Introduction
An increasing number of studies show an association between intrauterine growth retardation (IUGR) and underdevelopment of the fetal kidneys, with limited nephron number and decreased renal size [
1−
4]. Furthermore, birth weight appears to be a strong determinant of renal size, nephron number, glomerular volume, albuminuria and systolic blood pressure [
5,
6]. These findings add weight to the hypothesis that IUGR carries a risk of renal function loss as a result of nephron deficit, loss of filtration surface area, hyperfiltration, glomerular hypertension, and glomerular damage [
7]. As nephrogenesis continues until 36 weeks of gestation, very preterm babies (gestational age <32 weeks) are likely to show a nephron deficit at birth [
8]. In addition, preterm birth is known to be associated with impaired nephrogenesis [
9,
10] and limited postnatal kidney growth until the age of 18–24 months [
11,
12]. Whether adult renal size is also impaired after premature birth compared with full-term birth or whether renal catch-up growth during childhood is present has not yet been studied.
We report reduced renal size (length and volume) in 20-year-old individuals born very prematurely [
13]. Renal size was correlated with glomerular filtration rate (GFR) (ml/min/1.73 m
2) and effective renal plasma flow (ml/min/1.73 m
2). The data reported here documents an additional analysis on renal size in the same cohort.
Discussion
Renal ultrasound study revealed significantly smaller renal length and volume in 20-year-old female individuals born very prematurely, either SGA or AGA, compared with age-matched controls. The difference was most pronounced for the left kidney. Differences were observed for male individuals also, but statistical significance was reached only in female individuals. IUGR had no significant effect on renal size. These results are consistent with impaired fetal kidney development after preterm birth, with probably no more than a small effect of IUGR on renal size. Nephrogenesis starts in early pregnancy, but it peaks at the 32nd week of gestation, continues until 36 weeks of gestation, and is correlated to renal size [
5]. The AGA and SGA groups, both born before a gestational age of 32 weeks, did not differ in renal size, possibly because nephrogenesis was not complete at birth. We found differences in renal size between male and female individuals in both the SGA and AGA groups. Such gender differences have only been reported in an experimental IUGR rat model, suggestive of the importance of gender in outcomes in adulthood after IUGR [
17]. In our study, differences in renal size between male SGA, AGA, and control individuals seemed smaller than those between female study participants but still showed a trend for decreased absolute renal length and volume. The lack of significance might be due to insufficient power of the study.
Singh et al. described that lower renal volume in Australian Aborigines represents kidneys with reduced nephron number [
5]. As there is a limited postnatal nephrogenesis in preterm individuals [
9,
10], a nephron deficit after preterm birth probably persists throughout life. From a study in 56 deceased extremely premature infants and ten deceased full-term controls, it appeared that nephron number was highly correlated to gestational age and that nephrogenesis had stopped 40 days postnatally [
9]. As nephron deficit predisposes to reduced renal function in the adult [
5,
6], preterm individuals are at such risk. Earlier, we found higher blood pressure and poor renal function and microalbuminuria in these premature individuals [
14,
18]. Furthermore, restricted postnatal growth after premature birth may impair renal function over time [
19].
Decreased renal volume was also found in 33 low-birth-weight (LBW) Aboriginal children between 5–18 years of age [
3]. Their BSA-adjusted renal volume was 78.5 ml/m
2 compared with 85.7 ml/m
2 in 141 normal birth weight (NBW) individuals (
p = 0.018). Renal length was equal. The authors stated that LBW resulted from IUGR, but data on gestational age were unavailable in many participants. For that matter, our study found that IUGR did not affect renal size. Renal size differences between preterms and controls were most pronounced for the left kidney, in line with findings in Aboriginal children [
3]. Interestingly, hypertensive adults with chronic kidney failure showed smaller absolute left kidney volume (but not right kidney volume) compared with normotensive chronic kidney failure patients [
20]. The authors did not study whether renal size in these hypertensive patients was associated with birth weight and gestational age.
Thus, from results of other studies and this study, it would seem that very preterm individuals show limited early postnatal renal growth, especially of the left kidney. Other studies reported that postnatal renal growth after preterm birth was limited until 18−24 months of age but did not mention differences in left and right kidney growth [
11,
12]. To our knowledge, only one study described normal fetal kidney growth separately for the left and right kidney [
21]. Sonography at several gestational ages did not reveal significant difference between left and right kidney growth between 16 and 38 weeks of gestation. We can only speculate that the left kidney grows more rapidly than the right kidney after the gestational age of 32 weeks in normal gestation, but large studies are needed to confirm this speculation.
Ultrasonography revealed renal anomalies in eight very preterm participants versus none of the controls. The anomalies mainly comprised ectasia or dilatation of the ureters and pyelocaliceal system. All individuals were asymptomatic. It is not known whether the anomalies were already present at birth. They may have developed in the early postnatal period or in childhood but then remained unnoticed, as no ultrasound studies were performed. Some renal diseases, such as acute tubular necrosis and nephrocalcinosis, occur more frequently in prematurely born children, but higher incidences of renal anomalies we found have not yet been reported [
22,
23]. One possible biological pathway may be inferred from the observation that in-utero disturbance of the renin-angiotensin system affects normal kidney development [
24,
25].
The strength of our study lies in evaluating the effect of prematurity separately from that of IUGR. The difference in renal size was most pronounced between the AGA preterm and full-term participants. The additional effect of IUGR in these very preterm subjects was small and not significant for all renal sizes. Therefore, we suggest that limited renal growth after very preterm birth predisposes to decreased renal size at adult age.
Two possible limitations of the study should be mentioned. First, selection bias may have been introduced by selecting students only as controls. Second, three different radiologists obtained the data of renal size only once. However, to minimize the variability between the three radiologists, renal measurements were made by a standardized protocol, and all radiologists measured subjects from all three groups. Inter- and intraobserver variability testing showed a slight mean error in measurement, which was comparable with other studies [
26,
27]. Moreover, renal lengths measured in controls were similar to those reported by Miletic et al. [
28], indicating the radiologists in our study produced accurate measurements.
In conclusion, kidney development after preterm birth is probably stunted, leading to (relatively) smaller kidneys and a higher frequency of renal structural anomalies at the age of 20 years. There is only a small, nonsignificant, additional effect of IUGR on these observations. The effects of stunted development were more obvious in left kidneys and in female individuals. Detailed measurement of renal development, in both size and histological changes, in a large epidemiological study design is required to elucidate the pathophysiological mechanism of unilaterally decreased renal growth after very preterm birth.
Acknowledgements
This part of the POPS 19 study was supported by a grant of the Dutch Kidney Foundation. We thank TNO, Quality of Life (ETM Hille, P Verloove-Vanhorick) for the use of the POPS cohort database, MH Lequin for renal ultrasound measurements (Dept. Pediatric Radiology, Erasmus MC - Sophia, Rotterdam), and HA Kleinveld for her efforts in the data collection and analyses (Dept. Pediatric Nephrology, Erasmus MC - Sophia, Rotterdam).
Financial support: Dutch Kidney Foundation, Grant C-1924
No conflict of Interest