Biomarker for early renal microvascular and diabetic kidney diseases.

Recognition of early stage of diabetic kidney disease, under common practice using biomarkers, namely microalbuminuria, serum creatinine level above 1 mg/dL and accepted definition of diabetic kidney disease associated with creatinine clearance value below 60 mL/min/1.73 m2, is unlikely. This would lead to delay treatment associated with therapeutic resistance to vasodilator due to a defective vascular homoeostasis. Other alternative biomarkers related to the state of microalbuminuria is not sensitive to screen for early diabetic kidney disease (stages I, II). In this regard, a better diagnostic markers to serve for this purpose are creatinine clearance, fractional excretion of magnesium (FE Mg), cystatin C. Recently, renal microvascular disease and renal ischemia have been demonstrated to correlate indirectly with the development of diabetic kidney disease and its function. Among these are angiogenic and anti-angiogenic factors, namely VEGF, VEGF receptors, angiopoietins and endostatin. With respect to therapeutic prevention, implementation of treatment at early stage of diabetic and nondiabetic kidney disease is able to restore renal perfusion and function.

Early stage of vascular disease and diabetic kidney disease: an under-recognized entity.

Early stage of vascular disease and diabetic kidney disease (DKD stages 1 and 2) has been under-recognized, under common practice worldwide. The lack of sensitive diagnostic marker leads to late diagnosis and a progression of underlying vascular disease associated with chronic renal ischemia, which eventually intensifies the magnitude of DKD damage. Treatment at this late stage fails to correct the renal ischemia, or restore renal function, due to the altered vascular homeostasis associated with an impaired nitric oxide production. In contrast to the above information, early recognition of vascular disease and DKD with sensitive diagnostic markers would be able to implement an effective prevention of progression of vascular disease and DKD. Treatment at early stage under environment favorable for adequate vascular homeostasis is able to correct the renal ischemia and improve the renal function.

Renal microvascular disease predicts renal function in diabetes.

Renal microvascular disease reflected directly by peritubular capillary flow reduction and indirectly by renal function impairment has been documented in early diabetic nephropathy (DN) associated with normoalbuminuria and normal serum creatinine concentration. The renal microvascular disease observed in early DN [chronic kidney disease (CKD) stages 1-2] could progress under current practice to late DN (CKD stages 3-5) with a further reduction in peritubular capillary flow. This advanced renal microvascular disease in late DN is characterized by therapeutic resistance to vasodilators and altered vascular homeostasis associated with impaired nitric oxide production. The renal microvascular disease is progressive as the disease severity progresses and eventually induces chronic renal ischemia and a progressive tubulointerstitial fibrosis. Further study has revealed that early DN is associated with an adequately functional vascular homeostasis. Therefore, recognition and treatment of early renal microvascular disease at early DN (stages 1-2) could enhance renal perfusion and restore renal function.

A mildly altered vascular homeostasis in early stage of CKD.

BACKGROUND: A continuous increase in number of CKD patients entering ESRD is a growing public health threat, which reflects the present therapeutic failure usually initiating at the late stage of CKD. OBJECTIVE: To study the mechanism of vascular repair in CKD patients associated with mildly impaired renal function, which included angiogenic factors such as VEFG, angiopoietin-1, and flt-1 (VEGFR1); and antiangiogenic factors such as angiopoietin-2 and KDR (VEGFR2). RESULTS: A mild defect in angiogenic factor-namely, angiopoietin-1-was observed, whereas VEGF and flt-1 (VEGFR1) were within normal limit. Also, antiangiogenic factor-namely, angiopoietin-2-was mildly elevated, whereas KDR (VEGFR2) remained within normal limit. CONCLUSION: The mechanism of vascular repair appears to be adequately functional in the early stage of CKD. Therapeutic intervention at this stage can improve renal perfusion and restore renal function as indicated in normoalbuminuric, type 2 diabetic nephropathy. The authors encourage changing the conceptual view of treatment under common treatment at late stage of CKD to treatment at early stage of CKD under an environment favorable for renal regeneration.

Microalbuminuria--a biomarker of renal microvascular disease.

Microalbuminuria (amount greater than 30-300 mg/day) reflects an abnormal glomerular capillary permeability to protein. It is usually dependent upon three mechanisms. First, loss of negatively charged surface of the glomerular capillary wall secondary to circulating toxic substances injury-namely, oxidative stress and proinflammatory cytokines-allows the albumin with negatively charged surface to freely escape into the urine. Second, intraglomerular hypertension and hemodynamic maladjustment secondary to glomerular endothelial dysfunction increases filtration pressure and enhances sized selective proteinuria leakage. Third, podocyte injury leads to a vicious cycle of hemodynamic maladjustment and endothelial and podocyte injuries. All three of these mechanisms induce glomerular endothelial injury and microalbuminuria, which reflects renal microvascular disease.

Altered vascular homeostasis in type 2 diabetic nephropathy.

Type 2 diabetic nephropathy is a primary cause of ESRD worldwide. Therapeutic strategy in patients with microalbuminuric or macroalbuminuric type 2 diabetic nephropathy usually fails to restore renal function but merely slows the renal disease progression. In contrast, a recent study implies that the restoration of renal function as well as renal perfusion can be accomplished in early stage of type 2 diabetic nephropathy (normoalbuminuria) by correcting the hemodynamic maladjustment in renal microcirculation with vasodilators. Therefore, we intend to study the mechanism of vascular homeostasis to explain why treatment in the late stage of diabetic nephropathy during microalbuminuria or macroalbuminuria fails to enhance renal perfusion or restore renal function. The results indicate that such therapeutic failure in late-stage type 2 diabetic nephropathy likely relates to multiple defects in vascular repair, namely deficiencies in angiogenic factors such as endothelial progenitor cell, angiopoietin-1, flt-1 receptor, as well as elevated levels of antiangiogenic factors such as angiopoietin-2 and KDR.

Renal microvascular disease in an aging population: a reversible process?

Renal microvascular disease and tubulointerstitial fibrosis are usually demonstrated in aging in humans and animals. It has recently been proposed that renal microvascular disease is the crucial determinant of tubulointerstitial disease or fibrosis. Enhanced circulating endothelial cell loss is a biomarker that reflects glomerular endothelial injury or renal microvascular disease, and fractional excretion of magnesium (FE Mg) is a sensitive biomarker that reflects an early stage of tubulointerstitial fibrosis. In aging in humans, both of these biomarkers are abnormally elevated. In addition, a glomerular endothelial dysfunction determined by altered hemodynamics associated with peritubular capillary flow reduction is substantiated. A correction of such hemodynamic alteration with vasodilators can effectively improve renal perfusion and restore renal function. Thus, anti-aging therapy can reverse the renal microvascular disease and dysfunction associated with the aging process.

A defective angiogenesis in chronic kidney disease.

BACKGROUND: A progressive reduction in peritubular capillary flow is observed in chronic kidney disease (CKD) patients as the disease severity progresses. This suggests an altered vascular homeostasis in CKD patients, but such a defective mechanism needs to be verified. METHODS: To study the vascular injury as reflected by circulating endothelial cell (CEC), the balance between angiogenic factor, vascular endothelial growth factor (VEGF), and antiangiogenic factor, endostatin. RESULTS: A deficient VEGF was observed, whereas the value of endostatin and CEC were abnormally elevated in CKD patients. DISCUSSION: Enhanced CEC reflects an increased activity of vascular injury. A deficient VEGF in the presence of enhanced antiangiogenesis (endostatin) implies a defective angiogenesis. This may explain the progressive nature of renal microvascular disease observed in late stage of CKD patients.

Altered vascular homeostasis in chronic kidney disease.

Current treatments of chronic kidney disease (CKD) patients frequently result in progressive decline in renal perfusion, leading to the end-stage renal disease. Such renal failures may be a reflection of the progressive nature of renal microvascular disease. The aim of the present study is to elucidate the mechanism of microvascular homeostasis in CKD patients with moderately impaired renal function. We determined biomarkers relevant to vascular homeostasis, such as circulating endothelial cell (CEC), and biomarkers of vascular repair, such as vascular endothelial growth factor (VEGF), angiopoietin-1, tie-2, angiopoietin-2 and VEGF-R2. The present result revealed an enhanced vascular injury which was reflected by increased number of circulating endothelial cells. In addition, a defective vascular repair was also reflected by deficiencies in angiogenic factors such as VEGF, and angiopoietin-1, whereas the anti-angiogenic factors such as angiopoietin-2 and VEGF-R2 were elevated. In conclusion, the activity against vascular injuries increased under the presence of defective ability of vascular repair in CKD with moderately impaired renal function. This finding may explain the present therapeutic failure in treating these CKD patients, and imply that treatment at an earlier stage of CKD should be implemented.

Combined effects of curcumin and vitamin C to protect endothelial dysfunction in the iris tissue of STZ-induced diabetic rats.

This study was aimed to evaluate the combined effect of curcumin with vitamin C supplementation on hyperglycemic and dyslipidemia conditions and endothelial cell dysfunction induced in diabetic rats. Wistar Furth rats were used and divided into four groups: control (single injection of 0.9% sterile saline), STZ (streptozotocin, Sigma, 55 mg/kg.BW, i.v.), STZ-vitC (1 g/l ascorbic acid mixed in drinking water), STZ-cur (daily oral treatment of 300 mg/kg.BW curcumin; Cayman Chemical Co., USA), and STZ-cur+vitC (1 g/l ascorbic acid mixed in drinking water and oral treatment of 300 mg/kg.BW curcumin). On 8th week after STZ-injection, the microcirculation in the iris tissue was observed using intravital fluorescence videomicroscopy, and also leukocyte adhesion in the venule was examined for each group. Blood glucose (BG), lipid profiles, glycosylated hemoglobin (HbA1c) were measured in blood samples collected at the end of each experiment. The contents of liver malondialdehyde (MDA) were also quantified for each group. Feeding curcumin (STZ-cur) could decrease BG, HbA1c, dyslipidemia, and MDA significantly, compared to STZ. In cases of feedings curcumin with vitamin C, these results were more effective in all aspects, including leukocyte adhesion. In conclusion, curcumin might increase the effect of vitamin C in protecting the function of endothelial cells through its anti-oxidant with hypoglycemic and hypolipidemic actions.

Microvascular disease and endothelial dysfunction in chronic kidney diseases: therapeutic implication.

This paper was aimed to study biomarkers of endothelial injury in chronic kidney diseases. Fifty chronic kidney disease patients were subject to the following determinations: (i) circulating endothelial cells, (ii) soluble VCAM-1, (iii) transforming growth factor beta (TGFB), and (iv) intrarenal hemodynamics. Increased number of circulating endothelial cells was significantly observed. A significant depletion of vascular endothelial growth factor (VEGF) or a depleted VEGF/TGFB ratio was also documented. Results showed that sVCAM was not significantly different from normal control. Intrarenal hemodynamic alteration demonstrated a characteristic of hemodynamic maladjustment. Since increased number of circulating endothelial cells is a sensitive biomarker for endothelial cell injury in chronic kidney diseases, such injury is supported by the depletion of VEGF. The endothelial cell loss correlates with the glomerular endothelial dysfunction characterized by hemodynamic maladjustment at the efferent arteriole and reduction in peritubular capillary flow. In conclusion, correction of such hemodynamic maladjustment with multidrug vasodilators can effectively restore renal function in chronic kidney diseases.