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.

Cardiotrophin-1 attenuates experimental colitis in mice.

Cardiotrophin-1 (CT-1) holds potent anti-inflammatory, cytoprotective, and anti-apoptotic effects in the liver, kidneys, and heart. In the present study, the role of endogenous CT-1 and the effect of exogenous CT-1 were evaluated in experimental ulcerative colitis. Colitis was induced in CT-1 knockout and wild-type (WT) mice by administration of dextran sulphate sodium (DSS) in the drinking water during 7 days. CT-1 knockout mice showed higher colon damage and disease severity than WT mice. In addition, CT-1 (200 µg/kg/day, iv) or vehicle (as control) was administered during 3 days to WT, colitic mice, starting on day 4 after initiation of DSS. Disease activity index (DAI), inflammatory markers (tumor necrosis factor α (TNF-α), INFγ, IL-17, IL-10, inducible nitric oxide synthase (iNOS)), colon damage, apoptosis (cleaved caspase 3), nuclear factor κB (NFκB) and STAT-3 activation, and bacterial translocation were measured. Compared with mice treated with DSS, mice also treated with exogenous CT-1 showed lower colon damage, DAI, plasma levels of TNFα, colon expression of TNF-α, INFγ, IL-17, iNOS and cleaved caspase 3, higher NFκB and signal transducer and activator of transcription 3 (STAT3) pathways activation, and absence of bacterial translocation. We conclude that endogenous CT-1 plays a role in the defense and repair response of the colon against ulcerative lesions through an anti-inflammatory and anti-apoptotic effect. Supplementation with exogenous CT-1 ameliorates disease symptoms, which opens a potentially new therapeutic strategy for ulcerative colitis.

A systematic meta-analysis on the efficacy of pre-clinically tested nephroprotectants at preventing aminoglycoside nephrotoxicity.

Nephrotoxicity limits the use of aminoglycoside antibiotics. Kidney damage is produced mainly in the renal tubule due to an inflammatory and oxidative process. At preclinical level, many drugs and natural products have been tested as prospective protectors of aminoglycoside nephrotoxicity. The main objective of this work was to make a systematic literature review of preclinical studies about aminoglycoside nephrotoxicity protection and a statistical analysis based on the meta-analysis methodology. Studies published up to January 2016 were identified. After applying inclusion criteria, 54 studies were chosen. The size of the experimental groups, means and standard deviations of data on renal function (i.e. plasma creatinine and blood urea nitrogen [BUN] concentrations) were extracted and registered in a database. The studies were grouped according to the mechanism of nephroprotection and their route of administration. The Mean Difference (95% confidence interval) was calculated for each study and group. 40 of 54 products tested produced an amelioration of aminoglycoside nephrotoxicity based on creatinine results. Also a dose dependent protective effect was observed (both in creatinine and BUN). Products orally administered were more effective than via i.p. Products with attributed antioxidant activity were the most used and those which proved statistically significant nephroprotection as a class effect. Aminoglycoside tubular reuptake inhibitors, excretion inducers and calcium channel blockers also showed a promising and rather homogeneous class tendency towards nephroprotection, although more research is necessary to obtain solid and conclusive results, based on a larger number of studies.

Lamin A is involved in the development of vascular calcification induced by chronic kidney failure and phosphorus load.

Vascular calcification remains one of the main factors associated to morbidity and mortality in both ageing and chronic kidney disease. Both hyperphosphataemia, a well-known promoter of vascular calcification, and abnormal processing defects of lamin A/C have been associated to ageing. The main aim of this study was to analyse the effect of phosphorus load in the differential expression pattern of genes and proteins, particularly of lamin A/C, which are involved in phenotypic change of the vascular smooth muscle cells to osteoblast-like cells. The in vivo study of the calcified abdominal aortas from nephrectomized rats receiving a high phosphorus diet showed among others, a repression of muscle related proteins and overexpression of lamin A/C. Similar results were observed in vitro, where primary vascular smooth muscle cells cultured in calcifying medium showed increased expression of prelamin A and lamin A and abnormalities in the nuclear morphology. Co-immunoprecipitation assays showed novel and important physical interactions between lamin A and RUNX2 during the process of calcification. In fact, the knockdown of prelamin A and lamin A inhibited the increase of Runx2, osteocalcin and osteopontin gene expression, calcium deposition, nuclear abnormalities and the RUNX2 protein translocation into the nucleus of the cell. These in vivo and in vitro results highlight the important role played by lamin A in the process of vascular calcification.

Effects of deferasirox on renal function and renal epithelial cell death.

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.