Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice

Samodelov, Sophia L.; Visentin, Michele; Gai, Zhibo; Häusler, Stéphanie; Kullak‐Ublick, Gerd A.

doi:10.1128/aac.01650-19

Cited by 9 publications

(5 citation statements)

References 54 publications

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“…4c). The urinary secretion of KIM-1, a sensitive marker for damage in proximal tubular cells [32,33], was found to be the most sensitive of the tested biomarkers for kidney injury (Fig. 4d), followed by 2-microglobulin, clusterin, and albumin (Fig.…”

Section: Pharmacokinetics and Nephrotoxicity Of Ebl-1003 In Comparison To Gentamicinmentioning

confidence: 97%

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis

et al. 2021

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Section: Pharmacokinetics and Nephrotoxicity Of Ebl-1003 In Comparison To Gentamicinmentioning

confidence: 97%

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis

et al. 2021

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“…Thus, assuming comparable glomerular filtration rate among groups, urinary creatinine was used as a normalization element for urinary Kim-1 values. In a previous study, we showed that urinary Kim-1 outperformed urinary Cystatin-C and urinary glucose in the detection of colistin-induced kidney injury in mice 38 . Urinary Kim-1 was significantly elevated in mice treated with colistin.…”

Section: Resultsmentioning

confidence: 96%

“…Next, we assessed the effect of L-carnitine co-injection on colistin pharmacokinetics and accumulation in the kidney tissue in mice. The dose of colistin (20 mg/kg) was chosen based on our previous study, showing that all animals treated at this dose showed signs of acute kidney injury after 7 days of treatment 38 . The dose of L-carnitine (30 mg/kg) was chosen based on previous studies in rodents, and as well as on available pharmacokinetics and safety data generated in patients with primary carnitine deficiency 39 , 40 .…”

Section: Resultsmentioning

confidence: 99%

L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice

Samodelov,

Gai,

De Luca

et al. 2024

Sci Rep

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Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.

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“…Thus, assuming comparable glomerular filtration rate among groups, urinary creatinine was used as a normalization element for urinary Kim-1 values. In a previous study, we showed that urinary Kim-1 outperformed urinary Cystatin-C and urinary glucose in the detection of colistin-induced kidney injury in mice (Samodelov et al 2019). Urinary Kim-1 was significantly elevated in mice treated with colistin.…”

Section: Colistin-induced Nephrotoxicity In Mice Co-injected With L-c...mentioning

confidence: 92%

“…Next, we assessed the effect of L-carnitine co-injection on colistin pharmacokinetics and accumulation in the kidney tissue in mice. The dose of colistin (20 mg/kg) was chosen based on our previous study, showing that all animals treated at this dose showed signs of acute kidney injury after 7 days of treatment (Samodelov et al 2019). The dose of L-carnitine (30 mg/kg) was chosen based on previous studies in rodents, and as well as on available pharmacokinetics and safety data generated in patients with primary carnitine deficiency (Jafari et al 2013;Rasmussen et al 2015).…”

Section: Effect Of L-carnitine On the Antimicrobial Activity And Phar...mentioning

confidence: 99%

L-carnitine Prevents Colistin-induced Mitochondrial Permeability Transition and Reduces the Risk of Acute Kidney Injury in Mice

Samodelov,

Gai,

De Luca

et al. 2024

Preprint

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Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse proximal tubular cells. Consistently, the risk of colistin-induced kidney damage, assessed by histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.

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Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice

Cited by 9 publications

References 54 publications

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis

L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice

L-carnitine Prevents Colistin-induced Mitochondrial Permeability Transition and Reduces the Risk of Acute Kidney Injury in Mice

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