The article describes the distribution of renal volume and blood pressure in 6–7-year-olds born with ELBW in comparison to the control group—children of the same age but born at term and with normal birth weight. Microalbuminuria and cystatin C levels were also assessed. The main outcome variable was renal complications defined as presence of at least two of the following abnormalities: abnormal serum cystatin C level, microalbuminuria, hypertension, low renal volume. The renal complications were diagnosed only in six ELBW children. The difference was not statistically significant. However, statistically significant differences within secondary outcomes as mean serum cystatin C levels, night-time mean blood pressure, night-time blood pressure dipping and mean systolic and diastolic BP load were detected. Renal ultrasound assessments revealed significantly smaller renal volume in 6/7-year-old individuals born with ELBW, compared to age-matched controls.
The lack of statistically significant differences in the incidence of renal complications may be connected to the size of the study group. The study was designed to include 80 ELBW children and 40 children born at term. Eventually, renal complications were assessed in 78 and 38 children, respectively. The estimated power of the study is only 67% (to detect 8% difference of prevalence of primary outcome with alpfa –0.05). However, the study possesses significant value because: (1) the study group included all newborns from the whole Malopolska region born between September, 1, 2002 and August 31, 2004, who reached the age of 6–7 years. The data concerning the children involved in our multi-center study comes from all tertiary referral centers from the Malopolska region. So it is a complete group of patients, possibly the largest, with a high percentage of observation (up to 88%). (2) The renal ultrasound assessment was standardized. (3) Blood pressure was assessed using modern tools to receive very detailed information. Most previously published studies examined children with very low birth weight (VLBW), the current study limited the study group to children with ELBW.
Renal ultrasound standardization was crucial for the value of the study. Children in the control group were taller and heavier, and because of the wide disparity between the two groups the volume of the kidneys was not defined as an absolute value, but as the standardized value for height and weight. In the absence of specifics in literature, and the lack of a standardized cut-off point for kidney volume parameter, below which we can recognize the volume as being too low, a limit of 2/3 of the standard value was determined and any outcome, which was below this point was treated as an indicator of low kidney volume. Four patients from the control group had a decreased rate of renal volume. Three of them were diagnosed as overweight, therefore we may assume that the obtained results of low relative kidney volume in these children are connected with their obesity and, in fact, their kidney volume is correct.
The major limitations of the study may be: the assumed criteria of hypertension, the lack of GFR calculation, and the lack of serum creatinine evaluation.
The ABPM method is still not the reference method for the diagnosis of hypertension, while in patients with borderline arterial blood pressure it is much more objective than a standard blood pressure measurement. This is why this method was chosen in this study.
There are also studies in which ABPM results seem to be at least as good as, or even better than, standard blood pressure measurements. Currently, the gold standard of diagnosis of hypertension is office sphygmomanometry. However, we used ABPM in our study because it enables blood pressure observation to be performed throughout the day and night in a non-medical environment, and it helps to quantify the circadian BP variability [15
]. There are also publications suggesting a superior correlation of ABPM with end-organ damage in children and in adults [18
]. Due to the character of our study, and because subjects differed in age and height, we took into account not the direct results of ABPM, but we converted the data into z-scores (SDS scores) as described by Wühl et al. [10
It was expected that the patients in the study group, who were shorter and thinner, would have a slightly lower blood pressure than the control group. Yet, they had slightly higher blood pressure. Moreover, they do not have nocturnal dipping, which may be the first step in the development of hypertension. Several studies have shown that nocturnal dipping is characteristic for primary hypertension, while in secondary hypertension we do not see the decline [22
]. In our study, we observed no drop in pressure during the night, which according to Flynn et al. [23
] suggests an increased risk of secondary hypertension in the study group. In the Bayrakci et al. study [24
], which analyzes the ABPM in preterm patients born small for gestational age (SGA) at the age 5–17 years, nocturnal dipping was less than that of controls.
We did not measure serum creatinine levels in all subjects, so we cannot calculate GFR using standard formulas. Several studies in adult patients have shown that cystatin C correlates more or at least as strongly as creatinine with GFR [25
]. Bökenkamp et al. have reported similar results in children [27
]. According to Harmoinen et al., serum cystatin C appears to represent a useful and simple tool both for the identification of children with a reduced GFR (high sensitivity) and for the exclusion of children with a normal GFR (high specificity) [28
]. Moreover, cystatin C concentrations may reflect GFR in children born with ELBW more closely than serum creatinine levels, as these children are unaffected by muscle mass and body weight [29
], and at follow-up visits the ELBW children were significantly smaller and weighed less than the control group. However, due to the existing controversies associated with the conversion of the cystatin C level into GFR, such analysis was not performed.
It deserves attention that the study focused on a high-risk population for kidney complications development. The specific character of the studied population (e.g., low antenatal steroids use) might have influenced the results obtained and may also lead to difficulties in generalizing the results.
Very few reports assessing the influence of prematurity on the size and functioning of kidneys are available. Most of these reports either concentrate on more mature children or describe much smaller study groups treated in single medical centers that were assessed on short- or medium-term basis (up to 2–5 years).
The results of the longest observations were presented by Keijzer-Veen et al. [30
]. The authors evaluated 20-year-olds born as very preterm children. They showed that the absolute and relative kidney length and volume were significantly lower in the preterm children than in the control group, but there was no statistical difference in GFRs among groups of children born very preterm and full-term. Keizer-Veen et al. observed also that preterm children have a significantly higher systolic blood pressure [31
]. The major limitation of this study was a small sample size (n
53). Moreover, the Keizer-Veen et al. study involved more mature children (mean gestational age was 30 weeks) than ours [31
Drougia et al. [7
] published results of a prospective longitudinal study aimed to estimate the renal growth during the first 2 years of life in the group of 466 children born above 28 weeks of gestation. The authors found that the relative kidney volume in the group of not extremely preterm babies (28–36 weeks) is significantly impaired up to the second year of life.
Rodriguez-Soriano et al. [2
] evaluated 43 ELBW children aged between 6.1 and 12.4 years. Systolic, diastolic, and mean blood pressures did not differ from those of the controls. Mean percentiles for renal length and volume appeared normal. In comparison to the controls, plasma creatinine concentration was higher in preterm children. Only five study subjects (12.5%) fulfilled criteria for microalbuminuria. The reasons for differences in results can be associated with the following: the study included only children born in one center, with the follow-up rate 53%, ultrasound evaluations were done only in preterm children, not in the control group, and the authors compared casual BP measurements uncorrected for height of the patients.
Our observations correspond well with the results from the Singh and Hoy [32
] and Hughson et al. [33
] studies, who assumed that because nephron number, renal size and albuminuria are strongly interrelated in individuals at risk of renal diseases, very preterm infants may be at risk of developing microalbuminuria and renal disease in adult life.
Our results may suggest impaired fetal kidney development after preterm birth. Nephrogenesis starts in early pregnancy, peaks at the 32nd week of gestation, continues until 36 weeks of gestation, and is correlated to renal size [32
]. The patients from our study group were born at 27 weeks of gestation; therefore, at birth nephrogenesis was incomplete. According to Lampl et al. [34
] and Spencer et al. [35
] humans born with low birth weight have a reduced number of nephrons, and fetal weight is inversely related to kidney volume measured by ultrasound. As there is limited postnatal nephrogenesis in preterm individuals [5
], a nephron deficit after preterm birth may be present throughout life.
A histomorphometric study performed by Rodriguez et al. in extremely premature and full-term infants revealed that nephron number highly correlated with gestational age and that nephrogenesis had stopped 40 days postnatally [5
]. Nephron deficit predisposes to reduced renal function in the adult [32
], so babies born preterm, with restricted postnatal growth, are also at risk [37
One of the most interesting observations made in the course of this study is the fact that weight gain in early infancy is an independent factor of renal complications. As it has been mentioned, the development of the kidney in prematurely born infants is unfinished, and a suitable intake of calories and proteins is necessary for its proper completion. The results of experimental animal studies (on rats) indicate that undernutrition during gestation and early life can cause permanent reduction in the number of nephrons [38
]. Inadequate nutrition (whether enteral or parenteral) may impair nephron maturation as well as it may modify renal function in adulthood [39
]. In the future periods of life, the passage from an unfavorable environment to a “too favorable” environment can predispose to pathologies in adulthood (metabolic syndrome) [40
]. The results of a recent study concentrating on children born at term reveal a close connection between malnutrition and renal size in late infancy [41
In conclusion, our data demonstrate that both serum cystatin C and kidney volume are significantly impaired in school-age in ELBW children. All children who have experienced the end point defined by the protocol as a renal complication, belonged to the study group. In addition, in these children all other three endpoints (microalbuminuria, hypertension, low kidney volume) were observed, which illustrates the broad convergence between the ELBW and renal complications.
Long-term alterations in renal function and blood pressure could be determined only with following these patients up into late adulthood. If these initial findings are confirmed, the initiation of renoprotective therapy should be taken into consideration in formerly preterm children.