Is there a role for statins in the treatment of chronic progressive renal disease?Inflammation is a component of the pathophysiology of progressive renal disease and may also be associated with other major modifiable risk factors, such as atherosclerosis, hypertension, and diabetes mellitus.
Q: Is there a role for statins in the treatment of chronic progressive renal disease?
A: Inflammation is a component of the pathophysiology of progressive renal disease and may also be associated with other major modifiable risk factors, such as atherosclerosis, hypertension, and diabetes mellitus. To reduce inflammation and preserve kidney function, therapies for chronic renal insufficiency must address all primary risk factors. Statins may lower blood pressure, reduce proteinuria, and preserve or improve renal function.
Extensive experimental evidence and more recent clinical data support the concept that progressive renal failure is associated with an altered immune response and elevated proinflammatory cytokine levels. Moreover, research suggests that the earliest manifestations of renal injury--demonstrated by glomerular hyperfiltration or by minimal decreases in the glomerular filtration rate (GFR)--may also initiate an inflammatory response within the kidneys.1 In two thirds of patients with renal failure, death results from an acute atherosclerotic event.
Risk factors. Renal failure is associated with a number of traditional and uremia-related risk factors. These include hypertension, dyslipidemia and, in the case of diabetic nephropathy, diabetes. However, other risk factors--such as anemia, hemodynamic overload, hyperhomocysteinemia, and increased oxidative stress on the vascular system--play a significant role.
High-sensitivity C-reactive protein (hsCRP), an easily measured marker of inflammation, has emerged as an independent predictor of cardiovascular disease and has been associated with a significant putative effect on endothelial function and atherosclerosis. HsCRP is elevated in a significant proportion of patients with renal failure and has become an accurate predictor of cardiovascular mortality in this group.2
Collectively, these classic and uremia-related risk factors may all contribute to endothelial dysfunction and proinflammatory cytokine release, which make up the systemic inflammatory response and result in stimulation of inflammatory markers such as hsCRP. The result is acceleration of the atherosclerotic process and the increased cardiovascular mortality seen in patients with renal failure.
Dyslipidemia appears to be a major modifiable risk factor for the progression of renal disease. Agents such as salicylates, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) have beneficial anti-inflammatory effects. Statins appear to suppress cytokine formation; inhibit fibronectin and collagen formation; inhibit stimulation of vasoactive angiotensin II and endothelin; improve the availability of nitric oxide; and, perhaps, block calcium influx into vascular smooth muscle cells, a requirement for cellular contraction. In combination with other therapies, statins may suppress inflammation and contribute to the preservation of renal function.3
Evidence from the trials. A number of recent clinical observations support the hypothesis that statins are renoprotective. Several small trials have demonstrated antihypertensive effects. In one of these studies, lovastatin or pravastatin, when added to the regimen of patients receiving an ACE inhibitor, provided significant additional blood pressure reduction (Table).4 Aggressive blood pressure reduction is known to decrease proteinuria and slow the progression of chronic renal disease.
Another recent trial reported that the addition of atorvastatin to the regimen of patients with nondiabetic chronic renal insufficiency who had been treated for 1 year with an ACE inhibitor or an ARB was associated not only with additional reduction in proteinuria but also with further slowing of the progression of renal disease.5 Two other recent trials suggested that short- or long-term treatment with rosuvastatin or atorvastatin improved the estimated GFR compared with placebo.6,7 Improvement was evident in persons with a normal GFR at baseline as well as in smaller numbers of patients with a mildly to moderately impaired GFR at baseline.
These clinical observations require confirmation by large prospective randomized clinical trials. However, most patients with progressive renal disease have some degree of dyslipidemia and might benefit from statin therapy.
These patients are not generally offered statins because of concerns about toxicity. With the exception of rosuvastatin and pravastatin, however, statins are metabolized by the liver. All statins are well tolerated, with no significant increases in plasma concentrations at dosages of 10 to 20 mg/d in those with mild or moderate renal insufficiency. Extra caution is required when administering these agents, even in small doses, to patients with severe renal insufficiency (an estimated GFR of less than 30 mL/min).
Stuveling EM, Hillege HL, Bakker SJ, et al. C-reactive protein is associated with renal function abnormalities in a non-diabetic population.
Wannner C, Zimmermann J, Schwedler S, Metzger T. Inflammation and cardiovascular risk in dialysis patients.
Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition.
Ann Intern Med.
Sposito AC, Mansur AP, Coelho AR, et al. Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril).
Am J Cardiol.
Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease.
Am J Kidney Dis.
Vidt DG, Cressman MD, Harris S, et al. Rosuvastatin-induced arrest in progression of renal disease.
Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study.
J Clin Pathol.