Arch Gynecol Obstet (2014) 290:1055–1057 DOI 10.1007/s00404-014-3425-z

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Preterm infants, kidney, rickets and vitamin D intake: is it time for rewriting the history? Raffaella Mormile • Vassilios Fanos Giorgio Vittori



Received: 6 July 2014 / Accepted: 11 August 2014 / Published online: 24 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Great advances in neonatal intensive care have improved survival rates of infants who once had little chance for survival such as preterm babies [1, 2]. Organ system immaturity in preterm infants is connected with long term complications that have both clinical and public health importance [1]. Severe hypoxia occurs in most preterm infants leading to cell death which may be necrotic or apoptotic [1]. Significant elevation of apoptotic activity has been shown to play a prominent role in the pathogenesis of several diseases associated with prematurity such as renal dysfunction [1]. In the kidneys of preterm infants, apoptosis has been described in tubular epithelial cells [1]. Renal tubular cell apoptosis has been shown to play a critical role in the pathogenesis of acute renal failure [3]. The consequences of premature birth or low birth weight on nephrogenesis, final nephron number and long-term kidney function are still not well defined [2].The kidney of low birth weight preterm infants is characterized by a reduced number of mature nephrons at birth [4]. Active glomerulogenesis has been shown to continue even after birth for a short period (4–6 weeks), although it is not able to compensate a marked oligonephronia at birth [2]. The incomplete nephrogenesis

R. Mormile (&) Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci, 3, 81031 Aversa, Italy e-mail: [email protected] V. Fanos Department of Neonatology and Pediatrics, University of Cagliari, Cagliari, Italy G. Vittori Division of Gynecology, San Carlo di Nancy Hospital, Rome, Italy

typical of all extremely low birth weight preterm infants possibly results in a persistent oligonephronia leading to progressive renal disease in adulthood [2]. Concordantly, a higher risk of developing chronic kidney disease (CKD) for babies born prematurely has been found [4]. Preterm infants are often exposed to a variety of acute stressors that can negatively influence ongoing kidney development or cause additional nephron loss such as prenatal factors, hemodynamic alterations, nephrotoxic drugs, medical devices, infections and suboptimal nutrition [4, 5]. Acute kidney injury (AKI) is still considered as one of the main causes of mortality and morbidity in preterm neonates [5, 6]. It has been observed that AKI is independently linked to mortality in very low birth weight infants and it is significantly related to the onset of CKD [3, 5, 7]. According to Brenner’s hypothesis, patients with reduced nephron number are more likely to suffer from CKD due to secondary focal segmental glomerulosclerosis [4, 8]. It has been demonstrated that AKI induces the renoprotective upregulation of survivin expression in kidney epithelial cells [9]. Survivin has been shown to mediate renal proximal tubule recovery through STAT-3 (Signal transducer and activator of transcription 3)-dependent pathways [9]. STAT3 activity has been recognized to be involved in the regulation of tubule cell proliferation and morphogenesis during renal development [10]. STAT3 is extremely low in the adult kidney but it is rapidly activated in renal tubule cells in response to numerous forms of insults such as renal ischemia [10]. Survivin is the smallest member of the inhibitor of apoptosis gene family [11]. It is prominently expressed in fetal tissue and overexpressed in cancer cells where it has been described as a biomarker predictive of aggressive cancer [11, 12]. Even if it is scarcely detectable in normal adult tissues, survivin expression can be reactivated by a number of pro-survival

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stimuli such as ischemia [11, 12]. Although survivin is considered as an unfavorable prognostic factor in cancer, it seems to have a crucial anti-apoptosis role in vascular cell responses to injuries [11, 12]. Over-expression of survivin has been reported to have beneficial effects on renal ischemia–reperfusion injury [13]. Endothelial progenitor cells (EPC) are the major source of cells related to endothelium repair and re-endothelialisation [12]. The DNA binding 1 (Id1)/phosphatidylinositol-3kinase (PI3K)/Akt/nuclear factor kappa B (NFjB)/survivin signaling pathway has been described as a critical player in EPC proliferation after vascular injury [12]. Survivin has also been reported to have a protective role in toxin-induced acute renal failure interfering with deterioration of renal function and preserving the integrity of the kidneys and the renal tubular cells [3]. It is well known for a long time that preterm infants are at high-risk of rickets [14]. The European Society for Paediatrics Gastroenterology, Hepatology and Nutrition recommends vitamin D intake of 800–1,000 UI/day for preterm infants [15]. However, the exact timing and proportion of vitamin D-dependent absorption of calcium and phosphorus in preterm infants are unknown [14]. Furthermore, there is a possibility that these doses may occasionally result in vitamin D excess [16]. It has been documented that vitamin D inhibits cell proliferation and induction of apoptosis in vitro and in vivo in a variety of cancer cell models such as breast cancer, prostate cancer and human colon carcinoma [17–19]. Of note, it has been verified that vitamin D is linked to the inhibition of cell proliferation and induction of cancer cell through suppression of the expression of survivin [18, 19]. On the contrary, there is evidence that survivin expression could be significantly up-regulated by calcium [20]. Concordantly, the less calcemic analogue TX 527 has been shown to inhibit the proliferation of endothelial cells by negative modulation on NF-jB pathway [21]. Notably, altered vitamin D metabolism in type II diabetic mouse glomeruli has been proved to provide protection from diabetic nephropathy [22]. Taken together into account, we suggest that it might be safer to consider vitamin D for use in preterm infants only excluding and/or adequately treating potential risk factors for AKI. Vitamin D intake may down-regulate survivin that is a key mediator of cytoprotection in kidney injury. Research studies are needed to define whether supplementation with added calcium and phosphorous via ideal oral form may be a valid alternative for therapy of rickets in preterm infants with kidney failure in order to promote the restoration of renal tubular structure and also ameliorate renal function. The crosstalk between survivin and STAT3 should be targeted therapeutically to provide novel treatment for AKI planning for prevention of CKD.

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Arch Gynecol Obstet (2014) 290:1055–1057 Conflict of interest We certify that no actual or potential conflict of interest in relation to this article exists.

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Arch Gynecol Obstet (2014) 290:1055–1057 19. Koike H, Morikawa Y, Sekine Y, Matsui H et al (2011) Survivin is associated with cell proliferation and has a role in 1a,25-dihydroxyvitamin D3 induced cell growth inhibition in prostate cancer. J Urol 185(4):1497–1503 20. Gonza´lez-Pardo V, Verstuyf A, Boland R, Russo de Boland A (2013) Vitamin D analogue TX 527 down-regulates the NF-jB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus. Br J Pharmacol 169(7):1635–1645. doi:10.1111/bph.12219

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Preterm infants, kidney, rickets and vitamin D intake: is it time for rewriting the history?

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