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.

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.

Idiopathic nephrotic syndrome (NS) associated with focal segmental glomerulosclerosis (FSGS) and severe renal function impairment is usually refractory to the conventional treatment and progresses to end-stage renal disease. Herein, we reported 10 patients with NS-FSGS who had initially had CCr 34 +/- 12 mL/min/1.73 m2 (normal 120 mL/min/1.73 m2), FE Mg 7.8 +/- 2.6% (normal 2.2%), 24-h urinary protein 3.1 g (normal <200 mg) and been followed up for over 10 years. The initial intrarenal hemodynamic study revealed a marked elevation of efferent arteriolar resistance (RE 17289 +/- 8636 dyne x s x cm(-5); normal 3000 dyne x s x cm(-5)), intraglomerular hypertension (PG 57 +/- 1 mm Hg; normal 52 mm Hg), hyperfiltration (FF 0.24; normal 0.2), marked reductions in GFR 35 +/- 17 mL/min/1.73 m2, renal plasma flow (RPF 159 +/- 61 mL/min/1.73 m2; normal 600 mL/min/1.73 m2) and peritubular capillary flow (PTCF 123 +/- 57 mL/min/1.73 m2; normal 480 mL/min/1.73 m2). Such a hemodynamic alteration indicated a hemodynamic maladjustment with a preferential constriction at RE. Treatment consists of multidrugs, namely angiotensin converting enzyme inhibitor, calcium channel blocker, antiplatelet and anticoagulant, with or without angiotensin II receptor antagonist. Following the treatment, correction of hemodynamic maladjustment has been achieved which is characterized by reductions in RE 6046 +/- 2191 dyne x s x cm(-5), PG 52 +/- mm Hg, FF 0.19 +/- 0.1 and increments in RPF 341 +/- 118 mL/min/1.73 m2, PTCF 280 +/- 106 mL/min/1.73 m2 and GFR 64 +/- 17 mL/min/1.73 m2. Coinciding with hemodynamic improvement, there has been a steadily increased creatinine clearance and improvement in FE Mg 4.3 +/- 2.6% and suppression of proteinuria 0.29 +/- 0.4 g/24 h after the period of follow-up of greater than 10 years.

Present diagnostic tests such as serum creatinine determination and creatinine clearance are unable to reflect early tubulointerstitial disease. Because a kidney biopsy cannot be performed in every single patient, tubular epithelial function (namely, the fractional excretion of magnesium; FE Mg) that correlates directly with the degree of tubulointerstitial fibrosis would serve this purpose. FE Mg is normal in acute post-streptococcal glomerulonephritis and mesangial proliferative nephrosis with intact tubulointerstitial structure, and is abnormally elevated in nephrosis with focal segmental glomerulosclerosis (FSGS) and in chronic kidney diseases in which kidney biopsies have been obtained. FE Mg is useful in the screening of tubulointerstitial disease in patients when indication for kidney biopsy in not fulfilled, such as diabetic patients or patients with microscopic proteinuria, hematuria, and hypertension. Altered FE Mg is usually associated with a reduction in peritubular capillary flow. There is a linear correlation between FE Mg and peritubular capillary flow, which supports the chronic ischemic injury inducing altered tubular function and tubulointerstitial fibrosis.

Glomerular capillary loops are complex vascular filters composed of interdigitating podocytes and fenestrated endothelial cells with an intervening proteoglycan-rich extracellular matrix. This arrangement is crucial to maintaining the filtration barrier but renders the glomerulus difficult to analyze by conventional two-dimensional histochemical techniques. When pathologic lesions distort glomerular architecture, its complex morphology is even more challenging to interpret. Fortunately, recent advances in microscopes and computer software now enable glomerular enthusiasts to dissect this complex structure with finer detail. In this review we explore the application of new methodologies such as two-photon microscopy that optimize three-dimensional, multicolor imaging and single-cell segmentation of glomerular components.

A dysfunctioning glomerular endothelium was demonstrated in chronic kidney disease (CKD) patients by means of in vitro endothelial cell cytotoxicity test and of in vivo intrarenal hemodynamic study. An enhanced endothelial cell cytotoxicity in CKD patients was 26.5 +/- 12% as compared to 0.4 +/- 1% of control. An altered intrarenal hemodynamics revealed 1) a reduction in renal plasma flow, 190 +/- 67 mL/min/1.73 m2 versus control 595 +/- 45 mL/min/1.73 m2, and in peritubular capillary flow, 149 +/- 55 mL/min/1.73 m2 versus control 479 +/- 46 mL/min/1.73 m2, 2) an elevated intraglomerular hydrostatic pressure, 55 +/- 2 mmHg versus control 51 mmHg, elevated afferent arteriolar resistance, 13184 dyne x s x cm(-5) versus control 2443 +/- 154 dyne x s x cm(5), and elevated efferent arteriolar resistance, 13591 +/- 7591 dyne x s x cm(-5) versus control 3062 +/- 177 dyne x s x cm(-5). Both enhanced endothelial cell cytotoxicity and altered intrarenal hemodynamics reflect glomerular endothelial dysfunction which is likely responsible for the renal disease progression in CKD.