American Journal of Kidney Diseases
Volume 50, Issue 4 , Pages 531-534, October 2007

Low Birth Weight and Kidney Function: Is There a Relationship and Is it Determined by the Intrauterine Environment?

  • Michael D. Hughson, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Michael D. Hughson, MD, Department of Pathology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505.

University of Mississippi Medical Center, Jackson, Mississippi

Article Outline

 

Related Article, p. 542

There is an accumulating body of information that suggests low birth weight is associated with a lower number of glomeruli in the infant kidney and that affected adults are at increased risk for hypertension, impaired kidney function, and cardiovascular disease. Barker et al, in 1989,1 and in continuing studies with others,2, 3, 4 reported the longitudinal investigation of residents of several English communities who were born in the early 1900s. Death rates from cardiovascular disease were found to be higher for persons with lower birth weights, and at 64 to 71 years of age, an inverse relationship was found in which systolic blood pressure was estimated to be 5.2 mmHg higher for each kg decrease in birth weight after adjustment for adult body mass index (BMI). On the basis of these findings, the concept of the “fetal origins” of adult disease was proposed.

The “fetal origins” hypothesis suggests that low birth weight puts adults at risk for the spectrum of metabolic syndrome disorders encompassed by increased central fat storage, type 2 diabetes, hypertension, and coronary artery and kidney disease.5 It is also suggested that excessive childhood catch-up growth or adult weight gain stresses the individual compromised by intrauterine growth retardation (IUGR) and amplifies the risk of adult disease.

Subsequently, the “fetal origins” hypothesis has been both supported and contradicted.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 In supportive studies, the demonstration of an inverse relationship between birth weight and blood pressure frequently required adjustment for adult body size or catch-up growth in childhood.6, 9, 12

The appropriateness of adjustment for adult BMI has been questioned by several investigators.9, 16, 17 Hemachandra et al16 analyzed data from 29,710 term births in the US National Collaborative Perinatal Project and were able to show that birth weight had a significant direct, rather than inverse, relationship to blood pressure at age 7 in black children but had no association with blood pressure in white children. When the effect of birth weight on blood pressure was adjusted for BMI, the relationship inverted and became insignificant for blacks but significant for whites. Because BMI has a causal association with blood pressure,6, 9, 14, 16 correction for BMI is thought to introduce a spurious relationship between birth weight and blood pressure referred to as the “reversal paradox.”17

The few stereological studies that have been performed on human kidneys have demonstrated a direct correlation between glomerular number and birth weight in which there are approximately 250,000 fewer glomeruli per kidney for each kg decrease in birth weight.18, 19 Two autopsy studies have shown that hypertension in white adults and Australian Aborigines adults, but not in black adults, is associated with low nephron number.7, 20, 21 In one of the studies of white adults, the hypertension was linked to low birth weight without regard for adult weight.7

Most of the studies cited above largely evaluated the effects of birth weight in term or near term births and were not intended to account for a severe reduction in glomerular number that might be seen with IUGR or severe prematurity. Rodriquez et al22 showed that nephrogenesis continues after birth in premature infants for 40 days, but not beyond, and that nephrogenesis is further compromised by renal failure that commonly occurs in severely premature births. These findings indicated that prematurity, in addition to and separate from IUGR, can impair nephrogenesis.

In most organs, cell proliferation during intrauterine growth is complete before the beginning of the third trimester.23, 24 However, in the kidney, 60% of nephrons are formed during the third trimester with nephrogenesis ending at the 36th week of gestation.24 Approximately 70% of IUGR is the result of a late impairment of fetal growth due to compromised placental function and reduced fetal nutrition. This usually occurs during the third trimester when the interference with fetal growth has been shown to inhibit nephron and possibly pancreatic islet cell development.5, 23, 24

Because of the potential adverse effects of prematurity and IUGR on adult health, the Project on Prematures and Small for Gestational Age Infants (POPS) was designed to separately analyze the effects of prematurity and IUGR on a Dutch birth cohort born in 1983.25, 26, 27, 28, 29 These investigators developed an adjusted multivariate regression model to test the influence of childhood and adult growth on blood pressure and kidney function.25 The model is based upon standard deviation scores that are the residual of the difference between actual adult or childhood size and size predicted from birth weight.

This issue of AJKD features their most recent study,29 which evaluates at 20 years of age individuals born very premature (<32 weeks gestation) and small for gestational age (SGA premature), those born very premature with weights appropriate for gestational age (AGA premature), and a control group born at full term (37-42 weeks).

They previously investigated the influence of birth weight on insulin resistance and found that insulin resistance was related to obesity at age 19 but not to birth weight.26 In support of studies that have shown early catch-up growth in premature infants to be related to later type 2 diabetes, they found that rapid infant weight gain in combination with obesity at 19 years of age was associated with greater insulin resistance in SGA prematures compared to AGA prematures. They pointed out that the relationship between rapid infant weight gain and increased plasma insulin levels at 19 years of age was weak and lost significance when adjusted for confounding variables that included sex, race, and socioeconomic status.

Several additional POPS studies preceded the current AJKD article with 2 being specifically concerned with blood pressure and kidney disease.27, 28 Hypertension was found in 10.5% and prehypertension in 45.9% of the 19-year-olds, with blood pressure being related to BMI but not to birth weight or gestational age.27 In the second study,28 significant correlations were found directly between birth weight and estimated glomerular filtration rate (eGFR) and inversely between birth weight and urine albumin-to-creatinine ratios. The prevalence of microalbuminuria was 3.8% in those born premature SGA and 1.6% in those that were premature AGA. While the findings suggested an increased risk of adult renal disease in SGA premature infants, both studies compared SGA and AGA premature births with each other but not with subjects born at a normal gestational age.

In the current article,29 POPS investigators report on 23 SGA prematures, 29 AGA prematures, and 30 control subjects that were born full term. At 20 years of age, the subjects underwent testing that included measurements of baseline and stimulated GFR and effective renal plasma flow (ERPF), as well as kidney size, albuminuria, and blood pressure. They found that the SGA prematures were significantly smaller by height, weight, and body surface area (BSA) than either their AGA premature or normal counterparts. The AGA prematures grew almost normally and reached an adult body size that was not statistically different than controls. SGA and AGA prematures had ultrasonographic kidney volumes and kidney volumes relative to body mass that were smaller and systolic but not diastolic blood pressures that were higher than subjects born full-term.

These findings indicated that both prematurity and IUGR may have an adverse affect on kidney size and adult blood pressure, but data on kidney function were more ambiguous. Premature SGA subjects had lower baseline GFR and ERPF than either AGA prematures or full term controls, and the baseline filtration fraction (FF) for AGA but not SGA prematures was higher than controls. After adjustment for BSA, among–group differences were not significant for baseline GFR, and a lower ERPF between premature SGA subjects compared to controls just reached significance. Renal stimulation by low dose dopamine infusion and high protein meals increased GFR and ERPF and decreased FF in all three groups. Relative to BSA, the stimulated ERPF was increased in SGA prematures compared to controls, but between–group differences for stimulated GFR and FF were not significant. Postnatal catch-up growth did not influence either kidney size or function. Microalbuminuria was seen only in 2 premature SGA subjects.

While the findings were not striking and warrant the authors’ conclusion that they do not fully support the hypothesis that IUGR contributes to impaired kidney function in adults, the number of subjects in each group was relatively small. The trends certainly suggest a tendency for some degree of impairment and warrant the authors’ other suggestion that larger studies should be undertaken.

The smaller kidney volumes relative to body size in those born premature and both SGA and AGA may be of particular importance. There is a strong inverse relationship between glomerular number and glomerular volume, in which kidneys with lower numbers of glomeruli tend to have larger glomeruli and vice versa.6, 17 Table 2 of their current article29 shows that baseline and stimulated GFR relative to kidney volume is higher, although not significantly, for SGA and AGA prematures than for subjects born full-term. This may indicate that GFR is maintained in the smaller kidneys of both severely premature groups by an increased perfusion of a fewer number of larger glomeruli. The potential increase in single nephron filtration rates could lead to later glomerular injury, a complication possibly suggested by the rare examples of microalbuminuria encountered in this study with SGA prematures and in their prior study with prematures both SGA and AGA. The authors acknowledge that the absence of notable abnormalities at age 20 may not adequately determine whether kidney impairment will occur later in life. They also note that the effects of the metabolic syndrome may not be seen until middle age. The further longitudinal studies anticipated from POPS and other neonatal investigative groups may yet support the “fetal origins” hypothesis.

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Acknowledgements 

Support: Dr Hughson is supported by National Institute of Health grant 1 RO1 DK65970-01.

Financial Disclosure: None.

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References 

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PII: S0272-6386(07)01134-1

doi:10.1053/j.ajkd.2007.07.026

Refers to article:

  • Renal Function and Size at Young Adult Age After Intrauterine Growth Restriction and Very Premature Birth , 23 August 2007

    Mandy G. Keijzer-Veen, Hilda A. Kleinveld, Maarten H. Lequin, Friedo W. Dekker, Jeroen Nauta, Yolanda B. de Rijke, Bert J. van der Heijden
    American Journal of Kidney Diseases October 2007 (Vol. 50, Issue 4, Pages 542-551)

American Journal of Kidney Diseases
Volume 50, Issue 4 , Pages 531-534, October 2007

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