Cross-Talk between Two Organs: How the Kidney Responds to Disruption of Acid-Base Balance by the Lung

Madias, Nicolaos E.; Adrogué, Horacio J.

doi:10.1159/000069557

Cited by 29 publications

(17 citation statements)

References 31 publications

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“…Increased mortality in ABLC-treated animals, compared to L-AMB-treated animals, may have been due to a critical pH imbalance caused by the combined effect of respiratory acidosis (20) resulting from the severe pneumonia and renal tubular acidosis, a well-known side effect of amphotericin B nephrotoxicity (10,25). As noted by others, normal kidneys are thought to play a key role in the amelioration of respiratory acid-base disorders (35).…”

Section: Discussionmentioning

confidence: 91%

Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

Olson

Adler-Moore

Schwartz

et al. 2006

Antimicrob Agents Chemother

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Invasive aspergillosis, an important cause of morbidity and mortality in immunosuppressed (IS) patients, is often treated with amphotericin B lipid formulations. In the present study, liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) were compared in treatment of murine pulmonary aspergillosis. Uninfected, IS mice were treated for 4 days with 1, 4, 8, or 12 mg L-AMB or ABLC/kg of body weight, and their lungs were analyzed by high-performance liquid chromatography for drug concentrations. IS mice intranasally challenged with Aspergillus fumigatus were treated with 12, 15, or 20 mg/kg L-AMB or ABLC and monitored for survival, fungal burden (CFU), and tissue drug concentration. Blood urea nitrogen (BUN) levels and kidney histopathology were determined for uninfected and infected mice given 15 or 20 mg/kg L-AMB or ABLC. The results showed that both drugs had therapeutic levels of drug (>3.0 g/g) in the lungs of uninfected or infected mice, and 24 h after the last dose, ABLC levels were significantly higher than L-AMB levels (P < 0.02). L-AMB and ABLC at 12 mg/kg both produced 57% survival, but only L-AMB at 15 or 20 mg/kg further increased survival to 80 to 90%, with BUN levels and kidney morphology similar to those of controls. Survival at 15 or 20 mg/kg ABLC was not significantly different than that of controls, and BUN levels were significantly elevated, with tubular alterations in uninfected animals and acute necrosis in kidney tubules of infected animals. In conclusion, although both drugs were effective in prolonging survival at 12 mg/kg, the reduced nephrotoxicity of L-AMB increased its therapeutic index, allowing for its safe and effective use at 15 or 20 mg/kg.Invasive aspergillosis (IA) has become an increasingly important cause of morbidity and mortality in patients who have been immunocompromised due to allogeneic bone marrow transplantation or intensive chemotherapy (4,36,42,45). Although newer triazoles with activity against IA have reached the commercial market (11,27,30), amphotericin B deoxycholate (D-AMB) remains as one of the drugs used against severe cases of IA (40). Even so, infusion-related toxicities and nephrotoxicity limit the optimal use of D-AMB for many patients (10, 47). To reduce these toxicities, the lipid formulations of amphotericin B, i.e., liposomal amphotericin B (L-AMB) (AmBisome) and amphotericin B lipid complex (ABLC) (Abelcet), have been used to treat IA patients (9,19,34,44,46).With the reduced toxicity of the lipid formulations, a number of preclinical studies have been done which show that doses of L-AMB and ABLC ranging from 5 to 15 mg/kg of body weight have improved therapeutic efficacy in different animal models of invasive fungal infection (3, 13-18, 21, 28). These preclinical studies would suggest that improved efficacy might be correlated with increased levels of drug in tissues. Several investigations have, in fact, shown that increased tissue concentrations of L-AMB do correlate with increased antifungal activity. Garcia and coworkers (23) fo...

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Section: Discussionmentioning

confidence: 91%

Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

Olson

Adler-Moore

Schwartz

et al. 2006

Antimicrob Agents Chemother

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“…The group receiving this Anfo dose also had no significant reduction in lung fungal burden compared to controls. One possible explanation for the latter observation may be related to a severe pH imbalance in the lungs of the mice receiving 7.5 mg of Anfo/kg caused by the combined effect of respiratory acidosis and kidney damage, since normal kidneys play a significant role in modulating respiratory acid-base disorders associated with pneumonia (27). The lower pH may increase CO 2 in the lungs and decrease the concentration of oxygen, which may lead to a reduction in the oxidative activity of amphotericin B and result in a decrease in fungal lysis (38).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Olson

Adler-Moore

Jensen

et al. 2008

Antimicrob Agents Chemother

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Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K 50 values were significantly lower for Anfogen (0.9 g/ml) than for AmBisome (20 g/ml), and the LD 50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.The use of the broad-spectrum fungicidal agent amphotericin B (37) has been limited to 1 mg/kg of body weight/day with a maximum cumulative dose of 2 to 4 g (19) because of its well-documented acute infusion-related toxicities and chronic renal toxicity. Three lipid-amphotericin B formulations approved in the United States and Europe have been developed to reduce these toxicities: Amphotec, Abelcet, and AmBisome (hereinafter referred to as AmBi). Each formulation demonstrates significant reduction in toxicities, the extent of which varies among the products. Amphotec (Three Rivers Pharmaceuticals, LLC, Cranberry Township, PA) consists of amphotericin B in a complex with cholesteryl sulfate at a 1:1 molar ratio to form stable colloidal discoidal structures with diameters of 100 Ϯ 22 nm (21), and the single-administration 50% lethal dose (LD 50 ) for mice is 36 mg/kg (21). Abelcet (Enzon Pharmaceuticals, Inc., Bridgewater, NJ), composed of amphotericin B, dimyristoyl phosphatidylcholine, and dimyristoyl phosphatidylglycerol in a 1:1 drug-to-lipid molar ratio, forms ribbon-like complexes (1.6 to 11 m), with 90% of the particles being smaller than 6 m in diameter, and the single-administration LD 50 for mice is Ͼ40 mg/kg (7). AmBi (Gilead Sciences, Inc., Foster City, CA.), a unilamellar liposomal formulation of amphotericin B in which particle diameters are approximately 80 nm, is composed of hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, and amphotericin B in a 2:1:0.8:0.4 molar ratio, and the single-administration LD 50 for mice is Ͼ175 mg/kg (35).These different commercialized amphotericin B-lipid formulations vary in their pharmacokinetic profiles (4), although their efficacies in vivo at doses of 5 to 10 mg/kg are similar in preclinical models of candidiasis (17,20,34), cryptococcosis (10), aspergillosis (3,9,16,33), and coccidioidomycosis (13,18). The significantly lower toxicity of AmBi compared to the other formulations, however, has allowed t...

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“…Thus, the metabolic response to chronic hypocapnia is hyperchloremic acidosis, which can be recognized from a negative Base Excess Chloride . (23,24).…”

Section: Discussionmentioning

confidence: 99%

Equilibrium of acidifying and alkalinizing metabolic acid–base disorders in cirrhosis

Funk

Doberer

Österreicher

et al. 2005

Liver International

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Cross-Talk between Two Organs: How the Kidney Responds to Disruption of Acid-Base Balance by the Lung

Cited by 29 publications

References 31 publications

Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Equilibrium of acidifying and alkalinizing metabolic acid–base disorders in cirrhosis

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