Overview

Chronic kidney disease (CKD), defined by at least 3 months of impaired kidney function or albuminuria, has been shown in multiple studies to be associated with an increased risk of cardiovascular disease (CVD).¹ While CKD is often the result of hypertension and diabetes, both impaired kidney function and albuminuria are CVD risk factors independent of the presence of hypertension and diabetes.

In a meta-analysis of over 1.4 million people, there was a linear increase in cardiovascular mortality seen with decreasing estimated glomerular filtration rate (eGFR) below a threshold eGFR of 75 mL/min/1.73 m², with mortality rates twice as high in stage 3 CKD (eGFR 30-59 mL/min/1.73 m²) and three times as high in stage 4 CKD (eGFR 15-29 mL/min/1.73 m²).² Patients with CKD have also been shown to have similar rates of myocardial infarction (MI) or coronary heart disease (CHD) compared to those with diabetes, which is why it is considered a CHD equivalent by many thought leaders.³

Dyslipidemia is common but not ubiquitous in CKD, based on multiple factors including eGFR, the presence of diabetes and other co-morbidities, albuminuria severity, nutritional status, and use of other medications.³ Even though patients with CKD should be considered as part of the highest risk group for CVD, these patients are often underdiagnosed and undertreated with cholesterol lowering agents.⁴ Part of the issue may be the lack of management guidelines for dyslipidemia in CKD patients from national and international groups, including the American College of Cardiology/American Heart Association (ACC/AHA).

With the recent publication of multiple randomized controlled trials of statin therapy in CKD patients, the Kidney Disease: Improving Global Outcomes (KDIGO) organization updated their clinical practice guidelines in 2013 to summarize evidence and recommend lipid management for all forms of CKD.³ This set of 13 recommendations, spearheaded by prominent nephrologists, lipid specialists, and epidemiologists, abandons lipid targets and focuses more on risk assessment, driven mainly by age and eGFR.

Initial Lipid Assessment and Follow Up Measurements

In all adults with newly diagnosed CKD, KDIGO recommends baseline evaluation with a lipid profile including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. This is not only to help guide initiation of statin treatment in CKD patients under the age of 50 years, but also to provide information on secondary causes of dyslipidemia such as nephrotic syndrome and to identify hypertriglyceridemia, a common lipid abnormality in CKD patients.

Specialist involvement is suggested for patients with fasting triglyceride levels >1000 mg/dL or LDL-C levels >190 mg/dL. The KDIGO committee, however, does not recommend follow-up measurement of lipid levels except in special cases in which management would be affected. For example, a lipid profile every year or two in a CKD patient under the age of 50 years who is not currently on statin therapy would help to risk stratify this patient and determine when statin therapy should be initiated.

Pharmacotherapy and Dosing of Statins in Adults With CKD

Similar to the ACC/AHA guidelines, the KDIGO committee does not use specific LDL-C targets and focuses on statin therapy for managing dyslipidemia. They recommend that all adults ≥50 years with CKD, with the exception of those on chronic dialysis, be treated with a statin. In this same age group, in more advanced stages of CKD (Stage 3-5, eGFR <60 mL/min/1.73 m²), treatment with combination statin plus ezetimibe is recommended.³

The evidence behind these recommendations is partly based on the Alberta cohort of over one million people followed for more than 4 years, examining the rates of coronary death or nonfatal MI. Regardless of CKD stage ranging from Stage 1 to 4, the risk of coronary death or nonfatal MI in adults over the age of 50 was >10% over 10 years.⁵

The recommendation for a statin/ezetimibe combination comes from the Study of Heart and Renal Protection, or SHARP trial.6 This study randomized 9270 patients >40 years old with CKD to simvastatin 20 mg plus ezetimibe 10 mg daily regardless of baseline LDL-C levels. Patients were eligible if they had more than one creatinine measurement of ≥1.7 mg/dL in men or ≥1.5 mg/dL in women. The primary outcome of combined MI, coronary death, stroke, or arterial revascularization was reduced by 17% (95% CI 6-26%, p=0.0021) in the treatment group with a 32% mean reduction in LDL-C levels. This came at the expense of a minor excess risk of myopathy (0.2% in the treatment group vs. 0.1% in the placebo group), without any increased risk of hepatitis, gallstones, or excess death from non-vascular causes.⁶

In adults aged 18-49 years with CKD but not treated with chronic dialysis, the KDIGO group suggests statin treatment only for people with one of the following: 1) known coronary disease (MI or coronary revascularization), 2) diabetes mellitus, 3) prior ischemic stroke, or 4) estimated 10-year incidence of coronary death or nonfatal myocardial infarction of ≥10% based on the Framingham risk score used in the Adult Treatment Panel III Guidelines. However, predicting individual risk in this age group with a risk estimator is difficult because risk estimators are generally not validated in adults <40 years and often underestimate risk in CKD.^7,8

People with CKD are at higher risk of side effects from lipid medications due to reduced renal excretion, polypharmacy, and multiple co-morbidities.^1,3 Given the risk of toxicity with high-dose statins, KDIGO recommends statin dosing based on regimens that have been studied and shown to be beneficial in randomized trials done specifically in patients with eGFR <60 mL/min/1.73 m². This includes moderate-intensity statins such as daily atorvastatin 20 mg, rosuvastatin 10 mg, simvastatin 40 mg, pravastatin 40 mg, fluvastatin 80 mg, or pitavastatin 2 mg.³

Fibrates should be avoided in combination with statins in patients with CKD, and ezetimibe monotherapy is not recommended. Since drug toxicity is less of a concern with better renal excretion, those with Stage 1 or 2 CKD (eGFR >60 mL/min/1.73 m²) can be treated in the same way as the general population. Baseline transaminase levels should be measured in all CKD patients prior to starting statin therapy, though routine transaminase for CK levels is not recommended in the absence of clinical evidence of hepatotoxicity or myopathy.

Other lipid guidelines have some similarities to KDIGO, but differ on their approach to treating CKD patients. The National Lipid Association (NLA) 2015 guidelines recommend a step-wise approach to risk management, first identifying the highest ASCVD risk category then treating to specific non-HDL-C and LDL-C goals based on the risk category. Per the NLA approach, all patients with stage 3B (eGFR 30-44 mL/min/1.73 m²) or stage 4 CKD are considered high risk and would be treated to a goal non-HDL-C <130 mg/dL and LDL-C <100 mg/dL.⁸

While the NLA includes those with CKD as high risk for ASCVD, the ACC/AHA 2013 guidelines do not specifically address CKD.⁹ The ACC/AHA 2013 guidelines use a risk based approach for individuals without clinical atherosclerotic cardiovascular disease (ASCVD), LDL ≥190 mg/dL, or diabetes. This approach uses the Pooled Cohort Equations 10-year risk score to guide clinician-patient risk discussions and the potential role of statin therapy. Moderate- to high-intensity statin treatment is to be considered if 10-year risk ≥7.5% in those aged 40-75 years with LDL-C 70 to 189 mg/dL ("statin benefit group"). Even though the approach is different than KDIGO, in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, there was 92% agreement for when to initiate statin therapy between KDIGO and ACC/AHA for adults 50-79 years old with CKD (eGFR <60 mL/min/1.73 m² or albuminuria >30 mg/g and not on dialysis).4 In the 8% of patients who did not meet the ACC/AHA statin benefit group criteria, the incidence rate of CVD was low at 3/1000 person-years.

Special Populations

In adults with dialysis-dependent CKD, KDIGO recommends avoiding initiation of statins or statin/ezetimibe combinations. However, there is no recommendation to stop therapy in dialysis patients who are already receiving statins or statin/ezetimibe combinations.³ These recommendations are based on several trials including 4D (Die Deutsche Diabetes Dialyse), AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis), and sub-group analysis of SHARP.^6,10,11

In all three trials looking at treating hemodialysis patients with statins or statin plus ezetimibe versus placebo, the primary outcome of CVD death, MI, or stroke was not different between the treatment and placebo arms. When taken together, despite the high CVD risk of dialysis patients, there seems to be at best an uncertain benefit of statins in this population, likely due to high competing risk. The NLA and ACC/AHA guidelines do not have specific treatment goals for patients on dialysis because of the lack of clear evidence supporting statin therapy.^8,9

As the only guideline to address kidney transplant, KDIGO recommends treating all adult kidney transplant recipients with a statin, regardless of age. This recommendation is based mainly on the ALERT (Assessment of Lescol in Renal Transplantation) trial, which randomized 2102 renal transplant patients aged 30-75 with baseline total cholesterol 156– 51 mg/dL to fluvastatin 40 mg/day or placebo.¹² After 2 years, fluvastatin was increased to 80 mg/day based on the recommendation of the data safety and monitoring board and patients were followed for a mean of 5 years. While the primary endpoint of cardiac death, non-fatal MI, and coronary intervention was not significantly different between the two groups, fluvastatin reduced the risk of cardiac death by 38% (p=0.031).

Additional support for treating all kidney transplant patients with statins comes from the high rates of CVD death or MI (21.5 per 1000 patient-years) seen in ALERT.¹² While patients <30 years were not included in the trial, they are included in the KDIGO recommendations, though the committee suggests allowing younger transplant patients to opt out of treatment in the absence of traditional CVD risk factors.

Conclusions

People with CKD have a substantially increased risk of CVD, and lipid assessment and treatment is an important aspect of their care. While there is a clear benefit of statin treatment in stage 1-4 CKD and kidney transplant, there does not appear to be a benefit to treating people on chronic dialysis, likely due to excessive competing risk.

Table 1: Comparison of Guidelines Recommendations for Lipid Management Among Patients with CKD, on Dialysis, or Renal Transplant Recipients

Guideline	Population	CKD Stage*	Treatment Recommendations
KDIGO	Adults ≥ 50 y	1-2	Statin
		3-5 (not on HD)	Statin plus Ezetimibe; Statin
	Adults 18 – 49 y + ≥1 of the following: Known coronary disease (MI or coronary revascularization) Diabetes mellitus Prior ischemic stroke Estimated 10-y incidence of coronary death or non-fatal MI >10%	1-5 (not on HD)	Statin
	Adults with dialysis-dependent CKD	5 (HD or PD)	Statins or statin combinations should NOT be initiated; can be continued if already receiving at the time of dialysis initiation
	Adult kidney transplant recipient	1-5	Statin
ACC/AHA 2013	Adults with clinical ASCVD	1-5 (not on HD)	High-intensity statin preferred; moderate-intensity statin if not a candidate for high-intensity
	Adults with LDL ≥190 mg/dL	1-5 (not on HD)	High-intensity statin preferred; moderate-intensity statin if not a candidate for high-intensity
	Adults 40-75 y with diabetes and LDL 70-189 mg/dL (no ASCVD)	1-5 (not on HD)	High-intensity statin if estimated 10-y ASCVD risk ≥7.5%; moderate-intensity statin if not a candidate for high-intensity
	Adults 40-75 y with estimated 10-y ASCVD risk ≥7.5% (no diabetes, ASCVD)	1-5 (not on HD)	Moderate- or high-intensity statin
	Adults with dialysis-dependent CKD	5 (HD or PD)	No recommendation
NLA	Adults with advanced CKD	3B or 4	Treat to goal Non-HDL <130 mg/dL and LDL <100 mg/dL
	Adults with ASCVD or Diabetes mellitus ł	1-4	Moderate- or high- intensity statin to goal Non-HDL <100 mg/dL and LDL <70 mg/dL
	Adults with 0-1 major ASCVD risk factors ‡	1-3A	Consider starting drug therapy for Non-HDL ≥ 190 mg/dL or LDL ≥ 160 mg/dL. Treat to goal Non-HDL <130 mg/dL and LDL <100 mg/dL
	Adults with 2 major ASCVD risk factors	1-3A	Consider starting drug therapy for Non-HDL ≥ 160 mg/dL or LDL ≥ 130 mg/dL. Treat to goal Non-HDL <130 mg/dL and LDL <100 mg/dL
	Adults with ≥3 major ASCVD risk factors	1-3A	Consider starting drug therapy for Non-HDL ≥ 130 mg/dL or LDL ≥ 100 mg/dL. Treat to goal Non-HDL <130 mg/dL and LDL <100 mg/dL
	Adults with Stage 5 CKD or on HD	5	No recommendation

References

1. Harper CR, Jacobson TA. Managing dyslipidemia in chronic kidney disease. J Am Coll Cardiol 2008;51:2375-84.
2. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382:339-52.
3. 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.
4. Colantonio LD, Baber U, Banach M, et al. Contrasting cholesterol management guidelines for adults with CKD. J Am Soc Nephrol 2015;26:1173-80.
5. Tonelli M, Muntner P, Lloyd A, 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.
6. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and eenal protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92.
7. Sarnak MJ, Bloom R, Muntner P, et al. KDOQI US commentary on the 2013 KDIGO Clinical Practice Guideline for Lipid Management in CKD. Am J Kidney Dis 2015;65:354-66.
8. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol 2015;9:129-69.
9. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
10. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-48.
11. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-407.
12. Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-31.

Keywords: Albuminuria, Blood Pressure, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Creatinine, Diabetes Mellitus, Drug-Related Side Effects and Adverse Reactions, Dyslipidemias, Fatty Acids, Monounsaturated, Fibric Acids, Gallstones, Glomerular Filtration Rate, Hepatitis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Hypertriglyceridemia, Indoles, Kidney Transplantation, Lipoproteins, HDL, Muscular Diseases, Myocardial Infarction, Nephrotic Syndrome, Nutritional Status, Polypharmacy, Pravastatin, Quinolines, Randomized Controlled Trials as Topic, Renal Dialysis, Renal Insufficiency, Chronic, Risk Assessment, Risk Management, Risk Factors, Simvastatin, Smoking, Stroke, Transaminases, Triglycerides

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