Does lipid-lowering therapy slow progression of chronic kidney disease?

IT IS NOW more than 20 years since Moorhead and colleagues postulated that lipids contribute to glomerular and tubulointerstitial injury in the context of progressive chronic kidney disease (CKD).1Moorhead J.F. Chan M.K. El-Nahas M. Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease.Lancet. 1982; 2: 1309-1311Google Scholar At the time, the “lipid hypothesis” was based largely on observations from histopathologic studies dating back to the work of Virchow in the 1860s, but it was later supported by a series of in vivo experiments involving animal models.2Moorhead J.F. Wheeler D.C. Varghese Z. Glomerular structures and lipids in progressive renal disease.Am J Med. 1989; 87: 12N-20NGoogle Scholar, 3Kasiske B.L. O’Donnell M.P. Schmitz P.G. Keane W.F. The role of lipid abnormalities in the pathogenesis of chronic, progressive renal disease.Adv Nephrol Necker Hosp. 1991; 20: 109-125Google Scholar In these studies, correction of dyslipidemia by dietary or pharmacologic intervention reduced the degree of glomerulosclerosis and tubulointerstitial fibrosis following experimentally induced kidney disease while high-fat diets tended to exacerbate kidney injury. Further investigation of these models and numerous in vitro experiments have since defined the possible mechanisms by which lipids may mediate kidney damage, making the lipid hypothesis biologically plausible.4Wheeler D.C. Lipids—What is the evidence for their role in progressive renal disease?.Nephrol Dial Transplant. 1995; 10: 14-16Google Scholar For example, there is good evidence that circulating lipoproteins become deposited in the glomerular mesangium5Lee H.S. Lee J.S. Koh H.I. Ko K.W. Intraglomerular lipid deposition in routine biopsies.Clin Nephrol. 1991; 36: 67-75Google Scholar and that, following glomerular injury, filtered lipoproteins (including fatty-acid–laden albumin) are reabsorbed by tubular epithelial cells and accumulate in the tubulointerstitial space.6Brunskill N.J. Albumin signals the coming of age of proteinuric nephropathy.J Am Soc Nephrol. 2004; 15: 504-505Google Scholar Extravasated lipids promote an inflammatory reaction and are scavenged by infiltrating macrophages in a process that leads to the formation of foam cells.7Magil A.B. Interstitial foam cells and oxidized lipoprotein in human glomerular disease.Mod Pathol. 1999; 12: 33-40Google Scholar Although this might seem to represent a damage-limitation exercise, abolition of the inflammatory response by whole-body irradiation inhibits the development of kidney damage in cholesterol-fed rats.8Pesek-Diamond I. Ding G. Frye J. Diamond J.R. Macrophages mediate adverse effects of cholesterol feeding in experimental nephrosis.Am J Physiol. 1992; 263: F776-F783Google Scholar Even in the absence of inflammatory cells, exposure of different kidney cells to lipoproteins in vitro leads to a variety of functional changes, notably increased production of matrix components.9Wheeler D.C. Chana R.S. Interactions between lipoproteins, glomerular cells and matrix.Miner Electrolyte Metab. 1993; 19: 149-164Google Scholar Inevitably, such observations have reinforced the view that treatment strategies effective in the prevention of atherosclerosis may be appropriate in the management of chronic progressive kidney disease.10Keane W.F. Kasiske B.L. O’Donnell M.P. Lipids and progressive glomerulosclerosis A model analogous to atherosclerosis .Am J Nephrol. 1988; 8: 261-271Google Scholar Further support for the lipid hypothesis, this time in man, came from study of a rare inherited disorder termed lipoprotein glomerulopathy.11Saito T. Oikawa S. Sato H. Sasaki J. Lipoprotein glomerulopathy Renal lipidosis induced by novel apolipoprotein E variants .Nephron. 1999; 83: 193-201Google Scholar This condition results from mutations of apolipoprotein E (ApoE), a major constituent of plasma lipoproteins, and is characterized by both a type III pattern of hyperlipidemia and occlusion of glomerular capillary loops by lipoprotein aggregates. Affected patients develop CKD with proteinuria and a progressive loss of kidney function eventually leading to end-stage kidney failure. Less well established is whether more common polymorphisms of ApoE—which in part determine lipid levels in uremic patients—influence kidney disease progression.12Liberopoulos E. Siamopoulos K. Elisaf M. Apolipoprotein E and renal disease.Am J Kidney Dis. 2004; 43: 223-233Abstract Full Text Full Text PDF Scopus (77) Google Scholar Whether plugging of small vessels by lipoproteins contributes to loss of kidney function in other forms of kidney disease is also unclear. Despite the observations described above, robust evidence that lipid-lowering therapy slows progression of CKD in man has been lacking. Although statins and fibrates have proven to be effective in correcting lipid abnormalities in such individuals,13National Kidney FoundationK/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease.Am J Kidney Dis. 2003; 41: S1-S91Google Scholar most studies to date have been far too short and too small to provide reliable data on the impact of lipid-lowering therapy on hard clinical end points, such as rate of loss of kidney function (or indeed the occurrence of cardiovascular events). In a recent meta-analysis of 13 published placebo-controlled studies including a total of only 362 CKD patients, Fried et al concluded that pharmacologic correction of lipid abnormalities slowed the rate of loss of kidney function, although this effect was small.14Fried L.F. Orchard T.J. Kasiske B.L. Effect of lipid reduction on the progression of renal disease A meta-analysis .Kidney Int. 2001; 59: 260-269Google Scholar Unfortunately, all large trials published to date examining the impact of lipid-lowering therapy on cardiovascular end points have systematically excluded patients with CKD. However, because most investigators have used a serum creatinine threshold to do this, some patients with a reduced glomerular filtration rate (GFR) have been randomized, thus providing the opportunity to undertake “post hoc” analyses in an effort to establish the benefits of therapy in patients with impaired kidney function. In an article published in this issue of the American Journal of Kidney Diseases, Tonelli and colleagues15Tonelli M. Collins D. Robins S. Bloomfield H. Curhan G.C. Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease.Am J Kidney Dis. 2004; 44: 832-839Abstract Full Text Full Text PDF Scopus (51) Google Scholar examine the rate of change of estimated GFR in a subgroup of 399 patients with stage 3 CKD at the point of recruitment into the Veterans Administration–High-density lipoprotein Intervention Trial (VA-HIT). During a 61-month follow-up period, there was no difference in the rate of change of GFR when comparing participants in this subgroup who had been assigned to gemfibrozil (1,200 mg/d) with those who received placebo. In fact, assignment to gemfibrozil was associated with a higher incidence of transient, but not sustained, increases in serum creatinine. Such a phenomenon has previously been noted with other fibrates, but not with gemfibrozil,16Broeders N. Knoop C. Antoine M. Tielemans C. Abramowicz D. Fibrate-induced increase in blood urea and creatinine Is gemfibrozil the only innocuous agent? .Nephrol Dial Transplant. 2000; 15: 1993-1999Google Scholar and may be attributable to muscle injury rather than real changes in kidney function. In fact, fibrate-induced muscle injury was first described in patients with impaired kidney function almost 30 years ago and contributed to a general reluctance among nephrologists to treat dyslipidemia complicating CKD prior to the availability of statins.17Pierides A.M. Alvarez-Ude F. Kerr D.N. Clofibrate-induced muscle damage in patients with chronic renal failure.Lancet. 1975; 2: 1279-1282Google Scholar In contrast to these results from the VA-HIT study, post hoc analyses of subgroups of individuals with reductions in GFR included in large trials assessing the impact of statin therapy on vascular disease have generally supported the lipid hypothesis. In another publication, Tonelli et al18Tonelli M. Moye L. Sacks F.M. Cole T. Curhan G.C. Cholesterol and Recurrent Events Trial InvestigatorsEffect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.J Am Soc Nephrol. 2003; 14: 1605-1613Google Scholar identified 690 individuals recruited into the Cholesterol And Recurrent Events (CARE) study among whom GFR, calculated using the Modification of Diet in Renal Disease (MDRD) formula, was less than 60 mL/min/1.73 m2. While randomization of these individuals to pravastatin (40 mg/d) rather than placebo was not associated with a significant slowing of the rate of decline of kidney function, among 32 patients with the most severe kidney impairment (MDRD-GFR, <40 mL/min/1.73 m2), assignment to statin was associated with a 2.5 mL/min/1.73 m2/y slower decline in MDRD-GFR when compared with placebo. Similar results were observed in the Heart Protection Study (HPS),19Collins R. Armitage J. Parish S. Sleight P. Peto R. Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes A randomised placebo-controlled trial .Lancet. 2003; 361: 2005-2016Scopus (0) Google Scholar in which allocation to simvastatin was associated with a slower fall in MDRD-GFR versus placebo (difference, 0.8 mL/min/1.73 m2 over 4.6 years). In the 1,600 individuals with established coronary heart disease participating in the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) study, allocation to atorvastatin (mean dose, 24 mg/d) was associated with an 11.6% increase in calculated creatinine clearance as opposed to a 4.4% reduction in those receiving “usual care” during a 3-year follow-up period.20Athyros V.G. Mikhailidis D.P. Papageorgiou A.A. 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. 2004; 57: 728-734Google Scholar Finally, in a post hoc analysis of more than 7,000 individuals who received rosuvastatin (5-40 mg) for up to 3.8 years in a variety of clinical trials, a small increase in MDRD-GFR was observed, whereas there was no change in those who received placebo during the same period.21Vidt D.G. Cressman M.D. Harris S. Pears J.S. Hutchinson H.G. Rosuvastatin-induced arrest in progression of renal disease.Cardiology. 2004; 102: 52-60Google Scholar In contrast to these data from studies in patients with native kidneys, the only large study in renal transplant recipients did not show a difference in rate of loss of allograft function among individuals assigned to receive fluvastatin (40 to 80 mg) versus placebo during a 6-year follow-up period.22Holdaas H. Fellstrom B. Jardine A.G. et al.Assessment of LEscol in Renal Transplantation (ALERT) study investigatorsEffect of fluvastatin on cardiac outcomes in renal transplant recipients A multicentre, randomised, placebo-controlled trial .Lancet. 2003; 361: 2024-2031Google Scholar As acknowledged by Tonelli et al in their article in this issue,15Tonelli M. Collins D. Robins S. Bloomfield H. Curhan G.C. Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease.Am J Kidney Dis. 2004; 44: 832-839Abstract Full Text Full Text PDF Scopus (51) Google Scholar there are many limitations to post hoc analyses that may render the results of such studies unreliable. Importantly, the cause of kidney disease in these studies is not known and, in many cases, may have been due to atherosclerotic renovascular disease in which the benefits of lipid lowering may be more apparent. The generalizability of these findings to patients with other forms of kidney disease and to those with more severely impaired kidney function needs to be investigated in a trial specifically designed to address the lipid hypothesis. Such a trial is now recruiting. The Study of Heart and Renal Protection (SHARP) aims to randomize 9,000 CKD patients (defined as a serum creatinine level of ≥1.5 mg/dL [130 μmol/L] in women and ≥1.7 mg/dL [150 μmol/L] in men including patients receiving dialysis) to simvastatin (20 mg) plus ezetimibe (10 mg) or matched placebo.23Baigent C. Landray M.J. Study of Heart and Renal Protection (SHARP).Kidney Int Suppl. 2003; 84: S207-S210Google Scholar It is anticipated that two thirds of the patients recruited will not require dialysis at baseline, thus providing an opportunity to assess the benefits of lipid lowering on rate of loss of kidney function in a large cohort of patients. Regardless of benefits on kidney function, another important question is whether statins reduce the high risk of cardiovascular events in CKD patients. This topic has also been examined in subgroup analyses of the CARE study24Tonelli M. Moye L. Sacks F.M. Kiberd B. Curhan G. Cholesterol and Recurrent Events (CARE) Trial InvestigatorsPravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency.Ann Intern Med. 2003; 138: 98-104Google Scholar and HPS25Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals A randomised placebo-controlled trial .Lancet. 2002; 360: 7-22Google Scholar as documented in the article by Tonelli et al in this issue. As well as SHARP, other ongoing trials among dialysis patients, namely Die Deutsche Diabetes Dialyse (4D) study26Wanner C. Krane V. Ruf G. Marz W. Ritz E. Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis. Die Deutsche Diabetes Dialyse Studie Investigators.Kidney Int Suppl. 1999; 71: S222-S226Google Scholar and A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events (AURORA)27Fellstrom B.C. Holdaas H. Jardine A.G. Why do we need a statin trial in hemodialysis patients?.Kidney Int Suppl. 2003; 84: S204-S206Google Scholar will provide further information. In some ways, this is the more important question, because the risk of a patient with early CKD developing end-stage renal disease is greatly outweighed by the risk of suffering a cardiovascular event.28Keith D.S. Nichols G.A. Gullion C.M. Brown J.B. Smith D.H. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.Arch Intern Med. 2004; 164: 659-663Google Scholar Despite compelling data derived from observations in man and from laboratory studies, it has taken more than 20 years to progress from the hypothesis published by Moorhead et al1Moorhead J.F. Chan M.K. El-Nahas M. Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease.Lancet. 1982; 2: 1309-1311Google Scholar to the randomization of patients in a definitive clinical trial that will establish whether lipid-lowering therapy slows progression of kidney failure. If it does, and if cardiovascular benefits are also demonstrated, clinicians will be able to use lipid-lowering agents like antihypertensive drugs for dual cardio- and nephroprotection in patients with CKD. Unfortunately, we will still have to wait until 2009 for the results of the SHARP study to prove or disprove the lipid hypothesis.