Original ArticleDeterminants of thromboxane biosynthesis in patients with moderate to severe chronic kidney disease
Introduction
Cardiovascular disease (CVD) has been shown to be a critical factor influencing quality of life and mortality in patients with chronic kidney disease (CKD). There is a well-established association of CKD with the development of atherosclerosis and its thromboembolic complications [1], [2], [3], [4], [5]. In particular, an independent, graded, inverse relationship between estimated glomerular filtration rate (eGFR) and cardiovascular event rates has emerged from large-scale observational studies [1], [6] and CVD is increased in early-stage CKD [7].
Despite these findings, the mechanisms responsible for accelerated atherogenesis remain elusive. Clustering of cardiovascular risk factors such as sustained arterial hypertension, altered lipoprotein levels, diabetes mellitus, or obesity is often observed in CKD [8]. Nonetheless, classical risk factors poorly perform in the prediction of cardiovascular outcomes in this population, thus fostering interest into emerging risk factors.
Oxidative stress has been postulated to be a relevant risk factor for CVD in CKD patients [9], [10], [11], developing from an imbalance between increased free radical production due to dysfunctional mitochondria and reduced antioxidant defenses.
Increased reactive oxidant species (ROS) formation leads to increased lipid peroxidation. A series of bioactive prostaglandin (PG) F2-like compounds (isoprostanes) has been discovered, which represent specific end-products from free radical damage [12], [13]. Among these products, the most meaningful is 8-iso-PGF2Ξ±, which induces vasoconstriction and modulates the function of human platelets [12] and whose levels are increased in association with CVD [12], [14]. F2-isoprostanes can be reliably measured both in plasma and in urine [12]. However, since they are rapidly metabolized, any increase in plasma isoprostane concentration may be due not only to their increased formation from lipid peroxidation, but also to decreased metabolism [15]. Thus, only measurement of F2-isoprostanes in the urine provides a reliable measure of persistent whole-body oxidative stress [12], [15]. However, most of the available studies on isoprostane formation and loss of kidney function have reported increased plasma levels of these iso-eicosanoids, early in the progression of CKD [16], [17], [18].
Enhanced generation of 8-iso-PGF2Ξ± and other biologically active iso-eicosanoids could contribute to persistent platelet activation, as reflected by enhanced urinary 11-dehydro-thromboxane (TX)B2, an enzymatic metabolite of TXA2 [12], [19]. Therefore, the present study was specifically designed to investigate whether urinary 8-iso-PGF2Ξ± excretion rate is altered in CKD patients and whether it correlates with the rate of TXA2 biosynthesis. We also assessed the relative contribution of oxidative stress and TX-dependent platelet activation to CKD stage, impairment of eGFR, proteinuria, CVD factors including diabetes mellitus, plasma uric acid, and hemoglobin (Hb) levels, which have been inversely associated with mortality [20].
Section snippets
Study design and population
This is a cross-sectional observational study. A total of 115 adult Caucasians [median age (IQR) 63 (57β68) years, 81 (70.4%) males] were consecutively recruited from four nephrology outpatient clinics. All patients included in the study were diagnosed as having CKD according to National Kidney Foundation K/DOQI Guidelines [21].
We used a modified National Kidney Foundation classification of CKD, which classifies estimated GFR in the following ranges: at least 60Β mL per minute per 1.73Β m2 (stages
Characteristics of the subjects
Table 1 depicts clinical characteristics and laboratory data of CKD patients according to their eGFR group. Twenty-seven out of 115 CKD patients (23.5%) were diabetics, 88 (76.5%) had systemic arterial hypertension, and 26 (22.6%) had a history of major cardiovascular events (myocardial infarction/stroke). As expected, patients in stage 3β4 were older [69.7 (61.7β76.0) vs. 63.0 (57.0β68.0), PΒ =Β 0.001], and had more frequently arterial hypertension (84.6% vs. 59.5%, PΒ =Β 0.005), anemia (51.3% vs.
Discussion
The risk of developing CVD is high among CKD patients and, as a result, cardiovascular-related complications account for high morbidity and mortality [1], [6]. Multiple factors contribute to CVD in CKD patients, including not only cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia, but also non-traditional factors such as low-grade inflammation, anemia and hyperuricemia [27], [28], [29], [30], [31], [32], [33]. Each one of these complications needs to be identified and
Conclusion
In our study, we have characterized a sensitive marker of in vivo platelet activation, which is abnormal in a higher percentage of CKD patients in stages 3β4 as compared to stages 1β2. Although the mechanisms responsible for platelet activation are likely to be multifactorial in this setting (e.g. endothelial injury, disease-or-treatment metabolic disorders), we provide evidence that progressive renal disease is associated with in vivo TX-dependent platelet activation, which is also affected by
Declaration of interest
The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
Acknowledgments
We thank Dr. Rossella Liani and Dr. Francesca La Farina for their technical support and expert editorial assistance.
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Natale Vazzana and Francesca Santilli contributed equally to this manuscript and should be considered joint first authors.