Homocitrulline: a new marker for differentiating acute from chronic renal failure

Aurore Desmons; Stéphane Jaisson; Christine Pietrement; Philippe Rieu; Alain Wynckel; Philippe Gillery

doi:10.1515/cclm-2015-0398

Article

Homocitrulline: a new marker for differentiating acute from chronic renal failure

Aurore Desmons , Stéphane Jaisson , Christine Pietrement , Philippe Rieu , Alain Wynckel and Philippe Gillery

Published/Copyright: June 27, 2015

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 54 Issue 1

Abstract

Background: Carbamylation is a non-enzymatic post-translational modification of proteins characterized by the addition of isocyanic acid to amino groups. As isocyanic acid mainly originates from the spontaneous dissociation of urea, carbamylation rate is increased during renal failure. The aim of the study was to evaluate serum homocitrulline (HCit), which results from the carbamylation of ε-amino groups of lysine (Lys) residues, in acute renal failure (ARF) and to determine if it could be useful for differentiating acute from chronic renal failure (CRF).

Methods: In total, 213 patients with renal failure referred to the nephrology department of the university hospital of Reims were included. Patients were classified into three groups: patients with ARF (ARF group, n=39), patients with CRF complicated with ARF (A/CRF group, n=29) and patients with CRF (CRF group, n=145). Serum HCit concentrations were measured by LC-MS/MS. Concentration kinetics of HCit and urea were studied in patients suffering from ARF. The HCit thresholds distinguishing ARF and CRF were investigated.

Results: HCit concentrations increased in ARF patients reaching a peak delayed compared to urea concentration peak. HCit concentrations were positively correlated with urea concentrations (r=0.51) and with the time elapsed since the estimated onset of ARF (r=0.57). Serum HCit concentrations were higher (p<0.05) in CRF group compared to ARF group. The receiver operating characteristic curve analysis showed that HCit concentrations <289 μmol/mol Lys were predictive of ARF (Sensitivity: 83%, Specificity: 72%, AUC: 0.856).

Conclusions: Our results demonstrate that HCit is a promising biomarker for distinguishing between ARF and CRF patients.

Keywords: acute renal failure; biomarker; carbamylation; chronic renal failure; homocitrulline

Corresponding author: Dr. Aurore Desmons, Laboratory of Peadiatric Biology and Research, Hospital Maison Blanche, University Hospital of Reims, 45 Rue Cognacq-Jay, 51092 Reims, France, Phone: +33 3 26783952, Fax: +33 3 26783882, E-mail: adesmons@chu-reims.fr; and Laboratory of Biochemistry and Molecular Biology, Faculty of Medicine, University of Reims Champagne-Ardenne, UMR/CNRS/URCA n°7369, Reims, France

Acknowledgments

This work was supported by grants from the “VIVA” project (University Hospital of Reims and University of Reims Champagne-Ardenne). The authors thank Mrs. C. Desroches and N. Leroy for their skillful technical assistance.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Jaisson S, Gillery P. Evaluation of nonenzymatic posttranslational modification-derived products as biomarkers of molecular aging of proteins. Clin Chem 2010;56:1401–12.10.1373/clinchem.2010.145201Search in Google Scholar

2. Gonzalez P, Grisolia S. Carbamylation of glutamate dehydrogenase and other mitochondrial proteins by biosynthetic carbamyl phosphate. Physiol Chem Phys 1975;7:271–5.Search in Google Scholar

3. Ramponi G, Leaver JL, Grisolia S. Homocitrulline formation following carbamylation of histones with carbamyl phosphate. Febs Lett 1971;16:311–4.10.1016/0014-5793(71)80378-2Search in Google Scholar

4. Gillery P, Jaisson S. Post-translational modification derived products (PTMDPs): toxins in chronic diseases? Clin Chem Lab Med 2013;2:1–6.10.1515/cclm-2012-0880Search in Google Scholar PubMed

5. Berg AH, Drechsler C, Wenger J, Buccafusca R, Hod T, Kalim S, et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med 2013;5:175ra29.10.1126/scitranslmed.3005218Search in Google Scholar PubMed PubMed Central

6. Jaisson S, Pietrement C, Gillery P. Carbamylation-derived products: bioactive compounds and potential biomarkers in chronic renal failure and atherosclerosis. Clin Chem 2011;57:1499–505.10.1373/clinchem.2011.163188Search in Google Scholar PubMed

7. Kraus LM, Kraus AP Jr. Carbamoylation of amino acids and proteins in uremia. Kidney Int Suppl 2001;78:S102–7.10.1046/j.1523-1755.2001.07811.xSearch in Google Scholar

8. Jaisson S, Delevallée-Forte C, Touré F, Rieu P, Garnotel R, Gillery P. Carbamylated albumin is a potent inhibitor of polymorphonuclear neutrophil respiratory burst. Febs Lett 2007;581:1509–13.10.1016/j.febslet.2007.03.008Search in Google Scholar PubMed

9. Jaisson S, Larreta-Garde V, Bellon G, Hornebeck W, Garnotel R, Gillery P. Carbamylation differentially alters type I collagen sensitivity to various collagenases. Matrix Biol J Int Soc Matrix Biol 2007;26:190–6.10.1016/j.matbio.2006.10.008Search in Google Scholar PubMed

10. Apostolov EO, Ray D, Savenka AV, Shah SV, Basnakian AG. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J Am Soc Nephrol 2010;21:1852–7.10.1681/ASN.2010040365Search in Google Scholar PubMed PubMed Central

11. Holzer M, Gauster M, Pfeifer T, Wadsack C, Fauler G, Stiegler P, et al. Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxidants Redox Signal 2011;15:2337–46.10.1089/ars.2010.3640Search in Google Scholar PubMed PubMed Central

12. Mun KC, Golper TA. Impaired biological activity of erythropoietin by cyanate carbamylation. Blood Purif 2000;18:13–7.10.1159/000014403Search in Google Scholar

13. Park K-D, Mun K-C, Chang E-J, Park S-B, Kim H-C. Inhibition of erythropoietin activity by cyanate. Scand J Urol Nephrol 2004;38:69–72.10.1080/00365590310006291Search in Google Scholar

14. Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004;305:239–42.10.1126/science.1098313Search in Google Scholar

15. Gross M-L, Piecha G, Bierhaus A, Hanke W, Henle T, Schirmacher P, et al. Glycated and carbamylated albumin are more “nephrotoxic” than unmodified albumin in the amphibian kidney. Am J Physiol Renal Physiol 2011;301: F476–85.10.1152/ajprenal.00342.2010Search in Google Scholar

16. Davenport A, Jones SR, Goel S, Astley JP, Hartog M. Differentiation of acute from chronic renal impairment by detection of carbamylated haemoglobin. Lancet 1993;341:1614–7.10.1016/0140-6736(93)90757-8Search in Google Scholar

17. Koeth RA, Kalantar-Zadeh K, Wang Z, Fu X, Tang WH, Hazen SL. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol 2013;24:853–61.10.1681/ASN.2012030254Search in Google Scholar PubMed PubMed Central

18. Tang WH, Shrestha K, Wang Z, Borowski AG, Troughton RW, Klein AL, et al. Protein carbamylation in chronic systolic heart failure: relationship with renal impairment and adverse long-term outcomes. J Card Fail 2013;19:219–24.10.1016/j.cardfail.2013.02.001Search in Google Scholar PubMed PubMed Central

19. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 2014;371:58–66.10.1056/NEJMra1214243Search in Google Scholar PubMed

20. Jaisson S, Gorisse L, Pietrement C, Gillery P. Quantification of plasma homocitrulline using hydrophilic interaction liquid chromatography (HILIC) coupled to tandem mass spectrometry. Anal Bioanal Chem 2012;402:1635–41.10.1007/s00216-011-5619-6Search in Google Scholar PubMed

21. Pietrement C, Gorisse L, Jaisson S, Gillery P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PloS One 2013;8:e82506.10.1371/journal.pone.0082506Search in Google Scholar PubMed PubMed Central

22. Balion CM, Draisey TF, Thibert RJ. Carbamylated hemoglobin and carbamylated plasma protein in hemodialyzed patients. Kidney Int 1998;53:488–95.10.1046/j.1523-1755.1998.00777.xSearch in Google Scholar PubMed

23. Stim J, Shaykh M, Anwar F, Ansari A, Arruda JA, Dunea G. Factors determining hemoglobin carbamylation in renal failure. Kidney Int 1995;48:1605–10.10.1038/ki.1995.454Search in Google Scholar PubMed

24. Kalim S, Tamez H, Wenger J, Ankers E, Trottier CA, Deferio JJ, et al. Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease. Clin J Am Soc Nephrol 2013;8:1927–34.10.2215/CJN.04310413Search in Google Scholar PubMed PubMed Central

25. Wynckel A, Randoux C, Millart H, Desroches C, Gillery P, Canivet E, et al. Kinetics of carbamylated haemoglobin in acute renal failure. Nephrol Dial Transplant 2000;15:1183–8.10.1093/ndt/15.8.1183Search in Google Scholar PubMed

Received: 2015-4-27

Accepted: 2015-6-1

Published Online: 2015-6-27

Published in Print: 2016-1-1

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Articles in the same Issue

https://doi.org/10.1515/cclm-2015-0398

Keywords for this article

acute renal failure; biomarker; carbamylation; chronic renal failure; homocitrulline