and a severe form (SGBS type II).

The glypican 3 (GPC3) gene, located on Xq26, encodes a heparan sulfate proteoglycan, an extracellular matrix protein, which plays an important role in cell growth during development [65]. GPC3 mutations have been identified mostly in patients with SGBS type I, the most frequent form of SGBS. Renal anomalies are observed in 50 percent of patients with GPC3 mutations and consist of duplicated collecting, megaureter, VUR, and UPJO. Patients may have renal dysplasia and renal cysts, nephromegaly, and may develop Wilms tumor [66]. A second locus on chromosome Xp22 is associated with SGBS type II.

●Fraser syndrome – Fraser syndrome (OMIM #219000) is an autosomal recessive disease characterized by cryptophthalmos, cutaneous syndactyly, genital malformations with ambiguous genitalia, craniofacial anomalies, and malformations of the larynx (stenosis or atresia) and the kidneys. Cryptophthalmos is bilateral, or less frequently, unilateral. Other ocular malformations include coloboma, microphthalmia, or anophthalmia. Bilateral renal agenesis was reported in 23 percent of 117 cases [67]. Patients who survive may have unilateral renal agenesis and/or renal cystic dysplasia.

Fraser syndrome occurs in 1 in 10,000 live births. Mutations in the FRAS1 and FREM2 genes have been described in patients with this syndrome [68,69]. Both genes are involved in kidney development in the embryo.

●Pallister-Hall syndrome – Pallister-Hall syndrome (PHS; OMIM #146510) is a rare autosomal dominant disorder caused by mutations in GLI3, which encodes a transcriptional repressor (GLI3R). Clinical features include hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus, and renal abnormalities including renal dysplasia [70].

●Cenani-Lenz syndrome – Cenani-Lenz syndrome (CLS; OMIM #212780) is an autosomal recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is associated with facial dysmorphism and kidney agenesis or hypodysplasia. CLS is caused by mutations in the LRP4 gene, encoding the low-density lipoprotein receptor-related protein 4 [71].

●HDR syndrome – HDR syndrome (OMIM #146255) is an autosomal dominant genetic disease characterized by hypoparathyroidism, sensorineural deafness, and renal malformations including renal hypodysplasia, renal agenesis, and vesicoureteral reflux. Penetrance of these renal malformations is variable [72].

Haploinsufficiency for GATA3 is the underlying mechanism of HDR syndrome. This gene belongs to a family of zinc finger transcription factors that are involved in vertebrate embryonic development [73].

●CHARGE syndrome – Infants with CHARGE syndrome (coloboma of the retina or the iris, heart anomalies, choanal atresia, intellectual disability, genital and ear anomalies; OMIM #214800) [74] often have renal or urological anomalies, such as unilateral renal agenesis, renal hypoplasia, duplex kidneys, UPJO, or VUR [75]. Most cases of CHARGE syndrome are related to mutations of the gene coding for the chromodomain helicase DNA-binding protein-7 (CHD7) on chromosome 8q12 [76,77]. These are heterozygous mutations, suggesting that haploinsufficiency of the gene is responsible for CHARGE syndrome (autosomal dominant inheritance). Most cases are due to de novo mutations, although rare familial cases have been reported [78]. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'CHARGE syndrome'.)

Environmental causes of renal hypodysplasia — The following fetal and neonatal environmental factors have been suggested as contributing to reduced number of nephrons:

●Intrauterine growth restriction [79]

●Maternal vitamin A deficiency [80-82]

●Maternal low folate intake [83]

●Maternal hyperglycemia and diabetes [84-86]

●Maternal use of cocaine [87]

●Maternal excessive alcohol consumption [88]

●Maternal intake of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers [89]

ANTENATAL PRESENTATION — Renal hypoplasia may be detected by antenatal ultrasound screening after the third month of gestation.

The diagnosis of hypoplasia should be suspected when fetal renal measurements using reference charts demonstrate that the kidneys are less than fifth percentile (table 2). Ultrasound may demonstrate absence of corticomedullary differentiation, cysts, and dilatation of the urinary tract. In addition, oligohydramnios may also be a clue to bilateral renal malformation that results in decreased production of fetal urine (amniotic fluid). (See "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Antenatal screening' and "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations" and "Assessment of amniotic fluid volume".)

POSTNATAL PRESENTATION — Patients with a unilateral abnormality and normal contralateral kidney have normal renal function. In those with bilateral renal involvement, the clinical presentation is dependent on the degree of renal impairment. Patients with more severe involvement will present at a younger age. (See 'Progression to end stage renal disease (ESRD)' below.)

Neonate — The birth weight (BW) of patients with renal hypodysplasia is often below the normal mean because of the association with intrauterine growth restriction (IUGR).

In the neonatal period, patients may present with one or more of the following:

●Pneumothorax

●Feeding difficulties

●Metabolic acidosis

●Urinary sodium losses

●Impaired renal function based on elevated serum/plasma creatinine level

First year of life — During the first year of life, persistent anorexia with vomiting is the usual presentation of renal hypodysplasia. Failure to thrive is seen in more than 50 percent of cases. The degree of poor growth is greater than what would be expected based on the level of the infant's renal function impairment. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Infancy'.)

After one year of life — After one year of age, patients will commonly present with proteinuria discovered incidentally on routine urine examination. In other patients, the disease may be discovered because of poor growth, or symptoms of polyuria and polydipsia. Renal failure can also present as anemia or osteodystrophy secondary to hyperparathyroidism. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis" and "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Ultrasound findings — Kidney hypoplasia is defined as reduced kidney size (less than two standard deviation scores for length [90]) with normal corticomedullary differentiation, as detected on ultrasonography [91]. Ultrasonography typically reveals reduced corticomedullary differentiation when there is renal dysplasia [92,93]. Other findings may include reduced cortical thickness and cysts. Visualization of the urinary tract also may reveal urological malformations.

Renal hypodysplasia may be either bilateral or unilateral. In cases of unilateral involvement, compensatory hypertrophy of the contralateral kidney is generally present [94]. (See "Renal agenesis: Prenatal diagnosis".)

DIAGNOSIS AND EVALUATION

Diagnosis — Renal hypodysplasia is usually clinically diagnosed based on renal ultrasonography findings of a reduction of renal size by greater than two standard deviations for the mean size by age and loss of corticomedullary differentiation. The diagnosis can be confirmed by histologic examination; however, this is not usually performed since it would not impact management.

Postdiagnosis evaluation — No further work-up is needed for patients with isolated renal hypodysplasia unless there is concern for an underlying genetic disorder because (see 'Genetic disorders' above):

●There is a strong family history suggestive of a specific underlying genetic disorder.

Or

●Patients have concomitant features suggestive of an underlying genetic disorder (table 1).

In these cases, work-up is warranted for those specific disorders if genetic testing is available.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of renal hypodysplasia in children who present beyond the neonatal period includes disorders that result in renal scarring, particularly recurrent episodes of pyelonephritis. 99mTc-dimercaptosuccinic acid (DMSA) radionuclide scan can be performed to distinguish hypoplastic kidneys from those with renal scarring. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Kidney scintigraphy' and "Clinical presentation, diagnosis, and course of primary vesicoureteral reflux", section on 'Kidney scarring'.)

PROGRESSION TO END STAGE RENAL DISEASE (ESRD) — Over time, many patients with renal hypodysplasia develop ESRD [95]. Progressive renal failure is due, in part, to focal segmental glomerulosclerosis (FSGS), which develops in the reduced number of nephrons due to hyperfiltration, resulting in compensatory intraglomerular hypertension and hypertrophy. This process is similar to that seen with other renal conditions with nephron loss, and may be slowed by antihypertensive therapy, particularly with an angiotensin-converting enzyme (ACE) inhibitor. (See 'Renal histopathology of ESRD' below and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Large case series have provided information on the natural course of renal function, based on estimated glomerular filtration rate (eGFR) of patients with renal hypodysplasia, which can be separated into three phases [95-98]:

●During the first years of life, eGFR improves to a maximal level that is attained between one and six years of age. In general, maximal eGFR is achieved at a younger age in patients with the most severe degree of impairment.

●During the second phase, the maximal eGFR usually remains stable through early to middle childhood (<10 years of age).

●Near or at the onset of puberty, eGFR may deteriorate. Patients with proteinuria, recurrent urinary tract infections, hydronephrosis, and a solitary kidney are more likely to have a decline in eGFR and progress to ESRD. Proteinuria generally precedes the deterioration of renal function by several years.

Renal histopathology of ESRD — Kidneys removed in patients with end-stage renal disease (ESRD) due to renal hypodysplasia at the time of transplantation are very small in size with a reduced number of papillae. In this setting, histological examination allows the clinician to confirm or to make the diagnosis of renal hypodysplasia:

●The number of glomerular generations is extremely reduced, and varies from two to six depending in part upon the area of the kidney examined. By comparison, the normal number is at least 10.

●There is a relatively high proportion of hypertrophic glomeruli. The diameter of these glomeruli is increased to more than 300 microns and often reaches 400 microns (in contrast, normal glomeruli have a diameter of 100 to 150 microns). Adjacent proximal tubules are also similarly hypertrophied.

●Other findings include segmental sclerosis, hyalinosis of glomeruli, and interstitial fibrosis [96,99].

MANAGEMENT — Management is based on the probability of progression to chronic kidney disease (CKD), which is more likely with bilateral involvement.

●For patients with unilateral hypodysplasia, follow-up ultrasounds are used to monitor the growth of the contralateral kidney, which typically exhibits compensatory hypertrophy [94]. In addition, renal function studies are performed, particularly in patients who do not exhibit appropriate growth of the contralateral kidney.

●For patients with bilateral renal hypodysplasia, follow-up includes assessment of blood pressure and proteinuria twice a year and kidney function every six months for the first year, with subsequent assessments according to kidney function [91].

Such patients need supportive management, which includes maintaining fluid and electrolyte balance, and growth promotion. The latter may entail the use of recombinant human growth hormone (rHGH) therapy. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

As noted above, angiotensin-converting enzyme (ACE) inhibitors may be given in an attempt to slow the progression to end-stage renal failure, particularly in those patients who develop proteinuria. (See 'Progression to end stage renal disease (ESRD)' above and "Chronic kidney disease in children: Overview of management", section on 'Slow progression of chronic kidney disease' and "Antihypertensive therapy and progression of chronic kidney disease: Experimental studies".)

Other management issues are similar to those seen in children with CKD due to other disorders and are discussed separately. (See "Chronic kidney disease in children: Overview of management".)

For patients who progress to end-stage renal disease (ESRD), renal transplantation is the preferred replacement therapy. (See "Kidney transplantation in children: General principles", section on 'Advantages of kidney transplantation'.)

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Renal hypodysplasia is characterized by small kidneys (hypoplasia) with malformed renal tissue elements (dysplasia) including primitive tubules, interstitial fibrosis, and/or the presence of cartilage. It is thought to be caused by disruption of normal renal development between the 14^th and 20^th weeks of fetal life. During this time period, ureteric bud branching defects due to either a vascular or genetic abnormality result in the developmental arrest of the metanephric renal blastema. (See 'Renal malformations' above and 'Pathogenesis' above.)

●Causes – Renal hypodysplasia may occur as an isolated finding, in association with urinary tract malformations, or as a component of a genetic syndrome (table 1). (See 'Etiology' above.)

●Antenatal detection – Renal hypoplasia may be detected by antenatal ultrasound screening after the third month of gestation. The diagnosis of hypoplasia should be suspected when fetal renal measurements using reference charts demonstrate that the kidneys are less than fifth percentile (table 2). (See 'Antenatal presentation' above.)

●Postnatal clinical features – Postnatal presentation for patients not detected by antenatal ultrasound screening is dependent on the degree of renal impairment. Patients with more severe involvement will present at a younger age, often during the neonatal period. (See 'Postnatal presentation' above.)

•Neonates may present with pneumothorax, intrauterine growth restriction (IUGR), feeding difficulties, metabolic acidosis, and impaired renal function based on an elevated serum/plasma creatinine level.

•Older infants typically present with failure to thrive, anorexia, and vomiting.

•Children commonly present with proteinuria discovered incidentally on routine urine examination.

●Diagnosis by ultrasound – The clinical diagnosis of renal hypodysplasia is made by renal ultrasonography findings of a reduction of renal size by greater than two standard deviations for the mean size by age and loss of corticomedullary differentiation. (See 'Diagnosis' above.)

●Prognosis – Over time, many patients with renal hypodysplasia progress to end-stage renal disease (ESRD). Progressive renal failure is due, in part, to focal segmental glomerulosclerosis (FSGS), which develops in the reduced number of nephrons, because of hyperfiltration resulting in compensatory intraglomerular hypertension and hypertrophy. (See 'Progression to end stage renal disease (ESRD)' above.)

●Management – There is no specific treatment for renal hypodysplasia. Supportive care includes maintaining fluid and electrolyte balance and promoting growth. Renal transplantation is the preferred therapy in patients who progress to ESRD. (See 'Management' above.)