Dyslipidaemia in patients with chronic kidney disease and treatment

Introduction Treatment of dyslipidaemia complicated by chronic kidney disease is important for preventing the development of cardiovascular disease. The pathogenesis of dyslipidaemia associated with chronic kidney disease varies depending on urinary protein level and the stage of chronic kidney disease. Hypocholesterolaemia is associated with malnutrition and inflammation and also leads to the poor prognosis of dialysis patients. Statins are expected to prevent the development of cardiovascular disease in non-dialysis chronic kidney disease patients; however, there is no evidence of the efficacy of statins in preventing the development of cardiovascular disease in dialysis patients. Treatment strategies for dyslipidaemia in chronic kidney disease patients mainly include lifestyle changes, dietary therapies and medications such as statins; care should be taken with regard to the side effects of medicines. The aim of this article is to discuss dyslipidaemia in patients with chronic kidney disease. Conclusion Patients who showed abnormal findings in the lipid test should be treated by considering not only their test results but also their general condition including nutritional condition, medical history and complications. Personalised treatment of each patient, rather than across-the-board treatment, is necessary. Introduction Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) and must be prevented to improve their prognosis. Atherosclerosis is often a complication of CKD and adversely affects the prognosis of patients with CKD1–3. Dyslipidaemia is a cause of atherosclerosis. The relationship between pulse wave velocity (PWV) and very low-density lipoprotein cholesterol (VLDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and low-density lipoprotein cholesterol (LDL-C) levels has been reported4. The Lipid lowering and Onset of Renal Disease (LORD) trial showed that atorvastatin suppressed the decrease in PWV5. The Atherosclerosis Risk in Communities (ARIC) study showed that hypercholesterolaemia and hypertriglyceridaemia are the risk factors for CVD6. Dyslipidaemia can develop at any stage of CKD and is a risk factor for CVD; hence, methods to control dyslipidaemia should be examined. This article discusses dyslipidaemia in patients with CKD and also the methods to treat these patients. Discussion Pathogenesis of dyslipidaemia The pathogenesis of dyslipidaemia associated with CKD varies depending on the urinary protein level and the stage of CKD7. For patients with nephrotic syndrome who have high urinary protein levels, albumin production is enhanced in the liver to compensate for hypoproteinaemia. At the same time, the synthesis of apolipoprotein (apo) B (apoB) is enhanced, resulting in elevated levels of VLDL-C and LDL-C. For patients with CKD who do not have as high urinary protein levels as those with nephrotic syndrome, dyslipidaemia is mainly caused by dysfunction in the catabolism of lipoproteins in the peripheral tissues. Patients with CKD at stage 3 or later show abnormal levels of lipoproteins and apolipoproteins, that is, decreased levels of apoA-I, apoA-II, and apoA-IV. The level of apoC-III, an inhibitor of lipoprotein lipase (LPL), is elevated and the apoA-I/apoC-III ratio decreases. With increasing apoCIII level, the production of VLDL, which is less affected by LPL activity, is enhanced, resulting in an elevated VLDL-C level. In CKD patients with diabetes mellitus, the production of triglycerides (TGs) is also enhanced because of diabetes mellitus, which overlaps with the above-mentioned pathologies. In dialysis patients (CKD stage 5D), LPL activity decreases because of the accumulation of uremic toxins and secondary hyperparathyroidism. Because hepatic triglyceride lipase activity also decreases, the conversion of IDLs to LDLs becomes difficult, resulting in elevated IDL levels and decreased LDL levels. The increase in IDL level leads to an increase in TG level. Although LDL level decreases, its plasma residence time increases, leading to degeneration caused by oxidation and accelerating atherosclerosis. Haemodialysis patients may have hypertriglyceridaemia and hypo-high-density * Corresponding author Email: tokyo.kyosai.kanda@gmail.com 1 Department of Nephrology, Tokyo Kyosai Hospital, Meguroku, Tokyo, Japan 2 Bioethics Research Center, Tokyo Medical and Dental University, Bunkyoku, Tokyo, Japan 3 Department of Nephrology, Tokyo Medical and Dental University, Bunkyoku, Tokyo, Japan


Introduction
Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) and must be prevented to improve their prognosis.Atherosclerosis is often a complication of CKD and adversely affects the prognosis of patients with CKD [1][2][3] .Dyslipidaemia is a cause of atherosclerosis.The relationship between pulse wave velocity (PWV) and very low-density lipoprotein cholesterol (VLDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and low-density lipoprotein cholesterol (LDL-C) levels has been reported 4 .The Lipid lowering and Onset of Renal Disease (LORD) trial showed that atorvastatin suppressed the decrease in PWV 5 .The Atherosclerosis Risk in Communities (ARIC) study showed that hypercholesterolaemia and hypertriglyceridaemia are the risk factors for CVD 6 .Dyslipidaemia can develop at any stage of CKD and is a risk factor for CVD; hence, methods to control dyslipidaemia should be examined.This article discusses dyslipidaemia in patients with CKD and also the methods to treat these patients.

Pathogenesis of dyslipidaemia
The pathogenesis of dyslipidaemia associated with CKD varies depending on the urinary protein level and the stage of CKD 7 .For patients with nephrotic syndrome who have high urinary protein levels, albumin production is enhanced in the liver to compensate for hypoproteinaemia.At the same time, the synthesis of apolipoprotein (apo) B (apoB) is enhanced, resulting in elevated levels of VLDL-C and LDL-C.For patients with CKD who do not have as high urinary protein levels as those with nephrotic syndrome, dyslipidaemia is mainly caused by dysfunction in the catabolism of lipoproteins in the peripheral tissues.
Patients with CKD at stage 3 or later show abnormal levels of lipoproteins and apolipoproteins, that is, decreased levels of apoA-I, apoA-II, and apoA-IV.The level of apoC-III, an inhibitor of lipoprotein lipase (LPL), is elevated and the apoA-I/apoC-III ratio decreases.With increasing apoC-III level, the production of VLDL, which is less affected by LPL activity, is enhanced, resulting in an elevated VLDL-C level.In CKD patients with diabetes mellitus, the production of triglycerides (TGs) is also enhanced because of diabetes mellitus, which overlaps with the above-mentioned pathologies.
In dialysis patients (CKD stage 5D), LPL activity decreases because of the accumulation of uremic toxins and secondary hyperparathyroidism.Because hepatic triglyceride lipase activity also decreases, the conversion of IDLs to LDLs becomes difficult, resulting in elevated IDL levels and decreased LDL levels.The increase in IDL level leads to an increase in TG level.Although LDL level decreases, its plasma residence time increases, leading to degeneration caused by oxidation and accelerating atherosclerosis.Haemodialysis patients may have hypertriglyceridaemia and hypo-high-density Licensee OA Publishing London 2013.Creative Commons Attribution License (CC-BY) For citation purposes: Kanda E. Dyslipidemia in patients with chronic kidney disease and treatment.OA Nephrology 2013 Jun 01;1(1):10.
Competing interests: none declared.Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moreover, target lipid levels may differ between patients with and without malnutrition, requiring evidence under different conditions.

Treatment
Treatment of dyslipidaemia should start with lifestyle changes.This includes education about smoking cessation.In dietary therapies, a low-protein diet for CKD should be designed in addition to the restriction of total energy and fat intake.
Appropriate exercise therapy should be provided depending on the physical ability of individuals.Medications should be taken only when cholesterol remains high despite lifestyle changes.

CVD suppression by statins in patients with CKD
In a meta-analysis of 26 studies of patients with CKD stages 3-4, statins reduced the risk of mortality, risk of fatal CVD and risk of nonfatal CVD 21 .
A subgroup analysis in the TNT study and the MEGA study indicated that statins decrease CVD risk and total mortality in patients with CKD 11,20 .
Intervention trials using statins in haemodialysis patients include the Die Deutsche Diabetes Dialyse Study (4D Study), A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Haemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) and SHARP 13,22,23 .
In the 4D study of patients with type 2 diabetes mellitus, atorvastatin statistically significantly reduced the risk of cardiac events by 18% 22 .However, the risk of stroke increased.There were no significant differences in the risk of these end points in patients with an LDL-C level of 145 mg/ dl or lower.In the AURORA study of dialysis patients in a randomised trial of rosuvastatin, there were no significant differences in the risk of the composite end point (cardiovascular death, nonfatal myocardial infarction or brain infarction) 23 .In SHARP study of non-dialysis CKD patients of end-stage renal disease were observed between the groups with and without statin treatment 13 .In a metaanalysis of 11 studies, statins did not improve eGFR 10 .Prospective studies of the outcome of the treatment with statins in terms of preventing the progression of kidney dysfunction are expected.

Cholesterol paradox
Although dyslipidaemia is a cause of atherosclerosis and a risk factor for CVD, previous studies of dialysis patients showed that the risk of mortality increases with decreasing total cholesterol level [14][15][16][17] .This is called the cholesterol paradox.Moreover, studies also showed that the risk of mortality in dialysis patients without malnutrition or inflammation increases as total cholesterol level increases 14,15,18 .Therefore, decreased cholesterol levels may reflect malnutrition and chronic inflammation and increase the risk of mortality in dialysis patients with malnutrition and inflammation.To improve the prognosis of such dialysis patients, it is necessary to control atherosclerosis caused by dyslipidaemia and to maintain their good nutritional state.

Target cholesterol level
From the finding that dyslipidaemia is a risk factor for CVD, Kidney Disease Outcomes Quality Initiative guidelines recommend that the target LDL-C level in patients with CKD be lower than 100 mg/dL 19 .Although the lower limit of the target LDL-C level is not specified, a lower LDL-C level is considered to be better because Treating to New Targets (TNT) study revealed that CVD development is suppressed in patients with a target LDL-C level of 70 mg/dL 20 .However, considering the cholesterol paradox, it is unclear whether strictly following this guideline of lowering LDL-C level is beneficial for all patients.Dyslipidaemia of patients with malnutrition should be treated after malnutrition has been improved.lipoprotein (HDL) cholesterolaemia.The levels of small-dense LDLs and lipoprotein(a) [Lp(a)] are elevated, resulting in a decrease in the levels of apoA-I and apoA-II and an increase in the levels of apoB, apoC-III, and apoE.Although heparin used during dialysis has been considered to decrease LPL activity, the decrease in LPL level in blood plasma after the treatment with heparin is not statistically significant, indicating that the use of heparin does not strongly affect lipid metabolism.In peritoneal dialysis, the loss of protein and the absorption of glucose from the peritoneal dialysis solution occur, resulting in a larger elevation of the levels of total cholesterol, IDL-C, LDL-C, and Lp(a) than in haemodialysis.In peritoneal dialysis, the apoB level is elevated.The small-dense LDL level is also elevated by the decreased clearance of VLDL.

CKD progression
Dyslipidaemia is a risk factor for CKD progression.In an observational study of patients undergoing medical check-up in local communities, hypercholesterolaemia and hypertriglyceridaemia are the risk factors for CKD progression 8 .There have been many reports on the protective effect of statins on kidney functions.As statins have been reported to decrease urinary protein level, a metaanalysis of 15 studies demonstrated that the urinary albumin level decreased by 47% in patients with a urinary albumin level of at least 300 mg/d 9 .In a meta-analysis of six studies, statins decreased urinary protein level 10 .A subgroup analysis of a Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study and LIVALO Effectiveness and Safety (LIVES) study revealed that statin treatment improved the estimated glomerular filtration rate (eGFR) 11,12 .However, in the Study of Heart and Renal Protection (SHARP), no significant differences in the progression stage of CKD, and the combined use of fibrates and statins requires great care.Probucol is excreted with the bile but often has side effects, namely digestive symptoms such as diarrhoea and sometimes irregular heartbeat, requiring medical attention.When lowering LDL-C level using statin is not enough, combination regimens are needed to reach lipid even in patients with deteriorated kidney function.Ezetimibe is excreted with the bile and can be used with other drugs including statins.Sevelamer, although not a lipid-lowering drug, can be used to improve hyperphosphataemia in dialysis patients; it decreases LDL-C level and increases HDL-C level.Fibrates are excreted by the kidney and tend to have side effects in patients with an advanced and dialysis patients, simvastatin plus ezetimibe reduced the risk of the composite end point of atherosclerosis (nonfatal myocardial infarction, coronary mortality, non-haemorrhagic stroke or revascularisation) 13 .However, no significant differences were observed between haemodialysis patients with and without the above treatment.A meta-analysis of the efficacy of statins in reducing total mortality, cardiovascular death, and incidences of cardiovascular events, myocardial infarction, and stroke showed no significant differences 24 .
Although the above research results suggest that statins are not effective in preventing the development of CVD in dialysis patients, their benefit should not completely be denied.An observational study of haemodialysis patients showed that the size of LDL particles is related to the prognosis of patients; the prognosis of patients with an elevated level of very small LDLs is poor 25 .Statins do not alter the LDL profile; however, they can decrease small-dense LDL levels when the total LDL-C level is reduced.Therefore, the small-dense LDL level of haemodialysis patients can be reduced by administering statins and the progression of atherosclerosis might be suppressed.Statins might be effective in improving the prognosis of haemodialysis patients with a high LDL level, although not all haemodialysis patients might experience substantial benefits.Note that no evidence supports the cessation of the on-going treatment with statins.

Medications for dyslipidaemia
There are eight patterns of dyslipidaemia (Figure 1).Considering these patterns, medications should be selected.On the basis of efficacy and evidence of medications, statins are considered the first option of medication (Table 1).Almost all statins are metabolised by the liver and can be basically used at a typical dose   2).Statin and ezetimibe combination therapy shows an additional 12%-21% LDL-C level reduction 26 .A systematic review showed that adding colestipol or cholestyramine to a statin provides an additional 7%-20% LDL-C level reduction 27 .Combinations of statins with fibrates can treat combined dyslipidaemia by decreasing LDL-C level more than 40%, decreasing TG levels over 50% and increasing HDL-C levels more than 20% 28 .

Conclusion
In this article, we describe the pathogenesis of dyslipidaemia in patients with CKD, the association of dyslipidaemia with cholesterol, atherosclerosis, the prognosis of patients with CKD, and the treatment of dyslipidaemia.Treatment of dyslipidaemia complicated by CKD is important to prevent the development of CVD and the progression of kidney dysfunction.Because there is a wide range of characteristics of patients with CKD, personalised treatment of each patient, rather than across-the-board treatment, is necessary.

Table 1 Lipid lowering medications and estimated changes in lipid levels LDL-C HDL-C TG
goals.Although no second option (i.e. when statins are inapplicable or ineffective) is specified, ezetimibe and bile acid sequestrants have complementary effects that suggest they may be appropriate for use in combination with a statin (Table

Table 2 Combination therapies with statin and estimated changes in lipid levels LDL-C HDL-C TG
, decreases lipid levels; HDL-C, high-density lipoprotein cholesterol; increase, increases lipid levels; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride. Decrease