The Lipid Lowering and Onset of Renal Disease (LORD) Trial: a Randomized Double Blind Placebo Controlled Trial Assessing the Effect of Atorvastatin on the Progression of Kidney Disease

Robert G Fassett; Madeleine J Ball; Iain K Robertson; Dominic P Geraghty; Jeff S Coombes

Disclosures

BMC Nephrology 

In This Article

Abstract and Background

Background: There is evidence that dyslipidemia is associated with chronic kidney disease (CKD). Experimental studies have established that lipids are damaging to the kidney and animal intervention studies show statins attenuate this damage. Small clinical trials, meta-analyses, observational studies and post-hoc analyses of cardiovascular intervention studies all support the concept that statins can reduce kidney damage in humans. Based on this background, a double blind randomized placebo controlled trial was designed to assess the effectiveness of atorvastatin 10mg on slowing the progression of kidney disease in a population of patients with CKD.
Method/Design: The Lipid lowering and Onset of Renal Disease (LORD) trial is a three-year, single center, multi-site, double blind, randomized, placebo controlled trial. The primary outcome measure is kidney function measured by eGFR calculated by both Modification of Diet in Renal Disease (MDRD) and Cockcroft and Gault equations. Secondary outcome measures include kidney function measured by 24-hour urine creatinine clearance and also 24-hour urinary protein excretion, markers of oxidative stress, inflammation and drug safety and tolerability.
Discussion: The results of this study will help determine the effectiveness and safety of atorvastatin and establish its effects on oxidative stress and inflammation in patients with CKD.
Trial Registration: ANZCTRN012605000693628

End stage kidney disease (ESKD) is a major health problem resulting in a considerable increase in morbidity and mortality, decreased quality of life, and substantial health care costs.[1] Clinical trials attempting to slow the progression of kidney disease should be a major focus of research. As treatments directed at primary kidney diseases are few, therapies have been directed towards slowing the progression of kidney disease by controlling hypertension, using angiotensin converting enzyme inhibitors (ACEI's) and angiotensin receptor blockers (ARB's) and lowering the protein intake in the diet.[2,3,4,5,6] Dyslipidemia has been identified as an independent risk factor for the progression of kidney disease.[7] The deleterious effect of hyperlipidemia on the progression of kidney disease is based on a number of lines of evidence.

In a large number of different animal models hyperlipidemia has been clearly shown to accelerate the progression of kidney disease.[8] There is extensive evidence for the processes involved in lipid induced kidney damage, where multiple mechanisms appear to be involved but a common initiation by hyperlipidemia is present. In addition, intervention studies have assessed the effects of statins on limiting kidney damage, again, in a variety of animal models.[9,10] In these studies statins had a beneficial effect on kidney structure and function. Not only did statins reduce proteinuria, they attenuated inflammatory processes and prevented histological changes of inflammation and fibrosis in the kidney.

A comprehensive search of the literature has found 25 randomized controlled trials (RCT's) reporting on the effects of statins on kidney function however these have been mostly of small size, short duration, with narrow inclusion and exclusion criteria, often conducted on patients with normal or stable kidney function, using a variety of statins and doses, or with poor concealment and often no placebo group. Some were also potentially affected by the inclusion of other lipid lowering agents. The results of these are best summarized in the meta-analyses described below.

The large cardiovascular clinical trials such as GREACE, CARE and TNT provide data on a significant number of subjects exposed to statins.[11,12,13] These studies however, were primarily designed to assess cardiovascular outcomes in subjects presenting with cardiac disease or who were at a high risk of cardiac disease. They were not specifically designed to test kidney function outcomes. Post-hoc sub-analyses are commonly performed on these large trials to extract maximum benefit from the available data that takes years to accumulate at a high cost. Wang et al reported that such analyses introduce challenges and may lead to "overstated and misleading results".[14] The most important conclusion that can be drawn from these cardiovascular studies is that subjects with kidney dysfunction who meet the cardiovascular criteria of these trials, which for most include a prior myocardial infarction, will do well from the kidney function perspective when treated with a statin. In addition there are no data available from these cardiovascular trials regarding the kidney disease diagnosis thus no conclusions can be made regarding how to treat any specific kidney disease type.

There have been two published meta-analyses reporting on the effects of statins on kidney function, one by Fried et al,[15] and the most recent, reported by Sandhu et al (2006), that includes most of the 25 RCT's mentioned above.[16] The subject numbers are substantially larger in the Sandhu analysis as the larger cardiovascular trials were included. This however is a limitation as this inclusion mixes prospective studies with post-hoc, sub-studies of major randomized controlled trials. Thus the authors' conclusions must be interpreted with caution. The meta-analyses support the suggestion that statins have a beneficial effect on kidney function. The Sandhu et al meta-analysis also implies that statins have a more protective effect on kidney function in subjects recruited with a cardiovascular disease and that the more potent statin, atorvastatin, has a greater effect on protecting kidney function than the less potent statins such as pravastatin, fluvastatin, lovastatin and simvastatin.[16] Based on the need for further clarification and investigation of the role of statins in slowing CKD progression the LORD Trial was designed. This trial is intended to have inclusion criteria that reflected common clinical practice to enable the results to be as clinically relevant as possible.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....