Urinary GM2AP coincides with renal cortical damage and grades cisplatin nephrotoxicity severity in rats.

Nephrotoxicity, including electrolytic disorders and acute kidney injury (AKI), limits the clinical dosage and utility of platinated antineoplastics such as cisplatin. Cisplatin nephrotoxicity embodies a tubulopathy involving the medullary S2 and S3 segments of the proximal and the distal tubules. Higher dosage extends damage over the cortical S1 segment and intensifies overall injury. However, the standard diagnosis based on plasma creatinine as well as novel injury biomarkers lacks enough pathophysiological specificity. Further granularity in the detection of renal injury would help understand the implications of individual damage patterns needed for personalized patient handling. In this article, we studied the association of urinary ganglioside GM2 activator protein (GM2AP) with the patterns of tubular damage produced by 5 and 10mg/kg cisplatin in rats. Our results show that GM2AP appears in the urine only following damage to the cortical segment of the proximal tubule. The information provided by GM2AP is not redundant with but distinct and complementary to that provided by urinary neutrophil gelatinase-associated lipocalin (NGAL). Similarly, treatment with 150mg/kg/day gentamicin damages the renal cortex and increases GM2AP urinary excretion; whereas renal ischemia, which does not affect the cortex, has no effect on GM2AP. Because of the key role of the cortical proximal tubule in renal function, we contend GM2AP as a potential diagnostic biomarker to stratify AKI patients according to the underlying damage and follow their evolution and prognosis. Prospectively, urinary GM2AP may help grade the severity of platinated antineoplastic nephrotoxicity by forming part of a non-invasive liquid biopsy.

Oxidative stress and renal status of farmers exposed to pesticides in Seville (Spain).

The aim was to determine whether indirect exposure to pesticides, specifically a copper-based fungicide, induces alterations in oxidative stress and subclinical and early kidney biomarkers in male farmers tasked with olives harvesting. Furthermore, we tested whether sex influences the susceptibility to pesticide-induced renal damage by comparing the results of this study with those obtained previously. The study focused on olive farmers (n = 41) indirectly exposed to copper-based fungicides in Estepa (Sevilla, Spain), comparing them with a control group (n = 32). Blood samples were analyzed for metal concentrations (Cu, Mn, Se, and Zn), lipid peroxidation (MDA), protein oxidation (carbonyl groups), and antioxidant enzyme activities (SOD and CAT) while urine samples were assessed for biomarkers of early kidney damage (NGAL, KIM-1, transferrin, IGFBP7, TIMP-2). Although no significant, a tendency to increase lipid and protein oxidation was observed, together with the activity of antioxidant enzymes SOD and CAT, and a decrease in total antioxidants. Moreover, an increase in urinary NGAL and IGFBP7 among pesticide-exposed farmers suggests potential underdiagnosis of kidney damage. Farmers exhibit a subtle tendency to oxidative stress compared to control, while metal levels are significantly lower in farmers, suggesting potential compensatory responses. Furthermore, biomarkers for early kidney damage are elevated, emphasizing their vulnerability in both sexes. These findings highlight the need for investigations of renal health in pesticide-exposed farmers for preventative measures and regular health monitoring.

A wide scope, pan-comparative, systematic meta-analysis of the efficacy of prophylactic strategies for cardiac surgery-associated acute kidney injury.

Acute kidney injury (AKI) is the most common complication of cardiac surgery. Cardiac surgery-associated AKI (CSA-AKI) is caused by systemic and renal hemodynamic impairment and parenchymal injury. Prophylaxis of CSA-AKI remains an unmet priority, for which preventive strategies based on drug therapies, hydration procedures, and remote ischemic preconditioning (RIPC) have been tested in pre-clinical and clinical studies, with variable success. Contradicting reports and scarce or insufficiently pondered information have blurred conclusions. Therefore, with an aim to contribute to consolidating the available information, we carried out a wide scope, pan-comparative meta-analysis including the accessible information about the most relevant nephroprotective approaches assayed. After a thorough examination of 1892 documents retrieved from PubMed and Web of Science, 150 studies were used for the meta-analysis. Individual odds ratios of efficacy at reducing AKI incidence, need for dialysis, and plasma creatinine elevation were obtained for each alleged protectant. Also, the combined class effect of drug families and protective strategies was also meta-analyzed. Our results show that no drug family or procedure affords substantial protection against CSA-AKI. Only, a mild but significant reduction in the incidence of CSA-AKI by preemptive treatment with dopaminergic and adrenergic drugs, vasodilators, and the RIPC technique. The integrated analysis suggests that single-drug approaches are unlikely to cope with the variety of individual pathophysiological scenarios potentially underlying CSA-AKI. Accordingly, a theragnostic approach involving the etiopathological diagnosis of kidney frailty is necessary to guide research towards the development of pharmacological combinations concomitantly and effectively addressing the key mechanisms of CSA-AKI.

Effect of uric acid reduction on chronic kidney disease. Systematic review and meta-analysis.

Accumulating evidence suggests that hyperuricemia is a pathological factor in the development and progression of chronic kidney disease. However, the potential benefit afforded by the control of uric acid (UA) is controversial. Individual studies show discrepant results, and most existing meta-analysis, especially those including the larger number of studies, lack a placebo or control group as they aim to compare efficacy between drugs. On these grounds, we performed a me-ta-analysis restricted to studies including the action of any anti-gout therapies referenced to a control or placebo arm. This approach allows for a clearer association between UA reduction and renal effect. Of the twenty-nine papers included, most used allopurinol and febuxostat and, therefore, solid conclusions could only be obtained for these drugs. Both were very effective in reducing UA, but only allopurinol was able to significantly improve glomerular filtration rate (GFR), although not in a dose-dependent manner. These results raised doubts as to whether it is the hypouricemic effect of anti-gout drugs, or a pleiotropic effect, what provides protection of kidney function. Accordingly, in a correlation study that we next performed between UA reduction and GFR improvement, no association was found, which suggests that additional mechanisms may be involved. Of note, most trials show large inter-individual response variability, probably because they included patients with heterogeneous phenotypes and pathological characteristics, including different stages of CKD and comorbidities. This highlights the need to sub classify the effect of UA-lowering therapies according to the pathological scenario, in order to identify those CKD patients that may benefit most from them. Systematic Review Registration: CRD42022306646 https://www.crd.york.ac.uk/prospero/.

Hepatotoxicity due to dietary supplements: state-of-the-art, gaps and perspectives.

Food supplements are products intended to complement the normal diet and consist of concentrated sources of nutrients or other substances with a nutritional or physiological effect. Although they are generally considered safe if the manufacturer's recommendations are followed, many of them have shown hepatotoxic properties. This can cause many diseases (e.g. steatohepatitis and cirrhosis) characterized by progressive damage and malfunction of the liver that in the long term can lead to death. A review of the literature was carried out to elucidate which dietary supplements have been associated with cases of hepatotoxicity in recent years, with emphasis on those relevant to the consumer and the new trends (e.g. cannabidiol). It has been reported that the supplements described as hepatotoxic are mainly of botanical origin (e.g. green tea or turmeric) and those used in sports (mainly anabolic androgenic steroids). There is a great variability of compounds described as causing liver damage, although sometimes it is not possible to identify them, because they are contaminants or adulterants of the products. In addition, the prevalence of toxic effects after the administration of supplements is difficult to define due to underreporting and the lack of specific studies. Globally regarding hepatotoxicity of dietary supplements, there is a paucity of well-conducted clinical trials on the efficacy of these compounds and the frequency of related liver damage, as the use of these products is largely uncontrolled.

New Challenges in the Diagnosis of Kidney Damage Due to Immune Checkpoint Inhibitors Therapy: An Observational Clinical Study.

In recent years, immunotherapy has been postulated as one of the most effective strategies in the fight against cancer. The greatest success in this field has been achieved with the inhibition of molecules involved in slowing down the adaptive immune response by immune checkpoint inhibitors (ICIs). Despite its efficacy, ICI treatment has side effects. Regarding kidney damage, it is estimated that 4.9% of patients treated with ICIs develop renal injury. Furthermore, cancer patients who develop renal dysfunction have a worse prognosis. Current diagnostics are insufficient to predict the underlying renal injury and to identify the type of damage. Our hypothesis is that the renal injury could be subclinical, so the possibility of using new urinary biomarkers could be a useful diagnostic tool that would allow these patients to be managed in a preventive (risk biomarkers) and early (early biomarkers) way and even to clarify whether the renal damage is due to this therapy or to other factors (differential diagnostic biomarkers). A prospective study to validate risk and early and differential biomarkers in patients treated with ICIs is proposed to test this hypothesis. The results derived from this study will improve the clinical practice of cancer treatment with ICIs and therefore the life expectancy and quality of life of patients. Trial Registration: ClinicalTrials.gov, NCT04902846.

Identification of Pre-Renal and Intrinsic Acute Kidney Injury by Anamnestic and Biochemical Criteria: Distinct Association with Urinary Injury Biomarkers.

Acute kidney injury (AKI) is a syndrome of sudden renal excretory dysfunction with severe health consequences. AKI etiology influences prognosis, with pre-renal showing a more favorable evolution than intrinsic AKI. Because the international diagnostic criteria (i.e., based on plasma creatinine) provide no etiological distinction, anamnestic and additional biochemical criteria complement AKI diagnosis. Traditional, etiology-defining biochemical parameters, including the fractional excretion of sodium, the urinary-to-plasma creatinine ratio and the renal failure index are individually limited by confounding factors such as diuretics. To minimize distortion, we generated a composite biochemical criterion based on the congruency of at least two of the three biochemical ratios. Patients showing at least two ratios indicative of intrinsic AKI were classified within this category, and those with at least two pre-renal ratios were considered as pre-renal AKI patients. In this study, we demonstrate that the identification of intrinsic AKI by a collection of urinary injury biomarkers reflective of tubular damage, including NGAL and KIM-1, more closely and robustly coincide with the biochemical than with the anamnestic classification. Because there is no gold standard method for the etiological classification of AKI, the mutual reinforcement provided by the biochemical criterion and urinary biomarkers supports an etiological diagnosis based on objective diagnostic parameters.

Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury: State of the Art and Perspectives.

Diagnosis of cardiac surgery-associated acute kidney injury (CSA-AKI), a syndrome of sudden renal dysfunction occurring in the immediate post-operative period, is still sub-optimal. Standard CSA-AKI diagnosis is performed according to the international criteria for AKI diagnosis, afflicted with insufficient sensitivity, specificity, and prognostic capacity. In this article, we describe the limitations of current diagnostic procedures and of the so-called injury biomarkers and analyze new strategies under development for a conceptually enhanced diagnosis of CSA-AKI. Specifically, early pathophysiological diagnosis and patient stratification based on the underlying mechanisms of disease are presented as ongoing developments. This new approach should be underpinned by process-specific biomarkers including, but not limited to, glomerular filtration rate (GFR) to other functions of renal excretion causing GFR-independent hydro-electrolytic and acid-based disorders. In addition, biomarker-based strategies for the assessment of AKI evolution and prognosis are also discussed. Finally, special focus is devoted to the novel concept of pre-emptive diagnosis of acquired risk of AKI, a premorbid condition of renal frailty providing interesting prophylactic opportunities to prevent disease through diagnosis-guided personalized patient handling. Indeed, a new strategy of risk assessment complementing the traditional scores based on the computing of risk factors is advanced. The new strategy pinpoints the assessment of the status of the primary mechanisms of renal function regulation on which the impact of risk factors converges, namely renal hemodynamics and tubular competence, to generate a composite and personalized estimation of individual risk.

Early Diagnosis of Kidney Damage Associated with Tobacco Use: Preventive Application.

Although long-term smoking has been associated with chronic kidney disease, its effect on kidney function in early stages has not been clarified. Therefore, the proposed objectives were: (1) to identify subclinical kidney damage in smokers, through a panel of biomarkers; (2) to evaluate the progression of subclinical kidney damage after two years of consumption in these patients; and (3) study whether quitting smoking reduces kidney damage. A prospective study was carried out (patients recruited from a primary care centre and a clinical smoking unit). Kidney function was assessed using a panel of biomarkers and compared between smokers and non-smokers, taking into account potential risk factors for kidney damage. These results show, for the first time in the literature, the relationship between smoking and early (subclinical) kidney damage and provide a panel of biomarkers capable of detecting this condition (Neutrophil gelatinase-associated lipocalin, Kidney injury molecule-1, N-acetyl-beta-D-glucosaminidase, transferrin, and ganglioside-activating protein GM2). This study also indicates that subclinical damage is maintained when use continues, but can be reversed if patients stop smoking. The use of these biomarkers as diagnostic tools can be a preventive measure in the development of chronic kidney disease associated with smoking and in the prevention of acute events associated with potentially nephrotoxic pharmacological treatment in smokers. Trial registration number: NCT03850756.

Neural Network-Based Calculator for Rat Glomerular Filtration Rate.

Glomerular filtration is a pivotal process of renal physiology, and its alterations are a central pathological event in acute kidney injury and chronic kidney disease. Creatinine clearance (ClCr), a standard method for glomerular filtration rate (GFR) measurement, requires a long and tedious procedure of timed (usually 24 h) urine collection. We have developed a neural network (NN)-based calculator of rat ClCr from plasma creatinine (pCr) and body weight. For this purpose, matched pCr, weight, and ClCr trios from our historical records on male Wistar rats were used. When evaluated on the training (1165 trios), validation (389), and test sets (660), the model committed an average prediction error of 0.196, 0.178, and 0.203 mL/min and had a correlation coefficient of 0.863, 0.902, and 0.856, respectively. More importantly, for all datasets, the NN seemed especially effective at comparing ClCr among groups within individual experiments, providing results that were often more congruent than those measured experimentally. ACLARA, a friendly interface for this calculator, has been made publicly available to ease and expedite experimental procedures and to enhance animal welfare in alignment with the 3Rs principles by avoiding unnecessary stressing metabolic caging for individual urine collection.

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells.

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.

Are Antioxidants Useful in Preventing the Progression of Chronic Kidney Disease?

Chronic kidney disease (CKD) is a progressive impairment of renal function for more than three months that affects 15% of the adult population. Because oxidative stress is involved in its pathogenesis, antioxidants are under study for the prophylaxis of CKD progression. The objective of this work was to meta-analyze the efficacy of antioxidant therapy in CKD patients and to identify the most effective candidate antioxidants. Our meta-analysis showed that, despite being quite heterogeneous, overall antioxidant therapy apparently reduced CKD progression. Pentoxifylline and bardoxolone methyl demonstrated a robust and statistically significant protection, while other products showed a favorable but non-significant tendency, due to a high interindividual variability. Off-target (i.e., antioxidant-independent) effects, such as body weight reduction and heart failure-associated blood dilution, might totally or partially explain the protection provided by effective antioxidants. This potential pleiotropy introduces uncertainty on the role of oxidative stress in CKD progression and on antioxidant therapy in its prevention, which needs to be further investigated. Independently, identification of factors determining the nephroprotective effect of each candidate on each patient is thus necessary for a prospectively personalized antioxidant therapy. Finally, pentoxifylline should be further explored for the prophylaxis of CKD progression.

Albuminuria Pre-Emptively Identifies Cardiac Patients at Risk of Contrast-Induced Nephropathy.

Contrast-induced nephropathy (CIN) is a complication associated with the administration of contrast media (CM). The CIN diagnosis is based on creatinine, a biomarker late and insensitive. The objective proposed was to evaluate the ability of novel biomarkers to detect patients susceptible to suffering CIN before CM administration. The study was carried out with patients undergoing cardiac catheterization involving CM. Patients were divided into two groups: (1) CIN, patients who developed this pathology; (2) control, patients who did not suffer CIN. Prior to the administration of CM, urine samples were collected to measure proteinuria, N-acetyl-ß-d-glucosaminidase, neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, albumin, transferrin, t-gelsolin and GM2 ganglioside activator protein (GM2AP). The risk factors advanced age, low body mass index and low estimated glomerular filtration rate; and the urinary biomarkers albumin, transferrin and GM2AP showed significant predictive capacity. Of all of them, albuminuria demonstrated the highest diagnostic power. When a cutoff point was established for albuminuria at values still considered subclinical (10-30 µg/mg Cru), it was found that there was a high incidence of CIN (40-75%). Therefore, albuminuria could be applied as a new diagnostic tool to prevent and predict CIN with P4 medicine criteria, independently of risk factors and comorbidities.

Regression Modeling of the Antioxidant-to-Nephroprotective Relation Shows the Pivotal Role of Oxidative Stress in Cisplatin Nephrotoxicity.

The clinical utility of the chemotherapeutic drug cisplatin is significantly limited by its nephrotoxicity, which is characterized by electrolytic disorders, glomerular filtration rate decline, and azotemia. These alterations are consequences of a primary tubulopathy causing injury to proximal and distal epithelial cells, and thus tubular dysfunction. Oxidative stress plays a role in cisplatin nephrotoxicity and cytotoxicity, but its relative contribution to overall toxicity remains unknown. We studied the relation between the degree of oxidative reduction (provided by antioxidant treatment) and the extent of nephrotoxicity amelioration (i.e., nephroprotection) by means of a regression analysis of studies in animal models. Our results indicate that a linear relation exists between these two parameters, and that this relation very nearly crosses the value of maximal nephroprotection at maximal antioxidant effect, suggesting that oxidative stress seems to be a pivotal and mandatory mechanism of cisplatin nephrotoxicity, and, hence, an interesting, rationale-based target for clinical use. Our model also serves to identify antioxidants with enhanced effectiveness by comparing their actual nephroprotective power with that predicted by their antioxidant effect. Among those, this study identified nanoceria, erythropoietin, and maltol as highly effective candidates affording more nephroprotection than expected from their antioxidant effect for prospective clinical development.

Urinary Plasminogen Activator Inhibitor-1: A Biomarker of Acute Tubular Injury.

INTRODUCTION: Acute kidney injury (AKI) is a threatening, multiaetiological syndrome encompassing a variety of forms and damage patterns. AKI lacks sufficiently specific diagnostic tools to evaluate the distinct combination of pathophysiological events underlying each case, which limits personalized and optimized handling. Therefore, a pathophysiological diagnosis based on new urinary biomarkers is sought for practical (readiness and noninvasiveness) and conceptual reasons, as the urine is a direct product of the kidneys. However, biomarkers found in the urine may also have extrarenal origin, thus conveying pathophysiological information from other organs or tissues. Urinary plasminogen activator inhibitor-1 (PAI-1) has been associated to AKI, although its origin and traffic to the urine are not known. METHODS: Herein, we studied the blood or renal origin of urinary PAI-1 (uPAI-1) in experimental AKI in Wistar rats, by means of the in situ renal perfusion method. For this purpose, urine was collected while the kidneys of rats with AKI showing increased uPAI-1 excretion, and controls, were in situ perfused with a saline solution. RESULTS: Our results show that during perfusion, PAI-1 remained in the urine of AKI rats, suggesting that renal cells shed this protein directly to the urine. PAI-1 is also significantly increased in the urine of AKI patients. Its low correlation with other urinary markers such as NGAL or NAG suggests that PAI-1 provides complementary and distinct phenotypical information. CONCLUSION: In conclusion, uPAI-1 is a biomarker produced by damaged kidneys following AKI, whose precise pathophysiological meaning in AKI needs to be further investigated.

Adverse Health Effects in Women Farmers Indirectly Exposed to Pesticides.

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.

A Micellar Formulation of Quercetin Prevents Cisplatin Nephrotoxicity.

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.

The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats.

Acute kidney injury (AKI) diagnosis relies on plasma creatinine concentration (Crpl), a relatively insensitive, surrogate biomarker of glomerular filtration rate that increases only after significant damage befalls. However, damage in different renal structures may occur without increments in Crpl, a condition known as subclinical AKI. Thus, detection of alterations in other aspects of renal function different from glomerular filtration rate must be included in an integral diagnosis of AKI. With this aim, we adapted to and validated in rats (for preclinical research) the furosemide stress test (FST), a tubular function test hitherto performed only in humans. We also tested its sensitivity in detecting subclinical tubular alterations. In particular, we predisposed rats to AKI with 3 mg/kg cisplatin and subsequently subjected them to a triggering insult (ie, 50 mg/kg/d gentamicin for 6 days) that had no effect on nonpredisposed animals but caused an overt AKI in predisposed rats. The FST was performed immediately before adding the triggering insult. Predisposed animals showed a reduced response to the FST (namely, reduced furosemide-induced diuresis and K+ excretion), whereas nonpredisposed animals showed no alteration, compared to the controls. Computational modeling of epithelial transport of solutes and water along the nephrons applied to experimental data suggested that proximal tubule transport was only minimally reduced, the sodium-chloride symporter was upregulated by 50%, and the renal outer medullary potassium channel was downregulated by 85% in predisposed animals. In conclusion, serial coupling of the FST and computational modeling may be used to detect and localize subclinical tubular alterations.

A meta-analysis of preclinical studies using antioxidants for the prevention of cisplatin nephrotoxicity: implications for clinical application.

Cisplatin is an effective chemotherapeutic drug whose clinical use and efficacy are limited by its nephrotoxicity, which affects mainly the renal tubules and vasculature. It accumulates in proximal and distal epithelial tubule cells and causes oxidative stress-mediated cell death and malfunction. Consequently, many antioxidants have been tested for their capacity to prevent cisplatin nephrotoxicity. In this study, we made a systematic review of the literature and meta-analyzed 152 articles, which tested the nephroprotective effect of isolated compounds or mixtures of natural origin on cisplatin nephrotoxicity in preclinical models. This meta-analysis identified the most effective candidates and examined the efficacy obtained by antioxidants administered by the oral and intraperitoneal routes. By comparing with a recent, similar meta-analysis performed on clinical studies, this article identifies a disconnection between preclinical and clinical research, and contextualizes, discusses, and integrates the existing preclinical information toward the optimized selection of candidates to be further explored (clinical level). Despite proved efficacy, this article discusses the barriers limiting the clinical development of natural mixtures, such as those in extracts from Calendula officinalis flowers and Heliotropium eichwaldii roots. On the contrary, isolated compounds are more straightforward candidates, among which arjunolic acid and quercetin stand out in this meta-analysis.