Nephrogenesis and Nephron Endowment
The nephron endowment refers to the number of functioning nephrons that an individual has at birth. In the human fetus, renal development reaches completion at approximately 34-36 weeks of gestation. Thereafter, there is only loss of nephron mass through natural aging or by disease, trauma or surgical ablation.[61,62] At term birth, the total number of nephrons per kidney averages 1 million but this number is highly variable ranging widely from approximately 300,000 to over 2 million per kidney.[62,63] Hence, the 'bell-shaped' curve of the normal distribution of nephron endowment in any given population is wide. Females have fewer nephrons than males and certain ethnic populations are believed to be born with a relative nephron deficit (i.e., <5th percentile).[42,43,44,45,46] Infants born before completing 32 weeks' gestation and during active nephrogenesis will have a decrease in nephron number proportional to their abbreviated length of gestation. New nephrons do not form in the extrauterine environment. Individuals at the lower end of the normal distribution of the nephron endowment have been shown to be at an increased risk of hypertension and the late development of cardiovascular and renal diseases.[46,65,66]
In the context of pediatric kidney disease, reduced nephron mass and increased risk for end-stage kidney disease (ESKD) has been associated with individuals born small for gestational age (SGA) as well as those born preterm and appropriate for gestational age (AGA).[64,67] Epidemiologic studies indicate that low birthweight in conjunction with rapid postnatal growth imposes an increased risk for hypertension, insulin resistance and T2DM in later life.[68,69] Preterm infants fed fortified formulas in the newborn period are more likely to develop childhood and adult obesity than those preterm breast-fed infants.[70,71] Our previous clinical observations suggest that early excessive weight gain contributes to the progression of kidney disease in patients who have suffered neonatal acute kidney injury (AKI). It remains unclear whether these manifestations are the results of 'perinatal programming' induced by adverse environmental events in utero or during the vulnerable periods in early postnatal life.[68,69,70,71] The population of surviving low birthweight individuals born preterm are the focus of much research since they offer some insight into this phenomenon as regards glucose sensitivity,[30,67,68,69,70,71] low nephron mass[64,67] and cardiovascular disease risk.[17,44,73,74]
The kidney forms through a complex process termed 'branching morphogenesis', which involves a multiplicity of signaling molecules.[60,75,76] The initial glomeruli form at the site of the final bifid branching and become nephrons located in the first layers of the renal cortex near the medullary rays. The other nephrons develop through the poorly understood process of arcade formation and late-phase branching that occurs between 22 and 36 weeks' gestation. This creates a radial glomerular pattern, which lends itself to the technique used to estimate nephron numbers, a method similar to counting the rings in the trunk of a tree to estimate age.[64,75,76,77] Approximately one generation of new nephrons forms every 2 weeks during the last trimester, ultimately reaching 10-12 generations by term birth (Figure 2).[64,75,76,77]
Radial glomerular counts in the fetal kidney at different gestational ages.
(A) The preterm photomicrograph depicts a fetal kidney at 17 weeks of gestation. The radial glomerular count is calculated by drawing a straight line from the deepest glomerulus at the cortico–medullary junction to the most superficial glomerulus under the capsule. The radial glomerular count is three. Notice the active nephrogenesis with the S-shaped bodies under at the outermost layer. (B) The term photomicrograph shows the kidney is from a neonate born at 35 weeks. The radial glomerular count is six. The degree of nephrogenesis is minimal compared with A so that branching morphogenesis has neared completion.
The broad range in the number of nephrons in the human kidney[62,63,64,65,66] and the relative rarity of early overt renal disease attests to the wide flexibility and redundancy of the system and the likelihood of substitution of function for many involved growth factors. The renin-angiotensin hormonal axis appears to be a primary modulator of both angiogenesis and nephrogenesis in utero[75,76,78,79] affecting major stimulatory factors that include glial-derived neurotrophic factor, Wilm's tumor-suppressor gene 1 (Wt1), Paired-box gene 2 (Pax2) and many others.[64,78,79,80,81]
Ultimately, any defect in the mediators of early or late branching or renal angiogenesis may lead to alterations in nephron endowment with little discernible effect on early function but with significant implications for late manifestations of disease.[60,65,66] Since the early 1960s, experimental models of low nephron mass included feeding low-protein diets to pregnant animals or restricting specific nutrients including vitamin A or iron.[82,83,84] There is considerable evidence that subtle disruptions in the maternal-fetal environment can alter the function of major signaling molecules involved in nephrogenesis and result in a nephron deficit. Subsequently, human autopsy studies have demonstrated low glomerular counts in infants that were SGA or those born preterm.[64,67] Genetic polymorphisms of the PAX gene are associated with smaller kidneys at birth and low nephron counts in animals.[80,81] Hence, these many animal and human studies support the premise that the nephron endowment is determined by both genetic and epigenetic experiences of an individual in utero and in the early postnatal environments.
Pediatr Health. 2009;3(2):141-153. © 2009 Future Medicine Ltd.