Letter To The Editor: Early Detection of Endothelial Dysfunction and Early Therapeutic Correction Effectively Restore Renal Function in Type 2 Diabetic Nephropathy

• circulating endothelial cells
• transforming growth factor beta
• peritubular capillary flow
• type 2 DM

Dear Editor:

Macro- and microvascular disease have been noted to be the principal causes of morbidity and mortality in patients with type 2 diabetes mellitus.[1] Failure to recognize early such vascular pathology may be responsible for the unsuccessful prevention of renal disease progression and the late and inappropriate treatment that generally leads to end-stage renal disease. With respect to this view, we recently noted that there is an increased number of circulatory endothelial cells (1928 ± 1074 versus control 112 ± 85 cells/mL; p < 0.01) documented in the blood of normoalbuminuric type 2 diabetic patients. Such enhanced endothelial cell loss correlates with the decreasing vascular endothelial growth factor (VEGF)/transforming growth factor beta (TGFβ) ratio; 0.09 ± 0.08 versus control 0.3 ± 0.2, p < 0.01 and elevated transforming growth factor beta 7934 ± 4915 versus control 2014 ± 794 pg/mL, p < 0.05. Increased TGFB can induce apoptosis of both podocyte[2] and tubular epithelium,[3] which are the main sources of VEGF production, and may have relevance to the endothelial cell loss.

An increased number of circulating endothelial cells is a biomarker of endothelial injury that correlates with the glomerular endothelial dysfunction and hemodynamic maladjustment characterized by a preferential constriction of the efferent arteriole (efferent arteriolar resistance 4396 ± 1032 versus control 3042 ± 165 dyne/s/cm^{− 5}; p < 0.01). Such constriction induces proximally intraglomerular hypertension (54 ± 1 versus control 51 ± 0.02 mmHg; p < 0.001) and distally, reduction in peritubular capillary flow (PTCF 362 ± 65 versus control 483 ± 43 mL/min/1.73m²; p < 0.01), which supplies the tubulointerstitium. The PTCF reduction reflects glomerular endothelial dysfunction, which is being unable to secrete an adequate amount of endothelium-dependent vasodilators. Recently, it was demonstrated that the reduction in PTCF precedes and correlates with the development of tubulointerstitial fibrosis in the clinical setting of nephrotic syndrome.[4] Correction of such hemodynamic maladjustment by multidrug vasodilators (ACEI, AII receptor antagonist, calcium channel blocker, and antiplatelet) has been substantiated to improve renal perfusion and effectively restore renal function in focal segmental glomerulosclerotic nephrosis and chronic kidney disease.[5&6]

With respect to the above information, we conducted a therapeutic prevention of renal disease progression with multidrug vasodilators in addition to the control of blood sugar and dyslipidemia in 35 normoalbuminuric and 15 albuminuric type 2 diabetic patients with impaired renal function who were shown to have diabetic nephropathy by abnormal tubular function test (fractional excretion of magnesium; FE Mg 4.1 ± 1 versus control 1.4 ± 0.4%; p < 0.01) and 6.6 ± 2% in normoalbuminuric and albuminuric patients, respectively, which correlates directly with the magnitude of tubulointerstitial fibrosis.[7] Thus, FE Mg appears to be a more sensitive marker for diabetic nephropathy than microalbuminuria. A preliminary result indicates that such a therapeutic approach effectively increases mean creatinine clearance from 73 ± 80 to 103 ± 27 mL/min/1.73 m², p < 0.001, and 56 ± 26 to 75 ± 33 mL/min/1.73 m², p < 0.01 in normoalbuminuric and albuminuric type 2 diabetic patients, respectively.

In conclusion, early detection of endothelial injury and glomerular endothelial dysfunction by determining the number of circulating endothelial cells and hemodynamic study, respectively, in conjunction with early screening of diabetic nephropathy by FE Mg, would assist in early implementation of therapy and effectively prevent renal disease progression in type 2 diabetes mellitus.

Acknowledgments

We would like to acknowledge the support of the Thailand Research Fund and a Rachadapiseksompotch Research Grant.