Managing Chronic Kidney Disease

Managing Chronic Kidney Disease

Summarized by Robert W. Griffith, MD
August 14, 2007

Summary

A combination of pravastatin, vitamin E, and homocysteine-lowering medications given to patients with chronic kidney disease lowers the risk of cardiovascular disease, compared with placebo.

Introduction

People with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. This exists even after adjustments have been made for the risk factors for CKD (such as high blood pressure and diabetes), which are also risk factors for cardiovascular disease. A possible explanation may be a higher level of 'oxidative stress' in the kidney vessels. Reactive oxygen substances in the body, like free radicals and peroxides derived from environmental pollutants such as cigarette smoke and motor emissions, are removed by natural antioxidants. However an excess of free radicals over antioxidants can lead to tissue damage, which is associated with higher blood levels of substances like angiotensin II and inflammatory cytokines.

A clinical trial of a combination of antioxidants has been done in patients with CKD, and reported in the Archives of Internal Medicine. The aim was to study evidence of atherosclerosis in carotid and brachial (arm) arteries, as well as kidney function, over a 2-year period. Here's a summary of the study, which was done in Amsterdam, Netherlands.

What was done

Ninety-three patients with CKD were randomly assigned to one of two groups: one received an antioxidant regimen of pravastatin (Pravachol®), to which vitamin E was added after 6 months, and homocysteine-lowering therapy after another 6 months, and the other took matching placebos.

Patients with mild to moderate CDK were selected based on their creatinine clearance test result; it had to be between 15 and 70 mL/minute per 1.73m2 body surface area. For the analysis of results, two age groups were formed (below and above 50 years) and two creatinine groups (below and above 40 mL/min per 1.73m2).

After randomization to treatment or placebo, the treatment group patients were given pravastatin 40 mg daily. Vitamin E (alpha-tocopherol acetate) 300 mg daily was added after 6 months, and then 6 months later they were given folic acid 5mg daily, pyridoxine 100 mg daily, and cyanocobalamine 1 mg daily for a further 6 months, to lower homocysteine levels.

Patients with diabetes or raised total cholesterol levels were excluded, but those with high blood pressure were allowed, provided they stayed on standard antihypertensive medication.

Atherosclerosis was assessed using the intima-media thickness in the common carotid artery (CC-IMT) using ultrasound, and the flow-mediated dilatation of the brachial artery (BA-FMD), also using ultrasound. This was done at baseline, 6, 12, 18, and 24 months. Kidney function tests, including looking for albumen in the urine, was done at the same intervals. Oxidized low density lipoprotein (LDL) cholesterol and malondiadehyde levels were measured as indicators of oxidative stress.

What was found

The average age of the patients was 53; 56% of them were male. Their average BMI was 26.5 (i.e. 'overweight'), and 35% were smokers. The active treatment was linked to a reduced level of the oxidized LDL-cholesterol levels, but there were no treatment-related changes in the other measure of oxidative stress, plasma malondialdehyde.

After 18 months, the average intima-media thickness - a recognized surrogate marker for cardiovascular risk - had decreased by 0.05 mm in the treated group, compared with an increase of 0.06 mm in the placebo group. This is a significant difference in favor of the treatment. The greatest change in the treatment group was seen in the first 6 months (the pravastatin-only period).

Flow-mediated dilatation of the brachial artery - an indication of the arteries' elasticity - showed a similar benefit in the treatment group subjects; their BA-FMD after 18 months had increased from 4.66% to 7.56%, compared with a decrease from 6.21% to 4.73% in the placebo group. This, too, was a significant difference in favor of the treatment; and again the greatest effect was seen with pravastatin alone in the first 6 months.

After 24 months, the average glomerular filtration rate had decreased slightly in the placebo subjects, and increased in the treatment group; although these changes favored the treatment over placebo, the differences were not statistically significant. Average urinary albumin excretion was reduced 20% in the treatment group at 6 months, compared with the placebo group; this difference remained significant during the rest of the study.

Conclusions

This study shows that a combination of pravastatin, vitamin E, and homocysteine-lowering treatment in patients with mild to moderate CKD improves two indicators of atherosclerosis (CC-IMT and BA-FMD) as well as albuminuria, when compared with placebo. The investigators emphasize that there was formal control of blood pressure (to below 140/90 mm Hg) using a strict treatment protocol.

It is noteworthy that the greatest improvements in arterial tests came with the first 6 month period, when the statin was given alone. Previous studies of statins in patients with mild CKD have shown short-term benefits. Moreover, other studies have failed to demonstrate cardiovascular benefits from vitamin E and homocysteine-lowering in CDK. This suggests that the statin - in this case pravastatin - was chiefly responsible for the favorable outcome in this study. Once again, statins prove that they have more to offer than just lowering LDL-cholesterol.

Source

* Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on carotid-intima thickness, endothelial function, and renal function in patients with mild to moderate chronic renal disease. PWB. Nanayakkara, C. van Guldener, PM. ter Wee, et al. , Arch Intern Med, 2007, vol. 167, pp. 1262--1270

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