Imperial College London
Alternate

DrNicholasKirkby

Faculty of Medicine, National Heart & Lung Institute

Senior Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 3075n.kirkby

 
 
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Location

 

364Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Mitchell:2018:10.1161/CIRCRESAHA.117.312144,
author = {Mitchell, JA and Knowles, RB and Kirkby, NS and Reed, DM and Edin, ML and White, WE and Chan, MV and Longhurst, H and Yaqoob, MM and Milne, GL and Zeldin, DC and Warner, TD},
doi = {10.1161/CIRCRESAHA.117.312144},
journal = {Circulation Research},
pages = {555--559},
title = {Kidney transplantation in a patient lacking cytosolic phospholipase A2Proves renal origins of urinary PGI-M and TX-M},
url = {http://dx.doi.org/10.1161/CIRCRESAHA.117.312144},
volume = {122},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - RATIONALE: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF1α(PGI-M) and 11-dehydro-TXB2(TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. OBJECTIVE: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2in the circulation. METHODS AND RESULTS: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F1α) and thromboxane A2(measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2remained negligible. CONCLUSIONS: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromb
AU  - Mitchell,JA
AU  - Knowles,RB
AU  - Kirkby,NS
AU  - Reed,DM
AU  - Edin,ML
AU  - White,WE
AU  - Chan,MV
AU  - Longhurst,H
AU  - Yaqoob,MM
AU  - Milne,GL
AU  - Zeldin,DC
AU  - Warner,TD
DO  - 10.1161/CIRCRESAHA.117.312144
EP  - 559
PY  - 2018///
SN  - 0009-7330
SP  - 555
TI  - Kidney transplantation in a patient lacking cytosolic phospholipase A2Proves renal origins of urinary PGI-M and TX-M
T2  - Circulation Research
UR  - http://dx.doi.org/10.1161/CIRCRESAHA.117.312144
UR  - https://www.ncbi.nlm.nih.gov/pubmed/29298774
UR  - https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.312144
UR  - http://hdl.handle.net/10044/1/57335
VL  - 122
ER  -
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