Role of Lipid Control in Diabetic Nephropathy

Chen H-C, Guh J-Y, Chang J-M, Hsieh M-C, Shin S-J, Lai Y-H. Kidney Int. 2005;67(suppl 94):S60-S62.

Numerous lipoprotein abnormalities are associated with diabetic nephropathy, including increased very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and triglycerides. Conversely, high-density lipoprotein (HDL) is decreased. In addition to alterations in lipoprotein amounts, there are also structural abnormalities. Specifically, the diameter of LDL particles is smaller among people with nephropathy.

Evidence of the relationship between lipid alterations and nephropathy has been provided by animal studies. Specifically, hyperlipidemia has been associated with damage to the tubulointerstitium, which is a major feature of diabetic nephropathy. Research also has shown that hyperlipidemia and hyperglycemia may act in concert to cause renal damage in LDL receptor-deficient mice. Dyslipidemia is associated with a number of changes, including coagulation-fibrinolytic system alterations, membrane permeability changes, endothelial damage, and increased atherosclerosis, all of which may impact diabetic nephropathy.

Addressing the relationship between dyslipidemia and renal dysfunction in humans with diabetes is more complex, owing to the number of factors that covary with dislipidemia (eg, elevated blood glucose, proteinuria). However, elevated lipid levels at baseline are related to the development and progression of nephropathy in type 1 diabetes and to the development of nephropathy in type 2 diabetes. Results linking dyslipidemia to nephropathy progression have been equivocal in this population. Studies that have attempted to demonstrate an effect of lipid-lowering treatments on diabetic nephropathy in humans have also yielded inconsistent results. One study showed that pravastatin decreases albuminuria in type 2 patients, but other studies have shown null findings. Trials of longer duration and with larger sample sizes are needed.

Insight into the relationship between lipid control and diabetic nephropathy has been gained through experimental models of diabetes. Pravastatin has been shown to suppress the effects of elevated glucose levels on superoxide production in the mesangial cells. This finding has led to the speculation that cholesterol-lowering therapy may delay the progression of nephropathy if given early in its clinical course, as increased superoxide production occurs early in the process of nephropathy. The relationship between lipid-lowering therapy and nephropathy may be mediated, in part, by transforming growth factor-β (TGF- β). Elevated glucose levels have caused increased expression of glomerular TGF-β in an animal model, and pravastatin has been shown to suppress glucose-induced TGF-β activity. Pravastatin has also been shown to have beneficial effects on the mesangial cells by suppressing the negative effects of both LDL and oxidized LDL. Additional effects of statins include improved endothelial function, reduced LDL oxidation, reduced plated aggregability, reduced procoagulation factors, and inhibition of smooth muscle cell proliferation.

Overall, the data suggest that dyslipidemia may be an important factor in the development and progression of diabetic nephropathy. Large-scale randomized studies of appropriate duration are needed to examine the nature of this complex relationship.