Metabolomic study of cisplatin-induced nephrotoxicity

Portilla, Didier; Li, S.; Nagothu, Kiran K.; Megyesi, Judit; Kaissling, Brigitte; Schnackenberg, Laura K.; Safirstein, Robert; Beger, Richard D.

doi:10.1038/sj.ki.5000433

Cited by 162 publications

(137 citation statements)

References 45 publications

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“…Out of the markers elevated with the kidney damages, glucose and branched amino acids have been reported previously for cisplatin induced toxicity (Portilla et al, 2006;Boudonck et al, 2009). Here, we identifi ed additional markers, glycine and taurine.…”

Section: Discussionmentioning

confidence: 73%

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Identification of Urinary Biomarkers Related to Cisplatin-Induced Acute Renal Toxicity Using NMR-Based Metabolomics

He¹,

Yang²,

Choi³

et al. 2011

Biomolecules and Therapeutics

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Cisplatin is the founding member of the platin-group drugs that has platinum metal and ammonium group. Since its fi rst approval in 1978 by US Food and Drug Administration, it has been widely used for various types of cancer such as lung, ovarian, lymphomas, breast and bladder cancers (Smith and Talbot, 1992;von der Maase et al., 2000;Crino et al., 2001;Muggia, 2009). The mechanism of anticancer effect is cytotoxicity due to DNA cross-linking, oxidative damages and apoptosis (Gong et al., 1999;Pruefer et al., 2008). Due to these cytotoxic effect, cisplatin kills not only cancer cells but also normal cells, resulting in undesirable effects in various tissues including kidney, nerves, ear and gastroenteric ones (Loehrer and Einhorn, 1984). Among these, the nephrotoxicity is most common and can be a cause for the cessation of the drug therapy (Arany and Safi rstein, 2003;Yao et al., 2007). Typically, BloodCisplatin is widely used for various types of cancers. However, its side effects, most notably, renal toxicity often limit its clinical utility. Although previous metabolomic studies reported possible toxicity markers, they used small number of animals and statistical approaches that may not perform best in the presence of intra-group variation. Here, we identifi ed urinary biomarkers associated with renal toxicity induced by cisplatin using NMR-based metabolomics combined with Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA). Male Sprague-Dawley rats (n=22) were treated with cisplatin (10 mg/kg single dose), and the urines obtained before and after treatment were analyzed by NMR. Multivariable analysis of NMR data presented clear separation between non-treated and treated groups. The OPLS-DA statistical results revealed that 1,3-dimethylurate, taurine, glucose, glycine and branched-chain amino acid (isoleucine, leucine and valine) were signifi cantly elevated in the treated group and that phenylacetylglycine and sarcosine levels were decreased in the treated group. To test the robustness of the approach, we built a prediction model for the toxicity and were able to predict all the unknown samples (n=14) correctly. We believe the proposed NMR-based metabolomics with OPLS-DA approach and the resulting urine markers can be used to augment the currently available blood markers. AbstractUrea Nitrogen (BUN), and blood creatinine are checked to monitor the expression of renal toxicity. In addition, hydration and diuretic measures are taken to minimize possible kidney damages. Still, BUN and creatinine are measured from blood and are late stage kidney functional markers (Hewitt et al.,

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Section: Discussionmentioning

confidence: 73%

“…In evaluating kidney toxicities by cisplatin, metabolomics studies were also reported recently (Portilla et al, 2006;Boudonck et al, 2009). One study used NMR combined with Principal Component Analysis (PCA), and another used Mass spectroscopy with Classifi cation and Regression Trees (CART) or logistic regression.…”

Section: Introductionmentioning

confidence: 99%

Identification of Urinary Biomarkers Related to Cisplatin-Induced Acute Renal Toxicity Using NMR-Based Metabolomics

He¹,

Yang²,

Choi³

et al. 2011

Biomolecules and Therapeutics

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“…This can be caused by an effect similar to that of aminoglycoside toxicity. Aminoglycosides reduce glucose reabsorption in kidney tissue by reducing mRNA and protein expression and by disrupting the sodium-dependent glucose transporter (SGLT1) function, which is located in the apical membrane of the proximal tubule [121]. This causes a reduction in glucose reabsorption in the kidney [122].…”

Section: Oxaplatin and Cisplatinmentioning

confidence: 99%

“…This causes a reduction in glucose reabsorption in the kidney [122]. It has been suggested that one possible mechanism of cisplatin-induced proximal tubule toxicity is reduced expression of SGLTs [121,123]. However, in patients with familial renal glucosuria (mutations in SGLT1/SGLT2 coding gene, SLC5A2), no acid-base homeostasis disturbances have been reported [124,125].…”

Section: Oxaplatin and Cisplatinmentioning

confidence: 99%

Drug-induced acid-base disorders

et al. 2014

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The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal antiinflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g

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“…Our previous studies demonstrated reduced protein expression and enzyme activities of several kidney PPARα target genes in response to cisplatin nephrotoxicity, and also that the use of PPARα ligands such as fibrate compound Wy-14,643 protected renal function by preventing proximal tubule cell death in the animal models of ischemia-reperfusion and cisplatin-induced acute renal failure (ARF). We have examined the metabolic alterations that occur in ARF using high resolution 1 H NMR spectroscopy coupled with pattern recognition (9). Experimental acute renal failure was induced in 8-to 10-week-old male mice (strain Sv129) using cisplatin administration.…”

Section: Metabolomic Study Of Cisplatin Induced Acute Renal Failurementioning

confidence: 99%

Metabolomics as an Extension of Proteomic Analysis: Study of Acute Kidney Injury

Portilla

Schnackenberg

Beger

2007

Seminars in Nephrology

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While proteomics studies the global expression of proteins, metabolomics characterizes and quantifies their end products: the metabolites, produced by an organism under certain set of conditions. From this perspective it is apparent that proteomics and metabolomics are complementary and when joined allow a fuller appreciation of an organism's phenotype. Our studies using 1 H-nuclear magnetic resonance (NMR) spectroscopic analysis demonstrated the presence of glucose, aminoacids, and trichloroacetic acid cycle metabolites in the urine after 48 hr of cisplatin administration. These metabolic alterations precede changes in serum creatinine. Biochemical studies confirmed the presence of glucosuria, but also demonstrated the accumulation of nonesterified fatty acids, and triglycerides in serum, urine, and kidney tissue, in spite of increased levels of plasma insulin. These metabolic alterations were ameliorated by the use of fibrates. We propose that the injury-induced metabolic profile may be used as a biomarker of cisplatin-induced nephrotoxicity. These studies serve to illustrate that metabolomic studies add insight into pathophysiology not provided by proteomic analysis alone.

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Metabolomic study of cisplatin-induced nephrotoxicity

Cited by 162 publications

References 45 publications

Identification of Urinary Biomarkers Related to Cisplatin-Induced Acute Renal Toxicity Using NMR-Based Metabolomics

Identification of Urinary Biomarkers Related to Cisplatin-Induced Acute Renal Toxicity Using NMR-Based Metabolomics

Drug-induced acid-base disorders

Metabolomics as an Extension of Proteomic Analysis: Study of Acute Kidney Injury

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