Drug-induced nephrotoxicity in children is dependent upon the histological, anatomical and physiological features of their kidneys and the structural and functional characteristics of drugs. The kidney is mainly composed of microvascular network and tubulointerstitial tissue, so drug-induced nephrotoxicity is usually manifested by interstitial nephropathy. The mechanisms of drug-induced nephrotoxicity include cytotoxicity (necrosis or apoptosis), ischemic injury, and immunological injury. Individual drugs cause renal damage by various mechanisms due to differences in chemical structure and pharmacology. This article reviews the main features of nephrotoxicity induced by common antibiotics (cephalosporins, aminoglycosides, vancomycin, carbapenems and amphotericin B), non-steroidal anti-inflammatory drugs, and cyclosporine A.
Anti-Bacterial Agents ; toxicity ; Anti-Inflammatory Agents, Non-Steroidal ; toxicity ; Child ; Cyclosporine ; toxicity ; Humans ; Kidney Diseases ; chemically induced

OBJECTIVETo establish a new rat model of chronic cyclosporine A nephrotoxicity and explore its features.

METHODSTotally 24 male SD rats were equally randomized divided into 3 groups: sham-adrenalectomized (sham-ADX) group, ADX group and ADX plus cyclosporine A (CsA) group. Rats in ADX and CsA group first underwent adrenalectomy, followed by the administration of placebo or dexamethasone, respectively. Rats in sham-ADX group received sham adrenalectomy and distilled water as control. Six weeks later, all rats were sacrificed and the following indicators were evaluated: urine protein excretion, creatinine clearance, aldosterone level in serum and urine, aldosterone level and its synthase CYP11B2 gene expression in kidney, serum natrium and potassium, urine natrium and potassium excretion, and tubulointerstitial fibrosis by masson trichrome stain.

RESULTSIn ADX and CsA group, serum and urine aldosterone were undetectable on the second post-operative day, with other observations including natriuresis, hyponatremia, decreased urine potassium excretion, and hyperpotassemia, suggesting that adrenals were removed intact and the adrenalectomy was successful. Rats in CsA group showed increased urine protein, decreased creatinine clearance and tubulointerstitial fibrosis, suggesting that a model of chronic CsA nephrotoxicity was successfully established. At the endpoint, serum potassium, serum aldosterone, urine potassium and urine aldosterone excretion partially retrieved. Natrium in serum and urine was not significant different between ADX group/CsA group and sham-ADX group. Local renal aldosterone and its gene expression were remarkably upregulated.

CONCLUSIONSWe successfully established a new rat model of chronic CsA nephrotoxicity by adrenalectomy without low sodium diet. After adrenalectomy, local renal aldosterone in kidney may compensate for circulatory aldosterone deficit to maintain electrolyte balance.

Acute Kidney Injury ; chemically induced ; Adrenalectomy ; Aldosterone ; metabolism ; Animals ; Cyclosporine ; toxicity ; Disease Models, Animal ; Immunosuppressive Agents ; toxicity ; Kidney ; drug effects ; metabolism ; pathology ; Male ; Rats ; Rats, Sprague-Dawley

The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not been elucidated, but apoptosis is thought to play an important role in CsA induced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocytes. We investigated the ability of CsA to induce apoptosis in cultured human proximal tubular epithelial cells and also the effect of -MSH on them. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymerase (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubular epithelial cells demonstrated by increased number of TUNEL positive cells and it was accompanied by a significant increase in Fas mRNA and Fas ligand protein expressions. FADD and the cleavage product of PARP also increased, indicating the activation of caspase. In -MSH co-treated cells, apoptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these data suggest that tubular cell apoptosis mediated by Fas system may play a role in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of -MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.
Antigens, CD95/genetics ; Apoptosis/*drug effects ; Carrier Proteins/biosynthesis ; Caspases/physiology ; Cells, Cultured ; Cyclosporine/*toxicity ; Human ; Immunosuppressive Agents/*toxicity ; Kidney Tubules, Proximal/cytology/*drug effects/metabolism ; Membrane Glycoproteins/biosynthesis ; NAD+ ADP-Ribosyltransferase/metabolism ; RNA, Messenger/analysis ; alpha-MSH/*pharmacology

In order to clarify morphologic changes associated with cyclosporine (CS) nephrotoxicity, CS in ethyl alcohol at 25 mg/kg/day i.p. was administered to male Sprague-Dawley rats for periods of 1 to 8 weeks. Mean systolic BP was slightly increased in the CS group at 4 weeks (p < 0.05), but there was no difference compared to a control group at 8 weeks. Blood urea nitrogen was significantly elevated at 4 weeks and continued to rise (p < 0.005), whereas serum creatinine was elevated at 8 weeks. Microscopic examination of the kidneys from CS-treated rats at one week revealed cytoplasmic vacuolization in all segments of the proximal tubules, tubular inclusion bodies, and peritubular capillary congestion. Ultrastructurally, some vacuoles were neutral fat droplets, while others appeared as single membrane-bound structures due to dilatation of the endoplasmic reticulum. The tubular inclusion bodies were enlarged autolysosomes filled with distorted mitochondrial fragments. At two weeks, tubular regeneration was prominent, in addition to the above mentioned toxic tubulopathy. At four weeks, focal areas of interstitial fibrosis and tubular atrophy associated with cystic dilatation were seen. At 8 weeks, interstitial and intratubular microcalcification were present, in addition to patchy foci of interstitial fibrosis, but vascular lesions were not demonstrated. Although renal tubular changes characterized by vacuolization, inclusion bodies, and microcalcification and interstitial fibrosis are not specific for CS toxicity, these changes are commonly found in both humans and rats at high doses of CS.
Acute Disease ; Animal ; Body Weight/drug effects ; Chronic Disease ; Cyclosporine/*toxicity ; Immunosuppressive Agents/*toxicity ; Kidney Diseases/*chemically induced/*pathology ; Kidney Tubules/drug effects/pathology/ultrastructure ; Male ; Microscopy, Electron ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effect of tea polyphenols on cell apoptosis in rat model of cyclosporine-induced chronic nephrotoxicity.

METHODSFour groups of animals in rat model of cyclosporine-induced chronic nephrotoxicity were respectively treated by olive oil (n = 6), tea polyphenols (TP, n = 6), cyclosporine A (CsA, n = 8) and TP plus CsA (n = 8). At the end of 28th day of treatment, all animals were sacrificed and blood was analyzed for blood serum creatinine and creatinine clearance, kidney tissue for pathologic analysis. The TUNEL assay, caspase-3 mRNA expression detected by reverse transcription-polymerase chain reaction (RT-PCR) and caspase-3 activity were used for the analysis of cell apoptosis.

RESULTSCsA plus TP ameliorated the CsA-induced decrease of renal function and interstitial fibrosis. There was a significant increase in the number of apoptosis-positive cells in the CsA-vs-CsA plus TP-treated group at four weeks (18.9 +/- 3.3 vs. 7.7 +/- 1.4, P < 0.05). The expression of caspase-3 mRNA and caspase-3 activity of CsA-treated group was significantly higher than that of CsA plus TP-treated group (P < 0.05).

CONCLUSIONThese results indicate that antioxidant tea polyphenols significantly inhibit apoptosis of tubular and interstitial cells in rat model of chronic cyclosporine-induced nephrotoxicity, and suggest that the decrease of cell apoptosis exerted by tea polyphenols may be one of mechanisms to protect renal function and tissue structure.

Animals ; Antioxidants ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; Caspases ; genetics ; Cyclosporine ; toxicity ; Flavonoids ; Immunosuppressive Agents ; toxicity ; In Situ Nick-End Labeling ; Kidney ; drug effects ; Male ; Phenols ; pharmacology ; Polymers ; pharmacology ; Polyphenols ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Tea

OBJECTIVETo reconstitute an Alzheimer's disease model by administering bradykinin (BK) or cyclosporine A (CSA) to the rat hippocampus.

METHODSBK or CSA was administered to the rat hippocampus using a stereotaxic apparatus. The behavior of the rats was observed with an electronic attack jump platform. The phosphorylation of Tau protein was examined through immunohistochemical assay.

RESULTSBehavior studies showed that an obvious disturbance in learning and memory was seen in BK injected rats.No obvious dysfunction was observed in CSA injected rats. The results obtained by immunohistochemical assay indicated that the staining of M4, 12E8, paired helical filament-1 (PHF-1) and calcium/calmodulin-dependent protein kinase II (CaMKII) was stronger, and that of Tau-1 was weaker in BK injected rats compared with the control group. We also found that the binding of M4 and PHF-1 but not 12E8 to Tau was significantly increased in CSA injected rats. As for BK injection, binding of Tau-1 to Tau was decreased after CSA injection.

CONCLUSIONTo our knowledge, this is the first data showing in vivo that the activation of CaMKII induces both Alzheimer-like Tau phosphorylation and behavioral disturbances.

Alzheimer Disease ; etiology ; Animals ; Bradykinin ; toxicity ; Calcium ; metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; Calcium-Calmodulin-Dependent Protein Kinases ; metabolism ; Cyclosporine ; toxicity ; Disease Models, Animal ; Hippocampus ; drug effects ; metabolism ; Immunohistochemistry ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; tau Proteins ; analysis ; metabolism

PURPOSE: We recently reported that rosiglitazone (RGTZ), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has a protective effect against cyclosporine (CsA)- induced renal injury. Here we report the effect of RGTZ on peroxisome proliferator-activated receptor gamma (PPARgamma) expression in an experimental model of chronic cyclosporine (CsA) nephropathy. MATERIALS AND METHODS: Chronic CsA nephropathy was induced in Sprague-Dawley rats by administering CsA (15mg/kg per day) for 28 days, and control rats were treated with vehicle (VH group, olive oil 1mL/kg per day) for 28 days. RGTZ (3mg/kg) was concurrently administered via gavage to the CsA and VH groups. Expression of PPARgamma mRNA and protein was evaluated with RT-PCR, immunohistochemistry, and immunoblotting. RESULTS: PPARgamma mRNA expression was similar to the level of PPARgamma protein constitutively expressed in the kidneys of the VH treated rats, with expression in the glomerular epithelial, distal tubular cells, and collecting tubular cells. PPARgamma protein expression in CsA-treated rat kidneys was significantly less than in the VH group. However, concomitant administration of RGTZ restored PPARgamma protein expression in the kidneys of the CsA- reated rats. CONCLUSION: Exogenous administration of RGTZ treatment upregulates PPARgamma expression and that this mechanism may play a role in protecting against CsA-induced renal injury.
Transcription, Genetic/*drug effects ; Thiazolidinediones/*pharmacology ; Rats, Sprague-Dawley ; Rats ; RNA, Messenger/*genetics ; Protein Biosynthesis/*drug effects ; PPAR gamma/*genetics ; Male ; Kidney Diseases/genetics/pathology/*prevention & control ; Gene Expression Regulation/*drug effects ; Disease Models, Animal ; Cyclosporine/*toxicity ; Animals

Sirolimus (SRL) is a promising drug for replacing calcineurin inhibitors. We performed this study to determine the optimal time of conversion from cyclosporine (CsA) to SRL in an experimental model of chronic CsA nephropathy. Three separate studies were performed. In the first study, SRL was given to rats with or without CsA for 4 weeks. In the second study, rats were treated initially with CsA for 1 week, and then switched to SRL (early conversion). In the third study, CsA was given for 4 weeks and then replaced by SRL for 4 weeks treatment of CsA (late conversion). The influence of SRL on CsA-induced renal injury was evaluated by assessing renal function, histopathology (interstitial inflammation and fibrosis), and apoptotic cell death. Combined CsA and SRL treatment significantly impaired renal function, increased apoptosis, and interstitial fibrosis and inflammation compared with CsA or SRL treatment alone. Early conversion to SRL did not change renal function, histopathology, or apoptosis compared with early CsA withdrawal. By contrast, late conversion to SRL significantly aggravated these parameters compared with late CsA withdrawal. In conclusion, early conversion from CsA to SRL is effective in preventing CsA-induced renal injury in a setting of CsA-induced renal injury.
Animals ; Apoptosis/drug effects ; Chronic Disease ; Cyclosporine/*toxicity ; Immunosuppressive Agents/*pharmacology ; Intestines/drug effects/pathology ; Kidney Diseases/chemically induced/*pathology ; Male ; Models, Animal ; Rats ; Rats, Sprague-Dawley ; Sirolimus/*pharmacology

OBJECTIVETo investigate the gene expression of MAPEG in the cortex of concanavalin A (Con A)-induced mouse immune inflammatory model and the effect of cyclosporine A (Cs A).

METHODSMale Balb/c mouse immune inflammation model was developed by intravenous injection of Con A (20 mg/kg). Cs A (150 mg/kg) was intravenously infected prior to Con A administration. The MAPEG expressions were determined by RT-PCR.

RESULTmGST1, mGST3, LTC(4)S, FLAP and mPGES-1 were detected by RT-PCR but not mGST2. Eight hours after Con A treatment, mGST1 level was up-regulated to 1.2 approximately 1.5 folds of control with or without Cs A treatment. mGST3ìLTC(4)S, FLAP and mPGES-1 mRNA levels were not influenced by Con A administration.

CONCLUSIONImmune mechanism may be not involved in mGST1 up-regulation in this model and Con A does not alter arachidonic acid metabolism in cortex.

5-Lipoxygenase-Activating Proteins ; Animals ; Brain ; metabolism ; Carrier Proteins ; genetics ; metabolism ; Concanavalin A ; toxicity ; Cyclosporine ; pharmacology ; Eicosanoids ; metabolism ; Glutathione ; metabolism ; Glutathione Transferase ; genetics ; metabolism ; Intramolecular Oxidoreductases ; genetics ; metabolism ; Male ; Membrane Proteins ; genetics ; metabolism ; Mice ; Mice, Inbred BALB C ; Prostaglandin-E Synthases

BACKGROUND/AIMS: Hypoalbuminemia occurs frequently in renal transplant recipients immediately after renal transplantation. We studied the regulation of hepatic albumin synthesis by cyclosporin A (CsA) in Huh7 cells. METHODS: Huh7 cells were incubated with various concentrations of CsA for 4, 8, 16, and 24 hours. Albumin was measured in Huh7 cell-conditioned medium by sandwich enzyme-linked immunosorbent assay and Western blot. Albumin mRNA expression was analyzed by Northern blotting in CsA-treated cells. RESULTS: CsA (10(-7)-10(-4) M) inhibited albumin synthesis in Huh7 cells in a dose- dependent manner. A Western blot analysis for albumin in the conditioned medium released from CsA-treated (10(-7)-10(-5) M) cells also showed significant inhibition of albumin synthesis in a dose-dependent manner. Vehicle (olive oil) did not affect albumin synthesis. In contrast, a Northern blot analysis revealed no inhibition of albumin mRNA expression by CsA at any time point from 1-24 hours, indicating that the inhibition of albumin synthesis occurred at the translational level. CONCLUSIONS: Our results suggest that inhibition of hepatic albumin synthesis by high dose CsA contributes to the hypoalbuminemia in renal transplant recipients.
Blotting, Northern ; Blotting, Western ; Carcinoma, Hepatocellular/genetics/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Culture Media, Conditioned/metabolism ; Cyclosporine/*pharmacology/toxicity ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hypoalbuminemia/chemically induced/metabolism ; Immunosuppressive Agents/*pharmacology/toxicity ; Liver Neoplasms/genetics/*metabolism ; RNA, Messenger/metabolism ; Serum Albumin/genetics/*metabolism ; Time Factors