Normalization of kidney dysfunction in normotensive, normo-albuminuric type 2 diabetes

It has been a general consensus that a majority of diabetic nephropathic patients associated with stages 1, 2 (creatinine clearance 90–119, 60–89 mL/min/1.73 m², respectively) have been recognized prior to the onset of microalbuminuria. Such early impaired renal function usually correlates with (i) the altered renal hemodynamics characterized by reductions in renal plasma flow and peritubular capillary flow,1 an abnormally elevated renal arteriolar resistance and a glomerular hyperfiltration2,3 and (ii) an abnormally elevated value of fractional excretion of magnesium (FE Mg) − a biomarker, which directly reflects the presence of tubulointerstitial fibrosis in this early stage of diabetic nephropathy, since FE Mg has previously been demonstrated to correlate directly with the magnitude of tubulointerstitial fibrosis.4

The altered renal hemodynamics observed implies the presence of renal microvascular disease in this early stage of diabetic nephropathy. In addition, an enhanced number of circulating endothelial cells encountered in normoalbuminuric and normotensive diabetic nephropathy supports the status of renal microvascular disease.5 In this regard, renal ischemia secondary to renal microvascular disease appears to be a crucial factor that would be the determinant in the mechanism of renal disease progression. With respect to the hemodynamic characteristics, the preferential constriction at the efferent arteriole in the renal microcirculation induces not only a glomerular hyperfiltration but also an over reduction in peritubular capillary flow supplying the tubulointerstitial structure. A state of chronic renal ischemia would be developed. A persistent reduction in peritubular capillary flow to the level of 40 percent below normal has previously demonstrated to correlate with the development of tubulointerstitial fibrosis.6 Without therapeutic interruption, the state of renal ischemia would become progressive resulting in a continuous decline in peritubular capillary flow as the disease severity progresses.

The preceding body of knowledge is beneficial to the conceptual view of primary prevention of diabetic nephropathy at the early stage of renal function impartment. Under common general medical practice, therapeutic intervention of renal ischemia is usually initiated at a rather late stage (chronic kidney disease (CKD) stage 3; creatinine clearance less than 60 mL/min/1.73 m²) due to the insensitiveness of the available diagnostic marker such as serum creatinine determination or microalbuminuria, which recognizes only late stages CKD, but is unable to screen the early stages CKD.1,2 In this stage, therapeutic vasodilators fail to enhance the peritubular capillary flow, which is due to the altered vascular homeostasis associated with an impaired nitric oxide production.7 This would explain the therapeutic resistance observed under conventional medical practice at the late stage of diabetic nephropathy, as well as the progressive increment in number of diabetic nephropathic patients entering end-stage renal failure.

To overcome the present therapeutic resistance to vasodilator treatment in diabetic nephropathy, it would be appropriate to target the normotensive, normoalbuminuric diabetics associated with a mildly impaired renal function. This view has recently been supported by the adequate vascular homeostasis documented in early stage of diabetic nephropathy.7 Treatment with specific vasodilators such as angiotensin convert enzyme inhibitor (ACEI) and/or angiotensin recept blocker (ARB) that can relax both arterioles in particular the efferent arteriole, would enhance the peritubular capillary flow and eventually correct the renal ischemia. Treatment at this particular group of patients requires a modest initiative approach with a small titrating doses of vasodilator. To avoid certain side effect such as dizziness, patients are strongly recommended to adequately drink water (approximately 3 liters or more). It is preferred to start with a small dose of ACEI such as 5–10 mg/day with or without ARB such as Micardis 20–40 mg/day. A fully hydrated patient would assist to prevent the decline in glomerular filtration rate due to the correction of hyperfiltration phenomenon. A therapeutic strategy with vasodilators has recently been confirmed to be able to enhance the peritubular capillary flow as well as the glomerular filtration rate in normotensive and normoalbuminuric diabetic nephropathy with early renal function impartment.1,8

Declaration of interest

The study has been supported by Thailand Research Fund, National Research Council Fund of Thailand and the Bhumirajanagarindra Kidney Institute.