Organ-specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat

Serkova, Natalie J.; Klawitter, Jost; Niemann, Claus U.

doi:10.1111/j.1432-2277.2003.tb00235.x

Cited by 39 publications

(10 citation statements)

References 20 publications

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“…A likely explanation for this discrepancy in comparison with a previous study [37] is the difference in kidney tissue collection. ATP/ADP concentrations in tissue are extremely sensitive to hypoxia.…”

Section: Discussioncontrasting

confidence: 52%

“…Earlier studies assessing cyclosporine toxicity had shown that inhibition of oxidative phosphorylation in brain mitochondria and kidneys may lead to a decrease in high-energy metabolites [9, 37]. However, our analysis of high-energy metabolites in kidney tissue 7 days after kidney transplantation indicated a significant decrease in ATP and NAD kidney tissue concentrations only in group 6 compared with untreated nontransplant controls.…”

Section: Discussioncontrasting

confidence: 49%

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Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Schmitz

Klawitter

Bendrick-Peart³

et al. 2009

Nephron Exp Nephrol

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Background: Cyclosporine and/or sirolimus impair recovery of renal transplants. This study examines the changes in urine metabolite profiles as surrogate markers of renal cell metabolism and function after cyclosporine and/or sirolimus treatment employing a rat kidney transplantation model. Methods: Using inbred Lewis rats, kidneys were transplanted into bilaterally nephrectomized recipients followed by treatment with either CsA (cyclosporine) 10, Rapa (sirolimus) 1, CsA10/Rapa1 or CsA25/Rapa1 mg/kg/day for 7 days. On day 7, urine was analyzed by ¹H-NMR spectroscopy. Blood and kidney tissue drug concentrations, tissue high-energy compounds (including ATP, ADP) and oxidative stress markers (15-F_2t-isoprostanes) in urine were measured by HPLC mass spectrometry. Results: Changes in urine metabolites followed the order Rapa1 < CsA10 < CsA10/Rapa1 < CsA25/Rapa1. Compared with controls, CsA25/Rapa1 showed the greatest changes (creatinine –36%, succinate –57%, citrate –89%, α-ketoglutarate –75%, creatine +498%, trimethylamine +210% and taurine +370%). 15-F_2t-isoprostane concentrations in urine increased in the combined immunosuppressant-treated animals ([CsA25/Rapa1]: 795 ± 222, [CsA10/Rapa1]: 475 ± 233 pg/mg/creatinine) as compared with controls (165 ± 78 pg/mg creatinine). Rapa concentration in blood and tissues increased in the combined treatment (blood: 31 ± 8 ng/ml, tissue: 1.3 ± 0.4 ng/mg) as compared with monotherapy (blood: 14 ± 8 ng/ml, tissue: 0.35 ± 0.15 ng/mg). Drug blood concentrations correlated with isoprostane urine concentrations, which correlated negatively with citrate, α-ketoglutarate and creatinine concentrations in urine. Only CsA25/Rapa1 significantly reduced high-energy metabolite concentrations in transplant kidney tissue (ATP –55%, ADP –24%). Conclusion: Immunosuppressant drugs induce changes in urine metabolite patterns, suggesting that immunosuppressant-induced oxidative stress is an early event in the development of nephrotoxicity. Urine 15-F_2t-isoprostane concentrations and metabolite profiles may be sensitive markers of immunosuppressant-induced nephrotoxicity.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussioncontrasting

confidence: 49%

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Schmitz

Klawitter

Bendrick-Peart³

et al. 2009

Nephron Exp Nephrol

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“…The pH was adjusted to 5.65-5.75 with NaOD and DCl. Methanol : chloroform extraction of whole blood was carried out in the same manner as described previously [31][32][33]. All extraction steps were carried out on ice.…”

Section: Analysis Of Metabolite Profiles Using 1 H-nmr Spectroscopymentioning

confidence: 99%

“…Calibration curves of key metabolites as measured by 1 H-NMR. Heparinized whole blood was enriched with the metabolites and extracted using a methanol : chloroform extraction procedure [31][32][33]. Abbreviations: GSH, glutathione; Glu, glutamate; TMAO, trimethylamine oxide.…”

Section: Figurementioning

confidence: 99%

Toxicodynamic effects of ciclosporin are reflected by metabolite profiles in the urine of healthy individuals after a single dose

Klawitter

Haschke

Kahle

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • Ciclosporin's nephrotoxicity initially targets the proximal tubule and is, at least in part, driven by increased formation of oxygen radicals. • 1H‐nuclear magnetic resonance spectroscopy (NMR)‐ and mass spectrometry (MS)‐based biochemical profiling (metabolomics) allows for the sensitive detection of metabolite pattern changes in urine. • In systematic studies in rats we showed that ciclosporin caused urine metabolite pattern changes typical for proximal tubule damage and that these pattern changes seemed to be more sensitive than established clinical kidney function markers such as serum creatinine concentrations. WHAT THIS PAPER ADDS • This study showed that urine metabolite pattern changes as assessed by 1H‐NMR and HPLC‐MS are sensitive enough to detect the effect of ciclosporin as early as 4 h after a single oral dose. • In our previous rat studies, changes in urine metabolite pattern in response to ciclosporin translated into healthy humans, indicating the involvement of the same toxicodynamic mechanisms. • The results provide proof of concept for further development of this combination molecular marker strategy into diagnostic tools for the detection and monitoring of drug nephrotoxicity. AIMS The immunosuppressant ciclosporin is an efficient prophylaxis against transplant organ rejection but its clinical use is limited by its nephrotoxicity. Our previous systematic studies in the rat indicated urine metabolite pattern changes to be sensitive indicators of the negative effects of ciclosporin on the kidney. To translate these results, we conducted an open label, placebo‐controlled, crossover study assessing the time‐dependent toxicodynamic effects of a single oral ciclosporin dose (5 mg kg−1) on the kidney in 13 healthy individuals. METHODS In plasma and urine samples, ciclosporin and 15‐F2t‐isoprostane concentrations were assessed using HPLC‐MS and metabolite profiles using 1H‐NMR spectroscopy. RESULTS The maximum ciclosporin concentrations were 1489 ± 425 ng ml−1 (blood) and 2629 ± 1308 ng ml−1 (urine). The increase in urinary 15‐F2t‐isoprostane observed 4 h after administration of ciclosporin indicated an increase in oxidative stress. 15‐F2t‐isoprostane concentrations were on average 2.9‐fold higher after ciclosporin than after placebo (59.8 ± 31.2 vs. 20.9 ± 19.9 pg mg−1 creatinine, P < 0.02). While there were no conclusive changes in plasma 15‐F2t‐isoprostane concentrations or metabolite patterns, non‐targeted metabolome analysis using principal components analysis and partial least square fit analysis revealed significant changes in urine metabolites typically associated with negative effects on proximal tubule cells. The major metabolites that differed between the 4 h urine samples after ciclosporin and placebo were citrate, hippurate, lactate, TMAO, creatinine and phenylalanine. CONCLUSION Changes in urine metabolite patterns as a molecular marker are sufficiently sensitive for the detection of the negative effects of ciclosporin on the kidney after a si...

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“…tissue, cells and body fluids) in response to pathological stimuli or genetic modifications . Nuclear magnetic resonance (NMR) spectroscopy is one of the well‐suited and popular techniques in metabolomics, which permits the simultaneous detection, identification and quantification of several hundreds of metabolites in the biological matrix, and especially in urine . NMR‐based metabolomics studies of urine samples have been successfully used to identify the metabolomics fingerprints and potential biomarkers in a few renal diseases, including focal segmental glomerulosclerosis, renal transplant dysfunction and chronic renal failure; however, there are a limited number of metabolomics studies in IgAN.…”

Section: Introductionmentioning

confidence: 99%

1 H NMR‐based metabolomics study for identifying urinary biomarkers and perturbed metabolic pathways associated with severity of IgA nephropathy: a pilot study

Kalantari

Nafar

Samavat

et al. 2017

Magnetic Reson in Chemistry

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The severity of IgA nephropathy (IgAN), the most common primary glomerulonephritis, is judged on the basis of histologic and clinical features. A limited number of studies have considered molecular signature of IgAN for this issue, and no reliable biomarkers have been presented non-invasively for use in patient evaluations. This study aims to identify metabolite markers excreted in the urine and impaired pathways that are associated with a known marker of severity (proteinuria) to predict mild and severe stages of IgAN. Urine samples were analysed using nuclear magnetic resonance from biopsy-proven IgAN patients at mild and severe stages. Multivariate statistical analysis and pathway analysis were performed. The most changed metabolites were acetoacetate, hypotaurine, homocysteine, L-kynurenine and phenylalanine. Nine metabolites were positively correlated with proteinuria, including mesaconic acid, trans-cinnamic acid, fumaric acid, 5-thymidylic acid, anthranilic acid, indole, deoxyguanosine triphosphate, 13-cis-retinoic acid and nicotinamide riboside, while three metabolites were negatively correlated with proteinuria including acetoacetate, hypotaurine and hexanal. 'Phenylalanine metabolism' was the most significant pathway which was impaired in severe stage in comparison to mild stage of IgAN. This study indicates that nuclear magnetic resonance is a versatile technique that is capable of detecting metabolite biomarkers in combination with advanced multivariate statistical analysis. Copyright © 2017 John Wiley & Sons, Ltd.

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Organ-specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat

Cited by 39 publications

References 20 publications

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Toxicodynamic effects of ciclosporin are reflected by metabolite profiles in the urine of healthy individuals after a single dose

1 H NMR‐based metabolomics study for identifying urinary biomarkers and perturbed metabolic pathways associated with severity of IgA nephropathy: a pilot study

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