Development of the Kidneys and Urinary Tract in Relation to Renal Anomalies

Key Points

  • Development of the kidneys (nephrogenesis) occurs between the 5th and 32nd weeks of human gestation when the ureteric bud interacts with metanephric mesenchyme, which undergoes mesenchymal–epithelial conversion to form glomeruli and tubules and renal stroma, with coordinated vascular development and signalling being critical.

  • Nephron number is the major factor determining long-term kidney function. The development of the nephrons is finalised by the 32nd week; the average nephron number is about 900,000 per kidney; smaller babies with fewer nephrons have an increased long-term risk for hypertension and kidney failure.

  • There is an increased risk for hypertension in ex-premature children and young people, with a possible renal link to steroid use.

  • Congenital anomalies of the kidney and urinary tract (CAKUTs), such as aberrant renal development and urinary tract obstruction, have the potential to decrease the number of nephrons, and postnatal processes such as cyst formation, inflammation or infection can have similar effects on renal function by destroying mature nephrons.

  • There are several known causes of CAKUTs, including genetic defects; urinary tract obstruction; and maternal environment, diet and teratogens, although most CAKUT remains unexplained.

Introduction

Kidneys that produce urine and a lower urinary tract that permits urine flow into the amniotic fluid are essential for normal human in utero development. Kidneys generate urine from around the 12th week of gestation, which comprises the majority of the amniotic fluid from the second trimester and more than 90% by late gestation. Failure to either generate enough urine or expel it into the amniotic sac causes the eponymous ‘Potter sequence’ of severe oligohydramnios with limb and craniofacial malformations, such as clubbed feet, contractures, a flattened ‘parrot-beak’ nose, a recessed chin and low-set ears, accompanied by pulmonary hypoplasia. Potter described this sequence with bilateral renal agenesis but other causes include bilateral multicystic, dysplastic or polycystic kidneys or lower urinary tract obstruction with posterior urethral valves or urethral atresia, all of which represent the severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUTs).

Urine is produced in the kidneys by nephrons, with filtration of blood in the glomerulus, modification of the filtrate as it passes through tubules, loop of Henle and collecting duct, before transition through the renal pelvis into the ureters. Nephron number is determined by the 32nd week of gestation, by which point the kidneys can regulate fluid balance, electrolytes and acid–base balance. However, full renal function does not develop until birth, when renal blood flow increases, and then postnatally as nephrons elongate and mature. The fetal kidneys only receive around 3% to 5% of cardiac output compared with around 20% for the mature organs, and nephrons lack many specialised transporters in early developmental stages. Moreover, only dilute urine can be produced because the medulla is relatively small, and there is reduced aquaporin expression, which prevents development of a full medullary osmotic gradient and reabsorption of water, respectively. Such renal immaturity is unimportant if the mother has normal renal function because the placenta is an efficient biological dialysis machine to balance fetal biochemistry. This should be taken into consideration when considering early delivery of fetuses with renal dysfunction because it is much easier to dialyse a 3-kg rather than a 1.5-kg baby even without factoring in increased risk for respiratory and other prematurity-related problems.

Timeline of Kidney Development

Humans pass through three stages of renal development during nephrogenesis: the pronephros, mesonephros and metanephros, which arise sequentially on the dorsal body wall. Hence, those with normal development will have had six distinct kidneys before birth, with excretory function improving significantly at each stage. Whereas the pronephros and mesonephros regress and disappear in the fetus, the metanephros matures into the fully functioning definitive kidney. The pronephros is the functioning kidney of adult hagfish and some amphibians, as is the mesonephros in adult lampreys, some fishes and amphibians. Conservation of gene function across species means that valuable information pertinent to human development can still be gleaned from these different stages in animals; many recent investigations, for example, involve functional experiments in zebrafish larvae which have a pronephros containing just two glomeruli.

The timing of key events in human kidney development is outlined in Table 12.1 . The equivalent stages are also listed for mice, the most frequently used models of nephrogenesis. There is a distinct difference in later stages, however, because murine nephrogenesis continues after birth; this allows experimental surgical and pharmacologic interventions, but extrapolation of results may not always be applicable to humans, in whom nephrogenesis completes in the protected in utero environment (unless born prematurely).

TABLE 12.1
Comparative Timing of Human and Mouse Nephrogenesis a
Structure Human (Postconception Days Unless Stated) Mouse (Postconception Days)
Pronephros Appears 22 9
Regresses 25 10
Mesonephros Appears 24 10
Regresses 16 wk 14
Metanephros 32 11.5
First glomeruli 8 wk 14
End of nephrogenesis 32 wk 7 after birth
Length of gestation 40 wk 20

a Rats’ timing is about 1 day longer or later than mice.

The Pronephros

The human pronephros is first visible at the 10-somite stage, around 22 days postconception, which is morphologically equivalent to E9 in mice. It comprises a small group of nephrotomes with segmental condensations, grooves and vesicles between the second and sixth somites. Extrapolation from animal studies suggest that the pronephros does filter fluid, although human data are lacking. The pronephric duct develops from the intermediate mesoderm lateral to the notochord adjacent to the ninth somite. The duct elongates caudally and reaches the cloaca by day 26. It is renamed the mesonephric, or Wolffian duct, as mesonephric tubules develop. The nephrotomes and pronephric part of the duct involute and cannot be identified by day 25.

The Mesonephros

In humans, the long sausage-shaped mesonephros develops from around 24 days postconception with a duct that grows in a caudal direction connected to adjacent tubules. Mesonephric tubules originate from intermediate mesoderm medial to the duct by ‘mesenchymal–epithelial’ transformation, a process which is subsequently reiterated during nephron formation in metanephric development. In humans, a total of around 40 mesonephric tubules are produced (several per somite), but the cranial tubules regress at the same time as caudal ones are forming; hence, there are maximum of around 30 pairs at any time.

Each mesonephric ‘nephron’ has a medial cup-shaped sac encasing a knot of capillaries, functionally equivalent to Bowman’s capsule and glomerulus of the mature kidney. This connects to segments of the tubule that histologically resemble mature proximal and distal tubules but lack a loop of Henle. The human mesonephros is thought to produce small quantities of urine between weeks 6 and 10 that drains via the mesonephric duct, but again there is little direct evidence for this and much is extrapolated from sheep and cattle. The mouse metanephros organ is rudimentary and has poorly differentiated glomeruli. The mesonephros disappears by 16 weeks, except in male fetuses, in whom the proximal segments of some caudal mesonephric tubules contribute to the efferent ducts of the epididymis whilst the mesonephric duct is incorporated into ductular parts of the epididymis, the seminal vesicle and ejaculatory duct.

The Metanephros

The adult human kidney develops from the metanephros, which consists of two major cell types at its inception: the epithelial cells of the ureteric bud and the mesenchymal cells of the metanephric mesenchyme. A series of reciprocal interactions between epithelia and mesenchymal cells cause the ureteric bud to branch sequentially to form the ureter, renal pelvis, calyces and collecting tubules whilst the mesenchyme has a more varied fate; most focus has been on the portion of mesenchyme that undergoes epithelial conversion into nephrons, but other mesenchymal cells differentiate into interstitial cells or stroma in the mature kidney ( Fig. 12.1 ). Three-way induction between epithelia, tubular- and stromal-progenitor mesenchyme appears to be of importance in generating a normal kidney.

• Fig. 12.1
Cellular model of normal kidney development. Note that vascular development occurs concurrently via a combination of migration and in situ differentiation

Metanephric kidney development starts by day 28 in humans, when the ureteric bud sprouts from the distal part of the mesonephric duct. By day 32, the tip (ampulla) of the bud penetrates the metanephric blastema, a specialised area of sacral intermediate mesenchyme, and this condenses around the growing ampulla to generate the metanephros. The first glomeruli form by 8 weeks, and nephrogenesis continues in the outer rim of the cortex until somewhere between the 32nd and 36th week; this was originally suggested to continue longer, but more recent studies suggest 32 weeks. Many of the nephrons generated in early weeks of nephrogenesis only have transient function before being lost by apoptosis during increase in kidney size ; effectively, their initial ‘cortical’ position is overrun and remodelled as medulla growth expands outwards. In mice, the ureteric bud enters the metanephric mesenchyme by embryonic day 10.5, the first glomeruli form by embryonic day 14 and nephrogenesis continues for up to 1 week after birth (earlier reports incorrectly state 14 days).

New nephrons are never generated after completion of nephrogenesis, although strategies to restart nephron formation are actively being researched as an obvious treatment for both developmental and acquired kidney diseases. Kidney development is not complete at this point, however, because nephron segments elongate, the medulla expands and segment-specific differentiation continues, whilst blood supply increases, and glomerular filtration rate (GFR) increases over the first 18 months of life.

The Ureteric Bud and Collecting Duct Lineage

The ureteric bud grows into the metanephric blastema and the adjacent mesenchymal cells begin to condense around its tip. Signalling from the mesenchyme stimulates bifurcation of the ampulla to form a ‘t-shape’, and this process of growth and branching occurs repeatedly during nephrogenesis to generate a tree-like collecting duct system. Around 20 rounds of branching occur in humans, double that of mice. The bud tips connect to the distal part of developing nephrons while more central parts differentiate into collecting ducts that drain successively into minor calyces, major calyces, the renal pelvis and then the ureter.

Differentiation of the Mesenchyme

Renal stroma differentiates from one subset of the metanephric mesenchyme whilst nephrons are induced in mesenchymal cells adjacent to each ampullary tip of the ureteric bud. The mesenchyme is initially loosely arranged, but the cells destined to become nephrons grow closely together and compact or condense around the bud tips before undergoing phenotypic transformation into epithelial renal vesicles. Each vesicle elongates to form a comma shape, which folds back on itself to become an S-shaped body. The proximal S-shape develops into the glomerulus whilst the distal portion elongates and differentiates into all nephron segments from proximal convoluted tubule to distal convoluted tubule. It was suggested that sequential phases of nephron formation occurred with an initial bud branch–to–nephron ratio of 1 to 1, and then several branches per bud in an arcade extending outwards as the kidney grows and finally the terminal bud branch attached to as many as five nephrons. This theory was based on postmortem dissection rather than repeated, quantitative studies, but it appears plausible with recent mouse work also suggesting several distinct phases.

Development of the Vasculature

Blood is supplied to the kidneys via the renal arteries, which give rise to distinct microcirculations in glomerular capillaries, cortical vessels and vasa rectae which pass alongside loops of Henle into the medulla. Renal vessels develop from a combination of vasculogenesis, in which mesenchyme differentiates in situ to form capillary endothelia, and angiogenesis, which involves ingrowth of existing capillaries. Renal vascular resistance is high during fetal life, predominantly controlled via the renin–angiotensin system (RAS) and renal nerves, so the kidneys only receive 3% to 5% of cardiac output.

Measurement of GFR is contentious in neonates but appears low at birth at around 20 mL/min/1.73 m 2 in term infants (or 15 mL/min/1.73 m 2 in infants with low birth weight). Overall renal blood flow rises as systemic blood pressure increases and renal resistance falls after birth with the kidneys receiving 10% of the cardiac output by the end of the first postnatal week. GFR increases two- to threefold during the first month of life but does not reach adult levels until 18 months to 2 years of age.

Final Nephron Number

Final nephron number is important because this determines renal function into adulthood, before GFR starts to decline from around age 40 onwards. However, because the kidneys have the ability to adapt and compensate, it is possible for individuals with a wide range of nephron numbers to appear to have the same level of renal function as assessed by plasma creatinine or estimated GFR. The search for an accurate estimate of nephron number has evolved through many different techniques in the past 25 years with a broad range suggested of 0.6 to 1.3 million per kidney. The current gold-standard counting method is unbiased stereology, but this is time consuming and expensive and, more important, only possible when the kidney is dissected. Magnetic resonance imaging-based techniques are being developed for live estimates and seem to work in mice, with prospective clinical uses planned in future.

Using unbiased stereology, a more accurate range with a mean of around 900,000 nephrons per kidney has now been reported across many populations. Strikingly, as a population, Australian aboriginals have a much lower mean of around 680,000 ; this group has a high prevalence of both renal disease and hypertension, and similar links between low nephron count and primary hypertension are reported in other populations. Reiterating the possible high variability within a population without obvious immediate renal dysfunction, nephron number spanned a 12-fold range between 210,000 and 2.7 million in a large study of 176 African Americans.

Two hypotheses outlined by Barker and colleagues in Southampton, United Kingdom, and Brenner in Boston, Massachusetts, United States, have linked nephron number with in utero development and associated predisposition to progressive renal disease. Barker and colleagues initially demonstrated an inverse correlation between systolic blood pressure and birth weight and proposed that ‘the intrauterine environment influences blood pressure during adult life’. Their group (and many others) have subsequently confirmed the link between birth weight and hypertension but also associated risks of cardiovascular disease, type 2 diabetes and obesity. An important mechanism appears to be epigenetic modification of diverse tissues, including kidney, liver and pancreas. Direct proof linking the ‘Barker hypothesis’ with nephron number comes from maternal undernutrition or protein restriction and diabetic experimental models with consequent decreased nephron numbers, often linked to hypertension.

Although originally based on the deleterious effects of increased dietary protein, the ‘Brenner hypothesis’ is that glomerular hyperfiltration causes progressive glomerular sclerosis, proteinuria and nephron loss, which then exacerbates hyperfiltration in the surviving functional glomeruli, leading to a recurring cycle of nephron dropout and increased stress on remaining glomeruli. Hyperfiltration is inevitable when a low nephron number has been caused by disease or induced by fetal programming ; hence, it is important to identify potentially affected babies and follow up looking for proteinuria and hypertension so that early treatment can be given.

Types of Renal Anomalies

Renal anomalies are often detected on antenatal ultrasound examination, but many are incidental changes such as minor dilatation of the renal pelvis, usually nonpathological. The differential diagnosis of anomalies is reviewed in Chapter 33 , but a brief outline is given here in relation to their pathogenesis.

Agenesis, or absent kidney, is often associated with aberrant or absent ureters; hence, a potential underlying mechanism has been suggested as early failure of ureteric bud branching. Agenesis may be isolated, but it can also occur as part of multiorgan disorders such as Branchio-Oto-Renal, Kallmann, Fraser and DiGeorge syndromes. Bilateral agenesis has an incidence of 1 in 5,000 to 10,000, whilst unilateral is much commoner at 1 in 1,000.

Dysplasia includes conditions in which the kidney fails to undergo normal development and differentiation, with abnormal structure and which may contain metaplastic tissues such as cartilage. These pathological processes are depicted schematically in Fig. 12.2 , along with normal and abnormal histology in Fig. 12.3 . There is a spectrum of dysplasia from large kidneys distended with cysts, such as ‘multicystic dysplastic kidneys’, which are often attached to atretic ureters, or small echobright organs with a few rudimentary tubules that resemble ‘frustrated’ ureteric bud branches. Dysplasia can occur as an isolated anomaly or in a multi-organ syndrome, such as the renal cysts and diabetes (RCAD) or renal-coloboma syndromes. Around a third have an associated abnormal contralateral kidney, often with vesicoureteric reflux. The incidence of multicystic dysplastic kidney is around 1 in 2500, although this may be an underestimate because many involute and can be completely reabsorbed, which leads to an incorrect diagnosis of agenesis when detected later.

• Fig. 12.2
Conceptual cellular model underlying congenital anomalies of the kidney and urinary tract.
• Fig. 12.3
Histology of developing and dysplastic kidneys. 11-week ( A ) 12-week ( B and C ) gestation normal kidneys. D and E, Dysplastic kidney. A, Low-power view demonstrating ureteric buds radiating out from the centre (lower right) of the metanephros. Intermediate ( B ) and higher ( C ) magnification of nephrogenic cortex: multiple ureteric buds visible with condensing mesenchyme adjacent to tips. Each deeper layer shows progressive nephron differentiation from comma-shapes, through early to mature glomeruli. D, Dysplastic kidney demonstrating lack of normal renal tissues; instead there is stromal proliferation with a few primitive epithelia tubules and cysts. E, String of tortuous blood vessels (bottom left towards top right) , demonstrating vascular as well as nephron abnormalities in dysplastic kidneys.

Hypoplasia is defined pathologically as a kidney weighing less than 50% of expected, but the term is often used loosely to imply significantly fewer nephrons than normal. Dysplasia cannot be present, so all of the nephrons should appear normal, and undifferentiated tissues are not present. Again, this appears to represent a spectrum with some kidneys appearing grossly normal, albeit small on scan, whilst others are tiny. This raises a frequent question as to whether kidney size correlates with nephron number. The broad answer is yes, in that, given a normal radiologic appearance with no cysts or other structural abnormalities, a large kidney is likely to have more nephrons than a small one. However, this in itself does not necessarily mean that GFR will be different initially, but the smaller kidneys are likely to develop more severe kidney disease in the long term.

Duplex kidneys represent some degree of duplication of the renal pelvis and ureter. This finding is relatively common, occurring in about 5% of unselected autopsies. The range of anatomy includes simple bifurcation of the extrarenal renal pelvis through complete duplication with two distinct (but contiguous) kidneys, separate ureters and two ureterovesical openings. Many cases are asymptomatic, although up to half may develop complications requiring treatment; these classically include obstruction to the upper part and reflux into the lower moiety.

Ectopic kidneys and malrotation represent abnormal renal position. The kidneys should relatively ‘ascend’ to a progressively more rostral position during development, starting in the sacral region and ending between the 12th thoracic and 3rd lumbar vertebral bodies. There is also associated rotation such that the renal pelvis changes from an anterior- to a medial-facing orientation by term. Failure to ascend completely is relatively common, around 1 in 800 on routine renal imaging, and is usually associated with retention of a more anterior-facing renal pelvis. Occasionally, in crossed ectopia, the kidney is on the wrong side of the body as well as in the wrong position and may be fused to the contralateral kidney in cross-fused ectopia. Ectopic kidneys are often dysplastic and may also be associated with reflux or hydronephrosis or obstruction because of abnormal ureteric positioning and length. Kidneys can also be fused in a horseshoe kidney (1 in 600); these are usually situated lower than normal and, again, have an increased risk for vesicoureteric reflux or hydronephrosis.

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Mar 19, 2020 | Posted by in GYNECOLOGY | Comments Off on Development of the Kidneys and Urinary Tract in Relation to Renal Anomalies

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