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DOI: 10.1093/ndt/gfg259
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
Keywords: oligonephronia;
renal disease
primary
hypertension;
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 socioeconomic, 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 [4–8]. A recent
study by Keller et al. [9] showing an association
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: [email protected]
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,
ß 2003 European Renal Association–European Dialysis and Transplant Association
Nephrol Dial Transplant (2003) 18: Editorial Comments
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 700 000/kidney compared with
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 -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 11 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
1435
birth weight and cardiovascular and renal risk, many
of these associations were weak or were not found by
others [22–26]. In the human studies alluded to above
[17–21], 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 postnatal 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 (11 vs 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
1436
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 intrauterine 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 30%
fewer glomeruli than its wild-type controls [37].
Nephrol Dial Transplant (2003) 18: Editorial Comments
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 intrauterine 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 [19–21]. 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.
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.
Nephrol Dial Transplant (2003) 18: Editorial Comments
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 (2 ml/min) in response to a
standard amino acid load when compared with
matched controls without such a family history
(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]
1437
these clues should suggest the need for therapeutic
intervention during childhood if hypertension and renal
disease are to be prevented or ameliorated.
Acknowledgement. I would like to thank Dale Abrahamson, PhD,
for his helpful suggestions.
Conflict of interest statement.
None declared.
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