Development of the Kidney

The kidney develops from the intermediate mesoderm along the posterior abdominal wall. Both the urinary and genital systems arise from this common mesodermal ridge. Three pairs of excretory organs form in a cranial-to-caudal, overlapping temporal sequence:

Pronephric, mesonephric, and metanephric systems showing intermediate mesoderm origin and ureteric bud

1. Pronephros (Week 4 - rudimentary, non-functional)

Appears at the beginning of the 4th week in the cervical region
Represented by 7-10 solid cell groups (nephrotomal vestigial excretory units called nephrotomes)
Regress cranially before caudal ones form; completely disappear by the end of the 4th week
Contributes to the formation of the mesonephric (Wolffian) duct, which persists and is important for subsequent development

2. Mesonephros (Week 4-8 - temporarily functional)

Derived from intermediate mesoderm from upper thoracic to upper lumbar (L3) segments
Forms a large ovoid organ on each side of the midline together with the gonad, creating the urogenital ridge
Excretory units resemble primitive nephrons; produce small amounts of urine contributing to amniotic fluid
By week 16, mesonephric tubules regress in females; in males, a few caudal tubules and the mesonephric duct persist to form elements of the male genital duct system (epididymis, vas deferens, seminal vesicles)

3. Metanephros (Week 5 onwards - permanent kidney)

The definitive kidney appears in the 5th week and develops from two sources:

Ureteric bud penetrating metanephric blastema at the end of week 5

A. Ureteric Bud (Collecting System)

An outgrowth of the mesonephric duct close to its entrance into the cloaca, around day 28-32
Penetrates the metanephric mesenchyme (blastema) and becomes capped by it
Dilates to form the primitive renal pelvis, then splits into cranial and caudal portions - future major calyces
Each calyx forms more buds; through 12 or more generations of tubular subdivision, the entire collecting system forms: major calyces → minor calyces → collecting tubules → collecting ducts
Branching morphogenesis is complete by ~week 20-22 of gestation
Ultimately gives rise to: ureter, renal pelvis, major and minor calyces, and collecting ducts

B. Metanephric Mesoderm (Excretory Units / Nephrons)

The metanephric mesenchyme (metanephric blastema) undergoes mesenchymal-to-epithelial transition (MET) induced by ureteric bud signals
Mesenchymal cells condense around collecting tubule tips → form renal vesicles → S-shaped tubules
Capillaries grow into the pocket at one end of the S-shaped tubule and differentiate into glomeruli
Continuous lengthening of the excretory tubule produces: Bowman capsule → proximal convoluted tubule → loop of Henle → distal convoluted tubule
The distal end of each nephron forms an open connection with a collecting tubule, establishing a continuous passageway

Molecular Regulation

Key signaling molecules govern metanephric induction:

Signal	Source	Receptor / Target	Action
WT1 (transcription factor)	Metanephric mesenchyme	-	Makes mesenchyme competent to respond to induction
GDNF	Mesenchyme	RET (on ureteric bud)	Stimulates ureteric bud branching and growth
HGF (scatter factor)	Mesenchyme	MET (on ureteric bud)	Stimulates ureteric bud growth
FGF2 + BMP7	Ureteric bud	Mesenchyme	Block apoptosis, stimulate mesenchymal proliferation, maintain WT1
WNT9B / WNT6	Ureteric bud epithelium	Mesenchyme	Upregulate PAX2 and WNT4
WNT4	Mesenchyme (induced)	-	Drives mesenchyme-to-epithelium conversion (tubule formation)
PAX2	Mesenchyme (induced)	-	Promotes condensation of mesenchyme

Key Developmental Milestones

Timing	Event
Day 22	Pronephros appears
Day 25	Pronephros disappears
Week 4	Mesonephros develops
Day 28-32	Ureteric bud invades metanephric blastema
Week 5	Metanephros begins
Week 10	Glomerular capillaries begin to form
Week 12	Urine production begins
Week 20-22	Branching morphogenesis complete
Week 36	Nephrogenesis complete (~1 million nephrons per kidney)
Birth	Kidneys have lobulated appearance (disappears in infancy)

Clinical Correlates

Renal agenesis: Failure of ureteric bud to interact with metanephric mesoderm; bilateral agenesis causes Potter sequence (anuria, oligohydramnios, hypoplastic lungs, Potter facies, clubfeet)
Wilms tumor (Nephroblastoma): Mutation in WT1 gene (chromosome 11p13); associated with WAGR syndrome and Denys-Drash syndrome
Multicystic dysplastic kidney: Ureteric bud fails to branch; nephrons fail to develop
Polycystic kidney disease: Autosomal recessive (ARPKD, 1/5,000) or autosomal dominant (ADPKD) cyst formation

Sources: Langman's Medical Embryology; National Kidney Foundation Primer on Kidney Diseases, 8e

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