Oligonephronia, primary hypertension and renal disease: ‘is the child father to the man?’

Stephen G. Rostand

Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, the University of Alabama at Birmingham, AL, USA

Correspondence and offprint requests to: Stephen G. Rostand, MD, Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, the University of Alabama at Birmingham, Birmingham, AL 35294, USA. Email: srostand{at}uab.edu

Keywords: oligonephronia; primary hypertension; renal disease

In the US hypertension has been estimated to affect >40 million, or ~24% of the population [1]. Numerous physiologic, biochemical, genetic, developmental and environmental factors, including socio-economic, are felt to influence levels of blood pressure. However, the relative importance of these biologic and environmental forces and when in the course of human life they exert their influences are uncertain. It has been suggested that environmental forces occurring in early childhood, including those affecting intra-uterine growth and development, may pre-programme the organism for subsequent hypertension, cardiovascular and renal disease [2,3]. In this regard, a large body of evidence has demonstrated statistical associations between low birth weight and/or gestational age and hypertension, on the one hand, as well as cardiovascular and renal disease in adults and in children on the other [48]. A recent study by Keller et al. [9] showing an association between primary hypertension and reduced nephron number has further heightened interest in the possible relationship between low birth weight, hypertension and cardiovascular and renal disease risk.

Birth weight and nephron number

It has been proposed by Brenner and Chertow [10] that early gestational age and/or fetal growth retardation (FGR) might be associated with impaired nephrogenesis. The resulting reduced number of glomeruli might then serve to link the observed association of low birth weight with the subsequent development of increased childhood and adult blood pressure and increased risk for cardiovascular and renal disease in adults. They suggest that glomerular hyperfiltration resulting from reduced nephron number would stimulate physical and cellular factors leading to systemic hypertension, glomerular sclerosis and obsolescence, and progressive deterioration of renal function.

Support for the idea that FGR is associated with a reduced post-natal number of nephrons comes from several observations. Studies by Hinchcliffe et al. [11,12] have shown that FGR was associated with significant reductions in nephron number. Similarly, Mañalich et al. [13] found significantly fewer glomeruli and greater glomerular volumes in neonates with birth weights <2.5 kg when compared with those born weighing >2.5 kg. Using a more indirect analysis, Spencer et al. [14] found that Aboriginal children, aged 5–18 years, weighing <2.5 kg at birth, had reduced renal volumes compared with children of greater birth weight, suggesting fewer nephrons. Measurements of glomerular volume have also been used as surrogate markers for reduced numbers of nephrons and several studies have shown increased glomerular size in African Americans [15] and Aboriginal Australians [16], both at high risk for hypertension and progressive renal disease. Moreover, glomerular hypertrophy has been shown to be an early marker for the development of glomerulosclerosis [15,16].

Although the foregoing suggests that there is an inverse association between birth weight and nephron number, there are data that suggest that low birth weight, early gestational age or FGR may not be necessary for there to be a reduced nephron number. In this regard, the above noted study of Keller et al. [9] suggests that low birth weight may not be necessary for reduced nephron numbers due to impaired nephrogenesis. In their careful analyses, these authors found the median number of glomeruli in patients with hypertension was {approx}700 000/kidney compared with {approx}1.4 million for matched controls. The number of glomeruli in the hypertensives, although half that seen in controls, is nearly identical for the total number of glomeruli described in full-term human fetuses by Hinchcliffe et al. [17] and Osthanondh and Potter [18]. As there is no further increase in nephron number after birth in humans, the findings suggest a considerable variability in the final glomerular complement during full-term fetal gestation. Thus, one need not necessarily postulate FGR or pre-term delivery to have fewer glomeruli.

Animal studies also support this idea. One study using rats has shown that early in utero exposure of fetuses to ß-lactam antibiotics that cross the placental barrier could produce lower nephron numbers with minimal effect on birth weight [19]. In another rat study [20], early in utero exposure of fetuses to hyperglycaemia also produced oligonephronia with fetuses exposed to high glucose concentrations having 10–35% fewer nephrons in a model not traditionally associated with low birth weight. Conversely, rats exposed in utero to high levels of glucocorticoids are born with low birth weights and develop hypertension. This is thought to be due to a deficiency in placental 11ß hydroxylase that controls fetal glucocortcoid exposure [21].

Is birth weight associated with blood pressure and renal disease risk?

Although for more than a decade, there have been studies showing statistical associations between low birth weight and cardiovascular and renal risk, many of these associations were weak or were not found by others [2226]. In the human studies alluded to above [1721], stronger associations were found between blood pressure and current body mass index rather than birth weight [22,24,25] suggesting that an increased rate of post-natal growth rather than birth weight may be the more important risk factor [27,28]. Thus, childhood body mass index or growth rate, rather than birth weight, may better explain longitudinal studies that have shown an association of childhood and adolescent blood pressure with subsequent adult blood pressure [29,30].

In this regard, African Americans provide an interesting example. African Americans have a high prevalence of low birth weight babies [31] and, as a result, it has been theorized that FGR associated with attendant oligonephronia [32] might link their high prevalence of hypertension and renal disease. However, no such association with blood pressure has been established either in childhood [26,33] or in young adults [23]. Once again a stronger association between blood pressure and body mass index was found at the time of study [23]. With regard to renal disease, an association between ESRD and low birth weight in African Americans living in the South-eastern US was at best very weak [34]. However, in studies of children (blacks and whites) aged 7 to >13 years, Berenson et al. [35] found that creatinine clearances in black children >13 years old were statistically lower than those at younger ages. Moreover, the directional change in creatinine clearance between ages 7 and >13 years in black children was downward which was opposite to that observed in white children of the same ages. Although no anatomic or birth weight data were given, this observation might suggest that the black children had a smaller nephron complement, increased glomerular filtration, subsequent glomerular sclerosis—known to be highly prevalent in African Americans [36]—and a decline in glomerular filtration rate (GFR). However, it is also possible that the above noted changes and the increased susceptibility to glomerulosclerosis rather than being related to FGR could have been related to intra-uterine and post-natal influences that may not necessarily affect birth weight.

The overall importance of low birth weight and gestational age in the pathogenesis of the disorders of interest may also be questioned because the prevalence of FGR in the US is about half the prevalence of hypertension ({approx}11 vs {approx}24%) [31], an observation that also holds for the high risk African American population. Taken together these observations suggest either FGR is not necessary for hypertension and renal disease risk or that if early gestational age, FGR or reduced glomerular number has an effect on adult blood pressure and/or cardiovascular and renal risk, the effects are either very subtle, very likely modified by environmental factors, or else the time to manifestation of its effects is quite variable with clinically obvious end organ damage not appearing until well after childhood. Thus, the importance of low birth weight in the genesis of hypertension and subsequent renal and cardiovascular disease is uncertain.

Nephron number and disease

While it is known that FGR can be associated with a lower glomerular complement at birth, and that statistical associations have been found between low birth weight and childhood and adult hypertension, as well as with cardiovascular, and to a lesser extent, renal disease, the link between lower nephron number and the above mentioned disease has remained conjectural. In their carefully conducted stereologic autopsy analysis of kidneys of 10 middle aged white men, Keller et al. [9] provide an important link between reduced nephron number and hypertension. They clearly demonstrated that those with primary hypertension had fewer glomeruli per kidney than their normotensive controls. Moreover, the hypertensive subjects had significantly greater glomerular volumes and significantly more obliterated glomeruli. However, as birth data were not available it is unclear whether the lower nephron number was the result of FGR or the result of intra-uterine or post-partum changes that were independent of birth weight. Further support for a role of reduced nephron number comes from a recent experimental study that showed higher blood pressure in a genetic mouse model that had {approx}30% fewer glomeruli than its wild-type controls [37]. Hyperfiltration was felt to be responsible for the maintenance of normal GFR for 14 months.

Part of the difficulty in assessing the role of low birth weight and impaired nephrogenesis in the development of cardiovascular and renal disease relates to the many factors that can influence intra-uterine development as well as those affecting disease development and progression in post-natal life. Some of the environmental factors affecting nephrogenesis have been mentioned earlier [1921]. Others include nutritional factors, such as low maternal calorie and protein intake that can reduce nephron number, cause glomerular hypertrophy and subsequently increase post-natal glomerular fibrosis [38,39]; decreased maternal calcium intake during pregnancy that can promote pre-term delivery and adult hypertension [40]; and low potassium environments that have been shown in vitro to inhibit nephron induction [41].

Alternatively, or perhaps in conjunction with impaired nephrogenesis, post-partum environmental factors might contribute to or be responsible for childhood hypertension, glomerular sclerosis and obsolescence, lower glomerular counts and subsequent renal impairment and hypertension. Such factors might include, for example, elevated caloric intake that has been associated with increased glomerulosclerosis [42] and the post-partum maternal environment for it has been shown that cross-suckling pups of spontaneously hypertensive rats with WKY dams did not develop hypertension [43].

This concept, together with that proposed by Barker [3] and Chertow and Brenner [10] is presented in Figure 1.



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Fig. 1. Possible explanations for reduced nephron numbers suspected in the pathogenesis of hypertension and renal disease. (A) FGR produces oligonephronia with secondary development of hypertension and renal disease. (B) Oligonephronia is produced independently by FGR and by unrelated hypertension, renal disease and other factors occurring unrelated to FGR.

 
Early detection of renal dysfunction and subsequent renal risk

If fewer glomeruli and subsequent adult disease are related it would be important to be able to detect this as early as possible and use the information for prognosis and institution of preventive measures. Clearly, autopsy studies like those done by Keller et al. [9] are too late to be of clinical value and renal biopsy particularly in apparently normal children and adults is not indicated and unethical. However, subtle changes in renal function may provide important clues to the presence of reduced nephron number and to renal disease risk, whether or not the result of FGR. Based on the foregoing data, one would expect that a reduced nephron number would be associated with greater glomerular size and volume and such glomeruli would be hyperfiltering. Schmieder et al. [44] have demonstrated that glomerular hyperfiltration is an indicator of early end organ damage. In addition, one might expect hyperfiltration to be associated with a reduced renal reserve. In this regard, O’Connor et al. [45] found that normotensive offspring, aged 22–46, with family histories of hypertension had significantly blunted increases in GFR ({approx}2 ml/min) in response to a standard amino acid load when compared with matched controls without such a family history ({approx}31 ml/min). In addition, fractional renal sodium excretion was also blunted in this group. Another study also found blunted sodium excretion in children and adolescents with birth weights <3.1 kg [46]. States of hyperfiltration resulting from reduced glomerular number may also be responsible for microalbuminuria, a known early marker for renal disease and hypertension. Thus, blunted renal reserve and impaired sodium, osmolar and water clearances may be pathophysiologic indicators of reduced nephron number and may serve to predict future risk for renal disease and hypertension in susceptible populations if they are detected early before disease is clinically apparent.

In conclusion, the relative importance of FGR and oligonephronia as predetermining factors for hypertension and renal disease risk remains uncertain. Nevertheless, oligonephronia, whether or not associated with low birth weight, should be added to a growing list of factors for future hypertension and renal disease risk, which also includes: family history of hypertension and renal disease, including diabetes mellitus, microalbuminuria, obesity, dietary factors, insulin resistance, gestational diabetes and being of a susceptible ethnic group. In such groups the early detection of potential indicators of hyperfiltration, such as impaired renal reserve and blunted solute clearance may provide subtle clues to the presence of reduced nephron numbers and perhaps to increased numbers of obsolete glomeruli and thus may provide early objective evidence for future hypertension and renal risk. Thus, evidence for the origins of adult hypertension and renal deterioration may be found early in childhood and because it is clear ‘the child is father to the man’ [47] these clues should suggest the need for therapeutic intervention during childhood if hypertension and renal disease are to be prevented or ameliorated.

Acknowledgments

I would like to thank Dale Abrahamson, PhD, for his helpful suggestions.

Conflict of interest statement. None declared.

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