Kidney Graft Function in Long-term Cyclosporine and Tacrolimus Treatment: Comparative Study With Nephrotoxicity Markers

Marchewka, Zofia; Kuźniar, J; Zynek-Litwin, M; Falkiewicz, K; Szymańska, Beata; Roszkowska, Anna M.; Klinger, Marian

doi:10.1016/j.transproceed.2009.01.116

Cited by 9 publications

(12 citation statements)

References 26 publications

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“…In consequence, AlaAp activity has been widely used as a marker of renal dysfunction in animal models of nephrotoxicity induced with vancomicine [24] or amphotericin B [25], or in human diseases like glomerulopathies [26], IgA nephropathy [27], rheumatoid arthritis [28] or diabetes [29], and there are contradictory results about its utility as a marker in kidney transplanted patients [30], [31].…”

Section: Discussionmentioning

confidence: 99%

Urinary Aminopeptidase Activities as Early and Predictive Biomarkers of Renal Dysfunction in Cisplatin-Treated Rats

et al. 2012

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This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r2>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.

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Section: Discussionmentioning

confidence: 99%

Urinary Aminopeptidase Activities as Early and Predictive Biomarkers of Renal Dysfunction in Cisplatin-Treated Rats

et al. 2012

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“…Proteogenomic approach, MALDI-TOF [118] Acute rejection Titin, lipopolysaccharide-binding protein, peptidase inhibitor 16, complement factor D, mannose-binding lectin, protein Z-dependent protease, b2 microglobulin, kininogen-1, afamin, serine protease inhibitor, phosphatidyl choline-sterol acyltransferase, sex hormone-binding globulin in plasma iTRAQ labeling in combination with LC-MS, ELISA [119] Acute rejection 66 Proteins in peripheral blood including NF-B, STAT 1 and STAT3 iTRAQ labeling in combination with LC-MS [120] Acute rejection Seven signals in urine, protein signals were characterized based on their mass/charge, but the proteins associated with these signals were not identified SELDI-TOF [121] Acute rejection Five signals in urine, signals were characterized based on their mass/charge, but the proteins associated with these signals were not identified SELDI-TOF [122] Acute rejection 45 Signals in urine of which 16 were considered molecular marker candidates, signals were characterized based on their mass/charge, but the proteins associated with these signals were not identified SELDI-TOF [123] Acute rejection Three signal clusters in urine, signals were characterized based on their mass/charge, but the proteins associated with these signals were not identified SELDI-TOF [124] Acute tubular injury b2 Microglobulin fragments in urine SELDI-TOF [125] have been examined in renal transplant patients: neutrophil gelatinase-associated lipocalin (NGAL) [139][140][141][142][143][144][145][146], kidney injury molecule-1 (KIM-1) [147][148][149][150], netrin-1 [151], interleukin-18 [146,152], a and п-glutathione S-transferase [153], liver fatty-acid-binding protein kidney [154], N-acetyl-b-D-glucosaminidase [143,155,156], b2-microglobulin and cystatin C. Most of these can be measured by ELISA or protein bead-based multi-analyte assays [81], and for some such as NGAL, assays on analytical platforms est...…”

Section: Ce-ms [115]mentioning

confidence: 99%

Proteomics and metabolomics in renal transplantation-quo vadis?

et al. 2012

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The improvement of long-term transplant organ and patient survival remains a critical challenge following kidney transplantation. Proteomics and biochemical profiling (metabolomics) may allow for the detection of early changes in cell signal transduction regulation and biochemistry with high sensitivity and specificity. Hence, these analytical strategies hold the promise to detect and monitor disease processes and drug effects before histopathological and pathophysiological changes occur. In addition they will identify enriched populations and enable individualize drug therapy. However, proteomics and metabolomics have not yet lived up to such high expectations. Renal transplant patients are highly complex, making it difficult to establish cause-effect relationships between surrogate markers and disease processes. Appropriate study design, adequate sample handling, storage and processing, quality and reproducibility of bioanalytical multi-analyte assays, data analysis and interpretation, mechanistic verification and clinical qualification (=establishment of sensitivity and specificity in adequately powered prospective clinical trials) are important factors for the success of molecular marker discovery and development in renal transplantation. However, a newly developed and appropriately qualified molecular marker can only be successful if it is realistic that it can be implemented in a clinical setting. The development of combinatorial markers with supporting software tools is an attractive goal.

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“…NAG, a lysosomal enzyme present in renal proximal tubular cells, as well as APN and DPP IV, two brush border enzymes of proximal tubular cells had higher urinary activities in patients compared to controls ( 6 , 17 , 39 ). Also, Bone et al ( 40 ) showed that urinary activity of NAG was higher in patients taking CNI than in patients with native nephropathies or healthy volunteers, suggesting it as one of the most sensitive markers of renal proximal tubular cells injury.…”

Section: Discussionmentioning

confidence: 91%

“…Besides variability in pharmacokinetics that may complicate post-transplantation immunosuppressive treatment, chronic nephrotoxicity as well may lead to undesirable outcomes, foremost chronic allograft nephropathy (CAN), the main cause of late kidney graft loss. Both calcineurin inhibitors (CNI), TAC and cyclosporine A (CsA) may exert toxic effects on proximal tubular cells and endothelial function ( 6 , 7 ). Furthermore, oxidative stress is one of the pathophysiological mechanisms that underlie tubular damage as well as CAN and may be associated with CKD and the process of transplantation, but also generated through immunosuppressive treatment ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics May Influence Tacrolimus Daily Dose, But Not Urinary Tubular Damage Markers In The Long-Term Period After Renal Transplantation

Stefanović¹,

Cvetković²,

Veličković‐Radovanović³

et al. 2015

Journal of Medical Biochemistry

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SummaryBackgroundThe primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients.MethodsThe study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage.ResultsThe carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients’ genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes’ activities.ConclusionsOur findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug’s tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.

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Kidney Graft Function in Long-term Cyclosporine and Tacrolimus Treatment: Comparative Study With Nephrotoxicity Markers

Cited by 9 publications

References 26 publications

Urinary Aminopeptidase Activities as Early and Predictive Biomarkers of Renal Dysfunction in Cisplatin-Treated Rats

Urinary Aminopeptidase Activities as Early and Predictive Biomarkers of Renal Dysfunction in Cisplatin-Treated Rats

Proteomics and metabolomics in renal transplantation-quo vadis?

Pharmacogenetics May Influence Tacrolimus Daily Dose, But Not Urinary Tubular Damage Markers In The Long-Term Period After Renal Transplantation

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