FETAL RENAL DEVELOPMENT
Three successive kidneys formed in ALL mammals:
- pronephros
- mesonephros
- metanephros
- overlap chronologically
- derive components from precursor
- all arise from embryonic mesenchyme
Mesonephros
- appears relatively late in sheep, pigs and rabbits and remains prominant comparatively late
in fetal life
- appears early in man and rat but rapidly degenerates
- becomes nonfunctional vestigial ducts in females
- becomes the ducts of the epididymus, the ductus deferens, and the ejaculatory duct in
males
Nephrogenesis
- begins at 7-8 weeks and continues through 32-34 weeks in humans
- 20% nephrons morphologically mature at 11-13 weeks gestation (humans)
- 30% nephrons morphologically mature at 16-20 weeks gestation
- number of nephrons increases from 350,000 at 20 weeks to 820,000 at 40 weeks gestation
- single adrenocorticoid injection at birth to rabbits results in profound abnormalities in the
development of later generations of nephrons
- rabbits at birth functionally similar to 35 week human fetuses
- differences between fetal and adult renal function best explained by decreased numbers of
"mature" nephrons with a decreased surface area for reabsorption
Renal Development
- 20% of Loop's of Henle still found within the cortex at birth
- proximal tubules in fetus have a brush border that is less complex than adults, have
smaller mitochondria and numerous lysosome-like structures
- during glomerular development, there is a gap between the capillary endothelial cells and
the renal epithelial cells that becomes the basement membrane through deposition of
fine fibrils and the lamina densa
- At term, basement membrane is 1000 Å, gradually increasing to a normal adult
value of 2500 Å by 3 years of age
Fetal Fluids
- increasingly large volumes of urine are formed from about the 10th week of gestation
- at birth, the bladder may contain up to 44 ml of urine
- from about day 90 of gestation, the urethra is patent and urine passes into the amniotic sac
- hypotonic nature of fetal urine may help maintain the osmotic pressure of fetal plasma
such that fluid is not lost to the maternal circulation
- allantoic fluid remains hypotonic and reflects tonicity of fetal urine. This suggests either a
low rate of water transfer or that water transfer is balanced by electrolyte removal
- neonate is hypophosphatemic, which may contribute to PTH insufficiency, decreasing
glomerular filtration rate and renal unresponsiveness to PTH for first few weeks of
life
- newborns and premature newborns respond similarly to an adult to water loading, but
prior to 3 days postpartum there is no diuretic response to water loading. There
appears to be many species differences in terms of this response
- increase in urine osmolarity as gestation advances coincides with an increase in water
reabsorption
Blood Flow
- renal blood flow per unit body weight is significantly lower in the fetus than in the adult,
increasing postnatally but remaining depressed for an extended period
- renal vascular resistance is high in fetus, probably due to high percentage of blood flow to
placenta
BLOOD FLOW AND FILTRATION
Renal Blood Flow
- increases immediately after umbilical cord severed
- increased placental perfusion, increased renal flow
- thereafter, flow determined by combination of cardiac output and renal vascular resistance
- in piglets, cardiac output increases 7-fold during the first 7 weeks of life, while renal
vascular resistance decreases 86%, resulting in an 18-fold increase in renal blood
flow
- in puppies, renal flow triples between 6 and 16 weeks of age
- renal resistance decreases as a result of several factors:
- loss of turgid regulatory cells of the juxtaglomerular apparatus in afferent arterioles
that obstruct flow immediately after birth
- increase in arterial lumen diameter
- inner cortical flow higher than outer cortical flow at birth because of the higher number of
mature nephrons and greater flow in individual nephrons
- with maturation, a gradient of increased blood flow from the juxtamedullary region to the
outer cortex develops
- development of outer cortical region leads to a mature pattern of intrarenal flow by 2-3
months in lambs, 1-2 months in dogs, guineau pigs and rats
Glomerular Filtration
- increases in the number of glomeruli, capillary surface area, permeability, and perfusion
pressure all contribute to increase glomerular filtration rate
- increased postnatal nephrogenesis is important in increasing glomerular filtration rate in
those species lacking a complete set of glomeruli at birth (piglets, rats and puppies,
in particular)
- volume of the individula glomerulus not a factor
- deep nephrons assume most of the renal function immediately after birth, but are soon
thereafter replaced by accelerating maturation of superficial nephrons
- increases in glomerular filtration rate of superficial nephrons may be directly
related to the growth in length and functional development of proximal
tubules. This immature function of proximal tubules in newborns may lead
to less resorption of filtered solutes than in adults and a greater solute load in
the distal tubule
- this osmotisc load would increase renin secretion by the juxtaglomerular
apparatus, increasing angiotensin II production, mediating afferent arteriolar
constriction, thus restricting glomerular perfusion pressure and filtration
rate. Glomerulotubular balance may therefore mediate (at least in part) the
high intrarenal vascular resistance characteristics of the newborn
Proximal Tubule Function
- a major function of the epithelium of proximal renal tubules is extraction of organic
compounds from the peritubular capillary blood for secretion in the urine
- this function is low at birth (relative to adult function) and progressively increases to adult
values by 8-10 weeks of age
- between 3 days and 3 weeks after birth, glomerular filtration rate increases 7-fold while
proximal tubule function increases 3-fold. Because renal blood flow changes little
relative to kidney weight, while glomerular filtration rate is increasing markedly,
filtration fraction increases
- in infants less than 34 weeks gestation at birth, creatinine clearance is 0.45 ml/min,
increasing to 1.01 ml/min at 37 weeks and 2.24 ml/min at 41 weeks gestational age.
During the same time spans, glucose resorption increases from 92.5% to 99.2% to
99.4%, respectively
- puppies up to 3 weeks of age may develop a much greater osmotic diuresis in response to
the same solute concentration than do adult dogs. This is in part to to "leaky"
intracellular junctions in the epithelium of proximal tubules of neonatal kidneys,
causing a "back-leakage" and further imparing generation of a transtubular sodium
gradient. The enhanced diuretic effect declines as the length of the proximal tubules
and the activity of Na-K-ATPase increases toward adult levels
- immature function of distal nephrons and lower aldosterone levels contribute to the lack of
ability to conserve sodium. Fractional excretion of sodium decreases from 14.3% in
100-125 day-old lamb fetuses to 0.73% in 3-8 day-old lambs, corresponding to
increases in the length and function of the Loops of Henle, plasma renin and
aldosterone, and enhanced responsiveness of distal tubules to mineralcorticoid
modulation.
- although older children have a higher phosphate resorption capacity than infants, lower
rates of glomerular filtration in infants maintain higher plasma phosphate
concentrations. This may not be true in all species.
Acid-Base Balance
- excretion of hydrogen ions by:
- proton secretion and subsequent neutralization by bicarbonate (resulting in carbon
dioxide formation)
- proton uptake by tubule epithelial cells
- excretion of secreted proteins in combination with bases present in the filtrate,
such as phospate and sulfate
- trapping of protons with ammonia to form ammonium (excreted as the salt
ammonium chloride)
- incompatable with Stewarts definitions
- ammoniagenesis lower in newborns than adults
- urinary phosphate best reflects titratable acidity
- newborns excrete oral ammonium chloride loads more slowly than adults
Distal Nephron Function
- due to morphologic immaturity (especially decreased functional surface area), neonates are
unable to dilute distal nephron fluid maximally
- this limits ability to generate hypotonic urine, and accumulate solute in medulla
- lack of ability to accumulate solute in medulla limits the degree to which urine may be
concentrated
- ability to excrete a solute load impaired early in life
- unusually high plasma renin in neonates exposed to isotonic volume loading may
contribute, through stimulation of production of angiotensin II and aldosterone, to
high resorption of sodium in distal tubules which slows ability to excrete the
overload
Renal Function in Calves
- calves are unusual in that renal function is similar to adults within days of birth, although
some of the values may be biased due to the high surface area:weight ratio. This
may hold true for other large domestic species as well
- despite this bias, calves possess a more developed renal system in almost every respect
than other neonates studied, and explains their favorable response to fluid and
electrolyte resuscitation that would be intolerable to other species
Fluid Compartments and Drug Metabolism
- neonates have greater body water content and extracellular fluid compartment size relative
to adults
- this affects ability to metabolize certain drugs
- lower fat content affects distribution of fat-soluble drugs, also
- also have decreased protein-binding capacity, enhancing rate of extraction for
elimination
- hepatic biotransformation pathways underdeveloped, especially glucuronoside conjugation
abilities, prolonging half-lives and increasing toxicity, especially barbituates,
antiepileptics, non-steroidal anti-inflammatory drugs, and some antibiotics (e.g.
sulfonamides and chloramphenicol)
- immature kidney may also accumulate nephrotoxic drugs