Rev iew Ar t ic le

When birth comes early: Effects on nephrogenesisMARY JANE BLACK,1 MEGAN R SUTHERLAND,1 LINA GUBHAJU,1 ALISON L KENT,2 JANE E DAHLSTROM3 andLYNETTE MOORE4

1Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, 2Departments of Neonatology and 3Anatomical Pathology,

Canberra Hospital and the Australian National University Medical School, Canberra, Australian Capital Territory, and 4Department of Surgical Pathology, South

Australia Pathology, Women’s and Children’s Hospital, North Adelaide and The University of Adelaide, Adelaide, South Australia, Australia

KEY WORDS:glomerulogenesis, kidney, nephrogenesis,

preterm birth, renal.

Correspondence:Associate Professor Mary Jane Black,

Department of Anatomy & Developmental

Biology, Post Office Box 76, Monash University,

Vic. 3800, Australia. Email:

jane.black@monash.edu

Accepted for publication 3 December 2012.

Accepted manuscript online 28 December

2012.

doi:10.1111/nep.12028

SUMMARY AT A GLANCE

This review describes the current findings

regarding the adverse effects of preterm

birth on kidney development, and the risk

of long-term renal disease.

ABSTRACT:

Preterm birth (birth prior to 37 completed weeks of gestation) may occur ata time when the infant kidney is very immature and nephrogenesis is oftenongoing. In autopsied preterm human kidneys and in a baboon model ofpreterm birth it has been shown that nephrogenesis continues after pretermbirth, with a significant increase in the number of glomerular generationsand number of nephrons formed within the kidney after birth. Of concern,however, morphologically abnormal glomeruli (with a cystic Bowman’sspace) are often observed; the abnormal glomeruli are only located in theouter renal cortex, suggesting that it is the recently formed glomeruli(perhaps those formed in the extra-uterine environment) that are affected.The proportion of abnormal glomeruli within the renal cortex differsbetween infants with some kidneys appearing normal whereas others areseverely affected. This suggests that it may be haemodynamic factors and/orfactors in the neonatal care of the infant that lead to the glomerular abnor-malities. Indeed, the haemodynamic transition at birth where there is amarked increase in systemic blood pressure and renal blood flow are likelyto lead to injury of glomerular capillaries, although further studies arerequired to elucidate this. In order to optimize renal health at the beginningof life in the preterm infant, it is imperative in future studies to gain anunderstanding of the causes of the glomerular abnormalities in the pretermneonate.

Preterm birth is defined as birth prior to 37 completed weeksof gestation and comprises 9.6% of total births worldwide.1

Preterm birth can be further subclassified into near term(birth at 34–37 weeks gestation), moderately preterm (birthbetween 32 and 33 weeks of gestation), very preterm (birthbetween 28 and 31 weeks gestation) and extremely preterm(birth <28 weeks of gestation). The survival of neonates afterpreterm birth has improved dramatically over recentdecades, with babies born as young as 25 weeks gestationnow having up to an 80% chance of survival.2 Preterm birthhas the potential for deleterious developmental program-ming, and the kidney is particularly vulnerable. Nephrogen-esis normally ceases prior to term birth and any impact onnephron number at the beginning of life may have adverseconsequences for life-long renal health.3 In the human, thefirst nephrons are formed by 9 weeks of gestation and neph-rogenesis is completed between 32 and 36 weeks gestation.4

The majority of nephrons are formed in the third trimester ofpregnancy at the time when preterm infants are being deliv-ered. Emerging epidemiological studies have linked pretermbirth with altered renal function in childhood and adult-hood.5 In addition, there are a number of studies linkingpreterm birth with an increase in blood pressure later inlife.6,7

We have examined kidney development in a baboonmodel of extremely preterm birth, whereby baboon neonateswere delivered at a time-point equivalent to 27 weeks ges-tation in humans.8 In this model, the timing of nephrogen-esis and the morphology of the kidney closely resembles thatof humans, and the preterm baboon neonates are cared forin a neonatal intensive care in a similar manner to pretermhuman infants. We have shown using this model thatalthough there is no increase in body weight in the first 3weeks after birth, there is a marked increase in kidney size

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Nephrology 18 (2013) 180–182

© 2012 The AuthorsNephrology © 2012 Asian Pacific Society of Nephrology180

relative to control kidneys, with the kidney weight to bodyweight ratio markedly increased in the preterm kidneys. Thisis likely a compensatory response to the increased functionaldemands placed on the preterm kidney as a result of beingborn. There was evidence of ongoing nephrogenesis in theouter renal cortex of the preterm baboon kidneys at postna-tal day 21, with a clearly visible nephrogenic zone. Consist-ent with this, there was an increase in the number ofglomerular generations formed in the preterm kidneys afterbirth, and an increase in the total number of nephrons, albeitat the lower end of the normal range observed in the termkidneys. There was a strong correlation in the number ofnephrons formed per gram of kidney weight in both termand preterm kidneys; however, the number of nephronsformed per gram of kidney tissue was markedly different;there were around 84 000 nephrons formed per gram ofkidney tissue in the preterm kidneys versus approximately162 000 nephrons formed per gram of kidney tissue in theterm kidneys. Of particular concern, we observed highnumbers of abnormal glomeruli in some of the pretermkidneys. These abnormal glomeruli displayed a relativelyimmature form with scant capillarization, a cystic Bowman’sspace, and were only observed in the outer renal cortex,suggesting that it was the recently formed glomeruli or thoseformed in the extrauterine environment that were vulner-able to preterm birth. Not all kidneys exhibited abnormalglomeruli with the proportion of abnormal glomeruli perkidney ranging from 0.2% to 18.3%. Given the gross abnor-malities it is considered unlikely that these glomeruli wouldever be functional and so the neonates with a high propor-tion of abnormal glomeruli would have a marked reductionin the endowment of functioning nephrons at the beginningof life. To determine whether these abnormalities were alsopresent in the kidneys of preterm human infants, we con-ducted a study in autopsied kidneys of deceased pretermhuman infants who were born between 24 and 35 weeksgestation and lived for 2–68 days after birth.9 The kidneysfrom the preterm infants were compared with post-conceptional age-matched control infants who had diedacutely in utero. Similar to the preterm baboon kidneys, therewas evidence of ongoing nephrogenesis in the pretermkidneys. The number of glomerular generations was signifi-cantly increased in the preterm kidneys compared with thegestational controls. However, the width of the nephrogeniczone and the proportion of glomeruli in the most immaturestate of differentiation were significantly decreased in thepreterm kidneys. Taken together, these findings suggest thatthere may be accelerated postnatal renal maturation follow-ing preterm birth. At this stage, it is not possible to determinewhether the accelerated development results in the earlycessation of nephrogenesis. Similar to our observations in thepreterm baboon kidneys, there were marked glomerularabnormalities in the outer renal cortex in some, but not all,kidneys from the preterm infants (ranging from 0% to 13%).In addition, in the normally formed glomeruli there was a

significant increase in size, indicative of glomerular hyper-trophy and thus hyperfiltration.

The variability in the proportion of abnormal glomeruli inthe outer renal cortex between preterm infants suggeststhat there may be differences in haemodynamics, and/orother factors in the postnatal environment of the infant(such as exposure to nephrotoxic drugs, oxygen supple-mentation, mechanical ventilation and co-morbidities)which may be negatively impacting glomerulogenesis3

(Fig. 1). In this regard, there is a major haemodynamictransition at the time of birth when blood pressure andheart rate are markedly elevated10 and blood flow to thekidneys is increased.11 Hence, it is possible that the devel-oping capillaries of immature glomeruli are not prepared forthe haemodynamic transition at birth and their formation isadversely affected. Indeed, we have recently shown thatthere is injury to the wall of the aorta as a result of pretermdelivery.12

In future studies, it is imperative to determine the cause ofthe glomerular abnormalities in the preterm kidney, in orderto maximize the number of functional nephrons at thebeginning of life; this will likely lead to short-term and long-term benefits to renal health.

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reduced nephron endowment at birth.

The preterm kidney

© 2012 The AuthorsNephrology © 2012 Asian Pacific Society of Nephrology 181

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