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Arterial hypertension and cystatin C during neonatal physiologic dehydration

Journal of Human Hypertension volume 36, pages 554–560 (2022)Cite this article

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Abstract

A reduced nephron number may play a role in the pathogenesis of arterial hypertension (AH), and it is well recognized that individual nephron endowment is widely variable. However, nephrons count is technically impossible in vivo. Based on the observation that subjects with a reduced nephron mass exhibit an increase in renal functional biomarkers during acute dehydration, we hypothesized that cystatin C concentration during neonatal physiological dehydration could identify subjects with reduced nephron endowment. This is a prospective, observational, cohort study enrolling healthy, caucasian, term neonates born after an uneventful pregnancy. Two groups of newborns were compared: neonates born to fathers on antihypertensive treatment (HF) versus those born to proven normotensive fathers older than 40 years of age (NF). Enrolled newborns underwent cystatin C determination at the time of newborn screening. Forty newborns with HF and 80 with NF were enrolled. No differences in baseline characteristics were observed between the two groups except for the number of hypertensive grandparents higher among newborns to HF (47.8% vs. 21.1%; p: 0.001). Cystatin C was significantly higher in newborns with HF (1.62 ± 0.30 mg/L vs 1.41 ± 0.27 mg/L; p < 0.001). Linear regression analysis corrected for confounders confirmed that paternal hypertension was the only variable significantly associated with high cystatin C level during post-natal dehydration. Besides offering new insights on the pathogenesis of familial hypertension, our results support the specific role of nephron endowment and suggest the possibility of identifying subjects at risk for reduced nephron endowment as early as at birth.

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Fig. 1: Comparison between cystatin C value in neonates born to NF and HF.
Fig. 2: Receiver Operating Characteristic (ROC) curve for Cys-C levels.

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References

  1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2224–60.

    Article  Google Scholar 

  2. Gurusinghe S, Tambay A, Sethna CB. Developmental origins and nephron endowment in hypertension. Front Pediatr 2017;5:1–8.

    Article  Google Scholar 

  3. Narayan KMV, Ali MK, Koplan JP. Global noncommunicable diseases—were worlds meet. N. Engl J Med. 2010;363:1196–8.

    Article  CAS  Google Scholar 

  4. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.

    Article  Google Scholar 

  5. Ehret GB, Caulfield MJ. Genes for blood pressure: an opportunity to understand hypertension. Eur Heart J. 2013;34:951–61.

    Article  CAS  Google Scholar 

  6. Franceschini N, Chasman D, Cooper-DeHoff R, Arnett D. Genetics, ancestry, and hypertension: implications for targeted antihypertensive therapies. Curr Hypertens Rep. 2014;16:461.

    Article  Google Scholar 

  7. Kastl JT. Renal function in the fetus and neonate—the creatinine enigma. Semin Fetal Neonatal Med 2017;22:83–9.

    Article  Google Scholar 

  8. Bidani AK, Polichnowski AJ, Loutzenhiser R, Griffin KA. Renal microvascular dysfunction, hypertension and CKD progression. Curr Opin Nephrol Hypertens. 2013;22:1–9.

    Article  CAS  Google Scholar 

  9. Brenner BM, Garcia DL. Glomeruli anD Blood Pressure. Am J Hypertens. 1988;1:335–47.

    Article  CAS  Google Scholar 

  10. Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, et al. Renal outcome in patients with congenital anomalies of the kidney and urinary tract. Kidney Int. 2009;76:528–33.

    Article  Google Scholar 

  11. Hogan J, Dourthe ME, Blondiaux E, Jouannic JM, Garel C, Ulinski T. Renal outcome in children with antenatal diagnosis of severe CAKUT. Pediatr Nephrol. 2012;27:497–502.

    Article  Google Scholar 

  12. Whelton PK, Carey RM, Aronow WS, Ovbiagele B, Casey DE, Smith SC, et al. 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults A Report of the American College of Cardiology/American Heart Association T.; 2017. https://doi.org/10.1161/HYP.0000000000000065.

  13. Cai T, Karlaftis V, Hearps S, Matthews S, Burgess J, Monagle P, et al. Reference intervals for serum cystatin C in neonates and children 30 days to 18 years old. Pediatr Nephrol. 2020;35:1959–66.

    Article  Google Scholar 

  14. Finney H, Newman DJ, Thakkar H, Fell JME, Price CP. Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children. Arch Dis Child. 2000;82:71–5.

    Article  CAS  Google Scholar 

  15. Bökenkamp A, Domanetzki M, Zinck R, Schumann G, Brodehl J. Reference values for cystatin C serum concentrations in children. Pediatr Nephrol. 1998;12:125–9.

    Article  Google Scholar 

  16. Kandasamy Y, Smith R, Wright IMR. Measuring cystatin C to determine renal function in neonates. Pediatr Crit Care Med. 2013;14:318–22.

    Article  Google Scholar 

  17. Radhakrishna V, Kumaravel S, Priyamvada PS, Hanumanthappa N, Jindal B, Govindarajan K, et al. Clinico-Biochemical Profile of Children with Congenital Anomalies of the Kidney and Urinary Tract: A Cross-Sectional Study. Kidney Dis. 2019;5:51–7.

    Article  Google Scholar 

  18. Seeman T, Patzer L, John U, Dušek J, Vondrák K, Janda J, et al. Blood pressure, renal function, and proteinuria in children with unilateral renal agenesis. Kidney Blood Press Res. 2006;29:210–5.

    Article  Google Scholar 

  19. Munger RG, Prineas RJ, Gomez-Marin O. Persistent elevation of blood pressure among children with a family history of hypertension: The minneapolis children’s blood pressure study. J Hypertens. 1988;6:647–53.

    Article  CAS  Google Scholar 

  20. Mahmooda SS, Levyb D, Vasan RS, Wang TJ. The Framingham heart study and the epidemiology of cardiovascular diseases: a historical perspective. Lancet. 2014;383:999–1008.

    Article  Google Scholar 

  21. Patel RS, Masi S, Taddei S. Understanding the role of genetics in hypertension. Eur Heart J. 2017;38:2309–12.

    Article  Google Scholar 

  22. Bianchi G, Fox U, Di Francesco GF, Giovanetti AM, Pagetti D. Blood pressure changes produced by kidney cross transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med. 1974;47:435–48.

    CAS  PubMed  Google Scholar 

  23. Rettig R, Folberth C, Stauss H, Kopf D, Waldherr R, Unger T. Role of the kidney in primary hypertension: a renal transplantation study in rats. Am J Physiol Ren Fluid Electrolyte Physiol. 1990;258:F606–611.

    Article  CAS  Google Scholar 

  24. Strandgaard S, Hansen U. The donor factor in hypertension after renal transplantation. JIM. 1982;220:49–53.

    Google Scholar 

  25. Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel JD, Jones P, et al. Remission of essential hypertension after renal transplantation. NEJM. 1983;309:1009–15.

    Article  CAS  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. Wood-Bradley RJ, Barrand S, Giot A, Armitage JA. Understanding the role of maternal diet on kidney development; an opportunity to improve cardiovascular and renal health for future generations. Nutrients. 2015;7:1881–905.

    Article  CAS  Google Scholar 

  28. Barker DJP. Adult consequences of fetal growth restriction. Clin Obstet Gynecol. 2006;49:270–83.

    Article  Google Scholar 

  29. McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: Prediction, plasticity, and programming. Physiol Rev. 2005;85:571–633.

    Article  CAS  Google Scholar 

  30. Keller G, Zimmer G, Mall G, Ritz EAK. Nephron number in patients with primary hypertension. N Engl J Med.2003;248:101–08.

    Article  Google Scholar 

  31. Ritz E, Amann K, Koleganova N, Benz K. Prenatal programming—effects on blood pressure and renal function. Nat Rev Nephrol. 2011;7:137–44.

    Article  Google Scholar 

  32. Brenner BM, Charlton J, Luyckx V, Manfellotto D, Perico N, Remuzzi G, et al. The Impact of Kidney Development on the Life Course: A Consensus Document for Action. Nephron. 2017;136:3–49.

    Article  Google Scholar 

  33. Ardissino G, Tel F, Possenti I, Pavesi M, Perrone M, Forni G, et al. Serum creatinine during physiological perinatal dehydration may estimate individual nephron endowment. Eur J Pediatr. 2018;177:1383–8.

    Article  Google Scholar 

  34. Cataldi L, Mussap M, Bertelli L, Ruzzante N, Fanos V, Plebani M. Cystatin C in healthy women at term pregnancy and in their infant newborns: relationship between maternal and neonatal serum levels and reference values. Am J Perinatol. 1999;16:287–95.

    Article  CAS  Google Scholar 

  35. Bökenkamp A, Dieterich C, Dressler F, Mühlhaus K, Gembruch U, Bald R, et al. Fetal serum concentrations of cystatin C and β2-microglobulin as predictors of postnatal kidney function. Am J Obstet Gynecol. 2001;185:468–75.

    Article  Google Scholar 

  36. Flaherman VJ, Schaefer EW, Kuzniewicz MW, Li SX, Walsh EM, Paul IM. Early weight loss nomograms for exclusively breastfed newborns. Pediatrics. 2015;135:e16–e23.

    Article  Google Scholar 

  37. Kelly NM, Keane JV, Gallimore RB, Bick D, Tribe RM. Neonatal weight loss and gain patterns in caesarean section born infants: integrative systematic review. Matern Child Nutr. 2020;16:e12914.

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Acknowledgements

The authors would like to thank the parents who participated in the present study.

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Authors and Affiliations

  1. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy

    Beatrice L. Crippa, Stefano Ghirardello, Lorenzo Colombo, Lidia Zanotta & Fabio Mosca

  2. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Beatrice L. Crippa, Lorenzo Colombo & Fabio Mosca

  3. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplantation Unit, Milan, Italy

    Francesca Tel & Gianluigi Ardissino

  4. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Epidemiology Unit, Milan, Italy

    Dario Consonni

  5. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pediatric Cardiology, Milan, Italy

    Patrizia Salice & Silvia Ghiglia

Authors
  1. Beatrice L. Crippa
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  2. Stefano Ghirardello
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  4. Francesca Tel
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  10. Gianluigi Ardissino
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Contributions

BLC collected data, carried out the statistical analysis, contributed to the interpretation of results and drafted the initial manuscript. St.G contributed to design the study, contributed to the interpretation of results and reviewed and revised the manuscript. LC supervised data collection and reviewed the manuscript. FT contributed to design the study, reviewed and revised the manuscript. LZ collected data, reviewed and revised the manuscript. DC carried out the statistical analysis, contributed to the interpretation of results, reviewed and revised the manuscript. PS, Si.G contributed to the interpretation of results, reviewed and revised the manuscript. FM supervised data collection, contributed to the interpretation of results, reviewed and revised the manuscript. GA design the study, supervised data collection, carried out the statistical analysis, contributed to the interpretation of results, reviewed and revised the manuscript. All authors gave final approval of the manuscript version submitted for publication.

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Correspondence to Beatrice L. Crippa.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Crippa, B.L., Ghirardello, S., Colombo, L. et al. Arterial hypertension and cystatin C during neonatal physiologic dehydration. J Hum Hypertens 36, 554–560 (2022). https://doi.org/10.1038/s41371-021-00541-4

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