Effect of hyperbaric oxygen on cyclosporine-induced nephrotoxicity and oxidative stress in rats

Reactive oxygen species have been suggested to be involved in cyclosporine nephrotoxicity. Hyperbaric oxygen is known to induce the generation of reactive oxygen species in tissues. The aim of this study was to investigate whether the use of hyperbaric oxygen concurrently with cyclosporine potentiates cyclosporine nephrotoxicity by inducing oxidative stress in kidneys. The study consisted of four groups of rats: a control group, a cyclosporine group (15 mg/kg/day intraperitoneally for 14 days), a hyperbaric oxygen group (60 min. every day for five days at 2.5 atmosphere absolute), and a cyclosporine + hyperbaric oxygen group (cyclosporine 15 mg/kg/day intraperitoneally for 14 days + hyperbaric oxygen for 60 min at 2.5 atmosphere absolute every day for five days on the last five days of cyclosporine treatment). Oxidative stress was determined by measuring renal thiobarbituric acid-reactive substances content, renal superoxide dismutase, and glutathione peroxidase activities. Cyclosporine increased serum urea and creatinine levels, indicating the development of nephrotoxicity, and induced significant oxidative stress in rat kidneys. Hyperbaric oxygen alone did not alter any of the biochemical and oxidative stress parameters compared to the control group. When used concurrently with cyclosporine, hyperbaric oxygen significantly reduced cyclosporine-induced oxidative stress, but it neither attenuated nor aggravated cyclosporine-induced nephrotoxicity. These results suggest that reactive oxygen species are involved in cyclosporine nephrotoxicity, but are not the direct cause of the toxicity. Although concurrent use of cyclosporine and hyperbaric oxygen did not exacerbate cyclosporine nephrotoxicity in this model, we recommend that the renal functions of patients be monitored periodically when these treatments are used concurrently.     

茶多酚减轻环孢素A急性肾毒性的作用及其机理研究

目的探讨茶多酚(TP)减轻环孢素A(CsA)急性肾毒性的作用及其机制.方法按照分组,分别给予大鼠橄榄油、TP、CsA及TP+CsA,给药14*!d后,取血测尿素氮及血、尿肌酐,计算肌酐清除率,以病理评分法记录肾脏损害程度,硫代巴比妥酸法(TBA法)测定大鼠肾组织的脂质过氧化水平,黄嘌呤氧化法测定肾组织超氧化物歧化酶(SOD)的活力,二硫代二硝基苯甲酸(DTNB)比色法测定谷胱甘肽过氧化物酶(GSH-Px)活力.结果使用CsA后14*!d,大鼠的肾脏可见明显损害,肌酐清除率明显下降,组织丙二醛(MDA)水平升高,SOD与GSH-Px活性下降;TP具有减轻CsA肾毒性的作用.结论茶多酚能有效地减轻CsA所致的大鼠肾脏毒性,可能与其清除氧自由基、保护肾组织中SOD及GSH-Px活性有关.     

Tacrolimus rescue therapy for cyclosporine-induced nephrotoxicity

Following renal transplantation, the long-term use of cyclosporine can cause nephrotoxicity. This small study of ten patients looks at the effects of tacrolismus rescue therapy over a 6-month period. After conversion to tacrolismus, renal function improved in seven pateints, progressive graft dysfunction slowed and almost stabilized in two patients, and, in the remaining patient, deterioration continued and hemodialysis treatment was initiated at the end of the study period. A greater number of patients and a longer follow up are necessary to confirm these initially impressive results.     

Tacrolimus rescue therapy for cyclosporine-induced nephrotoxicity

Abstract Following renal transplantation, the long-term use of cyclosporine can cause nephrotoxicity. This small study of ten patients looks at the effects of tacrolismus rescue therapy over a 6-month period. After conversion to tacrolismus, renal function improved in seven pateints, progressive graft dysfunction slowed and almost stabilized in two patients, and, in the remaining patient, deterioration continued and hemodialysis treatment was initiated at the end of the study period. A greater number of patients and a longer follow up are necessary to confirm these initially impressive results.     

Prevention of cyclosporine-induced nephrotoxicity with pentoxifylline

Although cyclosporine (CSA) is established in the prevention of allograft rejection, its use has been associated with dose-limiting toxicities, most notably to the kidney and liver. To date, the pathogenesis of the acute form of nephrotoxicity is unclear but may be related to inhibition of vasodilatory prostaglandins resulting in vasoconstriction and ischemia. The present study investigated the coadministration of CSA with a unique hemorheologic agent, pentoxifylline (PTX), in the murine model. A total of 48 rats were orally dosed with CSA 25 mg/kg for 10 days with either PTX 45 mg/kg i.p. or saline every 12 hr. Posttreatment renal function, assessed by creatinine (CCR) and inulin (CIN) clearances and renal electrolyte handling, was compared with baseline data and between groups. In an attempt to assess prostaglandin-mediated changes in enteral absorption, oral CSA pharmacokinetics with and without PTX were compared to the pharmacokinetics of similar groups (N = 8) administered i.v. CSA. Mean CIN of rats coadministered CSA and PTX (942 +/- 214 microliters/min/g KW) was similar to control rats 884 +/- 185 microliters/min/g KW); both were significantly greater than CSA alone (537 +/- 211 microliters/min/g KW; p less than .01). Likewise, percent of baseline CCR was significantly reduced in rats treated CSA (61 +/- 24%) compared to controls 113 +/- 41%) and rats coadministered PTX (117 +/- 75%; p less than .05). No differences in percent change from baseline electrolyte handling were observed among groups. Further, no differences in CSA pharmacokinetics with or without PTX were found.(ABSTRACT TRUNCATED AT 250 WORDS)     

The antiproteinuric effects of green tea extract on acute cyclosporine-induced nephrotoxicity in rats

Background

It has been reported that the proteinuria is an early useful marker to detect cyclosporine (CsA) nephrotoxicity. The aim of this study was to investigate the antiproteinuric effects of green tea extract (GTE) on CsA-induced acute renal injury in rats.

Methods

The rats (n = 28) were divided into four groups (n = 7/group); controls intraperitoneally (IP) injected with 0.9% saline; CsA group IP injected CsA (50 mg/kg); inducible nitric oxide synthase (iNOS) inhibitor group administered in addition NG-nitro-L-arginine-methyl ester (12 mmol/L) subcutaneously and CsA-GTE group of CsA IP plus GTE (100 mg/kg) subcutaneously.

Results

The 24-hour urine proteins were significantly increased among the CsA (22.6 ± 3.1 mg/d) compared with the control (7.1 ± 1.5 mg/d) and significantly decreased in the CsA-GTE group (8.2 ± 1.8 mg/d, P < .01). Nitric oxide production induces by CsA treatment was significantly suppressed by GTE and iNOS inhibitor. Renal tissue malondialdehyde level was significantly increased in the CsA compared with controls and significantly decreased in the CsA-GTE group. The antioxidant enzyme activities of superoxide dysmutase and catalase, which were significantly suppressed in the CsA compared with the control group, were restored in the CsA-GTE cohort.

Conclusion

GTE treatment of rats showed meaningful antiproteinuric effects through antioxidative activity in kidneys from CsA-induced acute renal injury.     

Dietary potassium and magnesium supplementation in cyclosporine-induced hypertension and nephrotoxicity

BACKGROUND: Cyclosporine A (CsA)-induced hypertension and nephrotoxicity are aggravated by high sodium intake. Accumulating evidence suggests that potassium and magnesium supplementation could protect against the detrimental effects of dietary salt. In the present study, we tested the hypothesis of whether concurrent supplementation with potassium and magnesium could protect against the development of CsA-induced hypertension and nephrotoxicity more effectively than supplementation with one mineral alone. METHODS: Eight-week-old spontaneously hypertensive rats (SHRs) were divided into four groups (N = 10 in each group): (1) CsA group (5 mg/kg subcutaneously) receiving high-sodium diet (Na 2.6%, K 0.8%, Mg 0.2% wt/wt); (2) CsA group receiving a high-sodium, high-potassium diet (Na 2.6%, K 2.4%, Mg 0.2%); (3) CsA group receiving high-sodium, high-magnesium diet (Na 2.6%, K 0.8%, Mg 0.6%); and (4) CsA group receiving high-sodium, high-potassium, high-magnesium diet (Na 2.6%, K 2.4%, Mg 0.6%). RESULTS: CsA induced severe hypertension and deteriorated renal functions in SHRs on high-sodium diet. Histologically, the kidneys showed severe thickening of the media of the afferent artery with fibrinoid necrosis. Potassium supplementation lowered blood pressure (198 +/- 5 vs. 212 +/- 2 mm Hg, P < 0.05) and partially prevented the development of proteinuria (-25%, P < 0.05). Magnesium supplementation decreased blood pressure to the same extent but improved renal functions more effectively than potassium. The greatest protection against CsA toxicity was achieved when dietary potassium and magnesium supplementations were combined. Urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion, a marker for renal proximal tubular damage, increased progressively in CsA-treated SHRs on the high-sodium diet. Neither potassium nor magnesium influenced urinary NAG excretion. We also estimated the activity of the renal dopaminergic system by measuring 24-hour urinary dopamine excretion rates. CsA suppressed the renal dopaminergic system during high-sodium diet. Magnesium supplementation, alone and in combination with potassium, protected against the development of renal dopaminergic deficiency in CsA-treated SHRs on high-sodium diet. Magnesium supplementation increased plasma-free ionized magnesium (iMg) and bone magnesium by 50 and 16%, respectively. CONCLUSIONS: Our findings indicate that both potassium and magnesium supplementations showed beneficial effects against CsA-induced hypertension and nephrotoxicity. The protective effect of magnesium clearly exceeded that of potassium. The greatest protection against CsA toxicity was achieved when potassium and magnesium were combined. We also provide evidence that the development of CsA-induced glomerular, tubular, and vascular lesions are associated with renal dopaminergic deficiency.     

Melatonin: an antioxidant protects against cyclosporine-induced nephrotoxicity

BACKGROUND: Cyclosporine (CsA) causes a dose-related decrease in renal function in experimental animals. Different mediators for CsA nephrotoxicity have been suggested; oxygen free radicals are one of them. In experimental model of Wistar rats, the role of antioxidant melatonin (Mel), the main product of pineal secretion, was investigated in CsA nephrotoxicity. METHODS: Male Wistar rats were divided into four groups: saline control, 50 mg/kg CsA, 500 microg/kg Mel, and CsA + Mel. At the end of 14th day of treatment, blood urea, creatinine, malondialdehyde, and creatinine and lithium clearance were estimated. Histopathological examination of kidney from all the groups was performed. RESULTS: CsA caused marked elevation in blood urea, serum creatinine, and plasma malondialdehyde and a decrease in creatinine and lithium clearance. Mel significantly antagonized CsA-induced renal impairment. Microcalcification in corticomedullary junction seen with CsA was prevented by Mel. CONCLUSION: These results indicate that Mel, through its antioxidant properties, provides protection against CsA-induced nephrotoxicity.     

Effect of epigallocatechin gallate on renal function in cyclosporine-induced nephrotoxicity

INTRODUCTION: Nephrotoxicity is a clinically important side effect of cyclosporine (CsA). CsA-induced nephrotoxicity results from increased production of free radical species in the kidney. Epigallocatechin gallate (EGCG) acts as an antioxidant, thus, EGCG may have a protective effect on the alteration of renal function resultant from oxygen free radicals. The purpose of the present study was to investigate the protective effect of EGCG in a rodent model. METHODS: Experiments were performed on 3 groups. The normal control group (group 1) received normal saline solution. The CsA-treated group (group 2; 15 mg/kg body weight/d for 14 days) received subcutaneous injections. The EGCG-treated group (group 3) in addition received 25 mg of EGCG/kg body weight by intraperitoneal injection. RESULTS: There were significant increases in levels of blood urea nitrogen (BUN)(42.8 +/- 8.2 mg/dL; P < .001), serum creatinine (1.18 +/- 0.60 mg/dL; P < .05), and serum malondialdehyde (3.09 +/- 0.20 nmol/mL; P < .001), and a significant decrease in CCr(0.07 +/- 0.02 mL/min; P < .001) in group 2 compared with group 1. Levels of BUN (30.2 +/- 0.7 mg/dL; P < .01)and CCr (0.12 +/- 0.08 mL/min) were lower in group 3 than in group 2. Serum creatinine (0.71 +/- 0.04 mg/dL) and serum malondialdehyde level (2.13 +/- 0.15; P < .001 nmol/mL) were lower in group 3 than in group 2. There was no significant difference in CsA levels between group 2 (6.86 +/- 1.48 mug/mL) and group 3 (6.69 +/- 0.62 mug/mL). CONCLUSIONS: EGCG treatment significantly protected renal function and free radical-mediated injury in the kidney from CsA-induced changes.     

Reversibility of cyclosporine-induced hypoandrogenism in rats

In an attempt to determine whether the inhibition of the hypothalamic-pituitary-testicular axis induced by oral cyclosporine (CsA) is reversible, intact adult male rats were treated with 30 mg/kg oral CsA daily for 4 weeks, and then vehicle (orange juice) for the next 4 weeks. A second group of animals (control) was fed orange juice throughout the entire 8 weeks of the experiment. Serum testosterone (T) was decreased significantly (P less than 0.01) after 4 weeks of CsA treatment when compared with controls. After cessation of oral CsA for the next 4 weeks, there was no difference in serum T between the control and CsA-treated groups. Serum LH, intratesticular T, ventral prostate (VP) and seminal vesicle (SV) weights paralleled the serum T levels at 4 and 8 weeks--i.e., all values were decreased in the 4-week CsA-treated group when compared with controls, and these returned to normal at 8 weeks. Intratesticular 17 alpha-hydroxylase and 17,20-desmolase activities were significantly lower after 4 weeks of CsA treatment; following cessation of the CsA, these enzymatic values returned to normal within 4 weeks. These data demonstrate that at the duration of treatment and the dose studied, the CsA-induced inhibition of the hypothalamic-pituitary-testicular axis of the intact adult rat is completely reversible.     

Biochemical mechanisms underlying cyclosporine-induced nephrotoxicity. Effect of concomitant administration of prednisolone

Biochemical mechanisms underlying cyclosporine (CsA)-induced nephrotoxicity and the effect of concomitant administration of prednisolone (Pr) on the nephrotoxicity were studied. Male Wistar rats were treated with the vehicles used for CsA and Pr administration (group 1), Pr alone (group 2), CsA alone (group 3), or CsA plus Pr (group 4), respectively. The dose of CsA was 5 mg/kg/day, i.p. for the initial 7 days, and was decreased to 2.5 mg/kg/day i.p. thereafter. The dose of Pr was always maintained at one-tenth of that of CsA. At 10, 30, and 90 days after the initiation of these treatments, blood urea nitrogen (BUN) and serum levels of creatinine and CsA were determined. The syntheses of DNA, RNA, and protein, Na+, K+-adenosine triphosphate (ATP)ase activity, and ATP content were measured using homogenates of the renal cortex obtained from each experimental group. At an early stage (at 10 and 30 days) of CsA administration, the impairment of renal function and inhibition of the synthesis of DNA and RNA appeared in groups 3 and 4. The magnitude of these changes was found to be greater in group 3 (CsA alone) than in group 4 (CsA plus Pr). Group 3 also showed a significant reduction of Na+, K+-ATPase activity as well as ultrastructural abnormalities. At a later stage (at 90 days), however, such differences in nephrotoxicity between groups 3 and 4 were not detected. These results strongly suggest that inhibition of the synthesis of DNA and RNA and the activity of enzymes related to the functions of cell membrane, such as Na+, K+-ATPase, may be involved in the occurrence of CsA-induced nephrotoxicity. The present results also suggest that the concomitant administration of Pr with CsA may reduce the nephrotoxicity of CsA at early stages of CsA administration, but this preventive effect of Pr may disappear if the administration of CsA is prolonged.     

Selective enhancement of thromboxane in macrophages and kidneys in cyclosporine-induced nephrotoxicity. Dietary protection by fish oil

Cyclosporine (CsA) associated renal dysfunction is related in part to renal vasoconstriction. To identify the role of cyclooxygenase metabolites in the induction of vasoconstriction, we analyzed the effect of CsA on the synthesis of thromboxane (TxA2) prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the kidney and peritoneal macrophages. Groups of rats were pair-fed diets enriched with 20% fish oil (FO) or corn oil (CO) for 4 weeks and then were injected with CsA 12.5 mg/kg/day i.p. for 2 weeks. CsA induced the synthesis of TxA2 and modestly reduced PGE2 and PGI2 in renal cortex and peritoneal macrophages. Feeding rats a diet enriched in FO containing omega-3 fatty acids as compared with CO without these fatty acids suppressed the increase in TxA2 and decreased the vasodilators PGE2 and PGI2 in the kidney and peritoneal macrophages, while modifying the decrease in the glomerular filtration rate and vacuolization in proximal convoluted tubules characteristic of rodent CsA-associated nephrotoxicity. Thus, CsA-initiated renal vasoconstriction is related to an increase in the vasoconstrictive Tx molecule and the reduction in vasodilator metabolites. Intrarenal macrophages represent a likely source of this Tx production. Feeding rats diets containing omega-3 fatty acids, known to be competitive inhibitors of cyclooxygenase metabolites, prevents CsA from selectively increasing TxA2 and preserves renal function.