CJASN
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published ahead of print on February 14, 2007
Clin J Am Soc Nephrol 2: 334-342, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.03291006
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
CJN.03291006v1
2/2/334    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hershkovitz, D.
Right arrow Articles by Brenner, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hershkovitz, D.
Right arrow Articles by Brenner, B. M.

In-Depth Reviews

Fetal Programming of Adult Kidney Disease: Cellular and Molecular Mechanisms

Dov Hershkovitz*, Zvi Burbea{dagger}, Karl Skorecki*,{dagger},{ddagger}, and Barry M. Brenner§

* Laboratory of Molecular Medicine and {dagger} Department of Nephrology, Rambam Health Care Campus, and {ddagger} Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology, Haifa, Israel; and § Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Karl Skorecki, Department of Medical and Research Development, Rambam Medical Center, Haifa, Israel 31096. Phone: +972-4-8543250; Fax: +972-4-8542333; E-mail: skorecki{at}technion.ac.il


   Introduction
Top
 Introduction
Definition of LBW
 Mechanisms
 Conclusion
 Disclosures
 References
 
The role of the kidney in the pathogenesis of hypertension has long been established, although recent studies challenge renal hegemony and suggest an important role for vascular cells as well (1,2). In recent years, the formulation has expanded and now includes the concept that chronic hypertension and kidney disease are also related to events that occur during the prenatal period and usually result in low birth weight (LBW).

A recent overview considered the role of fetal programming in the development of adult kidney disease and hypertension (3). The aim of this review is to present further evidence to support an association between LBW and the increased prevalence of hypertension as well as progression toward chronic kidney disease (CKD) in adult life. Various potential mechanisms for this association are discussed, specifically the low nephron number (LNN) hypothesis and related cellular and molecular mechanisms that have been proposed.


   Definition of LBW
Top
 Introduction
 Definition of LBW
Mechanisms
 Conclusion
 Disclosures
 References
 
LBW infants are defined as infants who weigh ≤2500 g at birth. Infants who are delivered before 37 wk from the first day of the last menstrual period are termed preterm. The LBW infant population can be divided into preterm, appropriate for gestational age (AGA), or small for gestational age (SGA). The predominant cause of LBW infants in the United States is preterm birth, whereas in developing countries, the cause is often intrauterine growth restriction (IUGR). During the year 2004, 8.1% of births in the United States were LBW, and more than half of these were preterm. During the past two decades, there has been an increase in the prevalence of LBW as higher risk pregnancies progress to term and postnatal survival improves (4) (Figure 1).


Figure 1
View larger version (25K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 1. Percentage of infants who were born preterm and percentage who were born with low birth weight (LBW; defined in text): United States, 1990, 1995, 2000, and 2004. Adapted from Hamilton et al. (4).

 
Association between LBW and Adult Disease
The size that the fetus can attain depends on the maternal–fetal nutrient supply and the space that the maternal environment can provide (5). Low maternal socioeconomic status and poor maternal nutritional status will reduce nutrient supply to the developing fetus. Similarly, factors that frustrate the passage of nutrients through the placenta, such as smoking and hypertension, are associated with increased risk for LBW. Factors that affect intrauterine space availability, such as primiparity, low maternal height, and mothers who were born SGA, are additional risk factors for LBW. Nearly two decades ago, Barker (6) presented the theory of the fetal origins of adult diseases. The theory is based on observed epidemiologic associations between LBW and increased risk for ischemic heart disease, type 2 diabetes, and hypertension (7–9).

The first associations found were between LBW and later life hypertension and cardiovascular disease (7,10,11). High BP was found to occur at a higher incidence in children and adults who were of LBW (11). A systematic review of 80 studies that described the relationship of BP with birth weight reported that systolic BP was lower by approximately 2 mmHg for every 1-kg increase in birth weight (12). Among Pima Indians, patients who had type 2 diabetes and a history of LBW also displayed an increased risk for developing diabetic nephropathy (13). Moreover, LBW is associated with more rapid progression of other kidney diseases, such as IgA nephropathy, membranous nephropathy, and minimal-change disease, suggesting that the kidneys of LBW infants are more vulnerable to future insults (14–16).

Nevertheless, the strength of association between birth weight and subsequent hypertension remains widely debated. Several studies did not find an association (17,18). Moreover, others claim that the suggested association is the result of inadequate or inappropriate adjustments for confounding factors (19,20). For example, Huxley et al. (19) found a trend toward a weaker association between LBW and hypertension in larger compared with smaller studies. However, it seems that although the relation is not invariant, the totality of evidence does suggest an important direct or indirect interaction between birth weight and subsequent hypertension (21).

These observations have led to the formulation of an important conceptual construct that pertains to the fetal origins of adult disease. This theory states that during development, body organs pass through a period of plasticity and sensitivity to the environment, which leaves a durable imprint that affects subsequent health. Suboptimal intrauterine conditions may result in impaired fetal growth and the production of phenotypes that are better matched to the inadequate intrauterine environment. These adaptive processes are aimed to increase the likelihood of survival in utero and after birth, with expected continuation of borderline or inadequate environmental conditions. However, this response may result in adverse long-term consequences later in life (e.g., hypertension, renal disease, glucose intolerance), especially when the postnatal environment affords more favorable growth conditions to those that were experienced in utero.

One of the most studied aspects with regard to Barker’s theory has been the fetal origins of adult diabetes. Numerous reports have demonstrated an association between LBW and subsequent development of pancreatic endocrine insufficiency and type 2 diabetes in experimental animals and humans (9,22–28). Of particular notice is the role of rapid weight gain in early childhood, or "catch-up" growth, which was shown to encompass a significant risk for subsequent metabolic derangements in adult life (29–32). Type 2 diabetes has now emerged as the leading cause of kidney disease in the world. Accordingly, it is important to consider the relation between LBW and type 2 diabetes as a cause of CKD. However, a detailed consideration of the relationship between LBW and type 2 diabetes is beyond the scope of this review.

LBW and LNN
Beyond the connection with type 2 diabetes and hence diabetic nephropathy, the contribution of various additional factors has been invoked to explain the apparent greater risk and more rapid progression of adult kidney disease and the higher incidence of hypertension as a result of LBW. Among these, the major focus of attention has been on the role of LNN (33,34). LBW has been associated with LNN in human and animal studies. The induction of IUGR by restriction of protein in the diet resulted in reduced nephron number and impaired renal function in rats (35,36). Nephron number and GFR were significantly lower, even after correction for body weight, in piglets with IUGR compared with those with normal weight (37). Reduced nephron number has been achieved using other experimental models of LBW, such as calorie restriction and partial ligation of the uterine artery (38–41). Reduced glomerular number and function were found in spontaneous LBW as well as induced LBW in a rat model (42).

The findings in the animal models accord well with data from human studies. Hinchcliffe et al. (43) examined nephron number of stillborns and infants who died within 1 yr of birth and found that nephron number was significantly lower in the infants with IUGR compared with the AGA infants. A more recent study examined the kidneys of neonates in relation to their birth weight and found a lower nephron number and an increased glomerular volume in the growth-restricted group (44). A similar correlation was found in adults (45), and these correlations were found to be independent of gender (46). A significant correlation between birth weight and nephron number has been reported in white Americans, whereas no such correlation could be demonstrated for black Americans, although the study may not have been sufficiently powered to achieve statistical significance (47). In adult aboriginal Australians, a population with a high prevalence of LBW and kidney disease, fewer glomeruli and larger mean glomerular volume were found compared with the non-aboriginal Australian population. Glomerular number correlated with adult height, suggesting a relationship with birth weight (48). It should be noted that normal birth weight does not automatically suggest a normal nephron number, and some individuals with normal birth weight may have a low or suboptimal nephron number (silent nephron deficit) (49).

Ultrasound studies that examined the fetal kidney have supported the findings in the aforementioned histologic studies. Konje et al. (50) reported that during the third trimester, the fetal renal growth in SGA fetuses was slower and resulted in thinner kidneys of normal length, compared with AGA kidneys. This might suggest impairment of nephron number. LBW has also been associated with renal functional deficits. Studies of the Australian aboriginal community indicated that the urinary albumin-to-creatinine ratio is inversely related to birth weight (51).

Why Would LBW Infants Have LNN?
The relation between birth weight and hypertension may be the result of fetoplacental, maternal, or genetic factors. A twin study of 653 individuals found that the relationship is due mainly to fetoplacental factors and that genetic and maternal factors play a minor role (52). Similarly, in a cohort of female twin pairs, the differences in BP were suggested to result from delayed intrauterine growth (53). Other twin studies, however, have indicated an important contribution of genetic factors to adult hypertension in the LBW setting (54,55). A recent study sought to distinguish between the effects on kidney growth of preterm birth versus the SGA state. It was found that weight for gestational age is an important determinant of kidney size at birth and at 18 mo of age. The authors suggested that weight for gestational age rather than birth weight should be used in analysis of the impact of fetal growth on renal function (56). Similarly, in a study of 422 individuals who were 19 yr of age and were born preterm (<32 wk), birth weight was related to renal outcome. However, no convincing relation between gestational age and renal function was found, suggesting again that the important determinant of kidney function is the extent of IUGR (57).

The most prevalent animal models for LBW-induced adult disease are protein and calorie restriction. The "life history theory" states that if the total amount of energy to an animal is limited, then increased allocation of energy to one organ system must reduce allocation to one or more other organ systems (58). For example, the undernourished fetus protects its brain development by diverting more blood to the brain at the expense of blood supply to other organ systems. Lesser growth of the kidney, for example, might be a "trade off" to protect brain growth. Several cellular and molecular mechanisms have been suggested as contributing to the consequent impaired nephrogenesis.


   Mechanisms
Top
 Introduction
 Definition of LBW
 Mechanisms
Conclusion
 Disclosures
 References
 
Role of Telomere Integrity and Renal Cell Turnover
The ends of linear chromosomes are capped by complex nuclear protein structures, which include stretches of repetitive DNA sequences (TTAGGG)n, known as telomeres (59). Human telomeres shorten with each round of cell division, through various mechanisms, in a process that might have an important role in cellular senescence and organism aging (60). The starting telomere length after conception in humans is usually in the range of 12 to 15 MB (61). Replicative arrest is associated with telomere shortening to approximately 2 to 5 kB, for at least one or more chromosomes. In the absence of telomerase, abnormalities in DNA replication or sister chromatid separation are among the mechanisms that have been implicated to compromise genomic integrity in senescent cells with short telomeres (62). Most organ systems undergo continuous cellular turnover in health, and this process is often accelerated as part of the response to injury. It is postulated that a subset of cells (referred to as adult or tissue stem cells) may be retained in the postnatal state for this purpose. Accordingly, lifelong organ system maintenance depends on the number of renal cell divisions that are required during fetal organ development and growth, subsequent cellular turnover in health and disease, the rate of telomere shortening, and the action of mechanisms to preserve or restore telomere length/integrity. These factors are organ system and life history specific and expected to be markedly affected by intrauterine growth and subsequent postnatal catch-up growth. Indeed, after IUGR, longevity was reduced in male rats that experienced postnatal catch-up growth, compared with those that did not. Examination of telomeres correspondingly revealed shorter telomere lengths in the latter group (63,64). Renal catch-up growth with accelerated body growth involves both hyperplasia and hypertrophy. Each of these processes might be expected to have different effects on subsequent telomere integrity and cellular longevity. In particular, hyperplasia in the absence of telomerase might exhaust telomere length capacity in a subset of the renal cell population that contributes to organ maintenance. In such a situation, availability of a pool of cells for maintenance or for postinjury renal cellular turnover would be limited in kidneys that have already exhausted telomere capacity during a past period of catch-up growth (Figure 2). Although we would not expect significantly shorter telomeres in LBW infants, as has been reported (65), it would be of interest to follow telomere length longitudinally in LBW infants who have experienced catch-up growth in comparison with control counterparts. We would expect reduced telomere length (and hence limited subsequent replicative capacity) after a period of catch-up growth. A number of additional theories that relate telomere shortening to aspects of abnormal cellular physiology, which might be of relevance to renal function, have been proposed; among these are modulation of gene expression in subtelomeric regions, including genes that are involved in sodium transport and excretion (66).


Figure 2
View larger version (54K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 2. Role of telomere integrity. During normal development, initial telomere length and telomere maintenance mechanisms allow sufficient cell divisions to enable subsequent postnatal organ system cellular integrity. In LBW infants, however, a period of postnatal "catch-up" growth may be associated with telomere shortening, thereby requiring the recruitment and hence premature exhaustion of renal stem or progenitor cells (white circles). Consequently, the ability of the kidney to mount a cellular turnover response after injury may be compromised and render such individuals more susceptible to nephron attrition.

 
Additional Mechanisms in the Regulation of Nephron Cell Mass
The cellular mass of organ systems during development depends on a careful balance between cell proliferation and apoptosis. In animal models, IUGR was associated with evidence of higher levels of renal cellular apoptosis. Rat offspring that were born to a mother that was supplied a low-protein diet during pregnancy had fewer glomeruli than normal. Molecular and morphologic analysis found increased metanephric apoptosis in the group with IUGR. The authors suggested that fewer glomeruli were the result of increased apoptosis, leading to a reduction in renal progenitor cells (67). Several molecular mechanisms have been proposed for IUGR-induced renal cellular apoptosis.

The renin-angiotensin system (RAS) and the paired homeobox 2 gene (Pax-2) are critical factors in nephrogenesis (68–70). Angiotensin II was shown to increase Pax-2 gene expression, a process that might be important in renal development and repair. In rats with IUGR, the RAS is downregulated, leading to reduced Pax-2 expression, thereby causing a shift from proliferation toward apoptosis and resulting in LNN (71).

Bilateral partial ligation of the uterine arteries of the pregnant rat, another model for IUGR, resulted in reduced nephron number and an increase in apoptosis in the kidneys of juvenile rats. In this study, IUGR caused the increased expression of proapoptotic factors such as p53 and Bax. In the case of p53, this occurred through hypomethylation of the promoter. In addition, heightened p53 activity induced the downregulation of antiapoptotic factors, such as Bcl-2. As a consequence, an increase in the ratio between proapoptotic and antiapoptotic factors promotes renal cellular apoptosis, possibly leading to LNN in the offspring (72).

Mechanisms that involve mitochondria have also been postulated in the relationship among LBW, LNN, and adult disease. Mitochondrial dysfunction can give rise to abnormalities in any organ or tissue (73). In the kidneys, mitochondrial DNA (mtDNA) mutations have been associated with hypertension and ESRD (74,75). A mitochondrial gene variant was found to be more prevalent in a cohort of 58 black individuals with hypertension-associated ESRD compared with 58 normotensive individuals (74). Other mitochondrial mutations have been associated with hypertension and renal pathologies (75). In rats, IUGR may cause mitochondrial dysfunction. Protein malnutrition in utero causes changes in mtDNA content, impaired ß cell development, and a reduced insulin secretory response to glucose (76). In addition, partial ligation of both uterine arteries resulted in increased accumulation of mtDNA mutations and reduced mitochondrial activity in the pancreatic ß cells of offspring. The deterioration in mitochondrial function leads to a decline in ß cell function and the development of diabetes (77). Uteroplacental insufficiency was also shown to cause reduced mtDNA and mitochondrial protein production in the brain of juvenile rats (78). In another IUGR model, protein malnutrition in fetal life resulted in reduced mtDNA content in liver and skeletal muscle (79). Therefore, it seems likely, as has been shown in the case of pancreatic ß cells, that mtDNA mutations and mitochondrial dysfunction might play a role in the development of LNN in the kidney with IUGR, leading to the subsequent emergence of hypertension and kidney disease.

The predominant cause of LBW in the United States is preterm birth. Nephron development in humans begins in the ninth week of gestation and ceases during the 36th week. During the last trimester, there is a rapid rise in nephron number (80). A histomorphometric analysis of 56 extremely preterm infants demonstrated postnatal nephrogenesis. However, fewer glomeruli were generated, and glomerulogenesis ceased after 40 d. Moreover, it was noted that renal failure caused further inhibition of kidney development (81). Therefore, it is tempting to postulate that the extremely preterm infant will not experience an equivalent degree of kidney growth ex utero as compared with in utero and that this by itself would be a cause of LNN. However, as stated earlier, weight for gestational age rather than gestational age per se has been found to be associated with kidney function.

LNN as an Important Determinant of Hypertension and CKD
LNN is associated with an increased risk for hypertension and renal disease, an effect whose pathogenesis is attributed at least in part to glomerular hyperfiltration and/or hypertrophy (82). With reduced nephron mass, the remaining nephrons adapt and undergo hypertrophy to minimize the overall loss of function. Consequently, hyperfiltration occurs in each of the remaining nephrons to compensate for reduced nephron mass and function. This hyperfiltration has pathophysiologic implications: The glomeruli function under increased intracapillary hydraulic pressure, which over time damages the capillary walls. These abnormal conditions have been shown to lead to the development of proteinuria, FSGS, and a progressive decline in the GFR (82).

The postmortem quantitative analytical examination of kidneys of accident victims found that those with hypertension had fewer glomeruli and greater glomerular volume than those of matched normotensive controls (47,83). In animal models, lower renal mass has also been associated with a larger increment in BP in response to increased daily salt intake (84). In genetic models of hypertension in rats, diminished nephron endowment has been associated with hypertension and an increased tendency toward glomerulosclerosis (85–88).

Clinical support for the impact of LNN on future risk for hypertension and renal disease can also be deduced from studies of patients with solitary kidneys. In patients with a single kidney, as a result of either unilateral agenesis or nephrectomy, the incidence of proteinuria (>300 mg/24 h), hypertension, and chronic renal failure was significantly increased compared with control subjects (89–91). Reduced nephron number in the transplanted solitary kidney may likewise play a role in chronic allograft failure, especially when donor nephron number is not appropriately matched to the recipient. In support of this formulation is the finding that the frequency of graft loss 3 yr after transplantation was higher when the donors were women, individuals of African ancestry, or of age <3 or >61 yr (92). In a study of 31,515 cadaveric kidney transplant recipients, graft failure was significantly associated with donor age, gender, and population ancestry and recipient body surface area (93). Transplants into recipients who weighed >100 kg was associated with lower 1- and 3-yr graft survival rates (94). The findings are supported by animal studies that demonstrated the importance of nephron mass in the development of chronic allograft nephropathy (95–99).

The foregoing suggests that factors that are associated with lower donor nephron mass (child or elder donor, female to male) or increased recipient needs (obese recipients) play a significant role in kidney transplant loss. Furthermore, these findings indicate that the number of viable nephrons (i.e., "nephron dose") is an important determinant of renal survival in both transplanted and native kidneys. Unfortunately, this consideration has not been granted sufficient attention in setting kidney transplantation policy and practice guidelines.

The increased prevalence of CKD and hypertension in adults who are born at LBW can be explained by understanding the concepts of the developmental origins of adult chronic disease. The LBW infant begins life at a renal disadvantage, as a result of LNN. This individual is then vulnerable to developing overt nephropathy in the event of postnatal "second hits," such as diabetes or other forms of renal injury. Combined with nephron "overload" that is expected during catch-up growth, the risk for progression of these renal injury states toward CKD is enhanced (Figure 3).


Figure 3
View larger version (38K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 3. LBW and progression toward adult kidney disease. An unfavorable intrauterine environment results in the induction of fetal adaptive processes described in the text, at the cost of a reduced nephron number. The consequence is adult hypertension and the progression toward ESRD, if second hits such as diabetes, IgA nephropathy, pyelonephritis, and nephrotoxic exposure supervene.

 
Additional Mechanisms for LBW-Related Hypertension
Additional mechanisms have been studied in terms of the relationship between LBW and adult kidney disease and hypertension. Endocrine mechanisms have been proposed to be involved in the intrauterine programming of adult hypertension and renal disease. A number of hormones have an essential role in the regulation of fetal growth and fetal tissue development (100). Spontaneous and experimentally induced IUGR have been shown to induce postnatal changes in hormonal regulation. Of the hormones that are known to be involved in fetal development, the glucocorticoids are the most likely to cause tissue programming in utero (101). Reduced fetal nutrient availability increases levels of glucocorticoids, which may induce endocrine changes with long-term consequences on tissue growth and development. Maternal exposure to glucocorticoids during pregnancy caused hypertension and insulin resistance in the offspring rat and sheep models (102–105). The hypertensive effect of in utero glucocorticoids may be the result of cellular and molecular changes in various tissues. For example, in sheep, glucocorticoids induce functional changes in the kidneys and the brain by altering the expression of ion transporters and components of the RAS (104,106,107). Glucocorticoids and other hormones have a key role in regulating intrauterine development and therefore may significantly influence the evolution of adult disease.

Another possible mechanism involves the inappropriate retention of sodium. The maternal protein restriction model for IUGR in rats resulted in upregulation of two critical Na transporters. The Na-K-2Cl and the Na-Cl co-transporters but neither the Na/H nor the Na channel was significantly increased in the rats with IUGR (108). In addition, expression of the glucocorticoid receptor, as well as {alpha}1 and ß1 subunits of Na-K ATPase, was found to be increased after maternal protein restriction (109). These alterations lead to a lower rate of urinary sodium excretion with attendant sodium retention and hypertension.


   Conclusion
Top
 Introduction
 Definition of LBW
 Mechanisms
 Conclusion
Disclosures
 References
 
The increasing prevalence of patients with CKD at all stages presents a significant challenge to population health worldwide. Primary and secondary prevention measures have demonstrated beneficial effects when targeted to "high risk" groups (110,111). LBW is a risk factor whose prevalence and importance are also increasing. The LBW infant may have experienced during pregnancy significant obstacles that the embryo confronted during development, and success in overcoming these challenges may have untoward consequences in adult life.

Animal and human studies have shown impaired kidney maturation (LNN), "endocrine programming," and telomere-limited exhaustion of progenitor pools for cell turnover to be key factors in the development of adult disease in LBW infants. Various genetic and hormonal factors are altered as the fetus adapts to an unfavorable intrauterine environment. Among these are key regulators of nephrogenesis and nephron size. These adjustments result in the development of kidneys whose long-term integrity is compromised.

As indicated, LBW followed by catch-up growth is associated with adult hypertension and renal disease. Keeping in mind the importance of LBW and IUGR as risk factors for the development of hypertension and adult kidney disease, it is of utmost importance to follow these LBW patients longitudinally over time and try to reduce disease incidence.

It is said that "a very long journey begins with a small step." In the journey of life, special attention should be given to those who began with too small a step so that we can help them have a healthier journey.


   Disclosures
Top
 Introduction
 Definition of LBW
 Mechanisms
 Conclusion
 Disclosures
References
 
None.


   Acknowledgments
 
We acknowledge the support of the Barrie and Carol Rose Fund of the Canadian Technion Society for generous support.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received October 2, 2006. Accepted December 26, 2006.


   References
Top
 Introduction
 Definition of LBW
 Mechanisms
 Conclusion
 Disclosures
 References
 

  1. Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R, Flannery PJ, Spurney RF, Kim HS, Smithies O, Le TH, Coffman TM: Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest115 :1092 –1099,2005[CrossRef][Medline]
  2. Mendelsohn ME: In hypertension, the kidney is not always the heart of the matter. J Clin Invest115 :840 –844,2005[CrossRef][Medline]
  3. Zandi-Nejad K, Luyckx VA, Brenner BM: Adult hypertension and kidney disease: The role of fetal programming. Hypertension47 :502 –508,2006[Abstract/Free Full Text]
  4. Hamilton BE, Martin JA, Ventura SJ, Sutton PD, Menacker F: Births: Preliminary data for 2004. Natl Vital Stat Rep54 :1 –17,2005[Medline]
  5. McCance RA: Food, growth, and time. Lancet2 :671 –676,1962[Medline]
  6. Barker DJ: The fetal and infant origins of adult disease. BMJ301 :1111 ,1990[Medline]
  7. Barker DJ, Osmond C: Low birth weight and hypertension. BMJ297 :134 –135,1988[Medline]
  8. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ: Weight in infancy and death from ischaemic heart disease. Lancet2 :577 –580,1989[Medline]
  9. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD: Fetal and infant growth and impaired glucose tolerance at age 64. BMJ303 :1019 –1022,1991[Medline]
  10. Wadsworth ME, Cripps HA, Midwinter RE, Colley JR: Blood pressure in a national birth cohort at the age of 36 related to social and familial factors, smoking, and body mass. BMJ (Clin Res Ed)291 :1534 –1538,1985[Medline]
  11. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME: Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ298 :564 –567,1989[Medline]
  12. Huxley RR, Shiell AW, Law CM: The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: A systematic review of the literature. J Hypertens18 :815 –831,2000[CrossRef][Medline]
  13. Nelson RG, Morgenstern H, Bennett PH: Birth weight and renal disease in Pima Indians with type 2 diabetes mellitus. Am J Epidemiol148 :650 –656,1998[Abstract/Free Full Text]
  14. Duncan RC, Bass PS, Garrett PJ, Dathan JR: Weight at birth and other factors influencing progression of idiopathic membranous nephropathy. Nephrol Dial Transplant9 :875 ,1994[Medline]
  15. Zidar N, Avgustin Cavic M, Kenda RB, Ferluga D: Unfavorable course of minimal change nephrotic syndrome in children with intrauterine growth retardation. Kidney Int54 :1320 –1323,1998[CrossRef][Medline]
  16. Zidar N, Cavic MA, Kenda RB, Koselj M, Ferluga D: Effect of intrauterine growth retardation on the clinical course and prognosis of IgA glomerulonephritis in children. Nephron79 :28 –32,1998[CrossRef][Medline]
  17. Falkner B, Hulman S, Kushner H: Effect of birth weight on blood pressure and body size in early adolescence. Hypertension43 :203 –207,2004[Abstract/Free Full Text]
  18. Stanner SA, Bulmer K, Andres C, Lantseva OE, Borodina V, Poteen VV, Yudkin JS: Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. BMJ315 :1342 –1348,1997[Abstract/Free Full Text]
  19. Huxley R, Neil A, Collins R: Unravelling the fetal origins hypothesis: Is there really an inverse association between birthweight and subsequent blood pressure? Lancet360 :659 –665,2002[CrossRef][Medline]
  20. Tu YK, West R, Ellison GT, Gilthorpe MS: Why evidence for the fetal origins of adult disease might be a statistical artifact: The "reversal paradox" for the relation between birth weight and blood pressure in later life. Am J Epidemiol161 :27 –32,2005[Abstract/Free Full Text]
  21. Barker DJ, Bagby SP: Developmental antecedents of cardiovascular disease: A historical perspective. J Am Soc Nephrol16 :2537 –2544,2005[Abstract/Free Full Text]
  22. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ: Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation94 :3246 –3250,1996[Abstract/Free Full Text]
  23. Dahri S, Reusens B, Remacle C, Hoet JJ: Nutritional influences on pancreatic development and potential links with non-insulin-dependent diabetes. Proc Nutr Soc54 :345 –356,1995[CrossRef][Medline]
  24. Langley SC, Browne RF, Jackson AA: Altered glucose tolerance in rats exposed to maternal low protein diets in utero. Comp Biochem Physiol Physiol109 :223 –229,1994[Medline]
  25. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA: Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. BMJ312 :406 –410,1996[Abstract/Free Full Text]
  26. Phillips DI: Insulin resistance as a programmed response to fetal undernutrition. Diabetologia39 :1119 –1122,1996[Medline]
  27. Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark PM: Fetal growth and impaired glucose tolerance in men and women. Diabetologia36 :225 –228,1993[CrossRef][Medline]
  28. Whincup PH, Cook DG, Adshead F, Taylor SJ, Walker M, Papacosta O, Alberti KG: Childhood size is more strongly related than size at birth to glucose and insulin levels in 10–11-year-old children. Diabetologia40 :319 –326,1997[CrossRef][Medline]
  29. Barker DJ, Eriksson JG, Forsen T, Osmond C: Fetal origins of adult disease: Strength of effects and biological basis. Int J Epidemiol31 :1235 –1239,2002[Abstract/Free Full Text]
  30. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ: Early growth and coronary heart disease in later life: Longitudinal study. BMJ322 :949 –953,2001[Abstract/Free Full Text]
  31. Eriksson JG, Forsen TJ, Osmond C, Barker DJ: Pathways of infant and childhood growth that lead to type 2 diabetes. Diabetes Care26 :3006 –3010,2003[Abstract/Free Full Text]
  32. Forsen T, Eriksson J, Tuomilehto J, Reunanen A, Osmond C, Barker D: The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med133 :176 –182,2000[Abstract/Free Full Text]
  33. Brenner BM, Chertow GM: Congenital oligonephropathy: An inborn cause of adult hypertension and progressive renal injury? Curr Opin Nephrol Hypertens2 :691 –695,1993[Medline]
  34. Brenner BM, Garcia DL, Anderson S: Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens1 :335 –347,1988[Medline]
  35. Zeman FJ: Effects of maternal protein restriction on the kidney of the newborn young of rats. J Nutr94 :111 –116,1968[Abstract/Free Full Text]
  36. Woods LL, Weeks DA, Rasch R: Programming of adult blood pressure by maternal protein restriction: Role of nephrogenesis. Kidney Int65 :1339 –1348,2004[CrossRef][Medline]
  37. Bauer R, Walter B, Bauer K, Klupsch R, Patt S, Zwiener U: Intrauterine growth restriction reduces nephron number and renal excretory function in newborn piglets. Acta Physiol Scand176 :83 –90,2002[CrossRef][Medline]
  38. Almeida JR, Mandarim-de-Lacerda CA: Maternal gestational protein-calorie restriction decreases the number of glomeruli and causes glomerular hypertrophy in adult hypertensive rats. Am J Obstet Gynecol192 :945 –951,2005[CrossRef][Medline]
  39. Merlet-Benichou C, Gilbert T, Muffat-Joly M, Lelievre-Pegorier M, Leroy B: Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatr Nephrol8 :175 –180,1994[CrossRef][Medline]
  40. Sanders MW, Fazzi GE, Janssen GM, de Leeuw PW, Blanco CE, De Mey JG: Reduced uteroplacental blood flow alters renal arterial reactivity and glomerular properties in the rat offspring. Hypertension43 :1283 –1289,2004[Abstract/Free Full Text]
  41. Lucas SR, Costa Silva VL, Miraglia SM, Zaladek Gil F: Functional and morphometric evaluation of offspring kidney after intrauterine undernutrition. Pediatr Nephrol11 :719 –723,1997[CrossRef][Medline]
  42. Schreuder MF, Nyengaard JR, Fodor M, van Wijk JA, Delemarre-van de Waal HA: Glomerular number and function are influenced by spontaneous and induced low birth weight in rats. J Am Soc Nephrol16 :2913 –2919,2005[Abstract/Free Full Text]
  43. Hinchliffe SA, Lynch MR, Sargent PH, Howard CV, Van Velzen D: The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol99 :296 –301,1992[Medline]
  44. Manalich R, Reyes L, Herrera M, Melendi C, Fundora I: Relationship between weight at birth and the number and size of renal glomeruli in humans: A histomorphometric study. Kidney Int58 :770 –773,2000[CrossRef][Medline]
  45. Pesce C, Schmidt K, Fogo A: Glomerular size and the incidence of renal disease in African Americans and Caucasians. J Nephrol7 :355 –358,1994
  46. Hughson M, Farris AB 3rd, Douglas-Denton R, Hoy WE, Bertram JF: Glomerular number and size in autopsy kidneys: The relationship to birth weight. Kidney Int63 :2113 –2122,2003[CrossRef][Medline]
  47. Hughson MD, Douglas-Denton R, Bertram JF, Hoy WE: Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int69 :671 –678,2006[CrossRef][Medline]
  48. Hoy WE, Hughson MD, Singh GR, Douglas-Denton R, Bertram JF: Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for renal disease and hypertension. Kidney Int70 :104 –110,2006[CrossRef][Medline]
  49. Merlet-Benichou C, Gilbert T, Vilar J, Moreau E, Freund N, Lelievre-Pegorier M: Nephron number: Variability is the rule. Causes and consequences. Lab Invest79 :515 –527,1999[Medline]
  50. Konje JC, Bell SC, Morton JJ, de Chazal R, Taylor DJ: Human fetal kidney morphometry during gestation and the relationship between weight, kidney morphometry and plasma active renin concentration at birth. Clin Sci (Lond)91 :169 –175,1996[Medline]
  51. Hoy WE, Mathews JD, McCredie DA, Pugsley DJ, Hayhurst BG, Rees M, Kile E, Walker KA, Wang Z: The multidimensional nature of renal disease: Rates and associations of albuminuria in an Australian Aboriginal community. Kidney Int54 :1296 –1304,1998[CrossRef][Medline]
  52. Gielen M, Pinto-Sietsma SJ, Zeegers MP, Loos RJ, Fagard R, de Leeuw PW, Beunen G, Derom C, Vlietinck R: Birth weight and creatinine clearance in young adult twins: Influence of genetic, prenatal, and maternal factors. J Am Soc Nephrol16 :2471 –2476,2005[Abstract/Free Full Text]
  53. Poulter NR, Chang CL, MacGregor AJ, Snieder H, Spector TD: Association between birth weight and adult blood pressure in twins: Historical cohort study. BMJ319 :1330 –1333,1999[Abstract/Free Full Text]
  54. Christensen K, Stovring H, McGue M: Do genetic factors contribute to the association between birth weight and blood pressure? J Epidemiol Community Health55 :583 –587,2001[Abstract/Free Full Text]
  55. RG IJ, Stehouwer CD, Boomsma DI: Evidence for genetic factors explaining the birth weight-blood pressure relation. Analysis in twins. Hypertension36 :1008 –1012,2000[Abstract/Free Full Text]
  56. Schmidt IM, Chellakooty M, Boisen KA, Damgaard IN, Mau Kai C, Olgaard K, Main KM: Impaired kidney growth in low-birth-weight children: Distinct effects of maturity and weight for gestational age. Kidney Int68 :731 –740,2005[CrossRef][Medline]
  57. Keijzer-Veen MG, Schrevel M, Finken MJ, Dekker FW, Nauta J, Hille ET, Frolich M, van der Heijden BJ: Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. J Am Soc Nephrol16 :2762 –2768,2005[Abstract/Free Full Text]
  58. Barker DJ: Developmental origins of adult health and disease. J Epidemiol Community Health58 :114 –115,2004[Abstract/Free Full Text]
  59. Harley CB, Futcher AB, Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature345 :458 –460,1990[CrossRef][Medline]
  60. Harley CB: Telomere loss: Mitotic clock or genetic time bomb? Mutat Res256 :271 –282,1991[CrossRef][Medline]
  61. Greider CW: Telomere length regulation. Annu Rev Biochem65 :337 –365,1996[CrossRef][Medline]
  62. Yalon M, Gal S, Segev Y, Selig S, Skorecki KL: Sister chromatid separation at human telomeric regions. J Cell Sci117 :1961 –1970,2004[Abstract/Free Full Text]
  63. Jennings BJ, Ozanne SE, Dorling MW, Hales CN: Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett448 :4 –8,1999[CrossRef][Medline]
  64. Hales CN: Suicide of the nephron. Lancet357 :136 –137,2001[CrossRef][Medline]
  65. Akkad A, Hastings R, Konje JC, Bell SC, Thurston H, Williams B: Telomere length in small-for-gestational-age babies. BJOG113 :318 –323,2006[CrossRef][Medline]
  66. Aviv A, Aviv H: Reflections on telomeres, growth, aging, and essential hypertension. Hypertension29 :1067 –1072,1997[Abstract/Free Full Text]
  67. Welham SJ, Wade A, Woolf AS: Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int61 :1231 –1242,2002[CrossRef][Medline]
  68. Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ: In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest85 :417 –423,1990[Medline]
  69. Torres M, Gomez-Pardo E, Dressler GR, Gruss P: Pax-2 controls multiple steps of urogenital development. Development121 :4057 –4065,1995[Abstract]
  70. Woods LL, Rasch R: Perinatal ANG II programs adult blood pressure, glomerular number, and renal function in rats. Am J Physiol275 :R1593 –R1599,1998[Medline]
  71. Zhang SL, Guo J, Moini B, Ingelfinger JR: Angiotensin II stimulates Pax-2 in rat kidney proximal tubular cells: Impact on proliferation and apoptosis. Kidney Int66 :2181 –2192,2004[CrossRef][Medline]
  72. Pham TD, MacLennan NK, Chiu CT, Laksana GS, Hsu JL, Lane RH: Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol285 :R962 –R970,2003[Abstract/Free Full Text]
  73. Munnich A, Rustin P: Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet106 :4 –17,2001[CrossRef][Medline]
  74. Watson B Jr, Khan MA, Desmond RA, Bergman S: Mitochondrial DNA mutations in black Americans with hypertension-associated end-stage renal disease. Am J Kidney Dis38 :529 –536,2001[Medline]
  75. Schwartz F, Duka A, Sun F, Cui J, Manolis A, Gavras H: Mitochondrial genome mutations in hypertensive individuals. Am J Hypertens17 :629 –635,2004[CrossRef][Medline]
  76. Park HK, Jin CJ, Cho YM, Park do J, Shin CS, Park KS, Kim SY, Cho BY, Lee HK: Changes of mitochondrial DNA content in the male offspring of protein-malnourished rats. Ann N Y Acad Sci1011 :205 –216,2004[Abstract/Free Full Text]
  77. Simmons RA, Suponitsky-Kroyter I, Selak MA: Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure. J Biol Chem280 :28785 –28791,2005[Abstract/Free Full Text]
  78. Lane RH, Tsirka AE, Gruetzmacher EM: Uteroplacental insufficiency alters cerebral mitochondrial gene expression and DNA in fetal and juvenile rats. Pediatr Res47 :792 –797,2000[Medline]
  79. Park KS, Kim SK, Kim MS, Cho EY, Lee JH, Lee KU, Pak YK, Lee HK: Fetal and early postnatal protein malnutrition cause long-term changes in rat liver and muscle mitochondria. J Nutr133 :3085 –3090,2003[Abstract/Free Full Text]
  80. Hinchliffe SA, Sargent PH, Howard CV, Chan YF, van Velzen D: Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest64 :777 –784,1991[Medline]
  81. Rodriguez MM, Gomez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE: Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants. Pediatr Dev Pathol7 :17 –25,2004[Medline]
  82. Brenner BM, Lawler EV, Mackenzie HS: The hyperfiltration theory: A paradigm shift in nephrology. Kidney Int49 :1774 –1777,1996[Medline]
  83. Keller G, Zimmer G, Mall G, Ritz E, Amann K: Nephron number in patients with primary hypertension. N Engl J Med348 :101 –108,2003[Abstract/Free Full Text]
  84. Woods LL: Neonatal uninephrectomy causes hypertension in adult rats. Am J Physiol276 :R974 –R978,1999[Medline]
  85. Grond J, Beukers JY, Schilthuis MS, Weening JJ, Elema JD: Analysis of renal structural and functional features in two rat strains with a different susceptibility to glomerular sclerosis. Lab Invest54 :77 –83,1986[Medline]
  86. Kreutz R, Kovacevic L, Schulz A, Rothermund L, Ketteler M, Paul M: Effect of high NaCl diet on spontaneous hypertension in a genetic rat model with reduced nephron number. J Hypertens18 :777 –782,2000[CrossRef][Medline]
  87. Menini S, Ricci C, Iacobini C, Bianchi G, Pugliese G, Pesce C: Glomerular number and size in Milan hypertensive and normotensive rats: Their relationship to susceptibility and resistance to hypertension and renal disease. J Hypertens22 :2185 –2192,2004[CrossRef][Medline]
  88. Skov K, Nyengaard JR, Korsgaard N, Mulvany MJ: Number and size of renal glomeruli in spontaneously hypertensive rats. J Hypertens12 :1373 –1376,1994[Medline]
  89. Rugiu C, Oldrizzi L, Lupo A, Valvo E, Loschiavo C, Tessitore N, Gammaro L, Ortalda V, Fabris A, Panzetta G, et al.: Clinical features of patients with solitary kidneys. Nephron43 :10 –15,1986[Medline]
  90. Thorner PS, Arbus GS, Celermajer DS, Baumal R: Focal segmental glomerulosclerosis and progressive renal failure associated with a unilateral kidney. Pediatrics73 :806 –810,1984[Abstract/Free Full Text]
  91. Zucchelli P, Cagnoli L: Proteinuria and hypertension after unilateral nephrectomy. Lancet2 :212 ,1985[CrossRef][Medline]
  92. Cho YW, Cecka JM, Gjertson DW, Terasaki PI: The UNOS Scientific Renal Transplant Registry: Multistep regression models on kidney graft survival. Clin Transpl397 –405,1990
  93. Chertow GM, Milford EL, Mackenzie HS, Brenner BM: Antigen-independent determinants of cadaveric kidney transplant failure. JAMA276 :1732 –1736,1996[Abstract]
  94. Terasaki PI, Koyama H, Cecka JM, Gjertson DW: The hyperfiltration hypothesis in human renal transplantation. Transplantation57 :1450 –1454,1994[Medline]
  95. Azuma H, Nadeau K, Mackenzie HS, Brenner BM, Tilney NL: Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft. Transplantation63 :519 –528,1997[CrossRef][Medline]
  96. Heemann UW, Azuma H, Tullius SG, Mackenzie H, Brenner BM, Tilney NL: The contribution of reduced functioning mass to chronic kidney allograft dysfunction in rats. Transplantation58 :1317 –1322,1994[Medline]
  97. Mackenzie HS, Tullius SG, Heemann UW, Azuma H, Rennke HG, Brenner BM, Tilney NL: Nephron supply is a major determinant of long-term renal allograft outcome in rats. J Clin Invest94 :2148 –2152,1994[Medline]
  98. Mackenzie HS, Azuma H, Rennke HG, Tilney NL, Brenner BM: Renal mass as a determinant of late allograft outcome: Insights from experimental studies in rats. Kidney Int Suppl52 :S38 –S42,1995[Medline]
  99. Mackenzie HS, Azuma H, Troy JL, Rennke HG, Tilney NL, Brenner BM: Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats. Proc Assoc Am Physicians108 :127 –133,1996[Medline]
  100. Fowden AL: Endocrine regulation of fetal growth. Reprod Fertil Dev7 :351 –363,1995[CrossRef][Medline]
  101. Fowden AL, Forhead AJ: Endocrine mechanisms of intrauterine programming. Reproduction127 :515 –526,2004[Abstract/Free Full Text]
  102. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR: Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest101 :2174 –2181,1998[Medline]
  103. Moss TJ, Sloboda DM, Gurrin LC, Harding R, Challis JR, Newnham JP: Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Comp Physiol281 :R960 –R970,2001[Abstract/Free Full Text]
  104. Dodic M, Abouantoun T, O’Connor A, Wintour EM, Moritz KM: Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension40 :729 –734,2002[Abstract/Free Full Text]
  105. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR: Glucocorticoid exposure in utero: New model for adult hypertension. Lancet341 :339 –341,1993[CrossRef][Medline]
  106. Segar JL, Bedell K, Page WV, Mazursky JE, Nuyt AM, Robillard JE: Effect of cortisol on gene expression of the renin-angiotensin system in fetal sheep. Pediatr Res37 :741 –746,1995[Medline]
  107. Petershack JA, Nagaraja SC, Guillery EN: Role of glucocorticoids in the maturation of renal cortical Na+-K+-ATPase during fetal life in sheep. Am J Physiol276 :R1825 –R1832,1999[Medline]
  108. Manning J, Beutler K, Knepper MA, Vehaskari VM: Upregulation of renal BSC1 and TSC in prenatally programmed hypertension. Am J Physiol Renal Physiol283 :F202 –F206,2002[Abstract/Free Full Text]
  109. Bertram C, Trowern AR, Copin N, Jackson AA, Whorwood CB: The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: Potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology142 :2841 –2853,2001[Abstract/Free Full Text]
  110. Bello AK, Nwankwo E, El Nahas AM: Prevention of chronic kidney disease: A global challenge. Kidney Int SupplS11 –S17,2005
  111. Glassock RJ: The rising tide of end-stage renal disease: What can be done? Clin Exp Nephrol8 :291 –296,2004[CrossRef][Medline]




This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
CJN.03291006v1
2/2/334    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hershkovitz, D.
Right arrow Articles by Brenner, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hershkovitz, D.
Right arrow Articles by Brenner, B. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS