Enhanced peritubular capillary flow and renal function can be accomplished in normoalbuminuric type 2 diabetic nephropathy.

Under common practice, treatment of diabetic nephropathy (DN) is usually initiated at late stage of CKD due to the insensitiveness of the available diagnostic markers. Such treatment fails to restore renal perfusion and function. This is due to the defective mechanism of vascular homeostasis and impaired nitric oxide production observed in late stage of DN. In contrast, the mechanism of vascular repair is adequately functional in early stage of DN (normoalbuminuria). In this study, we treated 50 normoalbuminuric diabetic patients with multidrug vasodilators, namely ACE inhibitor, angiotensin receptor blocker, ± calcium channel blocker in conjunction with correction of metabolic disorders for 24-36 months. Following the treatment, increment in peritubular capillary flow in response to vasodilators was observed, and thus supports the adequate role of vascular repair. In addition, increase in renal function documented in this study also implies that an effective preventive strategy to minimize end-stage renal disease can be accomplished in normoalbuminuric DN.

Peritubular capillary flow determines tubulointerstitial disease in idiopathic nephrotic syndrome.

The spatial relationship between renal perfusion and nephronal structure was determined in 51 nephrotic patients consisting of 11 patients with steroid sensitive, minimal change (MC) nephrosis, 12 patients with steroid resistant, mesangial proliferative (MesP) nephrosis and without tubulointerstitial fibrosis (TIF), 11 patients with steroid resistant, MesP nephrosis and with low grade TIF and 17 patients with focal segmental glomerulosclerosis (FSGS). The intrarenal hemodynamic study revealed a unique correlation between renal perfusion and nephronal structure. A normal or slight reduction in peritubular capillary flow observed in MC or mild MesP nephrosis correlates with an intact tubulointerstitial structure. A moderate reduction in peritubular capillary flow observed in steroid resistant, MesP nephrosis induces a low incidence of TIF. A severe reduction in peritubular capillary flow denotes a higher incidence of TIF as that observed in nephrosis with FSGS. Thus, it is of notion that the reduction in renal perfusion precedes the development of tubulo-interstitial fibrosis and thereby supports the concept of renal perfusion as a crucial determinant of nephronal structure.

Enhanced tumor necrosis factor in the serum and renal hypoperfusion in nephrosis associated with focal segmental glomerulosclerosis.

Enhanced tumor necrosis factor alpha associated with immunocirculatory imbalance expressed as increased ratio between proinflammatory (TNFalpha) and antiinflammatory (IL-10) cytokines was observed in the serum of nephrosis associated with focal segmental glomerulosclerosis. Such altered immunocirculatory balance correlated with the reduction in renal plasma flow determined by the intrarenal hemodynamic study by which it implies that a glomerular endothelial cell injury associated with impaired renal perfusion is likely to be spontaneously induced by enhanced tumor necrosis factor in the presence of inadequate release of antiinflammatory cytokine (IL-10).

Renal perfusion and disease progression.

The pathogenetic concept of renal hyperperfusion and hyperfiltration in inducing glomerular pathology and disease progression documented in the renal ablation model in experimental animals to mimic renal disease with reduced nephron mass has recently been challenged. In contrast to the above, the intrarenal hemodynamic study in a variety of chronic glomerulonephropathies reveals a unique characteristic of renal hypoperfusion rather than hyperperfusion. This is associated with an elevated renal arteriolar resistance and reductions in renal plasma flow and peritubular capillary blood flow. The magnitude of reduction in peritubular capillary blood flow is inversely proportional to the degree of tubulointerstitial disease and tubular dysfunction. A progressive reduction in the vascular space due to nonvascular expansion with disease progression supports the concept of hypoperfusion of a whole kidney as well as a single nephron. In accordance with the renal ablation model and early diabetes mellitus, a similar hypoperfusion pattern is also subsequently observed in the chronic stage of renal ablation model in animals and late diabetic nephropathy. The disparity between the hyperperfusion and hypoperfusion in inducing renal disease progression can be enlightened by the Noble Truth of Lord Buddha stating "The Middle Tract is The Balance of Nature". Further support of this conceptual view of renal hypoperfusion as a determinant of tubulointerstitial disease and disease progression is in accordance with the therapeutic benefit with an enhanced-renal-perfusion formula per se in a variety of chronic glomerulonephropathies.

Tubular function and tubulointerstitial disease.

Tubular transport determined by the fractional excretion (FE) of filtered solutes was studied in 129 nephrotic patients; 72 patients with mesangial proliferation (MesP-NS) and intact tubulointerstitium (group 1), 13 patients with MesP-NS and superimposed tubulointerstitial fibrosis (TIF; group 2), 27 patients with mild focal segmental glomerulosclerosis (FSGS; group 3), and 17 patients with severe FSGS (group 4). In the 72 nephrotic patients with MesP-NS and normal tubulointerstitium (no TIF), tubular transport was intact (FE of sodium [FENa], 0.5 +/- 0.5; FE of calcium [FECa], 0.3 +/- 0.3; FE of phosphate [FEPO4], 14 +/- 13; FE of uric acid [FEUA], 9.8 +/- 5; FE of magnesium [FEMg], 1.3 +/- 0.5). In the 13 nephrotic patients with MesP-NS and superimposed TIF (4.9% +/- 2%), there was no difference in FE solutes from those in group 1 except for FEMg (3.3 +/- 0.9; P < 0.001). In the 27 nephrotic patients with mild FSGS (TIF, 28% +/- 9%), four of five variables of FE solutes (FENa, 1.2 +/- 0.7; P < 0.001; FECa, 0.9 +/- 0.8; P < 0.001; FEPO4, 17 +/- 12; P, not significant; FEUA, 16.5 +/- 8; P < 0.001; FEMg, 4. 1 +/-1; P < 0.001) were significantly different from those of patients with MesP-NS without TIF, and two of five variables (FECa, FEMg) were statistically different from those of patients with MesP-NS with TIF. In the severe category of FSGS (TIF, 69% +/-19%), all FE solutes were statistically different from the other groups (FENa, 4.8 +/- 3; FECa, 2 +/- 1; FEPO4, 47 +/- 24; FEUA, 37 +/- 18; FEMg, 12 +/- 6). Thus, the results imply that (1) normal tubular transport reflects an underlying intact tubulointerstitial structure, whereas tubular dysfunction indicates an underlying tubulointerstitial disease, and (2) FEMg is the most sensitive index to detect an early abnormality of tubular structure and function.

Renal dysfunction in glomerulonephropathy associated with rapid onset renal failure.

Eight patients between the ages of 5 and 26 years developed a rapid decline of renal function with a period of oliguria or anuria which ranged between 1 and 21 days. The initial assessment of renal function revealed a severe degree of glomerular, tubular, and vascular abnormalities. The magnitude of the renal dysfunction was quantified and expressed in terms of a clinical score. The degree of glomerular and tubular dysfunction was inversely proportional to the renal plasma flow and peritubular capillary blood flow, respectively. Similar findings have been observed in a variety of other glomerulonephropathies where a relationship exists between the reduction of peritubular capillary blood flow and the severity of the tubulointerstitial disease. Evidence to support the position that the reduction of peritubular capillary blood flow plays a primary role in inducing tubulointerstitial disease is as follows: (i) A reduction of peritubular capillary blood flow has been documented in mesangial proliferative nephrosis with steroid resistance prior to the detection of tubulointerstitial disease. (ii) Ischemic insults are capable of inducing tubulointerstitial disease in the experimental setting of renal artery occlusion in animals. (iii) As demonstrated in the present report, an improvement of tubular function can be achieved following an increase in peritubular capillary blood flow with therapy designed to enhance renal perfusion.

Glomerular endothelial dysfunction determines disease progression: a hypothesis.

A glomerular endothelial function with its hemodynamic impact is proposed to determine disease progression. In the clinical settings associated with an intact endothelial function, such as minimal-change steroid-sensitive nephrosis, the early phase of diabetes mellitus and the early stage of an experimental model of renal ablation in animals, it was observed that adequate renal perfusion correlates with the intact structure and function of the nephron with no evidence of disease progression. In contrast, the clinical settings associated with endothelial dysfunction, such as chronic glomerulonephropathy, the late stage of diabetes mellitus and a renal ablation model in animals, are usually associated with a reduction in renal perfusion. The magnitude of renal hypoperfusion observed in all forms of chronic glomerulonephropathies is proportional to the degree of clinical severity. A progressive pattern of renal hypoperfusion is uniquely observed when disease severity progresses. In this context, a new therapeutic maneuver aiming to improve renal perfusion is proposed for treating glomerulonephropathy with disease progression and preventing it from developing to end-stage renal disease.

Renal dysfunctions in glomerulonephropathy with rapidly declined renal failure.

Eight patients aged between 5 and 26 years developed rapid deterioration of renal function and became oliguric/anuric with duration ranging from 1 to 21 days. The initial functional assessment revealed severe degree of glomerular, tubular, and vascular dysfunctions. The magnitude of renal dysfunction was quantified and expressed in terms of a clinical score. The degree of glomerular and tubular dysfunctions were inversely proportional to the renal plasma flow and peritubular capillary blood flow (PTCB), respectively. Similar findings have been observed in a variety of severe glomerulonephropathies. In this aspect, it is likely that the reduction of peritubular capillary blood flow and tubulointerstitial disease are interrelated. Further evidence to support the primary role of reduction of PTCB in inducing tubulointerstitial disease is provided by the following: (a) Reduction of PTCB is documented in mesangial proliferative nephrosis with steroid resistance prior to the detection of tubulointerstitial disease. (b) Ischemic insult can induce tubulointerstitial disease in experimental setting of renal artery occlusion in animal, (c) Improved tubular function can be achieved following the increase in PTCB with the enhanced renal perfusion therapy.