DOI: 10.1542/neo.11-12-e714 2010;11;e714-e721 NeoReviews

Sharon W. Su and Barbara S. Stonestreet Core Concepts: Neonatal Glomerular Filtration Rate

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Core Concepts: Neonatal Glomerular Filtration RateSharon W. Su, MD,*

Barbara S. Stonestreet, MD†

Author Dislosure

Drs Su and

Stonestreet have

disclosed no financial

relationships relevant

to this article. This

commentary does

contain a discussion

of an unapproved/

investigative use of a

commercial product/

device.

AbstractAlthough the placenta is the primary organ responsible for fetal clearance and electrolytehomeostasis, fetal kidneys contribute to amniotic fluid production and fetal hemodynam-ics. Maternal factors can significantly influence fetal urinary output and blood pressure.Maturation of neonatal glomerular filtration rate (GFR) depends on the development ofrenal blood flow (RBF). After birth, a marked increase in systemic blood pressure anddecrease in renal vascular resistance results in elevated RBF and consequent increases inGFR. Vasoactive factors, including renin, angiotensin II, glucocorticoids, nonsteroidalanti-inflammatory drugs, nitric oxide, prostaglandins, bradykinin, and endothelin, eachplay vital roles in the regulation and development of neonatal GFR. Prematurity andintrauterine growth restriction (IUGR) may affect renal endowment and place infants atrisk for hypertension and accelerated loss of renal function later in life.

Objectives After completing this article, readers should be able to:

1. Describe renal development and the changes in GFR and RBF from in utero to birth.2. Recognize the differences in the rate of GFR maturation between preterm and term

infants.3. Review the concept of single-nephron GFR.4. Identify factors that regulate GFR and RBF in neonates.5. Explain how medications such as angiotensin-converting enzyme (ACE) inhibitors,

glucocorticoids, and indomethacin alter neonatal GFR.6. Discuss the long-term prognosis of GFR in infants born preterm or with IUGR.

Renal DevelopmentHuman kidneys are derived from three embryologic units: pronephros, mesonephros, andmetanephros. The first two eventually involute; the latter leads to the development of themature kidney. The formation of the pronephros occurs at 2 to 3 weeks of gestation,followed by the mesonephros, which appears at 4 to 5 weeks of gestation. However, thefirst glomeruli do not develop until 9 weeks’ gestation. The metanephros consists of twoportions: the metanephric blastema and the ureteric bud. The glomeruli, proximal tubules,loop of Henle, and the early part of the distal tubule arise from the metanephric blastema(Fig. 1). The calyces, pelvis, and collecting ducts arise from the ureteric buds. Nephro-genesis is complete by 34 to 36 weeks’ gestation, resulting in 0.7 to 1 million nephrons perkidney. Maturation of the nephrons begins in the juxtaglomerular region, extendingoutward toward the renal cortex. (1)(2)

Urine production begins at 10 to 12 weeks’ gestation. A total of 5 mL/hour of urine isproduced by 20 weeks’ gestation, which comprises 90% of the amniotic fluid volume bythis gestational age. The urine production rate continues to increase with gestational age,reaching 50 mL/hour by 40 weeks of gestation. Thus, fetal oliguria during the secondtrimester can lead to pulmonary hypoplasia and oligohydramnios sequence. (3)

*Division of Pediatric Nephrology, Department of Pediatrics, Hasbro Children’s Hospital, The Warren Alpert Medical School ofBrown University, Providence, RI.†Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Women and Infants Hospital of Rhode Island, The WarrenAlpert Medical School of Brown University, Providence, RI.

Article core concepts

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Renal Blood FlowThe maturational increases in RBF contribute to thematuration of neonatal GFR. Although adult kidneysreceive 20% to 25% of cardiac output, kidneys in the fetusreceive 3% to 4% and in 1-week-old infants receive 8% to10% of cardiac output. The developmental increase inthe proportion of cardiac output distributed to the kid-neys correlates with the growth-related redistribution ofRBF from the medulla (deepest portion of kidney) to theouter cortex because renal growth occurs centrifugally.RBF is 20 mL/min at 25 weeks and increases to 50 to60 mL/min by 40 weeks of gestation. These findingswere based on measurements of para-aminohippurateclearance, which traditionally has been used as a markerto measure effective RBF because such clearance is clin-ically feasible to use in humans. RBF doubles by 2 weeksof age and reaches mature levels by 2 years of age. RBF isdependent on two major factors: 1) renal perfusion pres-

sure, which is approximately equal to systemic arterialblood pressure; and 2) renal vascular resistance (RVR),which is regulated by renal afferent and efferent arte-rioles. (4)(5)(6)(7)

In neonates, renal perfusion pressure is low and RVRis high, resulting in low RBF. Fetal RBF can be affectedby several maternal factors, such as maternal hydrationstatus, maternal medications, and vasoactive substancesthat cross the placenta. For example, when hypotonicfluids were given to pregnant women, maternal serumosmolality decreased and fetal urinary output conse-quently increased. (8) When pregnant sheep were givenintravenous indomethacin, fetal RBF, GFR, and urineproduction decreased. (9) Basal production of nitricoxide (NO) in third-trimester fetal sheep maintainedRBF by inducing renal vasodilation. Blockade of NOproduction increased fetal RVR by 50%. (10)

After birth, RBF progressively increases as renal per-fusion pressure increases and RVR decreases. The largerfraction of cardiac output distributed to the kidneyscontributes to the higher renal perfusion pressures. Thedecline in RVR can be attributed to increases in both thediameter and the total number of renal blood vessels andto the production of vasoactive factors, such as angio-tensin II (AII), catecholamines, prostaglandins (PGs),and NO. (5)(6)(7)

Abbreviations

ACE: angiotensin-converting enzymeAII: angiotensin IIAT1: angiotensin type-1AT2: angiotensin type-2BK: bradykininCOX-2: cyclooxygenase-2D1: dopamine receptor 1D2: dopamine receptor 2ET: endothelinGFR: glomerular filtration rateIUGR: intrauterine growth restrictionKf: glomerular capillary ultrafiltration coefficientNO: nitric oxidePBS: Bowman space or proximal tubule hydraulic pressurePGC: glomerular capillary hydraulic pressurePG: prostaglandinQA: glomerular plasma flow rateRAS: renin-angiotensin systemRBF: renal blood flowRVR: renal vascular resistanceSCr: serum creatinineSNGFR: single-nephron glomerular filtration rateTGF: tubuloglomerular feedback�P: mean glomerular transcapillary hydraulic

pressure difference��: mean oncotic pressure difference�A: afferent arteriolar plasma oncotic pressure

Figure 1. Renal morphogenesis. The metanephric blastemadevelops into the glomeruli, proximal tubules, loop of Henle,and the early part of the distal tubule. The ureteric buddevelops into the calyces, pelvis, and collecting ducts. Re-printed with permission from Dressler GR. The cellular basisof kidney development. Annu Rev Cell Dev Biol. 2006;22:509–529.

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Glomerular Filtration RateA nephron is comprised of the glomerulus (filtration) andthe tubules (secretion and reabsorption). Each nephron hasits own GFR, known as the single-nephron glomerularfiltration rate (SNGFR). Multiplying SNGFR by the totalnumber of nephrons determines overall GFR. SNGFR isdependent on four factors:

1. Mean glomerular transcapillary hydraulic pressuredifference [�P�(PGC) � (PBS)]

2. Afferent arteriolar plasma oncotic pressure (�A)3. Glomerular plasma flow rate (QA)4. Glomerular capillary ultrafiltration coefficient

(Kf�k � S)

where PGC�glomerular capillary hydraulic pressure,PBS�Bowman space or proximal tubule hydraulic pres-sure, k�permeability of glomerular capillary to water,and S�total surface area available for filtration.

Therefore, SNGFR can be mathematically expressedas:

SNGFR�Kf � (�P � ��)�Kf � PUF

where �P�mean glomerular transcapillary hydraulicpressure difference, ���mean oncotic pressure differ-ence, Kf�glomerular capillary ultrafiltration coefficient,and PUF�glomerular capillary ultrafiltration pressure.

Increases in �P, QA, and Kf increase GFR; increases in�A decrease GFR. In young developing rats, markedincreases in QA and Kf were associated with increases inSNGFR. Furthermore, increases in QA correlated with a60% reduction in afferent and efferent arteriolar resis-tances. (11) In other animal studies, QA increased three-fold and significantly contributed to GFR maturation.Both PGC and PBS increase with age, with an overall neteffect of increasing �P. However, the contribution of�P to increasing GFR is only about 10% to 15%. Kf mayplay a greater role in GFR development; one studydemonstrated a 57% increase in Kf when comparing fetalsheep to young lambs. The increase in Kf is postulated toresult from greater glomerular surface area and not fromincreased permeability. The glomerular surface area isincreased by the recruitment of glomeruli located in theouter cortex of fetal kidneys. (12) Therefore, the post-natal combination of increases in systemic arterial bloodpressure and reductions in RVR alters factors involved inthe regulation of SNGFR. These changes in SNGFRthen result in increased GFR.

GFR in the fetus correlates with both gestational ageand body weight and parallels the increase in renal mass.Fetal GFR is low, even when corrected for body size.Three- to fivefold increases in GFR occur around 34 weeks

of gestation, coinciding with the completion of nephro-genesis by 36 weeks. Neonates born before 34 weeks ofgestation experience this same phenomenon when theyreach the corrected age of 34 weeks of gestation. (1)(6)After birth, GFR continues to correlate directly withgestational age and postnatal age. (13)(14)(15) In terminfants, GFR doubles after 2 weeks of age, reaching adultlevels by 2 years of age. (5) This rate of GFR maturationis markedly diminished in preterm infants. (13)(16) GFRin preterm infants eventually achieves adult levels, butthe interval to reach the mature GFR remains uncertainbecause limited comparative studies exist. In one study,Vanpee and colleagues (16) demonstrated that GFR inpreterm babies remained lower at 9 months correctedage than in term infants of the same postconceptual age(82�23 mL/min/1.73m2 and 125�18 mL/min/1.73m2,respectively). GFR in preterm infants did not reach nor-mal mature levels until 8 years of age.

Although GFR rapidly increases after birth, serumcreatinine (SCr) concentrations in the newborn peakduring the first few postnatal days. Miall and associates(17) demonstrated increasing SCr concentrations in thefirst 48 hours after birth, especially in neonates bornbefore 30 weeks’ gestation. The peak and prolongedincreases and subsequent decreases in SCr were pro-portional to the degree of prematurity. Gallini and col-leagues (14) observed a similar inverse correlation be-tween SCr concentration and gestational age of neonates.In their study, SCr values increased during the first 36 to96 hours after birth. Bueva and Guignard (13) reportedelevated SCr concentrations in 66 infants born at 28 to40 weeks of gestation, with preterm infants having sig-nificantly higher values compared with term infants. Thedifferences in SCr concentrations were not apparent by3 weeks of age in the preterm and term infants. Amongneonates of lower gestational ages, the increases in SCrwere higher and the decreases more gradual. The initialincreases in SCr are a reflection of maternal SCr concen-trations, reduced neonatal clearance resulting from im-mature glomerular filtration, and reabsorption of filteredcreatinine in the leaky renal tubules of the neonates.(17)(18) Thayyil and associates (19) recently publishedreference ranges for SCr in preterm infants ages 25 to28 weeks’ gestation. Stabilization of SCr occurred by5 weeks of age.

Inulin clearance is the gold standard marker for assess-ing GFR in children and adults because it is freely filteredand not secreted or reabsorbed. However, measurementof inulin clearance is tedious because a constant intrave-nous infusion is required over 3 to 4 hours to maintainconstant inulin concentrations. Timed urinary and plasma

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samples are collected every 30 minutes. For youngerinfants who cannot void on command, catheterization isnecessary. In contrast, measuring SCr requires a simpleblood sample determination, an easier, faster, and morecost-effective process. Consequently, it remains the pre-ferred method for estimating GFR in the clinical setting.However, clinicians should note that when neonatalGFR is calculated from SCr, initial values reflect a com-bination of maternal SCr concentrations and neonataltubular reabsorption from leaky, immature tubules.Stonestreet and colleagues (20) compared endogenouscreatinine clearance to inulin clearance in neonates bornat 30 to 36 weeks of gestation. They demonstrated thatendogenous creatinine clearance was a good estimationof inulin clearance, but there was overestimation of thiscorrelation at low GFR ranges and underestimation athigh GFR ranges. These investigators also published thefirst measured values of SCr in neonates born at 26 to36 weeks’ gestation. (21) SCr values in the first 10postnatal days ranged from 0.1 to 1.8 mg/dL (8.8 to159.1 mcmol/L), with a mean of 1.3�0.07 mg/dL(114.9�6.2 mcmol/L). They discovered a negative cor-relation between SCr concentra-tion and increasing postnatal age inpreterm infants. During the firstpostnatal month, SCr was inverselyrelated to postnatal age (Fig. 2). Inthe second and third months, SCrdid not vary with age.

Newer methods of measuringGFR in neonates are being investi-gated using cystatin C, a low-molecular weight protein from thecysteine protease inhibitors family.

Cystatin C is synthesized by all nucleated cells, freelyfiltered through the glomerulus, and completely reab-sorbed and catabolized by tubular cells. Serum concen-trations obtained in preterm infants, children, or adultsare not affected by sex, height, or muscle mass. (5)Reference ranges for plasma cystatin C measurements inpreterm infants, neonates, and older children were pub-lished in 2000. (22)

In 1976, Schwartz and associates (23) derived and vali-dated an uncomplicated formula to estimate GFR in chil-dren by means of SCr and height measurements. Ten yearslater, this group expanded this sentinel discovery to includepreterm infants (Tables 1 and 2). (24) To this day, theSchwartz equation remains the most widely used methodfor assessing GFR by clinicians throughout the world:

GFR (mL/min/1.73m2)�(k � Ht) � SCr

where k�constant proportional to age and sex*,Ht�height (cm), and SCr�serum creatinine (mg/dL)

*Age k

Low-birthweight infants �1 year 0.33Term to 1 year 0.452 to 12 years 0.55Female 13 to 21 years 0.55Male 13 to 21 years 0.70

Renal AutoregulationAdult human kidneys possess the ability to maintainconstant RBF and GFR during changes in renal perfu-sion pressures. Two mechanisms are postulated to par-ticipate in renal autoregulation: myogenic reflex andtubuloglomerular feedback (TGF). The myogenic reflexinvolves changes in renal arteriolar vascular tone, whichoccurs in response to changes in transmural pressure. Forexample, if systemic blood pressure increases, renal per-fusion and transmural pressures also increase, resulting inafferent arteriolar vasoconstriction and consequent pres-

Table 1. Serum Creatinine (mg/dL) Values BasedUpon Gestational Age (24)

Postnatal Age 25 to 28 Weeks 29 to 34 Weeks 38 to 42 Weeks

Week 1 1.4�0.8 0.9�0.3 0.5�0.1Weeks 2 through 8 0.9�0.5 0.7�0.3 0.4�0.1>Week 8 0.4�0.2 0.35* 0.4�0.1

Values represent mean � SD.*n�1, therefore no SD.

Figure 2. Serum creatinine values (mg/dL) during the first3 postnatal months in preterm, low-birthweight infants (ges-tational age range, 26 to 36 weeks; birthweight range, 515 to2,080 g). Reprinted with permission from Stonestreet and Oh.(21)

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ervation of RBF and GFR. This reflex is believed to bean inherent characteristic of the vessel, although themechanism has not been fully elucidated. TGF involvesa feedback system by which the macula densa senses therate of distal tubular flow. The vascular tone in theadjacent afferent arterioles then is altered and GFR isstabilized. An inverse relationship exists between tubularflow rate and GFR, with increased tubular flow resultingin decreased GFR and vice versa. This mechanism main-tains the constancy of solute and water delivery to thedistal tubule. Several vasoactive substances, includingendothelin, AII, NO, adenosine, and thromboxane A2,are considered to play important roles in the TGF path-way. Both autoregulatory processes function early in lifeand maintain renal function by preventing pressure-induced fluctuations in RBF and GFR. Renal autoregu-lation in neonates is highly dependent on the balance ofvasoconstrictive and vasoactive factors. Therefore, neo-natal GFR is more susceptible to fluctuations when ex-posed to insults such as hypoxemia, nonsteroidal anti-inflammatory drugs, and ACE inhibitors. (4)(5)(7)

Effects of the Renin-Angiotensin Systemon GFRThe renin-angiotensin system (RAS) (Fig. 3) plays a vitalrole in the regulation of RBF and GFR and in thedevelopment of renal vascular and tubular structures.The RAS is upregulated during fetal life and in thenewborn period. Renin, ACE, and AII concentrations allare elevated during the neonatal period. Plasma reninactivity correlates inversely with gestational and postnatalage. In term infants, a slight increase occurs at 3 to 5 daysafter birth, with activity decreasing over the next 1 to6 weeks. By 3 to 5 years of age, plasma renin activity issimilar to adults. In humans, most renin is contained incells located at the juxtaglomerular apparatus, irrespec-tive of gestational or postnatal age. Fetal kidneys alsocontain renin in the interlobular arteries and glomeruli.(3)(4) ACE values increase during late gestation and

peak after birth. (3)(25) In the de-veloping kidney, ACE expressionhas been localized to the endothe-lium of arterioles, glomerular capil-laries, descending vasa rectae, andepithelium of proximal tubularcells. (25) AII causes vasoconstric-tion of both afferent and efferentarterioles. However, because effer-ent arterioles are smaller in diame-ter, the net effect is potent vasocon-striction of efferent arterioles and

resultant increases in PGC and GFR. Numerous animalstudies have demonstrated that in utero exposure to ACEinhibitors affects renal hemodynamic function andgrowth in the fetus and newborn. For example, systemicadministration of ACE inhibitors resulted in decreasedarterial blood pressure and RVR in newborn lambs andnear-term fetuses (�130 days of gestation). (26) In fetalsheep, arterial pressure, GFR, and urine production de-creased when ewes were exposed to captopril. (27)

Fetal kidneys also express only angiotensin type-2(AT2) receptors, but after birth, expression is downregu-lated and angiotensin type-1 (AT1) receptors begin topredominate. The reason for these changes and the rela-tionship between AT1 and AT2 receptors is currentlyunder investigation. Although the RAS is highly activethroughout fetal development, the mechanism of howrenin, ACE, AII, and AT receptors interact with eachother and with other vasoactive factors, such as brady-kinin and PGs, during various stages of fetal develop-ment and postnatally remains to be determined. (28)

Effects of Glucocorticoids on GFRGlucocorticoids accelerate maturation of neonatal GFR.Injection of betamethasone in preterm lambs resulted

Table 2. Glomerular Filtration Rate (mL/min/1.73m2) Based Upon Gestational Age (24)

Postnatal Age 25 to 28 Weeks 29 to 34 Weeks 38 to 42 Weeks

Week 1 11.0�5.4 15.3�5.6 40.6�14.8Weeks 2 through 8 15.5�6.2 28.7�13.8 65.8�24.8>Week 8 47.4�21.5 51.4* 95.7�21.7

Values represent mean � SD.*n�1, therefore no SD.

Figure 3. The renin-angiotensin system and bradykinin path-way. AT�angiotensin, ACE�angiotensin-converting enzyme.From Yosipiv and El-Dahr. (25)

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in significantly higher GFRs compared with near-termlambs receiving placebo and term nontreated controls.(29) Pharmacologic doses of methylprednisolone givento rats resulted in an increase in QA but no differencein Kf, �P, or �A. (30) How glucocorticoids alter GFRremains unclear, but a link may exist between gluco-corticoids, RAS, and PG, a vasodilatory substance.Antenatal betamethasone administration to fetal sheepresulted in decreases in plasma renin, renin mRNA, andrenal cyclooxygenase-2 (COX-2) mRNA compared withewes until 1 year postnatal age. (31) The researcherspostulated that betamethasone suppressed COX-2 ex-pression and, thus, may affect PG synthesis. Anothermechanism by which glucocorticoids could affect GFR isthrough glucocorticoid-mediated increases in Na-K-ATPase activity in the renal cortex, with consequentincreases in urinary sodium reabsorption and increases insystemic blood pressure. (29)(32)(33) Increases in sys-temic blood pressure are known to alter RBF and GFR.

Effects of Hypoxemia on GFRNeonatal renal function is highly dependent on adequateoxygenation. Numerous studies have shown renal com-plications after perinatal asphyxia or hypoxemia in new-borns. However, data are conflicting regarding changesin GFR after a hypoxic event. The effects of hypoxia andasphyxia on the GFR most likely relate to several factors,including the duration of hypoxemia, severity of acidosis,presence and severity of concomitant hypotension, andthe severity of insults to other organs. Stonestreet andassociates (34) exposed newborn lambs to 25 minutes ofasphyxia and did not see significant changes in GFR.GFR did decrease after 1 hour of severe hypoxia in bothnewborn and intrauterine growth-restricted piglets. (35)In a prospective study of 87 term neonates suffering fromhypoxic-ischemic encephalopathy, 17% demonstrateddecreases in GFR, as defined by significant increases inSCr. (36) Neonates who had reduced GFR also tendedto have more severe neurologic outcomes.

Effects of Other Vasoactive Factors on GFRVasodilation

PGs are potent vasodilators that increase RBF by stimu-lating vasodilation of afferent arterioles. (9)(30) PG syn-thesis inhibitors, such as indomethacin, can cause severevasoconstriction in immature kidneys, leading to re-duced RBF, GFR, and urine output. Long-term mater-nal indomethacin treatment may decrease fetal urineoutput enough to alter amniotic fluid production. For-tunately, GFR reduction is often reversible once the drughas been discontinued. (3)(9)

NO maintains RBF and GFR via its vasodilatory ef-fects on the developing kidney. Blockade of NO synthe-sis in third-trimester fetal sheep resulted in significantincreases in RVR and decreases in RBF. (10) NO mayserve to offset the high level of RAS activity by modu-lating renin release and the effects of AII on vascularvasoconstriction and GFR. NO also may aid in pro-tecting the immature kidney from hypoxemic insults.Changes in GFR were significantly greater in newbornrabbits exposed to both hypoxemia and NO synthesisinhibition compared with hypoxemia alone. (37)

Bradykinin (BK) stimulates NO and PG production,resulting in vasodilation and natriuresis. BK production,via kallikrein, is markedly upregulated in the developingkidney. Increased expression of the kallikrein-kinin sys-tem correlates with maturation of RBF. Blockade of BKreceptors in newborn rabbits resulted in increases in RVRand consequent decreases in RBF. (38)

Dopamine can alter renal function by binding to re-ceptors (D1 and D2) located in the renal vessels, glomer-uli, renal tubule, and cortical and medullary collectingducts. Stimulation of D1 increases RBF, whereas activa-tion of both D1 and D2 may increase GFR. (39) Dopa-mine infusion rates of 2.5 mcg/kg per minute resulted inincreases in GFR and urine output, without changes inblood pressure or heart rate, in normotensive preterminfants whose mean gestational age was 34�2 weeks.(40) However, these changes were not observed at do-pamine infusion rates of 0.5 or 7.5 mcg/kg per minute.Other studies have described the efficacy of dopamine inregulating renal hemodynamics at doses ranging from0.5 to 4 mcg/kg per minute. (41)(42) Fenoldopam, aselective D1 agonist, was recently used off-label in 22neonates ages 24 to 39 weeks of gestation. This retro-spective study showed no significant improvement in SCror urine output. (43) Although animal models demon-strated evidence of dopamine’s effect on modulatingrenal hemodynamics, the previously cited studies dem-onstrate conflicting results regarding the clinical efficacyof dopamine receptor agonists in improving neonatalGFR.

VasoconstrictionEndothelin (ET) is a potent vasoconstrictor expressed byendothelial cells in renal vessels, mesangial cells, anddistal tubular cells. AII, BK, epinephrine, and shear stressregulate ET production. ET causes constriction of renalarterioles (afferent greater than efferent), resulting inincreased RVR and subsequent reductions in GFR. ETmay also stimulate a counterregulatory mechanism of

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vasodilation, possibly via NO secretion. The modulationof neonatal renal hemodynamics by ET may not be asstraightforward as a direct vasoconstrictive response butinstead may involve a complex balance between vasodi-latation and vasoconstriction via interactions with othervasoactive substances. (3)

Long-term Prognosis of GFR inPreterm NeonatesRecent studies have emerged suggesting that preterminfants may be at risk for developing long-term renalsequelae such as hypertension, proteinuria, glomerulo-sclerosis, and decline in GFR during childhood or adult-hood. Brenner and colleagues (44) first proposed thistheory when they postulated that preterm infants, partic-ularly those who had IUGR, are born with a decreasednumber of nephrons and, thus, reduced glomerular fil-tration surface area. To maintain GFR, the remainingglomeruli are required to hyperfilter to compensate forthe loss of renal endowment. Chronic hyperfiltrationsubsequently causes glomerular and systemic hyperten-sion, proteinuria, and glomerulosclerosis, ultimately lead-ing to worsening renal function. Ultrasonography hasdemonstrated reduced renal volume and size in small-for-gestational age fetuses and low-birthweight infants.(45)(46) In kidneys examined at autopsy, total glomer-ular number correlated directly with birthweight. Meanglomerular volume also demonstrated an inverse rela-tionship with total glomerular number. (47) Pretermbirth also was associated independently with lower kid-ney length and volume. (48) Children born preterm orwith IUGR had slightly but significantly lower GFR,although GFR remained in the normal range for theirages. (49) These studies can only suggest an associationbetween renal endowment and birthweight and age ofgestation. They do not clearly explain or prove howchanges in nephron number regulate long-term renalfunction in fetuses and newborns born preterm or withIUGR. (50)(51) Therefore, the association of nephronendowment with glomerular size and GFR in hyperten-sive children or hypertensive adults, born either pretermor with IUGR, requires further investigation. The clini-cal implications are of the highest importance.

ConclusionThe development and maturation of neonatal GFR in-volves a complex, multifactorial process consisting offetal and newborn hemodynamics, renal nephron en-dowment, birthweight, gestational age at birth, vaso-active substances, and maternal factors. Various endoge-nous and exogenous insults and therapeutic agents can

disrupt this highly regulated system and lead to progres-sive decline in renal function long term.

References1. Bestic M Reed MD. The ontogeny of human kidney develop-ment: influence on neonatal diuretic therapy. NeoReviews. 2005;6:e363–e3692. Woolf AS. Embryology. In: Avner ED, Harmon WE, Niaudet P,eds. Pediatric Nephrology. 5th ed. Philadelphia, Pa: LippincottWilliams & Wilkins; 2004:3–243. Waters AM. Functional development of the nephron. In: GearyDR, Schaefer F, eds. Comprehensive Pediatric Nephrology. Philadel-phia, Pa: Mosby; 2008:111–1294. Jose PA, Fildes RD, Gomez RA, et al. Neonatal renal functionand physiology. Curr Opin Pediatr. 1994;6:172–1775. Kon V, Ichikawa I. Glomerular circulation and function. In:Avner ED, Harmon WE, Niaudet P, eds. Pediatric Nephrology. 5thed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004:25–446. Seikaly MG, Arant BS Jr. Development of renal hemodynamics:glomerular filtration and renal blood flow. Clin Perinatol. 1992;19:1–137. Yao LP, Jose PA. Developmental renal hemodynamics. PediatrNephrol. 1995;9:632–6378. Oosterhof H, Haak MC, Aarnoudse JG. Acute maternal rehy-dration increases the urine production rate in the near-term humanfetus. Am J Obstet Gynecol. 2000;183:226–2299. Gleason CA. Prostaglandins and the developing kidney. SeminPerinatol. 1987;11:12–2110. Bogaert GA, Kogan BA, Mevorach RA. Effects of endothelium-derived nitric oxide on renal hemodynamics and function in thesheep fetus. Pediatr Res. 1993;34:755–76111. Kon V, Hughes ML, Ichikawa I. Physiologic basis for themaintenance of glomerulotubular balance in young growing rats.Kidney Int. 1984;25:391–39612. Turner AJ, Brown RD, Carlstrom M, et al. Mechanisms ofneonatal increase in glomerular filtration rate. Am J Physiol RegulIntegr Comp Physiol. 2008;295:R916–R92113. Bueva A, Guignard JP. Renal function in preterm neonates.Pediatr Res. 1994;36:572–57714. Gallini F, Maggio L, Romagnoli C, et al. Progression of renalfunction in preterm neonates with gestational age � or � 32 weeks.Pediatr Nephrol. 2000;15:119–12415. Ross B, Cowett RM, Oh W. Renal functions of low birth

American Board of Pediatrics Neonatal-PerinatalMedicine Content Specifications• Know the production sites and actions of

various types of vasoactive substances thataffect renal function.

• Know the production pathway and theactions of the components of the renin-angiotensin system.

• Know the effects of prostanoids, and their inhibitors, on renalfunction.

• Know how to interpret various renal function tests (eg,creatinine clearance).

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core concepts glomerular filtration rate

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DOI: 10.1542/neo.11-12-e714 2010;11;e714-e721 NeoReviews

Sharon W. Su and Barbara S. Stonestreet Core Concepts: Neonatal Glomerular Filtration Rate

 

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