Circulating toxins namely: free radicals, cytokines and metabolic products induce glomerular endothelial dysfunction, hemodynamic maladjustment and chronic ischemic state;this leads to tubulointerstitial fibrosis in chronic kidney disease (CKD). Altered vascular homeostasis observed in late stage CKD revealed defective angiogenesis and impaired nitric oxide production explaining therapeutic resistance to vasodilator treatment in late stage CKD. Under current practice, CKD patients are diagnosed and treated at a rather late stage due to the lack of sensitivity of the diagnostic markers available. This suggests the need for an alternative therapeutic strategy implementing the therapeutic approach at an early stage. This view is supported by the normal or mildly impaired vascular homeostasis observed in early stage CKD. Treatment at this early stage can potentially enhance renal perfusion, correct the renal ischemic state and restore renal function. Thus, this alternative therapeutic approach would effectively prevent end-stage renal disease.

Homeostasis of the vital organs in the body depends on the balance between nutrient supply through vascular perfusion and the integrity of structure and function of the organs. In this regard, kidney integrity depends mainly on the renal vascular supply. Philosophically, normal homeostasis of the kidney follows the so-called Natural Wisdom “The Middle Tract is the Balance of Nature”, which implies that the normal integrity of the kidney depends on normal vascular perfusion. Any deviation of blood perfusion, either too much or too little would be harmful to the kidney[1]. Such wisdom can be illustrated by the correlation between blood perfusion and its organ’s structure and function. Under normal circumstances, the intact tubulointerstitium has been shown to be surrounded by an adequate supply of peritubular capillary plexus. In contrast, under pathological conditions, such as in chronic kidney disease (CKD), the normal tubulointerstitial structure is replaced by tubulointerstitial fibrosis, along with the disappearance of peritubular capillary plexus which is replaced by renal microvascular disease[2,3]. The spatial relationship between renal perfusion and kidney integrity will be the context of the following issues: (1) Renal microvascular disease and tubulointerstitial fibrosis; (2) Why does the present therapeutic strategy fail to restore renal function in CKD (a) CKD is recognized and treated at a rather late stage; and (b) Altered vascular homeostasis in late CKD; and (3) An innovative therapeutic strategy to implement the treatment at early stage CKD.

Accumulating evidence supports the suggestion that there are toxins such as free radicals, cytokines and metabolic products circulating through the renal microcirculation in a variety of CKDs. Abnormally elevated oxidant and antioxidant deficiencies have been repeatedly documented in both mild as well as severe forms of CKD[4-11].

The circulating toxins can induce injury to renal microvasculature. Such vascular injury detaches the endothelial cell from the vascular wall and this is reflected in an increase in the number of circulating endothelial cells in a variety of CKD patients[12,13]. In addition to the increased number of circulating endothelial cells, the remaining endothelial cells also become dysfunctional. Glomerular endothelial dysfunction is characterized by upregulation of vasoconstrictors such as angiotensin II, endothelin, thromboxane A2, adhesion molecules, procoagulant activity and reactive oxygen species. Enhanced expression of vasoconstrictors induces hemodynamic maladjustment characterized by a preferential constriction at the efferent arteriole and thus a corresponding reduction in peritubular capillary flow supplying the tubulointerstitial structure (Figure 1). This phenomenon is well documented in CKD[14-17]. It is interesting to observe that an intact tubulointerstitial structure is usually associated with normal level of peritubular capillary flow. Reduced peritubular capillary flow has been observed in all CKD patients. A mild reduction in peritubular capillary flow has been noted to precede the development of tubulointerstitial fibrosis. An increased reduction in peritubular capillary flow leads to the appearance of tubulointerstitial fibrosis. A further reduction in peritubular capillary flow is associated with a higher degree of tubulointerstitial fibrosis (Table 1)[18-23]. This suggests that the reduction in peritubular capillary flow determines the development of tubulointerstitial fibrosis. In addition, the dysfunctioning endothelial cell expresses procoagulant activity which is reflected in blood hypercoagulalilty, blood hyperviscosity, a shortened platelet half life and a shortened fibrinogen half life, indicating an increased consumption of local intravascular coagulation, plausibly in the renal microcirculation. Thus correcting both the altered blood coagulability with anticoagulant and antiplatelet agents[22-24], as well as correcting the chronic ischemic state with vasodilators[13,14,17] is an appropriate therapeutic target.

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Figure 1 Hemodynamic maladjustment induces chronic renal ischemia and tubulointerstitial fibrosis.

The alternative therapeutic strategy would focus on early stage CKD patients, who mostly have been untreated or received inappropriate treatment. Our recent study on vascular homeostasis in early stage CKD supports this concept[47,48]. In type 2 diabetic nephropathy, the vascular homeostasis observed in the normoalbuminuric stage indicated that both angiogenic factors namely: VEGF, angiopoietin 1 and VEGF receptor 1; as well as antiangiogenic factors namely: angiopoietin 2 and VEGF receptor 2, were within normal limits. In non-diabetic early stage CKD patients, the vascular homeostasis indicated that angiopoietin 1 was the only angiogenic factor showing a mild decrease, and that angiopoietin 2 was the only antiangiogenic factor showing a mild elevation. Thus these findings render support the theory that vascular homeostasis would likely be adequately functional in early stage CKD. With the adequate vasculogenesis observed in early stage CKD, vasodilator treatment would relax the efferent arteriole by enhancing the peritubular capillary flow. Increased peritubular capillary flow would inhibit the process of tubulointerstitial fibrosis indicated by the decline in Fe-Mg value following vasodilator treatment - an index indicating renal regeneration. Vasodilator treatment would also relax the afferent arteriole and thereby increase the glomerular filtration rate - an index indicating renal function improvement. In fact, therapeutic implementation with appropriate vasodilators at this early stage in CKD has indeed been able to enhance peritubular capillary flow, as well restore renal function[49,50].

In conclusion, therapeutic implementation of vasodilator treatment in early stage CKD, in an environment favorable to renal angiogenesis and regeneration, can effectively prevent end-stage renal disease.