Does protein intake correlate with tubular function in very preterm neonates?

  • Henny Adriani Puspitasari Department of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo General Hospital, Jakarta
  • Partini Pudjiastuti Trihono Department of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo General Hospital, Jakarta
  • Pustika Amalia Wahidiyat Department of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo General Hospital, Jakarta
Keywords: very preterm neonates; protein; urinary neutrophil gelatinase-associated lipocalin; tubular injury


Background High protein intake in very preterm neonates (VPN) is important for growth. However, preterm kidneys have fewer functional nephrons and many of the ones present may be immature. Studies have shown that high protein intake induces nephron hypertrophy, proteinuria, and glomerular sclerosis, which lead to tubular injury. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is a biomarker that is released during proximal tubular cell injury. The uNGAL to creatinine (uNGAL/Cr) ratio is commonly performed for normalization.

Objective To assess for a possible association between protein intake and uNGAL/Cr ratio in VPN.

Methods A prospective cohort study was conducted in two NICUs in Jakarta. Subjects’ urine specimens were collected at 0-48 hours, 72 hours, and 21 days after birth to determine uNGAL/Cr ratio as a biomarker of tubular injury. Protein was administered according to study sites NICU guidelines. Protein intake was recorded daily from 14-21 days of age for formula and measured twice with a human milk analyzer for breast milk. ELISA was used to measure uNGAL concentration. Low protein intake was defined as <3g/kg/day and high protein intake was defined as ?3g/kg/day. Maternal and perinatal variables were recorded from medical records.

Results Fifty-nine VPN were recruited, of whom 39 completed the study. Median uNGAL/Cr ratio ranged from 0.32-104.11 ng/mg. The uNGAL/Cr ratio was not correlated with protein intake but was inversely correlated with gestational age and birth weight [r = -0.320, P=0.019 for the 72-hr (T2) urinary collection]. Higher uNGAL/Cr levels were associated with maternal infection [14.4 (range 4.4-104.1) vs 7.2 (range 0.5–32.4) ng/mg, P=0.004 at the 0-48-hr (T1)], maternal anemia [6.9 (range 1.2–66.6) vs 1.7 (range 0.3–89.2) ng/mg, P=0.001 at the 21-day (T3)] and nephrotoxic medication [15.9 (range 1.3–63.8) vs 1.0 (range 0.4–8.6) ng/mg, P=0.026 at the 72-hr].

Conclusion Protein intake according to current nutritional guidelines does not correlate with tubular injury in VPN, as measured by uNGAL/Cr ratio. Maternal infection, maternal anemia, lower birth weight, and nephrotoxic medication, were associated with higher uNGAL/Cr levels in VPN.


Chawanpaiboon S, Vogel JP, Moller AB, Lumbiganon P, Petzold M, Hogan D, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Heal. 2019;7:e37-e46. DOI:
2. Divisi Perinatologi Departemen Ilmu Kesehatan Anak FKUI RSCM. Profil Data Perinatologi Rumah Sakit Cipto Mangunkusumo; 2018.
3. Stritzke A, Thomas S, Amin H, Fusch C, Lodha A. Renal consequences of preterm birth. Mol Cell Pediatr. 2017;4:2. DOI:
4. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens. 1988;1:335-47. DOI:
5. Chaturvedi S, Ng KH, Mammen C. The path to chronic kidney disease following acute kidney injury: a neonatal perspective. Pediatr Nephrol. 2017;32:227-41. DOI:
6. Gaut JP, Liapis H. Acute kidney injury pathology and pathophysiology: a retrospective review. Clin Kidney J. 2020;14:526-36. DOI:
7. Jetton JG, Guillet R, Askenazi DJ, Dill L, Jacobs J, Kent AL, et al. Assessment of worldwide acute kidney injury epidemiology in neonates: design of a retrospective cohort study. Front Pediatr. 2016;4:68. DOI:
8. Devarajan P. Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury. Biomark Med. 2010;4:265-80. DOI:
9. Tang KWA, Toh QC, Teo BW. Normalisation of urinary biomarkers to creatinine for clinical practice and research – when and why. Singapore Med J. 2015;56:7-10. DOI:
10. DeFreitas MJ, Seeherunvong W, Katsoufis CP, RamachandraRao S, Duara S, Yasin S, et al. Longitudinal patterns of urine biomarkers in infants across gestational ages. Pediatr Nephrol. 2016;31:1179-88. DOI:
11. Askenazi DJ, Koralkar R, Patil N, Halloran B, Ambalavanan N, Griffin R. Acute kidney injury urine biomarkers in very low-birth-weight infants. Clin J Am Soc Nephrol. 2016;11:1527-35. DOI:
12. Su BH. Optimizing nutrition in preterm infants. Pediatr Neonatol. 2014;55:5-13. DOI:
13. Divisi Perinatologi Departemen Ilmu Kesehatan Anak FKUI RSCM. Standar Prosedur Operasional Neonatologi Rumah Sakit Cipto Mangunkusumo; 2019.
14. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307:652-9. DOI:
15. Herin P, Zetterstrom R. Studies in renal response to various protein intakes in preterm infants. Acta Paediatr Scand. 1987;76:447-52. DOI:
16. Kanmaz HG, Mutlu B, Erdeve O, Canpolat FE, Oguz SS, Uras N, et al. Does enteral protein intake affect renal glomerular and tubular functions in very low birth weight infants? Clin Nephrol. 2013;80:355-60. DOI:
17. Hulley SB, Cummings SR, Browner WS, Grady DG, Newman TB. Designing clinical research: an epidemiologic approach. Vol 78. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. ISBN 978-1-60831-804-9 (pbk.)
18. Fenton TR, Premji SS, Al-Wassia H, Sauve RS. Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database Syst Rev. 2014;2014:CD003959. DOI:
19. Villar J, Giuliani F, Bhutta ZA, Bertino E, Ohuma EO, Ismail LC et al. Postnatal growth standards for preterm infants: the Preterm Postnatal Follow-up Study of the INTERGROWTH-21st Project. The Lancet. 2015;3;E681-E691. DOI:
20. Stoops C, Stone S, Evans E, Dill L, Henderson T, Griffin R, et al. Baby NINJA (Nephrotoxic Injury Negated by Just-in-Time Action): reduction of nephrotoxic medication-associated acute kidney injury in the neonatal intensive care unit. J Pediatr. 2019;215:223-8. DOI:
21. Helguera-Repetto AC, Soto-Ramírez MD, Villavicencio-Carrisoza O, Yong-Mendoza S, Yong-Mendoza A, León-Juárez M, et al. Neonatal sepsis diagnosis decision-making based on artificial neural networks. Front Pediatr. 2020;8:525. DOI:
22. Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res. 2020;88:10-5. DOI:
23. Smith A, El-Khuffash AF. Defining “haemodynamic significance” of the patent ductus arteriosus: do we have all the answers? Neonatology. 2020;117:225-32. DOI:
24. Chen CN, Chou CH, Jeng SF, Tsai IJ, Chen PC, Chen CY, et al. Urinary neutrophil gelatinase-associated lipocalin levels in neonates. Pediatr Neonatol. 2016;57:207-12. DOI:
25. Murphy HJ, Thomas B, Van Wyk B, Tierney SB, Selewski DT, Jetton JG. Nephrotoxic medications and acute kidney injury risk factors in the neonatal intensive care unit: clinical challenges for neonatologists and nephrologists. Pediatr Nephrol. 2020;35:2077-88. DOI:
26. Mohamed TH, Klamer B, Mahan JD, Spencer JD, Slaughter JL. Diuretic therapy and acute kidney injury in preterm neonates and infants. Pediatr Nephrol. 2021;36:3981-91. DOI: htps://
27. Askenazi DJ, Koralkar R, Levitan EB, Goldstein SL, Devarajan P, Khandrika S, et al. Baseline values of candidate urine acute kidney injury biomarkers vary by gestational age in premature infants. Pediatr Res. 2011;70:302-6. DOI:
28. Luyckx VA, Bertram JF, Brenner BM, Fall C, Hoy WE, Ozanne SE, et al. Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet. 2013;382:273-83. DOI:
29. Lavery AP, Meinzen-Derr JK, Anderson E, Ma Q, Bennett MR, Devarajan P, et al. Urinary NGAL in premature infants. Pediatr Res. 2008;64:423-8. DOI:
30. Miklaszewska M, Korohoda P, Dro?d? D, Zachwieja K, Tomasik T, Moczulska A, et al. eGFR values and selected renal urine biomarkers in preterm neonates with uncomplicated clinical course. Adv Clin Exp Med. 2019;28:1657-66. DOI:
31. Firmani ND, Yuniati T, Rachmadi D. The differences of urinary neutrophil gelatinase-associated lipocalin (NGAL) levels between asphyxiated and non-asphyxiated neonates. Open J Pediatr. 2015;5:185-9. DOI: htttps://
How to Cite
Puspitasari H, Trihono P, Wahidiyat P. Does protein intake correlate with tubular function in very preterm neonates?. PI [Internet]. 31Jul.2023 [cited 20Jun.2024];63(4):245-5. Available from:
Pediatric Nephrology
Received 2022-06-07
Accepted 2023-07-31
Published 2023-07-31