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Differential Effects of Clinical Doses of Antenatal Betamethasone on Nephron Endowment and Glomerular Filtration Rate in Adult Sheep

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Abstract

Antenatal steroid administration is associated with alterations in fetal kidney development and hypertension. However, a causal relationship between nephron deficit and hypertension has not been established. In this study, we measured nephron number, renal function, and blood pressure in sheep exposed antenataly to betamethasone. Pregnant sheep were given 2 betamethasone doses (0.17 mg/kg) or vehicle at 80 and 81 days gestational age and allowed to deliver at term. Data were obtained from a fetal cohort and 2 adult cohorts and were analyzed by analysis of variance (ANOVA) and/or 2 sample t test. Antenatal betamethasone induced a 26% reduction in the number of nephrons in both males and females in the absence of intrauterine growth restriction and/or prematurity. Adult males presented a reduction in glomerular filtration rate (GFR; 132 ± 12.7 vs 114 ± 7.0 mL/min, P < .05). Betamethasone administration was also associated with an increase in arterial blood pressure of similar magnitude in male (mean arterial pressure [MAP] in mm Hg; 98 ± 2.7 vs 105 ± 2.4) and female (96 ± 1.9 vs 105 ± 2.4) adult sheep and the increase in blood pressure preceded the decrease in GFR in the males. Furthermore, we found no significant association between the magnitude of the decrease in nephron number and the magnitude of the increase in arterial blood pressure. Our data thus support the conclusion that exposure to glucocorticoids at a time of rapid kidney growth is associated with an elevation in blood pressure that does not appear related solely to the reduction in nephron number.

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References

  1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4): 515–525.

    CAS  PubMed  Google Scholar 

  2. Leviton LC, Goldenberg RL, Baker CS, et al. Methods to encourage the use of antenatal corticosteroid therapy for fetal maturation: a randomized controlled trial. JAMA. 1999; 281(1):46–52.

    Article  CAS  PubMed  Google Scholar 

  3. Doyle LW, Ford GW, Davis NM, Callanan C. Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci. 2000;98(2):137–142.

    Article  CAS  Google Scholar 

  4. Dalziel SR, Walker NK, Parag V, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet. 2005; 365(9474):1856–1862.

    Article  CAS  PubMed  Google Scholar 

  5. 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(3):317–322.

    Article  CAS  PubMed  Google Scholar 

  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 (Lond). 2003;549(3):929–935.

    Article  CAS  Google Scholar 

  7. Langley-Evans SC, Welham SJ, Jackson AA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999;64(11):965–974.

    Article  CAS  PubMed  Google Scholar 

  8. Hellmann H, Davis JM, Thurau K. Glomerulus number and blood pressure in the Prague hypertensive rat. Kidney Int Suppl. 1998;67:S211–S212.

    Article  CAS  PubMed  Google Scholar 

  9. Mackenzie HS, Lawler EV, Brenner BM. Congenital oligonephropathy: the fetal flaw in essential hypertension? Kidney Int. 1996;55:S30–S34.

    CAS  Google Scholar 

  10. Skov K, Nyengaard JR, Korsgaard N, Mulvany MJ. Number and size of renal glomeruli in spontaneously hypertensive rats. J Hypertens. 1994;12(12):1373–1376.

    Article  CAS  PubMed  Google Scholar 

  11. Fassi A, Sangalli F, Maffi R, et al. Progressive glomerular injury in the MWF rat is predicted by inborn nephron deficit. JAm Soc Nephrol. 1998;9(8):1399–1406.

    CAS  Google Scholar 

  12. Cullen-McEwen LA, Kett MM, Dowling J, Anderson WP, Bertram JF. Nephron number, renal function, and arterial pressure in aged GDNF heterozygous mice. Hypertension. 2003;41(2):335–340.

    Article  CAS  PubMed  Google Scholar 

  13. Poladia DP, Kish K, Kutay B, Bauer J, Baum M, Bates CM. Link between reduced nephron number and hypertension: studies in a mutant mouse model. Pediatr Res. 2006;59(4 pt 1):489–493.

    Article  PubMed  Google Scholar 

  14. Crocker JF, Brown DM, Vernier RL. Developmental defects of the kidney. A review of renal development and experimental studies of maldevelopment. Pediatr Clin North Am. 1971; 18(2):355–376.

    Article  CAS  PubMed  Google Scholar 

  15. Gimonet V, Bussieres L, Medjebeur AA, Gasser B, Lelongt B, Laborde K. Nephrogenesis and angiotensin II receptor subtypes gene expression in the fetal lamb. Am J Physiol. 1998; 274(6 pt 2):F1062–F1069.

    CAS  PubMed  Google Scholar 

  16. Figueroa JP, Rose JC, Massmann GA, Zhang J, Acuna G. Alterations in fetal kidney development and elevations in arterial blood pressure in young adult sheep after clinical doses of antenatal glucocorticoids. Pediatr Res. 2005;58(3):510–515.

    Article  PubMed  Google Scholar 

  17. Shaltout HA, Figueroa JP, Rose JC, Diz DI, Chappell MC. Alterations in circulatory and renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 in fetal programmed hypertension. Hypertension. 2009;53(2):404–408.

    Article  CAS  PubMed  Google Scholar 

  18. Wirtschafter DD, Danielsen BH, Main EK, et al. Promoting antenatal steroid use for fetal maturation: results from the California Perinatal Quality Care Collaborative. J Pediatr. 2006; 148(5):606–612.

    Article  CAS  PubMed  Google Scholar 

  19. Wapner RJ, Sorokin Y, Mele L, et al. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med. 2007;357(12):1190–1198.

    Article  CAS  PubMed  Google Scholar 

  20. Bains RK, Sibbons PD, Murray RD, Howard CV, Van Velzen D. Stereological estimation of the absolute number of glomeruli in the kidneys of lambs. Res Vet Sci. 1996; 60(2):122–125.

    Article  CAS  PubMed  Google Scholar 

  21. Brandon AE, Boyce AC, Lumbers ER, Zimanyi MA, Bertram JF, Gibson KJ. Glomerular hypertrophy in offspring of subtotally nephrectomized ewes. Anat Rec (Hoboken). 2008;291(3):318–324.

    Article  CAS  Google Scholar 

  22. Drake AJ, Walker BR, Seckl JR. Intergenerational consequences of fetal programming by in utero exposure to gluco-corticoids in rats. AJP—Reg Int Comp Phys. 2005;288(1): R34–R38.

    CAS  Google Scholar 

  23. Zohdi V, Moritz KM, Bubb KJ, et al. Nephrogenesis and the renal renin-angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation. AJP—Reg Int CompPhys. 2007;293(3):R1267–R1273.

    CAS  Google Scholar 

  24. Gray SP, Kenna K, Bertram JF, et al. Repeated ethanol exposure during late gestation decreases nephron endowment in fetal sheep. AJP—Reg Int Comp Phys. 2008;295(2): R568–R574.

    CAS  Google Scholar 

  25. Mitchell EK, Louey S, Cock ML, Harding R, Black MJ. Nephron endowment and filtration surface area in the kidney after growth restriction of fetal sheep. Pediatr Res. 2004;55(5): 769–773.

    Article  PubMed  Google Scholar 

  26. Gopalakrishnan GS, Gardner DS, Dandrea J, et al. Influence of maternal pre-pregnancy body composition and diet during early-mid pregnancy on cardiovascular function and nephron number in juvenile sheep. Br JNutr. 2005;94(6):938–947.

    CAS  Google Scholar 

  27. Gilbert JS, Lang AL, Grant AR, Nijland MJ. Maternal nutrient restriction in sheep: hypertension, decreased nephron number and altered renal RAS expression in offspring at nine months. J Physiol. 2005;565(1):137–147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hughson M, Farris AB III, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. 2003;63(6): 2113–2122.

    Article  PubMed  Google Scholar 

  29. 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(2):770–773.

    Article  CAS  PubMed  Google Scholar 

  30. Hughson MD, Gobe GC, Hoy WE, Manning RD Jr, Douglas-Denton R, Bertram JF. Associations of glomerular number and birth weight with clinicopathological features of African Americans and whites. Am J Kidney Dis. 2008;52(1):18–28.

    Article  PubMed  Google Scholar 

  31. Bagby SP. Maternal nutrition, low nephron number, and hypertension in later life: pathways of nutritional programming. J Nutr. 2007;137(4):1066–1072.

    Article  CAS  PubMed  Google Scholar 

  32. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens. 1988; 1(4 pt 1):335–347.

    Article  CAS  PubMed  Google Scholar 

  33. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996;49(6): 1774–1777.

    Article  CAS  PubMed  Google Scholar 

  34. Shaltout HA, Figueroa JP, Rose JC, Diz DI, Chappell MC. Alterations in circulatory and renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 in fetal programmed hypertension. Hypertension. 2009;53(2):404–408.

    Article  CAS  PubMed  Google Scholar 

  35. Tang L, Carey LC, Bi J, et al. Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep. Am J Physiol Regul Integr Comp Physiol. 2009; 296(2):R309–R317.

    Article  CAS  PubMed  Google Scholar 

  36. Massmann GA, Zhang J, Rose JC, Figueroa JP. Acute and long-term effects of clinical doses of antenatal glucocorticoids in the developing fetal sheep kidney. J Soc Gynecol Investig. 2006;13(3):174–180.

    Article  CAS  PubMed  Google Scholar 

  37. Dodic M, McAlinden AT, Jefferies AJ, et al. Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep. J Physiol. 2006; 571(pt 3):651–660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Levitt NS, Lindsay RS, Holmes MC, Seckl JR. Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology. 1996;64(6):412–418.

    Article  CAS  PubMed  Google Scholar 

  39. Dodic M, Tangalakis K, Moritz K, McFarlane A, Wintour EM. Fluid abnormalities occur in the chronically cannulated mid-gestation but not late gestation ovine fetus. Pediatr Res. 1998;44(6):894–899.

    Article  CAS  PubMed  Google Scholar 

  40. Dodic M, Abouantoun T, O’Connor A, Wintour EM, Moritz KM. Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension. 2002;40(5):729–734.

    Article  CAS  PubMed  Google Scholar 

  41. Dodic M, Hantzis V, Duncan J, et al. Programming effects of short prenatal exposure to cortisol. FASEB J. 2002;16(9): 1017–1026.

    Article  CAS  PubMed  Google Scholar 

  42. Seliem WA, Falk MC, Shadbolt B, Kent AL. Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up. Pediatr Nephrol. 2007;22(12):2081–2087.

    Article  PubMed  Google Scholar 

  43. Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics. 2000;105(6): E77–E84.

    Article  CAS  PubMed  Google Scholar 

  44. Finken MJ, Keijzer-Veen MG, Dekker FW, et al. Antenatal glucocorticoid treatment is not associated with long-term metabolic risks in individuals born before 32 weeks of gestation. Arch Dis Child Fetal Neonatal Ed. 2008;93(6): F442–F447.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Perinatal Research Laboratory, Department of Obstetrics and Gynecology, Center for Research in Obstetrics and Gynecology, Wake Forest University School of Medicine, Medical Center Boulevard, 27157, Winston-Salem, North Carolina, USA

    Jie Zhang MD, G. Angela Massmann MD, MS, James C. Rose PhD & Jorge P. Figueroa MD, PhD

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  1. Jie Zhang MD
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  2. G. Angela Massmann MD, MS
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  3. James C. Rose PhD
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  4. Jorge P. Figueroa MD, PhD
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Correspondence to Jorge P. Figueroa MD, PhD.

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Zhang, J., Massmann, G.A., Rose, J.C. et al. Differential Effects of Clinical Doses of Antenatal Betamethasone on Nephron Endowment and Glomerular Filtration Rate in Adult Sheep. Reprod. Sci. 17, 186–195 (2010). https://doi.org/10.1177/1933719109351098

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