Archief Roodbont

Abstract

Inflammation is highly prevalent in patients with chronic kidney disease (CKD) and is consistently associated with cardiovascular morbidity and mortality. Clinical event rates increase with declining renal function and activation of the acute-phase response. Statins are potent anti-inflammatory drugs that reduce the incidence of cardiovascular events. Owing to the increased prevalence of inflammation in patients with CKD and the potent effect of statins in individuals with elevated levels of C-reactive protein, these drugs should be especially effective in patients with CKD. Whereas data indicate that pravastatin may prevent loss of kidney function to a greater extent in individuals with evidence of increased inflammation than in those who show no inflammation, two large, randomized statin trials in patients on hemodialysis found no benefit of statin therapy, neither in the whole study group nor after stratifying for inflammation. Irrespective of inflammation, guidelines recommend treatment of dyslipidemia in early stages of CKD, which is supported by results from recent meta-analyses, and the Study of Heart and Renal Protection (SHARP), a large, randomized, placebo-controlled trial.

Introduction

Atherosclerosis is thought to be an inflammatory disease.^[1] C-reactive protein (CRP) is the most extensively studied marker of inflammation and has continuous associations with the risk of atherosclerotic diseases. Although it has been suggested that the associations between CRP and ischemic vascular disease depend considerably on conventional risk factors and other markers of inflammation,^[2] the ability of CRP to predict vascular risk might still be useful in identifying individuals who are at high risk of vascular events and who might benefit from therapies to reduce this risk. To study this relationship, investigators of the Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) randomly assigned 17,802 apparently healthy men and women with normal LDL-cholesterol levels, but with high-sensitivity CRP (hsCRP) levels of >19.1 nmol/l to double-blind treatment with rosuvastatin versus placebo.^[3] After a median follow-up of 1.9 years, rosuvastatin effectively lowered the hazard of the primary end point (occurrence of a first cardiovascular event) by 44% as compared with placebo; furthermore, hsCRP and LDL-cholesterol concentrations were reduced by 37% and 50%, respectively. The investigators concluded that in individuals without hyperlipidemia but with elevated hsCRP concentrations, rosuvastatin significantly reduced the incidence of major cardiovascular events as compared with placebo (P <0.001).^[3]

Inflammation is highly prevalent in patients with chronic kidney disease (CKD), with CRP levels of between 47.6 nmol/l and 76.2 nmol/l commonly reported.^[4-10] Reduced kidney function is associated with a considerably increased risk of death and cardiovascular events,^[11] resulting in mortality rates as high as 20% in the first year of renal replacement therapy.^[12,13] In these patients, CRP levels have been shown to be a potent risk marker for cardiovascular events and mortality.^[14] Identifying treatments that decrease inflammation in patients with CKD could, therefore, translate into improved outcomes. Following the results from JUPITER, the question arises as to whether statins would be effective for reducing cardiovascular events in patients with CKD with differing levels of CRP; that is, do patients with higher CRP levels benefit more from statin therapy than patients with lower CRP levels? Furthermore, statins have been proposed in the treatment of erythropoietin hyporesponsiveness and have also been shown to improve survival in sepsis events.^[15,16] These effects were observed in patients presenting with 'normal' LDL-cholesterol levels, similar to those in participants in JUPITER, suggesting that statins have benefits other than their lipid-lowering effects.

In this Review we describe the extent of the inflammatory state in patients with CKD and uremia, outlining the causes of the acute-phase response and its impact on prognosis. We also discuss the effect of statins on surrogate and hard outcomes in patients with CKD who show evidence of inflammation. A short overview of the benefit of statin therapy in patients with CKD and an outlook towards the future is also provided.

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