CLINICAL CONSEQUENCES OF IMPAIRED DEVELOPMENTAL PROGRAMMING IN THE KIDNEY
Nephron Number, Size, and Blood Pressure
In adult animals, surgical removal of one kidney under varying circumstances and in different species does not always result in spontaneous hypertension and renal disease.63
In contrast, however, uni-nephrectomy on postnatal day 1 in rats, or fetal uni-nephrectomy in sheep, i.e. loss of nephrons at a time when nephrogenesis is still on-going, does lead to adult hypertension prior to any evidence of renal injury.64–66
These data support the possibility that intrauterine or congenital reduction in nephron number may elicit different compensatory responses compared to later nephron loss, augmenting the risk of hypertension. Consistent with this view, kidneys from rats that underwent uni-nephrectomy at day 3 of age had similar total number but a greater proportion of immature glomeruli in adulthood, compared with those who underwent nephrectomy at day 120 of age.67
In addition, mean glomerular volume in neonatally nephrectomized rats was increased by 59% compared with 20% in adult nephrectomized rats, suggesting a greater degree of compensatory hypertrophy and hyperfunction in response to neonatal nephrectomy. One could argue that as the demand for filtration capacity highly depends on BSA and basal metabolic rate, the increment in BSA from infancy through childhood and adulthood may impose a much greater strain on a smaller kidney early in life, which may demand different and more robust adaptation than during adulthood, when no growth occurs except for changes in weight.15
Some suggest that when kidney growth is interrupted, fewer, yet normal, nephrons develop. Others challenge this, as nephrogenesis is a highly complex and regulated process, and expect some structural and/or functional defects in addition to the reduced nephron number. This question is difficult to address, but in GDNF (glial cell-derived neurotrophic factor) heterozygous mice, a model with low nephron number and in which 20% of animals have unilateral renal agenesis, single kidney nephron numbers were found to be identical in mice born with one or two kidneys.68 Although glomerular filtration rates (GFR) were similar, salt and water handling were different, suggesting possible alterations in nephron function in the mice with unilateral renal agenesis. In this model, a reduction in nephron number per se was not associated with elevated blood pressures, but when maintained on a high-salt diet GDNF-deficient mice became significantly hypertensive, and blood pressures were highest in those with fewest nephrons.68 This observation could be interpreted to suggest that a deficit in nephron number may in itself not be enough to result in disease but likely enhances susceptibility to a second “hit”, transforming subclinical into overt renal dysfunction.69
The association between low nephron number and higher blood pressures has been demonstrated in white adults and in Australian Aborigines but has not been proven among individuals of African origin.6,43,58,70 To our knowledge, the relationship has not been studied in other ethnic groups. Conversely, a higher nephron number appears to be protective in the Caucasian and Australian Aboriginal populations.17,43 Similarly, in some animal models restoration of nephron number has been found to abrogate the development of hypertension, suggesting that nephron number is an important factor in the pathogenesis of hypertension.71–73
Birth Weight Predicts Later Life Hypertension
Since the 1980s, when the inverse correlation between LBW and hypertension was reported, numerous studies in humans and animals have supported this observation.2,36,74–79
It is important to note that in LBW children, blood pressures tend to be higher than those of normal birth weight children but are not in the hypertensive range, but with time blood pressures increase and LBW individuals become overtly hypertensive with age. Although preterm birth itself is associated with increased blood pressure, LBW for gestational age has been more strongly associated with higher blood pressures at birth and at 18 months of age than LBW of prematurity, suggesting that an adverse intrauterine environment is an important factor.80–82
Consistent with this, a recent Swedish study of 16,265 twins found a correlation between LBW and later life hypertension within dizygotic and monozygotic twin pairs, suggesting that individual fetal growth is an important factor, independent of genetic background, impacting developmental programming of adult disease.83
Not all studies confirm the association between birth weight and subsequent blood pressures, however.84–86
The relationship appears to be least consistent among US black children but is maintained in African and Caribbean black children, suggesting that genetic and/or environmental factors may be more pivotal in the US population.75,77,78,87
Importantly, reduced nephron number is not the only link between LBW and hypertension.3,88 Salt sensitivity has also been shown to be associated with LBW in humans and in some animal models.68,89,90 Altered expression of renal sodium transporters and modulation of the renin–angiotensin–aldosterone system have been shown in prenatally programmed animals, which may contribute to salt sensitivity.91–95 Consistent with this, in elegant studies Dagan et al. have shown increased tubule sodium transport to be a likely contributor to high blood pressure in adult animals that were exposed to maternal low-protein diet or prenatal dexamethasone.96,97 Additional proposed mechanisms for developmental programming of blood pressure, studied mostly in animals but also in humans, include increased renal vascular reactivity, altered vascular reactivity, and increased sympathetic nervous system activity.33,98–102
Birth Weight and Renal Outcomes
Proteinuria. Studies in various populations have shown increased urine protein excretion in subjects who had been of LBW, although the significance does not always persist when adjusted for additional risk factors, e.g. current HbA1c in diabetic youth.80,103 Among Australian Aborigines, albuminuria was found to correlate strongly with LBW and to increase dramatically with age.104,105 In this population, overt proteinuria was a significant predictor of loss of GFR, renal failure, and natural death.106,107 Among Pima Indians, a U-shaped association was found between birth weight and albumin excretion in diabetics, i.e. both LBW and HBW (largely due to gestational diabetes) correlated with increased albumin excretion.44 Podocyte abnormalities have been described in LBW animals, which may play a role in the development of proteinuria.20,108 It is likely therefore that intrauterine programming of nephron development may be associated with increased risk of albuminuria.
Measures of Renal Function. A reduction in nephron number, in the absence of compensatory hyperfunction, would be expected to result in a lower total GFR and creatinine clearance, and, indeed, in 1-day-old neonates born premature or SGA, GFRs were found to be impaired compared to normal birth weight neonates.109 Lower GFR and higher serum creatinine were also found in LBW children, aged 6–12 years, compared with age-matched normal birth weight children.110 In contrast, however, no significant difference in GFR was found among three groups of 9–12-year-olds who had been either preterm, term SGA, or term AGA.61 Interestingly, in children, GFR measured by cystatin C was found to correlate better with birth weight than creatinine-based formulas, suggesting the validity of these formulas may need to be re-evaluated in LBW individuals.111,112 A positive correlation was found, however, between birth weight and creatinine-based GFR in a cohort of young adults, born very premature.80 Using 24-hour urine creatinine clearance within adult twin pairs, GFRs were found to be lower in the LBW twin, again suggesting an independent effect of the intrauterine environment on programming of renal function.113
A small cross-sectional study compared total GFR, effective renal plasma flow, and filtration fraction before and after renal stimulation with low-dose dopamine infusion and oral amino acid intake in 20-year-olds born premature and AGA, premature and SGA, or term and AGA.114 It would be expected that a kidney with fewer nephrons is already hyperfiltering to some degree, which may abrogate any change in serum creatinine, but would have a blunted increase in GFR when stimulated further. This study was limited by small sample size, but the relative increase in GFR tended to be lower in SGA compared with AGA and control subjects, and effective renal plasma flow was lower in both SGA and AGA preterm individuals, although not statistically significant.115 A recent study of non-diabetic young adults found a significant reduction in renal functional reserve in those with diabetic mothers (i.e. exposed to diabetic milieu in utero), compared to those with diabetic fathers, thereby excluding a genetic confounder, and strongly suggesting a long-term impact of gestational diabetes exposure.114 The authors postulate that reduced renal functional reserve may reflect a programmed reduction in nephron number in offspring of diabetic mothers. Evaluation of renal functional reserve may therefore be a more sensitive method to detect subtle changes in renal function due to reduced nephron number.
Chronic Kidney Disease. A recent meta-analysis of 31 studies found a 70% increase in relative risk of chronic kidney disease (CKD) with LBW.116 A U-shaped curve for risk of CKD and birth weight (< 2.5 kg or ≥ 4.5 kg) among adult men, but not women, was found in a large US cohort.117 Many animal studies of fetal programming also report increased susceptibility to hypertension and renal dysfunction in males, although the reasons for the gender differences are not entirely clear.118 A retrospective study of over 2 million Norwegians reported a relative risk of end-stage renal disease (ESRD) of 1.7 in males and females born below the 10th percentile in weight, but only in females with birth weights > 4.5 kg.119 A U-shaped curve was also described between birth weight and ESRD in both males and females in a predominantly black US population.120
Epidemiologic studies therefore support the relationship between high or low birth weights and risk of CKD. A relationship between nephron number and risk of CKD in humans, however, has not been directly studied. Hodgin et al. reported renal biopsy findings in six adults who had been born premature and LBW.121 They described consistent findings of focal and segmental glomerulosclerosis, associated with glomerulomegaly, most likely on the basis of a congenitally reduced nephron number. Nephron number per se, however, cannot be invoked as the sole cause of renal dysfunction in most patients. A kidney with a reduced nephron complement likely undergoes some degree of hyperfiltration, especially if body size and functional demand are high, and may have subtle structural abnormalities, both of which would enhance susceptibility, or reduce resistance, to additional renal injury or stress (Figure 1). Consistent with this possibility, LBW has been associated with poorer outcomes in patients with nephrotic syndrome, membranous nephropathy, IgA nephropathy, minimal change, and diabetic nephropathy.45,122–125 Abnormal glomerular adaptation and greater renal injury have also been shown in LBW animals with reduced nephron numbers.108,126 Suggested cellular and molecular mechanisms for the association between LBW and CKD in adult life include an imbalance between apoptosis and cell proliferation, accelerated senescence, and mitochondrial dysfunction.127
Born Small – Stay Small! The Catch-up Effect
The combination of LBW with a rapid increase in weight after birth amplifies the risks for hypertension and cardiovascular disease in later life.128–130
Rapid weight gain by as early as 2 weeks of age was associated with endothelial dysfunction in the same subjects 16 years later.131
The “thrifty phenotype hypothesis” states that in the event of a suboptimal intrauterine environment, embryonic and fetal adaptive responses limit fetal growth, resulting in a phenotype that is better suited to survive under adverse conditions, e.g. nutrient scarcity. These adaptive changes may become maladaptive when the postnatal environment offers better growth conditions, thereby enhancing the risk of hypertension and clinical renal disease.7,132
Animal models of LBW followed by accelerated postnatal growth have shown enhanced oxidative stress, telomere shortening, and accelerated senescence in kidneys, hearts, and aortas associated with premature death.133–136
Although more circumstantial, there is evidence pointing to accelerated senescence and increased oxidative stress in LBW humans consistent with “the dangerous road of catch-up growth”.137–140
Nephron Dosing in Renal Transplantation
In animal models of renal programming, e.g. maternal gestational low-protein diet or uterine artery ligation, offspring nephron numbers are generally reduced by 25%–30%, often resulting in adult hypertension and renal disease, suggesting that loss of a single kidney (i.e. 50% of nephrons) even in a normal individual, may carry similar risk.2,73
Indeed, long-term follow-up of 52 kidney donors over 10 years did find an increased risk of hypertension and proteinuria.141
Other reports, predominantly in white kidney donors, have reported a lower risk of hypertension, proteinuria, and renal dysfunction, suggesting that uni-nephrectomy is safe.142–145
More recently, however, warning flags have been raised about the possibility of harm of living kidney donation in other ethnic groups. Among Australian Aboriginal kidney donors, after a median of 16 years, the incidence of hypertension, CKD, and ESRD was very high compared to Caucasian donors.143
Similarly, among Aboriginal Canadian donors, the prevalence of hypertension was significantly more frequent than among Caucasians, with 100% of Aborigines having hypertension 20 years after donation.146
Estimated GFR was not different between populations in this study, however, although more Aboriginal donors had proteinuria. In US cohorts, hypertension and CKD were significantly more prevalent among black compared to white donors.147,148
Uni-nephrectomy, therefore, does appear to carry some risk in populations known to be at increased risk of hypertension and kidney disease. These same populations generally have a higher prevalence of extremes of birth weight, low among Australian Aboriginal and US black populations and high in the Canadian Aboriginal population, suggesting that associated low nephron number may be a contributory factor to the increased renal risk post-nephrectomy.
From the recipient’s point of view, the importance of nephron mass as an antigen-independent determinant of transplant outcomes, i.e. matching kidney size to the recipient’s demand, has not always been accepted.149 In animal models, independent of immunologic barriers, transplanted nephron mass has a significant impact on allograft survival.150–152 In humans, various methods have been employed to try to assess the impact of kidney size, utilizing ratios of recipient to donor BSA or body weight, kidney volume to recipient BSA, and kidney weight to recipient weight, on transplant outcomes.153–158 Several caveats must be borne in mind when interpreting these data: BSA is not always proportional to kidney weight, and two kidneys of the same size may differ in nephron number. The evidence, however, despite the variability in methods, appears to be fairly consistent that small kidneys or kidneys from small donors transplanted into larger recipients tend to fare worse, supporting a role for nephron “dosing” in transplantation.153–158
As with most clinical questions, a long duration of follow-up is necessary when looking for outcomes that may take many years to manifest. Giral et al. previously published a cohort of renal allograft recipients, with a mean of 32 months of follow-up, in whom they found no impact of graft weight on short-term graft survival.159 In their longer-term study, however, they used a donor kidney weight to recipient body weight (DKW/RBW) ratio of 2.3 to stratify recipients into two groups.160 The low DKW/RBW group showed a greater adaptive increase in GFR during the first 6 months post-transplant, which remained stable for 7 years but then declined faster after 7 years compared to the high DKW/RBW group. This observation suggests initial hyperfiltration in the smaller kidneys, which could not be sustained after 7 years, likely due to on-going nephron loss, as reflected in more proteinuria, more antihypertensive drug use, a greater degree of glomerulosclerosis, and a 55% increased risk for transplant failure by 2 years in the low DKW/RBW group. The authors conclude that incompatibility between graft and recipient weight is an independent predictor of long-term graft survival. These data strongly support the contention that nephron “dose”, relative to the recipient’s needs, should be an important consideration in organ allocation.
Strategies for Optimization of Nephron Number
Evidence is emerging that clinically feasible interventions, at a critical period of nephron development, can rescue nephron number and impact later life blood pressure. In rats, adequate postnatal nutrition, achieved by cross-fostering growth-restricted pups onto normal lactating females at birth, was found to restore nephron number and abrogate development of subsequent hypertension.73
Similarly, supplementation of maternal low-protein diet with glycine, urea, or alanine during gestation normalized nephron number in all rat offspring, although blood pressure was only normalized in those supplemented with glycine.71
Postnatal hypernutrition in normal rats was found to increase nephron number by 20%, but these rats went on to develop hypertension and glomerulosclerosis with age, likely as a result of obesity.72
Vitamin A deficiency has been shown to reduce nephron number in a dose-dependent manner, but encouragingly a single dose of retinoic acid, administered during early nephrogenesis, was enough to restore nephron numbers to levels of control rats in pups exposed to a low-protein diet in utero
Interestingly, administration of ouabain was also found to abrogate the effect of serum starvation and low-protein diet on nephron development in vitro
and in vivo
again in rats.162
Although still preliminary, taken together, these studies suggest possible mechanisms whereby nephron numbers could be rescued if at-risk fetuses were identified early enough. Likewise, avoidance or judicious use of drugs during pregnancy, that are known to impact kidney development as described above, are another means to optimize fetal nephron number.21–30,32–34,36,163–165
Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens. 1988;1:335–47.
Baum M. Role of the kidney in the prenatal and early postnatal programming of hypertension. Am J Physiol Renal Physiol. 2010;298:F235–47. doi:10.1152/ajprenal.00288.2009.
Bhathena DB, Julian BA, McMorrow RG, Baehler RW. Focal sclerosis of hypertrophied glomeruli in solitary functioning kidneys of humans. Am J Kidney Dis. 1985;5:226–32.
Hoy WE, Hughson MD, Bertram JF, Douglas-Denton R, Amann K. Nephron number, hypertension, renal disease, and renal failure. J Am Soc Nephrol. 2005;16:2557–64. doi:10.1681/ASN.2005020172.
Keller G, Zimmer G, Mall G, Ritz E, Amann K. Nephron number in patients with primary hypertension. N Engl J Med. 2003;348:101–8. doi:10.1056/NEJMoa020549.
McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: Prediction, plasticity, and programming. Physiol Rev. 2005;85:571–633. doi:10.1152/physrev.00053.2003.
Schreuder MF, Langemeijer ME, Bokenkamp A, Delemarre-Van de Waal HA, Van Wijk JA. Hypertension and microalbuminuria in children with congenital solitary kidneys. J Paediatr Child Health. 2008;44:363–8. doi:10.1111/j.1440-1754.2008.01315.x.
McNamara BJ, Diouf B, Douglas-Denton RN, Hughson MD, Hoy WE, Bertram JF. A comparison of nephron number, glomerular volume and kidney weight in Senegalese Africans and African Americans. Nephrol Dial Transplant. 2010;25:1514–20. doi:10.1093/ndt/gfq030.
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 Invest. 1991;64:777–84.
Hughson M, Farris AB, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular number and size in autopsy kidneys: The relationship to birth weight. Kidney Int. 2003;63:2113–22. doi:10.1046/j.1523-1755.2003.00018.x.
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 Int. 2000;58:770–3. doi:10.1046/j.1523-1755.2000.00225.x.
McNamara BJ, Diouf B, Hughson MD, Douglas-Denton RN, Hoy WE, Bertram JF. Renal pathology, glomerular number and volume in a West African urban community. Nephrol Dial Transplant. 2008;23:2576–85. doi:10.1093/ndt/gfn039.
McNamara BJ, Diouf B, Hughson MD, Hoy WE, Bertram JF. Associations between age, body size and nephron number with individual glomerular volumes in urban West African males. Nephrol Dial Transplant. 2009;24:1500–6. doi:10.1093/ndt/gfn636.
Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992;232:194–201. doi:10.1002/ar.1092320205.
Rodriguez MM, Gomez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE. Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants. Pediatr Dev Pathol. 2004;7:17–25. doi:10.1007/s10024-003-3029-2.
Zimanyi MA, Hoy WE, Douglas-Denton RN, Hughson MD, Holden LM, Bertram JF. Nephron number and individual glomerular volumes in male Caucasian and African American subjects. Nephrol Dial Transplant. 2009;24:2428–33. doi:10.1093/ndt/gfp116.
Hinchliffe SA, Howard CV, Lynch MR, Sargent PH, Judd BA, van Velzen D. Renal developmental arrest in sudden infant death syndrome. Pediatr Pathol. 1993;13:333–43. doi:10.3109/15513819309048221.
Gubhaju L, Sutherland MR, Yoder BA, Zulli A, Bertram JF, Black MJ. Is nephrogenesis affected by preterm birth? Studies in a non-human primate model. Am J Physiol Renal Physiol. 2009;297:F1668–77. doi:10.1152/ajprenal.00163.2009.
Villar-Martini VC, Carvalho JJ, Neves MF, Aguila MB, Mandarim-de-Lacerda CA. Hypertension and kidney alterations in rat offspring from low protein pregnancies. J Hypertens Suppl. 2009;27:S47–51. doi:10.1097/01.hjh.0000358838.71675.5e.
Gray SP, Kenna K, Bertram JF, et al. Repeated ethanol exposure during late gestation decreases nephron endowment in fetal sheep. Am J Physiol Regul Integr Comp Physiol. 2008;295:R568–74. doi:10.1152/ajpregu.90316.2008.
Amri K, Freund N, Van Huyen JP, Merlet-Benichou C, Lelievre-Pegorier M. Altered nephrogenesis due to maternal diabetes is associated with increased expression of IGF-II/mannose-6-phosphate receptor in the fetal kidney. Diabetes. 2001;50:1069–75. doi:10.2337/diabetes.50.5.1069.
Celsi G, Kistner A, Aizman R, et al. Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring. Pediatr Res. 1998;44:317–22. doi:10.1203/00006450-199809000-00009.
Gilbert T, Cibert C, Moreau E, Geraud G, Merlet-Benichou C. Early defect in branching morphogenesis of the ureteric bud in induced nephron deficit. Kidney Int. 1996;50:783–95. doi:10.1038/ki.1996.377.
Harrison M, Langley-Evans SC. Intergenerational programming of impaired nephrogenesis and hypertension in rats following maternal protein restriction during pregnancy. Br J Nutr. 2009;101:1020–30. doi:10.1017/S0007114508057607.
Komhoff M, Wang JL, Cheng HF, et al. Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int. 2000;57:414–22.
Lisle SJ, Lewis RM, Petry CJ, Ozanne SE, Hales CN, Forhead AJ. Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring. Br J Nutr. 2003;90:33–9. doi:10.1079/BJN2003881.
Magaton A, Gil FZ, Casarini DE, Cavanal Mde F, Gomes GN. Maternal diabetes mellitus – early consequences for the offspring. Pediatr Nephrol. 2007;22:37–43. doi:10.1007/s00467-006-0282-4.
Merlet-Benichou C, Vilar J, Lelievre-Pegorier M, Gilbert T. Role of retinoids in renal development: Pathophysiological implication. Curr Opin Nephrol Hypertens. 1999;8:39–43. doi:10.1097/00041552-199901000-00007.
Merlet-Benichou, C.; Gilbert, T.; Vilar, J.; Moreau, E.; Freund, N.; Lelievre-Pegorier, M. Lab Invest. Vol. 79. 1999. Nephron number: Variability is the rule. Causes and consequences; pp. 515–27.
Nathanson S, Moreau E, Merlet-Benichou C, Gilbert T. In utero and in vitro exposure to beta-lactams impair kidney development in the rat. J Am Soc Nephrol. 2000;11:874–84.
Tendron-Franzin A, Gouyon JB, Guignard JP, et al. Long-term effects of in utero exposure to cyclosporin a on renal function in the rabbit. J Am Soc Nephrol. 2004;15:2687–93. doi:10.1097/01.ASN.0000139069.59466.D8.
Moritz KM, Dodic M, Wintour EM. Kidney development and the fetal programming of adult disease. Bioessays. 2003;25:212–20. doi:10.1002/bies.10240.
Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res. 2001;49:460–7. doi:10.1203/00006450-200104000-00005.
Valero, De.; Bernabe, J.; Soriano, T.; Albaladejo, R., et al. Risk factors for low birth weight: A review. Eur J Obstet Gynecol Reprod Biol. 2004;116:3–15. doi:10.1016/j.ejogrb.2004.03.007.
Tierney-Gumaer R, Reifsnider E. Risk factors for low birth weight infants of Hispanic, African American, and white women in Bexar County, Texas. Public Health Nurs. 2008;25:390–400. doi:10.1111/j.1525-1446.2008.00723.x.
Fall C. Maternal nutrition: Effects on health in the next generation. Indian J Med Res. 2009;130:593–9.
Blumenshine P, Egerter S, Barclay CJ, Cubbin C, Braveman PA. Socioeconomic disparities in adverse birth outcomes: A systematic review. Am J Prev Med. 2010;39:263–72. doi:10.1016/j.amepre.2010.05.012.
Collins JW, Rankin KM, David RJ. Low birth weight across generations: The effect of economic environment. Matern Child Health J. 2011;15:438–45. doi:10.1007/s10995-010-0603-x.
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 Gynaecol. 1992;99:296–301. doi:10.1111/j.1471-0528.1992.tb13726.x.
Hoy WE, Bertram JF, Denton RD, Zimanyi M, Samuel T, Hughson MD. Nephron number, glomerular volume, renal disease and hypertension. Curr Opin Nephrol Hypertens. 2008;17:258–65. doi:10.1097/MNH.0b013e3282f9b1a5.
Nelson RG, Morgenstern H, Bennett PH. Birth weight and renal disease in Pima Indians with type 2 diabetes mellitus. Am J Epidemiol. 1998;148:650–6. doi:10.1093/aje/148.7.650.
Nelson RG, Morgenstern H, Bennett PH. Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima Indians. Diabetes. 1998;47:1489–93. doi:10.2337/diabetes.47.9.1489.
Amri K, Freund N, Vilar J, Merlet-Benichou C, Lelievre-Pegorier M. Adverse effects of hyperglycemia on kidney development in rats: In vivo
and in vitro
studies. Diabetes. 1999;48:2240–5. doi:10.2337/diabetes.48.11.2240.
Jones SE, Bilous RW, Flyvbjerg A, Marshall SM. Intra-uterine environment influences glomerular number and the acute renal adaptation to experimental diabetes. Diabetologia. 2001;44:721–8. doi:10.1007/s001250051681.
Tran S, Chen YW, Chenier I, et al. Maternal diabetes modulates renal morphogenesis in offspring. J Am Soc Nephrol. 2008;19:943–52. doi:10.1681/ASN.2007080864.
Moritz KM, Wintour EM, Black MJ, Bertram JF, Caruana G. Factors influencing mammalian kidney development: Implications for health in adult life. Adv Anat Embryol Cell Biol. 2008;196:1–78.
Dziarmaga A, Clark P, Stayner C, et al. Ureteric bud apoptosis and renal hypoplasia in transgenic pax2-bax fetal mice mimics the renal-coloboma syndrome. J Am Soc Nephrol. 2003;14:2767–74. doi:10.1097/01.ASN.0000094082.11026.EE.
Quinlan J, Lemire M, Hudson T, et al. A common variant of the pax2 gene is associated with reduced newborn kidney size. J Am Soc Nephrol. 2007;18:1915–21. doi:10.1681/ASN.2006101107.
Zhang Z, Quinlan J, Hoy W, et al. A common ret variant is associated with reduced newborn kidney size and function. J Am Soc Nephrol. 2008;19:2027–34. doi:10.1681/ASN.2007101098.
Weber S, Moriniere V, Knuppel T, et al. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: Results of the escape study. J Am Soc Nephrol. 2006;17:2864–70. doi:10.1681/ASN.2006030277.
Fulladosa X, Moreso F, Narvaez JA, Grinyo JM, Seron D. Estimation of total glomerular number in stable renal transplants. J Am Soc Nephrol. 2003;14:2662–8. doi:10.1097/01.ASN.0000088025.33462.B0.
Gilbert JS, Lang AL, Grant AR, Nijland MJ. Maternal nutrient restriction in sheep: Hypertension and decreased nephron number in offspring at 9 months of age. J Physiol. 2005;565:137–47. doi:10.1113/jphysiol.2005.084202.
Jones SE, Nyengaard JR, Flyvbjerg A, Bilous RW, Marshall SM. Birth weight has no influence on glomerular number and volume. Pediatr Nephrol. 2001;16:340–5. doi:10.1007/s004670000559.
Hoy WE, Douglas-Denton RN, Hughson MD, Cass A, Johnson K, Bertram JF. A stereological study of glomerular number and volume: Preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int Suppl. 2003:S31–7. doi:10.1046/j.1523-1755.63.s83.8.x.
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 Int. 2006;70:104–10. doi:10.1038/sj.ki.5000397.
Elia M, Betts P, Jackson DM, Mulligan J. Fetal programming of body dimensions and percentage body fat measured in prepubertal children with a 4-component model of body composition, dual-energy X-ray absorptiometry, deuterium dilution, densitometry, and skinfold thicknesses. Am J Clin Nutr. 2007;86:618–24.
Rakow A, Johansson S, Legnevall L, et al. Renal volume and function in school-age children born preterm or small for gestational age. Pediatr Nephrol. 2008;23:1309–15. doi:10.1007/s00467-008-0824-z.
Keijzer-Veen MG, Devos AS, Meradji M, Dekker FW, Nauta J, van der Heijden BJ. Reduced renal length and volume 20 years after very preterm birth. Pediatr Nephrol. 2010;25:499–507. doi:10.1007/s00467-009-1371-y.
Kett MM, Bertram JF. Nephron endowment and blood pressure: What do we really know? Curr Hypertens Rep. 2004;6:133–9. doi:10.1007/s11906-004-0089-2.
Woods LL, Weeks DA, Rasch R. Hypertension after neonatal uninephrectomy in rats precedes glomerular damage. Hypertension. 2001;38:337–42.
Singh RR, Denton KM, Bertram JF, et al. Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy. J Hypertens. 2009;27:386–96. doi:10.1097/HJH.0b013e32831bc778.
Nyengaard JR. Number and dimensions of rat glomerular capillaries in normal development and after nephrectomy. Kidney Int. 1993;43:1049–57. doi:10.1038/ki.1993.147.
Ruta LA, Dickinson H, Thomas MC, Denton KM, Anderson WP, Kett MM. High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment. Am J Physiol Renal Physiol. 2010;298:F1384–92. doi:10.1152/ajprenal.00049.2010.
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 Int. 2006;69:671–8. doi:10.1038/sj.ki.5000041.
Langley-Evans S, Langley-Evans A, Marchand M. Nutritional programming of blood pressure and renal morphology. Arch Physiol Biochem. 2003;111:8–16. doi:10.1076/apab.22.214.171.12436.
Boubred F, Buffat C, Feuerstein JM, et al. Effects of early postnatal hypernutrition on nephron number and long-term renal function and structure in rats. Am J Physiol Renal Physiol. 2007;293:F1944–9. doi:10.1152/ajprenal.00141.2007.
Wlodek ME, Mibus A, Tan A, Siebel AL, Owens JA, Moritz KM. Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat. J Am Soc Nephrol. 2007;18:1688–96. doi:10.1681/ASN.2007010015.
Forrester TE, Wilks RJ, Bennett FI, et al. Fetal growth and cardiovascular risk factors in Jamaican schoolchildren. Br Med J. 1996;312:156–60.
Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens. 1996;14:935–41. doi:10.1097/00004872-199608000-00002.
Levitt NS, Steyn K, De Wet T, et al. An inverse relation between blood pressure and birth weight among 5 year old children from Soweto, South Africa. J Epidemiol Community Health. 1999;53:264–8. doi:10.1136/jech.53.5.264.
Longo-Mbenza B, Ngiyulu R, Bayekula M, et al. Low birth weight and risk of hypertension in African school children. J Cardiovasc Risk. 1999;6:311–4.
Tian JY, Cheng Q, Song XM, et al. Birth weight and risk of type 2 diabetes, abdominal obesity and hypertension among chinese adults. Eur J Endocrinol. 2006;155:601–7. doi:10.1530/eje.1.02265.
Keijzer-Veen MG, Schrevel M, Finken MJ, et al. Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. J Am Soc Nephrol. 2005;16:2762–8. doi:10.1681/ASN.2004090783.
Schmidt IM, Chellakooty M, Boisen KA, et al. Impaired kidney growth in low-birth-weight children: Distinct effects of maturity and weight for gestational age. Kidney Int. 2005;68:731–40. doi:10.1111/j.1523-1755.2005.00451.x.
Keijzer-Veen MG, Dulger A, Dekker FW, Nauta J, van der Heijden BJ. Very preterm birth is a risk factor for increased systolic blood pressure at a young adult age. Pediatr Nephrol. 2010;25:509–16. doi:10.1007/s00467-009-1373-9.
Bergvall N, Iliadou A, Johansson S, et al. Genetic and shared environmental factors do not confound the association between birth weight and hypertension: A study among Swedish twins. Circulation. 2007;115:2931–8. doi:10.1161/CIRCULATIONAHA.106.674812.
Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: Is there really an inverse association between birthweight and subsequent blood pressure? Lancet. 2002;360:659–65. doi:10.1016/S0140-6736(02)09834-3.
Muhle A, Muhle C, Amann K, et al. No juvenile arterial hypertension in sheep multiples despite reduced nephron numbers. Pediatr Nephrol. 2010;25:1653–61. doi:10.1007/s00467-010-1512-3.
Hemachandra AH, Klebanoff MA, Furth SL. Racial disparities in the association between birth weight in the term infant and blood pressure at age 7 years: Results from the collaborative perinatal project. J Am Soc Nephrol. 2006;17:2576–81. doi:10.1681/ASN.2005090898.
de Boer MP, Ijzerman RG, de Jongh RT, et al. Birth weight relates to salt sensitivity of blood pressure in healthy adults. Hypertension. 2008;51:928–32. doi:10.1161/HYPERTENSIONAHA.107.101881.
Dagan A, Gattineni J, Cook V, Baum M. Prenatal programming of rat proximal tubule Na+/H+ exchanger by dexamethasone. Am J Physiol Regul Integr Comp Physiol. 2007;292:R1230–5. doi:10.1152/ajpregu.00669.2006.
Manning J, Beutler K, Knepper MA, Vehaskari VM. Upregulation of renal bsc1 and tsc in prenatally programmed hypertension. Am J Physiol Renal Physiol. 2002;283:F202–6.
Vehaskari VM, Stewart T, Lafont D, Soyez C, Seth D, Manning J. Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol Renal Physiol. 2004;287:F262–7. doi:10.1152/ajprenal.00055.2004.
Alwasel SH, Kaleem I, Sahajpal V, Ashton N. Maternal protein restriction reduces angiotensin II at(1) and at(2) receptor expression in the fetal rat kidney. Kidney Blood Press Res. 2010;33:251–9. doi:10.1159/000317739.
Dagan A, Gattineni J, Habib S, Baum M. Effect of prenatal dexamethasone on postnatal serum and urinary angiotensin II levels. Am J Hypertens. 2010;23:420–4. doi:10.1038/ajh.2009.274.
Salgado CM, Jardim PC, Teles FB, Nunes MC. Low birth weight as a marker of changes in ambulatory blood pressure monitoring. Arq Bras Cardiol. 2009;92:107–21.
Dagan A, Habib S, Gattineni J, Dwarakanath V, Baum M. Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone. Am J Physiol Regul Integr Comp Physiol. 2009;297:R93–9. doi:10.1152/ajpregu.91006.2008.
Dagan A, Kwon HM, Dwarakanath V, Baum M. Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance. Am J Physiol Renal Physiol. 2008;295:F29–34. doi:10.1152/ajprenal.00123.2008.
Dotsch J. Renal and extrarenal mechanisms of perinatal programming after intrauterine growth restriction. Hypertens Res. 2009;32:238–41. doi:10.1038/hr.2009.4.
Franco MC, Christofalo DM, Sawaya AL, Ajzen SA, Sesso R. Effects of low birth weight in 8- to 13-year-old children: Implications in endothelial function and uric acid levels. Hypertension. 2006;48:45–50. doi:10.1161/01.HYP.0000223446.49596.3a.
Franco Mdo C, Arruda RM, Fortes ZB, et al. Severe nutritional restriction in pregnant rats aggravates hypertension, altered vascular reactivity, and renal development in spontaneously hypertensive rats offspring. J Cardiovasc Pharmacol. 2002;39:369–77. doi:10.1097/00005344-200203000-00008.
Nuyt AM. Mechanisms underlying developmental programming of elevated blood pressure and vascular dysfunction: Evidence from human studies and experimental animal models. Clin Sci (Lond). 2008;114:1–17. doi:10.1042/CS20070113.
Maahs DM, Snively BM, Beyer J, et al. Birth weight [corrected] and elevated albumin to creatinine ratio in youth with diabetes: The search for diabetes in youth study. Pediatr Nephrol. 2008;23:2255–60. doi:10.1007/s00467-008-0921-z.
Hoy WE, Rees M, Kile E, Mathews JD, Wang Z. A new dimension to the barker hypothesis: Low birthweight and susceptibility to renal disease. Kidney Int. 1999;56:1072–7. doi:10.1046/j.1523-1755.1999.00633.x.
Hoy WE, Wang Z, VanBuynder P, Baker PR, McDonald SM, Mathews JD. The natural history of renal disease in Australian Aborigines. Part 2. Albuminuria predicts natural death and renal failure. Kidney Int. 2001;60:249–56. doi:10.1046/j.1523-1755.2001.00793.x.
Hoy WE, Wang Z, VanBuynder P, Baker PR, Mathews JD. The natural history of renal disease in Australian Aborigines. Part 1. Changes in albuminuria and glomerular filtration rate over time. Kidney Int. 2001;60:243–8. doi:10.1046/j.1523-1755.2001.00792.x.
Jones SE, White KE, Flyvbjerg A, Marshall SM. The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis. Diabetologia. 2006;49:191–9. doi:10.1007/s00125-005-0052-z.
Schreuder MF, Wilhelm AJ, Bokenkamp A, Timmermans SM, Delemarre-van de Waal HA, van Wijk JA. Impact of gestational age and birth weight on amikacin clearance on day 1 of life. Clin J Am Soc Nephrol. 2009;4:1774–8. doi:10.2215/CJN.02230409.
Rodriguez-Soriano J, Aguirre M, Oliveros R, Vallo A. Long-term renal follow-up of extremely low birth weight infants. Pediatr Nephrol. 2005;20:579–84. doi:10.1007/s00467-005-1828-6.
Franco MC, Nishida SK, Sesso R. Gfr estimated from cystatin c versus creatinine in children born small for gestational age. Am J Kidney Dis. 2008;51:925–32. doi:10.1053/j.ajkd.2008.02.305.
Ingelfinger JR. Weight for gestational age as a baseline predictor of kidney function in adulthood. Am J Kidney Dis. 2008;51:1–4. doi:10.1053/j.ajkd.2007.11.004.
Gielen M, Pinto-Sietsma SJ, Zeegers MP, et al. Birth weight and creatinine clearance in young adult twins: Influence of genetic, prenatal, and maternal factors. J Am Soc Nephrol. 2005;16:2471–6. doi:10.1681/ASN.2004030210.
Abi Khalil C, Travert F, Fetita S, et al. Fetal exposure to maternal type 1 diabetes is associated with renal dysfunction at adult age. Diabetes. 2010;59:2631–6. doi:10.2337/db10-0419.
Keijzer-Veen MG, Kleinveld HA, Lequin MH, et al. Renal function and size at young adult age after intrauterine growth restriction and very premature birth. Am J Kidney Dis. 2007;50:542–51. doi:10.1053/j.ajkd.2007.06.015.
White SL, Perkovic V, Cass A, et al. Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am J Kidney Dis. 2009;54:248–61. doi:10.1053/j.ajkd.2008.12.042.
Li S, Chen SC, Shlipak M, et al. Low birth weight is associated with chronic kidney disease only in men. Kidney Int. 2008;73:637–42. doi:10.1038/sj.ki.5002747.
Grigore D, Ojeda NB, Alexander BT. Sex differences in the fetal programming of hypertension. Gend Med. 2008;5(Suppl A):S121–32.
Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM. Low birth weight increases risk for end-stage renal disease. J Am Soc Nephrol. 2008;19:151–7. doi:10.1681/ASN.2007020252.
Lackland DT, Bendall HE, Osmond C, Egan BM, Barker DJ. Low birth weights contribute to high rates of early-onset chronic renal failure in the southeastern United States. Arch Intern Med. 2000;160:1472–6. doi:10.1001/archinte.160.10.1472.
Hodgin JB, Rasoulpour M, Markowitz GS, D’Agati VD. Very low birth weight is a risk factor for secondary focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2009;4:71–6. doi:10.2215/CJN.01700408.
Duncan RC, Bass PS, Garrett PJ, Dathan JR. Weight at birth and other factors influencing progression of idiopathic membranous nephronpathy. Nephrol Dial Transplant. 1994;9:875.
Na YW, Yang HJ, Choi JH, et al. Effect of intrauterine growth retardation on the progression of nephrotic syndrome. Am J Nephrol. 2002;22:463–7. doi:10.1159/000065275.
Teeninga N, Schreuder MF, Bokenkamp A, Delemarre-van de Waal HA, van Wijk JA. Influence of low birth weight on minimal change nephrotic syndrome in children, including a meta-analysis. Nephrol Dial Transplant. 2008;23:1615–20. doi:10.1093/ndt/gfm829.
Zidar N, Avgustin Cavic M, Kenda RB, Ferluga D. Unfavorable course of minimal change nephrotic syndrome in children with intrauterine growth retardation. Kidney Int. 1998;54:1320–3. doi:10.1046/j.1523-1755.1998.00121.x.
Plank C, Nusken KD, Menendez-Castro C, et al. Intrauterine growth restriction following ligation of the uterine arteries leads to more severe glomerulosclerosis after mesangioproliferative glomerulonephritis in the offspring. Am J Nephrol. 2010;32:287–95. doi:10.1159/000319045.
Hershkovitz D, Burbea Z, Skorecki K, Brenner BM. Fetal programming of adult kidney disease: Cellular and molecular mechanisms. Clin J Am Soc Nephrol. 2007;2:334–42. doi:10.2215/CJN.03291006.
Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med. 2005;353:1802–9. doi:10.1056/NEJMoa044160.
Cameron N, Demerath EW. Critical periods in human growth and their relationship to diseases of aging. Am J Phys Anthropol. 2002;(Suppl 35):159–84. doi:10.1002/ajpa.10183.
Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med. 2004;350:865–75. doi:10.1056/NEJMoa035698.
Singhal A, Cole TJ, Fewtrell M, Deanfield J, Lucas A. Is slower early growth beneficial for long-term cardiovascular health? Circulation. 2004;109:1108–13. doi:10.1161/01.CIR.0000118500.23649.DF.
Luyckx VA, Compston CA, Simmen T, Mueller TF. Accelerated senescence in kidneys of low-birth-weight rats after catch-up growth. Am J Physiol Renal Physiol. 2009;297:F1697–705. doi:10.1152/ajprenal.00462.2009.
Ozanne SE, Hales CN. Lifespan: Catch-up growth and obesity in male mice. Nature. 2004;427:411–2. doi:10.1038/427411b.
Tarry-Adkins JL, Martin-Gronert MS, Chen JH, Cripps RL, Ozanne SE. Maternal diet influences DNA damage, aortic telomere length, oxidative stress, and antioxidant defense capacity in rats. FASEB J. 2008;22:2037–44. doi:10.1096/fj.07-099523.
Tarry-Adkins JL, Ozanne SE, Norden A, Cherif H, Hales CN. Lower antioxidant capacity and elevated p53 and p21 may be a link between gender disparity in renal telomere shortening, albuminuria, and longevity. Am J Physiol Renal Physiol. 2006;290:F509–16. doi:10.1152/ajprenal.00215.2005.
Mohn A, Chiavaroli V, Cerruto M, et al. Increased oxidative stress in prepubertal children born small for gestational age. J Clin Endocrinol Metab. 2007;92:1372–8. doi:10.1210/jc.2006-1344.
Raqib R, Alam DS, Sarker P, et al. Low birth weight is associated with altered immune function in rural Bangladeshi children: A birth cohort study. Am J Clin Nutr. 2007;85:845–52.
Hakim RM, Goldszer RC, Brenner BM. Hypertension and proteinuria: Long-term sequelae of uninephrectomy in humans. Kidney Int. 1984;25:930–6. doi:10.1038/ki.1984.112.
Flanigan WJ, Burns RO, Takacs FJ, Merril JP. Serial studies of glomerular filtration rate and renal plasma flow in kidney transplant donors, identical twins, and allograft recipients. Am J Surg. 1968;116:788–94. doi:10.1016/0002-9610(68)90370-X.
Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360:459–69. doi:10.1056/NEJMoa0804883.
Kasiske BL, Ma JZ, Louis TA, Swan SK. Long-term effects of reduced renal mass in humans. Kidney Int. 1995;48:814–9. doi:10.1038/ki.1995.355.
Storsley LJ, Young A, Rush DN, et al. Long-term medical outcomes among Aboriginal living kidney donors. Transplantation. 2010;90:401–6. doi:10.1097/TP.0b013e3181e6e79b.
Lentine KL, Schnitzler MA, Xiao H, et al. Racial variation in medical outcomes among living kidney donors. N Engl J Med. 2010;363:724–32. doi:10.1056/NEJMoa1000950.
Gibney EM, Parikh CR, Garg AX. Age, gender, race, and associations with kidney failure following living kidney donation. Transplant Proc. 2008;40:1337–40. doi:10.1016/j.transproceed.2008.03.104.
Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol. 1992;3:162–9.
Azuma H, Nadeau K, Mackenzie HS, Brenner BM, Tilney NL. Nephron mass modulates the hemodynamic, cellular and molecular response of the rat renal allograft. Transplantation. 1997;63:519–28. doi:10.1097/00007890-199702270-00006.
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 Phys. 1996;108:127–33.
Szabo AJ, Muller V, Chen GF, Samsell LJ, Erdely A, Baylis C. Nephron number determines susceptibility to renal mass reduction-induced CKD in Lewis and Fisher 344 rats: Implications for development of experimentally induced chronic allograft nephropathy. Nephrol Dial Transplant. 2008;23:2492–5. doi:10.1093/ndt/gfn112.
Douverny JB, Baptista-Silva JC, Pestana JO, Sesso R. Importance of renal mass on graft function outcome after 12 months of living donor kidney transplantation. Nephrol Dial Transplant. 2007;22:3646–51. doi:10.1093/ndt/gfm487.
el-Agroudy AE, Hassan NA, Bakr MA, Foda MA, Shokeir AA, Shehab el-Dein AB. Effect of donor/recipient body weight mismatch on patient and graft outcome in living-donor kidney transplantation. Am J Nephrol. 2003;23:294–9. doi:10.1159/000072819.
Gaston RS, Hudson SL, Julian BA, et al. Impact of donor/recipient size matching on outcomes in renal transplantation. Transplantation. 1996;61:383–8. doi:10.1097/00007890-199602150-00010.
Kim YS, Moon JI, Kim DK, Kim SI, Park K. Ratio of donor kidney weight to recipient bodyweight as an index of graft function. Lancet. 2001;357:1180–1. doi:10.1016/S0140-6736(00)04377-4.
Moreso F, Seron D, Anunciada AI, et al. Recipient body surface area as a predictor of post-transplant renal allograft evolution. Transplantation. 1998;65:671–6. doi:10.1097/00007890-199803150-00012.
Giral M, Nguyen JM, Karam G, et al. Impact of graft mass on the clinical outcome of kidney transplants. J Am Soc Nephrol. 2005;16:261–8. doi:10.1681/ASN.2004030209.
Giral M, Foucher Y, Karam G, et al. Kidney and recipient weight incompatibility reduces long-term graft survival. J Am Soc Nephrol. 2010;21:1022–9. doi:10.1681/ASN.2009121296.
Makrakis J, Zimanyi MA, Black MJ. Retinoic acid enhances nephron endowment in rats exposed to maternal protein restriction. Pediatr Nephrol. 2007;22:1861–7. doi:10.1007/s00467-007-0572-5.
Li J, Khodus G, Kruusmagi M, et al. Ouabain protects against adverse developmental programming of the kidney. Nat Commun. 2010;1:42. doi:10.1038/ncomms1043.
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. Endocrinology. 2001;142:2841–53. doi:10.1210/en.142.7.2841.
Merlet-Benichou C. Influence of fetal environment on kidney development. Int J Dev Biol. 1999;43:453–6.
Wintour EM, Moritz KM, Johnson K, Ricardo S, Samuel CS, Dodic M. Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol. 2003;549:929–35. doi:10.1113/jphysiol.2003.042408.