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Editorial

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Myeloperoxidase Activity and Oxidized Amino Acids as Biomarkers in Chronic Kidney Disease and Coronary Artery Disease

Sharma K.a, b

Author affiliations

aCenter for Renal Translational Medicine, Institute of Metabolomic Medicine, Division of Nephrology-Hypertension, University of California San Diego, and bDivision of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA

Corresponding Author

Kumar Sharma

Center for Renal Translational Medicine, University of California San Diego/Veterans Affairs San Diego Healthcare System, Stein Clinical Research Building, 4th Floor, 9500 Gilman Drive, La Jolla, CA 92093-0711 (USA)

E-Mail kumarsharma@ucsd.edu

Related Articles for ""

Am J Nephrol 2017;46:71-72

The basis for enhanced vascular inflammation with chronic kidney disease (CKD) remains unknown, but it is of major clinical significance. If the mechanistic biochemical pathways that connect CKD to enhanced inflammation can be revealed, new therapies could be engineered to reduce the cardiovascular complications of CKD. In the new study by Afshinnia et al. [1], there is exciting data that addressed the link between CKD and cardiovascular complications.

Myeloperoxidase is predominantly present in lysosomes of neutrophils and macrophages and uses the substrates H2O2 and chloride to generate hypochlorous acid. A downstream consequence of enhanced MPO activity is the conversion of the aromatic amino acid tyrosine to 3-chlortyrosine. As increased plasma levels of tyrosine have been implicated in insulin-resistant states [2], there could be a potential clinical connection of this reaction for vascular disease. As the activity of a pro-inflammatory enzyme is more relevant to disease pathogenesis than the absolute levels of the protein itself, the measurement of both the protein and its activity would be more insightful.

In this study, the authors used the CPROBE cohort to address the question of myeloperoxidase levels and activity in linking CKD progression to coronary artery disease (CAD). CPROBE is a multicenter observational cohort study including both pediatric and adult patients with CKD stages 1-5 and covers several sites across the United States. The presence of CAD was defined by a history of unstable angina, myocardial infarction, or revascularization with stents or bypass surgery. Stored plasma was used and MPO measured by ELISA and oxidized amino acids by LC-ESI-MS/MS. Importantly, stable isotopes were used for identification and relative quantitation. Adequate quality control procedures were in place with intra-assay CVs for tyrosine and chloro-tyrosine of <10%.

The CKD cohort consisted of 111 patients with a preponderance of glomerular disease (41%), followed by HTN (19%) and diabetes (17%). Thus, this cohort has a high prevalence of glomerular disease. The levels of MPO showed an interesting pattern with higher levels in patients with stage 1 CKD and with CAD but lower levels in stages 4-5 CKD and no CAD. A concern was that there were few patients with documented CAD, as only 23 out of 111 patients were noted to have CAD. The opposite trends between CKD progression and presence or absence of CAD will need to be evaluated in larger studies.

Perhaps the most important finding is that MPO protein levels do not correlate with MPO activity. Although this finding is not unexpected, it is surprising that so many studies are focused on measuring biomarkers only at the protein level and without a functional readout of activity. This study demonstrates that there could be a large disparity between protein levels and activity of the protein, in this case, myeloperoxidase.

Another key finding is the recognition that 3-chlorotyrosine may play a key role in CKD. There is a clear increase in 3-chlorotyrosine levels in both CAD patients and in those with advanced CKD. Although the study is cross-sectional, there may be an important relationship between early to late stage CKD and accumulation of 3-chlorotyrosine. Nitrotyrosine may also be a modified oxidative product of myeloperoxidase and measurement of both products in the circulation would provide the more needed information [3]. As the role of metabolites themselves [4,5] and their oxidative adducts [6] could have important consequences as direct mediators of inflammation and fibrosis, new studies to measure these molecules may be closer to disease activity than the proteins that regulate them.

Disclosure Statement

The authors have no conflicts of interest to declare.


References

  1. Afshinnia F, Zeng L, Byun J, Gadegbeku C, Magnone M, Whatling C, Valastro B, Kretzler M, Pennathur S; Michigan Kidney Translational Core CPROBE Investigator Group: Myleoperoxidase levels and its product 3-chlorotyrosine predict chronic kidney disease severity and associated coronary artery disease. Am J Nephrol 2017;46:73-81.
  2. Tai ES, Tan ML, Stevens RD, et al: Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010;53:757-767.
  3. Mohiuddin I, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C: Nitrotyrosine and chlorotyrosine: clinical significance and biological functions in the vascular system. J Surg Res 2006;133:143-149.
  4. Peti-Peterdi J: High glucose and renin release: the role of succinate and GPR91. Kidney Int 2010;78:1214-1217.
  5. You YH, Quach T, Saito R, Pham J, Sharma K: Metabolomics reveals a key role for fumarate in mediating the effects of NADPH oxidase 4 in diabetic kidney disease. J Am Soc Nephrol 2016;27:466-481.
  6. Mu H, Wang X, Lin PH, Yao Q, Chen C: Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation. Atherosclerosis 2008;201:67-75.

Author Contacts

Kumar Sharma

Center for Renal Translational Medicine, University of California San Diego/Veterans Affairs San Diego Healthcare System, Stein Clinical Research Building, 4th Floor, 9500 Gilman Drive, La Jolla, CA 92093-0711 (USA)

E-Mail kumarsharma@ucsd.edu


Article / Publication Details

Published online: July 01, 2017
Issue release date: July 2017

Number of Print Pages: 2
Number of Figures: 0
Number of Tables: 0

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: https://www.karger.com/AJN


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References

  1. Afshinnia F, Zeng L, Byun J, Gadegbeku C, Magnone M, Whatling C, Valastro B, Kretzler M, Pennathur S; Michigan Kidney Translational Core CPROBE Investigator Group: Myleoperoxidase levels and its product 3-chlorotyrosine predict chronic kidney disease severity and associated coronary artery disease. Am J Nephrol 2017;46:73-81.
  2. Tai ES, Tan ML, Stevens RD, et al: Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010;53:757-767.
  3. Mohiuddin I, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C: Nitrotyrosine and chlorotyrosine: clinical significance and biological functions in the vascular system. J Surg Res 2006;133:143-149.
  4. Peti-Peterdi J: High glucose and renin release: the role of succinate and GPR91. Kidney Int 2010;78:1214-1217.
  5. You YH, Quach T, Saito R, Pham J, Sharma K: Metabolomics reveals a key role for fumarate in mediating the effects of NADPH oxidase 4 in diabetic kidney disease. J Am Soc Nephrol 2016;27:466-481.
  6. Mu H, Wang X, Lin PH, Yao Q, Chen C: Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation. Atherosclerosis 2008;201:67-75.
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