Correspondence *Nephro-Urology Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

Email a.woolf@ich.ucl.ac.uk

Introduction

Renal tract malformations are congenital anomalies of the kidneys and/or lower urinary tract. One challenging feature of managing these conditions is that they present to diverse clinical specialties. Some cases present prenatally; obstetricians might consider termination for severe cases. Live-born babies with less severe prenatally diagnosed renal tract malformations are generally managed by pediatric nephrologists and possibly pediatric urologists. Among children, many renal tract malformations are diagnosed by pediatricians after investigation of urosepsis, hypertension, proteinuria or renal impairment. When affected individuals reach adulthood, some will be referred to adult nephrologists and/or adult urologists, while others with milder disease might be followed up by primary care physicians only. Finally, some individuals with renal tract malformations remain undiagnosed prenatally and throughout childhood, only to present to nephrologists in adulthood with hypertension, proteinuria and renal impairment.

The focus of this Review is on the diagnosis, treatment, outcomes and genetics of human renal tract malformations. Because of space constraints, we have not reviewed the extensive insights into renal tract malformations gained from animal studies.¹ We have intentionally not covered diseases such as congenital nephrotic syndromes, polycystic kidney disease and nephronophthisis,^{2, 3, 4, 5} which, although they sometimes present perinatally, can better be considered as disorders of terminal differentiation than as primary malformations.

Types of malformation

Anatomical and histological characteristics

In her 1972 book Normal and Abnormal Development of the Kidney, Edith Potter⁶ summarized the detailed histology of normal and abnormal human renal tract development, from the inception of the metanephros to the end of nephron formation, which occurs at around 34 weeks of gestation.⁷ The most profound renal tract malformation, complete absence of kidney development, is called renal agenesis (Figure 1) and is often accompanied by an absent ureter. Embryologically, renal agenesis occurs because the ureteric bud has not interacted with the metanephric mesenchyme; as a result, the bud fails to form the ureter, renal pelvis and collecting ducts, and the mesenchyme fails to form nephrons.^{8, 9} On occasion, unilateral renal agenesis is accompanied by genital tract anomalies on the same side (e.g. seminal vesicle hypoplasia and absence of the vas deferens).¹⁰ The contention that isolated, minor ear anomalies, such as tags, are associated with renal agenesis or other renal tract malformations seems not to be based on any sound foundation.¹¹

Figure 1 Diagram of normal and abnormal kidney development.

Uppermost are the precursor structures of a single renal tract, as would be present in a human fetus of 4–5 weeks' gestation; note the mesonephric duct, metanephric mesenchyme (which will form nephrons), and ureteric bud. Solid arrows indicate normal developmental pathways and dotted arrows indicate abnormal pathways. In normal development, the ureteric bud grows into the metanephric mesenchyme and is followed by bud branching and nephron induction and, finally, development of a fully functional, normal kidney containing multiple layers of nephrons. Hypoplastic kidneys contain fewer layers of nephrons than normal but retain a moderate degree of excretory function. Cystic dysplastic kidneys contain malformed tubules and some small cysts but generally retain some excretory function. A discrete renal pelvis (white) is present in normal, hypoplastic and cystic dysplastic kidneys; this feature would appear distended (hydronephrotic) if the kidney was attached to an obstructed lower tract (not shown). The multicystic dysplastic kidney has no useful excretory function and its pelvis is absent or severely disorganized. Aplastic kidneys undergo no primary growth or development; a similar phenotype is seen in the organ remnant left after the spontaneous involution of a multicystic dysplastic kidney. In the most profound type of malformation, agenesis, the first steps of kidney development do not occur and the kidney (and often the ureter) is absent.

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Dysplastic kidneys (Figure 1) are so-called because the organs are present but development is abnormal and incomplete.^{6, 12} These organs contain incompletely branched ducts derived from cells of the ureteric bud–collecting duct lineage, surrounded by undifferentiated and metaplastic stroma. Sometimes the whole kidney is dysplastic, being either aplastic (perhaps only a few millimeters long), or large and distended by multiple cysts. Ureters attached to multicystic dysplastic kidneys are poorly formed and characteristically have nonpatent sections.^{6, 13} These severe types of dysplastic kidneys generally have no excretory function, at least when assessed postnatally. Edith Potter envisioned that multicystic dysplastic kidneys were examples of the consequences of a primary failure of nephron induction. Subsequent studies of the histology of fetal multicystic dysplastic kidneys have, however, reported that at least a few nephrons, containing relatively normal glomeruli and proximal tubules, can be present in these kidneys;^{14, 15} these structures seem to be mostly destroyed later in gestation or postnatally, during involution of these organs (as discussed below).^{16, 17, 18} Postnatally, isotope renography indicates that the presence of minimal function is rare in multicystic dysplastic kidneys, occurring, for example, in 3 out of 83 (4%) cases in one series of patients with unilateral multicystic disease. In these patients, the malformed kidney contributed to 3–7% of total function, as assessed by isotope renography.¹⁹

Potter's observations⁶ clearly distinguished dysplastic kidneys that contain cysts from polycystic kidneys: in dysplastic kidneys, cysts arise in the context of abnormal development whereas in polycystic kidneys, cysts arise from pre-existing tubules. Dysplasia is sometimes limited to the medulla and, in the presence of a duplex ureter, only the upper moiety is generally dysplastic.²⁰ Cystic dysplastic kidneys contain primitive tubules and cysts alongside normal nephrons and generally have some excretory function.¹² In the variant of kidney malformation associated with obstruction, the first layers of filtering nephrons form normally, but nephrogenesis subsequently halts, and subcapsular cysts originating from nephron precursors often develop.^{6, 13, 21} Renal tubular dysgenesis involves incomplete differentiation of proximal tubular nephron segments; there is often fetal anuria and subsequent oligohydramnios.²²

Hypoplastic kidneys contain fully formed nephrons but have a deficit in the number of nephrons present (Figure 1). One definition of kidney hypoplasia is, "Kidney mass below two standard deviations of that of age-matched normal [individuals] or a combined kidney mass of less than half normal for the patient's age."¹² Oligomeganephronia represents a severe variant of hypoplasia in which both "kidneys are one-eighth to one-half normal weight. Nephron number is reduced by 80% and nephrons are markedly hypertrophied, with glomerular diameter over twice normal."¹² Stereology enables three-dimensional information to be derived from two-dimensional data, permitting accurate measurements to be taken of glomerular numbers. This method has shown that there is wide variation in the number of glomeruli per kidney in healthy populations and, moreover, that the average number of glomeruli is (at least in white individuals) reduced in patients with essential hypertension.^{23, 24} These new histological insights raise the question of whether a more subtle but more common form of hypoplastic kidney exists than those encompassed by the above definitions.

Diagnosis

Although histology provides the purest way of classifying renal tract malformations, renal biopsies are rarely performed in suspected cases of dysplastic or hypoplastic kidneys, and such information is generally only available in cases of fetal termination. Thus, in clinical practice, most diagnoses of renal tract malformations are made on the basis of radiological findings^{30, 31, 32} (Table 1).

Table 1 Findings of fetal and postnatal radiological investigations of the main varieties of kidney malformations, and indications for further postnatal radiological assessment.

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Prevalence

Fetal examinations of more than 700,000 births, carried out as part of European renal anomaly detection programs, revealed unilateral multicystic dysplastic kidneys in 0.014%, unilateral renal agenesis in 0.008%, bilateral renal agenesis or dysplastic kidneys in 0.013%, and posterior urethral valves in 0.003%.³³ Among 3,856 fetuses in the last trimester assessed by ultrasonography in New Zealand, upper renal tract dilatation was seen in 298 (7.7%) but was generally transient, and 0.4% of the fetuses had persistent hydronephrosis attributed to pelviureteric junction obstruction.⁵⁷ The transience of the dilatations might be due to the relatively high rate of fetal urine flow. Alternatively, the transient dilatations might represent delays in ureteric smooth muscle maturation, because ureteric peristalsis is required to propel urine towards the bladder.⁵⁸ Up to 15% of fetuses with hydronephrosis can be shown postnatally to have primary vesicoureteric reflux.⁵⁹

Hiraoka et al.⁵³ performed ultrasonography in 4,000 apparently healthy neonates in Japan and found small kidneys in 8 (0.2%), among which 7 cases were unilateral and 1 was bilateral. Most of the affected individuals were boys, and vesicoureteric reflux was universally present. Sheih et al.⁶⁰ reported on ultrasonographic screening of 132,686 schoolchildren in Taiwan: 0.09% had hydronephrosis, 0.08% had unilateral renal agenesis and 0.10% had unilateral small kidneys. In an ultrasound study of adults, unilateral renal agenesis was reported in 0.3% of individuals.⁶¹ The apparently increased prevalence of unilateral renal agenesis in postnatal versus fetal studies³³ is probably explained by the unintentional inclusion of regressed dysplastic kidneys in the former.^{16, 17}

Contribution to end-stage renal disease

A major question for nephrologists is whether renal tract malformations can cause end-stage renal disease (ESRD), to which the answer is yes. The contribution of renal anomalies to ESRD is most obvious in children. Data from the UK Renal Registry⁶² show that unobstructed and obstructed dysplastic or hypoplastic kidneys together account for about 40% of all children on renal replacement therapy and are six times more common than nephronophthisis, congenital nephrotic syndromes or metabolic diseases (predominantly cystinosis and primary hyperoxaluria). Dysplastic or hypoplastic kidneys are 10 times more common than polycystic kidneys in children with ESRD. Other registries (e.g. the North American Pediatric Renal Trials and Collaborative Studies database⁶³) confirm the fact that renal tract malformations are the most common diagnoses in children with chronic kidney disease.

In registries of adults receiving renal replacement therapy, dysplastic or hypoplastic kidneys account for only a small proportion of primary diagnoses; for example, these conditions have a prevalence of 0.6% in the US Renal Data System.⁶⁴ Additional cases of dysplastic or hypoplastic kidneys might be misclassified or be classified as miscellaneous or unrecognized. We reported an extensive kindred with inherited dysplastic or hypoplastic kidneys, from which two individuals were incorrectly diagnosed as having primary glomerular disease.⁶⁵ Similarly, some adults with small 'scarred' kidneys might be classified as having chronic pyelonephritis, although they could have been born with dysplastic or hypoplastic kidneys associated with primary vesicoureteric reflux.^{27, 53, 54}

Fetal interventions

Therapeutic termination of pregnancy is often undertaken if a fetus has severe renal tract malformations.^{33, 66} In one series, almost half of fetuses in which posterior urethral valves were diagnosed underwent termination.⁶⁷ The main factor that leads to the decision to terminate is poor renal function and/or severe bladder outflow obstruction, which is manifested by reduced amniotic fluid, sometimes leading to impaired lung growth (oligohydramnios sequence or Potter's syndrome). However, with advances in dialysis for young babies and renal transplantation for young children,⁶⁸ termination might not always be necessary under these circumstances.⁶⁹ Some fetuses are found to have anomalies in other organ systems (e.g. brain, heart or gut), which are sometimes accompanied by gross chromosomal aberrations, such as trisomies;⁷⁰ these conditions might also drive the decision to terminate a pregnancy.

Even if infants with posterior urethral valves undergo bladder decompression, the risk of developing ESRD rises with increasing age into adulthood.^{71, 72} Animal data show that kidney development can be severely perturbed by experimental fetal urinary flow impairment.⁷³ If this phenomenon occurs in humans, it makes intuitive sense to unblock the obstructed kidneys at the prenatal stage. For several decades it has been technically feasible to decompress fetal bladders affected by outflow obstruction by use of vesico–amniotic shunts. Clark et al.,⁷⁴ however, noted no evidence of improvement in renal outcomes with such interventions, and only weak evidence that perinatal survival increased. Prospective trials that include interventional and observational arms and encompass several decades of follow-up will be needed to determine whether such prenatal surgery is warranted. One such trial is currently underway.⁷⁵

Long-term outcomes and postnatal therapies

For individuals born with severe unilateral renal tract malformations, such as renal agenesis or a multicystic dysplastic kidney, the risk of renal failure in childhood is minimal.^{42, 43} Few long-term (i.e. over several decades) follow-up data of large cohorts of such patients are available, however, although there are reports of selected individuals born with solitary functioning kidneys who developed hypertension, proteinuria and renal failure as adults.^{76, 77, 78, 79, 80} Perhaps such deteriorations in renal function are human examples of the hyperfiltration hypothesis presented by Hostetter and colleagues.⁸¹ Unfortunately, we cannot predict the long-term excess risk of renal failure for any particular baby born with a unilateral renal anomaly and an apparently normal solitary functioning kidney.

Prenatal hydronephrosis raises the risk of hospitalization for pyelonephritis in infancy.⁸² A systematic review and meta-analysis of idiopathic prenatal hydronephrosis indicated that spontaneous resolution occurred in most cases when the renal pelvic anterior–posterior diameter was less than 12 mm, but was less frequent when dilatation was greater than 12 mm.⁸³ In a prospective natural history study of prenatal hydronephrosis, Ransley et al.⁸⁴ reported that "Of the 100 kidneys in the good function group that were followed conservatively," about a quarter underwent pyeloplasty "primarily because of an observed decrease in function." The need for pyeloplasty in babies with pelviureteric junction obstruction can be successfully predicted by specific patterns of types of polypeptides in urine.⁸⁵ As with congenital solitary functioning kidneys, large-scale, long-term studies are needed to determine the risks of hypertension, proteinuria and renal impairment in patients with congenital pelviureteric junction obstruction.

After the classic observations by Hodson and Edwards⁴⁹ on the association between chronic pyelonephritis and vesicoureteric reflux, active treatment of individuals born with primary vesicoureteric reflux was seen as imperative to minimize kidney damage. The Cochrane Renal Group⁸⁶ found few data to support the primacy of either long-term antibiotic therapy or antireflux surgery for renoprotection in this setting. Craig et al.⁸⁷ demonstrated that the era of active therapy has not reduced the incidence of ESRD that occurs as a result of reflux nephropathy, which accords with the concept that reflux nephropathy is often caused by dysplasia or hypoplasia rather than by pyelonephritic damage, as discussed earlier.^{27, 53, 54} The risk of progression to ESRD positively correlates with the degree of kidney damage in children and adults with reflux nephropathy; thus, radiologically proven bilateral nephropathy, as well as proteinuria and decreased GFR predict poor outcome.^{71, 88} Similarly, the renal functional outcomes in children with bilateral nephropathy as a result of dysplastic kidneys are worse than those in children with uncomplicated unilateral disease,⁸⁹ and decreased GFR at presentation predicts progression of renal failure during childhood.⁴⁸

Several reports have indicated that progression of renal failure in children and adults with renal tract malformations correlates with proteinuria.^{71, 90, 91} In addition, nonrandomized and retrospective studies imply that angiotensin-converting-enzyme inhibitors slow such progression in both children and adults with dysplastic or hypoplastic kidneys.^{71, 92} A prospective study showed that, during 6 months of observation, ramipril lowered blood pressure and proteinuria in children with these diagnoses.⁹³ Ardissino et al.⁹⁴ reported, however, that angiotensin-converting-enzyme inhibitors had no significant beneficial effect on the progression of renal failure in children with dysplastic or hypoplastic kidneys over a mean of 5 years, compared with controls who were matched for sex, age, systemic blood pressure and baseline creatinine clearance. Both groups received supportive treatment, and approximately 10% of the control group received antihypertensive agents other than angiotensin-converting-enzyme inhibitors. Although this study was not randomized and lacked data on proteinuria, the results raise questions about the use of such drugs in children with renal tract malformations. Furthermore, few data are available on the safety of these agents in very young children born with dysplastic or hypoplastic kidneys. Moreover, GFR often spontaneously increases, although not to normal levels, in such children in the first few postnatal years.⁴⁸ Finally, a randomized study investigating the effect of a low protein diet on the progression of renal failure in children with dysplastic or hypoplastic kidneys showed no difference in the rate of progression between the diet and control groups.⁹⁵

Genetic and environmental influences

Although various diseases affecting the kidney have a Mendelian distribution of inheritance, what is less well appreciated is that renal tract malformations can also have a genetic basis and are sometimes also inherited in a Mendelian manner. This feature is clearest in multiorgan syndromes involving renal tract malformations, some of which are listed in Table 2.^{96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113}

Table 2 The symptoms and genetic mutations associated with a selection of multiorgan syndromes that feature renal tract malformations.

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Mutations of the gene that encodes the developmentally expressed transcription factor hepatocyte nuclear factor 1- (HNF1B), which are associated with renal cysts and diabetes (RCAD) syndrome, can be found in children with different types of renal tract malformations, including multicystic dysplastic kidneys, congenital solitary functioning kidneys, cystic dysplastic kidneys, hypoplastic kidneys and glomerulocystic kidneys.^{102, 114, 115, 116} In fact, diabetes mellitus is only sometimes present in patients with RCAD syndrome and de novo HNF1B mutations are not uncommon. HNF1B mutations are also a major cause of fetal bilateral hyperechogenic kidneys.¹¹⁶ In the Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE) study, Weber et al.¹¹⁴ found HNF1B mutations or variants in 8 out of 99 (8%) children who had dysplastic or hypoplastic kidneys and renal impairment; in the subset of 27 children who had cysts, 6 (22%) had mutations.¹¹⁴ Ulinski et al.¹¹⁵ emphasized that HNF1B mutations are more common in patients with dysplastic or hypoplastic kidneys when cysts and bilateral disease are present. Another indication of the presence of HNF1B mutations is a history of early-onset acute gout. This is an interesting observation because hepatocyte nuclear factor 1- activates the gene that encodes uromodulin (UMOD),¹¹⁷ mutations of which occur in autosomal dominant medullary cystic kidney disease type 2, which can also feature gout and hypoplastic kidneys.¹¹⁸ Thus, the kidney lesions in RCAD syndrome and those in autosomal dominant medullary cystic kidney disease type 2 might share a common molecular pathway.

Other genetically defined syndromes are associated with a spectrum of renal tract malformations; for example, Bardet–Biedl syndrome is associated with dysplastic kidneys, hypoplastic kidneys, tubulointerstitial lesions and lower urinary tract anomalies.^{105, 106} The genes that are mutated in such syndromes probably have roles in multiple stages of kidney and lower urinary tract morphogenesis.

Human nonsyndromic renal tract malformations can also be inherited. Dominant inheritance of primary vesicoureteric reflux,^{119, 120} of dysplastic or hypoplastic kidneys^{65, 121} and of pelviureteric junction obstruction¹²¹ has been described. In a few patients with primary vesicoureteric reflux and nephropathy, mutations have been defined in UPK3A,¹²² which encodes a protein that coats the urothelium, and ROBO2, which encodes a signaling receptor.¹²³

Preliminary studies indicate that a polymorphism of PAX2, another developmentally expressed transcription factor, is associated with reduced neonatal kidney size¹²⁴ and that a polymorphism in the angiotensin II type 2 receptor gene (AGTR2) is associated with diverse renal tract malformations.¹²⁵

One puzzling feature of the postulated genetic causes of human renal malformations is why such malformations sometimes affect one renal tract more than the other, the most extreme example being unilateral renal agenesis with an apparently normal contralateral kidney and ureter. We speculate that for some anomalies to manifest fully, there needs to be a second, somatic genetic aberration, for example in a cell or cells that would normally form a critical structure, such as the ureteric bud. Such genetic second 'hits' have been shown to occur in polycystic kidney epithelia and might be required for cyst growth.¹²⁶

Conclusions

Renal tract malformations are a clinically challenging collection of entities because of their diversity, the difficulties of making precise histological diagnoses while the patient is alive, and the fact that these disorders can present both before and after birth. The most severe anomalies can be devastating, resulting in neonatal renal failure and accompanying respiratory distress due to lung hypoplasia. At the other extreme, some of the milder, more common anomalies can be clinically benign. Each patient with a renal tract malformation, therefore, needs an individualized clinical approach, which might require pediatric and adult nephrologists to work closely with each other and with other specialists such as obstetricians and urologists.

We lack comprehensive, long-term follow-up studies in large cohorts of individuals born with different types of renal tract malformations. In addition, the contribution of renal tract malformations to chronic kidney disease and ESRD in adults could be more clearly defined. Whether prenatal decompression of obstructed renal tracts or initiation of postnatal therapies, such as prophylactic antibiotics or angiotensin blockade, in childhood improve long-term renal outcomes of patients with renal tract malformations is unclear. Such questions might be answered only by prospective, randomized trials that recruit patients in childhood and follow them up during adulthood.

Mutations of genes involved in renal tract development can now be identified in individuals with renal tract malformations. Most such genetic analyses are, however, available only on a research basis, and genetic diagnosis also raises the question of whether to screen relatives. In the future, the efficacy of genetic screening could be improved by establishing clinics in which nephrologists and clinical geneticists can jointly assess families, and by the introduction of array-based methods that enable screening for mutations in multiple genes simultaneously.

Acknowledgments

L Kerecuk is supported by a Medical Research Council Clinical Training Fellowship. MF Schreuder is supported by Fellowships from the Sophia Children's Hospital Foundation and from the European Renal Association–European Dialysis and Transplantation Association. Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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