|Year : 2021 | Volume
| Issue : 1 | Page : 2-5
Management of dyslipidemia in chronic kidney disease
Prit Pal Singh, Amresh Krishna, Om Kumar
Department of Nephrology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
|Date of Submission||23-Nov-2020|
|Date of Acceptance||10-Mar-2021|
|Date of Web Publication||12-Feb-2021|
Prit Pal Singh
Room No: 14, Department of Nephrology, Old Administrative Block, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna - 800 014, Bihar
Source of Support: None, Conflict of Interest: None
Dyslipidemia is one of the most important modifiable risk factors for cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Lipid profile in CKD differs from that in general population. Even at normal or near-normal lipid levels, subparticles are more atherogenic and more pro-inflammatory. Because of altered clearance and metabolism of various lipid-lowering agents in CKD, its safety on long-term use remains a serious concern. Statins and ezetimibe remain drug of choice for most of the patients. The lowest and the safest dose of the drugs is guided by various trials. Until recently, not much study was available to formulate a guideline for these patients. However, recent studies and meta-analysis have solved this problem to some extent and that's evident with latest guidelines published by KDIGO and ACC/AHA.
Keywords: Cardiovascular, chronic kidney disease, dyslipidemia, lipid-lowering agents, statin
|How to cite this article:|
Singh PP, Krishna A, Kumar O. Management of dyslipidemia in chronic kidney disease. J Indira Gandhi Inst Med Sci 2021;7:2-5
| Introduction|| |
Dyslipidemia is one of the important modifiable risk factors for cardiovascular diseases (CVDs). CVD still remains the most common cause of mortality in chronic kidney disease (CKD) accounting for more than 50% deaths in this population.,,,
CKD itself is a significant CVD risk. Dyslipidemia with concomitant CKD increases the risk of CVD many folds. As CKD stage progresses, the prevalence of dyslipidemia also increases. In the study done by NHANS (1999 to 2010), the prevalence of dyslipidemia increased from approximately 45% in Stage 1CKD to almost 67% in Stage 4 CKD. At the same time, the use of lipid-lowering agents increased from almost 18% to 44%. Tonelli et al. observed that low-density lipoprotein cholesterol (LDL-C) level and risk of myocardial infarction are associated in linear fashion, particularly LDL level above 100 mg/dL. In a study including a cohort of 1167 chronic dialysis patients, Iseli et al. concluded that dialysis patients with favorable lipid profile such as higher LDL-C and lower total cholesterol (TC) are at the highest risk of adverse CVD outcome. Five-year survival was highest in patients with serum cholesterol range between 200 and 219 mg/dL, while lowest in patients with cholesterol level <140 mg/dl. This paradoxical correlation also known as “reverse epidemiology” is likely due to high incidence of malnutrition, inflammation, and protein energy wasting in these patients apart from atherosclerosis.,
Properties of lipid particles in CKD populationw differ from that of general population. There is usually low, normal, or slightly elevated TC and LDL level while triglycerides (TGs) are significantly elevated. LDL particles are also not much elevated but change in their microparticle compositions such as change in apo-A/apo-B ratio increases their atherogenicity. Small, dense LDL is more atherogenic than larger LDL proteins.
Furthermore, high-density lipoprotein (HDL) in CKD is having lesser antioxidative and anti-inflammatory activity due to ongoing cascade of inflammatory process inherent to CKD. In kidney transplant patients, lipid abnormality is a result of continuum of the effect of previous comorbidities on serum lipid and use of medications, particularly immunosuppressants.
| Mechanism of Dyslipidemia in Chronic Kidney Disease|| |
There are many ongoing metabolic derangements in CKD that finally, contribute to specific lipid abnormalities. Lecithin-cholesterol acyltransferase enzyme (LCAT) is the rate-limiting enzyme of lipid metabolism. Excessive urinary loss of LCAT leads to its decreased activity in CKD. Decreased LCAT activity along with increased cholesteryl ester transfer protein activity results in low HDL level. There is impaired clearance of chylomicrons and very LDL (VLDL), resulting in high TG level. In patients with nephrotic-range proteinuria, the liver increases lipoprotein synthesis by upregulation of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in response to hypoalbuminemia. A reduction in lipoprotein lipase activity and underexpression of LDL receptors in CKD are also responsible for increased chylomicrons and VLDL. These circulating lipid microparticles along with altered characteristics finally lead to increased formation of reactive oxygen species such as superoxide anions, hydrogen peroxide, and increased vasoconstrictors. All these factors collectively make atherogenic potential of lipids much higher in CKD patients.
| Management of Dyslipidemia in Chronic Kidney Disease|| |
Lipid-lowering agents include statins (HMG-CoA reductase inhibitors), ezetimibe (cholesterol absorption inhibitors), bile acid sequestrants, fibrates and its derivatives, and niacin and its congeners [Table 1]. Statins remain the most commonly used drug among lipid-lowering agents. CKD patients are at higher risk of having adverse effects due to accompanying multiple comorbidities, polypharmacy, and decreased renal excretion of drugs. Till late, studies have failed to prove conclusively the effect of lipid lowering on CVD endpoints in CKD patients. Even with similar reduction of lipids as compared to general population, CVD risk reduction was not significant in CKD patients. This led to delay in formulating guidelines for clinicians for the use of lipid-lowering agents in CKD or transplant patients. Finally, based on few recent RCTs and meta-analysis, KDIGO and AHA/ACC came up with their guidelines for the management of lipids in CKD patients.,
| Use of Statins in Predialysis Patients|| |
As incidence of side effects is high in CKD patients, risk to benefit ratio needed to be assessed carefully and advices to be given accordingly to minimize risk of polypharmacy.
KDIGO recommends the use of statins or statin/ezetimibe in all CKD patients above 50 years of age except patients on maintenance dialysis (CKD G1-G 5-ND). ALBRTA cohort study on more than one million people with follow-up of 4 years showed that risk of death due to cardiovascular causes and nonfatal MI was >10% in patients >50 years of age regardless of their CKD stage ranging from Stages 1 to 4.
Colhaun et al. in their Collaborative Atorvastatin Diabetes Study showed that atorvastatin 10 mg reduced cholesterol level by 40% on average; cardiovascular causes (30%–36%), and fatal and nonfatal stroke (48%) among persons with type 2 diabetes mellitus in the absence of marked renal insufficiency.
| Use of Statins in Dialysis Patients|| |
4D (the German Diabetes and Dialysis Study group) included 1255 diabetic CKD 5D patients using atorvastatin 20 mg/day. During a median follow-up period of 4 years, LDL cholesterol was decreased to 42%; however, no significant effect on cardiovascular death, nonfatal MI, and stroke was noted.
AURORA study included 2776 CKD 5D patients randomized on rosuvastatin 10 mg or placebo suggested no significant lowering in cardiovascular deaths, MI, or stroke despite achieving 43% reduction in LDL cholesterol.
SHARP study included 9270 CKD patients with 3023 on dialysis. This study randomized patients on combination of simvastatin with ezetimibe with placebo. With a median follow-up period of 4.9 years, the study concluded that simvastatin plus ezetimibe combination decreased all-cause mortality and major cardiovascular adverse events in CKD patients including dialysis patients with no significant risk of adverse drug reactions.
It seems that it is too late to start statins once patient is on dialysis as the long duration of treatment needed to get any significant cardiovascular benefit and the attrition of patients due to cardiovascular causes during treatment period is high.,,, Based on these studies, KDIGO recommends not to start statin or statin/ezetimibe combination but at the same time suggests to continue the same if already receiving lipid-lowering agents.
| Use of Statins in Transplant Population|| |
KDIGO suggests starting statins in all transplant patients. This recommendation is based largely on the “Effect of fluvastatin on renal endpoints in the Assessment of Lescol in Renal Transplant (ALERT) trial finding. The study concluded that fluvastatin significantly improved lipid levels in renal transplant patients but had no significant effect on graft loss, death rates, or decline in serum creatinine compared to placebo., One theory for the unexpected lack of effect of fluvastatin on renal graft endpoints was that first 2 to 3 years of dyslipidemia is crucial for setting up long-term adverse consequences and starting fluvastatin earlier may have beneficial effects. ALERT extended study that followed these patients for 6.7 years have shown reduction in major adverse cardiac events by 30%.,
| Statins in Nephrotic Syndrome|| |
Most patients with nephrotic syndrome present with secondary hypercholesterolemia which usually is corrected as patient achieves remission. Further accurate CVD risk scoring is not possible in this population due to lack of validated scoring system and lack of adequate data. Hence, primary tool for correcting lipid abnormality should be dietary and nutritional counseling. KDIGO suggests not starting cholesterol-lowering agents in CKD patients less than 18 years of age. Severe dyslipidemia associated with high CVD risk in children >10 years of age, can be managed with statins after consent from parents.
| Dosing of Statins in Chronic Kidney Disease|| |
Glomerular filtration rate (GFR) and drug interactions are essential considerations before adjusting dosage of lipid-lowering drugs. For example, a renal transplant patient receiving cyclosporine may have decreased metabolism of statins leading to higher level and correspondingly increased side effects if reduced doses of statins were not used. Aforementioned studies have recommended the safe doses of statins as follows: fluvastatin (80 mg), atorvastatin (20 mg), rosuvastatin (10 mg), and simvastatin + ezetimibe (20 mg + 10 mg) in CKD.,,,
| Triglyceride-Lowering Agents in Chronic Kidney Disease|| |
Evidence suggesting efficacy of fibric acid derivatives and niacin are very weak while adverse effects and drug tolerability are of serious concerns. The Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) on gemfibrozil showed reduction in major cardiovascular risks by 42%in patients with GFR < 75 ml/min/1.73 m2 FIELD study and Diabetes Atherosclerosis Intervention Study both reported that fenofibrate significantly reduces risk of new-onset microalbuminuria in patients with diabetes. Participation of patients with GFR <60 ml/min/1.73m2 was insufficient to generalize these findings for all CKD population., Further, no other study supported outcome of these two studies.
Few studies raised concern regarding rise in S Cr and increased rate of hospitalizations after administration of fibric acid derivatives. Hence, most of the guidelines suggest that therapeutic lifestyle modification for correcting triglyceridemia in CKD dietary modifications should be done judiciously not to aggravate malnutrition.
| Conclusion|| |
Dyslipidemia in CKD population differs from general population. Lipid subparticles at even normal levels are more atherogenic and pro-inflammatory. Treatment of dyslipidemia in CKD is challenging due to altered metabolism and clearance of lipid-lowering agents leading to enhanced risk of side effects. Management has been made easy by the guidelines proposed by KDIGO, ACC/AHA, and other societies.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.
Briasoulis A, Bakris GL. Chronic kidney disease as a coronary artery disease risk equivalent. Curr Cardiol Rep 2013;15:340.
Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al
. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet 2010;375:2073-81.
van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, et al
. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 2011;79:1341-52.
Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Inter 2013;3:259-305.
Kuznik A, Mardekian J, Tarasenko L. Evaluation of cardiovascular disease burden and therapeutic goal attainment in US adults with chronic kidney disease: An analysis of national health and nutritional examination survey data, 2001-2010. BMC Nephrol 2013;14:132.
Tonelli M, Muntner P, Lloyd A, Manns B, Klarenbach S, Pannu N, et al
. Association between LDL-C and risk of myocardial infarction in CKD. J Am Soc Nephrol 2013;24:979-86.
Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002;61:1887-93.
Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink NE, et al
. Association between cholesterol level and mortality in dialysis patients: Role of inflammation and malnutrition. JAMA 2004;291:451-9.
Vaziri ND, Liang K, Parks JS. Acquired lecithin-cholesterol acyltransferase deficiency in nephrotic syndrome. Am J Physiol Renal Physiol 2001;280:F823-8.
Vaziri ND. Molecular mechanisms of lipid disorders in nephrotic syndrome. Kidney Int 2003;63:1964-76.
Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: A meta-analysis. J Am Soc Nephrol 2006;17:2006-16.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al
. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1046-81.
Tonelli M, Muntner P, Lloyd A, Manns B, Klarenbach S, Pannu N, et al
. Impact of age on the association between CKD and the risk of future coronary events. Am J Kidney Dis 2014;64:375-82.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al
. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: An analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009;54:810-9.
Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, et al
. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-48.
Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al
. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-407.
Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al
. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): A randomised placebo-controlled trial. Lancet 2011;377:2181-92.
Fellström B, Holdaas H, Jardine AG, Holme I, Nyberg G, Fauchald P, et al
. Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Kidney Int 2004;66:1549-55.
Holdaas H, Fellström B, Jardine AG, Holme I, Nyberg G, Fauchald P, et al
. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-31.
Holdaas H, Fellström B, Cole E, Nyberg G, Olsson AG, Pedersen TR, et al
. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: The ALERT extension study. Am J Transplant 2005;5:2929-36.
Holdaas H, Fellström B, Jardine AG, Nyberg G, Grönhagen-Riska C, Madsen S, et al
. Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation. Nephrol Dial Transplant 2005;20:974-80.
Tonelli M, Collins D, Robins S, Bloomfield H, Curhan GC, Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) Investigators. Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int 2004;66:1123-30.
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al
. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005;366:1849-61.
Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G, DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: Results from the diabetes atherosclerosis intervention study (DAIS). Am J Kidney Dis 2005;45:485-93.
Zhao YY, Weir MA, Manno M, Cordy P, Gomes T, Hackam DG, et al
. New fibrate use and acute renal outcomes in elderly adults: A population-based study. Ann Intern Med 2012;156:560-9.