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Nephron Number, Uric Acid, and Renal Microvascular Disease in the Pathogenesis of Essential Hypertension

2006; Lippincott Williams & Wilkins; Volume: 48; Issue: 1 Linguagem: Inglês

10.1161/01.hyp.0000223447.53155.d5

1524-4563

Daniel I. Feig, Bernardo Rodríguez‐Iturbe, Takahiko Nakagawa, Richard J. Johnson,

Neonatal Health and Biochemistry

HomeHypertensionVol. 48, No. 1Nephron Number, Uric Acid, and Renal Microvascular Disease in the Pathogenesis of Essential Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNephron Number, Uric Acid, and Renal Microvascular Disease in the Pathogenesis of Essential Hypertension Daniel I. Feig, Bernardo Rodriguez-Iturbe, Takahiko Nakagawa and Richard J. Johnson Daniel I. FeigDaniel I. Feig From the Division of Pediatric Nephrology (D.I.F.), Texas Children's Hospital, Baylor College of Medicine, Houston, Tex; Hospital Universitario and Universidad del Zulia (B.R.-I.), Maracaibo, Venezuela; and the Division of Nephrology, Hypertension and Transplantation (T.N., R.J.J.), University of Florida, Gainesville. , Bernardo Rodriguez-IturbeBernardo Rodriguez-Iturbe From the Division of Pediatric Nephrology (D.I.F.), Texas Children's Hospital, Baylor College of Medicine, Houston, Tex; Hospital Universitario and Universidad del Zulia (B.R.-I.), Maracaibo, Venezuela; and the Division of Nephrology, Hypertension and Transplantation (T.N., R.J.J.), University of Florida, Gainesville. , Takahiko NakagawaTakahiko Nakagawa From the Division of Pediatric Nephrology (D.I.F.), Texas Children's Hospital, Baylor College of Medicine, Houston, Tex; Hospital Universitario and Universidad del Zulia (B.R.-I.), Maracaibo, Venezuela; and the Division of Nephrology, Hypertension and Transplantation (T.N., R.J.J.), University of Florida, Gainesville. and Richard J. JohnsonRichard J. Johnson From the Division of Pediatric Nephrology (D.I.F.), Texas Children's Hospital, Baylor College of Medicine, Houston, Tex; Hospital Universitario and Universidad del Zulia (B.R.-I.), Maracaibo, Venezuela; and the Division of Nephrology, Hypertension and Transplantation (T.N., R.J.J.), University of Florida, Gainesville. Originally published8 May 2006https://doi.org/10.1161/01.HYP.0000223447.53155.d5Hypertension. 2006;48:25–26Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 8, 2006: Previous Version 1 One of the world's greatest epidemics is the epidemic of essential hypertension, which during the last 100 years has increased from a prevalence of 5% to 10% in the European and American population to >30% today. Hypertension was nonexistent in other places of the world but has risen to similar frequencies with the introduction of Western diet and culture. As a major cause of stroke, heart disease, and kidney disease, hypertension is a major underlying cause of morbidity and mortality, and therefore understanding its underlying etiology is critically important.The groundbreaking studies of Dahl and Guyton led to the recognition of the key role for the kidney in the pathogenesis, but controversy remains on the precise mechanism. The observations that several hereditary causes of hypertension result from genetic mutations that lead to increased sodium reabsorption in the nephron (particularly in the collecting duct) has led to a search for genetic causes.1 However, although genetic polymorphisms are clearly important, most studies suggest genetic mechanisms may only have a modest (20%) influence on the hypertensive phenotype.2A congenital mechanism, or fetal programming, has also been proposed (the "Barker-Brenner hypothesis").3,4 Low birth weights (LBWs) predispose to the later development of hypertension as well as other cardiovascular diseases, including obesity and diabetes. LBW infants often have impaired kidney development, resulting in a reduced nephron endowment. Following birth, the children have an increased risk for developing endothelial dysfunction and obesity, and by adulthood they have a relatively increased frequency of hypertension, obesity, and diabetes.3,4Although LBW is a predisposing factor, it can only account for a modest 20% of the variation. Small infants have a 29% risk of developing hypertension as adults, whereas the risk for large infants is 24%.5 The evidence for low nephron number is more compelling,6 but it remains unclear how a reduction in nephron number causes hypertension. The observation that kidney donation in adults only increases the risk for hypertension slightly has suggested that there may be something unique about the fetal environment that may be critical for the later phenotype.A third major hypothesis is that subtle renal microvascular and inflammatory injury to the kidney may result in increased salt-sensitivity and hypertension.7 The injury can develop via a variety of mechanisms that all have in common renal vasoconstriction and that lead to the development of microvascular disease and interstitial inflammation with the local generation of oxidants and angiotensin II. A central pathway that can drive the process is endothelial dysfunction with a reduction in local endothelial NO levels, and evidence has been provided that elevated uric acid may be one of the major causes of endothelial dysfunction, linking hyperuricemia with hypertension, metabolic syndrome, and kidney disease.8–10 These associations are supported by preliminary studies in humans.11,12 More definitive studies in humans are ongoing.The observation that uric acid may have a pathogenic role in essential hypertension led to a hypothesis to account for how a LBW and a low nephron number might predispose to hypertension later in life.11 Specifically, it is known that mothers at risk for having LBW babies are frequently hypertensive, obese, or preeclamptic, which are all conditions associated with elevated uric acid levels. In turn, elevated uric acid in the mother is a major risk factor for a LBW infant.13,14 Uric acid is a small molecular weight substance that passes freely into the fetal circulation13 where it has the potential for inhibiting glomerular endothelial cell proliferation.11 A rise in uric acid in the third trimester would preferentially affect nephron development since kidney development occurs late in pregnancy. The child would then be born with a low nephron number. Over time the child would also be predisposed to developing hyperuricemia, for the child would likely have similar dietary and hereditary predispositions to the mother, and hence would be at risk for the early development of hypertension. This hypothesis has support in in vitro studies and animal models in which reduction in nephron number in adult rats has also been shown to predispose to preglomerular arteriolar disease,15 which engages the cycle of microvascular injury and interstitial inflammation.Epidemiological evidence is now accruing to support this latter hypothesis. In this issue of Hypertension, Franco et al evaluated 78 children who were born at full term: 42 with LBW ( 3000 g.16 At 8 to 13 years old, children with a history of LBW had higher systolic blood pressure (albeit still in the normal range), markedly higher serum uric acid, and altered endothelial function as assessed by flow-mediated dilation studies. Because patients with birth weight between 2500 g and 3000 g were excluded from analysis it is not possible to know whether these patients fall between the 2 extreme groups.The link between LBW and future hypertension has been challenged by Falkner and colleagues, who evaluated 250 children, 36% of whom were LBW and found no inverse correlation with adolescent blood pressure or body mass index at 11 to 14 years old.17 In contrast, we found adolescents with newly diagnosed essential hypertension were hyperuricemic in nearly 90% of cases, and the uric acid levels correlated both with the severity of the systolic and diastolic hypertension and inversely with the birth weight.11,18 Children with normal blood pressure, white coat hypertension, and secondary hypertension did not have similar correlations.11Evidence is also accruing that it is the presence of renal microvascular disease and not nephron number that is the critical determinant of whether hypertension will develop. Hence, in the spontaneously hypertensive rat, cross-breeding was able to show that the hypertensive phenotype tracked with the progeny that had small renal arterioles as opposed to low nephron number.19,20 Low-protein diet feeding to pregnant rats also results in LBW pups that subsequently develop hypertension. However, recent studies show that these pups develop renal microvascular disease and interstitial inflammation early in life, and that if these structural changes are blocked with mycophenolate the subsequent development of hypertension can be prevented.21In conclusion, the ability of uric acid to induce endothelial dysfunction and inhibit angiogenesis makes it an attractive mechanism for providing the linkage between birth weight and future cardiovascular disease. The observation that Western diet, particularly fructose-containing sugars and purine-rich meats, can markedly raise uric acid levels also provides a mechanism to explain the rapid development of obesity and hypertension throughout the world.22 Of course, there is the alternative possibility that uric acid remains a secondary phenomenon and simply reflects early vascular dysfunction, as proposed by the authors in the accompanying article. It will thus be important to perform further experimental and clinical studies to determine the mechanistic pathways that are driving this epidemic of hypertension and cardiorenal disease.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingSupported by National Institutes of Health (NIH) grants HL-68607, DK-52121, and HL-79352. B.R.-I. is supported by Fondo Nacional de Ciencia y Technologia grant F-2005000283.D.I.F. was supported by NIH grants DK064587 and DK071223.DisclosuresRichard J. Johnson is a consultant for TAP Pharmaceuticals, Inc, Scios Inc, and Nephromics Inc. The remaining authors report no conflicts.FootnotesCorrespondence to Richard J. Johnson, University of Florida-Gainesville, PO Box 100224, Gainesville, FL 32610. E-mail [email protected] References 1 Lifton RP. Molecular genetics of human blood pressure variation. Science. 1996; 272: 676–680.CrossrefMedlineGoogle Scholar2 Province MA, Kardia SL, Ranade K, Rao DC, Thiel BA, Cooper RS, Risch N, Turner ST, Cox DR, Hunt SC, Weder AB, Boerwinkle E. A meta-analysis of genome-wide linkage scans for hypertension: The National Heart, Lung and Blood Institute Family Blood Pressure Program. Am J Hypertens. 2003; 16: 144–147.CrossrefMedlineGoogle Scholar3 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. Brit Med J. 1989; 298: 564–567.CrossrefMedlineGoogle Scholar4 Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease. The role of fetal programming. Hypertension. 2006; 47: 502–508.LinkGoogle Scholar5 Eriksson J, Forsén T, Tuomilehto J, Osmod C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000; 36: 790–794.CrossrefMedlineGoogle Scholar6 Keller J, Zimmer G, Mall G, Ritz E, Amann K. Nephron number in patients with primary hypertension. N Engl J Med. 2003; 348: 101–118.CrossrefMedlineGoogle Scholar7 Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002; 346: 913–923.CrossrefMedlineGoogle Scholar8 Johnson RJ, Feig DI, Kang DH, Herrera-Acosta J. Resurrection of uric acid as a causal risk factor for essential hypertension. Hypertension. 2005; 45: 18–20.LinkGoogle Scholar9 Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Johnson RJ. Uric acid is a causal factor in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006; 290: F625–F631.CrossrefMedlineGoogle Scholar10 Kang D-H, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ. A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002; 13: 2888–2897.CrossrefMedlineGoogle Scholar11 Feig DI, Nakagawa T, Karumanchi SA, Oliver WJ, Kang D-H, Finch J, Johnson RJ. Uric acid, nephron number, and the pathogenesis of essential hypertension. Kidney Int. 2004; 66: 281–287.CrossrefMedlineGoogle Scholar12 Siu YP, Leung KT, Tong MKH, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability in lowering serum uric acid level. Am J Kid Dis. 2006; 47: 51–59.CrossrefMedlineGoogle Scholar13 Chang FM, Chow SN, Huang HC, Hsieh FJ, Chen HY, Lee TY, Ouyang PC, Chen YP. The placental transfer and concentration difference in maternal and neonatal serum uric acid at parturition: comparison of normal pregnancy and gestosis. Biol Res Pregnancy Perinatol. 1987; 35: 35–39.Google Scholar14 Roberts JM, Bodnar LM, Lain KY, Hubel CA, Markovic N, Ness RB, Powers RW. Uric acid is as important as proteinuria in identifying fetal risk in women with gestational hypertension. Hypertension. 2005; 46: 1263–1269.LinkGoogle Scholar15 Sanchez-Lozada LG, Tapia E, Johnson RJ, Rodriguez-Iturbe B, Herrera-Acosta J. Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation. Kidney Int Suppl. 2003; 86: S9–S14.Google Scholar16 Franco MCP, Christofalo DMJ, 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.LinkGoogle Scholar17 Falkner B, Hulman S, Kushner H. Effect of birth weight on blood pressure and body size in early adolescence. Hypertension. 2004; 43: 203–207.LinkGoogle Scholar18 Feig DI, Johnson RJ. Hyperuricemia in childhood essential hypertension. Hypertension. 2003; 42: 247–252.LinkGoogle Scholar19 Black MJ, Briscoe TA, Constantinou M, Kett MM, Bertram JF. Is there an association between level of adult blood pressure and nephron number or surface area? Kidney Int. 2004; 65: 582–588.CrossrefMedlineGoogle Scholar20 Skov K, Mulvany MJ. Structure of renal afferent arterioles in the pathogenesis of hypertension. Acta Physiol Scand. 2004; 181: 397–405.CrossrefMedlineGoogle Scholar21 Stewart T, Jung FF, Manning J, Vehaskari VM. Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension. 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