Please cite this article in press as: Vicente-Vicente, L., et al., Increased urinary excretion of albumin, hemopexin, transferrin and VDBP correlates with chronic sensitization to gentamicin nephrotoxicity in rats. Toxicology (2012), http://dx.doi.org/10.1016/j.tox.2012.12.006 ARTICLE IN PRESS G Model TOX 51128 1–9 Toxicology xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Toxicology jou rn al hom epage: www.elsevier.com/locate/toxicol Increased urinary excretion of albumin, hemopexin, transferrin and VDBP correlates with chronic sensitization to gentamicin nephrotoxicity in rats 1 2 Laura Vicente-Vicente a,b , Laura Ferreira c , José Manuel González-Buitrago c,d , Q1 Francisco J. López-Hernández a,b,c,e , José Miguel López-Novoa a,b , Ana Isabel Morales a,b,∗ 3 4 a Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain 5 b Fundación Renal ͘ nigo Álvarez de Toledo, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain 6 c Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain 7 d Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain 8 e Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Soria, Spain 9 10 a r t i c l e i n f o 11 12 Article history: 13 Received 22 October 2012 14 Received in revised form 10 December 2012 15 16 Accepted 11 December 2012 17 Available online xxx 18 Keywords: 19 Acute kidney injury 20 Acquired predisposition 21 Chronic risk 22 Uranium 23 Urinary biomarkers 24 Preventive medicine 25 a b s t r a c t Drug nephrotoxicity is a serious health and economic problem worldwide. Rats can be acutely sensitized to acute kidney injury (AKI) by subnephrotoxic treatments with potentially nephrotoxic drugs. Acquired sensitization to AKI poses a silent risk impossible to diagnose pre-emptively with the technology available at the clinical level. Herein, we hypothesized whether a chronic, subnephrotoxic insult to the kidneys might result in chronically acquired sensitization to AKI, and whether chronic sensitization might be detected through specific urinary markers. To this end, rats were treated with a subtoxic dosage of the experimental nephrotoxin uranyl nitrate (UN) in the drinking water for 21 weeks, or plain water (as control), and then with low-dose gentamicin for 7 days. Renal function and renal tissue damage were evaluated through the experiment. The mild renal damage caused by gentamicin was markedly magnified in rats having received UN chronically, which was evident both at the functional and histological level. Four proteins, namely albumin, hemopexin, transferrin and vitamin D binding protein were increased in the urine in temporal association with the appearance of chronic predisposition. Although further studies are necessary, our results suggest that these proteins might be potentially used as markers of hidden, chronic predisposition to gentamicin nephrotoxicity, in order to appropriately and pre-emptively stratify and handle individuals according to their specific risk in the long term, and to conveniently optimize their life conditions or additional clinical procedures or treatments that might trigger the disease. This might reduce AKI incidence and severity and the associated costs. © 2012 Published by Elsevier Ireland Ltd. 1. Introduction 26 Drug nephrotoxicity is a serious and increasing health and 27 economic problem. Drug nephrotoxicity may cause acute kidney 28 injury (AKI). Acute drug nephrotoxicity is responsible for 10–20% 29 of all AKI cases (Brivet et al., 1996), which occurs in 2–7% of 30 hospitalized patients (Devarajan, 2008). In addition, one out of 31 four among the 100 most used drugs in intensive care units is 32 nephrotoxic (Taber and Mueller, 2006). Specifically, the aminogly- 33 coside antibiotic gentamicin causes AKI in 10–25% of therapeutic 34 courses, despite appropriate patient monitoring and hydration 35 ∗ Corresponding author at: Unidad de Toxicología, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain. Tel.: +34 923 294 400x1862; fax: +34 923 294 669. E-mail address: amorales@usal.es (A.I. Morales). state (Martinez-Salgado et al., 2007; López-Novoa et al., 2011). 36 Gentamicin nephrotoxicity derives from a combination of tubular, 37 glomerular and vascular alterations, whose involvement and extent 38 depend on the dosage (Martinez-Salgado et al., 2007; López-Novoa 39 et al., 2011). In general, AKI may range from a mild, reversible dam- 40 age to the kidneys with low or no functional alterations, to severe 41 forms of acute renal failure (ARF), which seriously compromise life. 42 This is a special concern in determined population groups, such as 43 critically ill patients, and those with multi-organ failure, among 44 which mortality due to ARF may reach to 50–80% (Kellum and 45 Hoste, 2008; Waikar et al., 2008). Even mild episodes of AKI, with 46 transient episodes of renal dysfunction and repairable parenchy- 47 mal injury are associated with higher short and long term mortality 48 rates (Basile, 2008; Sinning et al., 2010). A number of AKI patients 49 progress towards progressive and irreversible chronic kidney dis- 50 ease or will keep chronically a certain degree of renal dysfunction 51 (Basile, 2008; Yang et al., 2010) or need long or permanent dialysis 52 (Aspelin et al., 2003). AKI episodes, regardless of prognosis or future 53 0300-483X/$ – see front matter © 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.tox.2012.12.006