ORIGINAL ARTICLE

Race-specific relationship of birth weight and renal functionamong healthy young children

Andrea E. Cassidy-Bushrow & Ganesa Wegienka &

Charles J. Barone II & Rudolph P. Valentini & Jerry Yee &

Suzanne Havstad & Christine Cole Johnson

Received: 14 October 2011 /Revised: 19 January 2012 /Accepted: 13 February 2012 /Published online: 8 March 2012# IPNA 2012

AbstractBackground Low birth weight is associated with diminishedrenal function. However, despite African Americans beingat increased risk of low birth weight and chronic kidneydisease, little is known about the association between birthweight and renal function in diverse groups. We examinedracial differences in the relationship of birth weight andrenal function among healthy young children.Methods Birth weight and serum creatinine data were avail-able on 152 children (61.8% African American; 47.4%female) from a birth cohort. Estimated glomerular filtrationrate (eGFR) was calculated using the bedside Schwartzequation and gender- and gestational-age-adjusted birthweight Z-scores using the US population as a reference.

Race-specific linear regression models were fit to esti-mate the association between birth weight Z-score andeGFR.Results Mean age was 1.5±1.3 years at first eGFR measure-ment. African Americans had lower eGFR than non-AfricanAmericans (median eGFR082 vs. 95 ml/min per 1.73 m2;p00.06). Birth weight was significantly and positively as-sociated with eGFR among African American (p00.012)but not non-African American children (p00.33).Conclusions We provide, for the first time, evidence sug-gesting that birth weight is associated with renal function inAfrican American children. Future work is needed to deter-mine if prenatal programming helps explain racial disparitiesin adult health.

Keywords Prenatal programming . Race . Disparity .

Birth weight . Renal function

Introduction

Increasing evidence suggests that the predisposition to adultchronic disease may originate in the prenatal and gestationalperiods [1, 2]. Low birth weight is associated with smallerkidneys and fewer nephrons [3–7], and this pathophysiologi-cal change may predispose smaller infants to future kidneyand cardiovascular diseases. In a recent systematic review,low-birth-weight individuals were estimated to have a 70%higher risk of developing chronic kidney disease (CKD) inlater life [8]. Both conditions are more prevalent in AfricanAmericans relative to other race/ethnic groups in the UnitedStates. Chronic diseases of the kidney disproportionately af-fect African American adults; for example, among Medicarepatients, 11.4% of African Americans have prevalent CKD,

A. E. Cassidy-Bushrow (*) :G. Wegienka : S. Havstad :C. C. JohnsonDepartment of Public Health Sciences, Henry Ford Hospital,One Ford Place, 5C,Detroit, MI 48202, USAe-mail: acassid1@hfhs.org

C. J. Barone IIDepartment of Pediatrics, Henry Ford Hospital,One Ford Place,Detroit, MI, USA

R. P. ValentiniThe Carman and Ann Adams Department of Pediatrics, Divisionof Nephrology and Hypertension, Children’s Hospital ofMichigan, Wayne State University School of Medicine,Detroit, MI, USA

J. YeeDivision of Nephrology and Hypertension,Department of Medicine, Henry Ford Hospital,2799 West Grand Boulevard,Detroit, MI, USA

Pediatr Nephrol (2012) 27:1317–1323DOI 10.1007/s00467-012-2136-6

compared to only 7.3% of Caucasians [9, 10]. There is asimilar racial disparity in birth outcomes; African Americanwomen are 50% more likely to have preterm deliveries andtheir infants are over twice as likely to be small for gestationalage (SGA) as compared to non-Hispanic whites [11]. Birthweight depends on a complex interaction of many factors,including exposures occurring both before conception andduring pregnancy [12]. Despite notable differences in thepregnancy experiences of African American compared toother American women, little is known about racial variationin the relationship between fetal and early life exposures withrenal function in early childhood.

Fetal growth is associated with renal function in adults insome [13–15] but not all studies [16] and there are limitedstudies examining fetal growth with renal function in chil-dren. In a study comparing 40 children who were prematureand weighed <1,000 g at birth (mean age 8.6±1.8 years) to43 control children (mean age 8.5±1.8 years), creatinineclearance was significantly lower in children born premature(117±17 m/min) than controls (131±17 m/min) [17]. In astudy of 178 children born premature or SGA and 717children with normal birth weight (all of Danish origin),ultrasonography was performed at 0, 3, and 18 months todetermine kidney size [18]. At all ages, weight-for-gestationalage was positively associated with kidney volume and withrelative kidney growth from ages 0 to 18 months [18]. In asample of 73 healthy Caucasian children (mean age 9.5±0.4 years), lower birth weight was associated with increasedserum creatinine (SCr) and decreased estimated glomerularfiltration rate (eGFR) [19]. A similar birth weight and eGFRrelationship was found in study of 166 children (3–18 years) inGreece [20] and in a study of 50 white children in Switzerland[21].

Despite a similar burden of kidney disease and poorpregnancy outcomes among African Americans, there havebeen limited studies examining the race-specific relationshipof birth weight and renal function. The data that do exist areconflicting and are largely limited to autopsy studies inadults. In one autopsy study of 62 African American and60 European American adults, overall, birth weight waspositively correlated with total glomerular number; by race,however, birth weight was significantly correlated with totalglomerular number in European Americans but not AfricanAmericans [6]. In contrast, in another autopsy study ofslightly younger adults, birth weight was associated withglomerular number in both African Americans and Europe-an Americans [7].

To our knowledge, no studies have examined the race-specific relationship between birth weight and renal functionin a pediatric population, thus, we examined this relation-ship in healthy young children who were participants in theWayne County Health, Environment, Allergy, and AsthmaLongitudinal Study (WHEALS) birth cohort.

Methods

Study population

WHEALS, described in detail elsewhere [22, 23], recruitedpregnant women with due dates from September 2003 throughJanuary 2008, and who were seeing a Henry Ford HealthSystem (HFHS) practitioner at one of five clinics to establishan unselected birth cohort. All women were in their secondtrimester or later, were aged 21–49 years, and were living in apredefined geographic area in western Wayne County thatincluded the western portion of the city of Detroit as well asthe suburban areas immediately surrounding the city.WHEALSparticipants have been followed extensively for allergic diseaseand related phenotypes [22, 23] and the current investigation isa secondary data analysis of this cohort. All participants pro-vided written, informed consent and the study protocols wereapproved by the Institutional Review Board at HFHS.

The WHEALS cohort included 1,258 babies. We excluded18 twins. As some births occurred at non-HFHS hospitals, birthweight data was only available on 1,142 babies (92.1%). Renalfunctionmeasures were only available on a subset ofWHEALSchildren obtaining their medical care at HFHS. A total of 226renal function measures on 165 unique children with birthweight measures were available. Height was not available in13 children with renal function measurements, precluding esti-mation of GFR. The final analytic sample consisted of 152children with a total of 212 renal function measurements.

Renal function

Automated databases, which include all laboratory test resultsfor any encounter within HFHS, were searched based onWHEALS children’s medical record number for SCr testresults. All SCr measures were obtained from the samehospital-based laboratory system; thus the method used toestimate SCr was consistent for all participants. All SCr meas-ures obtained were part of the child’s routine medical care.Typical reasons for ordering these metabolic/biochemical pan-els included: abdominal pain, acute gastroenteritis, or fever, inaddition to being ordered as part of a well-child visit. TheBedside Schwartz equation was used to calculate eGFR as:eGFR (ml/min per 1.73 m2)00.413 × (Height (cm)/ SCr (mg/dl)) [24, 25]. Child height was abstracted from the electronicmedical record (EMR) on or near the date of SCr measure.When height at SCr measure was not available, a height beforeand after the SCr measure was obtained and linear interpola-tion was done to calculate estimated height at SCr measure.

Birth weight and gestational age

Delivery records for WHEALS women were abstracted toobtain birth weight and gestational age at time of delivery.

1318 Pediatr Nephrol (2012) 27:1317–1323

Gender- and gestational-age-adjusted birth weight Z-scoreswere calculated using the US population as a reference [26].Race was defined as maternal self-reported race.

Statistical analysis

Chi-square tests were used to compare dichotomous varia-bles between African American and non-African Americanchildren. For normally distributed continuous variables,such as age, Student’s t test was performed, but as eGFRhad a skewed distribution, a Wilcoxon rank-sum test wasused to compare between the two race groups. eGFR waslog-transformed prior to inclusion in all models to reducenon-normality.

Linear regression employing a generalized estimatingequation (GEE) to account for within-child correlation wasthen performed with log-transformed eGFR as the outcomeand birth weight (Z-score) as the main predictor. Race-specificmodels were fit unadjusted and adjusted for the child’s age atSCr measure. GEE allowed us to adjust for child age atmeasure, as well as reduce the potential bias in creating asummary statistic of all available eGFR measures [27].

Results

Table 1 presents characteristics of the study population byrace. Among non-African Americans, 39 (67.2%) were Cau-casian. Overall, SCr values are within the ranges reported inother healthy pediatric populations [28, 29]. eGFR was lower

among African American compared to non-African Americanchildren; however, it did not achieve statistical significance(p00.06). There was no difference in race, birth weight, orgestational age between WHEALS children with and withoutSCr measures (data not shown).

The average number of SCr measures per child was 1.4±0.9. Most children (76.3%; n0116) had one SCr measure;23 (15.1%), six (4.0%), four (2.6%), two (1.3%) and one(0.7%) had 2, 3, 4, 5 and 6 measures, respectively.

Overall, birth weight Z-score was statistically significant-ly and positively associated with eGFR (p00.026). Forevery one-unit increase in birth weight Z-score, there is anexpected 0.06±0.03 unit increase in mean log (eGFR).

The race-specific relationship of birth weight Z-score andeGFR is presented in Table 2. Birth weight Z-score was notassociated with eGFR in non-African American children. Inunadjusted models, birth weight Z-score was positivelyassociated with log (eGFR) in African Americans (p00.005). After adjustment for child’s age at measure, birthweight Z-score remained significantly and positively associ-ated with log (eGFR) among African American children (p00.012). For every one-unit increase in birth weight Z-score,among African American children, there is an expected 0.089unit increase (or 9% increase) in mean log (eGFR). Inferencesremained the same after adjusting for additional availablecovariates known to be associated with birth weight (maternalprenatal smoking, being first-born, and maternal age at birth;data not shown).

We conducted a sensitivity analysis among our non-African American children, restricting just to Caucasian

Table 1 Descriptive statistics ofstudy population, by race; dataare n (%) or mean (standarddeviation) unless otherwisenoted

a16 persons refused to answerbData are median(interquartile range)

SCr serum creatinine; eGFRestimated glomerular filtrationrate

African American (n094) Non-African American (n058) p

Maternal factors at delivery

Married 47 (50.0%) 50 (86.2%) <0.01

≥High school education 76 (80.9%) 52 (89.7%) 0.15

Age (years) 29.1 (5.7) 30.1 (5.3) 0.32

Prenatal smoking 9 (9.6%) 5 (8.6%) 0.84

Total household income <$40,000a 32 (40.0%) 13 (23.2%) 0.04

Child factors

Female 44 (46.8%) 28 (48.3%) 0.86

Firstborn 36 (38.3%) 31 (53.4%) 0.07

Birth weight (g) 3,242 (612) 3,301 (466) 0.53Range 1,032–5,150 Range 2,360–4,338

Birth weight Z-score –0.25 (1.00) –0.11 (1.00) 0.40

Gestational age (weeks) 38.6 (1.5) 38.8 (1.6) 0.45Range 32–42 Range 33–41

Child factors at first measurement

Age (years) 1.5 (1.3) 1.6 (1.4) 0.52

Height (cm) 77 (18) 78 (17) 0.57

SCr (mg/dl) 0.38 (0.12) 0.36 (0.15) 0.29

eGFR (ml/min per 1.73 m2)b 82 (71–99) 95 (69–130) 0.06

Pediatr Nephrol (2012) 27:1317–1323 1319

children. In this sub-group, birth weight Z-score was alsonot associated with eGFR. We also conducted a sensitivityanalysis removing children with ≥4 SCr measures; inferen-ces remained the same after removing these participants,suggesting that these children with the most measures werenot unduly influencing model results. Finally, restricting to asubsample of children with birth weight in the normal range(>2,500 g) [11] (n0128) inferences were the same; thus,even within the normal range of birth weight, AfricanAmerican children with lower birth weight Z-scores haddiminished renal function.

We a priori calculated eGFR with the 2009 bedsideSchwartz equation, which has not been validated outside therange of 15 to 75 ml/min per 1.73 m2 [24, 25]. However,inferences were the same using previous versions of the eGFRequation [30, 31]. Additionally, the age of 3 years appears tobe a critical age for the bedside Schwartz equation to switchfrom overestimating to underestimating eGFR [32]; repeatingthe analysis in 129 children with 178 measures taken at ages<3 years, all model inferences were the same.

Discussion

The current study describes, for the first time, an associationbetween birth weight and renal function, measured as eGFR,in African American but not in non-African American chil-dren. Strengths of the current study include use of a well-defined birth cohort unselected on the basis of any risk factorswith considerable racial and sociodemographic diversity andthe use of medical chart review to obtain birth weight andgestational age, rather than relying on self-reported measures.

During gestation, nephrogenesis continues until week 36,making the kidney particularly susceptible to prenatalinsults [33]. It is estimated that for every 1-kg increase inbirth weight, glomeruli number increases by approximately260,000 [7, 34]. Reduced nephron number is associated withcompensatory mechanisms including glomerular hyperfiltra-tion, which can ultimately lead to CKD; this process is exac-erbated by hypertension [35, 36]. Potential mechanisms for

the reduction in nephron number during gestation includealterations in DNA methylation, increased apoptosis in thedeveloping kidney, renin-angiotensin system alterations, vita-min A and other nutritional deficiencies, and increased fetalglucocorticoid exposure [37, 38].

African American infants are more likely to be pre-termor SGA [11]. Our results provide preliminary evidence thatsome of the racial disparities in adult chronic disease, suchas kidney disease, may have its origins in the prenatal periodand may be evident in early childhood. Previous studies inadults have provided contradictory evidence for a racialdifference in the relationship between birth weight andglomerular number [6, 7], however, these results may besubject to the inherent bias in autopsy studies [39]. Glomerularfunction and/or size, rather than total number, may be a betterindicator of renal health; for instance, hypertensive AfricanAmerican adults have a greater total glomerular volume,which may reflect glomerular filtration rate, compared to theirCaucasian counterparts [6]. Better identification of pre-conceptual or prenatal risk factors for lower birth weight andprematurity may lead to interventions to reduce disparities inboth birth outcomes and adult disease. Examples includematernal smoking, which is associated with kidney volumein the offspring [40] and preeclampsia, which is known toimpact birth outcomes [41] and the maternal kidney [42], andcould potentially damage the developing fetal kidney.

Evidence from studies of a related phenotype (bloodpressure) suggests a similar race-specific birth weight-health outcome relationship in children. In the US NationalCollaborative Perinatal Project, birth weight was positivelyassociated with systolic blood pressure (SBP) measured atage 7 years in African Americans but not in whites [43]. Inthe Successive Small for Gestational Age Study, birthweight was inversely associated with SBP in white children,but was positively associated with SBP in African Americanchildren at age 5 years [44]. Finally, among older children(ages 15 to 17 years) participating in the Bogalusa HeartStudy, birth weight accounted for racial differences in bloodpressure, suggesting that improving birth outcomes amongblack women could reduce hypertension at a later age [45].

Table 2 Unadjusted and adjusted relationship of birth weight Z-score with log (estimated glomerular filtration rate, eGFR), by race

Birth weight Z-score African American Non-African American

Parameter estimatea±SE p Parameter estimatea±SE p

Unadjusted 0.101±0.036 0.005 0.010±0.029 0.73

Adjusted for child age 0.089±0.036 0.012 –0.025±0.025 0.33

SE standard errora Due to log-transformation of dependent variables, parameter estimate (β) can be interpreted as (eβ – 1)% change with every 1 unit increase inbirth weight Z-score. So for African American children, unadjusted, (e0.101 01.11) is an 11% increase in eGFR, on average, when comparingchildren with a group of children with 1-unit-higher Z-score on their birth weight. This contrasts with a 1% (e0.010 01.01; non-significant at p00.73)change in the unadjusted non-African American children

1320 Pediatr Nephrol (2012) 27:1317–1323

The race-specific association detected in the current studymay be due to an underlying pathophysiological differencein the kidneys, a lower power to detect an association in ournon-African American sample or simple chance.

Nephron adaptation, in which structural and functionalchanges in the available nephrons occur to compensate forreduce nephron number, generally preserves GFR [46]. Giventhis adaptive mechanism, it may be surprising to detect anassociation between birth weight and eGFR among youngchildren, however, others have demonstrated similar associa-tions in slightly older children [19–21]. In animal models,protein intake modifies nephron adaptation [46]. Formula-fed infants have marked differences in kidney size relative tobreast-fed infants, most likely attributable to increased proteinlevels in formula [47]. African American women are lesslikely to initiate and sustain breast-feeding [48] and AfricanAmerican children consume more protein than Caucasianchildren [49]. These early life feeding-practice differencesmay also partially explain why we are detecting an associationin our African American but not non-African American chil-dren (i.e., in the kidney susceptible to further injury due to lowbirth weight, early life feeding-practice differences may pro-vide the second “injury” needed to cause demonstrable func-tion differences at an early age).

Extracellular volume depletion (EVD) may cause a tem-porary increase in SCr and a corresponding decrease ineGFR. Examining the EMR of a subset of children withthe highest SCr values, there was little evidence these valueswere elevated due to EVD or prerenal azotemia. We arerelying on measures of SCr that were obtained during rou-tine clinical care and which were run as part of a metabolicor biochemical laboratory profile. Although there was nodifference in race, birth weight, or gestational age betweenWHEALS children with and without SCr measures, it ispossible that this is a highly selected group of children,which may reduce our generalizability. Age at SCr measure-ment varied across the study population; although we adjustedfor age at measurement, we are unlikely fully accounting fornormal variability in renal function as part of growth anddevelopment. Still needed is replication of these results in alarger and broader cohort of similarly aged children.

Linear interpolation was done to estimate height at SCrmeasure for 71 observations. However, growth in stature,especially among pre-pubertal children, is not a steady pro-cess, but rather is typically comprised of periods of spurtsand stasis [50]. Any misclassification of height would mostlikely be non-differential with respect to both birth weightand renal function, and thus would attenuate our results.

Staples et al. (2010) recently validated the 2009 bedsideSchwartz equation in a predominantly non-CKD sample,suggesting that the equation is valid even in very youngchildren [32]. Under the age of 3 years, the equation tends tooverestimate eGFR while it underestimates eGFR in older

children [32]. In our sample, we would expect the bias to benon-differential with respect to birth weight, and thus if biaswas impacting the results demonstrated here, it would attenuateour results.

In children, renal function, measured as SCr, is associatedwith renal size [36]. However, serum cystatin C may be abetter marker of renal function in children, as it is less influ-enced by the increases in muscle mass that are part of normalgrowth [29]. Given the known difference in SCr betweenAfrican Americans and Caucasians, even at relatively youngages (12–19 years) [51], and the lack of a childhood equationfor eGFR with different coefficients for race (in contrast toadult eGFR equations, which do take into account race andgender) future studies examining fetal origins of racial dispar-ities in renal function should consider an additional measureof renal function such as cystatin C.

Anthropometric and metabolic characteristics of the chil-dren were largely unavailable at the time of SCr measure-ment, although there is evidence that they are associatedwith eGFR in healthy children (e.g., increasing numbers ofmetabolic syndrome components are positively associatedwith eGFR) [20]. Future studies should examine body com-position as well as other markers of renal and cardiovascularhealth (e.g., blood pressure) within the context of the rela-tionship between birth weight and renal function.

Summary

We provide preliminary evidence that lower birth weight isassociated with diminished renal function in healthy, youngAfrican American children. Future work is needed to deter-mine if prenatal programming events help explain racialdisparities in adult kidney health.

Acknowledgements This study was supported by the National Insti-tutes of Health (R01 AI050681) and the Fund for Henry Ford Hospital.

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