Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M
Rationale: The balance between vascular prostacyclin which is anti-thrombotic and platelet thromboxane A2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed following the concerted actions of cytosolic phospholipase A2 (cPLA2α) and 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 A2 formation with the circulation and used to explain cyclooxygenase 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 knock-in'. 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 A2 in the circulation.
Methods and Results: Metabolites were measured using LC-MS/MS. 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-ketoPGF1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following 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 while endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible.
Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying upon urinary metabolites of prostacyclin and thromboxane A2 as markers of whole body endothelial and platelet function now requires re-evaluation.
- phospholipase A2
- endothelial function
- Received October 1, 2017.
- Revision received December 14, 2017.
- Accepted December 20, 2017.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.