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.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here