Effect of chronic theophylline administration on amphotericin B nephrotoxicity in rats

The effect of chronic theophylline administration on amphotericin B nephrotoxicity was investigated in rats. A 7-day treatment of amphotericin B (5 mg/kg/day i.p.) significantly reduced the glomerular filtration rate (GFR) measured as inuline clearance and creatinine clearance (0.74 +/- 0.29 and 0.16 +/- 0.04 ml/min, respectively) in comparison to vehicle-treated rats (2.04 +/- 0.23 and 1.29 +/- 0.19 ml/min, respectively). The reduced GFR led to evaluations in serum creatinine and BUN concentrations (0.94 +/- 0.09 and 78 +/- 11 mg/dl) in comparison to their own values before treatment (0.45 +/- 0.11 and 19 +/- 3 mg/dl). In addition amphotericin B induced an increase in sodium and a decrease in potassium excretion, the fractional sodium excretion was elevated 50-fold. The methylxanthine, theophylline, had a beneficial effect on the outcome of amphotericin-B-induced renal failure. The inuline clearance was 1.17 +/- 0.04 ml/min, the creatinine clearance 0.43 +/- 0.03 ml/min, the serum creatinine concentration 0.76 +/- 0.05 mg/dl and the BUN concentration 40 +/- 6 mg/dl. Theophylline had no effect on total sodium excretion and potassium excretion. The fractional sodium excretion, however, improved significantly. Theophylline as well as sodium deoxycholate, the detergent of amphotericin B, given alone had no effect on renal hemodynamics measured after 7 days.     

Chronic amphotericin B nephrotoxicity in the rat, protective effect of prophylactic salt loading

Amphotericin B (AMPHO) is the most effective and widely used antifungal agent for the treatment of systemic fungal disease in man. Its use is frequently limited by the development of nephrotoxicity, including renal vasoconstriction with depressed glomerular filtration rate (GFR) and renal plasma flow (RPF), inability to concentrate the urine, and renal potassium wasting. We investigated the effects of oral NaCl loading during chronic administration of AMPHO, on renal function in the rat. Rats were provided 150 mmol/L NaCl (AMPHO plus NaCl) or tap water (AMPHO plus H2O) as drinking water, 3 days prior to, and during chronic AMPHO (5 mg/kg/d intraperitoneal [IP] for 21 days). At the end of the experimental period, renal functional parameters were determined, including serum creatinine, urinary volume and electrolyte excretion rates, ability to maximally concentrate the urine after water deprivation, and renal hemodynamics. NaCl supplementation prevented the rise in serum creatinine (AMPHO plus NaCl, initial v final, 0.39 +/- 0.03 v 0.40 +/- 0.03 mg/dL [34.6 +/- 2.7 v 35.4 +/- 2.7 mumol/L], P = NS) seen in AMPHO plus H2O (0.34 +/- 0.01 v 0.51 +/- 0.04 mg/dL [30.0 +/- 0.9 v 45.2 +/- 3.5 mumol/L], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nifedipine and amphotericin B nephrotoxicity in the rat

Amphotericin B nephrotoxicity limits its therapeutic use. The mechanisms involved in the deleterious effect on the kidney include a preglomerular vasoconstriction. Nifedipine, a calcium antagonist which acts also on the afferent arteriolar tone, did not, however, prevent renal impairment in the rats of our study. This could be due either to a negligible role of the hemodynamic changes in the development of renal failure or to a lack of efficacy of nifedipine on the vasoconstrictor mechanism induced by amphotericin B.     

Chronic amphotericin B nephrotoxicity in the rat: protective effect of calcium channel blockade

Amphotericin B is used despite predictable nephrotoxicity because it remains the most efficacious agent currently available for systemic fungal infections. It has been previously shown that calcium channel blockade prevents renal vasoconstriction and blunts the fall in glomerular filtration rate during acute amphotericin B infusion in the rat. Therefore, the effect of cotreatment with diltiazem on nephrotoxicity during chronic daily amphotericin therapy in rats was studied. Rats were given diltiazem (45 mg/kg, 1 h before and 1 h after amphotericin) or vehicle by gastric tube; and amphotericin B (5 mg/kg/day i.p.) for 10 days. Control rats received corresponding vehicles by gastric tube and daily i.p. infection. Renal function was determined 24 h after the last dose of amphotericin or vehicle. Serum creatinine rose significantly in rats receiving amphotericin alone (initial versus final, 0.50 +/- 0.07 versus 1.09 +/- 0.20 mg/dL; P less than 0.05) but not with amphotericin plus diltiazem (0.54 +/- 0.11 versus 0.84 +/- 0.23 mg/dL; P was not significant). Amphotericin rats had a marked decrease in glomerular filtration rate (amphotericin versus control, 0.28 +/- 0.04 versus 1.23 +/- 0.08 mL/min/g kidney wt; P less than 0.05) and renal plasma flow (1.63 +/- 0.19 versus 3.50 +/- 0.40 mL/min/g kidney wt; P less than 0.05). These adverse renal hemodynamic effects were prevented by cotreatment with diltiazem (amphotericin plus diltiazem; glomerular filtration rate, 0.82 +/- 0.18 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control; renal plasma flow, 3.24 +/- 0.63 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of oral magnesium supplementation on acute experimental cyclosporin nephrotoxicity

Hypomagnesaemia with magnesuria are common findings in cyclosporin-(CsA)-treatedpatients and have been proposed as both a cause and a consequenceof nephrotoxicity. To investigate the role of Mg depletion inthe pathogenesis of acute CsA nephrotoxicity, rats kept on alow-salt diet were maintained on plain water (Mg(–)group)or water supplemented with 2% MgCl₂ (Mg(+) group) and randomlyassigned to treatment with CsA 15mg/kg (CsA) or vehicle (VH)s.c. for 7 days. Water and food ingestion in VH animals wasadjusted to the intake of CsA animals. CsAMg(–)group showeda significant plasma magnesium (PMg) reduction as compared tobaseline (1.13 versus 1.53 mg/dl, P<0.001) or VH values (versus1.60 mg/dl, P< 0.001) and a significantly greater post-treatmentfractional excretion of magnesium (FeMg) as compared to VH (9.4versus 5.4%, P<0.0l). Magnesium supplementation increasedPMg (2.11 versus 1.57 mg/dl P<0.001) and FeMg (13.6 versus6.2%, P<0.001) but did not prevent a reduction in GFR withCsA treatment. Alanine aminopeptidase (AAP) excretion at 7 dayswas significantly greater than baseline (130 versus 44 IU/gCr,P<0.05) or VH (36 IU/gCr, P<0.05) values only in the CsAMg(–)rats. No differences were observed in intraerythrocyte Mg, bloodpressure, and urinary excretion of N-acetyl ß-D-glucosaminidaseamong groups. Renal histology was similar in CsA rats independentof magnesium supplementation: mild vacuolization and tubularcollapse in proximal tubules. In conclusion, Mg depletion couldnot be implicated in the pathogenesis of acute CsA-induced glomerulardysfunction, but Mg replacement may protect from some of thetubular toxicity of CsA.     

Influence of albumin dialysis on pharmacokinetics of amphotericin B colloidal dispersion and amphotericin B lipid complex

Albumin dialysis (AD) is a therapeutic option in severe cholestatic liver failure. However, it can significantly enhance drug elimination. Pharmacokinetic data on antimicrobial agents--in particular on antimycotics--administered under this clinical condition are very sparse. Therefore, amphotericin B (AMB) plasma concentrations were measured in two critically ill patients who were treated with AD because of severe cholestatic liver failure and were prescribed lipid formulated AMB--either AMB colloidal dispersion (ABCD) or AMB lipid complex (ABLC)--for suspected invasive fungal infection. AD was performed with the molecular adsorbent recirculating system (MARS). Lipid-associated and liberated AMB were separately quantified on and off AD. The clearance of the liberated AMB fraction was not essentially affected (ABLC) or moderately enhanced during AD by a factor of 2.5 (ABCD). The clearance of the lipid-formulated fraction was increased by a factor of 4 during AD (ABCD) or was similar (ABLC) on and off AD. Despite the fact that there was a four-fold higher clearance of the lipid-formulated fraction of ABCD, the clinically relevant area under the concentration time curve of the liberated AMB fraction was only moderately changed (by 37% in ABCD, 70% in ABLC) during AD. Thus, the effect of AD on lipid formulated AMB appears to be moderate. A daily dose of 5 mg/kg will probably lead to adequate plasma levels in patients on AD.     

Effect of rosiglitazone on cisplatin-induced nephrotoxicity

Aim: Nephrotoxicity is a major side effect of cisplatin (Cis), a widely used chemotherapeutic drug. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of Cis nephrotoxicity. Rosiglitazone (Ros), a peroxisome proliferator-activated receptor-gamma agonist has been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators and adhesion molecules. The aim of this study was to evaluate the effect of Ros on the prevention of Cis-induced nephrotoxicity. Methods: Eighteen male Sprague–Dawley rats weighing 150–200 g were included in the study. The rats were randomly divided into three groups: group 1: Cis-treated group; group 2: Cis–Ros-treated group; group 3: saline-treated group. Blood urea nitrogen (BUN) and serum creatinine concentrations were measured. In addition, extent of histological renal tubular injury in each animal was graded histologically. Results: Mean BUN and serum creatinine concentrations were significantly lower in group 3 than in group 1 (p < 0.05) and group 2 (p < 0.05). There were no significant differences in terms of BUN and serum creatinine concentrations between groups 1 and 2 (p > 0.05). Acute tubular injury with karyomegalic changes in corticomedullary junction was significantly higher in groups 1 and 2 than group 3 (p < 0.05). However, there were no significant differences between groups 1 and 2 (p > 0.05). Conclusion: This study indicates that post-insult administration of Ros does not seem to have a beneficial effect on prevention and severity of nephrotoxicity induced by Cis.     

Evaluation of salt supplementation in CF infants

BackgroundCF infants may be at increased risk of sodium depletion which may lead to impaired growth. The objective of this study was to evaluate their sodium supplementation requirements.MethodsTen CF infants had serial measurements of weight and plasma/urine sodium and creatinine. Sodium supplementation was adjusted with the aim of maintaining fractional excretion (FENa) between 0.5% and 1.5% and urinary sodium > 10 mmol/L.ResultsUrine sodium:creatinine (UNa:Cr) ratio strongly correlated with FENa [UNa:Cr (mmol/mmol) = 35.0 × FENa (r = 0.99)]. The FENa target range corresponded to UNa:Cr 17–52 mmol/mmol. All infants required sodium supplementation to achieve UNa:Cr >17 mmol/mmol. Sodium supplement requirements (mean ± SD) at ages 0–3, 3–6, 6–9 and 9–12 months were 1.9 ± 0.5, 1.8 ± 0.8, 1.9 ± 0.9 and 0.8 ± 0.4 mmol/kg/d. No infant required calorie supplementation to achieve expected weight gain.ConclusionsUsing current UK guidelines, many cases of sodium depletion may be overlooked. Some infants require more than the recommended 1–2 mmol/kg/d. UNa:Cr ratio is a useful non-invasive measure to monitor sodium supplementation.     

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.     

Comparison of the effect of amphotericin B desoxycholate and amphotericin B colloidal dispersion on renal functions and renal morphology in rats

BACKGROUND AND AIM: Amphotericin B (AmB) desoxycholate remains as one of the most efficacious agents currently available for the treatment of systemic fungal infections; however, amphotericin B colloidal dispersion (ABCD) has been developed because of AmB desoxycholate nephrotoxicity. The goal of our study was to compare the effect of administration of AmB desoxycholate and ABCD on renal functions and renal morphology in rats. RESULTS: Amophotericin B desoxycholate as well as ABCD causes damage to renal tubuli and polyuria. Amophotericin desoxycholate causes considerably more severe damage to tubuli than ABCD, but the morphological damage to renal glomeruli is minimal in both formulas. In tubular cells, AmB desoxycholate causes severe damage to mitochondria, vacuolation of cytoplasm, and increased values of volume density of peroxisomes. CONCLUSION: None of these formulas causes a decrease in glomerular filtration in rats when animals are properly hydrated.     

Effect of amiloride on experimental gentamicin nephrotoxicity

Potassium and magnesium deficiency have been reported as risk factors for experimental gentamicin nephrotoxicity. Amiloride, a potassium-sparing diuretic, also leads to increased renal magnesium reabsorption. Amiloride, 2 mg/kg/day, was given to groups of 8-12 Fischer 344 rats receiving gentamicin, 20 mg/kg b.i.d., for 3, 7, 10 and 14 days. Control animals received the vehicle for gentamicin, amiloride alone or gentamicin alone. The degree of renal failure and weight loss were similar in gentamicin and gentamicin + amiloride groups at all time points despite increases in serum potassium and magnesium in the amiloride-treated animals. Tubular dysfunction as assessed by depression of renal cortical slice uptake of p-aminohippurate and N-methylnicotinamide was not improved by the addition of amiloride. In addition, a comparable degree of tubular necrosis and regeneration was observed in all gentamicin-treated groups. Maximum gentamicin concentrations in the renal cortex did not differ. Thus, despite reduction of urinary losses of potassium and magnesium with resultant increased serum values, amiloride did not protect against experimental gentamicin nephrotoxicity. The tubular electrolyte wasting noted clinically is likely to be a result, rather than a cause of proximal tubular cell damage.     

Effect of levamisole supplementation on hepatitis B virus vaccination response in hemodialysis patients

Aim:   As an immune-modulating agent, levamisole has been reported to stimulate depressed T-cell activity, enhance B lymphocyte function and restore delayed hypersensitivity reactions in immune-depressed patients. There are a number of recent studies claiming that levamisole can improve response rate to hepatitis B virus (HBV) vaccination in haemodialysis patients. The present study has examined this hypothesis amongst some Iranian patients, using double-blind randomized clinical trial.
Methods:   During a 12 month period, 70 patients on maintenance haemodialysis with negative anti-hepatitis B surface antibody (HBsAb) and HBV core antibody (HBcAb), from four different dialysis centres were enrolled into the study. The patients were randomized to two groups. The first group (levamisole group) received 40 μg doses of recombinant HBV vaccine i.m. at 0, 1 and 6 months, plus 100 mg levamisole p.o., after each haemodialysis session. The second group (placebo group) received the same vaccination protocol, except for the placebo instead of levamisole. The patients were followed on serum HBsAb level. Those with an HBsAb level of above 10 mIU/mL, 1 month after the third dose of vaccination, were considered as responders.
Results:   The levamisole group was comprised of 38 patients and the placebo group of 32 patients. Thirty-one patients (81.6%) of levamisole group and 26 patients (81.3%) of placebo group responded to vaccination. The difference between two groups was not significant.
Conclusion:   This study indicated that in a haemodialysis population with high response to HBV vaccination, levamisole might have no significant effect in enhancing the response. Further studies with higher power can give more accurate results.     

Renal effects of amphotericin B lipid complex

A study was conducted to compare the renal effects of amphotericin B lipid complex (ABLC), a lipid formulation of the widely used antifungal medication, with conventional amphotericin B (AmB) in the treatment of serious fungal infections, including invasive candidiasis, cryptococcal meningitis, and aspergillosis. The clinical experience of ABLC includes two types of open-label studies: randomized comparative (ABLC 5 mg/kg/d compared with AmB 0.6 to 1 mg/kg) and emergency use. In the comparative studies, changes in serum creatinine were evaluated three ways: doubling of the baseline value, an increase from < or = 1.5 mg/dL at baseline to > or = 1.5 mg/dL, and an increase from < or = 1.5 mg/dL at baseline to > or = 2.0 mg/dL. More patients in the AmB group reached these end points than in the ABLC group (P < or = 0.007), and the time needed to reach each of these end points was significantly shorter for the AmB group (P < or = 0.02). Increased serum creatinine was reported as an adverse event more frequently by patients receiving AmB than by patients receiving ABLC. In the emergency use study, a steady and statistically significant decrease in serum creatinine was observed among patients who started ABLC treatment with serum creatinine greater than 2.5 mg/dL due to prior AmB treatment. ABLC offers the physician a valuable, less-nephrotoxic alternative to AmB for the treatment of patients with severe, invasive fungal infections.     

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients

BACKGROUND: Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined. METHODS: A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation. RESULTS: Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p=0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p=0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period. CONCLUSIONS: Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.     

Effect of animal sex on experimental ciclosporin nephrotoxicity

Experimental ciclosporin (CSA) nephrotoxicity is reported to be more severe in male versus female rodents. To investigate these sex differences further, groups of male and female Sprague-Dawley rats were pair fed and given either CSA 50 mg/kg or olive oil vehicle by gavage daily for 5 days. Both groups of treated animals showed azotemia and depression of CIn but there were no sex differences. CSA levels were 5,820 ng/ml in females and 6,480 ng/ml in males (p = NS). Although CSA did not produce enzymuria in either sex, females showed more extensive proximal tubular cell vacuolization. Conclusion: Female Sprague-Dawley rats are equally as susceptible to CSA nephrotoxicity as males. Strain differences or experimental design may account for apparently conflicting results in the literature.     

洛沙坦对环孢素A慢性肾毒性大鼠核因子κB的影响

目的 探讨洛沙坦对环孢素A(CsA)慢性肾毒性保护的分子机制。方法 雄性Sprague-Dawley大鼠随机分为3组：对照组、肾毒性组、洛沙坦组。皮下注射 CsA 4周建立 CsA慢性肾毒性大鼠模型，洛沙坦治疗组同时给予CsA和洛沙坦(10 mg/kg)。凝胶电泳迁移率试验检测核因子（NF）κB的活性，免疫印迹法检测其抑制蛋白IκB和转化生长因子(TGF-β1)诱导基因βig-h3的表达。结果 与对照组比较，CsA慢性肾毒性组NF-κB的结合活性明显增加 [(201±15)％比（104±7）％，P < 0.01]；IκB的表达减少[(19±25)％比(105±10)％，P < 0.01)]；βig-h3 的表达上调 [(300±35)％比(105±15)％，P < 0.01]。洛沙坦治疗使上述指标均逆转。 结论 洛沙坦对环孢素A慢性肾毒性的保护作用与减少NF-κB的活性和致纤维化因子βig-h3的表达有关。     

Amphotericin B and amphotericin B methylester: effect on brush border membrane permeability

In order to explain the nephrotoxicity of polyene antibiotics such as Amphotericin B (AM), an effect on the tubule membrane permeability has been postulated. However, studies on the action of AM have been complicated by the use of sodium deoxycholate (DOC), a membrane dissociating detergent as a solvent. Recently, a derivative, the methylester aspartate salt of Amphotericin B (AME) has been synthesized, which is highly water soluble in the absence of organic solvents. We have tested the action of AM, DOC, and AME on the sodium permeability of brush border (BBM) vesicles isolated from rat kidney cortex. It was found that both AM and AME increased the 22Na uptake as measured by a rapid filtration technique. However, a large fraction of the AM action was due to the effect of DOC on the BBM sodium permeability. We also investigated the time- and dose-dependent action of AME on 22Na and 3H-D-mannitol efflux from BBM vesicles. After 15 sec of exposure, efflux from 22Na-preloaded vesicles was unchanged in the presence of 1 microgram AME/mg protein compared to control vesicles. With 10, 50, and 100 micrograms AME/mg protein, the efflux increased 16, 25, and 35% respectively; 260 micrograms AME/mg protein did not elicit a further increment in the 22Na efflux. In the same membrane vesicles 3H-D-mannitol efflux did not change. After preincubation of the membranes for 60 min with different concentrations of AME, the 15 sec 22Na efflux increased 26% in the presence of 1 microgram/mg protein AME with no change in the 3H-D-mannitol efflux.(ABSTRACT TRUNCATED AT 250 WORDS)