The implications of aspirin resistance in renal failure.

Abstract

Sir, Aspirin resistance is a phenomenon where the expected inhibition of platelet responses is not obtained as evaluated by different biological tests [1]. In addition to non-compliance and other patient-related factors, one of the main reasons for aspirin resistance is its inability to inhibit thromboxane A2 (TXA2) biosynthesis in vivo. Many studies have also shown that patients with aspirin resistance are more likely to have an increased rate of recurrence of vascular events [2,3]. Interestingly, in a recent systematic review by Krasopoulos et al., the relationship between resistance to aspirin and a history of renal impairment was observed (P < 0.03) [4]. This was considered as possibly a chance finding, mainly because of lack of substantial data. However, an abnormality of platelet arachidonic acid metabolism has been well documented to exist in patients with renal impairment [5]. This leads to altered thromboxane synthesis that is a key factor for the development of resistance to aspirin. Initially thought to be due to a ‘functional cyclo-oxygenase defect’, it is now considered to be due to the increased activity of phospholipase A2 in the platelets of patients with uraemia [5,6]. Thromboxane has also been shown to play an important role in the physiological function of the kidney, and TXA2 receptors have been shown to exist in renal vasculature and other nephron segments in animal models [7,8]. Various studies have shown that TXA2 plays a key role in the regulation of renal haemodynamics mainly acting in conjunction with angiotensin II. TXA2, in addition to angiotensin II and arginine–vasopressin constrict larger vessels within the renal vascular tree via activation of a rho-associated kinase pathway [9]. Thromboxane receptor knockout mice demonstrated reduced renal blood flow and increased filtration fraction and renal vascular resistance, despite normal basal mean arterial blood pressure and glomerular filtration rate [10]. Enhanced production of thromboxane in the kidney has been demonstrated in several diseases including lupus nephritis, ureteral obstruction and nephrotoxic renal injury [11,12,13]. In a normal kidney, the production of TXA2 and prostaglandin I2 is well controlled, and the balance between them is important in maintaining homeostasis in vivo. In patients with the above conditions, however, TXA2 synthesis is higher compared to that of prostaglandin I2. The administration of thromboxane antagonists decreased the severity of these diseases, supporting the important role of thromboxane in their pathogenesis. Kwag et al. demonstrated that dietary vitamin E decreased the elevated phospholipase A2 in the kidney tissues of diabetic rats and improved the prostaglandin I2/TXA2 balance in the kidney microsomes thus improving vascular complications [14]. Chronic kidney disease is now recognized as an independent risk factor for cardiovascular events, and cardiovascular disease is the major cause of mortality in patients with the disease [15]. Possibly, the increased aspirin resistance in patients with renal failure may indicate that a similar vascular pathology, involving among others thromboxane, exists in these two different vascular beds. More work on the thromboxane pathway is required in the patients with renal impairment, who develop recurrent cardiovascular events, despite being on aspirin. This would pave the way for novel treatments that would help in preventing the progression of both the renal and cardiovascular pathologies. Conflict of interest statement. None declared.