Abstract 20347: Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Leads to Urinary Prostacyclin and Thromboxane A2 Metabolites Within Normal Ranges
Measurements of metabolites of prostacyclin and thromboxane A2 (TXA2) in the urine have been held as the best estimates of eicosanoid production in the circulation. As such, measurement of these urinary markers has been used to inform (i) drug action in clinical studies, (ii) personal risk of cardiovascular disease in patient groups and (iii) a plethora of basic science relating to eicosanoids, particularly in regard to cyclooxygenase biology and the general idea that prostacyclin in the circulation is formed by cyclooxygenase-2. However, urinary markers are not universally accepted as reflective of the circulation, with some studies indicating that they originate in the kidney. We have previously reported a patient with genetic cytosolic phospholipase A2 (cPLA2α) deficiency, who lacks the capacity to generate prostacyclin in endothelial cells and TXA2 in platelets. This patient has now undergone a kidney transplant receiving a genetically normal organ and creating a truly unique experimental model akin to a human ‘whole body cPLA2α knockout, kidney specific knock-in’, for the determination of sites of eicosanoid production. Here we have used samples from this individual including endothelial cells grown from blood progenitors, before and after kidney transplant, to allow us to definitively establish the role of the kidney versus the circulation in generation of urinary prostacyclin and TXA2 metabolites.
Before transplant, endothelial prostacyclin, platelet TXA2 and urinary metabolites of both PGI-M and TX-M were very greatly below the normal range. After transplantation, endothelial prostacyclin and platelet TXA2 production remained negligible whereas the urinary metabolites PGI-M and TX-M were brought into the normal range.
These results not only describe a unique clinical case but also demonstrate that the kidney alone can produce urinary metabolites of prostacyclin and TXA2 within the normal range. Consequently, urinary metabolites cannot be relied upon as surrogates for production in the systemic circulation. We must now revisit and reinterpret studies in which PGI-M and TX-M have been used as indicators of cardiovascular health, function and risk.
Author Disclosures: J.A. Mitchell: None. R. Knowles: None. N.S. Kirkby: None. D.M. Reed: None. W. White: None. M.L. Edin: None. H. Longhurst: None. M. Yaqoob: None. G.L. Milne: None. D.C. Zeldin: None. T.D. Warner: None.
- © 2016 by American Heart Association, Inc.