Under common practice, recognition and treatment of type 2 diabetic nephropathy (DN) are usually revealed at a rather late stage (CKD stages 3–5) due to the insensitiveness of available diagnostic markers. Accumulating data obtained from vascular homeostasis in late stage DN demonstrated (1) a defective angiogenesis and impaired NO production which explains the therapeutic resistance to vasodilators and the inability to correct chronic renal ischemia and (2) an abnormally elevated antiangiogenesis and a progressive vascular disease which correlates with the altered renal hemodynamics characterized by a progressive reduction in renal perfusion as the disease severity progressed. In contract, the vascular homeostasis is adequately functional in early stage DN. Thus, vasodilator treatment at early stage DN (CKD stages 1-2) can enhance renal perfusion, correct the renal ischemia, and restore renal function.
Under current practice, determinations of serum creatinine and microalbuminuria are used to screen for diabetic nephropathy (DN), which is reflected by microalbuminuria (30–300 milligrams of urinary albumin/gram creatinine, or greater) and serum creatinine concentration greater than 1 mg/dL. In accordance with the 5 stages of chronic kidney disease (CKD), serum creatinine usually does not change at the early stage (CKD stages 1-2; creatinine clearance 60–119 mL/min/1.73 m2), but becomes abnormally elevated only when the creatinine clearance drops to the level of fifty percent (CKD stages 3–5; creatinine clearance <60 mL/min/1.73 m2). Similarly, microalbuminuria is usually detected when the creatinine clearance is approaching fifty percent level as depicted in Figure
Clinical findings in early stage of type 2 DN (normoalbuminuria).
Pretreatment | Normal | ||
---|---|---|---|
Renal function | |||
S Cr mg/dL | 0.9 ± 0.5 | <1 | <.05 |
MA/Cr | 13 ± 5 | <30 | NS |
CCr ml/min/1.73 m2 | 84 ± 24 | <120 | <.01 |
FE Mg | 3.5 ± 1.3 | <2.2 | <.05 |
Hemodynamics | |||
Futrakul (2007) | |||
PTCF mL/min/1.73 m2 | 292 ± 41 | 485 ± 39 | <.01 |
GFR mL/min/1.73 m2 | 88 ± 28 | 119 ± 15 | <.001 |
Comparison between conventional and newdiagnostic markers.
The insensitiveness of the available diagnostic markers is responsible for the present therapeutic failure in restoring renal perfusion and function. Vasodilators treatment initiated at the late stage of DN is characterized by therapeutic ineffectiveness. In this regard, we have recently demonstrated that such therapeutic failure correlates with the progressive reduction in peritubular capillary flow. This would raise an interesting question as to whether what would be responsible for such therapeutic unresponsiveness to vasodilators in late stage of DN.
Normal vascular homeostasis is the balance between vascular injury and vascular repair. Vascular injury is usually induced by circulating triggers such as altered shear stress [
A predominant role of VEGFR2 correlates with PTCF reduction in late stage of DN.
Vascular homeostasis | Renal hemodynamics | ||||||
---|---|---|---|---|---|---|---|
Early DN | Normal | Early DN | Normal | ||||
VEGF R1 ng/mL | 60±12 | NS | 49 ± 5 | PTCF mL/min/1.73m2 | 379 ± 70 | <.05 | 483 ± 43 |
VEGF R2 ng/mL | 5715 ± 1400 | NS | 6126 ± 1066 | ||||
Late DN | Normal | Late DN | Normal | ||||
VEGF R1 ng/mL | 33 ± 17 | <.01 | 55 ± 11 | PTCF mL/min/1.73m2 | 277 ± 80 | <.001 | 483 ± 43 |
VEGF R2 ng/mL | 10414 ± 2198 | <.01 | 7696 ± 1892 |
The study of vascular homeostasis in the controls reveals normal values of both angiogenic factors, namely, VEGF, VEGFR1, endothelial progenitor cell, and angiopoietin 1, and antiangiogenic factors, namely, VEGFR2 and angiopoietin 2. In response to vascular injury under physiologic condition, both VEGFR1 and VEGFR2 are essential in coordinating endothelial cell assembly [
Vascular homeostasis under physiologic condition.
In diabetes, vascular injury is induced by a variety of circulating toxins, namely, high glucose [
Pathologic vascular homeostasis in late stage of DN.
(I) With respect to VEGF, we have studied VEGF value in the serum, which partly reflects a component of circulating endothelial cell-receptor-bound VEGF detached from the diseased vascular wall into the circulation. Our study demonstrated a wide range of VEGF values with the mean value of VEGF not significantly different from the control. This observation of VEGF in diabetic patient is quite contrast to the reduced VEGF value observed in the nondiabetic chronic kidney disease patient [
(II) With respect to defective VEGFR1 documented in this study in late stage of DN, the activation of VEGF through the classical VEGF
(III) With respect to the defective endothelial progenitor cell and angiopoietin 1, diabetic patients have been reported to have a reduced number of circulating endothelial progenitor cell as well as its function, with the extent of reduction directly proportional to plasma hemoglobin A1C level [
(IV) With respect to the abnormally elevated antiangiogenic VEGFR2 observed in late stage of DN, other studies showed conflicting results. Cooper et al. [
In accordance with the increased VEGFR2 observed in late stage of DN, it would pathologically activate Akt phosphorylation through the NO-independent pathway to induce endothelial cell proliferation and endothelial cell dysfunction. Previous study demonstrated that this excessive Akt activation under an impaired NO production would instigate the angiogenic response to VEGF, negatively regulat endothelial cell lifespan and inhibiting endothelial tubular formation via a p53/p21-dependent pathway [
(V) With respect to altered vascular homeostasis and angiogenesis in diabetic retinopathy, expressions of VEGFA, VEGFR1, and VEGFR2 were all increased in the retina of diabetic or insulin-resistant rats [
In contrast to the abnormal vascular homeostasis and angiogenesis observed in late stage of DN, our study demonstrated the values of vascular homeostasis observed in early stage of DN (normoalbuminuria) not significantly different from the control population [
In conclusion, the preceding information renders support that implementation of treatment at the early stage of DN under the environment favorable for renal angiogenesis and regeneration would effectively restore renal function and prevent the end-stage renal disease.
We are grateful to the supports of Thailand Research Fund, National Research Council Fund of Thailand, and the Thai Royal Society.