Preventive Nephrology: A Role for the Pediatrician

Abstract

See related article, p 923It is now more than 20 years ago since David Barker proposed that many chronic adult diseases originate from compromised fetal and early postnatal development.1Barker D.J. Childhood causes of adult diseases.Arch Dis Child. 1988; 63: 867-869Crossref PubMed Scopus (45) Google Scholar Barker’s proposal was mainly based on epidemiologic studies, but since then a wealth of experimental and clinical studies have provided evidence for a link between adverse events during fetal and early postnatal life and adult-onset diseases.2Nijland M.J. Ford S.P. Nathanielsz P.W. Prenatal origins of adult disease.Curr Opin Obstet Gynecol. 2008; 20: 132-138Crossref PubMed Scopus (105) Google ScholarAt approximately the same time as Barker first introduced his hypothesis, Barry Brenner proposed that low nephron endowment would predispose to renal disease and hypertension.3Brenner B.M. Garcia D.L. Anderson S. Glomeruli and blood pressure. Less of one, more of the other?.Am J Hypertens. 1988; 3: 335-347Crossref Scopus (1066) Google Scholar A large number of experimental studies, as well as studies of humans with a history of low birth weight, have since then provided unequivocal evidence for this hypothesis, and it is now generally agreed that the kidney is extremely sensitive to the effects of an adverse environment during the time of nephron formation.4Abitbol C.L. Ingelfinger J.R. Nephron mass and cardiovascular and renal disease risks.Semin Nephrol. 2009; 29: 445-454Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Fetal malnutrition is considered to be the most common cause of adverse developmental programming.The development of the metanephric kidney is driven by the formation of nephrons. As the ureteric bud divides and grows into the undifferentiated mesenchymal cells, it triggers the formation of nephrons. The crosstalk between the ureteric bud and the mesenchymal cells is dependent on a well-timed and well-coordinated expression of a large number of genes. The function of the adult kidney depends on its architecture, the order by which its functional units, the nephrons, are arranged. The majority of cells that do not participate in nephron formation will have to undergo apoptosis. Kidney development is therefore dependent on a delicate balance among cell differentiation, proliferation, and apoptosis. Fetal malnutrition results in excessive apoptosis, which is a major cause of low nephron endowment. Recent experimental studies have shown that activation of an antiapoptotic signal will protect the embryonic kidney exposed to malnutrition from adverse developmental programming.5Li J. Khodus G.R. Kruusmägi M. et al.Ouabain protects against adverse developmental programming of the kidney.Nat Commun. 2010; 27: 42https://doi.org/10.1038/ncomms1043Crossref Scopus (69) Google ScholarThe formation of nephrons is completed when the ureter bud has reached the outer cortex, which in humans occurs around the 36th gestational week. Thereafter no more nephrons can be formed, and loss of tissue will be structurally compensated by hyperplasia and/or hypertrophy and functionally compensated by increased workload for the existing glomeruli. The filtration pressure will rise due to a resetting of the tonus of hormones regulating renal vascular resistance. This compensation, which involves a resetting of the renal angiotensin tonus, carries a price, which is predisposition to glomerulosclerosis and hypertension.Will infants born before the 36th gestational week continue to form nephrons after birth and, if so, to which extent would nephrogenesis be inhibited by the condition of the very premature infant? Most of the studies of renal function, renal pathology, and predisposition to renal disease in humans have not discriminated between preterm birth and intrauterine growth restriction as cause of low birth weight. Rodents are, for obvious reasons, not suitable for experimental studies on the long-term effect of preterm birth on nephrogenesis. A recent study, performed on preterm baboons, ventilated for up to 21 days postnatally, showed that nephron endowment was not affected by preterm birth, but abnormal glomeruli with a shrunken glomerular tuft and cystic Bowman space were often observed in the outer cortex.6Gubhaju L. Sutherland M.R. Yoder B.A. Zulli A. Bertram J.F. Black M.J. Is nephrogenesis affected by preterm birth? Studies in a hon-human primate model.Am J Physiol Renal Physiol. 2009; 297: F1668-F1677Crossref PubMed Scopus (95) Google Scholar A study performed on tissue collected at autopsy from preterm neonates and stillborn gestational controls has also indicated that nephrogenesis continues postnatally. The outer cortical glomeruli, which should have been formed postnatally, did, however, often exhibit pathomorphologic changes.7Sutherland M.R. Gubhaju L. Moore L. et al.Accelerated maturation and abnormal morphology in the preterm neonatal kidney.J Am Soc Nephrol. 2011; 22: 1365-1374Crossref PubMed Scopus (214) Google Scholar Taken together, these studies indicate that although nephrogenesis continues after preterm birth, the postnatally formed nephrons may be incompletely developed and more prone to develop loss of function and glomerulosclerosis.The study by Vieux et al published in this issue of The Journal supports this assumption.8Vieux R. Hascoet J.M. Franck P. Guillemin F. Increased albuminuria in four-year old preterm-born infants with normal height.J Pediatr. 2012; 160: 923-928Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Albuminuria is the first laboratory sign as well as the hallmark of glomerulosclerosis. In a 4-year follow-up of 119 children with an average gestational age of 29.1 ± 1.4 weeks, they found high levels of albumin in the urine in 17 (14.4%) children. Albuminuria at the age of 4 years was found to be significantly more common in children who were treated for severe neonatal hypotension, indicating that adverse extrauterine conditions will contribute to the pathology of the postnatally formed nephrons. The kidney plays a central role for blood pressure regulation and hypertension is a common feature in chronic renal disease. Reduced capacity to regulate salt balance is considered to be the most common cause of renal hypertension, but changes in the renal vascular tonus are also a contributing factor. Increased blood pressure was observed in 15 (12.6%) of the children. It is too early to tell whether this increase in blood pressure is related to renal pathology or whether it is an independent effect of developmental programming.Chronic kidney diseases represent a major socioeconomical burden. The annual cost to treat kidney diseases in the United States is more than one quarter of Medicare expenditures, and there is now overwhelming evidence that adverse fetal and perinatal conditions endanger kidney development and result in increased risk for renal disease and hypertension. The report by Vieux et al raises several important questions about the role that pediatricians and pediatric research can play in reducing the burden of chronic kidney disease. To which extent should preterm infants be followed up with regard to renal function and blood pressure? The results from this study suggest that very preterm infants should be examined with regard to albuminuria, serum creatinine (or corresponding indicator of glomerular filtration rate), and blood pressure at the age of 2 to 4 years and that children who have albuminuria and/or increased blood pressure should be followed up with at least every second year. If such efforts will be coordinated between different centers, it will give a better understanding of the extent to which preterm birth is associated with increased risk for progressive renal disease and hypertension. What are the future perspectives? Will a drug be developed that, without severe side effects, would abolish the adverse effects of developmental programming of the embryonic and early postnatal kidney? Evidence from experimental studies has indicated that excessive apoptosis could be a major target for preventive therapy. A more immediate question is whether asymptomatic albuminuria in children born preterm should be treated prophylactically with drugs that block the renin-angiotensin system. Although it is well recognized that administration of these drugs will slow the progression in advanced nephropathy, it has not yet been convincingly shown that progression is slowed by early drug administration. Taking into account that we still know rather little about the role of the renin-angiotensin system for postnatal growth and differentiation, children with asymptomatic albuminuria and only a moderate reduction of glomerular filtration rate should not routinely be given drugs that block the renin-angiotensin system. See related article, p 923It is now more than 20 years ago since David Barker proposed that many chronic adult diseases originate from compromised fetal and early postnatal development.1Barker D.J. Childhood causes of adult diseases.Arch Dis Child. 1988; 63: 867-869Crossref PubMed Scopus (45) Google Scholar Barker’s proposal was mainly based on epidemiologic studies, but since then a wealth of experimental and clinical studies have provided evidence for a link between adverse events during fetal and early postnatal life and adult-onset diseases.2Nijland M.J. Ford S.P. Nathanielsz P.W. Prenatal origins of adult disease.Curr Opin Obstet Gynecol. 2008; 20: 132-138Crossref PubMed Scopus (105) Google Scholar See related article, p 923 See related article, p 923 At approximately the same time as Barker first introduced his hypothesis, Barry Brenner proposed that low nephron endowment would predispose to renal disease and hypertension.3Brenner B.M. Garcia D.L. Anderson S. Glomeruli and blood pressure. Less of one, more of the other?.Am J Hypertens. 1988; 3: 335-347Crossref Scopus (1066) Google Scholar A large number of experimental studies, as well as studies of humans with a history of low birth weight, have since then provided unequivocal evidence for this hypothesis, and it is now generally agreed that the kidney is extremely sensitive to the effects of an adverse environment during the time of nephron formation.4Abitbol C.L. Ingelfinger J.R. Nephron mass and cardiovascular and renal disease risks.Semin Nephrol. 2009; 29: 445-454Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Fetal malnutrition is considered to be the most common cause of adverse developmental programming. The development of the metanephric kidney is driven by the formation of nephrons. As the ureteric bud divides and grows into the undifferentiated mesenchymal cells, it triggers the formation of nephrons. The crosstalk between the ureteric bud and the mesenchymal cells is dependent on a well-timed and well-coordinated expression of a large number of genes. The function of the adult kidney depends on its architecture, the order by which its functional units, the nephrons, are arranged. The majority of cells that do not participate in nephron formation will have to undergo apoptosis. Kidney development is therefore dependent on a delicate balance among cell differentiation, proliferation, and apoptosis. Fetal malnutrition results in excessive apoptosis, which is a major cause of low nephron endowment. Recent experimental studies have shown that activation of an antiapoptotic signal will protect the embryonic kidney exposed to malnutrition from adverse developmental programming.5Li J. Khodus G.R. Kruusmägi M. et al.Ouabain protects against adverse developmental programming of the kidney.Nat Commun. 2010; 27: 42https://doi.org/10.1038/ncomms1043Crossref Scopus (69) Google Scholar The formation of nephrons is completed when the ureter bud has reached the outer cortex, which in humans occurs around the 36th gestational week. Thereafter no more nephrons can be formed, and loss of tissue will be structurally compensated by hyperplasia and/or hypertrophy and functionally compensated by increased workload for the existing glomeruli. The filtration pressure will rise due to a resetting of the tonus of hormones regulating renal vascular resistance. This compensation, which involves a resetting of the renal angiotensin tonus, carries a price, which is predisposition to glomerulosclerosis and hypertension. Will infants born before the 36th gestational week continue to form nephrons after birth and, if so, to which extent would nephrogenesis be inhibited by the condition of the very premature infant? Most of the studies of renal function, renal pathology, and predisposition to renal disease in humans have not discriminated between preterm birth and intrauterine growth restriction as cause of low birth weight. Rodents are, for obvious reasons, not suitable for experimental studies on the long-term effect of preterm birth on nephrogenesis. A recent study, performed on preterm baboons, ventilated for up to 21 days postnatally, showed that nephron endowment was not affected by preterm birth, but abnormal glomeruli with a shrunken glomerular tuft and cystic Bowman space were often observed in the outer cortex.6Gubhaju L. Sutherland M.R. Yoder B.A. Zulli A. Bertram J.F. Black M.J. Is nephrogenesis affected by preterm birth? Studies in a hon-human primate model.Am J Physiol Renal Physiol. 2009; 297: F1668-F1677Crossref PubMed Scopus (95) Google Scholar A study performed on tissue collected at autopsy from preterm neonates and stillborn gestational controls has also indicated that nephrogenesis continues postnatally. The outer cortical glomeruli, which should have been formed postnatally, did, however, often exhibit pathomorphologic changes.7Sutherland M.R. Gubhaju L. Moore L. et al.Accelerated maturation and abnormal morphology in the preterm neonatal kidney.J Am Soc Nephrol. 2011; 22: 1365-1374Crossref PubMed Scopus (214) Google Scholar Taken together, these studies indicate that although nephrogenesis continues after preterm birth, the postnatally formed nephrons may be incompletely developed and more prone to develop loss of function and glomerulosclerosis. The study by Vieux et al published in this issue of The Journal supports this assumption.8Vieux R. Hascoet J.M. Franck P. Guillemin F. Increased albuminuria in four-year old preterm-born infants with normal height.J Pediatr. 2012; 160: 923-928Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Albuminuria is the first laboratory sign as well as the hallmark of glomerulosclerosis. In a 4-year follow-up of 119 children with an average gestational age of 29.1 ± 1.4 weeks, they found high levels of albumin in the urine in 17 (14.4%) children. Albuminuria at the age of 4 years was found to be significantly more common in children who were treated for severe neonatal hypotension, indicating that adverse extrauterine conditions will contribute to the pathology of the postnatally formed nephrons. The kidney plays a central role for blood pressure regulation and hypertension is a common feature in chronic renal disease. Reduced capacity to regulate salt balance is considered to be the most common cause of renal hypertension, but changes in the renal vascular tonus are also a contributing factor. Increased blood pressure was observed in 15 (12.6%) of the children. It is too early to tell whether this increase in blood pressure is related to renal pathology or whether it is an independent effect of developmental programming. Chronic kidney diseases represent a major socioeconomical burden. The annual cost to treat kidney diseases in the United States is more than one quarter of Medicare expenditures, and there is now overwhelming evidence that adverse fetal and perinatal conditions endanger kidney development and result in increased risk for renal disease and hypertension. The report by Vieux et al raises several important questions about the role that pediatricians and pediatric research can play in reducing the burden of chronic kidney disease. To which extent should preterm infants be followed up with regard to renal function and blood pressure? The results from this study suggest that very preterm infants should be examined with regard to albuminuria, serum creatinine (or corresponding indicator of glomerular filtration rate), and blood pressure at the age of 2 to 4 years and that children who have albuminuria and/or increased blood pressure should be followed up with at least every second year. If such efforts will be coordinated between different centers, it will give a better understanding of the extent to which preterm birth is associated with increased risk for progressive renal disease and hypertension. What are the future perspectives? Will a drug be developed that, without severe side effects, would abolish the adverse effects of developmental programming of the embryonic and early postnatal kidney? Evidence from experimental studies has indicated that excessive apoptosis could be a major target for preventive therapy. A more immediate question is whether asymptomatic albuminuria in children born preterm should be treated prophylactically with drugs that block the renin-angiotensin system. Although it is well recognized that administration of these drugs will slow the progression in advanced nephropathy, it has not yet been convincingly shown that progression is slowed by early drug administration. Taking into account that we still know rather little about the role of the renin-angiotensin system for postnatal growth and differentiation, children with asymptomatic albuminuria and only a moderate reduction of glomerular filtration rate should not routinely be given drugs that block the renin-angiotensin system. Increased Albuminuria in 4-Year-Old Preterm-Born Children with Normal HeightThe Journal of PediatricsVol. 160Issue 6PreviewTo determine risk factors for high blood pressure (BP), increased markers of glomerulosclerosis, and tubular dysfunction in 4-year-old preterm-born children. Full-Text PDF