SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

The incidence of cardiovascular disease (CVD) is very high in patients with chronic kidney (CKD) disease and in kidney transplant recipients. Indeed, available evidence for these patients suggests that the 10-year cumulative risk of coronary heart disease is at least 20%, or roughly equivalent to the risk seen in patients with previous CVD. Recently, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) published guidelines for the diagnosis and treatment of dyslipidemias in patients with CKD, including transplant patients. It was the conclusion of this Work Group that the National Cholesterol Education Program Guidelines are generally applicable to patients with CKD, but that there are significant differences in the approach and treatment of dyslipidemias in patients with CKD compared with the general population. In the present document we present the guidelines generated by this workgroup as they apply to kidney transplant recipients. Evidence from the general population indicates that treatment of dyslipidemias reduces CVD, and evidence in kidney transplant patients suggests that judicious treatment can be safe and effective in improving dyslipidemias. Dyslipidemias are very common in CKD and in transplant patients. However, until recently there have been no adequately powered, randomized, controlled trials examining the effects of dyslipidemia treatment on CVD in patients with CKD. Since completion of the K/DOQI guidelines on dyslipidemia in CKD, the results of the Assessment of Lescol in Renal Transplantation (ALERT) Study have been presented and published. Based on information from randomized trials conducted in the general population and the single study conducted in kidney transplant patients, these guidelines, which are a modified version of the K/DOQI dyslipidemia guidelines, were developed to aid clinicians in the management of dyslipidemias in kidney transplant patients. These guidelines are divided into four sections. The first section (Introduction) provides the rationale for the guidelines, and describes the target population, scope, intended users, and methods. The second section presents guidelines on the assessment of dyslipidemias (guidelines 1–3), while the third section offers guidelines for the treatment of dyslipidemias (guidelines 4–5). The key guideline statements are supported mainly by data from studies in the general population, but there is an urgent need for additional studies in CKD and in transplant patients. Therefore, the last section outlines recommendations for research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

The rationale for these guidelines

These guidelines are the result of an ongoing effort by the National Kidney Foundation (NKF) to provide guidance to practitioners and investigators on the management of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and in kidney transplant recipients. This process was initiated by the formation of a NKF Task Force on CVD (Figure 1). This Task Force concluded that the incidence of atherosclerotic cardiovascular disease (ACVD) is higher in patients with CKD compared with the general population (1), and that patients with CKD and kidney transplant recipients should be considered to be in the highest risk category, i.e. a coronary heart disease (CHD) risk equivalent, for risk factor management. In response to recommendations of the NKF Task Force on CVD, the NKF Kidney Disease Outcomes Quality Initiative (K/DOQI) convened a Work Group to develop guidelines for the management of dyslipidemias, one of the risk factors for CHD in CKD. The Work Group first met on 27 November 2000. The general guidelines for the management of dyslipidemias in all patients with CKD have recently been published (2). What follows is a summary of the particular dyslipidemia guidelines that apply to kidney transplant recipients.

image

Figure 1. The evolution of National Kidney Foundation guidelines for the management of dyslipidemias in patients with chronic kidney disease.

Download figure to PowerPoint

During the development of the dyslipidemia guidelines, the NKF K/DOQI also completed guidelines on CKD (3). These CKD guidelines defined CKD, reiterated that CKD should be considered a CHD risk equivalent, and that risk factors should be managed accordingly (Figure 1).

In the CKD guidelines, the following CKD stages were based on measured or estimated glomerular filtration rate (GFR) (Table 1). The NKF Task Force on CKD recognized that some kidney transplant patients who have normal kidney function (GFR ≥ 90 mL/min/1.73 m2) may not have CKD according to the K/DOQI Guidelines defining CKD. Similarly, some transplant patients with GFR ≥ 60 mL/min/1.73 m2 may not fit the K/DOQI definition of CKD, because they do not have evidence of kidney damage, i.e. they may have normal urine protein excretion, urine sediment, histology, and radiographic imaging. However, the CKD guidelines and the dyslipidemia guidelines consider such patients to be at increased risk for CKD. As such, the Work Group decided to assume that all kidney transplant recipients have CKD, or are at increased risk for CKD, and to include kidney transplant recipients in the target population (4). However, once the transplanted patient develops abnormal proteinuria and/or their GFR falls below 60 mL/min/1.73 m2 they should be classified as having CKD and staged as per Table 1.

Table 1.  Stages of chronic kidney disease
StageDescriptionGFR (mL/min/1.73 m2)
  1. From the Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. GFR, glomerular filtration rate.

1Kidney damage with normal or [UPWARDS ARROW] GFR≥90
2Kidney damage with mild [DOWNWARDS ARROW] GFR60–89
3Moderate [DOWNWARDS ARROW] GFR30–59
4Severe [DOWNWARDS ARROW] GFR15–29
5Kidney failure<15 or dialysis

The number of patients with CKD, including kidney transplant recipients, is increasing. Unfortunately, the survival of CKD patients and kidney transplant recipients remains poor (5). This is, in large part, due to premature CVD that manifests itself as coronary heart disease, cerebrovascular disease, and/or peripheral vascular disease (Table 2). There are two major overlapping categories of CVD: (i) disorders of cardiovascular perfusion, which include ACVD; and (ii) disorders of cardiac function, such as heart failure and left ventricular hypertrophy. Some risk factors are unique to each category of CVD, and some risk factors are shared by both categories of CVD.

Table 2.  Definitions of some terms used in these guidelines
TermDefinition
Chronic kidney disease (CKD)At least 3 months of either: 1) structural or functional abnormalities of the kidney that can
 lead to kidney failure; or 2) GFR <60 mL/min/1.73 m2
Cardiovascular Disease (CVD)Coronary heart disease, cerebrovascular disease, renal artery stenosis, peripheral
 vascular disease, congestive heart failure, or left ventricular hypertrophy
Atherosclerotic cardiovascularCoronary heart disease, cerebrovascular disease, renal artery stenosis, disease
disease (ACVD)or peripheral vascular disease
Coronary heart disease (CHD)Atherosclerotic disease of the coronary arteries that causes myocardial
 ischemia
Cerebrovascular diseaseAtherosclerotic disease of the cerebral arteries that causes strokes and transient ischemic attacks
Peripheral vascular diseaseAtherosclerotic disease of arteries that causes ischemia of the extremities
DyslipidemiaAny abnormality in plasma lipoprotein concentration or composition that is associated with
 an increased risk for atherosclerotic cardiovascular disease
Lipid profilePlasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density
 lipoprotein cholesterol and triglycerides
AdultsIndividuals ≥18 years old
AdolescentsIndividuals <18 years old, but after the onset of puberty
GFRglomerular filtration rate.

Of the traditional risk factors for ACVD in kidney transplant patients, dyslipidemias may play a major role. In developing these guidelines, the Work Group was greatly aided by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, the Adult Treatment Panel III (ATP III) (4), and the National Cholesterol Expert Panel on Children (NCEP-C) (6). The definitions of dyslipidemias adopted by the Work Group were those of ATP III (Table 3). In the end, the major task of the Work Group was to decide how the ATP III and NCEP-C guidelines should be applied to kidney transplant patients.

Table 3.  Dyslipidemias as defined in the Adult Treatment Panel III Guidelines (4).
DyslipidemiaLevel (mg/dL)
  1. LDL, low-density lipoprotein; HDL, high-density lipoprotein. To convert mg/dL to mmol/L, multiply triglycerides by 0.01129 and cholesterol by 0.02586.

Total cholesterol
 Desirable<200
 Borderline high200–239
 High≥240
LDL cholesterol
 Optimal<100
 Near optimal100–129
 Borderline130–159
 High160–189
 Very high≥190
Triglycerides
 Normal<150
 Borderline high150–199
 High200–499
 Very high≥500
HDL cholesterol
 Low<40

There is evidence from observational studies that, in addition to dyslipidemias, some ‘nontraditional’ risk factors such as calcium, phosphorus, parathyroid hormone, (7,8) homocysteine, (9–16) and systemic inflammation (17–21) may also play a role in the pathogenesis of CVD in patients with CKD. However, unlike dyslipidemias, there are no intervention trials from patients in the general population (or the CKD population) demonstrating that the modification of these nontraditional risk factors reduces CVD. Therefore, these guidelines focus on the assessment and treatment of dyslipidemias in kidney transplant recipients. Since the publication of the general CKD dyslipidemias guidelines, a randomized, prospective, controlled trial on the effects of dyslipidemia management in transplant patients has been completed in Europe and in Canada (ALERT) (22). In the ALERT trial, the primary endpoint (cardiac death, nonfatal myocardial infarction, or coronary revascularization) was not significantly different between statin treatment and placebo. However, there were significant differences between the treatment and control groups in cardiac death and nonfatal myocardial infarction. In addition, the proportional reduction in cardiac events in ALERT was similar to that seen in statin trials in the general population. Nevertheless, questions remain about the safety and efficacy of lipid-modifying drugs in kidney transplant patients compared with the general population. These questions are based on the unique features of transplant patients, such as the use of immunosuppressive medications, which may not only contribute to the risk of ACVD after transplantation but also modify the metabolism of lipid-lowering drugs. Therefore, the Work Group concluded that additional, randomized, trials are still needed in transplant patients (see Research recommendations).

Target population

These guidelines will address exclusively the management of dyslipidemias in kidney transplant recipients. The general dyslipidemia guidelines included all patients with Stage 5 CKD, and all kidney transplant recipients (2).

Some kidney transplant patients may not meet the definition of CKD either because they have normal kidney function (GFR ≥ 90 mL/min/1.73 m2) and because they do not have evidence of kidney damage. However, the CKD guidelines and the dyslipidemia guidelines consider such patients to be at increased risk for CKD. Consequently, the Work Group decided to assume that all kidney transplant recipients have CKD, or are at increased risk for CKD, and to include kidney transplant recipients in the target population. Furthermore, the inclusion of transplanted patients in these guidelines was deemed to be a useful opportunity to emphasize several features of the diagnosis and management of these patients that may differ from that of the general population (4). The Work Group considered that the recently updated guidelines of the ATP III (3) were generally applicable to kidney transplant patients, except for:

  • • 
    classifying transplantion as a CHD risk equivalent;
  • • 
    considering complications of lipid-lowering therapies that may result from reduced kidney function;
  • • 
    considering complications of lipid-lowering therapies that may result from the concomitant use of immusuppressive mediations;
  • • 
    considering whether in kidney transplant recipients there might be indications for the treatment of dyslipidemias other than preventing ACVD;
  • • 
    determining whether the treatment of proteinuria might also be an effective treatment for dyslipidemias.

Finally, the Work Group considered whether to include children and adolescents in these guidelines (Figure 2). Although the ATP III covers only individuals ≥20 years (3), it was concluded that CKD individuals 18–20 years should also be included and considered as adults. Much has changed in the decade since the report of the NCEP-C (6). However, there are still very few studies of dyslipidemias in children and adolescents, either in the general population or in CKD. In the end, it was concluded that adolescents (defined by the onset of puberty) with a kidney transplant, should be included in these guidelines. Children (before the onset of puberty) should be managed according to existing guidelines, such as the NCEP-C (6).

image

Figure 2. Ages covered by the current guidelines, and those covered by previous guidelines developed for use in the general population.

Download figure to PowerPoint

Scope

The Work Group also considered the recommendations of the NKF Task Force on CVD concerning the management of risk factors other than dyslipidemias (1). There are two potential reasons to assess other risk factors for ACVD: (i) to categorize overall risk for the purpose of making decisions regarding the management of dyslipidemia; and (ii) to identify modifiable risk factors other than dyslipidemia that should also be treated. The first reason was considered unnecessary (for the purpose of these guidelines) by accepting the recommendation that a kidney transplant patient should be considered to have a CHD risk equivalent when deciding the appropriate management of dyslipidemia. However, the Work Group acknowledged that other risk factors are also important in the pathogenesis of ACVD and should be treated. Therefore, the Work Group concluded that for kidney transplant patients:

  • • 
    dyslipidemia management should be undertaken in conjunction with all other available measures to reduce the overall risk of ACVD;
  • • 
    modifiable, conventional risk factors (including hypertension, cigarette smoking, glucose intolerance or diabetes control, and obesity) should be assessed at initial presentation and at least yearly thereafter;
  • • 
    modifiable risk factors should be managed according to existing guidelines (Table 4), including, but not limited to:
Table 4.  Some government-sponsored web sites with information useful in risk factor management.
Risk factorWebsite address
  • *

    National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III. All web addresses as of 30 October 2002.

Diethttp://www.nutrition.gov
Body weighthttp://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm(click on Healthy Weight)
Exercisehttp://www.fitness.gov
Cholesterol*http://www.nhlbi.nih.gov/guidelines/cholesterol
Blood pressurehttp://www.nhlbi.nih.gov/guidelines/hypertension/index.htm
Hormone replacementhttp://www.nhlbi.nih.gov/health/women/index.htm
Smokinghttp://www.cdc.gov/tobacco/sgr/index.htm
  •  — 
    the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (23)
  •  — 
    the American Diabetes Association Clinical Practice Recommendations (24)
  •  — 
    Hormone Replacement Therapy and Cardiovascular Disease: A Statement for Health-Care Professionals from the American Heart Association (25)
  •  — 
    aspirin for the primary prevention of cardiovascular events (26)
  •  — 
    a statement for health-care professionals from the Nutrition Committee of the American Heart Association (27)
  •  — 
    Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, MD: National Heart, Lung and Blood Institute, 1998, http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm
  •  — 
    the American Heart Association/American College of Cardiology Guidelines for Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease (28)
  •  — 
    Primary Prevention of Ischemic Stroke: a Statement for Health-Care Professionals from the Stroke Council of the American Heart Association (29)
  •  — 
    A Clinical Practice Guideline for Treating Tobacco Use and Dependence: A US Public Health Service Report (30).

The task of the Work Group was greatly facilitated by the ATP III, (4) and the NCEP-C for children and adolescents (6). However, the ATP III and NCEP-C make few specific recommendations for the evaluation and treatment of dyslipidemias in CKD and in kidney transplant patients, and none of the guideline statements includes or excludes these patients. The ATP III notes that nephrotic syndrome is a cause of secondary dyslipidemia, and suggests that consideration be given to the use of cholesterol-lowering drugs if hyperlipidemia persists despite specific treatment for kidney disease. The ATP III also notes that various dyslipidemias have been reported in persons with kidney failure. However, it suggests that a cautious approach be taken, since these persons are prone to drug side-effects, e.g. they are at increased risk for myopathy from both fibrates and statins. In fact, the ATP III suggests that chronic kidney failure is a contraindication to fibrates.

The Work Group concluded that, in most areas, the ATP III and NCEP-C were applicable to adults and adolescents, respectively. It considered that defining areas where the ATP III and NCEP-C needed modification and refinement for patients with CKD, including kidney transplant recipients, to be its principal task. In the end, relatively few modifications were needed (Table 5).12

Table 5.  Key features of the NKF-K/DOQI Guidelines that differ from those of the National Cholesterol Education Program Adult Treatment Panel III and the Expert Panel on Children
Adult Treatment Panel III GuidelinesNKF-K/DOQI Guidelines
CKD and kidney transplant patients are not managedCKD and kidney transplant patients should be considered
differently from other patientsto be in the highest risk category
Evaluation of dyslipidemias should occur every 5 yearsEvaluation of dyslipidemias should occur at presentation, after a change in status, and annually
Drug therapy is considered optional for LDLDrug therapy should be used for LDL 100–129 mg/dL after
100–129 mg/dL3 months of TLC
Initial drug therapy for high LDL should be with a statin,Initial drug therapy for high LDL should be with a statin
bile acid sequestrant, or nicotinic acid
No recommendations are made for patients <20 years oldRecommendations are made for patients <20 years old
Fibrates are contraindicated in Stage 5 CKDFibrates may be used in Stage 5 CKD
 a) for patients with triglycerides ≥500 mg/dL; and b) for
 patients with triglycerides ≥200 mg/dL with non-HDL
 cholesterol ≥130 mg/dL, who do not tolerate statins
No preferences are indicated for which a fibrate shouldGemfibrozil may be the fibrate of choice for treatment of
be used to treat hypertriglyceridemiahigh triglycerides in patients with CKD and kidney
 transplant patients
Expert Panel on Children
  1. To convert mg/dL to mmol/L, multiply triglycerides by 0.01129 and cholesterol by 0.02586. *Currently, atorvastatin is the only statin approved by the US Food and Drug administration for use in children. NKF-K/DOQI, National Kidney Foundation Kidney Disease Outcomes Quality Initiative; CKD, chronic kidney disease; AHA, American Heart Association; LDL, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle changes; CVD, cardiovascular disease.

Adolescents with CKD are not managed differently fromAdolescents with CKD or kidney transplants should be
other patientsconsidered to be in the highest risk category
Evaluation of dyslipidemias should occur every 5 yearsEvaluation of dyslipidemias in adolescents with kidney
 transplants should occur at presentation, after a change
 in kidney status, and annually
If LDL >130 mg/dL, start TLC Step I AHA diet, followedIf LDL is 130–159 mg/dL, start TLC diet (if nutritional
in 3 months by Step II AHA diet if LDL >130 mg/dLstatus is adequate), followed in 6 months by a statin* if
 LDL ≥130 mg/dL
If LDL ≥160 mg/dL and family history of CHD or two If LDL ≥160 mg/dL, start TLC plus a statin
or more CVD risk factors, start drug therapy 

Intended users

These guidelines are intended for use by physicians, transplant coordinators, nurses, nurse practitioners, pharmacists, dietitians, and other healthcare professionals who care for kidney transplant recipients. The information contained in these guidelines can and should be conveyed to patients and their families in an understandable manner by their physician and/or other healthcare professionals. The development of educational support materials designed specifically for patients and their families should be part of the implementation of these guidelines.

Anticipated updates

All guidelines should be updated whenever new, pertinent information becomes available. To anticipate when these guidelines may need to be updated, the Work Group discussed ongoing clinical trials in the general population and in patients with CKD, as those results may be pertinent to some recommendations. Late in the course of development of these guidelines, the results of the Heart Protection Study were published (31). This study randomly allocated 20 536 adults with coronary artery disease (CAD) to 40 mg simvastatin vs. matching placebo. Patients treated with simvastatin had an 18% reduction in coronary deaths. Importantly, the reduction in mortality was seen irrespective of the baseline level of cholesterol. This raised the possibility that all patients with known CAD should be treated with a statin, regardless of the serum cholesterol level. Ultimately, these and other results from ongoing trials could conceivably change the recommended approach to treatment of dyslipidemias. Some other important ongoing trials in patients from the general population include:

  • • 
    Study Evaluating Additional Reductions in Cholesterol and Homocysteine (SEARCH) (32)
  • • 
    Treating to New Targets (TNT) (33)
  • • 
    Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) (34)
  • • 
    Aggressive Lipid Lowering Initiation Abates New Cardiac Events (ALLIANCE) (35)
  • • 
    Pravastatin or Atorvastatin in Evaluation and Infection Therapy (PROVE IT) (36)
  • • 
    Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) (37)
  • • 
    Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) (38)
  • • 
    Collaborative Atorvastatin Diabetes Study (CARDS) (34, 38)
  • • 
    Atorvastatin as Prevention of Coronary Heart Disease Endpoints in Patients with Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (34)
  • • 
    Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) (34)
  • • 
    Action to Control Cardiovascular Risk in Diabetes (ACCORD)

Some important, ongoing trials being conducted in patients with CKD include:

  • • 
    Die Deutsche Diabetes Dialyse Studie (4D) (39)
  • • 
    Prevention of REnal and Vascular ENdstage Disease Intervention Trial (PREVEND IT) (40)
  • • 
    The Study of Heart and Renal Protection (SHARP).

Thus, a number of potentially important trials will be completed within the next 3–5 years. Given the potential for these and other studies to provide information pertinent to the assessment and treatment of dyslipidemias in patients with CKD, it was concluded that these guidelines should be updated in about 3 years from the time of publication, and sooner if new pertinent information becomes available before then. The Work Group will monitor the progress of these trials and recommend updating these guidelines as indicated.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

Guideline development

These guidelines were developed using four basic principles set forth by the K/DOQI:

  • 1) 
    The guidelines were developed using a scientifically rigorous process, and the rationale and evidentiary basis for each guideline is clearly explained.
  • 2) 
    A multidisciplinary Work Group, with expertise in the management of kidney transplant patients, CKD, dyslipidemias, and ACVD developed the guidelines.
  • 3) 
    The Work Group members worked independently from any organizational affiliations and had final responsibility for determining guideline content.
  • 4) 
    The guidelines underwent widespread critical review before being finalized.

The guidelines were developed using an evidence-based approach similar to that endorsed by the Agency for Health-Care Research and Quality. The Work Group reviewed all pertinent, published evidence, and critically appraised the quality of studies and the overall strength of evidence supporting each recommendation. Details of the methods used to evaluate the evidence is in Appendix 1 of the complete guidelines. (2).

Rating the strength of guidelines and evidence

The overall strength of each guideline statement was rated by assigning either ‘A’, ‘B’, or ‘C’ (defined in Table 6). The strength of evidence was assessed using a rating system that takes into account (i) methodological quality of the studies; (ii) whether or not the study was carried out in the target population, i.e. kidney transplant patients, or in other populations; and (iii) whether the studies examined health outcomes directly, or examined surrogate measures for those outcomes, e.g. improving dyslipidemia rather than reducing CVD (Table 7). These three separate study characteristics were combined in rating the strength of evidence provided by pertinent studies.

Table 6.  Rating the Strength of Recommendations
GradeRecommendation
  1. Health outcomes are health-related events, conditions, or symptoms that can be perceived by individuals to have an important effect on their lives. Improving net health outcomes implies that benefits outweigh any adverse effects.

AIt is strongly recommended that clinicians routinely follow the guideline for eligible patients. There is strong
 evidence that the practice improves net health outcomes.
BIt is recommended that clinicians routinely follow the guideline for eligible patients. There is moderate evidence
 that the practice improves net health outcomes.
CIt is recommended that clinicians consider following the guideline for eligible patients. This recommendation is
 based on either weak evidence, poor evidence or on the opinions of the Work Group and reviewers that the practice
 may improve net health outcomes.
Table 7.  Rating the strength of evidence
  Methodological quality
Outcome (s)PopulationWell designed and analyzed (little, if any, potential bias)Some problems in design and/or analysis (some potential bias)Poorly designed and/or analyzed (large potential bias)
  • Strong: aEvidence includes results from well-designed, well-conducted study/studies in the target population that directly assess effects on net health outcomes. Moderate:

  • b

    Evidence is sufficient to determine effects on net health outcomes in the target population, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; or

  • c

    evidence is from a population other than the target population, but from well-designed, well-conducted studies; or

  • d

    evidence is from studies with some problems in design and/or analysis; or

  • e

    evidence is from well-designed, well-conducted studies on surrogate endpoints for efficacy and/or safety in the target population. Weak:

  • f

    Evidence is insufficient to assess the effects on net health outcomes because it is from studies with some problems in design and/or analysis on surrogate endpoints for efficacy and/or safety in the target population; or

  • g

    the evidence is only for surrogate measures in a population other than the target population; or

  • h

    the evidence is from studies that are poorly designed and/or analyzed.

Health outcome (s)Target populationStrongaModeratebWeakh
Health outcome (s)Other than the targetModeratecModeratedWeakh
 population   
Surrogate measureTarget populationModerateeWeakfWeakh
for health outcome (s)
Surrogate measureOther than the targetWeakgWeakgWeakg,h
for health outcome (s)population   

Literature retrieval and review

The Work Group collaborated with a professional Evidence Review Team to identify and summarize pertinent literature. The Work Group and the Evidence Review Team first identified the topics to be searched, and the Evidence Review Team conducted the literature search. The topics that were selected for search included the incidence or prevalence of dyslipidemia, the association of dyslipidemia with ACVD, and the treatment of dyslipidemia in kidney transplant patients. In addition, literature on adverse effects of dyslipidemia treatment, the effects of dyslipidemia treatment on kidney disease progression, and the effects of therapies that reduce proteinuria on dyslipidemias was retrieved and reviewed.

Briefly, the literature search included only full, peer-reviewed, journal articles of original data. Review articles, editorials, letters, case studies, and abstracts were excluded. Studies were identified primarily through MedLine searches of the English language literature up to May 2001. Studies published between May 2001 and November 2002 that were identified through means other than the systematic literature searches were included if appropriate.

Separate search strategies were developed for each topic. The text words or MeSH headings for all topics included kidney or kidney diseases, hemodialysis, peritoneal dialysis, or kidney transplant. The searches were limited to human studies, but included both adult and pediatric populations. Potential articles for retrieval were identified from printed abstracts and titles, based on study population, relevance to the topic, and document type. These were screened by clinicians on the Evidence Review Team. Overall, 10 363 abstracts were screened, 642 articles were retrieved, and 258 articles were subjected to structured review by members of the Work Group. Although systematic manual searches were not conducted, members of the Work Group supplied a number of articles that were not located by the MedLine searches.

Work Group members used forms that were developed by the Evidence Review Team to extract information from each article that was reviewed. The Evidence Review Team used the information from these forms to construct the evidence tables. The Evidence Review Team then used the evidence tables to construct the summary tables that are included with the guidelines in this report. The summary tables describe the information in the evidence tables according to four study dimensions: size, applicability, results, and methodological quality.

The study (sample) size was used as a measure of the weight of the evidence. In general, large studies provide more precise estimates of prevalence and associations. Applicability (generalizability or external validity) addresses the issue of whether the study population is sufficiently broad so that the results can be generalized to the population of interest. The applicability of each article was determined using a three-level scale: (i) the study sample is representative of the target population; (ii) the sample is representative of a relevant subgroup; or (iii) the sample is representative of a narrow subgroup of patients.

Methodological quality (internal validity) refers to the design, conduct, and reporting of the clinical study. Because studies with a variety of designs were evaluated, a broad classification system to rate the quality of individual studies was used: (i) least bias, most valid, i.e. a study that meets most generally accepted criteria for high quality; (ii) susceptible to some bias, but not sufficient to invalidate the results; and (iii) significant bias that may invalidate the results.

Guidelines, evidence, and research recommendations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

The key guideline statements in this document were graded ‘B’ or ‘C’. Some would argue that no guideline statements should be made in the absence of evidence from randomized trials in patients with CKD (yielding level ‘A’ recommendations). However, it was decided that when the strength of evidence for treatment efficacy was strong (based on trials in the general population) this evidence might be reasonably extrapolated to kidney transplant patients (Figure 3). Specifically, it was assumed that similar treatment efficacy to that reported in the general population would be found if the trials were carried out in kidney transplant patients. Evidence from one randomized trial in kidney transplant patients completed since the publication of the general CKD dyslipidemia guidelines supports this approach (22). This also assumes, of course, that treatment is safe and effective in ameliorating dyslipidemias in these patients.

image

Figure 3. The chain of logic for evidence supporting the treatment of low-density lipoprotein cholesterol in patients with chronic kidney disease.

Download figure to PowerPoint

The principal results of large multicenter trials in the general population have generally been applicable to most, if not all, major subgroups of patients that have been examined (Figure 4). For example, the benefit of reducing LDL cholesterol extends to men and women (4,41,42); the elderly and middle-aged (4,41,42); smokers and nonsmokers (4,42); hypertensive and nonhypertensive patients; (42) diabetics and nondiabetics (4,43); and individuals with higher or lower LDL, (4,42) higher or lower total cholesterol, (4,42) higher or lower triglycerides, (4,42) and higher or lower HDL (4,42,44,45). In other words, the results of lipid-lowering trials are usually generalizable to population subgroups. Therefore, it was reasonable to assume that the major findings from randomized trials in the general population are applicable to CKD and kidney transplant patients. The results of the first prospective randomized trial of the effects of dyslipidemia management on CVD outcomes in kidney transplant patients strongly support this assumption (22).

image

Figure 4. The relative coronary heart disease risk reduction in subgroups of patients from major lipid-lowering trials in the general population.

Download figure to PowerPoint

There are no prospective randomized trials on the effects of dyslipidemia management on CVD outcomes in CKD patients, and only one, the recently completed ALERT study, has been conducted in kidney transplant patients (22).Thus, there are reasonable doubts as to whether trial results from the general population can be extrapolated to all patients with CKD, particularly because most of these trials excluded patients with elevated serum creatinine. In kidney transplant patients, the ALERT study suggests that dyslipidemia management with statins is associated with a significant reduction in the incidence of cardiac death and of myocardial infarction (although differences in the combined primary endpoint were not statistically significant) (22). The Work Group concluded that studies are needed in dyslipidemia management in CKD patients and also that additional studies may be needed in transplant patients to confirm and extend the results of ALERT (see Research recommendations).

Assessment of dyslipidemias

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

Guideline 1

  • 1.1 
    All adult and adolescent kidney transplant recipients should be evaluated for dyslipidemias (B).
  • 1.2 
    For adult and adolescent kidney transplant recipients, the assessment of dyslipidemias should include a complete fasting lipid profile with total cholesterol, LDL, HDL, and triglycerides (B).
  • 1.3 
    For adult and adolescent kidney transplant recipients, dyslipidemias should be evaluated upon presentation (when the patient is stable), at 2–3 months after a change in treatment or other conditions known to cause dyslipidemias, and at least annually thereafter (B).
Associations between dyslipidemias and ACVD in CKD

The incidence of ACVD is very high in patients with CKD and in kidney transplant recipients (Figure 5). Therefore, the NKF Task Force on CVD and the K/DOQI Work Group on CKD both concluded that, in the management of risk factors such as dyslipidemia, patients with CKD and kidney transplant recipients should be considered to be in the highest risk category, i.e. equivalent to that of patients with known CHD (1,3). There is very strong evidence from the general population that dyslipidemias cause ACVD, and this evidence has led to the ATP III guidelines for evaluation and treatment (4). It is conceivable that the pathogenesis of ACVD is different in patients with CKD, and that dyslipidemias do not contribute to ACVD in CKD. However, the relationship between dyslipidemias and ACVD in the general population is robust, i.e. it is valid in men and women (4,41, 42); the elderly and middle-aged (4,41,42); smokers and nonsmokers (4,42;), hypertensive and nonhypertensive patients (42); diabetics and nondiabetics (4,43); and individuals with higher or lower LDL, total cholesterol, triglycerides, (4,42) and HDL (4,42,44,45) (Figure 4). There are no randomized, controlled intervention trials testing the hypothesis that dyslipidemias cause ACVD in CKD patients. However, there are no compelling reasons to believe that dyslipidemias do not contribute to ACVD in these patients.

image

Figure 5. Causes of death among period prevalent patients 1997–99, treated with hemodialysis, peritoneal dialysis, or kidney transplantation.

Download figure to PowerPoint

Associations between dyslipidemias and ACVD in kidney transplant recipients

Several studies have reported a positive association between total cholesterol and ACVD in kidney transplant recipients (Table 8). Unfortunately, few of these studies examined the relationship between LDL and ACVD. Lower levels of HDL were associated with ACVD in three of four studies. In three of six studies, higher levels of triglycerides were associated with ACVD. Altogether, these studies suggest that the relationship between ACVD and dyslipidemias in kidney transplant recipients is similar to that observed in the general population. However, each of these studies had design limitations; in particular, none were truly prospective. Kidney transplant recipients may also have nontraditional lipoprotein abnormalities that could theoretically contribute to ACVD (46–48). However, the role of these lipoprotein abnormalities in the pathogenesis of ACVD in CKD, as in the general population, is unclear. The association between dyslipidemia and ACVD in kidney transplant patients is supported by the results of the ALERT study, which showed that treatment of dyslipidemia with statins was associated with a significant reduction in cardiac death and nonfatal myocardial infarction (although differences in the combined primary endpoint were not statistically significant) (22).

Table 8.  Associations between dyslipidemias and cardiovascular disease in kidney transplant recipients
inline image
Evaluation of dyslipidemias in kidney transplant recipients

Measurements of total cholesterol, HDL, and triglycerides are readily available in most major clinical laboratories. The LDL that forms the foundation for treatment decisions in the ATP III Guidelines (4) is generally calculated from total cholesterol, HDL, and triglycerides using the Friedewald formula (see later). The ATP III Guidelines also recommend treatment of some dyslipidemias that may occur with normal or low LDL. These dyslipidemias, often seen in association with metabolic, or insulin resistance syndrome (syndrome of obesity, hypertension, insulin resistance, and hyperlipidemia) and characterized by increases in circulating lipoprotein remnants, can be most readily measured as non-HDL cholesterol, i.e. total cholesterol minus HDL (Figure 6) (4). All of the major treatment decisions for dyslipidemia in these guidelines, as in the ATP III Guidelines, are based on levels of triglycerides, LDL, and non-HDL cholesterol.

image

Figure 6. Example demonstrating the relative contributions of VLDL and IDL remnants to non-HDL cholesterol in two hypothetical patients with normal and high triglycerides, respectively.

Download figure to PowerPoint

Associations between dyslipidemias and kidney disease progression

The principal reason to evaluate dyslipidemias in patients with CKD is to detect abnormalities that may be treated to reduce the incidence of ACVD. However, there may be other reasons to evaluate and treat dyslipidemias in CKD. A number of observational studies have reported that various dyslipidemias are associated with decreased kidney function in the general population and in patients with CKD (Table 9). It is impossible to determine from these studies whether dyslipidemias cause reduced kidney function, result from reduced kidney function, or whether other conditions such as proteinuria cause both reduced kidney function and dyslipidemias. Each of these explanations is plausible, and only randomized, controlled trials can adequately test the hypothesis that dyslipidemias cause a decline in kidney function.

Table 9.  Relationship between dyslipidemias and kidney disease progression
inline image

Unfortunately, there are no large, adequately powered, randomized controlled trials testing the hypothesis that treatment of dyslipidemia preserves kidney function. However, there have been several small studies, (58–69) and a meta-analysis of these studies (71). This meta-analysis included prospective, controlled trials published before 1 July 1999. Three trials published only in abstract form were included in this meta-analysis (58,59,69); one of these studies has subsequently been published in a peer-reviewed journal (69). Unfortunately, none of these studies included transplant patients. All patients were followed for at least 3 months, but in only five studies were patients followed for at least 1 year. Statins were used in 10 studies, gemfibrozil in one study, and probucol in one. Altogether, 362 patients with CKD were included in the meta-analysis. The results suggested that the rate of decline in GFR was significantly less in patients treated with a cholesterol-lowering agent compared with placebo (70). No significant heterogeneity in treatment effect was detected between the studies. However, the quality of the studies was generally low, and their small sample sizes and relatively short duration of follow-up make it difficult to conclude that lipid-lowering therapies reduce the rate of decline in GFR in CKD. Therefore, the primary or secondary prevention of ACVD remains the principal reason to evaluate and treat dyslipidemias in patients with CKD.

Effect of dyslipidemia treatment on acute kidney transplant rejection

A pilot study in kidney transplant recipients suggested that pravastatin may reduce the incidence of acute rejection (71). However, a larger study found no effects of a statin on acute rejection after kidney transplantation (72). These negative results were recently confirmed by two other randomized controlled trials (73,74).

Thus, based on the results of these trials it appears that statins do not reduce the incidence of acute rejection in kidney transplant recipients.

Prevalence of dyslipidemias in kidney transplant recipients

The prevalence of dyslipidemias in kidney transplant recipients is very high (Table 10). Particularly common are increases in total cholesterol and LDL. Triglycerides are often increased, but HDL is usually normal.

Table 10.  The prevalence of dyslipidemias in kidney transplant recipients
inline image
Frequency of dyslipidemia evaluation in kidney transplant recipients

Many factors influence the prevalence of dyslipidemias in transplant patients. Immunosuppressive drugs or changes in proteinuria and GFR may alter lipoprotein levels. Therefore, it is prudent to evaluate dyslipidemias more often than is recommended in the general population. Lipoprotein levels may change during the first 3 months after kidney transplantation. On the other hand, waiting 3 months to measure the first lipid profile may needlessly delay effective treatment for patients who present with dyslipidemia. For patients whose lipid profile is normal at presentation, it is reasonable to repeat the lipid profile 3 months later, to confirm that the initial values were not low due to malnutrition or systemic disease. Reasons to repeat lipid measurements after 2–3 months include treatment with diet or lipid-lowering agents, immunosuppressive agents that affect lipids (e.g. prednisone, cyclosporine, or sirolimus), or other changes that may affect plasma lipids. During the post-transplant course, lipid levels frequently change. Therefore, the Work Group recommends measuring subsequent levels at least annually.

Dyslipidemias in adolescents

Young adults (20–40 years old) with Stage 5 CKD have at least a 10-fold higher risk for CVD mortality compared with the general population (100). There are limited data on ACVD in children with CKD. However, CVD accounts for approximately 23% of deaths in children and adults <30 years old who started treatment for Stage 5 CKD as children (101). Recent data from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study provide compelling evidence that in the general pediatric population, initial fatty streaks seen in adolescents develop into atheromatous plaques in young adults (102). Moreover, this atherosclerotic process is believed to be accelerated in uremia, thus putting children with Stage 5 CKD at high risk for developing ACVD. Indeed, studies of arteries from children with Stage 5 CKD have demonstrated early ACVD changes (103,104).

It is important to note that lipid levels in the general population change with age and puberty, and differ by gender (Table 11) (105). Very low levels at birth increase rapidly in the first year of life to a mean total cholesterol of 150 mg/dL (3.88 mmol/L), LDL 100 mg/dL (2.59 mmol/L), and HDL 55 mg/dL (1.42 mmol/L). From ages 1–12, lipid levels remain fairly constant, and are slightly lower in girls than boys. During puberty, there is a decrease in total cholesterol and LDL, and a slight decrease in HDL in boys. After puberty, i.e. by 17 years of age, cholesterol and LDL increase to adult levels in boys and girls. Boys continue to have a slightly lower HDL than girls. These changes dictate that the definitions of dyslipidemias be different in children and adults. These guidelines define dyslipidemias for children using lipid levels greater than the 95th percentile for age and gender (Table 11). Treatment thresholds for children do not differ by age and gender, but these thresholds are different from those of adults.

Table 11.  Serum total, HDL and LDL cholesterol, and triglycerides levels in US children and adolescents (mg/dL)
  Percentile
Age group (years)nMean5th10th25th50th75th90th95th
  1. Values were converted from plasma to serum (plasma value × 1.03 = serum value). *Insufficient data were available for children ages 0–4 years. To convert mg/dL to mmol/L multiply values by 0.02586. Data are from the Lipid Research Clinics Program (106). LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol.

Cholesterol
 Males
 0–4238159117129141156176192209
 5–91253165125134147164180197209
 10–142278162123131144160178196208
 15–191980154116124136150170188203
 Females
 0–4186161115124143161177195206
 5–91118169130138150168184201211
 10–142087164128135148163179196207
 15–192079162124131144160177197209
LDL
 White males
 5–91319565718293106121133
 10–42849966748397112126136
 15–192989764708296112127134
 White females
 5–9114103707591101118129144
 10–1424410070758397113130140
 15–192949961678096114133141
HDL
 White males
 5–91425739435056657276
 10–142965738414757637376
 15–192994831354047546165
 White females
 5–91245537394854636975
 10–142475438414654606672
 15–192955436394453637076
Triglycerides
 Males
 0–423858303441536987102
 5–9125330313441536788104
 10–142278683338466180105129
 15–191980803844567194124152
 Females
 0–418666353946617999115
 5–9111830333745577393108
 10–142087783845567293117135
 15–192079784045557090117136

Several studies have evaluated the prevalence of dyslipidemia after pediatric kidney transplantation (Table 11); 72–84% of these patients had LDL > 100 mg/dL (>2.29 mmol/L). In a longitudinal study of pediatric transplant patients, the prevalence of hypercholesterolemia declined from 70.4–35% at 10 years, with a decrease in hypertriglyceridemia from 46.3–15% (98). This decline in prevalence may reflect reductions in immunosuppressive medications and improved kidney function. Unfortunately, no longitudinal studies have defined the long-term risk of dyslipidemias in children with CKD, particularly those who survive into young adulthood.

Use of the Friedewald formula to calculate LDL

The Friedewald formula appears to be the most practical, reliable method for determining LDL cholesterol in clinical practice:

  • image

or

Two recent studies found the Friedewald formula to be reliable in dialysis patients, (108,109) although other investigators reported that the percentage error for the formula is higher in patients with CKD compared with the general population (110). No studies have examined the accuracy of the Friedewald formula in transplant recipients or in studies in other CKD patients, e.g. those with nephrotic syndrome.

Recent data from a study in the general population suggest that the Friedewald formula may underestimate LDL in patients with low LDL levels (28). Data from the general population also suggest that the Friedewald formula is not accurate when triglycerides are ≥400 mg/dL (≥4.52 mmol/L). Direct measurement of LDL with ultra-centrifugation or immunoprecipitation techniques is reasonably accurate when triglycerides are 400–800 mg/dL (4.52–9.03 mmol/L), but there are no reliable techniques for determining LDL when triglycerides are ≥800 mg/dL (≥9.03 mmol/L). Fasting triglycerides ≥800 mg/dL (≥9.03 mmol/L) generally indicate the presence of hyperchylomicronemia, the role of which in ACVD is unknown.

There are few studies in children, and none included children with CKD. However, in one study of children from the general population, calculating LDL using the Friedewald formula was more reliable in correctly classifying patients with high LDL than was the direct measurement of LDL (111).

Dyslipidemias in acute medical conditions

Some acute medical conditions may transiently alter plasma lipid levels (Table 12). For example, severe infections, surgery and acute myocardial infarction are often associated with lower-than-normal lipid levels. Other conditions, for example acute pancreatitis, may be associated with higher levels. In general, it is best to wait until acute conditions that may alter lipid levels have resolved before assessing dyslipidemias for possible ACVD risk. It should be noted, however, that the lipid profile is not significantly altered within the first 24 h after a myocardial infarction, and a lipid profile can be measured during this time (112–114).

Table 12.  Transient effects of some acute conditions on lipid levels
 Cholesterol
Acute conditionTotalLDLHDLTG
  1. LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; NC, no change; CMV, cytomegalovirus; TG, triglycerides

Myocardial infarction (112–114)[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]NC
Stroke (115)[DOWNWARDS ARROW][DOWNWARDS ARROW]NCNC
Bacterial sepsis (116–118)[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][UPWARDS ARROW]
Surgery (119–121)[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]
Acute pancreatitis (122, 123)[UPWARDS ARROW]NCNC[UPWARDS ARROW]
Transplant acute rejection (124)[DOWNWARDS ARROW][DOWNWARDS ARROW]NC[DOWNWARDS ARROW]/NC
Transplant CMV infection (124)[DOWNWARDS ARROW][DOWNWARDS ARROW]NC[DOWNWARDS ARROW]
Influence of immunosuppressive agents

Immunosuppressive medications, e.g. prednisone, cyclosporine, and sirolimus are among the several potential remediable causes of dyslipidemias in kidney transplant patients (Table 13). It is not clear how soon these agents exert their effects on lipoprotein metabolism, and when lipid levels reach a new steady state. However, the effects of diet and lipid-lowering agents may not be fully manifest for 2–3 months, and by analogy it may be best to measure a lipid profile 2–3 months after starting or stopping an immunosuppressive agent that is known to have a major effect on lipoprotein levels, e.g. prednisone, cyclosporine, or sirolimus.

Table 13.  Randomized trials evaluating the effects of immunosuppressive agents on dyslipidemias after kidney transplantation
inline image

The present guidelines are consistent with those of the American Society of Transplantation (AST), which recommend that a lipid profile should be measured during the first 6 months post-transplant, at 1 year after transplantation, and annually thereafter (125). The AST guidelines also suggest that changes in immunosuppressive therapy, graft function, or CVD risk warrant additional testing (125).

Guideline 2

For adult and adolescent kidney transplant recipients, a complete lipid profile should be measured after an overnight fast whenever possible (B).

Fasting

Eating raises plasma triglycerides, carried mostly in chylomicrons and very low-density lipoprotein (VLDL), and, as a result, total cholesterol levels also increase. The postprandial increases in triglycerides and cholesterol are quite variable, depending on the type of food ingested. In addition, substantial variability in postprandial lipid levels is attributable to inherited and acquired differences between individuals. Although these differences affect the risk for ACVD, the relationship between postprandial lipid levels and ACVD is not as well established as the relationship between fasting lipid levels and ACVD (4). Practical considerations may make nonfasting measurements the only alternative for some patients. While fasting lipid profiles are best, it is better to obtain nonfasting lipid profiles than to forgo evaluation altogether. If the lipid profile obtained in a nonfasting patient is normal, then no further assessment is needed at that time. However, an abnormal lipid profile in a nonfasting patient is an indication to obtain a fasting lipid profile.

Guideline 3

Kidney transplant recipients with dyslipidemias should be evaluated for remediable, secondary causes (B).

Rationale

Particularly relevant causes of secondary dyslipidemia in transplant patients include the use of immunosuppressive drugs such as corticosteroids (128,133,134), cyclosporine (126,131,135), and sirolimus (136,137). However, other causes of secondary dyslipidemias should be considered in transplant recipients including nephrotic syndrome (138–143), hypothyroidism (144–146), diabetes (147–149), excessive alcohol ingestion (150–154), and chronic liver disease (Table 14) (155–157). Additional medications that can cause dyslipidemias include 13-cis-retinoic acid (158–160), anticonvulsants (161–163), highly active antiretroviral therapy (164–166), beta-blockers (167), diuretics (167), androgens/anabolic steroids (168–171), and oral contraceptives (172–174) (Table 14). The assessment of these secondary causes with history, physical examination, and appropriate laboratory testing is recommended for any patient with dyslipidemia, since effective correction of these disorders may improve the lipid profile.

Table 14.  Secondary causes of dyslipidemias
Medical conditions
 Nephrotic syndrome
 Excessive alcohol consumption
 Liver disease
 Hypothyroidism
 Diabetes
Medications
 13-cis-retinoic acid
 Androgens
 Oral contraceptives
 Anticonvulsants
 Highly active anti-retroviral therapy
 Corticosteroids
 Cyclosporine
 Sirolimus
 Diuretics
 Beta-blockers

Urine protein excretion, especially if >3 g per 24 h, can also cause or contribute to dyslipidemias (138–143). Therefore, kidney transplant patients should have protein excretion measured, if this has not been done recently. In some cases, the underlying cause(s) of the proteinuria can be treated and effectively reversed. In other cases, ACE inhibitors or angiotensin II receptor blockers may help reduce protein excretion, and may thereby improve the lipid profile in some patients. Clinical hypothyroidism can cause dyslipidemia, (144–146) and even subclinical hypothyroidism may cause mild changes (145,175). Glucose intolerance can also cause dyslipidemias (147–149). Therefore, transplant patients with dyslipidemia should be assessed with fasting blood glucose and possibly glycosylated hemoglobin. Glycemic control can improve lipid profiles.

Treating dyslipidemias

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

In this section we will consider approaches to the management of adults (Guideline 4) and adolescents (Guideline 5) with dyslipidemias. The approach adopted for adults closely parallels that recommended by the ATP III Guidelines, (4) and is summarized in Figure 7 and Table 15. For the adult patient with markedly elevated serum triglyceride levels, triglyceride reduction is the principal focus of treatment in order to prevent pancreatitis. Otherwise, high levels of LDL are the focus of treatment. Patients with normal LDL, but high triglycerides, frequently have high levels of remnant lipoproteins. In general, the level of non-HDL cholesterol can be used as a surrogate for increased remnant lipoproteins, and elevated levels of non-HDL cholesterol should be considered for treatment (4). Non-HDL cholesterol is the total cholesterol minus HDL cholesterol (Figure 6).

image

Figure 7. The approach to treatment of dyslipidemias in adults with chronic kidney disease used in these guidelines.

Download figure to PowerPoint

Table 15.  The management of dyslipidemias in adult kidney transplant recipients
DyslipidemiaGoalInitiateIncreaseAlternative
  1. To convert mg/dL to mmol/L, multiply triglycerides by 0.01129, and cholesterol by 0.02586. TG, triglycerides; LDL, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle changes; seq., sequestrant; max.,maximum

TG ≥500 mg/dLTG <500 mg/dLTLCTLC + Fibrate or niacinFibrate or niacin
LDL 100–129 mg/dLLDL <100 mg/dLTLCTLC + low dose statinBile acid seq. or niacin
LDL ≥130 mg/dLLDL <100 mg/dLTLC + low dose statinTLC + max. dose statinBile acid seq. or niacin
TG ≥200 mg/dL and non-HDL ≥130 mg/dLNon-HDL <130 mg/dLTLC + low dose statinTLC + max. dose statinFibrate or niacin

The approach adopted for adolescents (Guideline 5) is similar to that for adults, but uses higher thresholds for treating LDL and non-HDL cholesterol (Figure 8). These higher thresholds are in deference to the relative lack of evidence for safety and efficacy of treatment in adolescents, and the likelihood that the benefit-to-risk ratio is higher at higher levels of LDL and non-HDL cholesterol.

image

Figure 8. The approach to treatment of dyslipidemias in adolescents with chronic kidney disease used in these guidelines.

Download figure to PowerPoint

Treatment of adults with dyslipidemias

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

Guideline 4

  • 4.1 
    For adult kidney transplant recipients with fasting triglycerides ≥500 mg/dL (≥5.65 mmol/L) that cannot be corrected by removing an underlying cause, treatment with therapeutic lifestyle changes (TLC) and a triglyceride-lowering agent should be considered (C).
  • 4.2 
    For adult kidney transplant recipients with LDL ≥ 100 mg/dL (≥2.59 mmol/L), treatment should be considered to reduce LDL to <100 mg/dL (<2.59 mmol/L) (B).
  • 4.3 
    For adult kidney transplant recipients with LDL < 100 mg/dL (<2.59 mmol/L), fasting triglycerides ≥200 mg/dL (≥2.26 mmol/L), and non-HDL cholesterol (total cholesterol minus HDL) ≥ 130 mg/dL (≥3.36 mmol/L), treatment should be considered to reduce non-HDL cholesterol to <130 mg/dL (<3.36 mmol/L) (C).
Rationale for treating very high triglycerides

The general approach to treating dyslipidemia in adult kidney transplant patients closely follows the approach adopted by the ATP III (Figure 7, Table 15). For patients with very high triglycerides, treatment of hypertriglyceridemia to reduce the risk for pancreatitis takes precedence over treatment of LDL cholesterol. The ATP III guidelines classify very high fasting triglycerides as ≥500 mg/dL (≥5.65 mmol/L) (4). Very high triglycerides are unusual in CKD patients and are generally due to an inherited abnormality in lipoprotein metabolism. However, this dyslipdemia pattern is seen more often in transplant patients as a consequence of the effects of immunosuppressive mediations. For individuals with very high triglycerides, the initial aim of therapy is to prevent acute pancreatitis through triglyceride lowering. Only when triglycerides are <500 mg/dL (<5.65 mmol/L) should attention be focused on LDL cholesterol reduction.

Rarely, severe hypertriglyceridemia can cause pancreatitis in the general population. The incidence of pancreatitis caused by hypertriglyceridemia in transplant patients is unknown, but it is probably also very low. Of 217 patients who received a kidney transplant, 12 (5.5%) developed pancreatitis, but in none of these cases was the pancreatitis believed to be caused by hyperlipidemia. Thus, these limited data suggest that hyperlipidemia is a rare cause of pancreatitis among patients with CKD. However, additional studies are needed to better ascertain the incidence of pancreatitis in CKD, and the possible role of dyslipidemias in its pathogenesis.

Treating very high triglycerides with therapeutic lifestyle changes

The ATP III guidelines suggest that triglycerides ≥500 mg/dL (≥5.65 mmol/L) should be treated with TLC. In the absence of data on the risk of acute pancreatitis from very high triglycerides in patients with kidney failure, it is reasonable to follow the ATP III guidelines. The ATP III guidelines recommend that TLC include diet, weight reduction, increased physical activity, abstinence from alcohol, and treatment of hyperglycemia (if present). For patients with fasting triglycerides ≥1000 mg/dL (≥11.29 mmol/L), the ATP III diet recommendations include a very low-fat diet (<15% total calories), medium-chain triglycerides and fish oils to replace some long-chain triglycerides. Diet should be used judiciously, if at all, in individuals who are malnourished.

Drug treatment of very high triglycerides

If TLC is not sufficient to reduce triglycerides to <500 mg/dL (<5.65 mmol/L), then treatment with a fibrate or nicotinic acid should be considered (Table 15). Studies from the general population suggest that fibrates and nicotinic acid lower triglycerides by 20–50% (Figure 9). Statins cause less triglyceride lowering, and bile acid sequestrants may actually increase triglyceride levels. Therefore, when triglycerides continue to be ≥500 mg/dL (≥5.65 mmol/L) despite TLC and/or withdrawal of causative agents, drug treatment should be considered. In general, fibrates are better tolerated than nicotinic acid. In any case, the benefits of drug therapy for hypertriglyceridemia should be weighed against the risks, and the risk of complications (particularly myositis and rhabdomyolysis) is increased in CKD.

image

Figure 9. Expected responses to treatment of low-density lipoprotein (upper panel), high-density lipoprotein (middle panel), and triglycerides (lower panel), based on studies in the general population.

Download figure to PowerPoint

Rationale for treating high LDL cholesterol

The ATP III Guidelines were developed using rigorous, evidence-based methods. The scant evidence available in kidney transplant recipients supports the assumption that the interventions recommended by the ATP III reduce ACVD in transplant patients. However, the single randomized trial of the effects of dyslipidemia management on CVD outcomes conducted in kidney transplant recipients used total serum cholesterol as the criteria for inclusion in the study, rather than LDL (22). In addition, the primary endpoint in this trial (cardiac death, nonfatal myocardial infarction, coronary artery bypass surgery, or percutaneous coronary intervention) was not significantly different in the fluvastatin treatment group compared with the control group (p = 0.139). Only the secondary endpoints (cardiac death, definite myocardial infarction, and the combined endpoint of cardiac death or nonfatal myocardial infarction) were significantly affected by treatment (5). Clearly, additional randomized trials proving that treatment of dyslipidemias reduce the incidence of ACVD in transplant patients are needed.

The risk of CHD events is markedly increased in transplant patients (3,1). Therefore, these patients should be considered to have a risk equivalent to that of CHD. This risk category in the ATP III Guidelines includes patients with known ACVD, patients with diabetes, and patients with an expected 10-year risk of CHD > 20%.

Treating proteinuria

Nephrotic-range proteinuria increases total and LDL cholesterol (138–143). In patients with severe proteinuria, triglycerides may also be increased. It may be possible to induce a remission in the nephrotic syndrome by treating the underlying glomerular disease. If not, it may be possible to reduce the level of proteinuria, and thereby improve the patient's lipid profile. Unfortunately, few randomized controlled trials have documented the lipid-lowering effects of therapies that reduce urine protein excretion, e.g. angiotensin II-converting-enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and/or low-protein diets. There are no published, randomized, controlled trials examing the effects of proteinuria reduction on plasma lipids in kidney transplant recipients.

In a randomized, controlled trial, treatment of 17 nephrotic (nontransplant) patients with an ACE inhibitor reduced urine protein excretion from a mean of 5.56–4.28 g per day, and decreased mean total cholesterol from 247 to 225 mg/dL (6.39–5.82 mmol/L) (176). There were no changes in protein excretion or cholesterol levels in nine placebo-treated controls (176). In a randomized trial of 94 type II diabetic patients with microalbuminuria, treatment with an ACE inhibitor reduced total cholesterol from 245 ± 24 mg/dL (6.4 ± 0.6 mmol/L) to 239 ± 29 mg/dL (6.2 ± 0.7 mmol/L), while cholesterol increased slightly in the placebo group (177). However, in other randomized trials of microalbuminuric type II diabetic patients, ACE inhibitors had little effect on lipid levels (178,179). There are few data on the effects of low-protein diets on lipid levels. In the feasibility phase of the Modification of Diet in Renal Disease study, serum total and LDL cholesterol levels tended to decrease with reduced dietary protein intake (180).

There is substantial evidence that ACE inhibitors reduce the rate of kidney disease progression in patients with proteinuria. Therefore, proteinuric patients with CKD should generally be treated with an ACE inhibitor or angiotensin II receptor antagonist, regardless of plasma lipids levels (3). However, whether this beneficial effect will also be seen in kidney transplant recipients has not yet been tested in controlled trials.

Some controlled trials in kidney transplant recipients have reported that ACE inhibitors or angiotensin II receptor antagonists reduce urine protein excretion (181–183). Others found no statistically significant effect on protein excretion (184–187). However, none of these trials selected patients with increased urine protein excretion for study, i.e. these trials were not designed to study whether these agents reduced high levels of urine protein excretion, e.g. >1 g/24 h. Similarly, none of the studies was designed to examine the effects of reducing high levels of urine protein excretion on plasma lipids. Thus, whether measures to reduce urine protein excretion in kidney transplant recipients are effective, and whether they also reduce plasma lipids, is unclear.

Treating high LDL with therapeutic lifestyle changes: diet

There are no randomized trials examining the safety and efficacy of a low-fat, low-cholesterol diet in kidney transplant patients. However, evidence from the general population suggests that a lipid-lowering diet can reduce LDL (2,27,188). Diet should be used judiciously, if at all, when there is evidence of protein–energy malnutrition. The diet should include < 7% of calories as saturated fat, up to 10% of calories as polyunsaturated fat, up to 20% of calories as monounsaturated fat, giving a total fat of 25–35% of total calories (Table 16, Appendix 1). The diet should also contain complex carbohydrates (50–60% of total calories), and fiber (20–30 g per day). Dietary cholesterol should be <200 mg/day. There are few, if any, adverse effects from this dietary regimen. Some patients with LDL 100–129 mg/dL (2.59–3.34 mmol/L) may achieve the goal of LDL <100 mg/dL (<2.59 mmol/L) with TLC alone (188). Thus, for patients with LDL 100–129 mg/dL (2.59–3.34 mmol/L), it is reasonable to attempt dietary changes for 2–3 months before beginning drug treatment. However, kidney transplant recipients often have a number of other nutritional concerns, (189) and it is important to consult a dietitian experienced in the care of these patients.

Table 16.  Therapeutic lifestyle changes (TLC) for adult kidney transplant recipients
  1. References (4;27;188;190–192); see also Appendix 1. NHANES, National Health and Nutrition Examination Survey.

Diet (consult a dietitian with expertise in chronic kidney disease)
 Emphasize reduced saturated fat:
 Saturated fat: <7% of total calories
 Polyunsaturated fat: up to 10% of total calories
 Monounsaturated fat: up to 20% of total calories
 Total fat: 25–35% of total calories
 Cholesterol: <200 mg per day
 Carbohydrate: 50–60% of total calories
 Emphasize components that reduce dyslipidemia
 Fiber: 20–30 g per day emphasize 5–10 g per day viscous (soluble) fiber
 Consider plant stanols/sterols 2 g per day
 Improve glycemic control
 Emphasize total calories to attain/maintain standard NHANES body weight
 Match intake of overall energy (calories) to overall energy needs
 Body mass index 25–28 kg/m2
 Waist circumference
 Men <40 inches (102 cm)
 Women <35 inches (88 cm)
 Waist–hip ratio (men <1.0; women <0.8)
Physical activity
 Moderate daily lifestyle activities
 Use pedometer to attain/maintain 10 000 steps per day
 Emphasize regular daily motion and distance (within ability)
 Moderate planned physical activity
 3–4 times per week 20–30 minute periods of activity
 Include 5-minute warm-up and cool-down
 Choose walking, swimming, supervised exercise (within ability)
 Include resistance exercise training
 Emphasize lean muscle mass and reducing excess body fat
Habits
 Alcohol in moderation: limit one drink per day with approval of physician
 Smoking cessation
Treating high LDL with therapeutic lifestyle changes: exercise and weight reduction

Controlled trials in the general population suggest that exercise training produces small, but significant improvements in dyslipidemias (188,193). Exercise has a number of beneficial effects, independent of those on dyslipidemias, and the lack of adverse effects makes a compelling case for recommending exercise in patients at risk for ACVD (4). Clearly, additional, controlled trials are needed to study the effects of exercise on dyslipidemias and other ACVD risk factors in kidney transplant recipients. Meanwhile, it is recommended that exercise be encouraged in these patients, based on data from studies in the general population.

There are also very few controlled trials examining the effects of weight reduction, with diet and/or exercise, on dyslipidemias in kidney transplant patients. The role of weight reduction in CKD patients, who often have a number of nutritional concerns, (189) is unclear. Again, additional studies are needed to define the role of diet, exercise, and weight reduction in dyslipidemic transplant patients.

Treating high LDL with a statin

The reduction in LDL that can be achieved with TLC is generally modest. Therefore, TLC alone is usually insufficient to reduce the LDL to the goal of <100 mg/dL (<2.59 mmol/L). In patients who cannot reduce LDL to <100 mg/dL (<2.59 mmol/L) by diet, a statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) should be prescribed, provided that there is no evidence of acute or chronic liver disease. Diet should be continued as an adjunct to the statin. The dose of statin needed to reach the goal of LDL < 100 mg/dL (<2.59 mmol/L) varies from patient to patient. Therefore, starting at a low dose and titrating the dose upwards is the best strategy for finding the lowest dose that achieves the goal. This approach will also minimize the frequency and severity of adverse effects. Statins reduced LDL by 18–55% in studies in the general population (Figure 9). Statins that are currently approved for use in the US include atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.

There is strong evidence from studies in the general population that statins reduce CHD events and all-cause mortality. The reduction in mortality and in CHD events is proportional to the reduction in LDL. There is substantial evidence that statins are safe and effective in reducing LDL in kidney transplant recipients (Table 17). Furthermore, statins reduce the incidence of cardiac death and acute myocardial infarction in these patients, although a reduction in the primary endpoint in this trial was not statistically significant (22). Statins are clearly the most effective class of antilipemic agents for reducing LDL.

Table 17.  Randomized trials evaluating the treatment of dyslipidemia in kidney transplant recipients
inline image

Elevated hepatic transaminases occur in 0.5–2.0% of patients treated with statins in the general population (204). Therefore, many recommend that baseline alanine and aspartate transferase levels should be obtained, although this is controversial (204). Indeed, whether statins cause hepatotoxicity is controversial. Statins have not been shown to worsen outcomes in patients with chronic transaminase elevations due to hepatitis B or C (204).

Patients should also be monitored for signs and symptoms of myopathy. The risk of myopathy from statins is increased by CKD, advanced age, small body frame, and concomitant medications (e.g. fibrates, nicotinic acid, cyclosporine, azole antifungals, macrolide antibiotics, protease inhibitors, nefazodone, nondihydropyridine calcium antagonists, and amiodarone) (204). Most experts recommend obtaining a baseline creatinine phosphokinase (CK) level to help in the interpretation of subsequent CK levels. Monitoring statin therapy with routine CK levels is probably not helpful. Patients who develop muscle pain or tenderness should discontinue statin therapy immediately and have CK levels measured. Elevations greater than 10 times the upper limit of normal are indicative of myositis and require at least temporary cessation of statin therapy (204). For patients with muscle soreness and either normal or mildly elevated CK, levels should be measured weekly, and the patient's symptoms monitored closely. Frequently, symptoms may improve with a reduction in the dose of the statin. However, if symptoms worsen, the statin should be discontinued. Other causes of myopathy should also be considered, e.g. strenuous exercise or hypothyroidism.

There are limited data on blood levels of statins in patients with reduced GFR (Table 18). In 19 patients with calculated creatinine clearances 13–143 mL/min, the level of kidney function did not affect the blood levels of atorvastatin (205). Pravastatin blood levels were not altered by the level of kidney function in 20 patients with creatinine clearance 15–112 mL/min, (206) or in 12 patients on chronic hemodialysis (207). Lovastatin blood levels were significantly higher in six patients with CKD (creatinine clearance 12–39 mL/min) (208). Therefore, the dose of lovastatin should probably be reduced by 50% in patients with Stages 4 or 5 CKD (GFR < 30 mL/min/1.73 m2) (Table 19). The doses of atorvastatin and pravastatin probably do not need to be altered for reduced kidney function per se. Since there are few published data on blood levels for fluvastatin or simvastatin in patients with CKD, we recommend that the doses of these agents be reduced by approximately 50% in patients with Stages 4 or 5 CKD (GFR < 30 mL/min/1.73 m2).

Table 18.  Lipid-lowering medication dose adjustments for reduced kidney function
 Adjust for reduced GFR (mL/min/1.73 m2)
Agent60–9015–59<15Notes
  1. GFR, glomerular filtration rate; USFDA, United States Food and Drug Administration.

Atorvastatin (205)NoNoNo 
Cerivastatin (209)No[DOWNWARDS ARROW] to 50%[DOWNWARDS ARROW] to 50%Withdrawn
Fluvastatin??? 
Lovastatin (208)No[DOWNWARDS ARROW] to 50%[DOWNWARDS ARROW] to 50% 
Pravastatin (206, 207)NoNoNo 
Simvastatin??? 
Nicotinic acid (210)NoNo[DOWNWARDS ARROW] to 50%34% kidney excretion
CholestipolNoNoNoNot absorbed
CholestyramineNoNoNoNot absorbed
ColesevelamNoNoNoNot absorbed
Bezafibrate (211–213)[DOWNWARDS ARROW] to 50%[DOWNWARDS ARROW] to 25%AvoidMay [UPWARDS ARROW] serum creatinine
Clofibrate (214–216)[DOWNWARDS ARROW] to 50%[DOWNWARDS ARROW] to 25%AvoidMay [UPWARDS ARROW] serum creatinine
Ciprofibrate???May [UPWARDS ARROW] serum creatinine
Fenofibrate (217)[DOWNWARDS ARROW] to 50%[DOWNWARDS ARROW] to 25%AvoidMay [UPWARDS ARROW] serum creatinine
Gemfibrozil (218, 2219)NoNoNoMay [UPWARDS ARROW] serum creatinine
Table 19.  Recommended daily statin dose ranges (4).
 Level of GFR (mL/min/1.73 m2)
Statin≥30>30 or dialysisWith cyclosporine
  1. Adult Treatment Panel III recommendations for GFR ≥ 30 mL/min/1.73 m2 (4). Most manufacturers recommend once daily dosing, but consider giving 50% of the maximum dose twice daily.

Atorvastatin10–80 mg10–80 mg10–40 mg
Fluvastatin20–80 mg10–40 mg10–40 mg
Lovastatin20–80 mg10–40 mg10–40 mg
Pravastatin20–40 mg20–40 mg20–40 mg
Simvastatin20–80 mg10–40 mg10–40 mg
Pleiotropic effects of statins

Recent data from studies in the general population have indirectly suggested that some of the reduction in ACVD from statins may be independent of their effects on plasma lipids (220,221). Although statins may have favorable effects on endothelial function, coagulation, and plaque stability, (222) it has been hypothesized that the effects of statins on systemic inflammation is one of the most important of these pleiotropic effects (221,223). If true, this observation could be important for transplant patients, who appear to have a high prevalence of elevated C-reactive protein and other markers of systemic inflammation (17–21). On the other hand, analysis of the data from multiple clinical trials in the general population suggests that most, but not all of the reduction in ACVD from statins can be explained by reductions in LDL (224).

The use of statins in patients receiving cyclosporine or tacrolimus

Cyclosporine has been shown to increase the blood levels of virtually every statin that has been investigated (Table 20). The degree to which levels are altered may depend on differences in the metabolic pathways of the different statins. The mechanisms for this interaction are not proven, but calcineurin inhibitors may compete with some of the same enzymes responsible for the metabolism of statins. For example, the cytochrome P450 3A4 enzyme, which is thought to be important in the metabolism of lovastatin, simvastatin, and atorvastatin, is inhibited by cyclosporine. Fluvastatin is metabolized through the cytochrome P-450 2C9 pathway. Pravastatin does not rely on the cytochrome P-450 system for metabolism, but is instead metabolized by sulfation. Nevertheless, increased levels of fluvastatin and pravastatin have been reported in patients treated with cyclosporine, although the increases in fluvastatin were not statistically significant in kidney transplant recipients (Table 20). Nevertheless, 10 heart transplant recipients treated with cyclosporine had a significant, 3.5-fold increase in the fluvastatin AUC0−24 compared with 10 normal controls (225).

Table 20.  Effects of cyclosporine on blood levels of statins in kidney transplant recipients
StatinIncrease in AUC (-fold)
  • a

    Withdrawn,

  • b

    P>0.05; Abbreviation: AUC, area under the concentration–time curve.

Atorvastatin (226)6
Cerivastatina (227)5
Simavastatin (228)3
Simavastatin (229)8
Lovastatin (230)2
Lovastatin (231)3
Lovastatin (232)20
Pravastatin (232)5
Fluvastatin (233)2b

There have been few comparison trials to determine if the increase in statin blood levels from cyclosporine is different for various statins (232). Moreover, our literature search identified only one study that examined blood levels of statins in patients treated with tacrolimus. In this study, four patients treated with tacrolimus had similar simvastatin blood levels compared with four controls that were treated with simvastatin alone (229). However, since the number of patients in this study was very small, and the metabolism of tacrolimus is very similar to that of cyclosporine, it should be assumed (until proven otherwise) that tacrolimus may cause elevations in statin blood levels.

Accumulating evidence suggests that statins can be used safely with cyclosporine if the dose of the statin is reduced (Table 20). It is recommended that the maximum doses of statins be reduced in patients receiving either cyclosporine or tacrolimus (Table 20). The addition of a third agent that is also metabolized by the cytochrome P450 system increases the risk of myositis and rhabdomyolysis, and therefore such combinations should be avoided. The new immunosuppressive agent everolimus had minimal effects on the blood levels of atorvastatin and pravastatin (234). The effects of sirolimus on statins are unknown.

Avoiding agents that increase the blood levels of statins

A number of medications may interact with the metabolism of statins and thereby increase statin blood levels. Medications known to increase statin blood levels should either be avoided, or, if necessary, the statin reduced or stopped. While this is true for all patients, it is especially true for patients with markedly reduced GFR, since some statin levels tend to be high in those patients (Table 18). It is even more critical for interactions to be avoided among kidney transplant patients receiving cyclosporine (and possibly tacrolimus), since cyclosporine often increases statin levels through mechanisms that may be exacerbated by the addition of a third interacting agent.

Most medications that are well-documented as increasing statin blood levels are also metabolized by the hepatic cytochrome P450 enzyme superfamily. These include macrolide antibiotics, azole antifungal agents, calcium-channel blockers, fibrates and nicotinic acid (Table 21). Other agents that may also increase statin levels include the serotonin re-uptake inhibitors, warfarin, and grapefruit juice (Table 22).

Table 21.  Effects of a macrolide antibiotic, azole antifunagl agents, calcium-channel blockers and nicotinic acid on blood levels of statins in normal individuals
Other compoundStatin (change in blood levels)
AgentP450 isoenzymeStatin (effect)P450 isoenzyme
  1. Shown are the effects of macrolide antibiotics on blood levels of statins. NC, no change (P>0.05); [UPWARDS ARROW]less than a 2-fold increase; and [UPWARDS ARROW][UPWARDS ARROW]greater than a 2-fold increase in the area under the plasma concentration–time curve. P450 indicates the subfamily of cytochrome -P450 hepatic oxygenase enzyme superfamily (3A4, 2C9, or none) felt to be important in the metabolism of the compound (1stcolumn) or statin (4th column).

Antibiotics
 Erythromycin3A4Atorvastatin ([UPWARDS ARROW]) (235)3A4
 Erythromycin3A4Simvastatin ([UPWARDS ARROW][UPWARDS ARROW])(236)3A4
Azole antifungal agents
 Itraconazole3A4Atorvastatin ([UPWARDS ARROW][UPWARDS ARROW]) (237)3A4
 Itraconazole3A4Atorvastatin ([UPWARDS ARROW][UPWARDS ARROW]) (238)3A4
 Itraconazole3A4Lovastatin ([UPWARDS ARROW][UPWARDS ARROW]) (239)3A4
 Itraconazole3A4Lovastatin ([UPWARDS ARROW][UPWARDS ARROW]) (240)3A4
 Itraconazole3A4Simvastatin ([UPWARDS ARROW][UPWARDS ARROW]) (241)3A4
 Fluconazole2C9Fluvastatin ([UPWARDS ARROW]) (242)2C9
 Itraconazole3A4Fluvastatin (NC) (240)2C9
 Itraconazole3A4Pravastatin ([UPWARDS ARROW]) (238)None
 Fluconazole (NC)2C9Pravastatin (242)None
 Itraconazole (NC)3A4Pravastatin (241)None
Calcium-channel blockers
 Diltiazem3A4Lovastatin ([UPWARDS ARROW][UPWARDS ARROW])(243)3A4
 Diltiazem3A4Simvastatin ([UPWARDS ARROW][UPWARDS ARROW]) (244)3A4
 Verapamil3A4Simvastatin ([UPWARDS ARROW][UPWARDS ARROW])(236)3A4
 Lacidipine3A4Simvastatin ([UPWARDS ARROW])(245)3A4
 Diltiazem3A4Pravastatin (NC) (243)None
 Gemfibrozil2C9Simvastatin ([UPWARDS ARROW][UPWARDS ARROW])(256)3A4
Fibrates
 FenofibrateNonePravastatin (NC) (257)None
 BezafibrateNoneLovastatin (NC) (258)3A4
 Gemfibrozil2C9Lovastatin ([UPWARDS ARROW][UPWARDS ARROW])(258)3A4
 Gemfibrozil2C9Fluvastatin (NC) (259)2C9
Table 22.  Agents that may alter statin blood levels
Statin (effect)AgentPossible mechanism
  1. Arrows indicate the direction, but not the magnitude, of change. 3A4 indicates the subfamily of cytochrome P450 hepatic oxygenase enzyme superfamily felt to be important in the interaction. aTroglitazone is no longer available in the US; other thizolidinediones are metabolized by the cytochrome P450 3A4 pathway and may have similar effects of statin levels.

Simvastatin ([UPWARDS ARROW])NefazodoneP450 3A4 (246)
Pravastatin ([UPWARDS ARROW])NefazodoneP450 3A4 (247)
Atorvastatin ([UPWARDS ARROW])Grapefruit juiceP450 3A4 (248)
Lovastatin ([UPWARDS ARROW])Grapefruit juiceP450 3A4 (249)
Simvastatin ([UPWARDS ARROW])Grapefruit juiceP450 3A4 (250)
Atorvastatin ([DOWNWARDS ARROW])TroglitazoneaP450 3A4 (251)
Simvastatin ([DOWNWARDS ARROW])TroglitazoneaP450 3A4 (252)
Simvastatin ([DOWNWARDS ARROW])RifampinP450 3A4 (253)
Simvastatin ([DOWNWARDS ARROW])Cholestyramine[DOWNWARDS ARROW] Absorption (254)
Adding a second LDL-lowering agent to a statin

Fibrates.  There are very few data on the safety and efficacy of combination therapies in patients with CKD. In general, it is probably wise to avoid the use of a fibrate together with a statin, at least until additional studies are conducted in patients with reduced GFR to establish the safety of this combination. Fibrates lower LDL by only 5–20% in normotriglyceridemic patients in the general population. They may actually increase LDL in patients with high triglycerides, and may increase the blood levels of statins (Table 21). The mechanisms for the interactions between fibrates and statins are not well understood. It was recently reported that gemfibrozil is a potent inhibitor of the cytochrome P450 2C9 isoform, but had minimal effect on 3A4 in vitro (255).

Bile acid sequestrants.  For patients who continue to have LDL ≥ 100 mg/dL (≥2.59 mmol/L) despite TLC and optimal treatment with a statin, consideration should be given to adding a bile acid sequestrant, if triglycerides are <400 mg/dL (<4.52 mmol/L) (Figure 7, Table 15). Bile acid sequestrants are contraindicated in patients with triglycerides ≥400 mg/dL (≥4.52 mmol/L), since they may increase triglycerides in some patients. They are relatively contraindicated for triglycerides ≥200 mg/dL (≥2.29 mmol/L). Evidence from studies in the general population indicate that bile acid sequestrants are safe and effective in lowering LDL by 15–30% (Figure 9). Bile acid sequestrants can be used in combination with a statin (260). However, there are few studies of the safety and efficacy of bile acid sequestrants in patients with CKD. Cholestyramine, colestipol, and colesevelam hydrochloride are approved for use in the US (Table 23). It should be noted that the new phosphate-binding agent, sevelamer hydrochloride, appears to lower lipid levels by mechanisms similar to those of bile acid sequestrants (261).

Table 23.  Bile acid sequestrant dose
Agent (g/day)Dose range
Cholestyramine4–16
Colestipol5–20
Colesevelam2.6–3.8

Bile acid sequestrants may interfere with the absorption of immunosuppressive medications, particularly immunosuppressive agents that bind to lipids. However, some small, uncontrolled studies suggest that a bile acid sequestrant can be used safely, without interfering with the absorption of cyclosporine. In one uncontrolled study, coadministration of cholestyramine and cyclosporine in five heart transplant recipients did not reduce the area under the concentration–time curve of cyclosporine (262). In another study of six kidney transplant patients, administration of cholestyramine 4 h after a dose of cyclosporine did not reduce the area under the concentration–time curve of cyclosporine (263). Based on these very limited data, it appears that bile acid sequestrants may not have a major effect on cyclosporine absorption. However, it may be prudent to avoid administering a bile acid sequestrant from 1 h before to 4 h after the dose of cyclosporine, and to monitor blood levels of cyclosporine.

Unfortunately, there are no published data on the effects of bile acid sequestrants on other immunosuppressive agents. In general, the risks and benefits of adding a bile acid sequestrant to an oral immunosuppression regimen should be carefully weighed. For many patients, the risk of transplant rejection resulting from poor absorption of immunosuppressive medication may outweigh the benefits of a further reduction in LDL from adding a bile acid sequestrant. However, for some patients (e.g. patients with severe CAD), the benefit of a further reduction in LDL may exceed the small risk of adding a bile acid sequestrant.

Similarly, bile acid sequestrants could theoretically interfere with the absorption of statins (254). Therefore, it is probably best to avoid taking the bile acid sequestrant at the same time as any other medication, if this is possible.

Nicotinic acid.  For patients who have triglycerides that preclude the use of a bile acid sequestrant, or for patients who do not tolerate a bile acid sequestrant, nicotinic acid can be considered as an alternative second agent in combination with a statin. Studies in the general population indicate that nicotinic acid reduces LDL by 5–25%, reduces triglycerides by 20–50%, and raises HDL by 15–35% (Figure 9). There are no data on the use of combination therapy with a statin and nicotinic acid in patients with CKD. Adverse effects of nicotinic acid include flushing, hyperglycemia and hepatotoxicity. Contraindications to nicotinic acid include liver disease, severe gout, and active peptic ulcer disease. There are no published data on the safety and efficacy of combination therapy with nicotinic acid and statins in kidney transplant recipients.

Ezetimibe.  Ezetimibe is the first in a new class of agents that inhibits cholesterol absorption. Randomized controlled trials in the general population have reported that coadministartion of ezetimibe with a statin caused an incremental decline in LDL of 15–25%(264–267). In these studies, triglycerides also declined slightly, and HDL increased by 2–5%. At present there are no data on the use of ezetimibe in transplant patients. Therefore, it should probably not be used in transplant patients until its safety is established in this population.

Treating high LDL in patients who cannot take a statin

Patients who develop minor adverse effects from a statin may be able to tolerate a reduced dose, or a different statin. However, for patients who do not tolerate a reduced dose or another statin, a second-line agent can be used. Either a bile acid sequestrant or nicotinic acid can effectively reduce LDL cholesterol. For patients who cannot afford the cost of a statin, nicotinic acid offers a cheaper alternative. The phosphate-binding agent sevelamer hydrochloride may also lower total and LDL cholesterol. There have been two randomized, controlled trials in CKD patients (268,269). In these studies, sevelamer hydrochloride caused significant reductions in total cholesterol.

Optimizing immunosuppressive agents in kidney transplant recipients

For kidney transplant recipients who have LDL ≥ 100 mg/dL (≥2.59 mmol/L), despite optimum medical management, consideration should be given to changing the immunosuppression protocol to one that is less likely to exacerbate high LDL levels, if this can be done without causing undue risk to the allograft. Options to consider include: (i) tapering and discontinuing prednisone (128,130,133,134) , with or without adding or increasing the dose of azathioprine or mycophenolate mofetil; (ii) replacing cyclosporine with tacrolimus (126,127,131); (iii) tapering and discontinuing cyclosporine (132) , with or without adding or increasing the dose of azathioprine or mycophenolate mofetil; or (iv) discontinuing or replacing sirolimus with an alternative immunosuppressive agent (136,137).

Evidence suggests that discontinuing or replacing prednisone, cyclosporine, or sirolimus may reduce the prevalence and severity of dyslipidemias and other ACVD risk factors such as hypertension and glucose intolerance (Table 13). However, in deciding to change or not to change immunosuppressive agents, the risk of rejection should be weighed against the risk of ACVD. Kidney transplant recipients who are diabetic and/or have known ACVD may have more to gain from changing immunosuppressive agents than patients at lower risk for ACVD. Moreover, the effects of immunosuppression on overall ACVD risk should be taken into account, not just their effects on dyslipidemias (Table 24). For example, different immunosuppressive agents have different effects on blood pressure and post-transplant diabetes, both of which can affect the incidence of ACVD. In any case, the decision to alter immunosuppression should be made only after fully informing the patient of the risks and benefits that are involved.

Table 24.  Relative effect of different immunosuppressive agents on cardiovascular disease risk factors after kidney transplantation.
 AZA or MMFPrednisoneCyclosporineTacrolimusSirolimus
  1. Arrows offer a crude, semiquantitative comparison of the relative effect of each agent on cardiovascular disease risk factors. Abbreviations: AZA, azathioprine; MMF, mycophenolate mofetil.

Hypertension[UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW]
Dyslipidemia[UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW]
Diabetes[UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW]
Rationale for treating non-HDL cholesterol in patients with high triglycerides

Non-HDL cholesterol is defined as total cholesterol minus HDL cholesterol. No evidence has directly linked low HDL, high fasting triglycerides, and increased non-HDL cholesterol to ACVD in kidney transplant patients. However, a growing body of evidence from the general population has suggested that this lipid profile is part of a metabolic syndrome (insulin resistance, obesity, hypertension, and dyslipidemia) that is associated with ACVD (4). Measures that safely and effectively improve this lipid profile should be considered to help reduce the incidence of ACVD in transplant patients.

Studies in the general population have implicated increased triglycerides as an independent risk factor for ACVD (270,271). It is considered most likely that the risk of high triglycerides is a result of atherogenic, remnant lipoproteins. These include small VLDL and intermediate density lipoproteins (IDL). Since VLDL cholesterol is highly correlated with remnant lipoproteins, VLDL can be combined with LDL cholesterol to enhance risk prediction when triglycerides are high. Non-HDL cholesterol is calculated as total cholesterol minus the HDL cholesterol. In persons with high triglycerides, e.g. 200–499 mg/dL (2.26–5.64 mmol/L), most of the cholesterol in non-HDL cholesterol is present as remnant VLDL. Recent data suggest that non-HDL cholesterol may actually be a better predictor of coronary mortality than LDL (272). Non-HDL cholesterol is also a reasonable surrogate marker for apolipoprotein B, the major apolipoprotein of all atherogenic lipoproteins (273).

Studies in the general population suggest that in individuals with triglycerides <200 mg/dL (2.26 mmol/L) VLDL is not particularly elevated, and non-HDL cholesterol correlates best with LDL cholesterol (Figure 6) (273). Therefore, using non-HDL cholesterol as the threshold and target for treatment makes little sense for individuals who do not have high triglycerides. Most clinical trials in the general population have not used non-HDL cholesterol as a target of therapy. Moreover, it is difficult to attribute the risk reduction in these trials to non-HDL cholesterol (compared with VLDL or LDL), because percentage changes in non-HDL cholesterol, VLDL, and LDL closely parallel each other.

Since a normal VLDL cholesterol is usually defined as <30 mg/dL (0.78 mmol/L) (274) , a reasonable goal for non-HDL cholesterol is one that is 30 mg/dL (0.78 mmol/L) higher than the LDL cholesterol goal of 100 mg/dL (2.59 mmol/L), i.e. <130 mg/dL (3.36 mmol/L) (4). The ATP III does not target triglycerides per se for therapy, since triglyceride levels have more day-to-day variability than non-HDL cholesterol, and targeting the latter allows more flexibility in the choice of therapies (4). The ATP III does not target apolipoprotein B for therapy, since: (i) standardized measures of apolipoprotein B are not readily available; (ii) measures of apolipoprotein B have not been shown to have greater predictability than non-HDL cholesterol in individuals with high triglycerides; and (iii) measurement of apolipoprotein B adds to the expense of the usual lipoprotein profile (4).

The Work Group concluded that, in the absence of data from randomized trials in kidney transplant patients, it is prudent to use the higher threshold of triglycerides recommended in the ATP-III. Using a triglyceride threshold 200–499 mg/dL (2.26–5.64 mmol/L) for treating non-HDL cholesterol in patients with low LDL means that only patients with very high VLDL and IDL will be treated. Clearly, additional studies are needed to establish whether therapy targeting lower levels of VLDL and IDL is safe and effective in kidney transplant patients.

Removing causes of hypertriglyceridemia and elevated non-HDL cholesterol

Potentially remediable causes of hypertriglyceridemia include obesity, physical inactivity, excessive alcohol intake, high carbohydrate diet, type 2 diabetes, nephrotic syndrome, and some medications such as estrogens, beta-blockers and immunosuppressive medications. Corticosteroid withdrawal may decrease plasma cholesterol and triglycerides (128,130,133,134). Similarly, the immunosuppressive agents cyclosporine (126,131) , and especially sirolimus, (136,137) cause dyslipidemias, and may occasionally cause triglycerides ≥500 mg/dL (≥5.65 mmol/L). For patients who have triglycerides ≥500 mg/dL (≥5.65 mmol/L), consideration should be given to reducing the dose or withdrawing the offending agent. Anabolic steroids can cause dyslipidemia (168–171).

Therapeutic lifestyle changes for high triglycerides and non-HDL cholesterol

Moderate alcohol consumption (30–60 mL alcohol per day) has been linked to a reduced risk for ACVD in the general population. However, excessive alcohol consumption increases the risk for hypertension, dyslipidemias, and ACVD in the general population. There are virtually no studies on the effects of alcohol consumption in kidney transplant patients.

Studies in the general population have shown that glycemic control with diet, oral hypoglycemic agents, and insulin are effective in raising HDL and lowering fasting triglycerides. However, such studies have produced conflicting results as to whether intensive (vs. usual) glycemic control reduces the risk for ACVD (275–277). Nevertheless, patients with low HDL and/or high triglycerides should be assessed for diabetes, and diabetic patients with this lipid profile should have as good glycemic control as possible without causing excessive hypoglycemia.

Obesity is also associated with low HDL and/or high triglycerides. Increased physical activity and nutritionally sound diets that restrict calories help to reduce weight in obese patients in the general population. However, there are few studies demonstrating successful weight reduction in obese kidney transplant patients.

Low-fat diets and increased physical activity have both been shown to raise HDL and reduce triglycerides in the general population. A limited number of studies suggest that these measures may also be effective in kidney transplant patients.

Dietary fish oil supplements have been shown to reduce triglycerides in studies in the general population. Few studies have examined the effects of fish oil supplements on lipoproteins in patients with CKD, and their results have been inconclusive (Table 17).

Drug therapy for high triglycerides and non-HDL cholesterol

Observational studies in the general population suggest that high triglycerides are independent risk factors for ACVD (270,271). Intervention trials have shown that statins, fibrates, and nicotinic acid reduce the risk of CHD, and indirect evidence suggests that not all of the benefit in these trials is the result of LDL reductions. However, few studies in patients with CKD have examined the relationships between low HDL, high triglycerides, and ACVD, and the results of these studies have been inconclusive (Table 8).

Patients who are not already receiving a statin for treatment of LDL, who have fasting triglycerides ≥200 mg/dL (≥2.26 mmol/L), non-HDL cholesterol ≥ 130 mg/dL (≥3.36 mmol/L), and who do not have liver disease, should be started on a statin along with TLC. In studies in the general population, statins lowered triglycerides by 7–30% and increased HDL by 5–15% (Figure 9). Similarly, most randomized trials of lipid-lowering agents in kidney transplant patients using statins showed a 15–25% reduction in triglycerides (Table 17). Furthermore, statins reduced the incidence of major coronary events, CHD mortality, and stroke and all-cause mortality in studies in the general population. Statins are contraindicated in patients with liver disease. A lipid profile and liver enzymes should be obtained within 2–3 months after starting a statin, and 2–3 months following any adjustment in the dose. The Work Group considered whether a statin or a fibrate should be the first-line agent for treatment of non-HDL cholesterol. Although there are compelling theoretical reasons for considering fibrates in this setting, the Work Group concluded that the safety and efficacy of statins for preventing CVD has been more conclusively established in randomized trials in the general population. Clearly, randomized trials examining both statins and fibrates are needed in patients with CKD.

If the statin is tolerated, no further treatment of non-HDL cholesterol is indicated. If the statin is not tolerated at a reduced dose or after switching to another statin, then consider discontinuing the statin and treating instead with a fibrate. The blood levels of bezafibrate, clofibrate, and fenofibrate are increased in patients with decreased kidney function compared with controls with normal kidney function (Table 18). In contrast, blood levels of gemfibrozil do not appear to be altered by decreased kidney function (Table 18). Bezafibrate (213,278–286), ciprofibrate (286,287), fenofibrate (286–295), and gemfibrozil (295) have been reported to cause increased serum creatinine and blood urea nitrogen levels (213,278,279,284,286, 287,289,295). The mechanism for this effect is not known. Since both serum creatinine and blood urea nitrogen are affected, the mechanism presumably involves a reduction in GFR. Indeed, in one study, tubular secretion of creatinine was not altered by bezafibrate (280). However, in a study of 13 patients with normal, or mild to moderate kidney disease, fenofibrate increased serum creatinine without altering GFR or plasma flow (293). Gemfibrozil was not thought to cause increased serum creatinine, (286,287) but recently there was a report of two cases where this occurred (295). Nevertheless, since dose modification for decreased kidney function is not required for gemfibrozil, unlike other fibrates (Table 25), gemfibrozil should probably be considered the fibrate of choice for most CKD patients including kidney transplant recipients.

Table 25.  Maximum doses of fibrates in patients with reduced kidney function
 Dose (mg) by level of GFR (mL/min/1.73 m2)
Fibrate>9060–9015–59<15
  1. Abbreviation: GFR, glomerular filtration rate.

Bezafibrate200 tid200 bid200 qdAvoid
Clofibrate1,000 bid1,000 qd500 qdAvoid
Ciprofibrate200 qd???
Fenofibrate201 qd134 qd67 qdAvoid
Gemfibrozil600 bid600 bid600 bid600 bid

Nicotinic acid can be used in place of fibrates for patients with elevated triglycerides. However, there are almost no data on blood levels of nicotinic acid in patients with reduced GFR. In one study, only 34% of a dose of nicotinic acid was excreted in the urine, suggesting that major dose modification may not be necessary in patients with reduced kidney function (Table 26). The incidence of adverse effects from nicotinic acid, e.g. flushing and hyperglycemia, is high (296,297). However, there are few studies examining whether the incidence of adverse effects of nicotinic acid is higher in patients with CKD compared with the general population (298). Insulin resistance is common in kidney transplant patients, and a higher than expected incidence of hyperglycemia from nicotinic acid would not be surprising in this population.

Table 26.  Nicotinic acid dose
Agent (g/day)Dose range
Immediate release1.5–3.0
Extended release1–2
Sustained release1–2
Isolated, low HDL cholesterol

Patients with isolated HDL of 40 mg/dL (1.03 mmol/L) should be treated with TLC. However, the pharmacological treatment of isolated low HDL cholesterol is not recommended. There are few data defining the risk of ACVD attributable to isolated, low HDL in the general population or in kidney transplant patients. The effects of pharmacological agents on HDL are modest, and the incidence of adverse effects is probably higher in patients with CKD than in the general population. Therefore, the risks of pharmacological therapy to raise HDL (in the absence of high LDL or high triglycerides) probably outweigh the benefits.

Treatment of adolescents with dyslipidemias

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

Guideline 5

  • 5.1 
    For adolescent kidney transplant recipients with fasting triglycerides ≥500 mg/dL (≥5.65 mmol/L) that cannot be corrected by removing an underlying cause, treatment with TLC should be considered (C).
  • 5.2 
    For adolescent kidney transplant recipients with LDL ≥ 130 mg/dL (≥3.36 mmol/L), treatment should be considered to reduce LDL to <130 mg/dL (<3.36 mmol/L) (C).
  • 5.3 
    Adolescent kidney transplant recipients with LDL < 130 mg/dL (<3.36 mmol/L), fasting triglycerides ≥200 mg/dL (≥2.26 mmol/L), and non-HDL cholesterol (total cholesterol minus HDL) ≥ 160 mg/dL (≥4.14 mmol/L), treatment should be considered to reduce non-HDL cholesterol to <160 mg/dL (<4.14 mmol/L) (C).
Rationale for treating very high triglycerides

Evidence that very high triglycerides can cause pancreatitis in children comes from case reports and small series of patients with familial dyslipidemias (299,300). The incidence of pancreatitis caused by hypertriglyceridemia in adolescent kidney transplant recipients is unknown. However, it seems prudent to treat very high triglycerides with TLC, if nutrition is otherwise adequate (Figure 8). The safety and efficacy of lowering triglycerides with fibrates and niacin have not been established in adolescents.

Isolated hypertriglyceridemia in adolescents should be treated with TLC. Cases of triglycerides persistently ≥500 mg/dL (≥5.65 mmol/L) are rare, and they are generally due to an inherited metabolic disorder. Drug therapy, e.g. low-dose fibrates or nicotinic acid, (301) may be warranted. The use of fibrates or nicotinic acid in adolescents has not been well studied; (302–304) therefore, routine use of these agents cannot be recommended at this time. Patients should be referred, however, to a pediatric lipid specialist for management and to rule out familial hypertriglyceridemia or rare, inherited disorders such as lipoprotein lipase deficiency or apolipoprotein C-II deficiency (305).

Rationale for treating high LDL and high non-cholesterol HDL

Atherosclerosis in young adults was first described in 1953 (306). Most recently, the PDAY study found that 50% of children 10–14 years old had early fatty streaks, and 8% had fibrous plaques, thus confirming that atherosclerosis begins in childhood (102). Risk factors associated with ACVD in adults are also associated with atherosclerosis in children (102,307). In the Bogalusa Heart Study, body mass index, LDL and systolic blood pressure were associated with atherosclerotic disease of the aorta and coronary vessels of children (308). Moreover, hypercholesterolemia in children and adolescents persists into adulthood (308). Recent studies of subclinical ACVD in children with familial hypercholesterolemia found an increase in intimal medial thickness of the aorta and carotid arteries compared with that of healthy young children (309). Thus, these and other studies in the general population suggest that ACVD begins in childhood, and that dyslipidemia in children may play an important role in the pathogenesis of ACVD. However, in children with kidney transplants, the relationship between dyslipidemia and subsequent ACVD is unknown.

Approach to treating high LDL and high non-HDL cholesterol

Secondary causes of dyslipidemias should be treated first (Guideline 3). Thereafter, for LDL 130–159 mg/dL (3.36–4.12 mmol/L), TLC should be used first (Figure 8). If, after 6 months of TLC, LDL is ≥130 mg/dL (≥3.36 mmol/L), then consider pharmacological management. If LDL is ≥160 mg/dL (≥4.13 mmol/L), then consider starting atrovastatin at the same time as TLC (Figure 8).

Therapeutic lifestyle changes

TLC for children are similar to those recommended for adults (Table 16). Recent studies in the general population have shown that dietary fat restriction is safe in children (310–313). In particular, there have been no adverse effects on growth and development, or nutrition (310–313). However, TLC should be used judiciously, or not at all, in children who are malnourished. If TLC has failed after 6 months, and potential secondary causes of dyslipidemia have been ruled out, drug therapy should be considered.

Drug therapy

There are few studies examining drug treatment of dyslipidemia in transplanted children. However, a limited number of small, randomized, controlled trials in children and adolescents from the general population have found that statins are safe and effective in lowering LDL (314–317). In particular, statins do not appear to have adverse effects on growth and development (318). A few, very small, uncontrolled trials have likewise reported that statins are safe and effective in patients with nephrotic syndrome (319–321). Thus, although most statins are not approved for use in children and adolescents, and additional studies are needed, preliminary data suggest they are safe and effective. Therefore, statins should be considered for therapy in adolescent kidney transplant recipients and elevated LDL, or in hypertriglyceridemic adolescent kidney transplant recipients and increased non-HDL cholesterol. Currently, the only statin approved by the US Food and Drug Administration (USFDA) for use in children and adolescents is atorvastatin. However, more recent data in boys with familial hypercholesterolemia suggests that lovastatin 10–40 mg can safely decrease LDL by 21–36% (322,323). Similar results were reported with pravastatin 5–20 mg (324). Additional data on long-term safety, especially with respect to growth and nutrition, are needed before statins can be recommended for use in children of all ages.

For adolescents who do not achieve the desired target with a statin, addition of a bile acid sequestrant can be considered (Figure 8). Bile acid sequestrants appear to be safe and effective in improving dyslipidemias in children. Cholestyramine is approved for use in children by the USFDA. Although bile acid resins are safe in children of all ages, adherence to therapy is often poor due to the high incidence of adverse effects (325–327). No dosage adjustment is required in patients with reduced GFR. However, pediatric dosages have not been established. In children 6–12 years of age, doses of anhydrous cholestyramine 80 mg/kg three times a day, not to exceed 8 g per day, can be used (328). Adverse effects are common and include constipation, abdominal discomfort, nausea, flatulence, vomiting, diarrhea, heartburn, anorexia, and indigestion. In children and adults treated with cyclosporine, bile acid sequestrants should probably be administered between cyclosporine doses to prevent possible interference with absorption. Bile acid sequestrant powders are generally mixed with 120–180 mL of fluid, and several glasses of water between doses are recommended. The fluid recommended with bile acid powders may limit their use in dialysis or CKD patients who have been prescribed strict fluid restrictions. The newer bile acid sequestrant colesevelam has not yet been studied in children, and thus cannot be recommended at this time. Similarly, the phosphate-binding (and lipid-lowering) agent sevelamer hydrochloride has not been studied in children.

Bile acid sequestrants can increase triglycerides, and hypertriglyceridemia is common in children with CKD. Bile acid resins are relatively contraindicated in patients with triglycerides ≥200 mg/dL (2.26 mmol/L), and definitely contraindicated in patients with triglycerides ≥500 mg/dL (≥5.65 mmol/L). Other potential, long-term adverse effects of bile acid resins include deficiencies of vitamins A, E, and folic acid. In studies with long-term follow-up, a folic acid supplement was required; however, anemia from folate deficiency was not observed (329, 330). In kidney transplant recipients, hyperhomocysteinemia is more common than in the general population, and therefore the potential for adverse effects from folate deficiency caused by bile acid sequestrants is potentially greater. Taken together, these considerations suggest that bile acid resins should be used with caution in children, and close monitoring for adverse effects such as vitamin deficiencies are warranted.

Research recommendations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

There are reasonable doubts as to whether trial results from the general population are applicable to kidney transplant patients. It is beyond the scope of these guidelines to recommend all research that should be conducted in kidney transplant patients with dyslipidemia, or to design clinical trials. However, it is apparent that some questions are particularly well suited for study.

For adults and children with a functioning kidney transplant, prospective cohort studies with long-term follow-up are recommended to determine:

  • • 
    the prevalence of dyslipidemias over time, particularly with newer immunosuppressive agents;
  • • 
    the associations between dyslipidemias, including those refected by nontraditional markers such as apolipoprotein B, and subsequent ACVD.

For children with CKD and/or a functioning kidney transplant, phase I and phase II trials, and pharmacokinetic dosing studies are recommended to establish the safety and lipid-lowering efficacy of agents (including, but not limited to):

  • • 
    bile acid sequestrants, e.g. colesevelam;
  • • 
    cholesterol uptake inhibitors, e.g. ezetibmide;
  • • 
    statins;
  • • 
    fibrates;
  • • 
    nicotinic acid;
  • • 
    sevelamer hydrochloride;
  • • 
    appropriate lipid-lowering drug combinations.

For adults with a functioning kidney transplant, phase I and phase II trials and pharmacokinetic dosing studies are recommended to establish the safety and lipid-lowering efficacy of new agents (including, but not limited to):

  • • 
    colesevelam;
  • • 
    cholesterol uptake inhibitors, e.g. ezetimibe;
  • • 
    appropriate lipid-lowering drug combinations.

For kidney transplant recipients, these and other appropriate studies are recommended to determine whether:

  • • 
    A statin safely reduces the incidence of ACVD and all-cause mortality in patients with any lipid profile.
  • • 
    A statin safely reduces the rate of decline in GFR in patients with any lipid profile.
  • • 
    A statin safely reduces the incidence of ACVD and all-cause mortality in patients with LDL ≥ 100 mg/dL (≥2.59 mmol/L).
  • • 
    A statin safely reduces the rate of decline in GFR in patients with LDL ≥ 100 mg/dL (≥2.59 mmol/L).

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative was supported by an unresetricted grant from Amgen, Inc. The development of these dyslipidemia guidelines was supported by an unrestricted grant from Fujisawa Healthcare, Inc.

The Work Group thanks the more than 100 reviewers whose helpful comments were incorporated into these guidelines. Also, special thanks to Lauren Bronich, RD, LD, CDE, Clinical Dietitian Specialist and Diabetes Educator, Johns Hopkins Bayview Medical Center for helping with the Appendix 1 diet information.

The following individuals provided written review of the draft guidelines: Kevin Abbott, MD; Anil Agarwal, MD; Mamta Agarwal, MD; Lawrence Agodoa, MD; Steve Alexander, MD; Cathy Allen, RD; Mouhammed Amir Habra, MD; Carolyn R. Atkins, RN, BS, CCTC; Colin Baigent, MD; Karen L. Basinger, MS, RD, LN; Bryan N. Becker, MD; Gavin J. Becker, MD, MBBS; Deborah Benner, MA, RD, CSR; Richard K. Bernstein, MD, FACE, FACN; Andrew T. Blair, MD; Marcia Bos, BScPhm; Deborah Bowen, MSN, RN, CNN; John Brandt, MD; Josephine P. Briggs, MD; Deborah I. Brommage, MS, RD, CSR, CDN; Joan Bryant, RD, LD; Karen Burchell, PA-C; Jerrilynn D. Burrowes, MS, RD, CDN; Marilyn Campbell; Alice Chan, RD, CSR, LD; Helen Chan, MS, RD, LD; Manju Chandra, MD; Jacqueline E. Chase, RD, CSR, LD; James Cleeman, MD; Peter W. Crooks, MD; Jeffrey Cutler, MD, MPH; Ira Davis, MD; Claudia Douglas, RN, MA, CNN, APNC; Sharon E. Ehlers, MA, RN; Mahmoud T. El-Khatib, MD; Nancy Ferrell, RN, CNN; Barbara A. Fivush, MD; Michael Flessner, MD; Joseph Flynn, MD; Edward Foote, PharmD; Linda Fried, MD; Richard S. Goldman, MD; Antonio Gotto, MD; Karen Graham; Tomas L. Griebling, MD; Ann P. Guillot, MD; Elizabeth Guthrie, RD, LD; William E. Haley, MD; L. Lee Hamm, MD; Jeff Harder, MSW, LICSW; Lori Hegel, RN, CNN; J. Harold Helderman, MD; Charles A. Herzog, MD; Hallvard Holdaas, MD; Linda Hopper, RD, CSR, LD; Alan R. Hull, MD; Abrar Husain, DO; Todd S. Ing, MD; Julie R. Ingelfinger, MD; Kathy Jabs, MD; J.A. Joles, DVM; Donald C. Jones; Nikolaos Kaperonis; Toros Kapoian, MD; Dee Kees-Folts, MD; Pamela S. Kent, MS, RD, LD; Carl Kincaid; Florian Kronenberg, MD; Justina Lambert; Bruce Lange, PharmD; Derrick L. Latos, MD; Phyllis Lawson, RN; Claude Lenfant, MD; Edgar Lerma, MD; Matthew Lewis, PharmD; Tom Lili, FRACP; Lyn Lloyd, NZRD; Ziad Massy, MD; Aletha Matsis, BSN, RN, CNN; Tej Mattoo, MD; Linda M. McCann, RD, LD, CSR; Peter A. McCullough, MD, MPH, FACC, FACP; Sandra McDonald-Hangach, RD, CSR; Rosemary McElroy, RN; Maureen McKinley, MSW, LCSW; Mary K. McNeely, MS, RD, LD, CSR; Maureen A. Michael, RN; Pat Michael, RN; Joyce Mooty, EdM, MPH, RD; Joseph V. Nally, Jr., MD; Jean M. Nardini, RN; Andrew S. Narva, MD; Martin S. Neff, MD; Linda Neff, PhD; Alicia Neu, MD; John M. Newmann, PhD, MPH; Allen R. Nissenson, MD; Philippa A. Norton, MED, RD, CSR, LD; Gregorio T. Obrador, MD; Neeta O'Mara, PharmD; Joni J. Pagenkemper, MS, MA, RD; Thakor G. Patel, MD; Jessie Pavlinac, MS, RD, CSR, LD; Glenda Payne, RN, MS, CNN; Sunil Prakash, MD; Sarah S. Prichard, MD, FRCP; William Primack, MD; Doris Ramirez de Pena; Vijaykumar M. Rao, MD; Susan M. Reams, RD, CSR, LD; Sally I. Rice, LCSW, DCSW; Patricia J. Roberts, MS, RN, CNN; Noreen K. Rogers; Michele E. Root; Anton C. Schoolwerth, MD, FAHA; Stephen Seliger, MD; Robert Shay, MD; Michael D. Sitrin, MD; David Siu, MD; D'Andrea F. Skipwith; Lance Sloan, MD, FACE; Jo Ellyn Smith, RD; Wendy L. St. Peter, PharmD; Theodore I. Steinman, MD; Peter Stenvinkel, MD, PhD; Dru Straatman; Sufi Suhail, MRCP; Ahmad Tarakji, MD; Nicola Thomas; Paul D. Thompson; Vicente E. Torres, MD; Wulf H. Utian, MD, PhD; Candace C. Walworth, MD; G. Warwick, MD; Steve Wassner, MD; Jean-Pierre Wauters, MD; Susan K. Webb, MS, RD; Daniel Weis, MD; Miriam F. Weiss, MD; Nanette Wenger, MD

Organizations that took part in the review process include: American Academy of Pediatrics; American Association of Clinical Endocrinology; American College of Cardiology; American Dietetic Association; American Geriatrics Society; American Heart Association; American Nephrology Nurses Association; American Pharmaceutical Association; American Society for Nutritional Sciences; American Society of Pediatric Nephrology (ASPN); American Society of Transplantation; Centers for Disease Control (CDC); European Dialysis and Transplant Nurses Association/European Renal Care Association; Forum of ESRD Networks; Genzyme Molecular Oncology; Indian Health Service (HQ); International Society For Hemodialysis; International Society for Peritoneal Dialysis (ISPD); N.Y. Diabetes Center; National Association of Nephrology Technicians/Technologists (NANT); National Heart Lung Blood Institute; National Kidney and Urologic Diseases Information; National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH); North American Transplant Coordinators Organization; Polycystic Kidney Disease Foundation; Renal Physicians Association; Sigma Tau Pharmaceuticals; The North American Menopause Society (NAMS)

Participation in the review does not necessarily constitute endorsement of the content of the report by the individuals or the organization or institution they represent.

Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References

Comprehensive nutrition counseling should be offered to all patients with CKD, given the high incidence of malnutrition and other nutritional abnormalities. Detailed guidelines of the K/DOQI Nutrition Work Group for adults and children recommend a regular assessment of nutritional status and intervention by a renal dietitian (331) However, dietary management of patients with dyslipidemias is not specifically addressed in the K/DOQI nutrition guidelines. Therefore, the Work Group made the following recommendations (Table 27).

Table 27.  Dietary modifications that may be appropriate for adults with chronic kidney disease (3)
Food ChoicesChooseDecrease
  • a

    Diet decisions should be made in consultation with a CKD dietitian to adapt food choices to the patient's individual medical and nutritional condition. Careful selection of foods within each category will be necessary to stay within phosphorus, potassium, and sodium restrictions (4,27,188,190–192).

  • b

    Animal-shaped biscuits;

  • c

    muesli.

Eggs (cholesterol <200 mg per day)Limit to 2 eggs per week, or useEgg yolks and whole eggs (often hidden
 2 egg whites in place of one egg,ingredients in cookies, cakes, desserts)
 or use cholesterol-free egg 
 substitutes regularly 
Meat, poultry, and alternativesLean meat products, well trimmedHigh-fat meats (sausage, bacon, organ meats
 of fatsuch as liver, sweetbreads, brain)
 Poultry without skinSandwich-style meats such as ham, 'cold
 Fish, shellfishcuts', processed meats
 Low-fat tofu; tempeh; soy protein 
 products 
Fish, shellfishFish or shellfish, baked orAvoid consuming bones of fish (sardines,
 broiled without additional fatanchovies, fish heads, etc.) due to phosphorus
  content
Fats and oils (saturated fat <7%Unsaturated oils - safflower, ,Hydrogenated and partially hydrogenated fats
total kcal) (total fat 25%-35% totalsunflower, corn, soybean,Coconut, palm kernel, palm oil, coconut and
kcal)cottonseed, canola, olive, peanutcoconut milk products
 Margarine - made from any of theButter, lard, shortening sold in cans, bacon fat,
 oils above, especially soft and liquidstick margarine
 formsDressing made with egg yolk, cheese, sour
 Salad dressings - made from anycream, or milk
 of the oils above 
Breads and grains (dietary fiber goalBreads without toppings or cheeseHomemade breads made with recommended
of >20 g per day may be difficult withingredientsfats and oils
fluid restriction; focus on viscous/Cereals: oat, wheat, corn, multigrainBreads of high-fat content such as croissants,
soluble fiber)Pasta, rice crackers - low-fat animalflaky dinner rolls
 crackersb, unsalted soda crackers Granolasc that contain coconut or
 and bread sticks, melba toasthydrogenated fats
  High-fat crackers (more than 3 g of fat per
  serving on label)
  Commercially baked pastries and biscuits
Fruits and vegetablesChoices within CKD diet parametersFried fruits or vegetables or served with butter
 in fresh, frozen, or low-sodiumor cream sauces; avocado
 canned forms 
Sweets (may be restricted forSweets: sugar, syrup, honey, jam,Candy made with chocolate, cream, butter,
diabetics or in presence of highpreserves, candy made without fatFrostings. Ice cream and regular frozen
triglycerides)(hard candy)desserts
 Frozen desserts: low-fat and non-fatCommercially baked cookies, cakes, cream
 sherbet, sorbet, fruit iceand regular pies
 Cookies, cakes, and pies made withCommercially fried pastries such as
 egg whites or egg substitutes ordoughnuts
 recommended fats; angel food cake;Whipped cream
 fig and other fruit bar cookies 
 Non-dairy regular and frozen 
 whipped toppings in moderation 

During the initial assessment and subsequent follow-up of patients with CKD, it is important to assess malnutrition and protein energy deficits. If the patient is well nourished, dietary modifications for dyslipidemias can be undertaken safely. In some patients with CKD, standard CKD diet recommendations may have already appropriately reduced many foods with high unsaturated fats such as milk products.

It is important to consider patients with low total cholesterol. A low total cholesterol level, especially in association with chronic protein-energy deficits and/or the presence of comorbid conditions, may signal malnutrition. Patients with cholesterol <150 mg/dL (<3.88 mmol/L) should be assessed for possible nutritional deficiencies. For patients with malnutrition or protein-energy deficits, improving nutrition should be the primary goal. Dietary recommendations may include high-protein foods, with a liberal intake of foods high in saturated fat. However, in the majority of cases, acceptable protein sources low in saturated fat should be encouraged (Table 28). Low-fat dairy products, nuts, seeds, and beans may provide protein, but potassium and phosphorus contents should still be limited. Overall, healthy food preparation should be encouraged, such as using peanut, canola, or olive oil in cooking, since these are high in monounsaturated fats.

Table 28.  Nutritional characteristics of some protein-source food itemsa
Protein SourceKcalTotal fat (g)Saturated fat (g)Cholesterol (mg)
  • a

    Three-ounce servings, trimmed after cooking, skin removed (332). Kcal, kilocalories.

  • b

    b Type of fish.

Beef eye of round, roasted1404260
Beef top round steak, broiled1504170
Pork tenderloin, roasted whole1404165
Chicken breast, baked1202170
Chicken drumstick, baked1304180
Turkey breast, baked1201055
Turkey wing, baked1403160
Ground beef (10%), broiled, well-done21011485
Ground beef (17%), broiled, well-done23013585
Ground turkey19512560
Orange roughy* broiled701020
Blue crab, steamed901080
Sole, broiled1001060
Halibut, broiled1202030

Plant sterols

Plant sterols block the absorption of cholesterol from the small intestine by entering into micelles, which are needed for cholesterol to dissolve. Consequently, endogenous and dietary cholesterol becomes insoluble, and is therefore excreted in the stool. Plant sterols themselves are not absorbed or excreted well. Studies in the general population have shown that the intake of 2–3 g of plant sterols per day lowers LDL by 6–15%, with minimal change to HDL or triglycerides (4) Reductions in LDL have been seen in hypercholesterolemic children (332,333) and adults (334–336) The use of esters needs to take into account daily total fat consumption, and adjustments in caloric intake may also be needed. There is no contraindication to the use of plant sterols in patients with CKD; however, they should be used as a fat substitute and not for other therapeutic reasons. Unfortunately, some commercial products are expensive (Table 29).

Table 29.  Margarines containing plant sterol/stanol estersa
Nutritional compositionBenecol®Benecol Light®Take Control®Take Control Light®
  • a

    One serving (15 g) of margarines (331). Benecol®and Benecol Light® are registered trademarks of Neil Consumer Health-Care, (Fort Washington, PA), a division of Johnson & Johnson (http://www.benecol.com). Take Control® and Take Control Light® are registered trademarks of Unilever Bestfoods, Engelwood Cliffs, NJ (http://www.takecontrol.com).

  • *

    *Insignificant amount.

Kilocalories80458045
Kilocalories from fat80455040
Total fat (g)9585
Saturated fat (g)10.510.5
Polyunsaturated fat (g)3222
Monounsaturated fat (g)42.54.52
Cholesterol (mg)00<55
Sodium (mg)1101108585
Carbohydrate (g)0000
Protein (g)0000
Potassium (mg)3.53.5**
Phosphorus (mg)<1<1**
Plant sterol content1.7 g stanol esters1.7 g stanol esters1.65 g soybean extract1.65 g soybean extract
CommentsCook, bake or fry Can be used in cooking; contains 60% soybean and canolaContains 35% soybean and canola oils

Fiber

Viscous fiber should be increased by 5–25 g per day to help reduce total cholesterol and LDL (4) High-fiber diets require additional fluid intake, which may be difficult for the anuric dialysis patient who is often limited to 1 L of fluid per day. Many high-fiber foods are also restricted in the renal diet due to their high phosphorus and/or potassium content. These foods may have to be included more often, and the phosphate binder or potassium content of the dialysate may need to be adjusted, to maintain normal serum phosphorus and potassium. Since each company varies the ingredients in their brands, it is essential to read nutrition labels, and to use those lowest in potassium and phosphorus. For example, a 1-cup portion of Kellogg's Raisin Bran® (Kelloggs, Battle Creek, MI) has less potassium and phosphorus than Post's Raisin Bran® (Kraft Foods, Inc., Northfield, IL). Common foods containing natural fiber are described in Table 30.

Table 30.  Contents of some commercially available cereals high in fiber (332)
ProductServing sizeFiber (g)K (mg)P (mg)
  • a

    May be soaked to remove additional potassium. Soak for several hours, drain this water, replace with new water, and cook the vegetable as usual. Registered trademarks: All Bran®, Common Sense Oat Bran®, and Kellogg's Raisin Bran®, Kellogg USA Inc, Battle Creek, MI; Post Bran Flakes®and Post Raisin Bran®, Kraft Foods Inc., Northfield, IL; Cheerios®, Fiber One®, General Mills Raisin Bran®, and Wheaties®, General Mills, Minneapolis, MN; Quaker Crunchy Bran®and Quaker Old Fashioned Oatmeal®, Quaker Oats Company, Chicago, IL; Ralston Oatmeal®, Ralston Foods, a division of Ralcorp, St. Louis, MO. K, potassium; P, phosphorus

Cereals
 All Bran®113.4 g10310300
 Post Bran Flakes®151.2 g6180150
 Cheerios®151.2 g390100
 Quaker Crunchy Bran®170 g55636
 Fiber One®113.4 g13230150
 Common Sense Oat Bran®113.4 g4120150
 General Mills Raisin Bran®170 g3220150
 Kellogg's Raisin Bran®226.8 g8.2350200
 Post Raisin Bran®226.8 g8380250
 General Mills Wheaties®226.8 g3110100
 Quaker Old Fashioned Oatmeal®113.4 g dry3.7143183
 Ralston Oatmeal®170 g cooked4.6116110
Fruit
 Apple, raw, skin onMedium3.715910
 Blackberries, raw113.4 g3.814115
 Orange, navel, raw1 fruit3.123325
 Peaches, canned in water 226.8 g3.224224
 Pear, canned in water p226.8 g4.012917
 Raspberries, raw113.4 g4.2948
Vegetables
 Broccoli, boileda113.4 g2.32284.6
 Brussels sprouts, boiled113.4 g224744
 Carrots, sliced, boiled113.4 g2.617723
 Corn, boiled113.4 g2.320484
 Mixed vegetables, frozen113.4 g415446
 Green peas, frozen, boiled113.4 g4.413472
 Spinach, boileda113.4 g2.2419150
Bread
 Pumpernickel1 slice2.16757
 American rye1 slice1.95340
 Whole wheat1 slice1.97164

Patients who are unable to consume adequate fiber through their diet can add natural fiber in the form of a tasteless powder to their meals (Table 31). Psyllium is a viscous fiber recommended by the ATP III (4) The most common commercial product is Metamucil® (Proctor and Gamble, Cincinnati, OH). It should be mixed with 236.58 mL of fluid per dose, which may be difficult due to strict fluid restrictions in the dialysis patient. Magnesium may also be an excipient in some psyllium products, and those should be avoided. Sugar-free products are available for use in diabetics. Psyllium is also made generically, and it is imperative to review the product insert before use to ensure that it contains low amounts of potassium, sodium, and magnesium. Unifiber® (Niche Pharmaceuticals, Inc., Roanoke, TX, USA) contains powdered cellulose, corn syrup solids and xanthan gum, and can easily be blended into applesauce, Cream of Wheat, or 88.72 mL of apple juice or water to provide 3 g of natural fiber. These products do not interfere with the absorption of medications or vitamins. Constipation is a chronic problem for dialysis patients who are restricted in the actual amount of fiber and fluid they can consume. Osmotic agents such as Polyethylene Glycol 3350, NF Powder, e.g. Miralax® 17 g p.o (Braintree Laboratories, Braintree, MA, USA) or other products, may be needed to relieve constipation.

Table 31.  The electrolyte content of some commonly used fiber supplements
ProductFiber (g)kCalNa (mg)K (mg)P (mg)
  1. Metamucil®and Metamucil Wafers® are registered trademarks of Procter and Gamble, Cincinnati, OH; Unifiber® is a registered trademark of Niche Pharmaceuticals, Inc., Roanoke, TX; Hyfiber® is a registered trademark of National Nutrition Lancaster, PA. kCal, kilocalories; tbsp, tablespoon; K, potassium; P, phosphorus

Metamucil®3 g per dose30 mg per dose
MetamucilWafers®3 g per 2 wafers60 mg per dose
Unifiber®1 tbsp (3 g)4000
Hyfiber®1 tbsp (3 g)141512

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Guidelines, evidence, and research recommendations
  6. Assessment of dyslipidemias
  7. Treating dyslipidemias
  8. Treatment of adults with dyslipidemias
  9. Treatment of adolescents with dyslipidemias
  10. Research recommendations
  11. Acknowledgements
  12. Appendix 1. therapeutic lifestyle change diet for patients with chronic kidney disease
  13. References
  • 1
    Levey AS, Beto JA, Coronado BE et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32: 853906.
  • 2
    National Kidney Foundation. K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kidney Dis 2003; 41 (Suppl. 3): S1S91.
  • 3
    National Kidney Foundation Kidney. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39 (Suppl. 1): S1S266.
  • 4
    Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 24862497.
  • 5
    United States Renal Data System. USRDS 2000 Annual Data Report. Atlas of End-Stage Renal Disease in the United States. 12th Annual Report. Bethesda, MD: Division of Kidney, Urologic, and Hematological Diseases, National Institute of Diabetes and Digestive Kidney Diseases, National Institues of Health, 2000.
  • 6
    Anonymous. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992; 89: 525584.
  • 7
    Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31: 607617.
  • 8
    Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO (4), Ca x PO (4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001; 12: 21312138.
  • 9
    Massy ZA, Chadefaux-Vekemans B, Chevalier A et al. Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant 1994; 9: 11031108.
  • 10
    Bostom AG, Shemin D, Lapane KL et al. Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: a case-control study. Atherosclerosis 1995; 114: 93103.
  • 11
    Bostom AG, Shemin D, Verhoef P et al. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study. Arterioscler Thromb Vasc Biol 1997; 17: 25542558.
  • 12
    Jungers P, Chauveau P, Bandin O et al. Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients. Miner Electrolyte Metab 1997; 23: 170173.
  • 13
    Moustapha A, Naso A, Nahlawi M et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998; 97: 138141.
  • 14
    Kunz K, Petitjean P, Lisri M et al. Cardiovascular morbidity and endothelial dysfunction in chronic haemodialysis patients: is homocyst (e) ine the missing link? Nephrol Dial Transplant 1999; 14: 19341942.
  • 15
    Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11: 134137.
  • 16
    Mallamaci F, Zoccali C, Tripepi G et al. Hyperhomocysteinemia predicts cardiovascular oucomes in hemodialysis patients. Kidney Int 2002; 61: 609614.
  • 17
    Stenvinkel P, Heimburger O, Paultre F et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55: 18991911.
  • 18
    Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55: 648658.
  • 19
    Stenvinkel P, Lindholm B, Heimburger M, Heimburger O. Elevated serum levels of soluble adhesion molecules predict death in pre–dialysis patients: association with malnutrition, inflammation, and cardiovascular disease. Nephrol Dial Transplant 2000; 15: 16241630.
  • 20
    Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2000; 35: 469476.
  • 21
    Haubitz M, Brunkhorst R. C-reactive protein and chronic Chlamydia pneumoniae infection – long-term predictors for cardiovascular disease and survival in patients on peritoneal dialysis. Nephrol Dial Transplant 2001; 16: 809815.
  • 22
    Holdaas H, Fellström B, Jardine A et al. Prevention of cardiac death and non-fatal coronary events with fluvastatin in renal transplant patients: a mulicentre randomised placebo controlled trial. Lancet 2003; 361: 202431.
  • 23
    Anonymous. The Sixth Report Of The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 24132446.
  • 24
    American Diabetes Association. Clinical practice recommendations. Diabetes Care 2002; 25 (Suppl. 1): 2AD.
  • 25
    Mosca L, Collins P, Herrington DM et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 104: 499503.
  • 26
    U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: Recommendaion and rationale. Ann Intern Med 2002; 136: 157160.
  • 27
    Krauss RM, Eckel RH, Howard B et al. AHA Dietary Guidelines: revision. A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation 2000; 102: 22842299.
  • 28
    Smith SC Jr, Blair SN, Bonow RO et al. AHA/ACC Scientific Statement: AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease. update: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 2001; 104: 15771579.
  • 29
    Goldstein LB, Adams R, Becker K et al. Primary prevention of ischemic Stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001; 103: 163182.
  • 30
    The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives. A clinical practice guideline for treating tobacco use and dependence: A US Public Health Service report. JAMA 2000; 283: 32443254.
  • 31
    MRC/BHF. Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 722.
  • 32
    Macmahon M, Kirkpatrick C, Cummings CE et al. A pilot study with simvastatin and folic acid/vitamin B12 for the Study Of The Effectiveness Of Additional Reductions In Cholesterol and Homocysteine (SEARCH). Nutr Metabol Cardiovasc Dis 2000; 10: 195203.
  • 33
    Brown WV. Cholesterol lowering in atherosclerosis. Am J Cardiol 2000; 86: 29H32H.
  • 34
    Gotto AM. Ongoing clinical trials of statins. Am J Cardiol 2001; 88 (Suppl.): 36F40F.
  • 35
    Isaacsohn JL, Davidson MH, Hunninghake D, Singer R, Mclain R, Black DM. Aggressive Lipid-Lowering Initiative Abates New Cardiac Events (ALLIANCE): rationale and design of atorvastatin versus usual care in hypercholesterolemic patients with coronary artery disease. Am J Cardiol 2000; 86: 250252.
  • 36
    Cannon CP, Mccabe CH, Belder R, Breen J, Braunwald E. Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trial. Am J Cardiol 2002; 89: 860861.
  • 37
    Shepherd J, Blauw GJ, Murphy MB et al. The design of a Prospective Study Of Pravastatin In The Elderly At Risk (PROSPER). Am J Cardiol 1999; 84: 11921197.
  • 38
    Steiner G. Lipid intervention trials in diabetes. Diabetes Care 2000; 23 (Suppl. 2): B49B53.
  • 39
    Wanner 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: S222S226.
  • 40
    Diercks GF, Janssen WM, Van Boven AJ et al. Rationale, design, and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive, nonhypercholesterolemic subjects with microalbuminuria (the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [PREVEND IT]). Am J Cardiol 2000; 86: 635638.
  • 41
    Larosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282: 23402346.
  • 42
    Sacks FM, Tonkin AM, Shepherd J et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. The prospective pravastatin pooling project. Circulation 2000; 102: 1900.
  • 43
    Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20: 614620.
  • 44
    the Long-term Intervention with Pravastatin in Ischaemic Disease (Lipid) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339: 13491357.
  • 45
    Goldberg RB, Mellies MJ, Sacks FM et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The CARE Investigators. Circulation 1998; 98: 25132519.
  • 46
    Ghanem H, Van Den Dorpel MA, Weimar W, Man in ‘t Veld AJ, El-Kannishy MH, Jansen H. Increased low density lipoprotein oxidation in stable kidney transplant recipients. Kidney Int 1996; 49: 488493.
  • 47
    Van Den Dorpel MA, Ghanem H, Rischen-Vos J, Man in ‘t Veld AJ, Jansen H, Weimar W. Conversion from cyclosporine A to azathioprine treatment improves LDL oxidation in kidney transplant recipients. Kidney Int 1997; 51: 16081612.
  • 48
    Quaschning T, Mainka T, Nauck M, Rump LC, Wanner C, Kramer-Guth A. Immunosuppression enhances atherogenicity of lipid profile after transplantation. Kidney Int Suppl 1999; 71: S235S237.
  • 49
    Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996; 7: 158165.
  • 50
    Aker S, Ivens K, Grabensee B, Heering P. Cardiovascular risk factors and diseases after renal transplantation. Int Urol Nephrol 1998; 30: 777788.
  • 51
    Aakhus S, Dahl K, Widerøe TE. Cardiovascular morbidity and risk factors in renal transplant patients. Nephrol Dial Transplant 1999; 14: 648654.
  • 52
    Kasiske BL, Chakkera H, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11: 17351743.
  • 53
    Ong CS, Pollock CA, Caterson RJ, Mahony JF, Waugh DA, Ibels LS. Hyperlipidemia in renal transplant recipients: Natural history and response to treatment. Medicine 1994; 73: 215223.
  • 54
    Barbagallo CM, Pinto A, Gallo S et al. Carotid atherosclerosis in renal transplant recipients: relationships with cardiovascular risk factors and plasma lipoproteins. Transplantation 1999; 67: 366371.
  • 55
    Roodnat JI, Mulder PG, Zietse R et al. Cholesterol as an independent predictor of outcome after renal transplantation. Transplantation 2000; 69: 17041710.
  • 56
    Massy ZA, Mamzer-Bruneel MF, Chevalier A et al. Carotid atherosclerosis in renal transplant recipients. Nephrol Dial Transplant 1998; 13: 17921798.
  • 57
    Biesenbach G, Margreiter R, Konigsrainer A et al. Comparison of progression of macrovascular diseases after kidney or pancreas and kidney transplantation in diabetic patients with end-stage renal disease. Diabetologia 2000; 43: 231234.
  • 58
    Scanferla F, Toffoletto PP, Roncali D, Bazzato G. Associated effect of hepatic hydroxymethylglutaryl coenzyme A reductase + angiotensin converting enzyme inhibitors on the progression of renal failure in hypertensive subjects. Am J Hypertens 1991; 4: 868.
  • 59
    Hommel E, Andersen P, Gall M-A et al. Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy. Diabetologia 1992; 35: 447451.
  • 60
    Nielsen S, Schmitz O, Mæller N et al. Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria. Diabetologia 1993; 36: 10791086.
  • 61
    Thomas ME, Harris KPG, Ramaswamy C et al. Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria. Kidney Int 1993; 44: 11241129.
  • 62
    Aranda Arcas JL, Sanchez R, Guijarro C et al. [Effect of pravastatin on hypercholesterolemia associated with proteinuria]. Ann Med International 1994; 11: 523527.
  • 63
    Lam KSL, Cheng IKP, Janus ED, Pang RWC. Cholesterol-lowering therapy may retard the progression of diabetic nephropathy. Diabetologia 1995; 38: 604609.
  • 64
    Rayner BL, Byrne MJ, Van Zyl Smit R. A prospective clinical trial comparing the treatment of idiopathic membranous nephropathy and nephrotic syndrome with simvastatin and diet, versus diet alone. Clin Nephrol 1996; 46: 219224.
  • 65
    Smulders YM, Van Eeden AE, Stehouwer CDA, Weijers RNM, Slaats EH, Silberbusch J. Can reduction in hypertriglyceridemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? Eur J Clin Invest 1997; 27: 9971002.
  • 66
    Tonolo G, Ciccarese M, Brizzi P et al. Reduction of albumin excretion rate in normotensive microalbumiuric type 2 diabetic pateints during long-term simvastatin treatment. Diabetes Care 1997; 20: 18911895.
  • 67
    Olbricht CJ, for the Simvastatin in Nephrotic Syndrome Study Group. Simvastatin in nephrotic syndrome. International Symposium on Lipids and Renal Disease, Kashikojima, Japan, 1999.
  • 68
    Nishimura M, Sasaki T, Oishi A et al. Angiotensin converting enzyme inhibitor and probucol suppress time-dependent increase in urinary type IV collagen excretion of NIDDM with early nephropathy. J Am Soc Nephrol 1999; 10: 131A.
  • 69
    Buemi M, Allegra A, Corica F et al. Effect of fluvastatin on proteinuria in patients with immunoglobulin A nephropathy. Clin Pharmacol Ther 2000; 67: 427431.
  • 70
    Fried LF, Orchard TJ, Kasiske BL. The effect of lipid reduction on renal disease progression: a meta-analysis. Kidney Int 2001; 59: 260269.
  • 71
    Katznelson S, Wilkinson AH, Kobashigawa JA et al. The effect of pravastatin on acute rejection after kidney transplantation – A pilot study. Transplantation 1996; 61: 14691474.
  • 72
    Kasiske BL, Heim-Duthoy KL, Singer GG, Watschinger B, Germain MJ, Bastani B. The effects of lipid-lowering agents on acute renal allograft rejection. Transplantation 2001; 72: 223227.
  • 73
    Holdaas H, Jardine AG, Wheeler DC et al. Effect of fluvastatin on acute renal allograft rejection: A randomized multicenter trial. Kidney Int 2001; 60: 199097.
  • 74
    Sahu K, Sharma R, Gupta A et al. Effect of lovastatin, an HMG CoA reductase inhibitor, on acute renal allograft rejection. Clin Transplant 2001; 15: 173175.
  • 75
    Walker WG. Hypertension-related renal injury: a major contributor to end-stage renal disease. Am J Kidney Dis 1993; 22: 164173.
  • 76
    Hunsicker LG, Adler S, Caggiula A et al. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 1997; 51: 19081919.
  • 77
    Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med 1998; 158: 9981004.
  • 78
    Klein R, Klein BE, Moss SE, Cruickshank KJ, Brazy PC. The 10-year incidence of renal insufficiency in people with type 1 diabetes. Diabetes Care 1999; 22: 743751.
  • 79
    Hovind P, Rossing P, Tarnow L, Smidt UM, Parving H-H. Progression of diabetic nephropathy. Kidney Int 1997; 59: 702709.
  • 80
    Massy ZA, Khoa TN, Lacour B, Descamps-Latscha B, Man NK, Jungers P. Dyslipidaemia and the progression of renal disease in chronic renal failure patients. Nephrol Dial Transplant 1999; 14: 2397.
  • 81
    Samuelsson O, Attman PO, Knight-Gibson C et al. Plasma levels of lipoprotein (a) do not reflect progression of human chronic renal failure. Nephrol Dial Transplant 1996; 11: 22372243.
  • 82
    Yokoyama H, Tomonaga O, Hirayama M et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia 1997; 40: 405411.
  • 83
    Samuelsson O, Mulec H, Knight-Gibson C et al. Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency. Nephrol Dial Transplant 1997; 12: 19081915.
  • 84
    Nielsen S, Schmitz A, Rehling M, Mogensen CE. The clinical course of renal function in NIDDM patients with normo- and microalbuminuria. J Intern Med 1997; 241: 133141.
  • 85
    Gall M-A, Nielsen FS, Smidt UM. Parving H-H. The course of kidney function in type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy. Diabetologia 1993; 36: 10711078.
  • 86
    Locatelli F, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A. Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Northern Italian Cooperative Study Group. Lancet 1991; 337: 12991304.
  • 87
    Dillon IJ. The quantitative relationship between treated blood pressure and progression of diabetic renal disease. Am J Kidney Dis 1993; 22: 802.
  • 88
    Biesenbach G, Janko O, Zazgornik J. Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant 1994; 9: 10971102.
  • 89
    Toth T, Takebayashi S. Factors contributing to the outcome in 100 adult patients with idiopathic membranous glomerulonephritis. Int Urol Nephrol 1994; 26: 93106.
  • 90
    Aakhus S, Dahl K, Widerøe TE. Hyperlipidaemia in renal transplant patients. J Intern Medical 1996; 239: 407415.
  • 91
    Gonyea JE, Anderson CF. Weight change and serum lipoproteins in recipients of renal allografts. Mayo Clinic Proc 1992; 67: 653657.
  • 92
    Brown JH, Murphy BG, Douglas AF et al. Influence of immunosuppressive therapy on lipoprotein (a) and other lipoproteins following renal transplantation. Nephron 1997; 75: 277282.
  • 93
    Moore R, Thomas D, Morgan E et al. Abnormal lipid and lipoprotein profiles following renal transplantation. Transplant Proc 1993; 25: 10601061.
  • 94
    Querfeld U, Lang M, Friedrich JB, Kohl B, Fiehn W, Scharer K. Lipoprotein (a) serum levels and apolipoprotein (a) phenotypes in children with chronic renal disease. Pediatr Res 1993; 34: 772776.
  • 95
    Silverstein DM, Palmer J, Polinsky MS, Braas C, Conley SB, Baluarte HJ. Risk factors for hyperlipidemia in long-term pediatric renal transplant recipients. Pediatr Nephrol 2000; 14: 105110.
  • 96
    Goldstein S, Duhamel G, Laudat MH et al. Plasma lipids, lipoproteins and apolipoproteins AI, AII. and B in renal transplanted children: what risk for accelerated atherosclerosis? Nephron 1984; 38: 8792.
  • 97
    Van Gool S, Van Damme-Lombaerts R, Cobbaert C, Proesmans W, Eggermont E. Lipid and lipoprotein abnormalities in children on hemodialysis and after renal transplantation. Transplant Proc 1991; 23: 13751377.
  • 98
    Milliner DS, Morgenstern BZ, Murphy M, Gonyea J, Sterioff S. Lipid levels following renal transplantation in pediatric recipients. Transplant Proc 1994; 26: 112114.
  • 99
    Singh A, Tejani C, Benfield M, Tejani A. Sequential analysis of the lipid profile of children post-renal transplantation. Pediatr Transplant 1998; 2: 216223.
  • 100
    Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112S119.
  • 101
    Parekh RS, Carroll CE, Wolfe RA, Port FK. Cardiovascular mortality in children and young adults with end-stage kidney disease. J Pediatr 2002; 141: 191197.
  • 102
    Strong JP, Malcom GT, Mcmahan CA et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999; 281: 727735.
  • 103
    Antikainen M, Sariola H, Rapola J, Taskinen M-R, Holthöfer H, Holmberg C. Pathology of renal arteries of dyslipidemic children with congenital nephrosis. APMIS 1994; 102: 129134.
  • 104
    Nayir A, Bilge I, Kilicaslan I, Ander H, Emre S, Sirin A. Arterial changes in paediatric haemodialysis patients undergoing renal transplantation. Nephrol Dial Transplant 2001; 16: 20412047.
  • 105
    Olson RE. Atherogenesis in children. implications for the prevention of atherosclerosis. Adv Pediatr 2000; 47: 5578.
  • 106
    National Heart LaBI. The Lipid Research Clinics Population Studies Data Book, vol 1: the Prevalence Study. Bethesda, MD: US Department of Health and Human Services 1980: NIH Pub no. 801527.
  • 107
    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499502.
  • 108
    Nauck M, Kramer-Guth A, Bartens W, Marz W, Wieland H, Wanner C. Is the determination of LDL cholesterol according to Friedewald accurate in CAPD and HD patients? Clin Nephrol 1996; 46: 319325.
  • 109
    Bairaktari E, Elisaf M, Tzallas C et al. Evaluation of five methods for determining low-density lipoprotein cholesterol (LDL-C) in hemodialysis patients (1). Clin Biochem 2001; 34: 593602.
  • 110
    Sentí M, Pedro-Botet J, Noguës X, Rubiës-Prat J. Influence of intermediate-density lipoproteins on the accuracy of the Friedewald formula. Clin Chem 1991; 37: 13941397.
  • 111
    Ticho BS, Neufeld EJ, Newburger JW, Harris N, Baker A, Rifai N. Utility of direct measurement of low-density lipoprotein cholesterol in dyslipidemic pediatric patients. Arch Pediatr Adolesc Med 1998; 152: 787791.
  • 112
    Gore JM, Goldberg RJ, Matsumoto AS, Castelli WP, Mcnamara PM, Dalen JE. Validity of serum total cholesterol level obtained within 24 hours of acute myocardial infarction. Am J Cardiol 1984; 54: 722725.
  • 113
    Ryder REJ, Hayes TM, Mulligan IP, Kingswood JC, Willimas S, Owens DR. How soon after myocardial infarction should plasma lipid values be assessed? BMJ 1984; 289: 16511653.
  • 114
    Henkin Y, Crystal E, Goldberg Y et al. Usefulness of lipoprotein changes during acute coronary syndromes for predicting postdischarge lipoprotein levels. Am J Cardiol 2002; 89: 711.
  • 115
    Mendez I, Hachinski V, Wolfe B. Serum lipids after stroke. Neurology 1987; 37: 507511.
  • 116
    Gallin JI, Kaye D, O'Leary WM. Serum lipids in infection. N Engl J Med 1969; 281: 10811086.
  • 117
    Alvarez C, Ramos A. Lipids, lipoproteins, and apoproteins in serum during infection. Clin Chem 1986; 32: 142145.
  • 118
    Sammalkorpi K, Valtonen V, Kerttula Y, Nikkilä E, Taskinen M-R. Changes in serum lipoprotein pattern induced by acute infections. Metabolism 1988; 37: 859865.
  • 119
    Figueroa O, Franco-Saenz R, Mulrow PJ, Montesinos E. Changes in cholesterol levels after coronary artery bypass surgery. Am J Med Sci 1992; 303: 7377.
  • 120
    Aufenanger J, Walter H, Kattermann R. [Studies of lipid and lipoprotein metabolism in man after surgical interventions]. Langenbecks Arch Chir 1993; 378: 4148.
  • 121
    Akgun S, Ertel NH, Mosenthal A, Oser W. Postsurgical reduction of serum lipoproteins: interleukin-6 and the acute-phase response. J Lab Clin Med 1998; 131: 103108.
  • 122
    Dominguez-Munoz JE, Malfertheiner P, Ditschuneit HH et al. Hyperlipidemia in acute pancreatitis. Relationship with etiology, onset, and severity of the disease. Int J Pancreatol 1991; 10: 261267.
  • 123
    Glueck CJ, Lang J, Hamer T, Tracy T. Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. J Lab Clin Med 1994; 123: 5964.
  • 124
    Kasiske BL, Heim-Duthoy KL. Transient reductions in serum cholesterol after renal transplantation. Am J Kidney Dis 1992; 20: 387393.
  • 125
    Kasiske BL, Vazquez MA, Harmon WE et al. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000; 11: S1.
  • 126
    Johnson C, Ahsan N, Gonwa T et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69: 834841.
  • 127
    Mccune TR, Thacker LRII, Peters TG et al. Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation 1998; 65: 8792.
  • 128
    Vanrenterghem Y, Lebranchu Y, Hené R, Oppenheimer F, Ekberg H. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclsporine for prevention of acute renal allograft rejection. Transplantation 2000; 70: 13521359.
  • 129
    Curtis JJ, Galla JH, Woodford SY, Lucas BA, Luke RG. Effect of alternate-day prednisone on plasma lipids in renal transplant recipients. Kidney Int 1982; 22: 4247.
  • 130
    Hollander AA, Hene RJ, Hermans J, Van Es LA, Van Der Woude FJ. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997; 8: 294301.
  • 131
    Hilbrands LB, Demacker PN, Hoitsma AJ, Stalenhoef AF, Koene RA. The effects of cyclosporine and prednisone on serum lipid and (apo) lipoprotein levels in renal transplant recipients. J Am Soc Nephrol 1995; 5: 20732081.
  • 132
    John GT, Dakshinamurthy DS, Jeyaseelan L, Jacob CK. The effect of cyclosporin A on plasma lipids during the first year after renal transplantation. Natl Med J India 1999; 12: 1417.
  • 133
    Kupin W, Venkat KK, Oh HK, Dienst S. Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients. Transplantation 1988; 45: 5355.
  • 134
    Ingulli E, Tejani A, Markell M. The beneficial effects of steroid withdrawal on blood pressure and lipid profile in children postTransplantation in the cyclosporine ERA. Transplantation 1993; 55: 10291033.
  • 135
    Hricik DE, Mayes JT, Schulak JA. Independent effects of cyclosporine and prednisone on posttransplant hypercholesterolemia. Am J Kidney Dis 1991; 18: 353358.
  • 136
    Groth CG, Backman L, Morales JM et al. Sirolimus (rapamycin) -based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 10361042.
  • 137
    Hoogeveen RC, Ballantyne CM, Pownall HJ et al. Effect of sirolimus on the metabolism of ApoB100-containing lipoproteins in renal transplant patients. Transplantation 2001; 72: 12441250.
  • 138
    Joven J, Villabona C, Vilella E, Masana L, Albert IR, Vallës M. Abnormalities of lipoprotein metabolism in patients with the nephrotic syndrome. N Engl J Med 1990; 323: 579584.
  • 139
    Joven J, Espinel E, Simo JM, Vilella E, Camps J, Oliver A. The influence of hypoalbuminemia in the generation of nephrotic hyperlipidemia. Atherosclerosis 1996; 126: 243252.
  • 140
    Kaysen GA, Don B, Schambelan M. Proteinuria, albumin synthesis and hyperlipidaemia in the nephrotic syndrome. Nephrol Dial Transplant 1991; 6: 141149.
  • 141
    Warwick GL, Packard CJ, Demant T, Bedford DK, Boulton-Jones JM, Shepherd J. Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria. Kidney Int 1991; 40: 129138.
  • 142
    Stenvinkel P, Berglund L, Ericsson S, Alvestrand A, Angelin B, Eriksson M. Low-density lipoprotein metabolism and its association to plasma lipoprotein (a) in the nephrotic syndrome. Eur J Clin Invest 1997; 27: 169177.
  • 143
    Demant T, Mathes C, Gütlich K et al. A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients. Kidney Int 1998; 54: 20642080.
  • 144
    O'Brien T, Dinneen SF, O'Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin Proc 1993; 68: 860866.
  • 145
    Tsimihodimos V, Bairaktari E, Tzallas C, Miltiadus G, Liberopoulos E, Elisaf M. The incidence of thyroid function abnormalities in patients attending an outpatient lipid clinic. Thyroid 1999; 9: 365368.
  • 146
    Morris MS, Bostom AG, Jacques PF, Selhub J, Rosenberg IH. Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. Atherosclerosis 2001; 155: 195200.
  • 147
    Verges BL. Dyslipidaemia in diabetes mellitus. Review of the main lipoprotein abnormalities and their consequences on the development of atherogenesis. Diabet Metab 1999; 25 (Suppl. 3): 3240.
  • 148
    Best JD, O'Neal DN. Diabetic dyslipidaemia: current treatment recommendations. Drugs 2000; 59: 11011111.
  • 149
    Betteridge DJ. Diabetic dyslipidaemia. Diabet Obes Metab 2000; 2 (Suppl. 1): S31S36.
  • 150
    Avogaro P, Cazzolato G. Changes in the composition and physico-chemical characteristics of serum lipoproteins during ethanol-induced lipaemia in alcoholic subjects. Metab Clin Exp 1975; 24: 12311242.
  • 151
    Castelli WP, Doyle JT, Gordon T et al. Alcohol and blood lipids. The cooperative lipoprotein phenotyping study. Lancet 1977; 2: 153155.
  • 152
    Lifton L, Scheig R. Ethanol-induced hypertriglyceridemia. Prevalence and contributing factors. Am J Clin Nutr 1978; 31: 614618.
  • 153
    Marth E, Cazzolato G, Bittolo BG, Avogaro P, Kostner GM. Serum concentrations of Lp (a) and other lipoprotein parameters in heavy alcohol consumers. Ann Nutr Metab 1982; 26: 5662.
  • 154
    Taskinen MR, Nikkila EA, Valimaki M et al. Alcohol-induced changes in serum lipoproteins and in their metabolism. Am Heart J 1987; 113: 458464.
  • 155
    Seidel D. Hyperlipoproteinemias and liver disease. Adv Exp Medical Biol 1973; 38: 143153.
  • 156
    Muller P, Felin R, Lambrecht J et al. Hypertriglyceridaemia secondary to liver disease. Eur J Clin Invest 1974; 4: 419428.
  • 157
    Iglesias A, Arranz M, Alvarez JJ et al. Cholesteryl ester transfer activity in liver disease and cholestasis, and its relation with fatty acid composition of lipoprotein lipids. Clin Chim Acta 1996; 248: 157174.
  • 158
    Flynn WJ, Freeman PG, Wickboldt LG. Pancreatitis associated with isotretinoin-induced hypertriglyceridemia. Ann Int Med 1987; 107: 63.
  • 159
    Tangrea JA, Adrianza E, Helsel WE et al. Clinical and laboratory adverse effects associated with long-term, low-dose isotretinoin: incidence and risk factors. The Isotretinoin-Basal Cell Carcinomas Study Group. Cancer Epidemiol Biomarkers Prev 1993; 2: 375380.
  • 160
    Koistinen HA, Remitz A, Gylling H, Miettinen TA, Koivisto VA, Ebeling P. Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid. Diabetes Metabol Res Rev 2001; 17: 391395.
  • 161
    Luoma PV, Myllyla VV, Sotaniemi EA, Hokkanen TE. Plasma HDL cholesterol in epileptics with elevated triglyceride and cholesterol. Acta Neurol Scand 1979; 60: 5663.
  • 162
    Verrotti A, Domizio S, Angelozzi B, Sabatino G, Morgese G, Chiarelli F. Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants. J Paediatr Child Health 1997; 33: 242245.
  • 163
    Papacostas S. Oxcarbazepine versus carbamazepine treatment and induction of serum lipid abnormalities. J Child Neurol 2000; 15: 138140.
  • 164
    Dube MP, Sprecher D, Henry WK et al. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis 2000; 31: 12161224.
  • 165
    Vergis EN, Paterson DL, Wagener MM, Swindells S, Singh N. Dyslipidaemia in HIV–infected patients: association with adherence to potent antiretroviral therapy. Int J STD AIDS 2001; 12: 463468.
  • 166
    Rakotoambinina B, Medioni J, Rabian C, Jubault V, Jais JP, Viard JP. Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1-infected patients receiving triple combination antiretroviral therapy with a protease inhibitor. J Acquir Immune Defic Syndr 2001; 27: 443449.
  • 167
    Kasiske BL, Ma JZ, Kalil RSN, Louis TA. Effects of antihypertensive agents on serum lipids. Ann Intern Med 1995; 122: 133141.
  • 168
    Webb OL, Laskarzewski PM, Glueck CJ. Severe depression of high-density lipoprotein cholesterol levels in weight lifters and body builders by self-administered exogenous testosterone and anabolic-androgenic steroids. Metabol Clin Exp 1984; 33: 971975.
  • 169
    Thompson PD, Cullinane EM, Sady SP et al. Contrasting effects of testosterone and stanozolol on serum lipoprotein levels. JAMA 1989; 261: 11651168.
  • 170
    Teruel JL, Lasuncion MA, Rivera M et al. Nandrolone decanoate reduces serum lipoprotein (a) concentrations in hemodialysis patients. Am J Kidney Dis 1997; 29: 569575.
  • 171
    Castelo-Branco C, Vicente JJ, Figueras F et al. Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Maturitas 2000; 34: 161168.
  • 172
    Van Stiphout WA, Grobbee DE, Hofman A, De Bruijn AM. Do oral contraceptives increase blood pressure and serum total cholesterol in young women? Prev Med 1990; 19: 623629.
  • 173
    Flint PM, Lapane KL, Barbour MM, Derby CA, Carleton RA, Hume AL. Cardiovascular risk profiles of oral contraceptive users and nonusers: a population-based study. Prev Med 1995; 24: 586590.
  • 174
    Connelly PW, Stachenko S, Maclean DR, Petrasovits A, Little JA. The prevalence of hyperlipidemia in women and its association with use of oral contraceptives, sex hormone replacement therapy and nonlipid coronary artery disease risk factors. Canadian Heart Health Surveys Research Group. Can J Cardiol 1999; 15: 419427.
  • 175
    Vierhapper H, Nardi A, Grosser P, Raber W, Gessl A. Low-density lipoprotein cholesterol in subclinical hypothyroidism. Thyroid 2000; 10: 981984.
  • 176
    Keilani T, Schlueter WA, Levin ML, Batlle DC. Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin-converting enzyme inhibitor. Ann Intern Med 1993; 118: 246254.
  • 177
    Ravid M, Neumann L, Lishner M. Plasma lipids and the progression of nephropathy in diabetes mellitus type II: effect of ACE inhibitors. Kidney Int 1995; 47: 907910.
  • 178
    Schnack C, Hoffmann W, Hopmeier P, Schernthaner G. Renal and metabolic effects of 1-year treatment with ramipril or atenolol in NIDDM patients with microalbuminuria. Diabetologia 1996; 39: 16111616.
  • 179
    Agardh CD, Garcia-Puig J, Charbonnel B, Angelkort B, Barnett AH. Greater reduction of urinary albumin excretion in hypertensive type II diabetic patients with incipient nephropathy by lisinopril than by nifedipine. J Hum Hypertens 1996; 10: 185192.
  • 180
    Coggins CH, Dwyer JT, Greene T, Petot G, Snetselaar LG, Van Lente F. Serum lipid changes associated with modified protein diets: results from the feasibility phase of the Modification of Diet in Renal Disease Study. Am J Kidney Dis 1994; 23: 514523.
  • 181
    Borchhardt K, Haas N, Yilmaz N et al. Low dose angiotensin converting enzyme inhibition and glomerular permselectivity in renal transplant recipients. Kidney Int 1997; 52: 16221625.
  • 182
    Hausberg M, Barenbrock M, Hohage H, Muller S, Heidenreich S, Rahn KH. ACE inhibitor versus beta-blocker for the treatment of hypertension in renal allograft recipients. Hypertension 1999; 33: 862868.
  • 183
    Takahara S, Moriyama T, Kokado Y et al. Randomized prospective study of effects of benazapril in renal transplantation: an analysis of safety and efficacy. Clin Exp Nephrol 2002; 6: 242247.
  • 184
    Mourad G, Ribstein J, Mimran A. Converting-enzyme inhibitor versus calcium antagonist in cyclosporine- treated renal transplants. Kidney Int 1993; 43: 419425.
  • 185
    Van Der Schaaf MR, Hene RJ, Floor M, Blankestijn PJ, Koomans HA. Hypertension after renal transplantation. Calcium channel or converting enzyme blockade? Hypertension 1995; 25: 7781.
  • 186
    Midtvedt K, Hartmann A, Foss A et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared with lisinopril. Transplantation 2001; 72: 17871792.
  • 187
    Martinez-Castelao A, Hueso M, Sanz V et al. Double-blind, crossover, comparative study of doxazosin and enalapril in the treatment of hypertension in renal transplant patients under cyclosporine immunosuppression. Transplant Proc 2002; 34: 403406.
  • 188
    Yu, -et al. Etherton T, Naglak M, Jonnalagadda S, Kris-Etherton PM. Effects of the National Cholesterol Education Program's Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis. Am J Clin Nutr 1999; 69: 632646.
  • 189
    Nutrition Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/Doqi). Kidney Disease Outcomes quality initiative clinical practice gudielines for nutrition in chronic renal failure. Am J Kidney Dis 2000; 35: S1S140.
  • 190
    NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. Physical activity and cardiovascular health. JAMA 1996; 276: 241246.
  • 191
    Castaneda C, Grossi L, Dwyer J. Potential benefits of resistance exercise training on nutritional status in renal failure. J Ren Nutr 1998; 8: 210.
  • 192
    Wenger NK. Lipid metabolism, physical activity, and postmenopausal hormone therapy. Am J Kidney Dis 1998; 32: S80S88.
  • 193
    Halbert JA, Silagy CA, Finucane P, Withers RT, Hamdorf PA. Exercise training and blood lipids in hyperlipidemic and normolipidemic adults: a meta-analysis of randomized, controlled trials. Eur J Clin Nutr 1999; 53: 514522.
  • 194
    Bennett WM, Carpenter CB, Shapiro ME et al. Delayed omega-3 fatty acid supplements in renal Transplantation. A double-blind, placebo-controlled study. Transplantation 1995; 59: 352356.
  • 195
    Urakaze M, Hamazaki T, Yano S, Kashiwabara H, Oomori K, Yokoyama T. Effect of fish oil concentrate on risk factors of cardiovascular complications in renal Transplantation. Transplant Proc 1989; 21: 21342136.
  • 196
    Maachi K, Berthoux P, Burgard G, Alamartine E, Berthoux F. Results of a 1-year randomized controlled trial with omega-3 fatty acid fish oil in renal Transplantation under triple immunosuppressive therapy. Transplant Proc 1995; 27: 846849.
  • 197
    Arnadottir M, Eriksson L-O, Germershausen JI, Thysell H, Eriksson LO. Low-dose simvastatin is a well-tolerated and efficacious cholesterol-lowering agent in cyclosporine-treated kidney transplant recipients: double-blind, randomized, placebo-controlled study in 40 patients. Nephron 1994; 68: 5762.
  • 198
    Martinez Hernandez BE, Persaud JW, Varghese Z, Moorhead JF. Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients. Nephrol Dial Transplant 1993; 8: 637641.
  • 199
    Castro R, Queiròs J, Fonseca I et al. Therapy of post-renal transplantation hyperlipidaemia: comparative study with simvastatin and fish oil. Nephrol Dial Transplant 1997; 12: 21402143.
  • 200
    Kliem V, Wanner C, Eisenhauer T et al. Comparison of pravastatin and lovastatin in renal transplant patients receiving cyclosporine. Transplant Proc 1996; 28: 31263128.
  • 201
    Kasiske BL, Tortorice KL, Heim-Duthoy KL, Goryance JM, Rao KV. Lovastatin treatment of hypercholesterolemia in renal transplant recipients. Transplantation 1990; 49: 95100.
  • 202
    Renders L, Mayer-Kadner I, Koch C et al. Efficacy and drug interactions of the new HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal transplant recipients. Nephrol Dial Transplant 2001; 16: 141146.
  • 203
    Santos AF, Keitel E, Bittar AE et al. Safety and efficacy of simvastatin for hyperlipidemia in renal transplant recipients: a double-blind, randomized, placebo-controlled study. Transplant Proc 2001; 33: 11941195.
  • 204
    Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical advisory on the use and safety of statins. Stroke 2002; 33: 23372341.
  • 205
    Stern RH, Yang BB, Horton M, Moore S, Abel RB, Olson SC. Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin. J Clin Pharmacol 1997; 37: 816819.
  • 206
    Halstenson CE, Triscari J, Devault A, Shapiro B, Keane W, Pan H. Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impariment. J Clin Pharmacol 1992; 32: 124132.
  • 207
    Gehr TWB. Sica DA, Slugg PH, Hammett JL, Raymond R, Ford NF. The pharmacokinetics of pravastatin in patients on chronic hemodialysis. Eur J Clin Pharmacol 1997; 53: 117121.
  • 208
    Quérin S, Lambert R, Cusson JR et al. Single-dose pharmacokinetics of 14C-lovastatin in chronic renal failure. Clin Pharmacol Ther 1991; 50: 437441.
  • 209
    Mazzu AL, Lettieri JT, Kelly E et al. Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults. Eur J Clin Pharmacol 2000; 56: 6974.
  • 210
    Lesne M, Sturbois X, Mercier M. Etude pharmacocinetique comparative de deux formes galeniques d'acide nicitinique. Pharmaceutica Acta Helvetica 1976; 51: 367370.
  • 211
    Abshagen U, Kösters W, Kaufman B, Lang PD. Pharmacokinetics of bezafibrate after single and multiple doses in the presence of renal failure. Klin Wochenschr 2001; 58: 889896.
  • 212
    Anderson P, Norbeck HE. Clinical pharmacokinetics of bezafibrate in patients with impaired renal function. Eur J Clin Pharmacol 1981; 21: 209214.
  • 213
    Williams AJ, Baker F, Walls J. The short term effects of bezafibrate on the hypertriglyceridaemia of moderate to severe uraemia. Br J Clin Pharmacol 1984; 18: 361367.
  • 214
    Goldberg AP, Sherrard DJ, Haas LB, Brunzell JD. Control of clofibrate toxicity in uremic hypertriglyceridemia. Clin Pharmacol Ther 1977; 21: 317325.
  • 215
    Viikari J, Anttila M, Kasanen A. The use of clofibrate in patients with renal insufficiency. Int J Clin Pharmacol Ther Toxicol 1983; 21: 7780.
  • 216
    Merk W, Graben N, Hartmann H, Nikolaus C, Schlierf G, Schwandt P. Serum levels of free non-protein bound clofibrinic acid after single dosing to patients with impaired renal function of various degrees – a multicenter study. Int J Clin Pharmacol Ther Toxicol 1987; 25: 5962.
  • 217
    Desager JP, Costermans J, Verberckmoes R, Harvengt C. Effect of hemodialysis on plasma kinetics of fenofibrate in chronic renal failure. Nephron 1982; 31: 5154.
  • 218
    Knauf H, Kolle EU, Mutschler E. Gemfibrozil absorption and elimination in kidney and liver disease. Klin Wochenschr 1990; 68: 692698.
  • 219
    Evans JR, Forland SC, Cutler RE. The effect of renal function on the pharmacokinetics of gemfibrozil. J Clin Pharmacol 1987; 27: 9941000.
  • 220
    Ridker PM, Rifai N, Clearfield M et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 195965.
  • 221
    Albert MA, Danielson E, Rifai N, Ridker PM. PRINCE I. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286: 6470.
  • 222
    Gotto AM, Farmer JA. Pleitropic effects of statins: do they matter? Curr Opin Lipidol 2001; 12: 391394.
  • 223
    Munford RS. Statins and the acute-phase response. N Engl J Med 2001; 344: 20162018.
  • 224
    Simpson RJ Jr. Placing PRINCE in perspective. JAMA 2001; 286: 9193.
  • 225
    Park JW, Siekmeier R, Lattke P et al. Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001; 6: 351361.
  • 226
    Åsberg A, Hartmann A, Fjeldså E, Bergan S, Holdaas H. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in reanl transplant recipients. Am J Transplant 2001; 1: 382386.
  • 227
    Mück W, Mai I, Fritsche L et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999; 65: 251261.
  • 228
    Arnadottir M, Eriksson L-O, Thysell H, Karkas JD. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without cyclosporine. Nephron 1993; 65: 410413.
  • 229
    Ichimaru N, Takahara S, Kokado Y et al. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 2001; 158: 417423.
  • 230
    Velosa JA, La Belle P, Ronca PD. et al. Pharmacokinetics of lovastatin in renal transplant patients on azathioprine or cyclosporine. J Am Soc Nephrol 1990; 1: 325 (Abstract).
  • 231
    Cooper GR, Myers GL, Smith SJ, Schlant RC. Blood lipid measurements. Variations and practical utility. JAMA 1992; 267: 16521660.
  • 232
    Olbricht C, Wanner C, Eisenhauer T et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62: 311321.
  • 233
    Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation 1996; 62: 15591564.
  • 234
    Kovarik JM, Hartmann S, Hubert M et al. Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus. J Clin Pharmacol 2002; 42: 222228.
  • 235
    Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999; 39: 501504.
  • 236
    Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177182.
  • 237
    Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 5865.
  • 238
    Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000; 68: 391400.
  • 239
    Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 5461.
  • 240
    Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 4953.
  • 241
    Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332341.
  • 242
    Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000; 56: 225229.
  • 243
    Azie NE, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64: 369377.
  • 244
    Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267274.
  • 245
    Ziviani L, Da Ros L, Squassante L, Milleri S, Cugola M, Iavarone LE. The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects. Br J Clin Pharmacol 2001; 51: 147152.
  • 246
    Jacobson RH, Wang P, Glueck CJ. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA 1997; 277: 296297.
  • 247
    Alderman CP. Possible interaction between nefazodone and pravastatin. Ann Pharmacother 1999; 33: 871.
  • 248
    Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118127.
  • 249
    Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998; 63: 397402.
  • 250
    Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice–simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477483.
  • 251
    Ditusa L, Luzier AB. Potential interaction between troglitazone and atorvastatin. J Clin Pharm Ther 2000; 25: 279282.
  • 252
    Lin JC, Ito MK. A drug interaction between troglitazone and simvastatin. Diabetes Care 1999; 22: 21042106.
  • 253
    Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 2000; 68: 592597.
  • 254
    Nakai A, Nishikata M, Matsuyama K, Ichikawa M. Drug interaction between simvastatin and cholestyramine in vitro and in vivo. Bio Pharm Bull 1996; 19: 12311233.
  • 255
    Wen X, Wang J-S, Backman JT, Kivstö KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 2001; 29: 13591361.
  • 256
    Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 2000; 68: 122129.
  • 257
    Pan W-J, Gustavson LE, Achari R et al. Lack of a clinicallly significant pharmacokinenic interaction between fenofibrate and pravstatin in healthy volunteers. J Clin Pharmacol 2000; 40: 316323.
  • 258
    Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001; 69: 340345.
  • 259
    Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol 1995; 76: 80A83A.
  • 260
    Hunninghake D, Insull Wjr Toth P, Davidson D, Donovan JM, Burke SK. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis 2001; 158: 407416.
  • 261
    Braunlin W, Zhorov E, Guo A et al. Bile acid binding to sevelamer HCl. Kidney Int 2002; 62: 611619.
  • 262
    Keogh A, Day R, Critchley L, Duggin G, Baron D. The effect of food and cholestyramine in the absorption of cyclosporine in cardiac transplant recipients. Transplant Proc 1988; 20: 2730.
  • 263
    Jensen RA, Lal SM, Diaz-Arias A et al. Does cholestyramine interfere with cyclosporine absorption? A prospective study in renal transplant patients. ASAIO J 1995; 41: M704M706.
  • 264
    Kosoglou T, Meyer I, Veltri EP et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002; 54: 309319.
  • 265
    Gagne C, Bays HE, Weiss SR et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90: 10841091.
  • 266
    Davidson MH, Mcgarry T, Bettis R et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40: 21252134.
  • 267
    Kerzner B, Corbelli J, Sharp S et al. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003; 91: 418424.
  • 268
    Chertow GM, Burke SK, Lazarus JM et al. Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis 1997; 29: 6671.
  • 269
    Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62: 245252.
  • 270
    Austin MA, Hokanson JE, Edwards, KL Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998; 81: 7B12B.
  • 271
    Assmann G, Schulte H, Funke H, Von Eckardstein A. The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J 1998; 19 (Suppl. M): M8M14.
  • 272
    Cui Y, Blumenthal RS, Flaws JA et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001; 161: 14131419.
  • 273
    Abate N, Vega GL, Grundy SM. Variability in cholesterol content and physical properties of lipoproteins containing apolipoprotein B-100. Atherosclerosis 1993; 104: 159171.
  • 274
    The Lipid Research Clinics Program Epidemiology Committee. Plasma lipid distributions in selected North American populations. The Lipid Research Clinics Program Prevalence Study. Circulation 1979; 60: 427439.
  • 275
    Anonymous. Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 1995; 75: 894903.
  • 276
    Lawson ML, Gerstein HC, Tsui E, Zinman B. Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes. A systematic review and meta-analysis. Diabetes Care 1999; 22 (Suppl. 2): B35B39.
  • 277
    UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837853.
  • 278
    Lageder H. [Comparative double-blind investigation of bezafibrate and clofibrate in patients with primary hyperlipoproteinaemia]. Wien Klin Wochenschr 1980; 92: 95101.
  • 279
    Dick TB, Marples J, Ledermann HM, Whittington J. Comparative study of once and 3-times daily regimens of bezafibrate in patients with primary hyperlipoproteinaemia. Curr Medical Res Opin 1981; 7: 489502.
  • 280
    Mertz DP, Lang PD, Vollmar J. Bezafibrate: lack of effect on creatinine excretion and muscular proteins. Res Exper Med 1982; 180: 9598.
  • 281
    Olsson AG, Lang PD, Vollmar J. Effect of bezafibrate during 4.5 years of treatment of hyperlipoproteinaemia. Atherosclerosis 1985; 55: 195203.
  • 282
    Barbir M, Hunt B, Kushwaha S et al. Maxepa versus bezafibrate in hyperlipidemic cardiac transplant recipients. Am J Cardiol 1992; 70: 15961601.
  • 283
    Lipkin GW, Tomson CRV. Severe reversible renal fairlue with bezafibrate. Lancet 1993; 341: 371.
  • 284
    Bruce R, Daniels A, Cundy T. Renal function changes in diabetic nephropathy induced by bezafibrate. Nephron 1996; 73: 490.
  • 285
    Hirai M, Tatuso E, Sakurai M, Ichikawa M, Matsuya F, Saito Y. Elevated blood concentrations of cyclosporine and kidney failure after bezafibrate in renal graft recipient. Ann Pharmacother 1996; 30: 883884 (Letter).
  • 286
    Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only inonocuous agent? Nephrol Dial Transplant 2000; 15: 19931999.
  • 287
    Devuyst O, Goffin E, Pirson Y, Van Ypersele de Strihou Ch. Creatinine rise after fibrate therapy in renal graft recipients. Lancet 1993; 341: 840.
  • 288
    Rössner S, Orö L. Fenofibrate therapy of hyperlipoproteinaemia. A dose–response study and a comparison with clofibrate. Atherosclerosis 1981; 38: 273282.
  • 289
    Rouffy J, Chanu B, Bakir R, Djian F, Goy-Loeper J. Comparative evaluation of the effects of ciprofibrate and fenofibrate on lipids, lipoproteins and apoproteins A and B. Atherosclerosis 1985; 54: 273281.
  • 290
    De Lorgeril M, Boissonnat P, Bizollon CA et al. Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation. Lack of interaction with the lipid-lowering agent, fenofibrate. Eur J Clin Pharmacol 1992; 43: 161165.
  • 291
    Boissonnat P, Salen P, Guidollet J et al. The long-term effects of the lipid-lowering agent fenobibrate in hyperlipidemic heart transplant recipients. Transplantation 1994; 58: 245247.
  • 292
    Ellen RL, Mcpherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol 1998; 81: 60B65B.
  • 293
    Hottelart C, El Esper N, Achard JM, Pruna A, Fournier A. [Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patinets with mild renal insufficicency]. Nephrologie 1999; 20: 4144.
  • 294
    Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354: 219220.
  • 295
    Lipscombe J, Lewis GF, Cattran D, Bargman JM. Deterioration in renal function associated with fibrate therapy. Clin Nephrol 2001; 55: 3944.
  • 296
    Gibbons LW, Gonzalez V, Gordon N, Grundy S. The prevalence of side effects with regular and sustained-release nicotinic acid. Am J Med 1995; 99: 378385.
  • 297
    Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): Efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol 1998; 82: 29U34U.
  • 298
    Gokal R, Mann JI, Oliver DO, Ledingham JGG, Carter RD. Treatment of hyperlipidaemia in patients on chronic haemodialysis. BMJ 1978; 1: 8283.
  • 299
    Spratt P, Esmore D, Keogh A, Chang V. Comparison of three immunosuppressive protocols in cardiac transplantation. Transplant Proc 1989; 21: 24812483.
  • 300
    Chen HH, Lin LH. Recurrent pancreatitis secondary to type V hyperlipidemia: report of one case. Acta Paediatr Taiwan 2000; 41: 276278.
  • 301
    Colletti RB, Neufeld EJ, Roff NK, Mcauliffe TL, Baker AL, Newburger JW. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993; 92: 7882.
  • 302
    Steinmetz J, Morin C, Panek E, Siest G, Drouin P. Biological variations in hyperlipidemic children and adolescents treated with fenofibrate. Clin Chim Acta 1981; 112: 43.
  • 303
    Chicaud P, Demange J, Drouin P, Debry G. [Action of fenofibrate in hypercholesterolemic children. 18-month follow-up]. Presse Med 1984; 13: 417419.
  • 304
    Wheeler KA, West RJ, Lloyd JK, Barley J. Double blind trial of bezafibrate in familial hypercholesterolaemia. Arch Dis Child 1985; 60: 3437.
  • 305
    Kwiterovich PO Jr. Diagnosis and management of familial dyslipoproteinemia in children and adolescents. Pediatr Clin North Am 1990; 37: 14891523.
  • 306
    Enos WF, Holmes RH, Beyer J. Coronary artery diseas among United States soldiers killed in action in Korea. JAMA 1953; 152: 10901093.
  • 307
    Mcgill HC, Mcmahan CA, Herderick EE et al. Effects of coronary heart disease risk factors on atherosclerosis of selected regions of the aorta and right coronary artery. PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth. Arterioscler Thromb Vasc Biol 2000; 20: 836845.
  • 308
    Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. New Engl J Med 1998; 338: 16501656.
  • 309
    Järvisalo MJ, Jartti L, Näntö-Salonen K et al. Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation 2001; 104: 29432947.
  • 310
    Kwiterovich PO, Barton BA, Mcmahon RP et al. Effects of diet and sexual maturation on low-density lipoprotein cholesterol during puberty: the Dietary Intervention Study in Children (DISC). Circulation 1997; 96: 25262533.
  • 311
    Niinikoski H, Viikari J, Ronnemaa T et al. Regulation of growth of 7- to 36-month-old children by energy and fat intake in the prospective, randomized STRIP baby trial. Pediatrics 1997; 100: 810816.
  • 312
    Niinikoski H, Koskinen P, Punnonen K et al. Intake and indicators of iron and zinc status in children consuming diets low in saturated fat and cholesterol: the STRIP baby study. Special Turku Coronary Risk Factor Intervention Project for Babies. Am J Clin Nutr 1997; 66: 569574.
  • 313
    Niinikoski H, Lapinleimu H, Viikari J et al. Growth until 3 years of age in a prospective, randomized trial of a diet with reduced saturated fat and cholesterol. Pediatrics 1997; 99: 687694.
  • 314
    Lambert M, Lupien PJ, Gagne C et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group. Pediatrics 1996; 97: 619628.
  • 315
    Knipscheer HC, Boelen CC, Kastelein JJ et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatr Res 1996; 39: 867871.
  • 316
    Couture P, Brun LD, Szots F et al. Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1998; 18: 10071012.
  • 317
    Vohl MC, Szots F, Lelie'vre M et al. Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia. Atherosclerosis 2002; 160: 361368.
  • 318
    Stefanutti C, Lucani G, Vivenzio A, Di Giacomo S. Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood. Drugs Exp Clin Res 1999; 25: 2328.
  • 319
    Coleman JE, Watson AR. Hyperlipidaemia, diet and simvastatin therapy in steroid–resistant nephrotic syndrome of childhood. Pediatr Nephrol 1996; 10: 171174.
  • 320
    Sanjad SA, Al Abbad A, Al Shorafa S. Management of hyperlipidemia in children with refractory nephrotic syndrome: the effect of statin therapy. J Pediatr 1997; 130: 470474.
  • 321
    Kano K, Hoshi E, Ito S et al. Effects of combination therapy consisting of moderate-dose intravenous immunoglobulin G, pulsed methylprednisolone and pravastatin in children with steroid-resistant nephrosis. Nephron 2000; 84: 99100.
  • 322
    Marcucci R, Zanazzi M, Bertoni E et al. Risk factors for cardiovascular disease in renal transplant recipients: new insights. Transplant Int 2000; 13 (Suppl. 1): S419S424.
  • 323
    Stein EA, Illingworth DR, Kwiterovich PO Jr et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA 1999; 281: 137144.
  • 324
    Knipscheer HC, Boelen CC, Kastelein JJ et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatr Res 1996; 39: 867871.
  • 325
    Mccrindle BW, O'Neill MB, Cullen-Dean G, Helden E. Acceptability and compliance with two forms of cholestyramine in the treatment of hypercholesterolemia in children: a randomized, crossover trial. J Pediatr 1997; 130: 266273.
  • 326
    West RJ, Lloyd JK, Leonard JV. Long-term follow-up of children with familial hypercholesterolaemia treated with cholestyramine. Lancet 1980; 2: 873875.
  • 327
    West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut 1975; 16: 9398.
  • 328
    Product Information Questran and Questran Light, 2000. Available at http://www.bms.com/products.
  • 329
    Schwarz KB, Goldstein PD, Witztum JL, Schonfeld G. Fat-soluble vitamin concentrations in hypercholesterolemic children treated with colestipol. Pediatrics 1980; 65: 243250.
  • 330
    Schlierf G, Vogel G, Kohlmeier M, Vuilleumier JP, Huppe R, Schmidt-Gayk H. [Long-term therapy of familial hypercholesterolemia in young patients with colestipol: availability of minerals and vitamins]. Klin Wochenschr 1985; 63: 802806.
  • 331
    National Kidney Foundation. K/DOQI clinical practice guidelines for nutrition in chronic renal failure. K/DOQI. Am J Kidney Dis 2000; 35: S1S140.
  • 332
    Gylling H, Siimes MA, Miettinen TA. Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia. J Lipid Res 1995; 36: 18071812.
  • 333
    Williams CL, Bollella MC, Strobino BA, Boccia L, Campanaro L. Plant stanol ester and bran fiber in childhood. effects on lipids, stool weight and stool frequency in preschool children. J Am Coll Nutr 1999; 18: 572581.
  • 334
    Miettinen TA, Puska P, Gylling H, Vanhanen H, Vartiainen E. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med 1995; 333: 13081312.
  • 335
    Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1998; 52: 334343.
  • 336
    Hallikainen MA, Sarkkinen ES, Uusitupa MI. Plant stanol esters affect serum cholesterol concentrations of hypercholesterolemic men and women in a dose-dependent manner. J Nutr 2000; 130: 767776.