Fetal Kidney Development

Question 1

What are the 4 main steps in kidney development?

Answer 1

1. Pronephros development
2. Mesonephros development
3. Metanephros development
4. Nephrogenesis

Question 2

Describe Pronephros development:

Answer 2

• First stage of kidney development
• The pronephros develops from intermediate mesoderm at around day 20 of gestation at the cranial end of the embryo
• The pronephros development involves the formation of a pronephric duct in a cranial to caudal direction and then later the development of the pronephric tubules
• A non-functional structure that creates a framework for the formation of later structures

Question 3

Describe Mesonephros development:

Answer 3

• Present from week 4-12 and then disintegrates between week 12-16
• As the pronephric duct and tubules elongate down the embryo they influence the differentiation of other cells in the intermediate mesoderm to form a more complex duct and tubule known as the mesonephric duct and tubule
• The pronephros then disintegrates
• The mesonephric duct connects with the cloaca and the mesonephros recieves blood supply from the aorta
• The structure then functions as a primitive kidney

Question 4

Describe Pronephros Development:

Answer 4

• Begins at the 5th week of gestation and is completed at 34-36 weeks gestation
• The mesonephric duct develops as an out-poaching of the mesonephros (metanephric diverticulum) near where it joins to the cloaca
• The metanephic diverticulum elongates and integrates with the metanephric mesenchyme
• The metanephric mesenchyme begins to brand and expand and forms the renal tubules
• Vascular endothelial cells at the tips of the renal tubules begin to differentiate into the cells of the glomerulus
• The metanephric kidney moves upwards in a caudal to cranial direction and the ureters extend in length

Question 5

Describe nephrogenesis:

Answer 5

• Nephrogenesis is the formation of the nephrons which are the functional units of the kidney
• The process is not complete until 34-36 weeks gestation (majority formed between week 20-36)
• There is a limited capacity for nephrogenesis ex utero so it is considered that the number of nephrons a neonate is born with is the number it will have for life

Question 6

What is the primary function of the kidneys in the fetus?

Answer 6

• The primary function of the kidneys in utero is the production of large volumes of dilate urine that contribute the majority of amniotic fluid
• There is continuous urine flow from 7-8 weeks and by week 20 the kidneys produce over 90% of amniotic fluid
• The amount of amniotic fluid has a major impact on fetal health and development

Question 7

What factors impact urine flow rate in utero?

Answer 7

1. Renal blood flow:
   - The fetal kidneys only recieve 2-4% of combined ventricular output
   - The low renal blood flow in the fetus results in a low filtration fraction
2. Glomerular filtration rate:
   - How much blood passes through the glomeruli in the kidney each minute
   - Indicates the kidneys overall functional ability
   - GFR is low during fetal life due to low RBF and the need for nephron development and maturation
   - GFR increases during gestation proportional to increasing nephron number, functionality, increased size of the kidneys and overall fetal body weight
3. Tubular function:
   - Depends on the stage of kidney maturation
   - Begins by 12-24 weeks
   - When tubules are very immature during gestation there is greater sodium and water loss in urine
   - The ability for the fetus/neonate to excrete an acid load via the tubules is only mature at 6 weeks post-birth
4. Fetal RAAS system:
   - Hormone system that regulates blood pressure and fluid balance
   - Necessary for growth and organogenesis
   - Fetal angiotensin II has a major role in regulation of BP and RBF in the fetus

Question 8

What is oligohydramnios and what are its effects on the fetus?

Answer 8

• Oligohydramnios is insufficient amniotic fluid volume (<300mL in humans)
• Has a major impact on lung development (lung hypoplasia) and skeletal muscle development

Question 9

Describe IUGR and its relationship with the fetal kidneys:

Answer 9

• One of the main causes of IUGR is placental insufficiency which results in chronic low oxygen in the fetus
• Chronic hypoxemia causes a redistribution of blood to the brain, heart and adrenal glands and away from non-vital organs such as the kidneys
• The lack of oxygen and nutrient supply to the kidney slows/stunts nephrogenesis
• Lower nephron number and lower renal blood flow results in lower urine production can lead to complications associated with low amniotic fluid volumes
• IUGR babies are born with a lower nephron number than healthy term babies

Question 10

Describe the effect preterm birth has on the kidneys:

Answer 10

• Nephrogenesis can only take place effectively in utero, nephrogenesis appears to continue ex utero but a large number of these newly formed nephrons are abnormal and non-functional
• Preterm birth is define as the birth of a baby at less than 37 weeks gestational age
• Renal insufficiency in preterm infants admitted to the NICU is 8-24%
• Premature birth is linked to a lower nephron endowment which is life-long

Question 11

Describe the Brenner Hypothesis:

Answer 11

The Brenner hypothesis is that a low nephron number at birth -> reduced filtration area and reduced sodium excretion -> glomerular and systemic hypertension -> hypertrophy of glomeruli and sclerosis (scarring) -> reduced nephron number

• Therefore a reduced nephron number at birth can increase an individuals likelihood of developing a range of diseases including hypertension, metabolic syndrome, cardiovascular disease, chronic kidney disease and kidney complications associated with diabetes

Question 12

Describe the renal transition that takes place at birth:

Answer 12

1. Increase in cardiac output to the kidneys from 2-4% to 15-25%
2. Increase in RBF x 3
3. Decrease in vascular resistance
4. Increase in GFR 3 fold

• This transition is very drastic, so complications during birth such as asphyxia can cause significant damage to the kidneys

Question 13

How does birth asphyxia impact the kidneys?

Answer 13

• Birth asphyxia: leads to low delivery of oxygen to the fetus
• Acute kidney injury occurs in 50-72% of asphyxiated newborns (the kidney is very susceptible to damage due to oxygen depravation)
• AKI is strongly correlated with increased mortality following asphyxia
• The AKI caused by asphyxia combined with the immaturity of the kidney acid-base buffering system means it is very difficult for a newborn to bring acid-base and electrolyte levels back to homeostasis after asphyxiation (which often causes acidosis) which causes further kidney damage and other issues
• AKI is difficult to diagnose and there are no current treatments to reduce it
• AKI is linked to chronic kidney disease later in life