The antioxidant flavonoid quercetin has been shown to prevent nephrotoxicity in animal models and in a clinical study and is thus a very promising prophylactic candidate under development. Quercetin solubility is very low, which handicaps clinical application. The aim of this work was to study, in rats, the bioavailability and nephroprotective efficacy of a micellar formulation of Pluronic F127-encapsulated quercetin (P-quercetin), with improved hydrosolubility. Intraperitoneal administration of P-quercetin leads to an increased plasma concentration and bioavailability of quercetin compared to the equimolar administration of natural quercetin. Moreover, P-quercetin retains overall nephroprotective properties, and even slightly improves some renal function parameters, when compared to natural quercetin. Specifically, P-quercetin reduced the increment in plasma creatinine (from 3.4 ± 0.5 to 1.2 ± 0.3 mg/dL) and urea (from 490.9 ± 43.8 to 184.1 ± 50.1 mg/dL) and the decrease in creatinine clearance (from 0.08 ± 0.02 to 0.58 ± 0.19 mL/min) induced by the nephrotoxic chemotherapeutic drug cisplatin, and it ameliorated histological evidence of tubular damage. This new formulation with enhanced kinetic and biopharmaceutical properties will allow for further exploration of quercetin as a candidate nephroprotector at lower dosages and by administration routes oriented towards its clinical use.

Nephrotoxicity is an important limitation to the clinical use of many drugs and contrast media. Drug nephrotoxicity occurs in acute, subacute and chronic manifestations ranging from glomerular, tubular, vascular and immunological phenotypes to acute kidney injury. Pre-emptive risk assessment of drug nephrotoxicity poses an urgent need of precision medicine to optimize pharmacological therapies and interventional procedures involving nephrotoxic products in a preventive and personalized manner. Biomarkers of risk have been identified in animal models, and risk scores have been proposed, whose clinical use is abated by their reduced applicability to specific etiological models or clinical circumstances. However, our present data suggest that the urinary level of transferrin may be indicative of risk of renal damage, where risk is induced by subclinical tubular alterations regardless of etiology. In fact, urinary transferrin pre-emptively correlates with the subsequent renal damage in animal models in which risk has been induced by drugs and toxins affecting the renal tubules (i.e. cisplatin, gentamicin and uranyl nitrate); whereas transferrin shows no relation with the risk posed by a drug affecting renal hemodynamics (i.e. cyclosporine A). Our experiments also show that transferrin increases in the urine in the risk state (i.e. prior to the damage) precisely as a consequence of reduced tubular reabsorption. Finally, urinary transferrin pre-emptively identifies subpopulations of oncological and cardiac patients at risk of nephrotoxicity. In perspective, urinary transferrin might be further explored as a wider biomarker of an important mechanism of predisposition to renal damage induced by insults causing subclinical tubular alterations.

Farmers are among the most vulnerable populations because of the exposure to low levels of pesticides. Acetylcholinesterase and butyrylcholinesterase activities are considered as biomarkers of pesticides poisoning. However, biomarkers of oxidative stress are also playing an important role in toxicity of these contaminants. Further, increased activities of gamma-glutamyltransferase, alanine aminotransferase, urea and creatinine have been linked with hepatic and nephrotoxic cell damage, respectively. The aim of this study was to ascertain if the indirect exposure to pesticides leads to some biochemical parameter changes. Thus, cholinesterase activities, oxidative stress status (lipid and protein oxidation), hepatic function (AST and ALT levels), hormonal function (TSH, T4, FSH, LH and AMH), renal function (serum creatinine and urea), as well as possible subclinical kidney damage (urinary proteins and biomarkers of early kidney damage) were evaluated in farmer women who collect fruits and vegetables comparing with a group of women non-occupational exposed to pesticides but living in the same rural environment. Samples were taken periodically along one year to relate the observed effects to a chronic exposure. Our main results showed for the first time a subclinical kidney damage in a rural setting with indirect chronic exposure to pesticides.

Quercetin, a flavonoid with promising therapeutic potential, has been shown to protect from cisplatin nephrotoxicity in rats following intraperitoneal injection, but its low bioavailability curtails its prospective clinical utility in oral therapy. We recently developed a micellar formulation (P-quercetin) with enhanced solubility and bioavailability, and identical nephroprotective properties. As a first aim, we herein evaluated the oral treatment with P-quercetin in rats, which displayed no nephroprotection. In order to unravel this discrepancy, quercetin and its main metabolites were measured by HPLC in the blood and urine after intraperitoneal and oral administrations. Whilst quercetin was absorbed similarly, the profile of its metabolites was different, which led us to hypothesize that nephroprotection might be exerted in vivo by a metabolic derivate. Consequently, we then aimed to evaluate the cytoprotective capacity of quercetin and its main metabolites (quercetin 3-O-glucoside, rutin, tamarixetin, isorhamnetin and quercetin 3-O-glucuronide) against cisplatin toxicity, in HK-2 and NRK-52E tubular cell lines. Cells were incubated for 6 h with quercetin, its metabolites or vehicle (pretreatment), and subsequently 18 h in cotreatment with 10–300 μM cisplatin. Immediately after treatment, cell cultures were subject to the MTT technique as an index of cytotoxicity and photographed under light microscopy for phenotypic assessment. Quercetin afforded no direct cytoprotection and quercetin-3-O-glucuronide was the only metabolite partially preventing the effect of cisplatin in cultured tubule cells. Our results identify a metabolic derivative of quercetin contributing to its nephroprotection and prompt to further explore exogenous quercetin-3-O-glucuronide in the prophylaxis of tubular nephrotoxicity.