CKD is recognized and treated at a rather late stage
Under the current definition of CKD, which includes only patients associated with creatinine clearance under 60 mL/min per 1.73 m2, or serum creatinine greater than 1 mg/dL, recognition of CKD is practically limited to late CKD (stages 3-5) since serum creatinine does not change until the creatinine clearance drops to the 50% level[25-27]. This implies that treatment of CKD is usually initiated at a rather late stage. Early stage CKD patients have generally been left untreated, and the disease allowed to progress without any appropriate therapeutic intervention. Treatment of these CKD patients with vasodilators shows therapeutic unresponsiveness and fails to correct the chronic ischemic state[28-33]. This issue leads us to propose that vascular homeostasis explains such therapeutic failure.
Altered vascular homeostasis in late CKD
It has been recently demonstrated that altered vascular homeostasis and impaired nitric oxide (NO) production are responsible for therapeutic resistance to vasodilators in late CKD.
With respect to vascular homeostasis, a normal vascular homeostasis is the balance between vascular injury and vascular repair (Figure 2). Under normal circumstances, vascular injury results in an increased number of endothelial cells detaching from the diseased vascular wall into the circulation, so-called circulating endothelial cells which express receptor-bound vascular endothelial growth factor (VEGF) as suggested by Hohenstein et al. Such vascular injury would trigger vascular repair by recruiting angiogenic factors such as VEGF which would activate through VEGF receptor 1 (VEGFR 1) inducing Akt phosphorylation, coupled with endothelial nitric oxide synthase (eNOS), and enhanced NO production[35-37]. Enhanced NO production, in conjunction with endothelial progenitor cells and angiopoietin 1, stimulate endothelial cell proliferation, maturation and reendothelialization. Collectively, they would integrate in a normal vascular repair and angiogenesis[38,39].
Figure 2 Normal vascular homeostasis.
VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptor; eNOS: Endothelial nitric oxide synthase; NO: Nitric oxide.
In late stage CKD, we as well as others[40-44] have recently demonstrated that there is an altered vascular homeostasis characterized by defective angiogenic factors namely VEGF, VEGFR 1, endothelial progenitor cells and angiopoietin 1, in conjunction with abnormally elevated antiangiogenic factors namely: VEGFR 2 and angiopoietin 2. Such altered vascular homeostasis observed in late stage CKD canbe summarized as follows.
With respect to defective angiogenic factors, as indicated on the left hand side of Figure 3, the defective VEGF and VEGFR 1 would impair the Akt phosphorylation, uncouple eNOS, and impair NO production. An impaired NO production in conjunction with defective endothelial progenitor cells and defective angiopoietin 1 would impair the physiological stimulation of endothelial cell proliferation and maturation. They would integrate together in an insufficient vasculogenesis and vascular repair. With respect to the abnormally elevated antiangiogenic factors, VEGF activates through VEGFR 2 inducing abnormal Akt phosphorylation through an NO-independent pathway, resulting in a proliferation of abnormally immature endothelial cells. The presence of defective angiopoietin 1, is responsible for the immature endothelial cell proliferation. In addition, in the presence of abnormally elevated angiopoietin 2, endothelial cells would be further destabilized and endothelial apoptosis induced. Collectively, they would integrate in the formation of abnormally immature endothelial cells, which would be consistent with endothelial myofibroblast transition cell indicated by Li. With respect to the vascular smooth muscle cell (VSMC) proliferation, this is triggered by the upregulation of angiotensin II secondary to endothelial cell dysfunction, activating NADPH oxidase, oxidative stress, NFKB and p 38, JAK STAT and eventually stimulating VSMC proliferation. The VSMC proliferation would induce a thickening of the vascular wall, a narrowing of vascular lumen, and eventually a reduction in vascular perfusion, which eventually leading to the development of neoangiogenesis and progressive vascular disease. The altered vascular homeostasis observed in late stage CKD indicates both an insufficient vasculogenesis associated with an impaired NO production, which explains the therapeutic resistance to vasodilators, as well as the clinical progression of renal microvascular disease of increasing severity. Also, the progression of renal microvascular disease correlates with the altered renal hemodynamics characterized by a progressive reduction in peritubular capillary flow along with a progressive decline in renal function. Such therapeutic failure of current practice with vasodilators in late stage CKD requires an alternative strategy to focus the treatment at the new target group of CKD patients at the early stage of renal function impairment (Figure 3).
Figure 3 Altered vascular homeostasis in late chronic kidney disease.
VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptor; eNOS: Endothelial nitric oxide synthase; VSMC: Vascular smooth muscle cell; NO: Nitric oxide.