Renal Module Lectures 1-2: The Development and Structure of the

Evolution and development of the kidneys The purpose of the urinary system is to dispose of unwanted substances, such as , from the body fluids without also removing substances that are still required, such as sugars, amino , ions and . The most basic requirements are a filtration mechanism, a solute recovery system and some plumbing to take the fluid formed () out of the body. Life on land demands great efficiency from these systems, and also adds requirements for the temporary storage and controlled release of urine.

Primitive vertebrates such as lamprey larvae have very simple kidneys, pronephroi (singular = pronephros); ‘higher’ vertebrates also form these during embryogenesis, though they lose them later. They consist of funnel-shaped glomeruli linked by short resorptive tubes to the (pro)nephric duct. Fish and amphibia use more complex kidneys called mesonephroi (singular = mesonephros), which consist of a long series of primitive (glomeruli + resorptive ) connected to the (meso)nephric duct. Mammals also form these during embryogenesis, though they are temporary, being destroyed completely in the female and being adapted for transport of sperm in the male (as the epididymis and vas deferens - see later).

Amniotes (reptiles, mammals and birds) form a third type of , the metanephros, that consists of a large number of long nephrons connected to a highly branched . The metanephros forms when a branches out from the caudal end of the nephric duct and invades a specialised area of the called the metanephrogenic mesenchyme. Once in the mesenchyme, the ureteric bud, the shaft of which will mature to form the , branches repeatedly to make a tree-like system of collecting ducts. As the ureteric bud branches, clumps of metanephrogenic mesenchyme cells next to it become epithelial and develop into excretory nephrons, producing a Bowman’s Capsule at one end and connecting to the collecting ducts at the other. Developing blood capillaries invade the cup of each Bowman’s capsule and form a : there are between 100,000 and 1,000,000 nephrons in a human kidney (the number reflects, to some extent, foetal nutrition).

We now understand that is orchestrated by a series of signals (secreted proteins) that pass from adjacent tissues. For example, the metanephrogenic mesenchyme makes a protein called GDNF to ‘attract’ a ureteric bud to itself; aggregating clumps of mesenchyme make a protein called Wnt4, and when the level of this protein reached a high enough level, they can conclude that the clump has enough cells in it for them to go on to form a .

The from week 10 or so, the kidneys appear to ‘ascend’ in the body from their original position between the hind limbs to the adult location; this ‘ascent’ is really passive - the kidneys remain more or less in place and much of the rest of the body elongates and descends past them.

Timetable (humans): Nephric duct forms in week 4 and extends to reach the cloaca around week 6; in females it disappears from week 12. The pronephros forms in week 4 and disappears by the end of week 5. The mesonephros forms a few days after the pronephros, and ceases to function in week 10, disappearing in week 12 except for the few nephrons that become epididymis in males. The ureteric bud forms in week 6 and branches until about week 30, inducing nephrons to form at the branch tips in a continuous process during this time. The kidneys ‘ascend’ from week 10 or so.

By the end of this section you should; • Know the purpose of the urinary system • Understand the basic requirements of such a system • Understand the differences between pro-, meso- and metanephric kidneys • Understand where are approximately when each type of kidney forms in a developing human. • Be able to sketch the arrangement of the developing urinary system in a foetus.

The Anatomy of the Metanephros

Gross: In the adult, kidneys are located on each side of the body just under the diaphragm, dorsally. The lobed structure obvious in a foetus is discernible in an adult only as a series of ‘poles’, although in a sectioned kidney the lobes are still obvious. The kidneys are covered in a capsule, inside which is a layer of dense tissue that does not look particularly fibrous - this is the cortex (where glomeruli live). Inside this layer is the medulla, that looks fibrous because of all of the tubes that radiate through it to and from the cortex. Inside this is the pelvis, a cavity into which the collecting ducts drain (this is just an enlargement of the first few branches made by the ureteric bud).

Glomeruli: The nephron begins in a cup-like Bowman’s Capsule, the outer surface of which is smooth but the inner surface of which is in intimate contact with a tangle of capillaries - the glomerulus proper. The endothelial cells of these capillaries are fenestrated (have holes in them) where they meet the foot processes of that form the inner surface of the Bowman’s capsule. These holes allow the blood to make contact with the of the podocytes, which is specialised for filtration and allows small solutes and water to pass through it and through a slit diaphragm (a deliberately leaky connection between adjacent podocytes) into the urinary space of the Bowman’s capsule, which is continuous with the inside of the nephron.

The rest of the nephron: The Bowman’s capsule drains into a proximal convoluted , a fairly wide tube with thick walls composed of a single layer of epithelial cells with prominent microvilli poking into the lumen. The then leads to the Loop of Henlé, a very thin, fragile-looking tube that plunges down into the medulla of the kidney and then back up again. Loops from cortical nephrons plunge only about 1/3 of the way into the medulla, while those from juxtamedullary nephrons reach most of the way down the medulla. The Loop of Henlé leads to a , a tube with fairly thick walls but a much larger lumen than that of the proximal tubule, which passes very close to the blood supply to the glomerulus itself. It then leads to the collecting ducts, which have thinnish walls and wide lumens. The segments of the nephrons are in intimate association with blood vessels; this association allows them to concentrate urine by mechanisms that will be considered elsewhere in this course.

Plumbing to and from the kidney: Each kidney is supplied by a , which comes off the abdominal aorta. Just outside the kidney the renal artery splits into segmental arteries which serve the different lobes of the kidney. Each segmental artery then gives rise to perirenal arteries, which serve the outer capsule of the kidney, and which split into arcuate areries which then split to form arterioles serving each glomerulus. The vascular return is similar and uses similar names (eg interlobar vein). The precise arrangment of the blood supply varies quite a lot between individuals. Urine drains to the bladder via (one for each kidney).

Innervation: Innervation of the kidney arises from the renal plexus, which is formed from branches of the thoracic splanchnic nerves and 1st lumbar splanchnic nerves.

By the end of this section you should; • Know where in the body the kidneys are to be found • Be able to describe the gross anatomy of a normal kidney • Understand the sequence of structures through which urine flows in the kidney • Know the blood supplies and nerve supplies to the kidneys. The Lower Urinary Tract

Development of the bladder: In the early embryo, gut and nephric ducts empty into the cloaca (lat: sewer). This becomes subdivided by the action of 3 folds, a Tourneaux Fold which pushes outwards from inside the embryo, between the urinary and gut systems, and the left and right Rathke folds that push in sideways. These divide the cloaca into the anorectal canal and the urogenital sinus. The upper parts of the urogenital sinus, into which the nephric ducts still run, expand to form the bladder. The lower ends of the neprhic ducts ‘melt’ into the bladder wall; once this process has passed beyond the junction between ureter and nephric duct, these two tubes each have their own opening into the bladder. The part of the bladder wall that arises from this, visible as a triangular smooth patch in adults, is called the trigone. Meanwhile, the route to the allantois from the top end of the bladder closes off.

Fate of the nephric ducts: In females, the nephric ducts disappear and another pair of ducts that follow a similar course to the nephric ducts, called the Müllerian ducts, survive, fuse at their lower ends, and contact the urogenital sinus. The unfused parts of the Müllerian ducts will become the fallopian tubes, while the fused parts become the ureterus and the top of the vagina (lat: sword-sheath) (the lower vagina develops from the urogenital sinus). In males, a few mesonephric tubules invade the adjacent developing testis (gonads develop in the thoracic region in both sexes - they move later) and form an epidydymis that connects each testis to its nephric duct. Each nephric duct becomes the vas deferens, its distal end sprouts seminal vesicles and the to which it connects sprouts the prostate and bulbourethral glands.

Downstream of the bladder: This should be simple - just a valve and a pipe out of the body, but it is complicated by issues of sex. Downstream of the bladder, the urethra of males passes through the prostate (which develops from the urethra in foetal life) and is joined by the ejaculatory ducts - the name given to the old nephric duct downstream of the seminal vesicles. Females are simpler. The exit of urethra from the body is modified by the sex-specific development of the urogenital sinus (from which the urethra develops). In both sexes at a very early stage, the urogenital sinus opens to the body wall ventrally to the anorectal canal, and ventral to this is a mound called the genital tubercle. Again in both sexes, the genital tubercle begins to grow and extend, its tip becoming the glans (lat: acorn) and the sides becoming the shaft of a developing phallus. Tissues at the side of the genital tubercle swell to become the labioscrotal swelling (labium - lat: lip; scrotum - lat: sack).

In females, the enlargement of the phallus ceases quite early and the structure becomes the clitoris (gk: cleit=key); the urethral folds are not incorporated into the clitoris but instead form the labia minora which encircle the urogenital sinus, the anterior part of which contains the opening of the urethra and the more posterior part forms the outer portion of the vagina (the inner part of which comes from the Müllerian duct - see above). The labioscrotal folds become the labia majora (which engulf the whole of the vulval area).

In males, the enlargement of the phallus continues and the structure incorporates the urethral fold on its lower surface. The opening of the urethra migrates along this fold towards the tip of the organ, the urethral fold ‘zipping up’ behind it. In this way the opening of the urethra is moved to the tip of the developing penis (lat: tail). The skin of the shaft also grows forward to almost cover the glans area and extend forwards a little to form the prepuce (fore-skin): this is removed in some cultures. The inside of the penis is occupied by corpora spongiosa and cavernosa, which when engorged with blood become hard, thus achieving penile erection. Penis growth continues to exceed by far that of the clitoris - by adulthood, mean penis length is 8.4±2.7cm flaccid [16.2±3.2cm erect] compared with just 1.6±0.4cm for the clitoris {large deviations from these means have no physiological effect in terms of reproduction, but can cause psychological problems you will come across in other courses}.

Blood Supplies to the lower urinary tract. Ureters: From the inferior and superior vesical atreries, which in turn come from the anterior iliac artery. Females also gain a supply from the uterine artery. Bladder: From the Anterior Iliac via the umbilical artery (females), the superior vesical artery, the inferior vesical artery and the uterine artery (females). Urethra: Internal pudendal artery -> urethral artery and from the perineal artery.

Innervation: pudendal nerve and prostatic plexus (males)

By the end of this section you should; • Understand how division of the cloaca separates urinary and gut systems • Understand how the bladder forms and how the trigone develops • Understand the how the different male and female structures develop from (mainly) the same initial tissues • Know the blood supplies and nerve supplies to the lower urinary tract.

Congenital Abnormalities of the urinary system

• Bilateral agenesis - no kidneys form. Rare and fatal after birth. • Unilateral agenesis - quite common (1/500) • Congential cystic diseases - common - overgrowth of collecting ducts and/or fluid pumps oriented the wrong way round. • Wilms’ Tumour - ‘islands’ of kidney remain in primitive state and make a tumour very similar to normal developing kidney. • Supernumerary ureters - while one enters trigone normally, the other often ends up elsewhere on the urogential sinus and therefore empties somewhere silly (vagina, gut etc) • Pelvic kidney: kidney gets caught in aortic bifurcation and fails to ascend • Horseshoe kidney - 2 kidneys fuse, often when 2 pelvic kidneys are forced together. • Urachial Fistula - passage to allantois should have closed but does not. • Urachial Cyst - while passage to allantois closes at the body wall end, parts remain between there and the bladder. • Urethral valve - the ureter opens too low so that the prostate balloons under pressure and traps urine, causing more pressure etc. • Rectovaginal,. Rectoprostatic and rectocloacal canals all result from failure of the folds to separate the cloaca • Hypospadias - urethra fails to migrate to end of penis.

Useful textbooks: • “Human Body” (Dorling Kindersley, available at £9.99 from The Natural World in the Waverley Centre, & probably other places too – a superb general anatomy book with excellent labelled drawings). • “Color Atlas of Embryology” Ulrich Drews (Thieme). Copies in Erskine; book costs about £26 from Thins. Excellent drawings of development. • “Introduction to Histology” (Cormack) – copies in Erskine (other histology texts will be equally good). • Langman’s “Medical Embryology” – lots of copies in the Erskine library And a bed-time reading (not that we expect medical students to sleep!…): • A novel based on real history - “The Anatomist” (Black Swan paperback, about £5.99) – the story of the discovery of the clitoris to medicine by the anatomist Matteo di Columbo (“discovery” in the sense of recognising the homology between male and female anatomies). NB – this novel paints a vivid picture of the great days of anatomy, and also how medical knowledge has been misapplied to mutilate and to oppress, but it is sexually explicit and you should not read it if you are easily shocked or offended. • Wallen K, Lloyd EA (2008) Clitoral variability compared with penile variability supports nonadaptation of female orgasm. Evolution and Development 10: 1-2. This paper uses anatomical measurements and evolutionary arguments to deduce that the female clitoral orgasm is an ‘accident’ caused by evolutionary pressures on male development. You may find a gaping hole in the central argument, if you think hard…