Chapter Outline
DEVELOPMENTAL PROGRAMMING, 694
DEVELOPMENTAL PROGRAMMING IN THE KIDNEY, 694
PROGRAMMING OF RENAL FUNCTION AND DISEASE, 703
PROPOSED MECHANISMS FOR DEVELOPMENTAL PROGRAMMING IN THE KIDNEY, 713
Genetic Variants Associated with Kidney Size and Nephron Number in Humans, 713
Maternal Nutrient Restriction, 715
Fetal Exposure to Glucocorticoids, 717
Fetal Exposure to Hyperglycemia and the Role of Insulin-like Growth Factors and Their Receptors, 717
Apoptosis, 718
Glial Cell Line–Derived Neurotrophic Factor and c-Ret Receptor Function, 719
Fetal Drug Exposure, 719
Obstruction of the Developing Kidney, 719
Impact of Sex, 720
Potential for Rescue of Nephron Number, 720
Catch-up Growth, 721
IMPACT OF NEPHRON ENDOWMENT IN TRANSPLANTATION, 723
Implications of Nephron Endowment for the Donor, 723
Implications of Nephron Endowment for the Recipient, 723
CONCLUSION, 724
Genetic factors are important determinants of the development and function of major organ systems as well as of susceptibility to disease. Rare genetic and congenital abnormalities leading to abnormal kidney development are associated with the occurrence of subsequent renal dysfunction, often manifest very early in life. Most renal disease in the general population, however, is not ascribable to genetic mutations, with the most common etiologic associations with end-stage kidney disease (ESKD) worldwide being the polygenic disorders diabetes and hypertension. Hypertension and renal disease prevalences vary among populations from different ethnic backgrounds, with very high rates being observed in Aboriginal Australians, Native Americans, and people of African descent. It is well established that lifestyle factors pose significant risk for the development and persistence of hypertension and diabetes in the general population, with obesity becoming an increasing concern, especially in the developing world. Of note there is evidence linking mutations in the apolipoprotein-1 (APOL1) gene in people of African descent with increased predisposition to the development of human immunodeficiency virus (HIV)–associated nephropathy and focal and segmental glomerulosclerosis (FSGS) in African Americans. Searches for specific gene polymorphisms or mutations have not implicated global culprit genes, however, but instead point to a likely complex interplay between polygenic predisposition and environmental factors in the development of hypertension, diabetes, and renal disease. Furthermore, evidence highlighting the far-reaching effects of the intrauterine environment and early postnatal growth on organ development, organ function, and subsequent susceptibility to adult disease is quite compelling. These data suggest that stresses experienced during early development (for which low birth weight or prematurity may be a surrogate marker), “program” long-term organ function and may be the first in a succession of “hits” that ultimately manifest in overt disease. This chapter outlines the effects of fetal and early-life programming on renal development (particularly nephrogenesis), nephron endowment, and the risks of hypertension and kidney disease in later life. Major congenital renal anomalies are discussed elsewhere in this book. In addition, it must be borne in mind that low birth weight and prematurity also predict later-life diabetes, cardiovascular disease, and metabolic syndrome, so renal function may be additionally impacted through developmental programming of these organ systems and, in turn, affect outcomes of these diseases, the discussion of which is beyond the scope of the current chapter.
Developmental Programming
The process through which an environmental insult experienced early in life can predispose to adult disease is known as developmental programming, which refers to the observation that an environmental stimulus experienced during a critical period of development in utero or early after birth can induce long-term structural and functional effects in the organism. This phenomenon, nowadays often termed developmental origins of health and disease or DOHaD, can have far-reaching implications in that the effects can be perpetuated across generations. The association between adverse intrauterine events and subsequent cardiovascular disease has long been recognized. In early studies, adults of low birth weight were found to have higher cardiovascular morbidity and mortality than those of normal birth weight. Subsequently, evidence from diverse populations has confirmed these findings and expanded them to include other conditions, such as hypertension, impaired glucose tolerance, type 2 diabetes, obesity, preeclampsia, and chronic kidney disease (CKD). Of these, the associations between low birth weight and prematurity and subsequent hypertension have been the most studied. Attention had largely focused on prematurity and low birth weight as markers for developmental programming of hypertension and renal disease, but high birth weight, often the result of a diabetic pregnancy or maternal obesity, is also emerging as a risk factor. Currently birth weight and prematurity are the best available surrogates for an adverse intrauterine environment, but some intrauterine stresses may not manifest as such and therefore may not be recognized. Ongoing work is required to develop more sensitive measures of developmental stress. Table 23.1 outlines the definitions of birth weight and gestational age categories that are referred to throughout this chapter. Globally, the respective incidences of low birth weight and prematurity are around 15% and 9.6%. The global incidence of high birth weight, which ranges from 5% to 20%, is rising. A significant number of infants born yearly therefore likely undergo developmental programming and are at risk for chronic disease later in life.
| Category | Definition |
|---|---|
| Birth Weight Categories | |
| Normal birth weight | >2500 g and <4000 g (usually) |
| Large for gestational age | >2 standard deviations above the mean birth weight for gestational age |
| Low birth weight | <2500 g |
| Very low birth weight | <1500 g |
| Appropriate for gestational age | Within ±2 standard deviations of the mean birth weight for gestational age |
| Small for gestational age | >2 standard deviations below the mean birth weight for gestational age |
| Intrauterine growth restriction | Evidence of fetal malnutrition and growth restriction at any time during gestation |
| Gestational Categories | |
| Extremely preterm | <28 weeks of gestation |
| Very preterm | <32 and >28 weeks of gestation |
| Moderately preterm | <34 and >32 weeks of gestation |
| Late preterm | <37 and >34 weeks of gestation |
| Full term | >37 weeks of gestation |
Developmental Programming in the Kidney
The kidney is the organ central to the development of hypertension. The relationship between renal sodium handling, intravascular volume homeostasis, and hypertension is well accepted. That factors intrinsic to the kidney itself affect blood pressure has been demonstrated clinically in kidney transplantation, in which the blood pressure in the recipient after transplantation has been shown to be related to the blood pressure or hypertension risk factors of the donor; that is, hypertension “follows” the kidney. In 1988 Brenner and colleagues proposed that a congenital (programmed) reduction in nephron number may be a factor explaining why some individuals are susceptible to hypertension and renal injury whereas others may seem relatively resistant under similar circumstances (e.g., sodium excess or diabetes mellitus). Reductions in nephron number and whole kidney glomerular surface area would result in lower sodium excretory capacity, enhancing susceptibility to hypertension, and a reduced renal reserve, limiting compensation for renal injury. This hypothesis was attractive in that an association between a reduced nephron number and low birth weight, for example, could explain differences in hypertension and renal disease prevalence observed in populations of different ethnicity, among whom those who tend to have lower birth weights often have a greater prevalence of hypertension and renal disease.
Plausibility of the Nephron Number Hypothesis
An obstacle to investigation of the nephron number hypothesis has been the difficulty of accurately counting or estimating the total number of nephrons in a kidney. Review of early studies shows that humans were believed to have an average of approximately one million nephrons per kidney. Such studies, however, were performed using techniques such as acid maceration or traditional model-based stereologic approaches, which are prone to bias because of required assumptions, extrapolations, and operator sensitivity. Over the past 20 years, the “unbiased” dissector (counting method)/fractionator (sampling method) has emerged as the “gold standard” for counting glomeruli, and it generates accurate and precise estimates. Importantly, all reported glomerular counting techniques have been performed on autopsy samples. To date, no validated technique permits determination of nephron number in vivo, although a magnetic resonance imaging (MRI) technique using cationic ferritin shows promise.
In one study using the dissector/fractionator combination method in 37 normal Danish adults, the average glomerular (nephron) number was reported to be 617,000 per kidney (range 331,000-1,424,000). A positive correlation was noted between glomerular number and kidney weight, which has subsequently been used as a surrogate marker for nephron number. In general, numbers of viable glomeruli are reduced in kidneys from older subjects, owing to age-related glomerulosclerosis and obsolescence. Later studies among patients of varying ethnicities have reported an up to 13-fold variation in total nephron number, with values ranging from 210,332 to 2,702,079 per kidney ( Table 23.2 ). This large variability in total nephron number in subjects without kidney disease may influence susceptibility to hypertension and kidney disease.
| Reference | Population | Sample Size | Mean | Range | Fold |
|---|---|---|---|---|---|
| Nyengaard et al | Danish | 37 | 617,000 | 331,000-1,424,000 | 4.3 |
| Merlet-Benichou et al * | French | 28 | 1,107,000 | 655,000-1,554,000 | 2.4 |
| Keller et al | German | 20 | 1,074,414 | 531,140-1,959,914 | 3.7 |
| Hypertensive | 10 | 702,379 | 531,140-954,893 | 1.8 | |
| Normotensive | 10 | 1,429,200 | 884,458-1,959,914 | 2.2 | |
| Douglas-Denton et al | African Americans | 105 | 884,938 | 210,332-2,026,541 | 9.6 |
| White Americans | 84 | 843,106 | 227,327-1,660,232 | 7.3 | |
| Hoy et al | non-Aboriginal Australians | 24 | 861,541 | 380,517-1,493,665 | 3.9 |
| Aboriginal Australians | 19 | 713,209 | 364,161-1,129,223 | 3.1 | |
| McNamara et al † | Senegalese | 47 | 992,353 | 536,171-1,764,421 | 3.3 |
| Hoy et al | African and white Americans, Australian Aborigines and non-Aborigines non-Aboriginal Australians, and Senegalese | 420 | 901,902 | 210,232-2,702,079 | 12.8 |
* Used acid maceration technique. All other studies used unbiased stereology.
† Values for 47 participants were combined from two publications.
In support of the nephron number hypothesis, it is known that progressive proteinuria, glomerulosclerosis, and renal dysfunction develop with time in persons born with severe nephron deficits, for example, unilateral renal agenesis, bilateral renal hypoplasia, and oligomeganephronia. Analogously, therefore, people born with nephron numbers at or below the median level may be more susceptible to superimposed postnatal factors that act as subsequent “hits”; thus, a significant proportion of the population may be at risk for the development of hypertension and renal disease, given that some 30% of the world’s adult population is hypertensive.
The counter-argument to the nephron number hypothesis is that in experimental animals and in humans, removal of one kidney (presumed reduction in nephron number by 50%) under varying circumstances may be associated with higher blood pressures or low-grade proteinuria but does not always lead to hypertension and renal disease. It is of interest, however, that uninephrectomy on postnatal day 1 in rats or fetal uninephrectomy in sheep—that is, loss of nephrons at a time when nephrogenesis is not yet completed—does lead to adult hypertension prior to any evidence of renal injury. These data support the hypothesis that intrauterine or congenital reduction in nephron number may be associated with compensatory mechanisms or a reduced compensatory capacity that are different from those associated with later nephron loss, resulting in increased risk of hypertension. Consistent with this notion, kidneys from rats that underwent unilateral nephrectomy at 3 days of age showed a similar total glomerular number but a significantly smaller number of mature glomeruli in the remaining kidney than kidneys from those that underwent nephrectomy at 120 days of age. Furthermore, after unilateral nephrectomy in the neonatal period, the mean glomerular volume in the remaining kidney of rats increased by 59% in comparison with 20% in adult rats, likely indicating a greater burden of compensatory hypertrophy and hyperfiltration in response to neonatal nephrectomy.
In potential contrast, however, a study of 97 subjects aged 2.5 to 25 years who had radiologically normal single kidneys, found that renal function declined faster over time in those with acquired single kidneys (surgical removal of other kidney) than in those with congenital single kidneys, although blood pressures and proteinuria were not different. However, these findings may be confounded by indication for nephrectomy, because approximately 25% of the nephrectomies were performed for obstruction, which may affect contralateral kidney development, as discussed later. In addition, unilateral in utero nephrectomy in sheep was associated with significant hypertrophy and a 45% increase in nephron number in the remaining kidney; therefore, a congenital solitary kidney may have a higher-than-normal nephron endowment and therefore may be relatively protected in comparison with an acquired single kidney. Timing of nephron loss is likely a crucial factor in determining the compensatory capacity of remaining nephrons.
Nephron Number and Glomerular Volume
Human glomeruli have been reported to increase in size up to sevenfold from infancy to adulthood. Glomerular size also increases in adulthood in people without overt renal disease, and the increase is associated with rising age, increasing body size, and lower birth weight. Mean glomerular volume has also been consistently noted to vary inversely with total glomerular number although the correlation appears stronger among whites and Aboriginal Australians than in people of African origin. This relationship suggests that larger glomeruli may reflect compensatory hyperfiltration and hypertrophy in subjects with fewer nephrons and may therefore be a surrogate marker for reduced nephron number. In fact, Hoy and coworkers found that, although mean glomerular volume was increased in subjects with reduced nephron number, total glomerular tuft volume (a surrogate for total filtration surface area) was no different among groups with different nephron numbers ( Table 23.3 ). This observation suggests that total filtration surface area may initially be maintained in the setting of reduced nephron number but at the expense of glomerular hypertension and hypertrophy, which are maladaptive and predict poor outcomes. Consistent with this possibility, glomerulomegaly is common in renal biopsy specimens from Aboriginal Australians, a population with high rates of low birth weight and renal disease, and has also been associated with faster rate of decline of glomerular filtration rate (GFR) in Pima Indians. Furthermore, in a study of donor kidneys, maximal planar area of glomeruli was found to be higher in kidneys from African Americans than in those from whites and to be a predictor of poorer transplant function. Among 111 adult males from four ethnic groups, mean glomerular volume and variability were highest among African Americans and Aboriginal Australians, likely associated with susceptibility to hypertension and renal disease. In populations at high risk for kidney failure, therefore, large glomeruli are a common finding at early stages of renal disease and may reflect programmed reductions in nephron number in these populations, in which access to prenatal and subsequent health care is often suboptimal. An increase in glomerular volume, however, is not always associated with lower glomerular number, and individual glomerular volume varies considerably within kidneys. Nevertheless, overall, glomerulomegaly and greater intrasubject variability in glomerular volume have been found to be associated with older age, fewer nephrons, lower birth weight, hypertension, obesity, and severity of cardiovascular disease.
| Mean Birth Weight (Range) | N | Mean Number of Glomeruli (Range) * | Mean Glomerular Tuft Volume (µm 3 x10 6 ) | Total Glomerular Tuft Volume (cm 3 ) |
|---|---|---|---|---|
| 2.65 kg (1.81-3.12) | 29 | 770,860 (658,757-882,963) | 9.2 | 6.7 |
| 3.27 kg (3.18-3.38) | 28 | 965,729 (885,714-1,075,744) | 7.2 | 6.8 |
| 3.93 kg (3.41-4.94) | 30 | 1,005,356 (900,094-1,110,599) | 6.9 | 6.6 |
Evidence for Programming in the Kidney
Developmental Programming of Nephron Endowment
Experimental Evidence for Programming of Nephron Endowment
Developmental programming of nephron number has been the most rigorously studied link to later-life hypertension and kidney disease so far. Numerous animal models have demonstrated the association of low birth weight (induced by gestational exposure to low-protein or low-calorie diets, uterine ischemia, dexamethasone, or vitamin A deprivation) with subsequent hypertension. The link between adult hypertension and low birth weight in these animal models appears to be mediated, at least in part, by an associated congenital nephron deficit. Corresponding blood pressures and nephron numbers associated with various programming models are outlined in Table 23.4 . As shown, the association between birth weight, nephron numbers, and blood pressures varies among models, underscoring the complexity of developmental programming and the need for better markers than birth weight.
| Experimental Evidence | |||||
|---|---|---|---|---|---|
| Experimental Model | Animal | Glomerular Number (%) | Birth Weight | Blood Pressure | Renal Function |
| Reduction in Nephron Number | |||||
| Maternal calorie restriction | Rat | ↓ 20-40 | ↓ | ↑ | ↓ GFR Proteinuria |
| Uterine artery ligation | Rat | ↓ 20-30 | ↓ | ↑ | Impaired proteinuria |
| Low-protein diet during gestation | Rat | ↓ 25 ↓ 17 ↓ 16 | ↓/↔ | ↑ | ↓ GFR Proteinuria ↓ longevity |
| Postnatal nutrient restriction | Rat | ↓ 27 | Normal | ↑ | NA |
| Iron deficiency | Rat | ↓ 22 | ↓ | ↑ | NA |
| Vitamin A deficiency | Rat | ↓ 20 | ↔ | NA | NA |
| Zinc deficiency | Rat | ↓ 25 | NA | ↑ | ↓ GFR Proteinuria |
| Ethanol | Sheep | ↓ 11 | ↔ | NA | NA |
| Hypoxia | Rat | ↓ 26-52 | ↓ | NA | NA |
| Cigarette smoke | Mouse | NA | ↓ | NA | ↓ kidney mass |
| Ureteral obstruction—neonatal | Rat | ↓ 50 | NA | ↑ | ↓ GFR ↓ renal growth after relief of obstruction |
| Prematurity | Mouse | ↓ 17-24 | ↓ | ↑ | ↓ GFR ↑ albuminuria |
| Glucocorticoids | Rat | ↓ 20 | ↓/↔ | ↑ | Glomerulosclerosis |
| Sheep | ↓ 38 | ↔ | ↑ | ↑ collagen deposition | |
| Maternal diabetes | Rat | ↓ 10-35 | ↔ | ↑ | Salt sensitivity |
| Gentamicin | Rat | ↓ 10-20 | ↓ | NA | NA |
| β-lactams | Rat | ↓ 5-10 | ↔ | NA | Tubular dilatation Interstitial inflammation |
| Cyclosporine | Rabbit | ↓ 25-33 | ↓/↔ | ↑ | ↓ GFR ↑ RVR Proteinuria |
| Dahl salt-sensitive | Rat | ↓ 15 | ↑ with Na intake | Accelerated FSGS | |
| Munich-Wistar-Fromter | Rat | ↓ 40 | ↑ with age | ↑ Single-nephron GFR FSGS | |
| Milan hypertensive | Rat | ↓ 17 | ↑ | NA | |
| PVG/c | Rat | ↑ 122 | Resistant | Resistant to FSGS | |
| PAX2 mutations | Mouse Human | ↓ 22 | NA | Renal coloboma syndrome in humans Small kidneys | |
| GDNF heterozygote | Mouse | ↓ 30 | ↔ | ↑ | Normal GFR Enlarged glomeruli |
| c-Ret null mutant | Mouse | ↓ | NA | NA | Severe renal dysplasia |
| hIGFBP-1 overexpression | Mouse | ↓18-25 | ↓ | NA | Glomerulo-sclerosis |
| Bcl-2 deficiency | Mouse | ↓ | NA | NA | ↑ blood urea nitrogen and creatinine |
| p53 transgenic | Mouse | ↓ 50 | NA | NA | Glomerular hypertrophy Renal failure |
| COX2 null mutant | Mouse | NA | ↔ | ↔ | ↓ GFR |
| Augmentation of Nephron Number | |||||
| Vitamin A supplementation (with low-protein diet) | Rat | Normalized | NA | NA | NA |
| Amino acid (glycine, urea, or alanine) supplementation to maternal low-protein diet | Rat | Normalized | NA | Normalized with glycine only | NA |
| Restoration of post-natal nutrition post-intrauterine growth restriction | Rat | Normalized | ↓ | Normalized | NA |
| Iron supplementation to iron-deficient mothers | Rat | Partial rescue | NA | NA | NA |
| Ouabain administration (with low-protein diet) | Mouse | Prevented ↓ | NA | NA | NA |
| Maternal uninephrectomy prior to gestation | Rat | ↑ | NA | NA | NA |
| Post-natal overfeeding, normal birthweight | Rat | ↑ 20 | ↔ | ↑ | Glomerulosclerosis |
| Human Evidence | |||||
| Clinical Circumstance | Population | Glomerular Number/Kidney Volume (%) * | Birth Weight | Blood Pressure | Renal Function |
| Low birth weight | Human 0-1 yr | ↓ 13-35 | ↓ | NA | NA |
| Prematurity | Human | ↓ correlated with gestational age | ↓ | NA | NA |
| Females vs. males | Human | ↓ 12 | NA | Variable | Variable |
| Hypertensive vs. normotensive Caucasians | Human 35-59 yr | ↓ 19-50 | NA | ↑ | No ↑ Glomerulo-sclerosis |
| Hypertensive vs. normotensive African Americans | Human 35-59 yr | NS ↓ | NA | ↑ | No ↑ Glomerulosclerosis |
| Aboriginal Australians vs. Caucasian Australians | Human 0-85 yr | ↓ 23% | ↓ | NA | |
| Senegalese Africans | Human 5-70 yr | NA | NA | NA | ↑ variability of glomerular size ↓ glomerular numbers |
| Maternal vitamin A deficiency | Indian vs. Canadian newborns | ↓ newborn renal volume | NA | NA | NA |
| Genetic polymorphisms: | |||||
| RET(1476A) polymorphism | Newborns | ↓ 10 * | NA | NA | NA |
| PAX2 AAA haplotype | Newborns | ↓ 10 * | NA | NA | NA |
| Combined RET(1476A) polymorphism and PAX2 AAA haplotype | Newborns | ↓ 23 * | NA | NA | NA |
| I/D ACE polymorphism | Newborns | ↓ 8 | NA | NA | NA |
| BMPR1A rs7922846 polymorphism | Newborns | ↓ 13 * | NA | NA | NA |
| OSR1 rs12329305(T) polymorphism | Newborns | ↓ 12 * | NA | NA | NA |
| Combined OSR1 and RET polymorphisms | Newborns | ↓ 22 * | NA | NA | NA |
| Combined OSR1 and PAX2 polymorphisms | Newborns | ↓ 27 * | NA | NA | NA |
| ALDH1A2 rs7169289(G) polymorphism | Newborns | ↑ 22 * | NA | NA | NA |
Vehaskari and colleagues demonstrated an almost 30% reduction in glomerular number in offspring of pregnant rats fed a low-protein diet in comparison with those fed a normal-protein diet during pregnancy. As shown in Figure 23.1 , tail-cuff systolic blood pressures in the low-protein offspring were 20 to 25 mm Hg higher by 8 weeks of age. Similarly, prenatal administration of dexamethasone was associated with low birth weight and fewer glomeruli in the offspring. In these nephron-deficient rats, GFR was reduced, albuminuria was increased, and urinary sodium excretion was lower than in those with a greater nephron complement. Uteroplacental insufficiency, induced by maternal uterine artery ligation late in gestation, has also been found to result in low nephron number and was associated with increased profibrotic renal gene expression with age, although hypertension developed only in males. Conversely, adequate postnatal nutrition, achieved by cross-fostering of the offspring of mothers with uteroplacental insufficiency onto normal lactating females at birth, restored nephron number and prevented subsequent hypertension in the males. In a later study of the impact of prematurity, mice delivered 1 to 2 days early (normal mouse gestation 21 days) had reduced nephron numbers, lower GFR, and higher blood pressures than mice born at term, as well as albuminuria. Interestingly, nephron numbers were lower in mice delivered 2 days early than in those delivered 1 day early, suggesting the degree of prematurity is important in determining final nephron endowment, even though nephrogenesis continues after birth in the normal mouse. Not surprisingly, in animal studies, timing of the gestational insult has been found to be crucial in renal programming, with the greatest impact on nephron number occurring during periods of most active nephrogenesis.
Programming of Nephron Number in Humans
As noted previously, total nephron number varies widely in the normal human population (see Table 23.2 ). A significant proportion of the interindividual variability in nephron number appears to be already present perinatally, demonstrating a strong developmental effect. Overall, the data support a direct relationship between nephron number and birth weight and an inverse relationship between nephron number and glomerular volume. Hughson and colleagues reported a linear relationship between glomerular number and birth weight and calculated a regression coefficient predicting an increase of 257,426 glomeruli per kilogram increase in birth weight, although the generalizability of the regression coefficient to populations in which the distribution of nephron number appears bimodal, such as among African Americans, may not be valid. It has also been calculated that in the normal population without renal disease, approximately 4500 glomeruli are lost per kidney per year after age 18. Glomerular numbers tend to be lower in females than in males. A kidney starting with a lower nephron number, therefore, would conceivably reach a critical reduction of nephron mass, either with age or in response to a renal insult, earlier than a kidney with a greater nephron complement, predisposing to hypertension and/or renal dysfunction.
Nephrogenesis in humans begins during the 9th week of gestation and continues until the 34th to 36th week. Nephron number at birth therefore largely depends on the intrauterine environment and gestational age. It is generally believed that no new nephrons are formed in humans after term birth. To investigate whether glomerulogenesis does continue postnatally in premature infants, Rodriguez and colleagues studied kidneys at autopsy from 56 extremely premature infants and compared them with kidneys of 10 full-term infants as controls. The radial glomerular counts (an estimate of glomerular number based on the number of layers of glomeruli in the cortex) were lower in premature than in full-term infants and correlated with gestational age. Furthermore, evidence of active glomerulogenesis, indicated by the presence of S-shaped bodies immediately under the renal capsule, was seen in premature infants who died before 40 days but was absent in those who died after 40 days of life, suggesting that nephrogenesis may continue for up to 40 days after premature birth. These investigators also stratified their cases by presence or absence of renal failure. Among infants surviving longer than 40 days, those with renal failure (serum creatinine > 2.0 mg/dL) had significantly fewer glomeruli than those without renal failure. This cross-sectional observation may suggest that renal failure inhibited glomerulogenesis or, conversely, that the presence of fewer glomeruli lowered the threshold for development of renal failure in these infants. Those premature infants surviving longer than 40 days without renal failure exhibited glomerulomegaly, which may reflect, at least in the short term, a compensatory renoprotective response.
Faa and colleagues also reported evidence of active glomerulogenesis in kidneys of premature infants and two term infants who died at birth, but not in a child who died at age 3 months, suggesting that glomerular maturation may continue for a short period even after term birth. In contrast, Hinchliffe and associates studied nephron number in premature and full-term stillbirths and in infants who died at 1 year of age and who were born either with appropriate weight for gestational age or small for gestational age. At both time points, growth-restricted infants had fewer nephrons than controls. In addition, the number of nephrons in growth-restricted infants dying at 1 year of age had not increased in comparison with that in the growth-restricted stillbirths, demonstrating a lack of postnatal nephrogenesis ( Figure 23.2 A ). Manalich and coworkers examined the kidneys of neonates dying within 2 weeks of birth in relation to their birth weights ( Figure 23.2 B ). A significant direct correlation was found between glomerular number and birth weight, and a strong inverse correlation between glomerular volume and glomerular number, independent of sex and race. These studies all support the hypothesis that an adverse intrauterine environment, which may manifest as low birth weight or prematurity, is associated with a congenital reduction in nephron endowment and an early, compensatory increase in glomerular volume.
In a population of 140 adults aged 18 to 65 years who died of various causes, a significant correlation was also observed between birth weight and glomerular number. Glomerular volume was inversely correlated with glomerular number. Total glomerular number did not differ statistically among African American and white subjects, although the distribution among African Americans appeared bimodal. The range of nephron number was greatest among African Americans. Significantly, however, none of the subjects in this study had been of low birth weight; therefore, no conclusion can be drawn as to whether an association between low birth weight and nephron number existed in either population group. It may be argued that because low birth weight is more prevalent among African Americans, this cohort was more representative of the general white population than the general black population, having included only subjects of normal birth weight. In a European study comparing 26 subjects with non–insulin-dependent diabetes compared with 19 age-matched nondiabetic controls, no difference in glomerular number was found, but again, all subjects had birth weights above 3000 g, and, therefore, the impact of low birth weight on nephron number could not be assessed.
Kidney Size as a Correlate for Nephron Number.
Analysis of the relationship between kidney weight and nephron number in infants less than 3 months of age (a time at which compensatory hypertrophy has likely not yet occurred) revealed a direct relationship ( Figure 23.3 ). Regression analysis predicted an increase of 23,459 nephrons per gram of kidney weight. Renal mass is therefore proportional to nephron number, and renal volume is proportional to renal mass; for that reason, renal volume has been analyzed as a surrogate for nephron endowment in infants in vivo. Ultrasonographic evaluation of fetal renal function in utero revealed a reduction in hourly urine volume, higher prevalence of oligohydramnios, reduced renal perfusion, and reduced renal volume in growth-restricted fetuses. These findings may represent reduced fetal perfusion in situations of uterine compromise, however, and do not necessarily reflect altered renal development. Similarly, among premature infants, another study found that kidney volume at a corrected age of 38 weeks was significantly lower than that in term infants and was associated with a significantly lower GFR estimated from serum cystatin C.
Analysis of kidney size and postnatal growth measured by ultrasonography in 178 children born premature or small for gestational age in comparison with 717 mature children with appropriate weight for gestational age at 0, 3, and 18 months found that weight for gestational age was positively associated with kidney volume at all three time points. Slight catch-up in kidney growth was observed in growth-restricted infants but not in premature infants. Among term neonates, renal parenchymal thickness, proposed as a more accurate screening tool than renal volume estimation, was significantly reduced in those with low compared to normal birth weights. In Australian Aboriginal children, low birth weight was also found to be associated with lower renal volumes on ultrasonography. Comparison of renal volume between children aged 9 to 12 years who were born premature, either small or at appropriate weight for gestational age and controls found that kidneys were smallest in those who had been preterm and small for gestational age, but when findings were adjusted for body surface area (BSA), there were no significant differences between the groups. A smaller kidney size, therefore, may be a surrogate marker for reduced nephron endowment, but importantly, growth in kidney size on ultrasonography cannot distinguish between normal growth with age and renal hypertrophy.
Evidence of Additional Programming Effects in the Kidney
Taken together, the findings in animals and humans lend credence to the hypothesis that a congenital deficit in nephron number can be programmed during development and is likely to be an independent factor determining susceptibility to essential hypertension and subsequent renal injury. Low nephron number alone, however, does not account for all observed programmed hypertension (see Table 23.4 ). In one study, supplementation of a low-protein diet during gestation with glycine, urea, or alanine resulted in a normalization of nephron number in rat offspring, but blood pressure normalized only in those supplemented with glycine. Likewise, augmentation of nephron number by postnatal hypernutrition in another study resulted in a 20% increase in nephron number but also in development of obesity, hypertension, and glomerulosclerosis with age. These findings suggest that additional factors contribute to the developmental programming of hypertension. Later evidence has shown alterations in renal tubular sodium handling and vascular function in developmentally programmed kidneys that likely also contribute to later-life blood pressure and renal function changes as listed in Table 23.5 .
|
Altered Sodium Handling by the Kidney
The pressure-natriuresis curve is shifted to the right in most forms of hypertension. A reduction in filtration surface area associated with a reduction in nephron number is one plausible hypothesis to explain the associated higher blood pressures. Consistent with this association, salt sensitivity has been reported in several animal models to be associated with low birth weight and reduced nephron number. Some investigators have reported the presence of salt-sensitive hypertension in rats in which low birth weight was induced by maternal uterine artery ligation, whereas others report no salt sensitivity in rats in which low birth weight was induced by maternal protein restriction, although timing of dietary intervention and age at study appear to play a role. Elevations in blood pressure in response to high-salt diet have been more consistently observed in aging than in young rats, suggesting either an early adaptive mechanism that may decline with age or worsening salt sensitivity as nephron number declines with age. In young rats, however, despite no change in blood pressure, an increase in plasma volume was observed, consistent with sodium retention. Similar salt sensitivity was observed in adult rat offspring exposed to maternal gestational diabetes, a model also associated with reduced nephron number.
The effect of nephron “dose” and filtration surface area on salt sensitivity was examined in glial cell line–derived neurotrophic factor (GDNF) heterozygous mice that have either one kidney and a 65% reduction in total nephron number (HET1K) or two kidneys and a 25% reduction in total nephron number (HET2K). Given the accompanying glomerular hypertrophy, total glomerular surface area was normal in HET2K but remained reduced in HET1K mice. At baseline the mice did not have elevated blood pressures, but both groups became hypertensive in response to high-sodium feeding. A gradient of increasing blood pressure was observed from wild-type to HET2K to HET1K, suggesting dependence on nephron number and filtration surface area, given that no change in expression of tubular sodium transporters was observed. In the converse experiment transforming growth factor-β 2 heterozygous (Tgfβ2 +/− ) mice, which have 30% higher nephron number, were relatively protected against development of high blood pressure on a chronic high salt diet compared with wild-type mice. Surprisingly, however, the Tgfβ2 +/− mice did develop increased blood pressures in response to an acute sodium load, suggesting that the benefit conferred by the higher nephron number requires time for adaptation to occur. Early change in sodium diet in itself has been found to have a long-term impact on programming of hypertension in low-birth-weight (LBW) rats. Two studies have found that short-term feeding of a low-salt diet from weaning to 6 weeks of age abrogated, whereas high-salt feeding exacerbated, hypertension at 10 and 51 weeks despite re-institution of normal-salt diet at 6 weeks. The role of sodium intake on long-term renal programming requires further study.
Salt sensitivity therefore does appear to be developmentally programmed. From the GDNF mouse data, filtration surface area may be crucial in determining salt sensitivity but, as discussed previously, is often not reduced initially in the setting of low nephron number. Expression and activity of renal tubule sodium transporters has therefore been investigated. Expression of the Na-K-2Cl (NKCC2) and Na-Cl (NCC) cotransporters was significantly higher in prehypertensive offspring of rats fed a protein-restricted diet during gestation than in controls, although expression of the sodium-hydrogen exchanger isoform 3 (NHE3) and epithelial sodium channel (ENaC) was not changed ( Figure 23.4 A ). Higher activity of NKCC2 was shown by increases in chloride transport and lumen-positive transepithelial potential difference in the medullary thick ascending limb in offspring of protein-restricted or dexamethasone-treated mothers ( Figure 23.4 B ). Furthermore, after development of hypertension, furosemide administration reduced the blood pressure, supporting increased NKCC2 activity as a mediator of hypertension in the protein restriction model. Expression of the glucocorticoid receptor and the glucocorticoid-responsive α 1 – and β 1 -subunits of Na- + K + -adenosine triphosphatase (ATPase) were increased in offspring of pregnant rats fed a low-protein diet. In rats who were suckled by mothers given low-protein feedings during lactation, expression of Na + -K + -ATPase was increased by 40%, but its activity was increased by 300%, demonstrating that expression levels may not fully reflect activity levels. Prenatal dexamethasone administration was associated with increased expression of proximal tubular NHE3 as well as of the more distal NKCC2 and NCC, but there was no change in ENaC expression. Interestingly, renal denervation reduced systolic blood pressure and sodium transporter expression in this model, suggesting indirect regulation of these genes via sympathetic nerve activity. In another study, baseline expression of β– and γ-ENaC, but not α-ENaC, as well as of Na + -K + -ATPase was significantly higher in rats subjected to maternal diabetes than in controls. Despite several studies showing no change in ENaC expression in programmed animals, an enhanced natriuretic response to the ENaC inhibitor benzamil demonstrated increased ENaC activity in offspring of mothers fed a low-protein diet ( Figure 23.4 C ). Taken together, despite differences among models, the data suggest increased sodium transport in all segments of the renal tubule. Whether a reduced nephron number may contribute indirectly to increased sodium transport through increased single-nephron GFR (SNGFR), necessitating glomerulotubular balance or sodium transporter activity is independently programmed has not yet been elucidated.
Renin Angiotensin Aldosterone System
All components of the renin angiotensin aldosterone system (RAAS) are expressed in the developing kidney. Alterations in the RAAS have been studied in various programming models, but a consistent pattern of upregulation or downregulation of RAAS components has not been found. For example, expression of angiotensinogen and renin messenger RNA (mRNA) was decreased in neonatal kidneys of rats subjected to uterine ischemia but increased in the kidneys of mouse offspring of diabetic mothers. Such differences likely also reflect species differences, differences in timing of intervention, timing of study, and so on, as summarized in Table 23.6 . The importance of angiotensin II (Ang II) in nephrogenesis was demonstrated by the administration of the Ang II subtype 1 receptor (AT 1 R) blocker losartan to normal rats during the first 12 days of life (while nephrogenesis is proceeding), which resulted in a reduction in final nephron number and subsequent development of hypertension. Ang II can stimulate the expression of Pax-2 (an anti-apoptotic factor) through AT 2 R. AT 2 R expression, therefore, is likely to affect nephrogenesis and kidney development, but its role in programming is still unclear. Administration of an angiotensin-converting enzyme inhibitor (ACEI), captopril, or losartan to LBW rats from 2 to 4 weeks of age, abrogated the development of adult hypertension in these animals. Similarly, administration of Ang II or an ACEI to adult rats subjected to a low-protein diet in utero resulted in a more exaggerated hypertensive or hypotensive response, respectively, than in control rats. Differential regulation of the RAAS by sex hormones during development is thought to contribute to the observation that the effects of developmental programming are often less severe in young females. Overall, programmed suppression of the intrarenal RAAS during nephrogenesis is likely to contribute to the reduction in nephron number under adverse circumstances, and postnatal upregulation of the AT 1 R, possibly mediated by an increase in glucocorticoid activity or sensitivity, may contribute to the subsequent development of hypertension and glomerular hyperfiltration, as reviewed in detail elsewhere.
| Model | Species | Timing of Insult | Age and Sex of Offspring at Study | mRNA or Protein Expression | Physiologic Response | Reference(s) |
|---|---|---|---|---|---|---|
| Glucocorticoids | Sheep | Early gestation | 40 mo ♀ | ↔ Plasma renin, Ang II or aogen | ↑ Basal MAP, females only | |
| Rat | 6-7 mo ♂♀ | ↔ Renal aogen | ↑ Basal TBP, females only | |||
| ↑ PRA, plasma aogen in females only | ||||||
| Rat | Mid- to late gestation | 6 mo | ↑ Renal ACE and renin in males and females | ND | ||
| Rat | Mid- to late gestation | 4 and 8 wk ♂ | ↔ PRA, plasma Ang II, and renal Ang II levels | ↑ Basal TBP at 8 but not 4 wk of age | ||
| ↑ Urine Ang II at 4 and 8 wk | ||||||
| Maternal nutrient restriction or low-protein diet | Sheep | Early to mid-gestation | 9 mo | ↑ Renal cortical ACE protein | ↑ Basal MAP | |
| ↔ AT 1 R in the renal cortex and medulla | ||||||
| ↔ Renal cortical but ↑ renal medulla AT 2 R | ||||||
| Rat | Mid- to late gestation | 4-12 wk ♂♀ | ↑ PRA | ↑ Basal TBP from 8 wk of age | ||
| Rat | Throughout gestation | 1-5 days and 22 wk ♂ | ↓ Renal renin mRNA and Ang II levels at 1 to 5 days of age | ↑ Basal MAP at 22 wk of age | ||
| ↔ No change GFR or RBF | ||||||
| Rat | Throughout gestation | 16 wk ♂ | ↓ Renal AT 1 R and AT 2 R protein | ↑ Basal TBP, ↓ sodium excretion, ↔ GFR | ||
| Rat | Throughout gestation | 4 wk ♂ | ↑ Renal AT 1 R protein | ↑ Basal MAP (anesthetized) | ||
| ↓ Renal AT 2 R protein | ↑ Basal renal vascular resistance | |||||
| ↑ Ang II receptor binding | ↔ No change GFR or RBF | |||||
| ↔ Renal renin and Ang II tissue levels | ||||||
| Rat | Mid- to late gestation | 1-11 mo ♂♀ | ↑ Basal TBP at 8 wk of age | |||
| 1-2 mo | ↓PRA | Salt-sensitive TBP | ||||
| ↓ Renal AT 1 R protein and mRNA | TBP normalized by ACE inhibition and low-salt diet | |||||
| ↓ Renal AT 2 R protein, ↑ AT 2 R mRNA | Urinary protein/creatinine ratio increased in males only | |||||
| 6 to 11 mo | ↑ PRA | |||||
| ↔ Plasma or renal Ang I and Ang II | ||||||
| ↑ AT 1 R protein and mRNA | ||||||
| ↑ AT 2 R protein, ↔ AT 2 R mRNA | ||||||
| Placental insufficiency | Rat | Late gestation | 0-16 wk ♂ | |||
| Newborn | ↓ renal renin and aogen | ↑ Basal MAP that was abolished by ACEi treatment | ||||
| 16 wk | ↑ Renal renin and aogen mRNA, ↑ ACE activity | ↑ Pressor response to ANG II in presence of ACEi | ||||
| ↔ Renal AT 1 R and Ang II, ↔ PRA and plasma ACE | ↓ GFR | |||||
| Maternal renal hypertension | Rabbit | Throughout gestation | 10-45 wk ♂♀ | ↓ PRA 5 and 10 wk | ↑ Basal MAP at 30 and 45 wk | |
| ↔ PRA 30 and 45 wk |
Underscoring the relevance of the RAAS in developmental programming of blood pressure, Ajala and colleagues found that ACE activity was significantly higher in children of low birth weight than in those with normal birth weight and that there was a greater frequency of the ACE gene DD genotype among LBW children with the highest blood pressures. The latter finding suggests that the programming effect of blood pressure may be modulated in part by ACE gene polymorphisms.
The Sympathetic Nervous System and Renal Vascular Reactivity
Within the kidney, the sympathetic nervous system modulates activity of the RAAS, sodium transport and vascular function, and thereby contributes to blood pressure through regulation of vascular tone and volume status. Development of the renal sympathetic nervous system, and how it may be programmed during nephrogenesis and modulated by the RAAS, is expertly reviewed by Kett and Denton. Renal denervation has been shown to abrogate development of adult hypertension as well as alter sodium transporter expression in the prenatal dexamethasone and uterine ischemia programming models, and the age-associated hypertension that develops in growth-restricted female rats. Consistent with the findings in whole animals, an increase in baseline renal vascular resistance within the kidney has been described in different programming models. For example, Sanders and colleagues reported that renal arterial responses to β-adrenergic stimulation and sensitivity to adenylyl cyclase were increased in 21-day-old growth-restricted offspring subjected to placental insufficiency. Although the renal expression of β 2 -adrenoreceptor mRNA was increased in these pups, there was also evidence of adaptations to the signal transduction pathway that contributed to the β-adrenergic hyperresponsiveness. Intriguingly, these findings were much more marked in the right than in the left kidney, an observation that remains unexplained but that is not without precedent: Asymmetry of renal blood flow was found in 51% of a cohort of hypertensive patients without renovascular disease. In the Sanders study, growth-restricted rats had reduced glomerular numbers, exhibited glomerular hyperfiltration and hyperperfusion, and had significantly increased proteinuria in comparison with the controls, suggesting alteration in glomerular pressures that likely were mediated by renal vasoreactivity. Interestingly, in a cohort of white and black U.S. subjects, the effect of birth weight on subsequent blood pressures was significantly modified by β-adrenergic receptor genotype, further underscoring a relationship among birth weight, sympathetic activity, and blood pressure.
Programming of Renal Function and Disease
In contrast to premature infants or those of low birth weight, in whom nephron numbers have been shown to be reduced, there are no data on nephron numbers in adults who were known to be of low birth weight. The association between nephron number and birth weight and prematurity, however, is a consistent finding in infants, so it seems reasonable to extrapolate that nephron numbers would remain reduced in adults of low birth weight. The determination of nephron number in vivo is not yet reliable enough; therefore, the most utilized in vivo surrogate markers at present are birth weight and prematurity. Importantly, however, in some animal models, low nephron numbers have been observed also in the setting of normal birth weight (see Table 23.4 ); therefore, among humans, if birth weight is the only surrogate marker used, the impact of renal programming on any outcome is likely to be underestimated. Other clinical surrogates for an adverse intrauterine environment and low nephron numbers are outlined in Table 23.7 .
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Experimental Evidence
Glomerulomegaly is consistently observed in the setting of low nephron number (see Figure 23.2 B ). In rats in which low birth weight was induced by maternal protein restriction, GFR was reduced by 10%, although nephron number was reduced by 25%, implying some degree of compensatory hyperfunction per nephron. Although the hyperfunction may be a compensatory mechanism to restore filtration surface area, it is conceivable that renal reserve in these kidneys is reduced. If so, these kidneys may be expected to be less able to compensate further in the setting of additional renal insults and to begin to manifest signs of renal dysfunction (i.e., proteinuria, elevations in serum creatinine, and hypertension). To investigate this hypothesis, diabetes was induced by streptozotocin injection in subgroups of LBW (induced by maternal protein restriction) and normal-birth-weight (NBW) rats. LBW rats had reduced nephron numbers and higher blood pressures compared to NBW rats. Among those rendered diabetic, there was a greater proportional increase in renal size and glomerular hypertrophy in the LBW rats than in NBW controls after 1 week ( Figure 23.5 ). This study demonstrates that the renal response to injury in the setting of a reduced nephron number may be exaggerated and could lead to accelerated loss of renal function.
Subsequently, the same researchers reported outcomes in LBW and NBW diabetic rats at 40 weeks. Histologically, the podocyte density was reduced and the average area covered by each podocyte was greater in the LBW diabetic rats than in the NBW controls. These findings correlated with urine albumin excretion rate, which was higher in LBW diabetic rats, although the difference did not reach statistical significance. In support of the role of altered podocyte physiology in renal disease progression, similar findings were observed in the Munich Wistar Frömter rat, a strain that has congenitally reduced nephron numbers and demonstrates spontaneous renal disease. Whether these podocyte changes are secondary to an increase in glomerular pressure in the setting of reduced nephron numbers or constitute a primary programmed structural change leading to glomerular injury is not yet known. The role of podocyte depletion, either absolute (loss of podocytes) or relative (podocyte density), in disease progression deserves more research focus, and currently nothing is known about the possible effects of developmental programming on podocyte endowment.
Of interest, in contrast, in low-birth-weight rats exposed to prenatal dexamethasone and subsequently fed a high-protein diet, GFR was similar to that in NBW controls. Nephron numbers were reduced by 13% in only male LBW rats. This study may suggest that there is a threshold reduction in nephron number above which compensation is adequate or that the high-protein diet induced supranormal GFRs in both groups, masking subtle differences in baseline GFR. Another study that measured GFR in LBW rats, induced by placental insufficiency, also failed to demonstrate lower GFRs in LBW rats, but they were significantly hypertensive compared with NBW controls. Conceivably, in this study, the higher intra-glomerular pressure due to elevated blood pressure and reduced nephron mass in LBW rats may have led to a compensatory increase in SNGFR and, thus, normalization of whole-kidney GFR.
The definitive pathophysiologic impact of a reduction in nephron number on the development of renal dysfunction is difficult to elucidate from the existing literature, which comprises studies using very varied experimental conditions. Overall, however, it is possible that, although whole-kidney GFR may not change, SNGFR is likely to be increased in the setting of a reduced nephron number and exacerbated in the presence of renal injury. Interestingly, SNGFR was found to be significantly higher in the Munich Wistar Frömter rat, which has reduced nephron numbers and is known to demonstrate spontaneous progressive glomerular injury, than in the control Wistar rat strain. Renal dysfunction may also result from a programmed predisposition to inflammation and scarring that may be independent of glomerular pressures. In a glomerulonephritis model, injection of anti–Thy-1 antibody in LBW rats resulted in significant upregulation of inflammatory markers and development of sclerotic lesions by day 14, but with no difference in blood pressure or proteinuria, in comparison with NBW controls.
Human Evidence
Most human data rely on the surrogates birth weight, prematurity, renal size, and so on to reflect the risk of renal programming. Although there is no direct proven relationship with nephron number, the consistency of the data is strongly suggestive of a programming effect.
Birth Weight, Prematurity, and Blood Pressure
Two meta-analyses and systematic reviews have shown consistent associations of lower birth weight and prematurity with higher blood pressures in later life. Meta-analysis of 27 studies investigating the relationship between birth weight and blood pressure found that systolic blood pressures were 2.28 mm Hg (95% confidence interval [CI], 1.24 to 3.33 mm Hg) higher in subjects with birth weights lower than 2.5 kg than in subjects with birth weights higher than 2.5 kg ( Figure 23.6 A ). Many studies do not discriminate between low birth weight occurring as a result of growth restriction (a marker of intrauterine stress) at any gestational age and that occurring as a result of prematurity with an appropriate (low) weight for that gestational age. Therefore, the relative effect of growth restriction and prematurity on subsequent blood pressures is not always easy to dissect. To investigate this question, a study of 232 50-year-old subjects all born at term, one group with and one group without growth restriction, reported an odds ratio (OR) of 1.9 (95% CI, 1.1 to 3.3) for hypertension among those who had experienced growth restriction in comparison with those who had normal birth weights. Growth restriction before birth per se therefore is associated with subsequent higher blood pressure.
A systematic review of 10 studies comparing premature subjects with those born at term found that in premature subjects, having a mean gestational age of 30.2 weeks and a mean birth weight of 1280 g, systolic blood pressures in later life were 2.5 mm Hg higher (95% CI, 1.7 to 3.3 mm Hg) than in those born at term ( Figure 23.6 B ). Prematurity therefore is also independently associated with higher blood pressure, which in some studies meets the definition of hypertension by 1 to 2 years of age. Whether the risk of higher blood pressure is greater among premature subjects who were born small for gestational age (growth restricted) than in those born appropriate for gestational age is not yet clear, however, with some studies suggesting an additional effect of growth restriction and others not.
Ultimately, the importance of dissecting the risk from low birth weight and that from prematurity may lie in the future potential for prevention. Given that effect estimates for risk of higher blood pressures were similar in the meta-analyses and systematic reviews cited previously, however, at present both conditions must be deemed important risk factors for subsequent high blood pressure.
Importantly, blood pressures of LBW and NBW subjects, although different, may be still within the normal range in childhood, but differences become amplified with age, such that adults who had been of low birth weight often experience overt hypertension that increases with age. Although the majority of studies have been conducted in white populations, generally consistent data are accumulating in other populations. An association of higher blood pressure with lower birth weight in African American children has been reported in some studies, but not all, suggesting that additional factors may contribute to the greater severity of blood pressure in those of African origin. An important effect modifier of the association with low birth weight or prematurity and blood pressure, noted in diverse populations, is current body mass index, which may override an effect of birth weight, especially in children at different stages of growth. Furthermore, in most populations, blood pressures are highest in those born premature or of low birth weight who “catch up” fastest in postnatal weight (i.e. rapid upward crossing of weight percentiles), highlighting the importance of early postnatal nutrition in developmental programming.
Associations between blood pressure and other markers of potential developmental stresses have also been reported. A meta-analysis of 31 studies found that blood pressures were higher in children who had high birth weights but interestingly tended to be lower in high-birth-weight adults, suggesting that age may modify this risk differently from how it does in LBW subjects. Additionally, a systematic review and meta-analysis investigating the impact of a diabetic pregnancy on blood pressure found an overall association with higher blood pressure in offspring aged 2 to 20 years after exposure to diabetes during gestation, but this effect was seen only in males. The researchers did not discuss the potential impact of birth weight in this study, however, and whether these effects may have been modified by high birth weight in offspring is not reported. Another potential risk factor for higher offspring blood pressure is maternal gestational hypertension or preeclampsia. Whether this effect is mediated by the often accompanying fetal growth restriction or prematurity, or whether it is associated with circulating anti-angiogenic factors or other humoral changes in preeclampsia, requires further investigation. Having been born small for gestational age is in turn a risk factor for subsequent development of preeclampsia, emphasizing the far-reaching effects of developmental programming.
Gender differences in programming effects on blood pressure have been inconsistently reported. In some studies programming effects appear more pronounced in males, and in others the differential effects of gender are modified by age of study, ethnicity, and body mass index. In a meta-regression of 20 Nordic cohorts including 183,026 males and 14,928 women, a linear inverse association between birth weight and systolic blood pressure was present across all birth weights in males, which strengthened with age, whereas the relationship was U-shaped in women, with increasing risk also observed with birth weights above 4 kg. Potential mechanisms whereby developmental programming may be expressed differently in males and females are discussed later in this chapter and are reviewed in detail elsewhere.
The relative importance of genetics and environmental factors in programming of blood pressure has been studied in twins. In a large Swedish cohort of 16,265 twins, the overall adjusted OR for hypertension was 1.42 (95% CI, 1.25 to 1.62) for each 500-g decrease in birth weight. Consistently, within like-sexed twin pairs, the ORs were 1.43 (95% CI, 1.07 to 1.69) and 1.74 (95% CI, 1.13 to 2.70) for dizygotic and monozygotic pairs, respectively, suggesting that environmental factors that contributed to differences in birth weight had a greater impact than genetics in this cohort, a suggestion consistent with a developmental programming effect.
Nephron Number and Blood Pressure
In support of the potential association of nephron number and hypertension, a study of whites aged 35 to 59 years who died in accidents found that in 10 subjects with a history of essential hypertension the number of glomeruli per kidney was significantly lower, and glomerular volume significantly higher, than in 10 normotensive matched controls ( Figure 23.7 ). Birth weights were not reported in this study, but the investigators concluded that a reduced nephron number is associated with susceptibility to essential hypertension. Similarly, among a subset of 63 subjects in whom mean arterial pressures and birth weights were available, Hughson and coworkers reported a significant correlation between birth weight and glomerular number, mean arterial pressure and glomerular number as well as mean arterial pressure and birth weight among the white but not African American subjects. Among African Americans having nephron numbers below the mean, however, twice as many were hypertensive as normotensive, suggesting a possible contribution of lower nephron number in this group as well. The relationship of low birth weight and nephron number was similar in a study of black and white Cuban neonates ; therefore, it is expected that a similar relationship between low birth weight and low nephron number exists in the black population. Glomerular volumes were found to be higher among the hypertensive African American subjects than in the hypertensive whites. The consistent finding of larger glomeruli among African Americans suggests either a greater prevalence of low nephron number in this population as a result of higher prevalence of low birth weight or independent or additional programming of glomerular size. This topic warrants further research attention, especially in light of the discovery of the APOL1 gene association with kidney disease among African Americans.
