Fenofibrate Increases Serum Creatinine in a Patient with Familial Nephropathy Associated to Hyperuricemia

Background: Kidney function progressively deteriorates in patients with familial juvenile hyperuricemiac nephropathy (FJHN, OMIN 162000) and chronic renal disease is commonly associated to dyslipidemia. We report for the first time abrupt renal insufficiency in a patient with FJHN and hypertrygliceridemia following fenofibrate administration.Case report: A 53-year-old man was diagnosed clinically with FJHN at age 24 years which was subsequently confirmed by genotypic analysis of the UMOD gene at age 40 years. His mother and two brothers suffered the disease. At that time, renal size and function were normal, as was his blood pressure and serum lipids. At age 34 years, serum urate was 8.5 mg/dL and creatinine 1.7 mg/dL (GFR, 58 mL/min/1.73 m²). He was treated with allopurinol, losartan, and lovastatin. Serum TG levels ranged between 150 and 250 mg/dL. At age 52 years, serum urate was 4.1 mg/dL, creatinine 3.2 mg/dL, LDLc 99 mg/dL (atorvastatin 40 mg/d), and TG 275 mg/dL. Fenofibrate (160 mg/d) was added. One month later, serum creatinine increased to 4.2 mg/dL and TG decreased to 125 mg/dL. He did not complain of muscle pain, weakness, or changes in urinary frequency or color and rabdomyolysis was discarded. Fenofibrate was withheld and three months later serum creatinine decreased to baseline levels (3.2 mg/dL) and TG increased to 197 mg/dL.Conclusion: To our knowledge, this is the first patient with FJHN in whom fenofibrate administration was associated to a further impairment in renal function not attributable to rabdomyolysis.     

Role of surfactant and pH on dissolution properties of fenofibrate and glipizide—A technical note

Depending on the dose size and solubility characteristics of low solubility drugs, a meaningful and discriminatory power of dissolution rate testing can be demonstrated. Saturation solubility of fenofibrate and glipizide in different media were determined. Solubility of fenofibrate increased directly with SLS concentration. For a 54-mg fenofibrate tablet, SLS at 0.025 M level is required for a discriminative dissolution test, while for 160-mg tablet, dissolution condition and levels of SLS should be optimized; higher concentrations may be effective (ie, 0.052 M, ∼1.5%). A pH 6.8 phosphate buffer medium is appropriate for glipizide 10-mg tablet dissolution study, when formulation ingredients include excipients with surface activity (eg, HPMC).     

Determination of a peptide-doxorubicin,prostate-specific antigen activated prodrug,and its active metabolites in human plasma using high-performance liquid chromatography with fluorescence detection. Stabilization of the peptide prodrug with EDTA

A method for the determination of I, a peptide-doxorubicin conjugate that was evaluated for the treatment of prostate cancer, and two of its active metabolites, doxorubicin and leucine-doxorubicin is described. Blood samples were chilled immediately after being drawn in order to prevent ex vivo entry of the metabolites into red blood cells. EDTA (10 mg/ml final concentration) was used to prevent plasma-mediated degradation of the peptide portion of the prodrug. After the addition of internal standard, plasma was prepared for analysis using a C-8 solid-phase extraction column. In order to overcome secondary ionic interactions with the silica-based extraction column, the analytes were eluted with ammonium hydroxide in methanol. The extracts were evaporated to dryness, reconstituted, and assayed by step change, gradient, reverse phase HPLC with fluorescence detection. Two interfering metabolites found in post dose plasma were chromatographically separated by an adjustment of the mobile phase pH. The within-day reproducibility of the doxorubicin and leucine-doxorubicin chromatographic retention times was improved by a brief washing of the analytical column with 90% acetonitrile after each injection. The range of the standard curve was 12.5-1250 ng/ml for doxorubicin and 25-2500 ng/ml for I and leucine-doxorubicin.     

Significance of zinc in nephrotoxicity of contrast media used in imaging diagnostics of the cardiovascular system

Nephrotoxicity is an undesirable reaction of contrast media used in X-ray or magnetic resonance diagnostics. In addition to a direct toxic effect on renal tubules, the hemodynamic factor is considered to be the main cause of kidney damage and malfunction. The factors that increase the probability of a nephrotoxic effect of contrast media include oldage, diabetes, arterial hypertension, circulatory system insufficiency, neoplastic diseases, and prior kidney damage. Decreased serum zinc is observed in all those conditions. In this article, the influence of contrast media on zinc homeostasis and the possibility of a nephrotoxic reaction caused by these agents is discussed.     

The effect of fenofibrate treatment on endothelium-dependent relaxation induced by oxidative modified low density lipoprotein from hyperlipidemic patients

The objective of the research project was to investigate whether fenofibrate treatment may alter the biochemical content of the oxidized LDL and consequently its ability to impair the endothelium-dependent relaxation in hyperlipidemic patients. We hypothesized that fenofibrate treatment of hyperlipidemic patients may attenuate the ability of their oxidized LDL to impair the endothelium-dependent relaxation of the blood vessels as a consequence of fenofibrate-induced changes to the content and composition of lysoPC in the LDL molecule.Hyperlipidemic patients (Type IIb and Type IV) were recruited from the Lipid Clinic, HSC, Winnipeg, Canada, for this study. A blood sample was taken immediately after the recruitment, a second sample was taken after 6 weeks of dietary treatment, and a third sample was taken after 8 weeks of fenofibrate treatment. LDL was isolated from the plasma and oxidized by copper sulfate. Fenofibrate was shown to be highly effect in the reduction of total cholesterol, LDL cholesterol and triglycerides in these patients. Fenofibrate treatment also caused the attenuation of impairment of endothelium-dependent relaxation by the oxidized LDL from these patients. A slight reduction of lysophosphatidylcholine level was also found in the oxidized LDL of the fenofibrate treated patients, relative to LDL isolated after dietary treatment. In addition there were no changes in the fatty acid levels of the lysophosphatidylcholine isolated from LDL. Taken together, our results suggest that while the reduced lysophosphatidylcholine levels may contribute to the attenuated impairment of the endothelium-dependent relaxation of the aortic ring, other unidentified factors impacted by fenofibrate are likely to contribute to the attenuated effects.     

Differential effects of cisplatin on mouse hepatic and renal mitochrondrial DNA

The objective of this study was to determine if the nephrotoxic effects induced by cisplatin were correlated to mitochondrial DNA damage. Comparisons were made with the liver since hepatotoxicity is rarely observed. Cisplatin doses of 10, 20 and 40 mg/kg were administered intraperitoneally to C57BL/6J mice. Mitochrondrial DNA was isolated from both the hepatic and renal tissues and quantitated by hybridization with a specific mitochondrial probe. Cisplatin caused differential effects on mouse hepatic and renal mitochondrial DNA. The 10 and 20 mg/kg dose caused an elevation in mitochondrial DNA levels in the hepatic, but no increase in the renal tissue was observed. This is the first study demonstrating an organ specific effect of cisplatin at the DNA level.     

Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system

Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo-oxygenase-2 (COX-2) or activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX-2 inhibitor) or pioglitazone (Actos, PPAR-gamma agonist) will reduce the LPS-induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post-LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation-induced dopaminergic neurodegeneration, anti-inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro-inflammation and PD.     

Differential Toxicity of Cis and Trans Isomers of Dichlorodiammineplatinum

Nephrotoxicity is the dose-limiting toxic effect of cis-dichlorodiammineplatinum (cis-platin) in humans. Its stereoisomer transplatin does not have any toxicity at equimolar concentrations, and it also possesses little antitumor activity. In this study, subcellular localization of both the platinum isomers was examined in the liver and kidney of the mouse 24 hours following the drug administration. Levels of the platinum isomers were measured using flame-less atomic absorption. The results showed that higher concentrations of the cis isomer were localized in the liver and kidney, while the concentration of the trans isomer was higher in blood. This indicates that trans isomer is sequestered in the central compartment, whereas cis isomer is distributed in the organs. We also measured metallothionein mRNA and protein levels in both liver and kidney following cisdichlorodiammineplatinum and transdichlorodiammine-platinum treatment to distinguish if the differential toxicity of the two stereo-isomers could be related to metallothionein induction. We report here that cisplatin was capable of inducing metallothionein expression in mice in vivo and that there is an inverse relationship between metallothionein expression and the pattern of tissue toxicity induced by the drug.     

Calcineurin regulation of cytoskeleton organization: a new paradigm to analyse the effects of calcineurin inhibitors on the kidney

Calcineurin is a serine/threonine phosphatase originally involved in the immune response but is also known for its role as a central mediator in various non-immunological intracellular signals. The nuclear factor of activated T cell (NFAT) proteins are the most widely described substrates of calcineurin, but ongoing work has uncovered other substrates among which are the cytoskeleton organizing proteins (i.e. cofilin, synaptopodin, WAVE-1). Control over cytoskeletal proteins is of outmost interest because the phenotypic properties of cells are dependent on cytoskeleton architecture integrity, while rearrangements of the cytoskeleton are implicated in both physiological and pathological processes. Previous works investigating the role of calcineurin on the cytoskeleton have focused on neurite elongation, myocyte hypertrophic response and recently in kidney cells structure. Nuclear factor of activated T cell activation is expectedly identified in the signalling pathways for calcineurin-induced cytoskeleton organization, however new NFAT-independent pathways have also been uncovered. The aim of this review is to summarize the current knowledge on the effects of calcineurin on cytoskeletal proteins and related intracellular pathways. These newly described properties of calcineurin on cytoskeletal proteins may explain some of the beneficial or deleterious effects observed in kidney cells associated with the use of the calcineurin inhibitors, cyclosporine and tacrolimus.     

HucMSC exosome-transported 14-3-3ζ prevents the injury of cisplatin to HK-2 cells by inducing autophagy in vitro

Background aims

On the basis of previous studies, exosomes secreted by human umbilical cord mesenchymal stromal cell (hucMSC-ex) could prevent and repair acute kidney injury induced by cisplatin in rats. However, its potential mechanism is still unclear. In the present study, the model with hucMSC-ex pretreated human renal tubular epithelial cell lines HK-2 that could prevent the injury of cisplatin was successfully established.

Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1

Cisplatin is one of the most potent chemotherapy agents. However, its use is limited due to its toxicity in normal tissues, including the kidney and ear. In particular, nephrotoxicity induced by cisplatin is closely associated with oxidative stress and inflammation. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the heme metabolism, has been implicated in a various cellular processes, such as inflammatory injury and anti-oxidant/oxidant homeostasis. Capsaicin is reported to have therapeutic potential in cisplatin-induced renal failures. However, the mechanisms underlying its protective effects on cisplatin-induced nephrotoxicity remain largely unknown. Herein, we demonstrated that administration of capsaicin ameliorates cisplatin-induced renal dysfunction by assessing the levels of serum creatinine and blood urea nitrogen (BUN) as well as tissue histology. In addition, capsaicin treatment attenuates the expression of inflammatory mediators and oxidative stress markers for renal damage. We also found that capsaicin induces HO-1 expression in kidney tissues and HK-2 cells. Notably, the protective effects of capsaicin were completely abrogated by treatment with either the HO inhibitor ZnPP IX or HO-1 knockdown in HK-2 cells. These results suggest that capsaicin has protective effects against cisplatin-induced renal dysfunction through induction of HO-1 as well as inhibition oxidative stress and inflammation.     

Potential use of isolated glomeruli and cultured mesangial cells as in vitro models to assess nephrotoxicity

The purpose of this short review is to present the potential of using isolated glomeruli and cultured mesangial cells as two differentin vitro models to assess the glomerular effect of molecules with nephrotoxic properties. The advantage of using isolated renal glomeruli is that they conserve the architecture of this anatomical region of the kidney; moreover, they are free of any vascular, nervous or humoral influences derived from other regions of the kidney. Mesangial cells are perivascular pericytes located within the central portion of the glomerular tuft between capillary loops. Mesangial cells have a variety of functions including synthesis and assembly of the mesangial matrix, endocytosis and processing of plasma macromolecules, and control of glomerular hemodynamics, mainly the ultrafiltration coefficient K _f, via mesangial cell contraction or release of vasoactive hormones. Most authors agree that mesangial cells play a major role in glomerular contraction, filtration surface area, and K _f regulation. One of the major effects of toxicants on glomerular structures is contraction. We can assess quantitatively the degree of toxicant-induced mesangial cell contraction or glomerular contraction by measuring the changes in planar cell surface area or apparent glomerular cross-sectional area after exposition to the toxicant. Thesein vitro models can also reveal glomerular effects of xenobiotics that are difficult or impossible to observe in vivo. In addition, these studies permit a fundamental examination of the mechanism of action of xenobiotics on glomerular cells, including the possibility that at least a part of their effects are mediated by local mediators released by glomerular cells. We review the effects and the mechanisms of action of several toxicants such as gentamicin, cyclosporin, cisplatin, and cadmium on isolated glomeruli or cultured mesangial cells. As suchin vitro results confirmin vivo renal hemodynamic changes caused by toxicants, we conclude that these models are fruitful tools for the study of renal toxicity. Thesein vitro systems might also serve as a predictive tool in the evaluation of drugs inducing changes in glomerular filtration rate and as a way to propose protective agents against these dramatic hemodynamic effects. This revised version was published online in July 2006 with corrections to the Cover Date.