Abstract
Background
Premature and/or intrauterine growth-restricted neonates have an increased risk of developing postnatal renal injuries in later life. Studies on renal physiology in these neonates at a corrected age of 30–40 days are scarce and mostly relate to preterm infants. The data from these studies often lack the results of correlation analyses between biochemical parameters and nephron number—data which could provide additional insight and/or improve recognition of individuals at higher risk of renal failure.
Methods
Urinary total protein and albumin levels and N-acetyl-β-D-glucosaminidase and cathepsin B activity were evaluated in preterm and intrauterine growth-restricted infants at a corrected age of 30–40 days and compared to data from a healthy control neonate population. The data were then associated with predominant susceptibility factors of renal damage related to low nephron number, such as gestational age, birth weight, total renal volume and renal cortex volume.
Results
Compared to the control neonate population, we found significantly increased levels of all biochemical parameters tested in the intrauterine growth-restricted neonates, whereas in the preterm infants we observed a significant increase in cathepsin B activity, total protein level and, to a lesser extent, albumin level. Cathepsin B activity showed a significant, strong and inverse correlation with all surrogate markers of nephron number and was also strongly and positively correlated with urinary albumin level.
Conclusions
At this postnatal age, we found that lower nephron number in low birth weight neonates was associated to tubular impairment/injury that could be concurrent with a dysfunction of glomerular permeability. Urinary cathepsin B activity may be a candidate marker for the early prediction of renal susceptibility to damage in low birth weight neonates.
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References
Hoy WE, Rees M, Kile E, Mathews JD, Wang Z (1999) A new dimension to the Barker hypothesis: low birthweight and susceptibility to renal disease. Kidney Int 56:1072–1077
Lackland DT, Bendall HE, Osmond C, Egan BM, Barker DJ (2000) Low birth weights contribute to high rates of early-onset chronic renal failure in the Southeastern United States. Arch Intern Med 160:1472–1476
Fan Z, Lipsitz S, Egan B, Lackland D (2000) The impact of birth weight on the racial disparity of end-stage renal disease. Ann Epidemiol 10:459–466
Drukker A, Guignard JP (2002) Renal aspects of the term and preterm infant: a selective update. Curr Opin Pediatr 14:175–182
Abitbol CL, Bauer CR, Montane B, Chandar J, Duara S, Zilleruelo G (2003) Long-term follow- up of extremely low birth weight infants with neonatal renal failure. Pediatr Nephrol 18:887–893
Choker G, Gouyon JB (2004) Diagnosis of acute renal failure in very preterm infants. Biol Neonate 86:212–216
Rodríguez-Soriano J, Aguirre M, Oliveros R, Vallo A (2005) Long-term renal follow-up of extremely low birth weight infants. Pediatr Nephrol 20:579–584
Andreoli SP (2004) Acute renal failure in the newborn. Semin Perinatol 28:112–123
Klahr S, Schreiner G, Ichikawa I (1988) The progression of renal disease. N Engl J Med 318:1657–1666
Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116:288–296
Taal MW, Brenner BM (2006) Predicting initiation and progression of chronic kidney disease developing renal risk scores. Kidney Int 70:1694–1705
Kandasamy Y, Smith R, Wright IM, Lumbers ER (2013) Extra-uterine renal growth in preterm infants: oligonephropathy and prematurity. Pediatr Nephrol 28:1791–1796
Tsuboi N, Kanzaki G, Koike K, Kawamura T, Ogura M, Yokoo T (2014) Clinicopathological assessment of the nephron number. Clin Kidney J 7:107–114
Charlton JR, Springsteen CH, Carmody JB (2014) Nephron number and its determinants in early life: a primer. Pediatr Nephrol 29:2299–2308
Schreuder MF (2012) Safety in glomerular numbers. Pediatr Nephrol 27:1881–1987
Brenner BM, Mackenzie HS (1997) Nephron mass as a risk factor for progression of renal disease. Kidney Int Suppl 63:124–127
Hoy WE, Bertram JF, Douglas-Denton R, Zimanyi M, Samuel T, Hughson MD (2008) Nephron number, glomerular volume, renal disease and hypertension. Curr Opin Nephrol Hypertens 17:258–265
Cappuccini B, Torlone E, Ferri C, Arnone S, Troiani S, Bini V, Di Renzo GC (2013) Renal echo-3D and microalbuminuriauria in children of diabetic mothers: a preliminary study. J Dev Orig Health Dis 4:285–289
Rowe DJF, Dawnay A, Watts GF (1990) Microalbuminuria in diabetes mellitus: review and recommendations for the measurement of albumin in urine. Ann Clin Biochem 27:297–312
Shihabi ZK, Konen JC, O’Connor ML (1991) Albuminuria vs urinary total protein for detecting chronic renal disorders. Clin Chem 37:621–624
Iseki K, Ikemiya Y, Iseki C, Takishita S (2003) Proteinuria and the risk of developing end-stage renal disease. Kidney Int 63:1468–1474
Viazzi F, Leoncini G, Conti N, Tomolillo C, Giachero G, Vercelli M, Deferrari G, Pontremo R (2010) Microalbuminuria is a predictor of chronic renal insufficiency in patients without diabetes and with hypertension: the MAGIC study. Clin J Am Soc Nephrol 5:1099–1106
Skálová S (2005) The diagnostic role of urinary N-acetyl-B-D-glucosaminidase (NAG) activity in the detection of renal tubular impairment. Acta Med (Hradec Kralove) 48:75–80
Kojima T, Sasai-Takedatsu M, Hirata Y, Kobayashi Y (1994) Characterization of renal tubular damage in preterm infants with renal failure. Acta Paediatr Jpn 36:392–395
Tsukahara H, Hori C, Tsuchida S, Hiraoka M, Sudo M, Haruki S, Suehiro F (1994) Urinary N-acetyl-beta-D-glucosaminidase excretion in term and preterm neonates. J Paediatr Child Health 30:536–538
Schaefer L, Gilge U, Heidland A, Schaefer RM (1994) Urinary excretion of cathepsin B and cystatins as parameters of tubular damage. Kidney Int Suppl 46:64–67
Liu WJ, Xu BH, Ye L, Liang D, Wu HL, Zheng YY, Deng JK, Li B, Liu HF (2015) Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells. Am J Physiol Renal Physiol 308:639–649
Smulders YM, Slaats EH, Rakic M, Smulders FT, Stehouwer CD, Silberbusch J (1998) Short-term variability and sampling distribution of various parameters of urinary albumin excretion in patients with non-insulin-dependent diabetes mellitus. J Lab Clin Med 132:39–46
Beccari T, Mancuso F, Costanzi E, Tassi C, Barone R, Aisa MC, Orlacchio O (2000) beta-hexosaminidase, alpha-D-mannosidase, and beta-mannosidase expression in serum from patients with carbohydrate-deficient glycoprotein syndrome type I. Clin Chim Acta 302:125–132
Aisa MC, Rahman S, Senin U, Maggio D, Russell RG (1996) Cathepsin B activity in normal human osteoblast-like cells and human osteoblastic osteosarcoma cells (MG-63): regulation by interleukin-1 beta and parathyroid hormone. Biochim Biophys Acta 21:29–36
Rousian M, Verwoerd-Dikkeboom CM, Koning AH, Hop WC, Van der Spek PJ, Exalto N, Steegers EA (2009) Early pregnancy volume measurements: validation of ultrasound techniques and new perspectives. BJOG 116:278–285
Aperia A, Broberger O, Elinder G, Herin P, Zetterstrom R (1981) Postnatal development of renal function in pre-term and full-term infants. Acta Paediatr Scand 2:183–187
Tsukahara H, Yoshimoto M, Saito M, Sakaguchi T, Mitsuyoshi I, Hayashi S, Nakamura K, Kikuchi K, Sudo M (1990) Assessment of tubular function in neonates using urinary beta 2-microglobulin. Pediatr Nephrol 4:512–514
Awad H, El-Safty I, El-Barbary M, Imam S (2002) Evaluation of renal glomerular and tubular functional and structural integrity in neonates. Am J Med Sci 324:261–266
Gubhaju L, Sutherland MR, Horne RS, Medhurst A, Kent AL, Ramsden A, Moore L, Singh G, Hoy WE, Black MJ (2014) Assessment of renal functional maturation and injury in preterm neonates during the first month of life. Am J Physiol Renal Physiol 307:149–158
Chen JY, Lee YL, Liu CB (1991) Urinary beta 2-microglobulin and N-acetylbeta-D-glucosaminidase (NAG) as early markers of renal tubular dysfunction in sick neonates. J Formos Med Assoc 90:132–137
Hayashi M, Tomobe K, Hirabayashi H, Hoshimoto K, Ohkura T, Inaba N (2001) Increased excretion of N-acetyl-beta-D-glucosaminidase and beta-2-microglobulin in gestational week. Am J Med Sci 321:168–172
Perrone S, Mussap M, Longini M, Fanos V, Bellieni CV, Proietti F, Cataldi L, Buonocore G (2007) Oxidative kidney damage in preterm newborns during perinatal period. Clin Biochem 40:656–660
Clark PM, Bryant TN, Hall MA, Lowes JA, Rowe DJ (1989) Neonatal renal function assessment. Arch Dis Child 64:1264–1269
Fell JM, Thakkar H, Newman DJ, Price CP (1997) Measurement of albumin and low molecular weight proteins in the urine of newborn infants using a cotton wool ball collection method. Acta Paediatr 86:518–522
Galaske RG (1986) Renal functional maturation: renal handling of proteins by mature and immature newborns. Eur J Pediatr 145:368–371
Tsukahara H, Fujii Y, Tsuchida S, Hiraoka M, Morikawa K, Haruki M, Sudo M (1994) Renal handling of albumin and beta-2-microglobulin in neonates. Nephron 68:212–216
Pflueger AC, Larson TS, Hagl S, Knox FG (1999) Role of nitric oxide in intrarenal hemodynamics in experimental diabetes mellitus in rats. Am J Physiol 277:725–733
Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17:2974–2984
Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V (2001) Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 107:217–224
Vallon V, Blantz RC, Thomson S (2003) Glomerular hyperfiltration and the salt paradox in early (corrected) type 1diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol 14:53–59
Nusken E, Spencer L, Wohlfarth M, Lippach G, Lechner F, Dotsch J, Nusken KD (2015) Whole-transcript expression analysis identifies new candidate genes involved in renal tubular programming after utero-placental insufficiency in rats. J Dev Orig Health Dis 6[Suppl 2]:S140
Nielsen R, Courtoy PJ, Jacobsen C, Dom G, Lima WR, Jadot M, Willnow TE, Devuyst O, Christensen EI (2007) Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc Natl Acad Sci USA 104:5407–5412
Barbati A, Cappuccini B, Aisa MC, Grasselli C, Zamarra M, Bini V, Bellomo G, Di Renzo GC (2016) Increased urinary cystatin-C levels correlate with reduced renal volumes in neonates with intrauterine growth restriction. Neonatology 109:154–160
Liu D, Wen Y, Tang TT, Lv LL, Tang RN, Liu H, Ma KL, Crowley SD, Liu BC (2015) Megalin/cubulin-lysosome-mediated albumin reabsorption is involved in the tubular cell activation of NLRP3 inflammasome and tubulointerstitial inflammation. J Biol Chem 290:18018–18028
Acknowledgments
This study was supported by “Fondazione Cassa di Risparmio di Perugia “ (Code Project 2014.0252.021) and Gebisa Research Foundation Perugia, Italy.
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The process for obtaining informed consent was approved by the appropriate Institutional Review Committee. This study was conducted in compliance with ethical standards.
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Aisa, M.C., Cappuccini, B., Barbati, A. et al. Biochemical parameters of renal impairment/injury and surrogate markers of nephron number in intrauterine growth-restricted and preterm neonates at 30–40 days of postnatal corrected age. Pediatr Nephrol 31, 2277–2287 (2016). https://doi.org/10.1007/s00467-016-3484-4
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DOI: https://doi.org/10.1007/s00467-016-3484-4