Clinical Practice Guidelines for Managing Dyslipidemias in Kidney

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Copyright # Blackwell Munksgaard 2004 Blackwell Munksgaard Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative

National Kidney Foundation kidney transplant patients. These guidelines are divided WorkGroupMembers:B.Kasiske,F.G.Cosio, into four sections. The first section (Introduction) pro- J.Beto,K.Bolton,B.M.Chavers,R.GrimmJr., vides the rationale for the guidelines, and describes the target population, scope, intended users, and methods. A. Levin, B. Masri, R. Parekh, C. Wanner, The second section presents guidelines on the assess- D.C. Wheeler and P.W.F. Wilson ment of dyslipidemias (guidelines 1–3), while the third section offers guidelines for the treatment of dyslipid- Correspondence: Karen Glowacki, National Kidney emias (guidelines 4–5). The key guideline statements Foundation 30 E. 33rd Street, 11th Fl. New York, are supported mainly by data from studies in the general NY 10016, USA; email: [email protected] population, but there is an urgent need for additional studies in CKD and in transplant patients. Therefore, the last section outlines recommendations for research. ABSTRACT

The incidence of cardiovascular disease (CVD) is very high in patients with chronic kidney (CKD) disease and in kidney transplant recipients. Indeed, available evi- INTRODUCTION dence for these patients suggests that the 10-year cumulative risk of coronary heart disease is at least The rationale for these guidelines 20%, or roughly equivalent to the risk seen in patients These guidelines are the result of an ongoing effort by the with previous CVD. Recently, the National Kidney National Kidney Foundation (NKF) to provide guidance to Foundation’s Kidney Disease Outcomes Quality Initia- practitioners and investigators on the management of cardio- tive (K/DOQI) published guidelines for the diagnosis and treatment of dyslipidemias in patients with CKD, includ- vascular disease (CVD) in patients with chronic kidney dis- ing transplant patients. It was the conclusion of this ease (CKD) and in kidney transplant recipients. This process Work Group that the National Cholesterol Education was initiated by the formation of a NKF Task Force on CVD Program Guidelines are generally applicable to patients (Figure 1). This Task Force concluded that the incidence of with CKD, but that there are significant differences in atherosclerotic cardiovascular disease (ACVD) is higher in the approach and treatment of dyslipidemias in patients patients with CKD compared with the general population with CKD compared with the general population. In the (1), and that patients with CKD and kidney transplant recipi- present document we present the guidelines generated ents should be considered to be in the highest risk category, by this workgroup as they apply to kidney transplant i.e. a coronary heart disease (CHD) risk equivalent, for risk recipients. Evidence from the general population factor management. In response to recommendations of the indicates that treatment of dyslipidemias reduces CVD, and evidence in kidney transplant patients suggests NKF Task Force on CVD, the NKF Kidney Disease Outcomes that judicious treatment can be safe and effective in Quality Initiative (K/DOQI) convened a Work Group to improving dyslipidemias. Dyslipidemias are very com- develop guidelines for the management of dyslipidemias, mon in CKD and in transplant patients. However, until one of the risk factors for CHD in CKD. The Work Group recently there have been no adequately powered, first met on 27 November 2000. The general guidelines for randomized, controlled trials examining the effects of the management of dyslipidemias in all patients with CKD dyslipidemia treatment on CVD in patients with CKD. have recently been published (2). What follows is a summary Since completion of the K/DOQI guidelines on dyslipid- of the particular dyslipidemia guidelines that apply to kidney emia in CKD, the results of the Assessment of Lescol transplant recipients. in Renal Transplantation (ALERT) Study have been pre- sented and published. Based on information from randomized trials conducted in the general population During the development of the dyslipidemia guidelines, the and the single study conducted in kidney transplant NKF K/DOQI also completed guidelines on CKD (3). These patients, these guidelines, which are a modified version CKD guidelines defined CKD, reiterated that CKD should be of the K/DOQI dyslipidemia guidelines, were developed considered a CHD risk equivalent, and that risk factors to aid clinicians in the management of dyslipidemias in should be managed accordingly (Figure 1).

13 National Kidney Foundation

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 clas- sified as having CKD and staged as per Table 1.

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.

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 Choles- terol 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 Figure 1: The evolution of National Kidney Foundation guidelines for the management of dyslipidemias in patients with chronic guidelines should be applied to kidney transplant patients. kidney disease. There is evidence from observational studies that, in addition to dyslipidemias, some ‘nontraditional’ risk factors such as cal- In the CKD guidelines, the following CKD stages were based cium, phosphorus, parathyroid hormone, (7,8) homocysteine, on measured or estimated glomerular filtration rate (GFR) (9–16) and systemic inflammation (17–21) may also play a role (Table 1). The NKF Task Force on CKD recognized that some in the pathogenesis of CVD in patients with CKD. However, kidney transplant patients who have normal kidney function 2 unlike dyslipidemias, there are no intervention trials from (GFR 90 mL/min/1.73 m ) may not have CKD according to patients in the general population (or the CKD population) the K/DOQI Guidelines defining CKD. Similarly, some transplant 2 demonstrating that the modification of these nontraditional risk patients with GFR 60 mL/min/1.73 m may not fit the K/DOQI factors reduces CVD. Therefore, these guidelines focus on the definition of CKD, because they do not have evidence of kidney assessment and treatment of dyslipidemias in kidney transplant damage, i.e. they may have normal urine protein excretion, urine recipients. Since the publication of the general CKD dyslipid- sediment, histology, and radiographic imaging. However, the emias guidelines, a randomized, prospective, controlled trial on CKD guidelines and the dyslipidemia guidelines consider such the effects of dyslipidemia management in transplant patients patients to be at increased risk for CKD. As such, the Work has been completed in Europe and in Canada (ALERT) (22). In Group decided to assume that all kidney transplant recipients the ALERT trial, the primary endpoint (cardiac death, nonfatal myocardial infarction, or coronary revascularization) was not Table 1: Stages of chronic kidney disease significantly different between statin treatment and placebo. GFR However, there were significant differences between the treat- Stage Description (mL/min/1.73 m2) ment and control groups in cardiac death and nonfatal myocar- 1 Kidney damage with normal or " GFR 90 dial infarction. In addition, the proportional reduction in cardiac 2 Kidney damage with mild # GFR 60–89 events in ALERT was similar to that seen in statin trials in the 3 Moderate # GFR 30–59 general population. Nevertheless, questions remain about the 4 Severe # GFR 15–29 safety and efficacy of lipid-modifying drugs in kidney transplant 5 Kidney failure <15 or dialysis patients compared with the general population. These ques- From the Kidney Disease Outcomes Quality Initiative Clinical tions are based on the unique features of transplant patients, Practice Guidelines for Chronic Kidney Disease: Evaluation, Clas- such as the use of immunosuppressive medications, which sification and Stratification. GFR, glomerular filtration rate. may not only contribute to the risk of ACVD after transplantation

14 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 2: Definitions of some terms used in these guidelines Term Definition 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 cardiovascular Coronary 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 disease Atherosclerotic disease of the cerebral arteries that causes strokes and transient ischemic attacks Peripheral vascular disease Atherosclerotic disease of arteries that causes ischemia of the extremities Dyslipidemia Any abnormality in plasma lipoprotein concentration or composition that is associated with an increased risk for atherosclerotic cardiovascular disease Lipid profile Plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides Adults Individuals 18 years old Adolescents Individuals <18 years old, but after the onset of puberty GFR glomerular filtration rate. but also modify the metabolism of lipid-lowering drugs. There- not have evidence of kidney damage. However, the CKD fore, the Work Group concluded that additional, randomized, guidelines and the dyslipidemia guidelines consider such trials are still needed in transplant patients (see Research patients to be at increased risk for CKD. Consequently, recommendations). 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 target population. Furthermore, the inclusion of trans- These guidelines will address exclusively the manage- planted patients in these guidelines was deemed to be ment of dyslipidemias in kidney transplant recipients. a useful opportunity to emphasize several features of The general dyslipidemia guidelines included all patients the diagnosis and management of these patients that with Stage 5 CKD, and all kidney transplant recipients (2). may differ from that of the general population (4). The Work Group considered that the recently updated guide- Some kidney transplant patients may not meet the defini- lines of the ATP III (3) were generally applicable to kidney tion of CKD either because they have normal kidney transplant patients, except for: function (GFR 90 mL/min/1.73 m2) and because they do

Table 3: Dyslipidemias as defined in the Adult Treatment Panel III classifying transplantion as a CHD risk equivalent; Guidelines (4). considering complications of lipid-lowering therapies Dyslipidemia Level (mg/dL) that may result from reduced kidney function; Total cholesterol considering complications of lipid-lowering therapies Desirable <200 that may result from the concomitant use of immusup- Borderline high 200–239 High 240 pressive mediations; LDL cholesterol considering whether in kidney transplant recipients Optimal <100 there might be indications for the treatment of dyslipid- Near optimal 100–129 emias other than preventing ACVD; Borderline 130–159 High 160–189 determining whether the treatment of proteinuria might Very high 190 also be an effective treatment for dyslipidemias. Triglycerides Normal <150 Borderline high 150–199 Finally, the Work Group considered whether to include High 200–499 children and adolescents in these guidelines (Figure 2). Very high 500 Although the ATP III covers only individuals 20 years HDL cholesterol (3), it was concluded that CKD individuals 18–20 years Low <40 should also be included and considered as adults. Much LDL, low-density lipoprotein; HDL, high-density lipoprotein. To has changed in the decade since the report of the NCEP-C convert mg/dL to mmol/L, multiply triglycerides by 0.01129 and (6). However, there are still very few studies of dyslipid- cholesterol by 0.02586. emias in children and adolescents, either in the general

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 15 National Kidney Foundation

Table 4: Some government-sponsored web sites with information useful in risk factor management. Risk factor Website address Diet http://www.nutrition.gov Body weight http://www.nhlbi.nih.gov/ guidelines/obesity/ob_home.htm (click on Healthy Weight) Exercise http://www.fitness.gov Cholesterol* http://www.nhlbi.nih.gov/ guidelines/cholesterol Figure 2: Ages covered by the current guidelines, and those covered Blood pressure http://www.nhlbi.nih.gov/guidelines/ by previous guidelines developed for use in the general population. hypertension/index.htm Hormone http://www.nhlbi.nih.gov/health/ replacement women/index.htm population or in CKD. In the end, it was concluded that Smoking http://www.cdc.gov/tobacco/ adolescents (defined by the onset of puberty) with a kid- sgr/index.htm ney transplant, should be included in these guidelines. Children (before the onset of puberty) should be managed *National Cholesterol Education Program Expert Panel on Detec- tion, Evaluation, and Treatment of High Blood Cholesterol in Adults, according to existing guidelines, such as the NCEP-C (6). Adult Treatment Panel III. All web addresses as of 30 October 2002. Scope The Work Group also considered the recommendations of the NKF Task Force on CVD concerning the manage- — aspirin for the primary prevention of cardiovascular ment of risk factors other than dyslipidemias (1). There events (26) are two potential reasons to assess other risk factors — a statement for health-care professionals from the Nutri- for ACVD: (i) to categorize overall risk for the purpose of tion Committee of the American Heart Association (27) making decisions regarding the management of dyslipidemia; and (ii) to identify modifiable risk factors other than — Clinical Guidelines on the Identification, Evaluation, dyslipidemia that should also be treated. The first reason and Treatment of Overweight and Obesity in was considered unnecessary (for the purpose of these Adults. Bethesda, MD: National Heart, Lung and guidelines) by accepting the recommendation that a Blood Institute, 1998, http://nhlbi.nih.gov/guidelines/ kidney transplant patient should be considered to have obesity/ob_home.htm a CHD risk equivalent when deciding the appropriate — the American Heart Association/American College of management of dyslipidemia. However, the Work Cardiology Guidelines for Preventing Heart Attack Group acknowledged that other risk factors are also and Death in Patients with Atherosclerotic Cardio- important in the pathogenesis of ACVD and should be vascular Disease (28) treated. Therefore, the Work Group concluded that for kidney transplant patients: — Primary Prevention Of Ischemic Stroke: a Statement for Health-Care Professionals from the Stroke Council of the American Heart Association (29) dyslipidemia management should be undertaken in conjunction with all other available measures to reduce — A Clinical Practice Guideline for Treating Tobacco the overall risk of ACVD; Use and Dependence: A US Public Health Service Report (30). modifiable, conventional risk factors (including hypertension, cigarette smoking, glucose intolerance or The task of the Work Group was greatly facilitated by the diabetes control, and obesity) should be assessed at ATP III, (4) and the NCEP-C for children and adolescents initial presentation and at least yearly thereafter; (6). However, the ATP III and NCEP-C make few specific modifiable risk factors should be managed according to recommendations for the evaluation and treatment of existing guidelines (Table 4), including, but not limited to: dyslipidemias in CKD and in kidney transplant patients, and none of the guideline statements includes or excludes — the Sixth Report of the Joint National Committee on these patients. The ATP III notes that nephrotic syndrome Prevention, Detection, Evaluation, and Treatment of is a cause of secondary dyslipidemia, and suggests that High Blood Pressure (23) consideration be given to the use of cholesterol-lowering drugs if hyperlipidemia persists despite specific treatment — the American Diabetes Association Clinical Practice for kidney disease. The ATP III also notes that various Recommendations (24) dyslipidemias have been reported in persons with kidney — Hormone Replacement Therapy and Cardiovascular failure. However, it suggests that a cautious approach be Disease: A Statement for Health-Care Professionals taken, since these persons are prone to drug side-effects, from the American Heart Association (25) e.g. they are at increased risk for myopathy from both

16 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients fibrates and statins. In fact, the ATP III suggests that Anticipated updates chronic kidney failure is a contraindication to fibrates. All guidelines should be updated whenever new, pertinent information becomes available. To anticipate The Work Group concluded that, in most areas, the ATP III when these guidelines may need to be updated, the and NCEP-C were applicable to adults and adolescents, Work Group discussed ongoing clinical trials in the general respectively. It considered that defining areas where the population and in patients with CKD, as those results may ATP III and NCEP-C needed modification and refinement be pertinent to some recommendations. Late in the for patients with CKD, including kidney transplant recipi- course of development of these guidelines, the results ents, to be its principal task. In the end, relatively few of the Heart Protection Study were published (31). This modifications were needed (Table 5).12 study randomly allocated 20 536 adults with coronary artery disease (CAD) to 40mg simvastatin vs. matching Intended users placebo. Patients treated with simvastatin had an 18% These guidelines are intended for use by physicians, transplant reduction in coronary deaths. Importantly, the reduction coordinators, nurses, nurse practitioners, pharmacists, diet- in mortality was seen irrespective of the baseline level of itians, and other healthcare professionals who care for kidney cholesterol. This raised the possibility that all patients transplant recipients. The information contained in these guide- with known CAD should be treated with a statin, regard- lines can and should be conveyed to patients and their families less of the serum cholesterol level. Ultimately, these in an understandable manner by their physician and/or other and other results from ongoing trials could conceivably healthcare professionals. The development of educational sup- change the recommended approach to treatment of port materials designed specifically for patients and their families dyslipidemias. Some other important ongoing trials in should be part of the implementation of these guidelines. patients from the general population include:

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 Guidelines NKF-K/DOQI Guidelines CKD and kidney transplant patients are not managed CKD and kidney transplant patients should be considered differently from other patients to be in the highest risk category Evaluation of dyslipidemias should occur every 5 years Evaluation of dyslipidemias should occur at presentation, after a change in status, and annually Drug therapy is considered optional for LDL Drug therapy should be used for LDL 100–129 mg/dL after 100–129 mg/dL 3 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 old Recommendations are made for patients <20 years old Fibrates are contraindicated in Stage 5 CKD Fibrates 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 should Gemfibrozil may be the fibrate of choice for treatment of be used to treat hypertriglyceridemia high triglycerides in patients with CKD and kidney transplant patients Expert Panel on Children Adolescents with CKD are not managed differently from Adolescents with CKD or kidney transplants should be other patients considered to be in the highest risk category Evaluation of dyslipidemias should occur every 5 years Evaluation 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, followed If LDL is 130–159 mg/dL, start TLC diet (if nutritional in 3 months by Step II AHA diet if LDL >130 mg/dL status 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 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.

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Study Evaluating Additional Reductions in Cholesterol 3) The Work Group members worked independently from and Homocysteine (SEARCH) (32) any organizational affiliations and had final responsibility for determining guideline content. Treating to New Targets (TNT) (33) 4) The guidelines underwent widespread critical review Incremental Decrease in Endpoints Through Aggressive before being finalized. Lipid Lowering (IDEAL) (34) The guidelines were developed using an evidence-based Aggressive Lipid Lowering Initiation Abates New Cardiac approach similar to that endorsed by the Agency for Health- Events (ALLIANCE) (35) Care Research and Quality. The Work Group reviewed all Pravastatin or Atorvastatin in Evaluation and Infection pertinent, published evidence, and critically appraised the Therapy (PROVE IT) (36) quality of studies and the overall strength of evidence supporting each recommendation. Details of the methods Prospective Study of Pravastatin in the Elderly at Risk used to evaluate the evidence is in Appendix 1 of the (PROSPER) (37) complete guidelines. (2). Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) (38) Rating the strength of guidelines and evidence Collaborative Atorvastatin Diabetes Study (CARDS) (34, 38) The overall strength of each guideline statement was rated by assigning either ‘A’, ‘B’, or ‘C’ (defined in Table 6). The Atorvastatin as Prevention of Coronary Heart Disease strength of evidence was assessed using a rating system Endpoints in Patients with Non-Insulin-Dependent that takes into account (i) methodological quality of the Diabetes Mellitus (ASPEN) (34) studies; (ii) whether or not the study was carried out in the Stroke Prevention by Aggressive Reduction in Choles- target population, i.e. kidney transplant patients, or in other terol Levels (SPARCL) (34) populations; and (iii) whether the studies examined health outcomes directly, or examined surrogate measures for Action to Control Cardiovascular Risk in Diabetes (ACCORD) those outcomes, e.g. improving dyslipidemia rather than reducing CVD (Table 7). These three separate study charac- Some important, ongoing trials being conducted in patients teristics were combined in rating the strength of evidence with CKD include: provided by pertinent studies.

Die Deutsche Diabetes Dialyse Studie (4D) (39) Literature retrieval and review Prevention of REnal and Vascular ENdstage Disease The Work Group collaborated with a professional Evidence Intervention Trial (PREVEND IT) (40) Review Team to identify and summarize pertinent litera- The Study of Heart and Renal Protection (SHARP). ture. The Work Group and the Evidence Review Team first identified the topics to be searched, and the Evidence Thus, a number of potentially important trials will be com- Review Team conducted the literature search. The topics pleted within the next 3–5 years. Given the potential for these that were selected for search included the incidence or and other studies to provide information pertinent to the prevalence of dyslipidemia, the association of dyslipidemia assessment and treatment of dyslipidemias in patients with with ACVD, and the treatment of dyslipidemia in kidney CKD, it was concluded that these guidelines should be transplant patients. In addition, literature on adverse updated in about 3 years from the time of publication, and effects of dyslipidemia treatment, the effects of dyslipid- sooner if new pertinent information becomes available before emia treatment on kidney disease progression, and the then. The Work Group will monitor the progress of these effects of therapies that reduce proteinuria on dyslipid- trials and recommend updating these guidelines as indicated. emias was retrieved and reviewed.

Briefly, the literature search included only full, peer-reviewed, METHODS journal articles of original data. Review articles, editorials, letters, case studies, and abstracts were excluded. Studies Guideline development were identified primarily through MedLine searches of the These guidelines were developed using four basic prin- English language literature up to May 2001. Studies published ciples set forth by the K/DOQI: between May 2001 and November 2002 that were identified through means other than the systematic literature searches 1) The guidelines were developed using a scientifically were included if appropriate. rigorous process, and the rationale and evidentiary basis for each guideline is clearly explained. Separate search strategies were developed for each topic. 2) A multidisciplinary Work Group, with expertise in the The text words or MeSH headings for all topics included management of kidney transplant patients, CKD, kidney or kidney diseases, hemodialysis, peritoneal dialysis, dyslipidemias, and ACVD developed the guidelines. or kidney transplant. The searches were limited to human

18 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 6: Rating the Strength of Recommendations Grade Recommendation A It is strongly recommended that clinicians routinely follow the guideline for eligible patients. There is strong evidence that the practice improves net health outcomes. B It is recommended that clinicians routinely follow the guideline for eligible patients. There is moderate evidence that the practice improves net health outcomes. C It 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. 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. studies, but included both adult and pediatric populations. tables according to four study dimensions: size, applicabil- Potential articles for retrieval were identified from printed ity, results, and methodological quality. abstracts and titles, based on study population, relevance to the topic, and document type. These were screened by The study (sample) size was used as a measure of the weight clinicians on the Evidence Review Team. Overall, 10 363 of the evidence. In general, large studies provide more precise abstracts were screened, 642 articles were retrieved, and estimates of prevalence and associations. Applicability (gener- 258 articles were subjected to structured review by mem- alizability or external validity) addresses the issue of whether bers of the Work Group. Although systematic manual the study population is sufficiently broad so that the results can searches were not conducted, members of the Work be generalized to the population of interest. The applicability Group supplied a number of articles that were not located of each article was determined using a three-level scale: by the MedLine searches. (i) the study sample is representative of the target population; (ii) the sample is representative of a relevant subgroup; or (iii) Work Group members used forms that were developed by the sample is representative of a narrow subgroup of patients. the Evidence Review Team to extract information from each article that was reviewed. The Evidence Review Methodological quality (internal validity) refers to the design, Team used the information from these forms to construct conduct, and reporting of the clinical study. Because studies the evidence tables. The Evidence Review Team then with a variety of designs were evaluated, a broad classifica- used the evidence tables to construct the summary tables tion system to rate the quality of individual studies was that are included with the guidelines in this report. The used: (i) least bias, most valid, i.e. a study that meets most summary tables describe the information in the evidence generally accepted criteria for high quality; (ii) susceptible to

Table 7: Rating the strength of evidence Methodological quality

Well designed and Some problems in Poorly designed analyzed (little, if any, design and/or analysis and/or analyzed Outcome (s) Population potential bias) (some potential bias) (large potential bias) Health outcome (s) Target population Stronga Moderateb Weakh Health outcome (s) Other than the target Moderatec Moderated Weakh population Surrogate measure Target population Moderatee Weakf Weakh for health outcome (s) Surrogate measure Other than the target Weakg Weakg Weakg,h for health outcome (s) population Strong: aEvidence includes results from well-designed, well-conducted study/studies in the target population that directly assess effects on net health outcomes. Moderate: bEvidence 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 cevidence is from a population other than the target population, but from well-designed, well-conducted studies; or devidence is from studies with some problems in design and/or analysis; or eevidence is from well-designed, well-conducted studies on surrogate endpoints for efficacy and/or safety in the target population. Weak: fEvidence 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 gthe evidence is only for surrogate measures in a population other than the target population; or hthe evidence is from studies that are poorly designed and/or analyzed.

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 19 National Kidney Foundation some bias, but not sufficient to invalidate the results; and study, has been conducted in kidney transplant patients (iii) significant bias that may invalidate the results. (22).Thus, there are reasonable doubts as to whether trial results from the general population can be extrapolated to GUIDELINES, EVIDENCE, AND RESEARCH all patients with CKD, particularly because most of these trials RECOMMENDATIONS excluded patients with elevated serum creatinine. In kidney transplant patients, the ALERT study suggests that dyslipidemia management with statins is associated with a significant The key guideline statements in this document were graded reduction in the incidence of cardiac death and of myocardial ‘B’ or ‘C’. Some would argue that no guideline statements infarction (although differences in the combined primary end- should be made in the absence of evidence from random- point were not statistically significant) (22). The Work Group ized trials in patients with CKD (yielding level ‘A’ recom- concluded that studies are needed in dyslipidemia manage- mendations). However, it was decided that when the ment in CKD patients and also that additional studies may be strength of evidence for treatment efficacy was strong needed in transplant patients to confirm and extend the (based on trials in the general population) this evidence results of ALERT (see Research recommendations). 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 ASSESSMENT OF DYSLIPIDEMIAS would be found if the trials were carried out in kidney transplant patients. Evidence from one randomized trial in kidney Guideline 1 transplant patients completed since the publication of the 1.1 All adult and adolescent kidney transplant recipients general CKD dyslipidemia guidelines supports this approach should be evaluated for dyslipidemias (B). (22). This also assumes, of course, that treatment is safe and effective in ameliorating dyslipidemias in these patients. 1.2 For adult and adolescent kidney transplant recipients, the assessment of dyslipidemias should include a The principal results of large multicenter trials in the gen- complete fasting lipid profile with total cholesterol, eral population have generally been applicable to most, LDL, HDL, and triglycerides (B). 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).

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

Figure 3: The chain of logic for evidence supporting the Figure 4: The relative coronary heart disease risk reduction in treatment of low-density lipoprotein cholesterol in patients with subgroups of patients from major lipid-lowering trials in the chronic kidney disease. general population.

20 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

1.3 For adult and adolescent kidney transplant recipients, with ACVD. Altogether, these studies suggest that the relation- dyslipidemias should be evaluated upon presentation ship between ACVD and dyslipidemias in kidney transplant (when the patient is stable), at 2–3 months after a recipients is similar to that observed in the general population. change in treatment or other conditions known to However, each of these studies had design limitations; in cause dyslipidemias, and at least annually thereafter (B). particular, none were truly prospective. Kidney transplant recipients may also have nontraditional lipoprotein abnormalities that Associations between dyslipidemias and ACVD in CKD could theoretically contribute to ACVD (46–48). However, the The incidence of ACVD is very high in patients with CKD and role of these lipoprotein abnormalities in the pathogenesis of in kidney transplant recipients (Figure 5). Therefore, the ACVD in CKD, as in the general population, is unclear. The NKF Task Force on CVD and the K/DOQI Work Group on association between dyslipidemia and ACVD in kidney trans- CKD both concluded that, in the management of risk factors plant patients is supported by the results of the ALERT study, such as dyslipidemia, patients with CKD and kidney trans- which showed that treatment of dyslipidemia with statins was plant recipients should be considered to be in the highest associated with a significant reduction in cardiac death and risk category, i.e. equivalent to that of patients with known nonfatal myocardial infarction (although differences in the com- CHD (1,3). There is very strong evidence from the general bined primary endpoint were not statistically significant) (22). 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 Evaluation of dyslipidemias in kidney transplant ACVD is different in patients with CKD, and that dyslipid- recipients emias do not contribute to ACVD in CKD. However, the Measurements of total cholesterol, HDL, and triglycerides relationship between dyslipidemias and ACVD in the general are readily available in most major clinical laboratories. The population is robust, i.e. it is valid in men and women (4,41, LDL that forms the foundation for treatment decisions in 42); the elderly and middle-aged (4,41,42); smokers and the ATP III Guidelines (4) is generally calculated from total nonsmokers (4,42;), hypertensive and nonhypertensive cholesterol, HDL, and triglycerides using the Friedewald patients (42); diabetics and nondiabetics (4,43); and individ- formula (see later). The ATP III Guidelines also recom- uals with higher or lower LDL, total cholesterol, triglycer- mend treatment of some dyslipidemias that may occur ides, (4,42) and HDL (4,42,44,45) (Figure 4). There are no with normal or low LDL. These dyslipidemias, often seen randomized, controlled intervention trials testing the hypothe- in association with metabolic, or insulin resistance syn- sis that dyslipidemias cause ACVD in CKD patients. How- drome (syndrome of obesity, hypertension, insulin resis- ever, there are no compelling reasons to believe that tance, and hyperlipidemia) and characterized by increases dyslipidemias do not contribute to ACVD in these patients. 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 Associations between dyslipidemias and ACVD in decisions for dyslipidemia in these guidelines, as in the kidney transplant recipients ATP III Guidelines, are based on levels of triglycerides, Several studies have reported a positive association between LDL, and non-HDL cholesterol. total cholesterol and ACVD in kidney transplant recipients (Table 8). Unfortunately, few of these studies examined the Associations between dyslipidemias and kidney relationship between LDL and ACVD. Lower levels of HDL disease progression were associated with ACVD in three of four studies. In three The principal reason to evaluate dyslipidemias in patients of six studies, higher levels of triglycerides were associated 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.

Figure 5: Causes of death among period prevalent patients Unfortunately, there are no large, adequately powered, 1997–99, treated with hemodialysis, peritoneal dialysis, or kidney randomized controlled trials testing the hypothesis that transplantation. treatment of dyslipidemia preserves kidney function.

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 21 National Kidney Foundation

Table 8: Associations between dyslipidemias and cardiovascular disease in kidney transplant recipients Cardiovascular disease risk with worsening dyslipidemiad

Study n Qualitya Applicabilityb Adjustedc CHOL LDL HDL TG Kasiske, 1996 (49) 675 * fflfflffl Yes ŒØ Aker, 1998 (50) 427 * fflffl Yes ØØŒ Aakhus, 1999 (51) 406 * ffl No Ø Kasiske, 2000 (52) 1124 £ fflffl Yes Ø æ Ø Ong, 1994 (53) 192 £ fflffl No Ø Barbagallo, 1999 (54) 57 £ fflffl Yes æ Roodnat, 2000 (55) 676 * fflffl Yes æ Massy, 1998 (56) 79 * fflffl Yes Ø æ Biesenbach, 2000 (57) 21 * ffl No aStudy quality was graded: *, least bias, results are valid; £, susceptible to some bias, but not sufficient to invalidate the results; *, significant bias that may invalidate the results. bApplicability:fflfflffl, representative of a wide spectrum of patients; fflffl, representative of a relevant subgroup; or ffl, representative of a narrow subgroup. cIndicates whether results were statistically adjusted for covariates. d , indicates no association between dyslipidemia and cardiovascular disease; Œ, indicates that dyslipidemia was associated with less cardiovascular disease or there was a trend that was not statistically significant (); Ø, indicates that dyslipidemia was associated with more cardiovascular disease or there was a trend that was not statistically significant (æ). n, Number of subjects in the study; CHOL, cholesterol; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG, triglycerides.

However, there have been several small studies, (58–69) gemfibrozil in one study, and probucol in one. Altogether, and a meta-analysis of these studies (71). This meta- 362 patients with CKD were included in the meta-analysis. analysis included prospective, controlled trials published The results suggested that the rate of decline in GFR was before 1 July 1999. Three trials published only in abstract significantly less in patients treated with a cholesterol- form were included in this meta-analysis (58,59,69); one of lowering agent compared with placebo (70). No significant these studies has subsequently been published in a peer- heterogeneity in treatment effect was detected between reviewed journal (69). Unfortunately, none of these studies the studies. However, the quality of the studies was included transplant patients. All patients were followed for generally low, and their small sample sizes and relatively at least 3 months, but in only five studies were patients short duration of follow-up make it difficult to conclude that followed for at least 1 year. Statins were used in 10 studies, 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 recipi- Figure 6: Example demonstrating the relative contributions of VLDL and IDL remnants to non-HDL cholesterol in two ents is very high (Table 10). Particularly common are hypothetical patients with normal and high triglycerides, increases in total cholesterol and LDL. Triglycerides are respectively. often increased, but HDL is usually normal.

22 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 9: Relationship between dyslipidemias and kidney disease progression GFR Rangec (mL/min/1.73 m2) Results

Kidney diseases Applic- Study n examined Qualitya abilityb 0 30 60 90 120 Unid Multie Cholesterol Walker, 1993 (75) 5524 DM, HTN * fflffl SCr 1.1 ± 0.14 mg/dL Hunsicker, 1997(76) 826 No IDDM * (<3) fflffl Ravid, 1998 (77) 574 DM * fflffl ND Ø Klein, 1999 (78) 555 IDDM * fflffl Ø Hovind, 2001 (79) 301 IDDM * fflffl ØØ Massy, 1999 (80) 138 All £ fflfflffl Samuelsson, 1996 (81) 49 All £ fflfflffl Yokoyama, 1997 (82) 182 DM £ (<3) fflffl Ø Samuelsson, 1997 (83) 73 No DM £ fflffl Ø Nielsen, 1997 (84) 32 DM £ fflffl Gall, 1993 (85) 26 DM £ fflffl Locatelli, 1991 (86) 456 No DM * (<3) fflffl SCr 1.3-7.0 mg/dL Dillon,1993 (87) 59 DM * (<3) fflffl ØØ Biesenbach, 1994 (88) 32 DM * fflffl Toth, 1994 (89) 100 Membranous * ffl Ø GN Triglycerides Walker, 1993 (75) 5524 DM, HTN * fflffl SCr 1.1 ± 0.14 mg/dL Massy, 1999 (80) 138 All £ fflfflffl Ø æ Samuelsson, 1996 (81) 49 All £ fflfflffl Yokoyama, 1997 (82) 182 DM £ (<3) fflffl Ø Samuelsson, 1997 (83) 73 No DM £ fflffl Nielsen, 1997 (84) 32 DM £ fflffl Biesenbach, 1994 (88) 32 DM * fflffl Low HDL Hunsicker, 1997 (76) 826 No IDDM * (<3) fflffl ØØ Ravid,1998 (77) 574 DM * fflffl ND Ø Klein, 1999 (78) 555 IDDM * fflffl ØØ Massy, 1999 (80) 138 All £ fflfflffl Ø Samuelsson, 1996 (81) 49 All £ fflfflffl Yokoyama, 1997 (82) 182 DM £ (<3) fflffl Samuelsson, 1997 (83) 73 No DM £ fflffl Nielsen, 1997 (84) 32 DM £ fflffl Gall, 1993 (85) 26 DM £ fflffl LDL Hunsicker, 1997 (76) 826 No IDDM * (<3) fflffl Ravid, 1998 (77) 574 DM * fflffl ND Ø Samuelsson, 1996 (81) 49 All £ fflfflffl Ø Samuelsson, 1997 (83) 73 No DM £ fflffl Ø aStudy quality was graded:* least bias, results are valid; £ susceptible to some bias, but not sufficient to invalidate the results; or * significant bias that may invalidate the results. <3, a mean or median duration of follow-up <3 years. bApplicability was rated:fflfflffl, representative of a wide spectrum of patients;fflffl, representative of a relevant subgroup; orfflrepresent- ative of a narrow subgroup. cAt baseline; d,eØ, dyslipidemia measurement associated with faster GFR decline (statistically significant);æ, dyslipidemia measurement associated with faster GFR decline; , dyslipidemia measurement not associated with rate of GFR decline. Uni, univariate; multi, multivariate.

Frequency of dyslipidemia evaluation in kidney Therefore, it is prudent to evaluate dyslipidemias more transplant recipients often than is recommended in the general population. Many factors influence the prevalence of dyslipidemias in Lipoprotein levels may change during the first 3 months transplant patients. Immunosuppressive drugs or changes after kidney transplantation. On the other hand, waiting in proteinuria and GFR may alter lipoprotein levels. 3 months to measure the first lipid profile may needlessly

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 23 National Kidney Foundation

Table 10: The prevalence of dyslipidemias in kidney transplant recipients Time after Mean values (mg/dL) and percent elevatedc Applic- initiation of Study n Age (years) Qualitya abilityb treatment CHOL >200 LDL >100 HDL <40 TG Adults Aakhus, 403 47 £ fflffl 48 months 94% est. 18% 1996 (90) (281 ± 52.5) (55.5 ± 17) Gonyea, 100 — £ fflffl 1 year 83% est. 90% est. 21% est 199 (91) (250 ± 53) (167 ± 53) (51 ± 14) Brown, 100 41.8 £ fflffl CsA 83% est. 93% est. 30% est. [163 1997 (92) 36 months (258 ± 61) (168 ± 47) (48 ± 15) (11–1912)] AZA+P 87% est 92% est. 14% est. [159 98 months (262 ± 55) (167 ± 48) (55 ± 14) (61–687)] Moore, 214 44.7 * ffl >1 year 90% est. 97% est. 48% est. 1993 (93) (278 ± 62) (213 ± 58) (46 ± 123) (195 ± 106) Adolescents Querfeld, 23 14.8 £ fflffl 3.6 years 61% est. 84% est. 67% est. 1993 (94) (213.8 ± 47.2) (141.9 ± 42.2) (44.9 ± 10.8) (154 ± 73) Silverstein, 62 15.4 £ fflffl 6.7 years 51.6% 2000 (95) 55% est. (206 ± 44) (157 ± 88) Goldstein, 30 9.9 * fflffl 2.5–5.0 66% est. 1984 (96) years (218 ± 44) (109.5) Van Gool, 20 13.6 * ffl — 63% est. 72% est. 84% est. 1991 (97) (218 ± 57) (129 ± 50) (55 ± 15) (156 ± 77) Milliner, 69 14.4 * ffl 1 year 66% est. 81% est. 19% est 1994 (98) (219 ± 45) (130 ± 34) (53 ± 15) (142 ± 98) Singh, 29 14.5 * ffl — 242 148 59 167 1998 (99) aStudy quality was graded:* least bias, results are valid; £ susceptible to some bias, but not sufficient to invalidate the results; or * significant bias that may invalidate the results. bApplicability was rated:fflfflffl representative of a wide spectrum of patients;fflffl representative of a relevant subgroup; orffl representative of a narrow subgroup. cShown is the percent of patients with dyslipidemia at the threshold indicated (if available), the percent with dyslipidemia estimated (est.) from the mean and standard deviation, and (in parentheses) the mean and standard deviation. To convert mg/dL to mmol/L, multiply triglycerides by 0.01129 and cholesterol by 0.02586.

delay effective treatment for patients who present with who started treatment for Stage 5 CKD as children (101). dyslipidemia. For patients whose lipid profile is normal at Recent data from the Pathobiological Determinants of presentation, it is reasonable to repeat the lipid profile Atherosclerosis in Youth (PDAY) study provide compelling 3 months later, to confirm that the initial values were not evidence that in the general pediatric population, initial fatty low due to malnutrition or systemic disease. Reasons to streaks seen in adolescents develop into atheromatous pla- repeat lipid measurements after 2–3 months include treat- ques in young adults (102). Moreover, this atherosclerotic ment with diet or lipid-lowering agents, immunosuppres- process is believed to be accelerated in uremia, thus putting sive agents that affect lipids (e.g. prednisone, children with Stage 5 CKD at high risk for developing ACVD. cyclosporine, or sirolimus), or other changes that may Indeed, studies of arteries from children with Stage 5 CKD affect plasma lipids. During the post-transplant course, have demonstrated early ACVD changes (103,104). lipid levels frequently change. Therefore, the Work Group recommends measuring subsequent levels at least It is important to note that lipid levels in the general popula- annually. tion 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 Dyslipidemias in adolescents (3.88 mmol/L), LDL 100 mg/dL (2.59 mmol/L), and HDL Young adults (20–40 years old) with Stage 5 CKD have at 55 mg/dL (1.42 mmol/L). From ages 1–12, lipid levels remain least a 10-fold higher risk for CVD mortality compared with fairly constant, and are slightly lower in girls than boys. the general population (100). There are limited data on ACVD During puberty, there is a decrease in total cholesterol and in children with CKD. However, CVD accounts for approxi- LDL, and a slight decrease in HDL in boys. After puberty, i.e. mately 23% of deaths in children and adults <30 years old by 17 years of age, cholesterol and LDL increase to adult

24 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 11: Serum total, HDL and LDL cholesterol, and Several studies have evaluated the prevalence of dyslipid- triglycerides levels in US children and adolescents (mg/dL) emia after pediatric kidney transplantation (Table 11); Percentile 72–84% of these patients had LDL >100 mg/dL (>2.29 mmol/L). In a longitudinal study of pediatric trans- Age group (years) n Mean 5th 10th 25th 50th 75th 90th 95th plant patients, the prevalence of hypercholesterolemia declined from 70.4–35% at 10 years, with a decrease in Cholesterol Males hypertriglyceridemia from 46.3–15% (98). This decline in 0–4 238 159 117 129 141 156 176 192 209 prevalence may reflect reductions in immunosuppressive 5–9 1253 165 125 134 147 164 180 197 209 medications and improved kidney function. Unfortunately, 10–14 2278 162 123 131 144 160 178 196 208 no longitudinal studies have defined the long-term risk of 15–19 1980 154 116 124 136 150 170 188 203 dyslipidemias in children with CKD, particularly those who Females survive into young adulthood. 0–4 186 161 115 124 143 161 177 195 206 5–9 1118 169 130 138 150 168 184 201 211 10–14 2087 164 128 135 148 163 179 196 207 Use of the Friedewald formula to calculate LDL 15–19 2079 162 124 131 144 160 177 197 209 The Friedewald formula appears to be the most practical, LDL reliable method for determining LDL cholesterol in clinical White males practice: 5–9 131 95 65 71 82 93 106 121 133 10–4 284 99 66 74 83 97 112 126 136 15–19 298 97 64 70 82 96 112 127 134 White females LDL ¼ Cholesterol HDL ðtriglycerides 5Þ; ðinmg=dLÞ; 5–9 114 103 70 75 91 101 118 129 144 10–14 244 100 70 75 83 97 113 130 140 15–19 294 99 61 67 80 96 114 133 141 or HDL White males 5–9 142 57 39 43 50 56 65 72 76 LDL ¼ Cholesterol HDL ðtriglycerides 2:19Þ; ðinmmol=LÞð107Þ 10–14 296 57 38 41 47 57 63 73 76 15–19 299 48 31 35 40 47 54 61 65 White females 5–9 124 55 37 39 48 54 63 69 75 10–14 247 54 38 41 46 54 60 66 72 Two recent studies found the Friedewald formula to be reli- 15–19 295 54 36 39 44 53 63 70 76 able in dialysis patients, (108,109) although other invest- Triglycerides igators reported that the percentage error for the formula is Males higher in patients with CKD compared with the general 0–4 238 58 30 34 41 53 69 87 102 population (110). No studies have examined the accuracy of 5–9 1253 30 31 34 41 53 67 88 104 the Friedewald formula in transplant recipients or in studies in 10–14 2278 68 33 38 46 61 80 105 129 other CKD patients, e.g. those with nephrotic syndrome. 15–19 1980 80 38 44 56 71 94 124 152 Females Recent data from a study in the general population suggest 0–4 186 66 35 39 46 61 79 99 115 5–9 1118 30 33 37 45 57 73 93 108 that the Friedewald formula may underestimate LDL in 10–14 2087 78 38 45 56 72 93 117 135 patients with low LDL levels (28). Data from the general 15–19 2079 78 40 45 55 70 90 117 136 population also suggest that the Friedewald formula is not accurate when triglycerides are 400 mg/dL (4.52 mmol/L). Values were converted from plasma to serum (plasma value 1.03 = serum value). *Insufficient data were available for children Direct measurement of LDL with ultra-centrifugation or ages 0–4 years. To convert mg/dL to mmol/L multiply values by immunoprecipitation techniques is reasonably accurate 0.02586. Data are from the Lipid Research Clinics Program (106). when triglycerides are 400–800 mg/dL (4.52–9.03 mmol/L), LDL, low-density lipoprotein cholesterol; HDL, high-density lipo- but there are no reliable techniques for determining LDL protein cholesterol. 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 levels in boys and girls. Boys continue to have a slightly ACVD is unknown. lower HDL than girls. These changes dictate that the definitions of dyslipidemias be different in children and adults. There are few studies in children, and none included chil- These guidelines define dyslipidemias for children using dren with CKD. However, in one study of children from lipid levels greater than the 95th percentile for age and the general population, calculating LDL using the gender (Table 11). Treatment thresholds for children do not Friedewald formula was more reliable in correctly classifying differ by age and gender, but these thresholds are different patients with high LDL than was the direct measurement of from those of adults. LDL (111).

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 25 National Kidney Foundation

Dyslipidemias in acute medical conditions Fasting Some acute medical conditions may transiently alter Eating raises plasma triglycerides, carried mostly in chylo- plasma lipid levels (Table 12). For example, severe infec- microns and very low-density lipoprotein (VLDL), and, as a tions, surgery and acute myocardial infarction are often result, total cholesterol levels also increase. The postprand- associated with lower-than-normal lipid levels. Other con- ial increases in triglycerides and cholesterol are quite vari- ditions, for example acute pancreatitis, may be associated able, depending on the type of food ingested. In addition, with higher levels. In general, it is best to wait until acute substantial variability in postprandial lipid levels is attribut- conditions that may alter lipid levels have resolved before able to inherited and acquired differences between individ- assessing dyslipidemias for possible ACVD risk. It should uals. Although these differences affect the risk for ACVD, be noted, however, that the lipid profile is not significantly the relationship between postprandial lipid levels and ACVD altered within the first 24 h after a myocardial infarction, is not as well established as the relationship between fast- and a lipid profile can be measured during this time ing lipid levels and ACVD (4). Practical considerations may (112–114). 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 eval- Influence of immunosuppressive agents uation altogether. If the lipid profile obtained in a nonfasting Immunosuppressive medications, e.g. prednisone, cyclospor- patient is normal, then no further assessment is needed at ine, and sirolimus are among the several potential remediable that time. However, an abnormal lipid profile in a nonfasting causes of dyslipidemias in kidney transplant patients patient is an indication to obtain a fasting lipid profile. (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 Guideline 3 diet and lipid-lowering agents may not be fully manifest for Kidney transplant recipients with dyslipidemias should be 2–3 months, and by analogy it may be best to measure a lipid evaluated for remediable, secondary causes (B). profile 2–3 months after starting or stopping an immunosuppressive agent that is known to have a major effect on Rationale lipoprotein levels, e.g. prednisone, cyclosporine, or sirolimus. Particularly relevant causes of secondary dyslipidemia in transplant patients include the use of immunosuppressive drugs such as corticosteroids (128,133,134), cyclosporine The present guidelines are consistent with those of the (126,131,135), and sirolimus (136,137). However, other American Society of Transplantation (AST), which recom- causes of secondary dyslipidemias should be considered mend that a lipid profile should be measured during the first in transplant recipients including nephrotic syndrome 6 months post-transplant, at 1 year after transplantation, (138–143), hypothyroidism (144–146), diabetes (147–149), and annually thereafter (125). The AST guidelines also sug- excessive alcohol ingestion (150–154), and chronic liver gest that changes in immunosuppressive therapy, graft disease (Table 14) (155–157). Additional medications that function, or CVD risk warrant additional testing (125). can cause dyslipidemias include 13-cis-retinoic acid (158–160), anticonvulsants (161–163), highly active antire- Guideline 2 troviral therapy (164–166), beta-blockers (167), diuretics For adult and adolescent kidney transplant recipients, a (167), androgens/anabolic steroids (168–171), and oral complete lipid profile should be measured after an over- contraceptives (172–174) (Table 14). The assessment of night fast whenever possible (B). these secondary causes with history, physical examination, and appropriate laboratory testing is recommended for any patient with dyslipidemia, since effective correc- Table 12: Transient effects of some acute conditions on lipid tion of these disorders may improve the lipid profile. levels Cholesterol Urine protein excretion, especially if >3gper24h,canalso cause or contribute to dyslipidemias (138–143). Therefore, Acute condition Total LDL HDL TG kidney transplant patients should have protein excretion Myocardial infarction (112–114) ###NC measured, if this has not been done recently. In some Stroke (115) ##NC NC cases, the underlying cause(s) of the proteinuria can be Bacterial sepsis (116–118) ###" treated and effectively reversed. In other cases, ACE inhibi- Surgery (119–121) #### tors or angiotensin II receptor blockers may help reduce Acute pancreatitis (122, 123) " NC NC " protein excretion, and may thereby improve the lipid profile Transplant acute rejection (124) ##NC #/NC in some patients. Clinical hypothyroidism can cause dyslipid- Transplant CMV infection (124) ##NC # emia, (144–146) and even subclinical hypothyroidism may LDL, low-density lipoprotein cholesterol; HDL, high-density lipo- cause mild changes (145,175). Glucose intolerance can protein cholesterol; NC, no change; CMV, cytomegalovirus; TG, also cause dyslipidemias (147–149). Therefore, transplant triglycerides patients with dyslipidemia should be assessed with fasting

26 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 13: Randomized trials evaluating the effects of immunosuppressive agents on dyslipidemias after kidney transplantation Change compared with baseline (%)c

Study n Qualitya Applicabilityb Treatment CHOL LDL HDL TG Johnson, 223 * fflfflffl Tacrolimus+azathioprine vs. +14 +18 2000 (126) CsA+MMF vs. Tacrolimus+MMF +25* +30* +12 +1 McCune, 53 * fflfflffl Tacrolimus vs. CsA 16* 25* NC 1998 (127) NC NC NC Vanrenterghem, 500 * fflffl MMF+CsA+half dose corticosteroid +6 3 2000 (128) (low stop) vs. MMF+CsA+full dose +29* +10* corticosteroid (control) Curtis, 1982 (129) 28 £ fflffl Alternate day vs. daily prednisone 12 28 +4d 7d Hollander, 84 £ fflffl Prednisone continuation vs. 10 12 7 14 1997 (130) withdrawal 8 7 17 4 Hilbrands, 122 £ fflffl Azathioprine+prednisone vs. 1995 (131) CsA monotherapy 4+215 12* 0 0 19 +24 John, 1999 (132) 208 £ fflffl High dose CsA vs. low dose CsA 13 +9 19 +3 aStudy quality was graded: *, least bias, results are valid; £, susceptible to some bias, but not sufficient to invalidate the results; or *, significant bias that may invalidate the results. bApplicability was rated:fflfflffl, representative of a wide spectrum of patients;fflffl, representative of a relevant subgroup; orffl, representative of a narrow subgroup. cThe percent change within each group is indicated. dResults were estimated from figures. *, A statistically significant difference between treatment and control. CsA, cyclosporine A; MMF, mycophenolate mofetil; NC, the study reported ‘‘no change.’’ blood glucose and possibly glycosylated hemoglobin. Glyce- and is summarized in Figure 7 and Table 15. For the adult mic control can improve lipid profiles. 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 TREATING DYSLIPIDEMIAS are the focus of treatment. Patients with normal LDL, but high triglycerides, frequently have high levels of remnant In this section we will consider approaches to the manage- lipoproteins. In general, the level of non-HDL cholesterol ment of adults (Guideline 4) and adolescents (Guideline 5) can be used as a surrogate for increased remnant lipo- with dyslipidemias. The approach adopted for adults closely proteins, and elevated levels of non-HDL cholesterol should parallels that recommended by the ATP III Guidelines, (4) be considered for treatment (4). Non-HDL cholesterol is the total cholesterol minus HDL cholesterol (Figure 6). Table 14: Secondary causes of dyslipidemias The approach adopted for adolescents (Guideline 5) is Medical conditions Nephrotic syndrome similar to that for adults, but uses higher thresholds for Excessive alcohol consumption treating LDL and non-HDL cholesterol (Figure 8). These Liver disease higher thresholds are in deference to the relative lack of Hypothyroidism evidence for safety and efficacy of treatment in adoles- Diabetes cents, and the likelihood that the benefit-to-risk ratio is higher at higher levels of LDL and non-HDL cholesterol. Medications 13-cis-retinoic acid Androgens Oral contraceptives Anticonvulsants TREATMENT OF ADULTS WITH Highly active anti-retroviral therapy DYSLIPIDEMIAS Corticosteroids Cyclosporine Guideline 4 Sirolimus 4.1 For adult kidney transplant recipients with fasting tri- Diuretics glycerides 500 mg/dL (5.65 mmol/L) that cannot Beta-blockers be corrected by removing an underlying cause,

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 27 National Kidney Foundation

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 Figure 7: The approach to treatment of dyslipidemias in adults with chronic kidney disease used in these guidelines. to better ascertain the incidence of pancreatitis in CKD, and the possible role of dyslipidemias in its pathogenesis. treatment with therapeutic lifestyle changes (TLC) and a triglyceride-lowering agent should be considered (C). Treating very high triglycerides with therapeutic lifestyle changes 4.2 For adult kidney transplant recipients with The ATP III guidelines suggest that triglycerides 500 mg/ LDL 100 mg/dL (2.59 mmol/L), treatment should dL (5.65 mmol/L) should be treated with TLC. In the be considered to reduce LDL to <100 mg/dL absence of data on the risk of acute pancreatitis from (<2.59 mmol/L) (B). very high triglycerides in patients with kidney failure, it is 4.3 For adult kidney transplant recipients with LDL reasonable to follow the ATP III guidelines. The ATP III <100 mg/dL (<2.59 mmol/L), fasting triglycerides guidelines recommend that TLC include diet, weight 200 mg/dL (2.26 mmol/L), and non-HDL choles- reduction, increased physical activity, abstinence from terol (total cholesterol minus HDL) 130 mg/dL alcohol, and treatment of hyperglycemia (if present). For (3.36 mmol/L), treatment should be considered to patients with fasting triglycerides 1000 mg/dL reduce non-HDL cholesterol to <130 mg/dL (11.29 mmol/L), the ATP III diet recommendations (<3.36 mmol/L) (C). include a very low-fat diet (<15% total calories), medium-chain triglycerides and fish oils to replace some long- Rationale for treating very high triglycerides chain triglycerides. Diet should be used judiciously, if at all, The general approach to treating dyslipidemia in adult in individuals who are malnourished. kidney transplant patients closely follows the approach adopted by the ATP III (Figure 7, Table 15). For patients with very high triglycerides, treatment of hypertriglyceri- Drug treatment of very high triglycerides demia to reduce the risk for pancreatitis takes precedence If TLC is not sufficient to reduce triglycerides to <500 mg/dL over treatment of LDL cholesterol. The ATP III guidelines (<5.65 mmol/L), then treatment with a fibrate or nico- classify very high fasting triglycerides as 500 mg/dL tinic acid should be considered (Table 15). Studies from (5.65 mmol/L) (4). Very high triglycerides are unusual in the general population suggest that fibrates and nicotinic CKD patients and are generally due to an inherited acid lower triglycerides by 20–50% (Figure 9). Statins abnormality in lipoprotein metabolism. However, this dys- cause less triglyceride lowering, and bile acid sequestrants lipdemia pattern is seen more often in transplant patients may actually increase triglyceride levels. Therefore, when as a consequence of the effects of immunosuppressive triglycerides continue to be 500 mg/dL (5.65 mmol/L)

Table 15: The management of dyslipidemias in adult kidney transplant recipients Dyslipidemia Goal Initiate Increase Alternative TG 500 mg/dL TG <500 mg/dL TLC TLC + Fibrate or niacin Fibrate or niacin LDL 100–129 mg/dL LDL <100 mg/dL TLC TLC + low dose statin Bile acid seq. or niacin LDL 130 mg/dL LDL <100 mg/dL TLC + low dose statin TLC + max. dose statin Bile acid seq. or niacin TG 200 mg/dL and Non-HDL <130 mg/dL TLC + low dose statin TLC + max. dose statin Fibrate or niacin non-HDL 130 mg/dL 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

28 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

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

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 percuta- neous 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 Figure 9: Expected responses to treatment of low-density of dyslipidemias reduce the incidence of ACVD in lipoprotein (upper panel), high-density lipoprotein (middle panel), transplant patients are needed. and triglycerides (lower panel), based on studies in the general population. 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 may also be increased. It may be possible to induce a category in the ATP III Guidelines includes patients with remission in the nephrotic syndrome by treating the under- known ACVD, patients with diabetes, and patients with an lying glomerular disease. If not, it may be possible to reduce expected 10-year risk of CHD > 20%. 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 Treating proteinuria reduce urine protein excretion, e.g. angiotensin II-converting- Nephrotic-range proteinuria increases total and LDL cholesterol enzyme (ACE) inhibitors, angiotensin II receptor antagonists, (138–143). In patients with severe proteinuria, triglycerides and/or low-protein diets. There are no published, randomized,

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 29 National Kidney Foundation controlled trials examing the effects of proteinuria reduction 25–35% of total calories (Table 16, Appendix 1). The diet on plasma lipids in kidney transplant recipients. should also contain complex carbohydrates (50–60% of total calories), and fiber (20–30 g per day). Dietary choles- In a randomized, controlled trial, treatment of 17 nephrotic terol should be <200 mg/day. There are few, if any, adverse (nontransplant) patients with an ACE inhibitor reduced urine effects from this dietary regimen. Some patients with LDL protein excretion from a mean of 5.56–4.28 g per day, and 100–129 mg/dL (2.59–3.34 mmol/L) may achieve the goal of decreased mean total cholesterol from 247 to 225 mg/dL LDL <100 mg/dL (<2.59 mmol/L) with TLC alone (188). (6.39–5.82 mmol/L) (176). There were no changes in protein Thus, for patients with LDL 100–129 mg/dL (2.59–3.34 excretion or cholesterol levels in nine placebo-treated con- mmol/L), it is reasonable to attempt dietary changes for trols (176). In a randomized trial of 94 type II diabetic 2–3 months before beginning drug treatment. However, patients with microalbuminuria, treatment with an ACE kidney transplant recipients often have a number of other inhibitor reduced total cholesterol from 245 ± 24 mg/dL nutritional concerns, (189) and it is important to consult a (6.4 ± 0.6 mmol/L) to 239 ± 29 mg/dL (6.2 ± 0.7 mmol/L), dietitian experienced in the care of these patients. while cholesterol increased slightly in the placebo group (177). However, in other randomized trials of microalbumi- nuric type II diabetic patients, ACE inhibitors had little effect Treating high LDL with therapeutic lifestyle changes: on lipid levels (178,179). There are few data on the effects exercise and weight reduction of low-protein diets on lipid levels. In the feasibility phase of Controlled trials in the general population suggest the Modification of Diet in Renal Disease study, serum total that exercise training produces small, but significant and LDL cholesterol levels tended to decrease with reduced dietary protein intake (180). Table 16: Therapeutic lifestyle changes (TLC) for adult kidney transplant recipients There is substantial evidence that ACE inhibitors reduce the rate of kidney disease progression in patients with Diet (consult a dietitian with expertise in chronic kidney proteinuria. Therefore, proteinuric patients with CKD disease) Emphasize reduced saturated fat: should generally be treated with an ACE inhibitor or angio- Saturated fat: <7% of total calories tensin II receptor antagonist, regardless of plasma lipids Polyunsaturated fat: up to 10% of total calories levels (3). However, whether this beneficial effect will also Monounsaturated fat: up to 20% of total calories be seen in kidney transplant recipients has not yet been Total fat: 25–35% of total calories tested in controlled trials. Cholesterol: <200 mg per day Carbohydrate: 50–60% of total calories Some controlled trials in kidney transplant recipients have Emphasize components that reduce dyslipidemia reported that ACE inhibitors or angiotensin II receptor Fiber: 20–30 g per day emphasize 5–10 g per day viscous antagonists reduce urine protein excretion (181–183). (soluble) fiber Others found no statistically significant effect on protein Consider plant stanols/sterols 2 g per day Improve glycemic control excretion (184–187). However, none of these trials Emphasize total calories to attain/maintain standard NHANES selected patients with increased urine protein excretion body weight for study, i.e. these trials were not designed to study Match intake of overall energy (calories) to overall energy needs whether these agents reduced high levels of urine protein Body mass index 25–28 kg/m2 excretion, e.g. >1 g/24 h. Similarly, none of the studies Waist circumference was designed to examine the effects of reducing high Men <40 inches (102 cm) levels of urine protein excretion on plasma lipids. Thus, Women <35 inches (88 cm) whether measures to reduce urine protein excretion in Waist–hip ratio (men <1.0; women <0.8) kidney transplant recipients are effective, and whether Physical activity they also reduce plasma lipids, is unclear. Moderate daily lifestyle activities Use pedometer to attain/maintain 10 000 steps per day Emphasize regular daily motion and distance (within ability) Treating high LDL with therapeutic lifestyle changes: Moderate planned physical activity diet 3–4 times per week 20–30 minute periods of activity Include 5-minute warm-up and cool-down There are no randomized trials examining the safety and Choose walking, swimming, supervised exercise (within ability) efficacy of a low-fat, low-cholesterol diet in kidney trans- Include resistance exercise training plant patients. However, evidence from the general popu- Emphasize lean muscle mass and reducing excess body fat lation suggests that a lipid-lowering diet can reduce LDL Habits (2,27,188). Diet should be used judiciously, if at all, when Alcohol in moderation: limit one drink per day with approval of there is evidence of protein–energy malnutrition. The diet physician should include <7% of calories as saturated fat, up to Smoking cessation 10% of calories as polyunsaturated fat, up to 20% References (4;27;188;190–192); see also Appendix 1. NHANES, of calories as monounsaturated fat, giving a total fat of National Health and Nutrition Examination Survey.

30 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients improvements in dyslipidemias (188,193). Exercise has a Patients should also be monitored for signs and symp- number of beneficial effects, independent of those on dys- toms of myopathy. The risk of myopathy from statins is lipidemias, and the lack of adverse effects makes a com- increased by CKD, advanced age, small body frame, and pelling case for recommending exercise in patients at risk concomitant medications (e.g. fibrates, nicotinic acid, for ACVD (4). Clearly, additional, controlled trials are needed cyclosporine, azole antifungals, macrolide antibiotics, pro- to study the effects of exercise on dyslipidemias and other tease inhibitors, nefazodone, nondihydropyridine calcium ACVD risk factors in kidney transplant recipients. Meanwhile, antagonists, and amiodarone) (204). Most experts recom- it is recommended that exercise be encouraged in these mend obtaining a baseline creatinine phosphokinase (CK) patients, based on data from studies in the general population. level to help in the interpretation of subsequent CK levels. Monitoring statin therapy with routine CK levels is prob- There are also very few controlled trials examining the ably not helpful. Patients who develop muscle pain or effects of weight reduction, with diet and/or exercise, on tenderness should discontinue statin therapy immediately dyslipidemias in kidney transplant patients. The role of and have CK levels measured. Elevations greater than 10 weight reduction in CKD patients, who often have a num- times the upper limit of normal are indicative of myositis ber of nutritional concerns, (189) is unclear. Again, add- and require at least temporary cessation of statin therapy itional studies are needed to define the role of diet, exercise, (204). For patients with muscle soreness and either nor- and weight reduction in dyslipidemic transplant patients. mal or mildly elevated CK, levels should be measured weekly, and the patient’s symptoms monitored closely. Treating high LDL with a statin Frequently, symptoms may improve with a reduction in The reduction in LDL that can be achieved with TLC is the dose of the statin. However, if symptoms worsen, the generally modest. Therefore, TLC alone is usually insuffi- statin should be discontinued. Other causes of myopathy cient to reduce the LDL to the goal of <100 mg/dL should also be considered, e.g. strenuous exercise or (<2.59 mmol/L). In patients who cannot reduce LDL to hypothyroidism. <100 mg/dL (<2.59 mmol/L) by diet, a statin (3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor) should be There are limited data on blood levels of statins in patients prescribed, provided that there is no evidence of acute or with reduced GFR (Table 18). In 19 patients with calculated chronic liver disease. Diet should be continued as an adjunct creatinine clearances 13–143 mL/min, the level of kidney to the statin. The dose of statin needed to reach the goal of function did not affect the blood levels of atorvastatin LDL < 100 mg/dL (<2.59 mmol/L) varies from patient to (205). Pravastatin blood levels were not altered by the level patient. Therefore, starting at a low dose and titrating the of kidney function in 20 patients with creatinine clearance dose upwards is the best strategy for finding the lowest 15–112 mL/min, (206) or in 12 patients on chronic hemodia- dose that achieves the goal. This approach will also mini- lysis (207). Lovastatin blood levels were significantly higher mize the frequency and severity of adverse effects. Statins in six patients with CKD (creatinine clearance 12–39 mL/min) reduced LDL by 18–55% in studies in the general population (208). Therefore, the dose of lovastatin should probably be (Figure 9). Statins that are currently approved for use in the reduced by 50% in patients with Stages 4 or 5 CKD (GFR US include atorvastatin, fluvastatin, lovastatin, pravastatin, <30 mL/min/1.73 m2) (Table 19). The doses of atorvastatin and simvastatin. and pravastatin probably do not need to be altered for reduced kidney function per se. Since there are few pub- There is strong evidence from studies in the general popula- lished data on blood levels for fluvastatin or simvastatin in tion that statins reduce CHD events and all-cause mor- patients with CKD, we recommend that the doses of these tality. The reduction in mortality and in CHD events is agents be reduced by approximately 50% in patients with proportional to the reduction in LDL. There is substantial Stages 4 or 5 CKD (GFR <30 mL/min/1.73 m2). evidence that statins are safe and effective in reducing LDL in kidney transplant recipients (Table 17). Further- more, statins reduce the incidence of cardiac death and Pleiotropic effects of statins acute myocardial infarction in these patients, although a Recent data from studies in the general population have reduction in the primary endpoint in this trial was not indirectly suggested that some of the reduction in ACVD statistically significant (22). Statins are clearly the most from statins may be independent of their effects on plasma effective class of antilipemic agents for reducing LDL. lipids (220,221). Although statins may have favorable effects on endothelial function, coagulation, and plaque stability, Elevated hepatic transaminases occur in 0.5–2.0% of (222) it has been hypothesized that the effects of statins patients treated with statins in the general population on systemic inflammation is one of the most important of (204). Therefore, many recommend that baseline alanine these pleiotropic effects (221,223). If true, this observation and aspartate transferase levels should be obtained, could be important for transplant patients, who appear to although this is controversial (204). Indeed, whether sta- have a high prevalence of elevated C-reactive protein and tins cause hepatotoxicity is controversial. Statins have not other markers of systemic inflammation (17–21). On the been shown to worsen outcomes in patients with chronic other hand, analysis of the data from multiple clinical trials transaminase elevations due to hepatitis B or C (204). in the general population suggests that most, but not all of

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 31 National Kidney Foundation

Table 17: Randomized trials evaluating the treatment of dyslipidemia in kidney transplant recipients Change compared with baseline (%)c

Study n Qualitya Applicabilityb Treatment CHOL LDL HDL TG Bennett, 1995 (194) 90 £ ffl High–dose vs. +6 10 low–dose EPA +6* 5 Urakaze, 1989 (195) 30 £ ffl Fish oil vs. –25* placebo +4 Maachi, 1995 (196) 80 * ffl Fish oil vs. — — — — placebo — — — — Holdaas, 2001 (22) 364 * fflfflffl Fluvastatin vs. 18* 41* +5 25* placebo +28 +26 +29 +44 Kasiske, 2001 (72) 141 £ fflfflffl Simvastatin vs. * * — — gemfibrozil vs. — — — — placebo — — — — Arnadottir, 1994 (197) 37 £ fflffl Simvastatin vs. 22* 32* +13* 12 placebo 3 4—+4 Martinez–Hernandez, 21 £ fflffl Simvastatin vs. 16* 20* +7 15 1993 (198) placebo +5 +1 +4 +8 Castro, 1997 (199) 36 £ fflffl Simvastatin vs. 16 18 3 26 fish oil 10 2 16 23 Katznelson , 1996 (71) 48 £ fflffl Pravastatin vs. 15 * * control +30 — — Kliem, 1996 (200) 44 £ fflffl Pravastatin vs. 16 21 — 6 lovastatin 26 31 6 25 Sahu, 2001 (74) 65 £ fflffl Lovastatin vs. placebo — — — Kasiske, 1990 (201) 11 £ fflffl Lovastatin vs. diet 20 27 +4 17 Renders, 2001 (202) 10 £ fflffl Atorvastatin vs. 30 43 +16 23 cerivastatin 32 35 +6 23 Santos, 2001 (203) 67 * fflffl Simvastatin vs. 23* 35* +7 c10 placebo 2 2 8+2 aStudy quality was graded: *, least bias, results are valid; £, susceptible to some bias, but not sufficient to invalidate the results; or *, significant bias that may invalidate the results. bApplicability:fflfflffl, representative of a wide spectrum of patients;fflffl, representative of a relevant subgroup; orffl, representative of a narrow subgroup. cThe percent change within each group is indicated. *A statistically significant difference between treatment and control. EPA, eicosapentaenoic acid (20:n-3). the reduction in ACVD from statins can be explained by levels of fluvastatin and pravastatin have been reported in reductions in LDL (224). patients treated with cyclosporine, although the increases in fluvastatin were not statistically significant in kidney transplant recipients (Table 20). Nevertheless, 10 heart The use of statins in patients receiving cyclosporine or transplant recipients treated with cyclosporine had a signifi- tacrolimus cant, 3.5-fold increase in the fluvastatin AUC024 compared Cyclosporine has been shown to increase the blood levels with 10 normal controls (225). of virtually every statin that has been investigated (Table 20). The degree to which levels are altered may There have been few comparison trials to determine if the depend on differences in the metabolic pathways of the increase in statin blood levels from cyclosporine is different different statins. The mechanisms for this interaction are for various statins (232). Moreover, our literature search not proven, but calcineurin inhibitors may compete with identified only one study that examined blood levels of some of the same enzymes responsible for the metabolism statins in patients treated with tacrolimus. In this study, of statins. For example, the cytochrome P450 3A4 enzyme, four patients treated with tacrolimus had similar simvastatin which is thought to be important in the metabolism of blood levels compared with four controls that were treated lovastatin, simvastatin, and atorvastatin, is inhibited by with simvastatin alone (229). However, since the number cyclosporine. Fluvastatin is metabolized through the cyto- of patients in this study was very small, and the metabo- chrome P-450 2C9 pathway. Pravastatin does not rely on lism of tacrolimus is very similar to that of cyclosporine, it the cytochrome P-450 system for metabolism, but is should be assumed (until proven otherwise) that tacrolimus instead metabolized by sulfation. Nevertheless, increased may cause elevations in statin blood levels.

32 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 18: Lipid-lowering medication dose adjustments for reduced kidney function Adjust for reduced GFR (mL/min/1.73 m2)

Agent 60–90 15–59 <15 Notes Atorvastatin (205) No No No Cerivastatin (209) No # to 50% # to 50% Withdrawn Fluvastatin ? ? ? Lovastatin (208) No # to 50% # to 50% Pravastatin (206, 207) No No No Simvastatin ? ? ? Nicotinic acid (210) No No # to 50% 34% kidney excretion Cholestipol No No No Not absorbed Cholestyramine No No No Not absorbed Colesevelam No No No Not absorbed Bezafibrate (211–213) # to 50% # to 25% Avoid May " serum creatinine Clofibrate (214–216) # to 50% # to 25% Avoid May " serum creatinine Ciprofibrate ? ? ? May " serum creatinine Fenofibrate (217) # to 50% # to 25% Avoid May " serum creatinine Gemfibrozil (218, 2219) No No No May " serum creatinine GFR, glomerular filtration rate; USFDA, United States Food and Drug Administration.

Accumulating evidence suggests that statins can be used kidney transplant patients receiving cyclosporine (and safely with cyclosporine if the dose of the statin is reduced possibly tacrolimus), since cyclosporine often increases (Table 20). It is recommended that the maximum doses of statin levels through mechanisms that may be exacerbated statins be reduced in patients receiving either cyclosporine by the addition of a third interacting agent. or tacrolimus (Table 20). The addition of a third agent that is also metabolized by the cytochrome P450 system increases Most medications that are well-documented as increasing the risk of myositis and rhabdomyolysis, and therefore such statin blood levels are also metabolized by the hepatic cyto- combinations should be avoided. The new immunosuppres- chrome P450 enzyme superfamily. These include macrolide sive agent everolimus had minimal effects on the blood antibiotics, azole antifungal agents, calcium-channel block- levels of atorvastatin and pravastatin (234). The effects of ers, fibrates and nicotinic acid (Table 21). Other agents sirolimus on statins are unknown. that may also increase statin levels include the serotonin re-uptake inhibitors, warfarin, and grapefruit juice (Table 22). Avoiding agents that increase the blood levels of statins Adding a second LDL-lowering agent to a statin A number of medications may interact with the metabolism Fibrates. There are very few data on the safety and effi- of statins and thereby increase statin blood levels. Medica- cacy of combination therapies in patients with CKD. In gen- tions known to increase statin blood levels should either be eral, it is probably wise to avoid the use of a fibrate together avoided, or, if necessary, the statin reduced or stopped. with a statin, at least until additional studies are conducted in While this is true for all patients, it is especially true for patients with reduced GFR to establish the safety of this 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 Table 20: Effects of cyclosporine on blood levels of statins in kidney transplant recipients Statin Increase in AUC (-fold) Table 19: Recommended daily statin dose ranges (4). Atorvastatin (226) 6 Level of GFR (mL/min/1.73 m2) Cerivastatina (227) 5 Simavastatin (228) 3 Statin 30 >30 or dialysis With cyclosporine Simavastatin (229) 8 Atorvastatin 10–80 mg 10–80 mg 10–40 mg Lovastatin (230) 2 Fluvastatin 20–80 mg 10–40 mg 10–40 mg Lovastatin (231) 3 Lovastatin 20–80 mg 10–40 mg 10–40 mg Lovastatin (232) 20 Pravastatin 20–40 mg 20–40 mg 20–40 mg Pravastatin (232) 5 Simvastatin 20–80 mg 10–40 mg 10–40 mg Fluvastatin (233) 2b Adult Treatment Panel III recommendations for GFR 30 mL/min/ aWithdrawn, 1.73 m2 (4). Most manufacturers recommend once daily dosing, but bP>0.05; Abbreviation: AUC, area under the concentration–time consider giving 50% of the maximum dose twice daily. curve.

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 33 National Kidney Foundation

Table 21: Effects of a macrolide antibiotic, azole antifunagl combination. Fibrates lower LDL by only 5–20% in normo- agents, calcium-channel blockers and nicotinic acid on blood triglyceridemic patients in the general population. They may levels of statins in normal individuals actually increase LDL in patients with high triglycerides, and Other compound Statin (change in blood levels) may increase the blood levels of statins (Table 21). The mechanisms for the interactions between fibrates and P450 P450 statins are not well understood. It was recently reported Agent isoenzyme Statin (effect) isoenzyme that gemfibrozil is a potent inhibitor of the cytochrome Antibiotics P450 2C9 isoform, but had minimal effect on 3A4 in vitro Erythromycin 3A4 Atorvastatin (") (235) 3A4 (255). Erythromycin 3A4 Simvastatin ("")(236) 3A4 Azole antifungal agents Bile acid sequestrants. For patients who continue to have Itraconazole 3A4 Atorvastatin ( ) (237) 3A4 "" LDL 100 mg/dL (2.59 mmol/L) despite TLC and optimal Itraconazole 3A4 Atorvastatin ("") (238) 3A4 treatment with a statin, consideration should be given to add- Itraconazole 3A4 Lovastatin ("") (239) 3A4 Itraconazole 3A4 Lovastatin ("") (240) 3A4 ing a bile acid sequestrant, if triglycerides are <400 mg/dL Itraconazole 3A4 Simvastatin ("") (241) 3A4 (<4.52 mmol/L) (Figure 7, Table 15). Bile acid sequestrants Fluconazole 2C9 Fluvastatin (") (242) 2C9 are contraindicated in patients with triglycerides 400 mg/dL Itraconazole 3A4 Fluvastatin (NC) (240) 2C9 (4.52 mmol/L), since they may increase triglycerides in some Itraconazole 3A4 Pravastatin (") (238) None patients. They are relatively contraindicated for triglycerides Fluconazole (NC) 2C9 Pravastatin (242) None 200 mg/dL (2.29 mmol/L). Evidence from studies in the Itraconazole (NC) 3A4 Pravastatin (241) None general population indicate that bile acid sequestrants are Calcium-channel blockers safe and effective in lowering LDL by 15–30% (Figure 9). Bile Diltiazem 3A4 Lovastatin ("")(243) 3A4 acid sequestrants can be used in combination with a statin Diltiazem 3A4 Simvastatin ("") (244) 3A4 (260). However, there are few studies of the safety and Verapamil 3A4 Simvastatin ("")(236) 3A4 Lacidipine 3A4 Simvastatin (")(245) 3A4 efficacy of bile acid sequestrants in patients with CKD. Diltiazem 3A4 Pravastatin (NC) (243) None Cholestyramine, colestipol, and colesevelam hydrochloride Gemfibrozil 2C9 Simvastatin ("")(256) 3A4 are approved for use in the US (Table 23). It should be noted Fibrates that the new phosphate-binding agent, sevelamer hydrochlo- Fenofibrate None Pravastatin (NC) (257) None ride, appears to lower lipid levels by mechanisms similar to Bezafibrate None Lovastatin (NC) (258) 3A4 those of bile acid sequestrants (261). Gemfibrozil 2C9 Lovastatin ("")(258) 3A4 Gemfibrozil 2C9 Fluvastatin (NC) (259) 2C9 Bile acid sequestrants may interfere with the absorption of Shown are the effects of macrolide antibiotics on blood levels of immunosuppressive medications, particularly immunosup- statins. NC, no change (P>0.05); " less than a 2-fold increase; and pressive agents that bind to lipids. However, some small, "" greater than a 2-fold increase in the area under the plasma uncontrolled studies suggest that a bile acid sequestrant concentration–time curve. P450 indicates the subfamily of cyto- can be used safely, without interfering with the absorption chrome -P450 hepatic oxygenase enzyme superfamily (3A4, 2C9, of cyclosporine. In one uncontrolled study, coadministration or none) felt to be important in the metabolism of the compound of cholestyramine and cyclosporine in five heart transplant (1stcolumn) or statin (4th column). 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 Table 22: Agents that may alter statin blood levels 4 h after a dose of cyclosporine did not reduce the area under the concentration–time curve of cyclosporine (263). Based on Statin (effect) Agent Possible mechanism these very limited data, it appears that bile acid sequestrants Simvastatin (") Nefazodone P450 3A4 (246) may not have a major effect on cyclosporine absorption. Pravastatin (") Nefazodone P450 3A4 (247) However, it may be prudent to avoid administering a bile Atorvastatin ( ) Grapefruit juice P450 3A4 (248) " acid sequestrant from 1 h before to 4 h after the dose of Lovastatin (") Grapefruit juice P450 3A4 (249) cyclosporine, and to monitor blood levels of cyclosporine. Simvastatin (") Grapefruit juice P450 3A4 (250) Atorvastatin (#) Troglitazonea P450 3A4 (251) Simvastatin (#) Troglitazonea P450 3A4 (252) Unfortunately, there are no published data on the effects Simvastatin (#) Rifampin P450 3A4 (253) of bile acid sequestrants on other immunosuppressive Simvastatin (#) Cholestyramine # Absorption (254) agents. In general, the risks and benefits of adding a bile Arrows indicate the direction, but not the magnitude, of change. acid sequestrant to an oral immunosuppression regimen 3A4 indicates the subfamily of cytochrome P450 hepatic oxyge- should be carefully weighed. For many patients, the risk nase enzyme superfamily felt to be important in the interaction. of transplant rejection resulting from poor absorption of aTroglitazone is no longer available in the US; other thizolidine- immunosuppressive medication may outweigh the bene- diones are metabolized by the cytochrome P450 3A4 pathway fits of a further reduction in LDL from adding a bile acid and may have similar effects of statin levels. sequestrant. However, for some patients (e.g. patients

34 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 23: Bile acid sequestrant dose Optimizing immunosuppressive agents in kidney transplant recipients Agent (g/day) Dose range For kidney transplant recipients who have LDL 100 mg/dL Cholestyramine 4–16 (2.59 mmol/L), despite optimum medical management, Colestipol 5–20 consideration should be given to changing the immunosup- Colesevelam 2.6–3.8 pression 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 with severe CAD), the benefit of a further reduction in and discontinuing prednisone (128,130,133,134) , with or LDL may exceed the small risk of adding a bile acid without adding or increasing the dose of azathioprine or sequestrant. mycophenolate mofetil; (ii) replacing cyclosporine with tacrolimus (126,127,131); (iii) tapering and discontinuing Similarly, bile acid sequestrants could theoretically interfere cyclosporine (132) , with or without adding or increasing with the absorption of statins (254). Therefore, it is prob- the dose of azathioprine or mycophenolate mofetil; or (iv) ably best to avoid taking the bile acid sequestrant at the discontinuing or replacing sirolimus with an alternative same time as any other medication, if this is possible. immunosuppressive agent (136,137).

Nicotinic acid. For patients who have triglycerides that Evidence suggests that discontinuing or replacing pre- preclude the use of a bile acid sequestrant, or for patients dnisone, cyclosporine, or sirolimus may reduce the pre- who do not tolerate a bile acid sequestrant, nicotinic acid valence and severity of dyslipidemias and other ACVD risk can be considered as an alternative second agent in com- factors such as hypertension and glucose intolerance bination with a statin. Studies in the general population (Table 13). However, in deciding to change or not to indicate that nicotinic acid reduces LDL by 5–25%, change immunosuppressive agents, the risk of rejection reduces triglycerides by 20–50%, and raises HDL by should be weighed against the risk of ACVD. Kidney trans- 15–35% (Figure 9). There are no data on the use of com- plant recipients who are diabetic and/or have known ACVD bination therapy with a statin and nicotinic acid in patients may have more to gain from changing immunosuppres- with CKD. Adverse effects of nicotinic acid include flush- sive agents than patients at lower risk for ACVD. More- ing, hyperglycemia and hepatotoxicity. Contraindications over, the effects of immunosuppression on overall ACVD to nicotinic acid include liver disease, severe gout, and risk should be taken into account, not just their effects on active peptic ulcer disease. There are no published data dyslipidemias (Table 24). For example, different immuno- on the safety and efficacy of combination therapy with suppressive agents have different effects on blood pres- nicotinic acid and statins in kidney transplant recipients. sure and post-transplant diabetes, both of which can affect the incidence of ACVD. In any case, the decision to alter Ezetimibe. Ezetimibe is the first in a new class of agents immunosuppression should be made only after fully inform- that inhibits cholesterol absorption. Randomized con- ing the patient of the risks and benefits that are involved. trolled 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 Rationale for treating non-HDL cholesterol in patients these studies, triglycerides also declined slightly, and with high triglycerides HDL increased by 2–5%. At present there are no data on Non-HDL cholesterol is defined as total cholesterol minus the use of ezetimibe in transplant patients. Therefore, it HDL cholesterol. No evidence has directly linked low HDL, should probably not be used in transplant patients until its high fasting triglycerides, and increased non-HDL choles- safety is established in this population. terol to ACVD in kidney transplant patients. However, a growing body of evidence from the general population has Treating high LDL in patients who cannot take a suggested that this lipid profile is part of a metabolic statin syndrome (insulin resistance, obesity, hypertension, and Patients who develop minor adverse effects from a statin dyslipidemia) that is associated with ACVD (4). Measures may be able to tolerate a reduced dose, or a different that safely and effectively improve this lipid profile should statin. However, for patients who do not tolerate a be considered to help reduce the incidence of ACVD in reduced dose or another statin, a second-line agent can transplant patients. be used. Either a bile acid sequestrant or nicotinic acid can effectively reduce LDL cholesterol. For patients who cannot Studies in the general population have implicated afford the cost of a statin, nicotinic acid offers a cheaper increased triglycerides as an independent risk factor for alternative. The phosphate-binding agent sevelamer hydro- ACVD (270,271). It is considered most likely that the risk chloride may also lower total and LDL cholesterol. There of high triglycerides is a result of atherogenic, remnant have been two randomized, controlled trials in CKD patients lipoproteins. These include small VLDL and intermediate (268,269). In these studies, sevelamer hydrochloride density lipoproteins (IDL). Since VLDL cholesterol is highly caused significant reductions in total cholesterol. correlated with remnant lipoproteins, VLDL can be

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 35 National Kidney Foundation

Table 24: Relative effect of different immunosuppressive agents on cardiovascular disease risk factors after kidney transplantation. AZA or MMF Prednisone Cyclosporine Tacrolimus Sirolimus Hypertension — "" "" " — Dyslipidemia — "" "" — """ Diabetes — "" ""— Arrows offer a crude, semiquantitative comparison of the relative effect of each agent on cardiovascular disease risk factors. Abbrevia- tions: AZA, azathioprine; MMF, mycophenolate mofetil. combined with LDL cholesterol to enhance risk prediction Clearly, additional studies are needed to establish whether when triglycerides are high. Non-HDL cholesterol is calcu- therapy targeting lower levels of VLDL and IDL is safe and lated as total cholesterol minus the HDL cholesterol. In effective in kidney transplant patients. persons with high triglycerides, e.g. 200–499 mg/dL (2.26–5.64 mmol/L), most of the cholesterol in non-HDL Removing causes of hypertriglyceridemia and elevated cholesterol is present as remnant VLDL. Recent data sug- non-HDL cholesterol gest that non-HDL cholesterol may actually be a better Potentially remediable causes of hypertriglyceridemia predictor of coronary mortality than LDL (272). Non-HDL include obesity, physical inactivity, excessive alcohol cholesterol is also a reasonable surrogate marker for apo- intake, high carbohydrate diet, type 2 diabetes, nephrotic lipoprotein B, the major apolipoprotein of all atherogenic syndrome, and some medications such as estrogens, beta-- lipoproteins (273). blockers and immunosuppressive medications. Cortico- steroid withdrawal may decrease plasma cholesterol Studies in the general population suggest that in individuals and triglycerides (128,130,133,134). Similarly, the immuno- with triglycerides <200 mg/dL (2.26 mmol/L) VLDL is not suppressive agents cyclosporine (126,131) , and especially particularly elevated, and non-HDL cholesterol correlates sirolimus, (136,137) cause dyslipidemias, and may occa- best with LDL cholesterol (Figure 6) (273). Therefore, sionally cause triglycerides 500 mg/dL (5.65 mmol/L). using non-HDL cholesterol as the threshold and target for For patients who have triglycerides 500 mg/dL treatment makes little sense for individuals who do not (5.65 mmol/L), consideration should be given to reducing have high triglycerides. Most clinical trials in the general the dose or withdrawing the offending agent. Anabolic population have not used non-HDL cholesterol as a target steroids can cause dyslipidemia (168–171). 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- Therapeutic lifestyle changes for high triglycerides HDL cholesterol, VLDL, and LDL closely parallel each other. and non-HDL cholesterol Moderate alcohol consumption (30–60 mL alcohol per day) Since a normal VLDL cholesterol is usually defined as has been linked to a reduced risk for ACVD in the general <30 mg/dL (0.78 mmol/L) (274) , a reasonable goal for population. However, excessive alcohol consumption non-HDL cholesterol is one that is 30 mg/dL (0.78 mmol/L) increases the risk for hypertension, dyslipidemias, and higher than the LDL cholesterol goal of 100 mg/dL ACVD in the general population. There are virtually no (2.59 mmol/L), i.e. <130 mg/dL (3.36 mmol/L) (4). The studies on the effects of alcohol consumption in kidney ATP III does not target triglycerides per se for therapy, transplant patients. since triglyceride levels have more day-to-day variability than non-HDL cholesterol, and targeting the latter allows Studies in the general population have shown that more flexibility in the choice of therapies (4). The ATP III glycemic control with diet, oral hypoglycemic agents, and does not target apolipoprotein B for therapy, since: (i) insulin are effective in raising HDL and lowering fasting standardized measures of apolipoprotein B are not readily triglycerides. However, such studies have produced available; (ii) measures of apolipoprotein B have not been conflicting results as to whether intensive (vs. usual) glyce- shown to have greater predictability than non-HDL mic control reduces the risk for ACVD (275–277). Never- cholesterol in individuals with high triglycerides; and theless, patients with low HDL and/or high triglycerides (iii) measurement of apolipoprotein B adds to the expense should be assessed for diabetes, and diabetic patients of the usual lipoprotein profile (4). with this lipid profile should have as good glycemic control as possible without causing excessive hypoglycemia. The Work Group concluded that, in the absence of data from randomized trials in kidney transplant patients, it is Obesity is also associated with low HDL and/or high trigly- prudent to use the higher threshold of triglycerides recom- cerides. Increased physical activity and nutritionally sound mended in the ATP-III. Using a triglyceride threshold diets that restrict calories help to reduce weight in obese 200–499 mg/dL (2.26–5.64 mmol/L) for treating non-HDL patients in the general population. However, there are few cholesterol in patients with low LDL means that only studies demonstrating successful weight reduction in patients with very high VLDL and IDL will be treated. obese kidney transplant patients.

36 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Low-fat diets and increased physical activity have both been function (Table 18). Bezafibrate (213,278–286), ciprofibrate shown to raise HDL and reduce triglycerides in the general (286,287), fenofibrate (286–295), and gemfibrozil (295) population. A limited number of studies suggest that these have been reported to cause increased serum creatinine measures may also be effective in kidney transplant patients. and blood urea nitrogen levels (213,278,279,284,286, 287,289,295). The mechanism for this effect is not Dietary fish oil supplements have been shown to reduce known. Since both serum creatinine and blood urea triglycerides in studies in the general population. Few nitrogen are affected, the mechanism presumably involves studies have examined the effects of fish oil supplements a reduction in GFR. Indeed, in one study, tubular secretion on lipoproteins in patients with CKD, and their results have of creatinine was not altered by bezafibrate (280). However, been inconclusive (Table 17). 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 Drug therapy for high triglycerides and non-HDL thought to cause increased serum creatinine, (286,287) but cholesterol recently there was a report of two cases where this Observational studies in the general population suggest that occurred (295). Nevertheless, since dose modification for high triglycerides are independent risk factors for ACVD decreased kidney function is not required for gemfibrozil, (270,271). Intervention trials have shown that statins, unlike other fibrates (Table 25), gemfibrozil should probably fibrates, and nicotinic acid reduce the risk of CHD, and indir- be considered the fibrate of choice for most CKD patients ect evidence suggests that not all of the benefit in these trials including kidney transplant recipients. is the result of LDL reductions. However, few studies in patients with CKD have examined the relationships between Nicotinic acid can be used in place of fibrates for patients low HDL, high triglycerides, and ACVD, and the results of with elevated triglycerides. However, there are almost these studies have been inconclusive (Table 8). no data on blood levels of nicotinic acid in patients with reduced GFR. In one study, only 34% of a dose of nico- Patients who are not already receiving a statin for treatment tinic acid was excreted in the urine, suggesting that of LDL, who have fasting triglycerides 200 mg/dL (2.26 major dose modification may not be necessary in mmol/L), non-HDL cholesterol 130 mg/dL (3.36 mmol/L), patients with reduced kidney function (Table 26). The and who do not have liver disease, should be started on a incidence of adverse effects from nicotinic acid, e.g. flush- statin along with TLC. In studies in the general population, ing and hyperglycemia, is high (296,297). However, there statins lowered triglycerides by 7–30% and increased HDL are few studies examining whether the incidence of by 5–15% (Figure 9). Similarly, most randomized trials of adverse effects of nicotinic acid is higher in patients with lipid-lowering agents in kidney transplant patients using sta- CKD compared with the general population (298). Insulin tins showed a 15–25% reduction in triglycerides (Table 17). resistance is common in kidney transplant patients, and a Furthermore, statins reduced the incidence of major coron- higher than expected incidence of hyperglycemia from nico- ary events, CHD mortality, and stroke and all-cause mortality tinic acid would not be surprising in this population. 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 Isolated, low HDL cholesterol starting a statin, and 2–3 months following any adjustment Patients with isolated HDL of 40 mg/dL (1.03 mmol/L) in the dose. The Work Group considered whether a statin or should be treated with TLC. However, the pharmacologi- a fibrate should be the first-line agent for treatment of non- cal treatment of isolated low HDL cholesterol is not HDL cholesterol. Although there are compelling theoretical recommended. There are few data defining the risk of reasons for considering fibrates in this setting, the Work ACVD attributable to isolated, low HDL in the general Group concluded that the safety and efficacy of statins for population or in kidney transplant patients. The effects preventing CVD has been more conclusively established in of pharmacological agents on HDL are modest, and the randomized trials in the general population. Clearly, randomized trials examining both statins and fibrates are needed in patients with CKD. Table 25: Maximum doses of fibrates in patients with reduced kidney function If the statin is tolerated, no further treatment of non-HDL Dose (mg) by level of GFR (mL/min/1.73 m2) cholesterol is indicated. If the statin is not tolerated at a reduced dose or after switching to another statin, then Fibrate >90 60–90 15–59 <15 consider discontinuing the statin and treating instead with Bezafibrate 200 tid 200 bid 200 qd Avoid a fibrate. The blood levels of bezafibrate, clofibrate, and Clofibrate 1,000 bid 1,000 qd 500 qd Avoid fenofibrate are increased in patients with decreased kid- Ciprofibrate 200 qd ? ? ? ney function compared with controls with normal kidney Fenofibrate 201 qd 134 qd 67 qd Avoid function (Table 18). In contrast, blood levels of gemfibro- Gemfibrozil 600 bid 600 bid 600 bid 600 bid zil do not appear to be altered by decreased kidney Abbreviation: GFR, glomerular filtration rate.

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 37 National Kidney Foundation

Table 26: Nicotinic acid dose Rationale for treating high LDL and high non- cholesterol HDL Agent (g/day) Dose range Atherosclerosis in young adults was first described in 1953 Immediate release 1.5–3.0 (306). Most recently, the PDAY study found that 50% of Extended release 1–2 children 10–14 years old had early fatty streaks, and 8% had Sustained release 1–2 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). incidence of adverse effects is probably higher in patients In the Bogalusa Heart Study, body mass index, LDL and with CKD than in the general population. Therefore, the systolic blood pressure were associated with atherosclerotic risks of pharmacological therapy to raise HDL (in the disease of the aorta and coronary vessels of children (308). absence of high LDL or high triglycerides) probably Moreover, hypercholesterolemia in children and adolescents outweigh the benefits. persists into adulthood (308). Recent studies of subclinical ACVD in children with familial hypercholesterolemia found an TREATMENT OF ADOLESCENTS WITH increase in intimal medial thickness of the aorta and carotid DYSLIPIDEMIAS arteries compared with that of healthy young children (309). Thus, these and other studies in the general population suggest Guideline 5 that ACVD begins in childhood, and that dyslipidemia in children 5.1 For adolescent kidney transplant recipients with may play an important role in the pathogenesis of ACVD. However, in children with kidney transplants, the relationship fasting triglycerides 500 mg/dL (5.65 mmol/L) that cannot be corrected by removing an underlying between dyslipidemia and subsequent ACVD is unknown. cause, treatment with TLC should be considered (C). Approach to treating high LDL and high non-HDL 5.2 For adolescent kidney transplant recipients with cholesterol LDL 130 mg/dL (3.36 mmol/L), treatment should Secondary causes of dyslipidemias should be treated first be considered to reduce LDL to <130 mg/dL (Guideline 3). Thereafter, for LDL 130–159 mg/dL (3.36– (<3.36 mmol/L) (C). 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 5.3 Adolescent kidney transplant recipients with consider pharmacological management. If LDL is 160 mg/dL LDL < 130 mg/dL (<3.36 mmol/L), fasting triglycerides (4.13 mmol/L), then consider starting atrovastatin at the 200 mg/dL (2.26 mmol/L), and non-HDL cholesterol same time as TLC (Figure 8). (total cholesterol minus HDL) 160 mg/dL (4.14 mmol/ L), treatment should be considered to reduce non-HDL Therapeutic lifestyle changes cholesterol to <160 mg/dL (<4.14 mmol/L) (C). TLC for children are similar to those recommended for adults (Table 16). Recent studies in the general population have Rationale for treating very high triglycerides shown that dietary fat restriction is safe in children (310–313). Evidence that very high triglycerides can cause pancreati- In particular, there have been no adverse effects on growth and tis in children comes from case reports and small series of development, or nutrition (310–313). However, TLC should be patients with familial dyslipidemias (299,300). The inci- used judiciously, or not at all, in children who are malnourished. dence of pancreatitis caused by hypertriglyceridemia in If TLC has failed after 6 months, and potential secondary adolescent kidney transplant recipients is unknown. How- causes of dyslipidemia have been ruled out, drug therapy ever, it seems prudent to treat very high triglycerides with should be considered. TLC, if nutrition is otherwise adequate (Figure 8). The safety and efficacy of lowering triglycerides with fibrates Drug therapy and niacin have not been established in adolescents. There are few studies examining drug treatment of dyslipidemia in transplanted children. However, a limited number Isolated hypertriglyceridemia in adolescents should be of small, randomized, controlled trials in children and ado- treated with TLC. Cases of triglycerides persistently lescents from the general population have found that statins 500 mg/dL (5.65 mmol/L) are rare, and they are generally are safe and effective in lowering LDL (314–317). In parti- due to an inherited metabolic disorder. Drug therapy, e.g. cular, statins do not appear to have adverse effects on low-dose fibrates or nicotinic acid, (301) may be warranted. growth and development (318). A few, very small, uncon- The use of fibrates or nicotinic acid in adolescents has not trolled trials have likewise reported that statins are safe and been well studied; (302–304) therefore, routine use of these effective in patients with nephrotic syndrome (319–321). agents cannot be recommended at this time. Patients Thus, although most statins are not approved for use in should be referred, however, to a pediatric lipid specialist children and adolescents, and additional studies are needed, for management and to rule out familial hypertriglyceridemia preliminary data suggest they are safe and effective. There- or rare, inherited disorders such as lipoprotein lipase defi- fore, statins should be considered for therapy in adolescent ciency or apolipoprotein C-II deficiency (305). kidney transplant recipients and elevated LDL, or in

38 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients hypertriglyceridemic adolescent kidney transplant recipients RESEARCH RECOMMENDATIONS and increased non-HDL cholesterol. Currently, the only statin approved by the US Food and Drug Administration There are reasonable doubts as to whether trial results (USFDA) for use in children and adolescents is atorvastatin. from the general population are applicable to kidney trans- However, more recent data in boys with familial hyper- plant patients. It is beyond the scope of these guidelines cholesterolemia suggests that lovastatin 10–40 mg can to recommend all research that should be conducted in safely decrease LDL by 21–36% (322,323). Similar results kidney transplant patients with dyslipidemia, or to design were reported with pravastatin 5–20 mg (324). Additional clinical trials. However, it is apparent that some questions data on long-term safety, especially with respect to are particularly well suited for study. growth and nutrition, are needed before statins can be recommended for use in children of all ages. For adults and children with a functioning kidney transplant, prospective cohort studies with long-term follow- For adolescents who do not achieve the desired target up are recommended to determine: with a statin, addition of a bile acid sequestrant can be considered (Figure 8). Bile acid sequestrants appear to be the prevalence of dyslipidemias over time, particularly safe and effective in improving dyslipidemias in children. with newer immunosuppressive agents; Cholestyramine is approved for use in children by the USFDA. Although bile acid resins are safe in children of the associations between dyslipidemias, including those all ages, adherence to therapy is often poor due to the refected by nontraditional markers such as apolipopro- high incidence of adverse effects (325–327). No dosage tein B, and subsequent ACVD. adjustment is required in patients with reduced GFR. For children with CKD and/or a functioning kidney transplant, However, pediatric dosages have not been established. In children 6–12 years of age, doses of anhydrous choles- phase I and phase II trials, and pharmacokinetic dosing studies are recommended to establish the safety and lipid- tyramine 80 mg/kg three times a day, not to exceed 8 g lowering efficacy of agents (including, but not limited to): per day, can be used (328). Adverse effects are common and include constipation, abdominal discomfort, nausea, flatulence, vomiting, diarrhea, heartburn, anorexia, and bile acid sequestrants, e.g. colesevelam; indigestion. In children and adults treated with cyclo- cholesterol uptake inhibitors, e.g. ezetibmide; sporine, bile acid sequestrants should probably be administered between cyclosporine doses to prevent possible statins; interference with absorption. Bile acid sequestrant fibrates; powders are generally mixed with 120–180 mL of fluid, and several glasses of water between doses are recom- nicotinic acid; mended. The fluid recommended with bile acid powders sevelamer hydrochloride; may limit their use in dialysis or CKD patients who have been prescribed strict fluid restrictions. The newer bile appropriate lipid-lowering drug combinations. acid sequestrant colesevelam has not yet been studied in children, and thus cannot be recommended at this time. For adults with a functioning kidney transplant, phase I and Similarly, the phosphate-binding (and lipid-lowering) agent phase II trials and pharmacokinetic dosing studies are sevelamer hydrochloride has not been studied in children. recommended to establish the safety and lipid-lowering efficacy of new agents (including, but not limited to): Bile acid sequestrants can increase triglycerides, and hypertriglyceridemia is common in children with CKD. colesevelam; Bile acid resins are relatively contraindicated in patients cholesterol uptake inhibitors, e.g. ezetimibe; with triglycerides 200 mg/dL (2.26 mmol/L), and definitely contraindicated in patients with triglycerides 500 mg/dL appropriate lipid-lowering drug combinations. (5.65 mmol/L). Other potential, long-term adverse effects of bile acid resins include deficiencies of vitamins A, E, and For kidney transplant recipients, these and other appro- folic acid. In studies with long-term follow-up, a folic acid priate studies are recommended to determine whether: supplement was required; however, anemia from folate deficiency was not observed (329, 330). In kidney transplant A statin safely reduces the incidence of ACVD and all- recipients, hyperhomocysteinemia is more common than in cause mortality in patients with any lipid profile. the general population, and therefore the potential for A statin safely reduces the rate of decline in GFR in adverse effects from folate deficiency caused by bile acid patients with any lipid profile. sequestrants is potentially greater. Taken together, these considerations suggest that bile acid resins should be used A statin safely reduces the incidence of ACVD and with caution in children, and close monitoring for adverse all-cause mortality in patients with LDL 100 mg/dL effects such as vitamin deficiencies are warranted. (2.59 mmol/L).

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 39 National Kidney Foundation

A statin safely reduces the rate of decline in GFR in Walworth, MD; G. Warwick, MD; Steve Wassner, MD; Jean-Pierre Wauters, patients with LDL 100 mg/dL (2.59 mmol/L). 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 ACKNOWLEDGEMENTS Academy of Pediatrics; American Association of Clinical Endocrinology; American College of Cardiology; American Dietetic Association; American The National Kidney Foundation Kidney Disease Outcomes Quality Initia- Geriatrics Society; American Heart Association; American Nephrology tive was supported by an unresetricted grant from Amgen, Inc. The devel- Nurses Association; American Pharmaceutical Association; American opment of these dyslipidemia guidelines was supported by an unrestricted Society for Nutritional Sciences; American Society of Pediatric Nephrology grant from Fujisawa Healthcare, Inc. (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 The Work Group thanks the more than 100 reviewers whose helpful Oncology; Indian Health Service (HQ); International Society For Hemo- comments were incorporated into these guidelines. Also, special thanks dialysis; International Society for Peritoneal Dialysis (ISPD); N.Y. Diabetes to Lauren Bronich, RD, LD, CDE, Clinical Dietitian Specialist and Diabetes Center; National Association of Nephrology Technicians/Technologists Educator, Johns Hopkins Bayview Medical Center for helping with the (NANT); National Heart Lung Blood Institute; National Kidney and Urologic Appendix 1 diet information. Diseases Information; National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH); North The following individuals provided written review of the draft guidelines: American Transplant Coordinators Organization; Polycystic Kidney Disease Kevin Abbott, MD; Anil Agarwal, MD; Mamta Agarwal, MD; Lawrence Foundation; Renal Physicians Association; Sigma Tau Pharmaceuticals; The Agodoa, MD; Steve Alexander, MD; Cathy Allen, RD; Mouhammed Amir North American Menopause Society (NAMS) 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; Participation in the review does not necessarily constitute endorsement of Deborah Benner, MA, RD, CSR; Richard K. Bernstein, MD, FACE, FACN; the content of the report by the individuals or the organization or institution Andrew T. Blair, MD; Marcia Bos, BScPhm; Deborah Bowen, MSN, RN, they represent. 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, APPENDIX 1. THERAPEUTIC LIFESTYLE CSR, LD; James Cleeman, MD; Peter W. Crooks, MD; Jeffrey Cutler, MD, CHANGE DIET FOR PATIENTS WITH MPH; Ira Davis, MD; Claudia Douglas, RN, MA, CNN, APNC; Sharon E. CHRONIC KIDNEY DISEASE Ehlers, MA, RN; Mahmoud T. El-Khatib, MD; Nancy Ferrell, RN, CNN; Barbara A. Fivush, MD; Michael Flessner, MD; Joseph Flynn, MD; Edward Comprehensive nutrition counseling should be offered to Foote, PharmD; Linda Fried, MD; Richard S. Goldman, MD; Antonio Gotto, MD; all patients with CKD, given the high incidence of malnu- Karen Graham; Tomas L. Griebling, MD; Ann P. Guillot, MD; Elizabeth trition and other nutritional abnormalities. Detailed guide- 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. lines of the K/DOQI Nutrition Work Group for adults and Herzog, MD; Hallvard Holdaas, MD; Linda Hopper, RD, CSR, LD; Alan R. children recommend a regular assessment of nutritional Hull, MD; Abrar Husain, DO; Todd S. Ing, MD; Julie R. Ingelfinger, MD; status and intervention by a renal dietitian (331) However, Kathy Jabs, MD; J.A. Joles, DVM; Donald C. Jones; Nikolaos Kaperonis; dietary management of patients with dyslipidemias is not Toros Kapoian, MD; Dee Kees-Folts, MD; Pamela S. Kent, MS, RD, LD; Carl specifically addressed in the K/DOQI nutrition guidelines. Kincaid; Florian Kronenberg, MD; Justina Lambert; Bruce Lange, PharmD; Therefore, the Work Group made the following recom- Derrick L. Latos, MD; Phyllis Lawson, RN; Claude Lenfant, MD; Edgar mendations (Table 27). Lerma, MD; Matthew Lewis, PharmD; Tom Lili, FRACP; Lyn Lloyd, NZRD; Ziad Massy, MD; Aletha Matsis, BSN, RN, CNN; Tej Mattoo, MD; Linda M. During the initial assessment and subsequent follow-up of McCann, RD, LD, CSR; Peter A. McCullough, MD, MPH, FACC, FACP; patients with CKD, it is important to assess malnutrition Sandra McDonald-Hangach, RD, CSR; Rosemary McElroy, RN; Maureen McKinley, MSW, LCSW; Mary K. McNeely, MS, RD, LD, CSR; Maureen A. and protein energy deficits. If the patient is well nourished, Michael, RN; Pat Michael, RN; Joyce Mooty, EdM, MPH, RD; Joseph V. Nally, dietary modifications for dyslipidemias can be undertaken Jr., MD; Jean M. Nardini, RN; Andrew S. Narva, MD; Martin S. Neff, MD; Linda safely. In some patients with CKD, standard CKD diet Neff, PhD; Alicia Neu, MD; John M. Newmann, PhD, MPH; Allen R. recommendations may have already appropriately Nissenson, MD; Philippa A. Norton, MED, RD, CSR, LD; Gregorio T. Obrador, reduced many foods with high unsaturated fats such as MD; Neeta O’Mara, PharmD; Joni J. Pagenkemper, MS, MA, RD; Thakor G. milk products. Patel,MD;JessiePavlinac,MS,RD,CSR,LD;GlendaPayne,RN,MS,CNN; Sunil Prakash, MD; Sarah S. Prichard, MD, FRCP; William Primack, MD; Doris It is important to consider patients with low total cholesterol. Ramirez de Pena; Vijaykumar M. Rao, MD; Susan M. Reams, RD, CSR, LD; A low total cholesterol level, especially in association with Sally I. Rice, LCSW, DCSW; Patricia J. Roberts, MS, RN, CNN; Noreen K. chronic protein-energy deficits and/or the presence of 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. comorbid conditions, may signal malnutrition. Patients with Skipwith; Lance Sloan, MD, FACE; Jo Ellyn Smith, RD; Wendy L. St. Peter, cholesterol <150 mg/dL (<3.88 mmol/L) should be assessed PharmD; Theodore I. Steinman, MD; Peter Stenvinkel, MD, PhD; Dru for possible nutritional deficiencies. For patients with mal- Straatman; Sufi Suhail, MRCP; Ahmad Tarakji, MD; Nicola Thomas; Paul D. nutrition or protein-energy deficits, improving nutrition Thompson; Vicente E. Torres, MD; Wulf H. Utian, MD, PhD; Candace C. should be the primary goal. Dietary recommendations may

40 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 27: Dietary modifications that may be appropriate for adults with chronic kidney disease (3) Food Choices Choose Decrease Eggs (cholesterol <200 mg per day) Limit to 2 eggs per week, or use Egg 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 alternatives Lean meat products, well trimmed High-fat meats (sausage, bacon, organ meats of fat such as liver, sweetbreads, brain) Poultry without skin Sandwich-style meats such as ham, ’cold Fish, shellfish cuts’, processed meats Low-fat tofu; tempeh; soy protein products Fish, shellfish Fish or shellfish, baked or Avoid consuming bones of fish (sardines, broiled without additional fat anchovies, 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% total sunflower, corn, soybean, Coconut, palm kernel, palm oil, coconut and kcal) cottonseed, canola, olive, peanut coconut milk products Margarine - made from any of the Butter, lard, shortening sold in cans, bacon fat, oils above, especially soft and liquid stick margarine forms Dressing made with egg yolk, cheese, sour Salad dressings - made from any cream, or milk of the oils above Breads and grains (dietary fiber goal Breads without toppings or cheese Homemade breads made with recommended of >20 g per day may be difficult with ingredients fats and oils fluid restriction; focus on viscous/ Cereals: oat, wheat, corn, multigrain Breads of high-fat content such as croissants, soluble fiber) Pasta, rice crackers - low-fat animal flaky dinner rolls crackersb, unsalted soda crackers Granolasc that contain coconut or and bread sticks, melba toast hydrogenated fats High-fat crackers (more than 3 g of fat per serving on label) Commercially baked pastries and biscuits Fruits and vegetables Choices within CKD diet parameters Fried fruits or vegetables or served with butter in fresh, frozen, or low-sodium or cream sauces; avocado canned forms Sweets (may be restricted for Sweets: sugar, syrup, honey, jam, Candy made with chocolate, cream, butter, diabetics or in presence of high preserves, candy made without fat Frostings. Ice cream and regular frozen triglycerides) (hard candy) desserts Frozen desserts: low-fat and non-fat Commercially baked cookies, cakes, cream sherbet, sorbet, fruit ice and regular pies Cookies, cakes, and pies made with Commercially fried pastries such as egg whites or egg substitutes or doughnuts recommended fats; angel food cake; Whipped cream fig and other fruit bar cookies Non-dairy regular and frozen whipped toppings in moderation aDiet 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). bAnimal-shaped biscuits; cmuesli. include high-protein foods, with a liberal intake of foods high Plant sterols in saturated fat. However, in the majority of cases, accept- Plant sterols block the absorption of cholesterol from able protein sources low in saturated fat should be encour- the small intestine by entering into micelles, which are aged (Table 28). Low-fat dairy products, nuts, seeds, and needed for cholesterol to dissolve. Consequently, beans may provide protein, but potassium and phosphorus endogenous and dietary cholesterol becomes insoluble, contents should still be limited. Overall, healthy food prepara- and is therefore excreted in the stool. Plant sterols them- tion should be encouraged, such as using peanut, canola, or selves are not absorbed or excreted well. Studies in olive oil in cooking, since these are high in monounsaturated the general population have shown that the intake of fats. 2–3 g of plant sterols per day lowers LDL by 6–15%, with

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 41 National Kidney Foundation

Table 28: Nutritional characteristics of some protein-source food itemsa Protein Source Kcal Total fat (g) Saturated fat (g) Cholesterol (mg) Beef eye of round, roasted 140 4 2 60 Beef top round steak, broiled 150 4 1 70 Pork tenderloin, roasted whole 140 4 1 65 Chicken breast, baked 120 2 1 70 Chicken drumstick, baked 130 4 1 80 Turkey breast, baked 120 1 0 55 Turkey wing, baked 140 3 1 60 Ground beef (10%), broiled, well-done 210 11 4 85 Ground beef (17%), broiled, well-done 230 13 5 85 Ground turkey 195 12 5 60 Orange roughy* broiled 70 1 0 20 Blue crab, steamed 90 1 0 80 Sole, broiled 100 1 0 60 Halibut, broiled 120 2 0 30 aThree-ounce servings, trimmed after cooking, skin removed (332). Kcal, kilocalories. bType of fish. minimal change to HDL or triglycerides (4) Reductions These foods may have to be included more often, and the in LDL have been seen in hypercholesterolemic children phosphate binder or potassium content of the dialysate (332,333) and adults (334–336) The use of esters needs may need to be adjusted, to maintain normal serum phos- to take into account daily total fat consumption, and adjust- phorus and potassium. Since each company varies the ments in caloric intake may also be needed. There is no ingredients in their brands, it is essential to read nutrition contraindication to the use of plant sterols in patients with labels, and to use those lowest in potassium and phos- CKD; however, they should be used as a fat substitute and phorus. For example, a 1-cup portion of Kellogg’s Raisin not for other therapeutic reasons. Unfortunately, some Bran1 (Kelloggs, Battle Creek, MI) has less potassium and commercial products are expensive (Table 29). phosphorus than Post’s Raisin Bran1 (Kraft Foods, Inc., Northfield, IL). Common foods containing natural fiber are Fiber described in Table 30. Viscous fiber should be increased by 5–25 g per day to help reduce total cholesterol and LDL (4) High-fiber diets require Patients who are unable to consume adequate fiber additional fluid intake, which may be difficult for the anuric through their diet can add natural fiber in the form of a dialysis patient who is often limited to 1 L of fluid per day. tasteless powder to their meals (Table 31). Psyllium is a Many high-fiber foods are also restricted in the renal diet viscous fiber recommended by the ATP III (4) The most due to their high phosphorus and/or potassium content. common commercial product is Metamucil1 (Proctor and

Table 29: Margarines containing plant sterol/stanol estersa Nutritional composition Benecol1 Benecol Light1 Take Control1 Take Control Light1 Kilocalories 80 45 80 45 Kilocalories from fat 80 45 50 40 Total fat (g) 9 5 8 5 Saturated fat (g) 1 0.5 1 0.5 Polyunsaturated fat (g) 3 2 2 2 Monounsaturated fat (g) 4 2.5 4.5 2 Cholesterol (mg) 0 0 <55 Sodium (mg) 110 110 85 85 Carbohydrate (g) 0 0 0 0 Protein (g) 0 0 0 0 Potassium (mg) 3.5 3.5 * * Phosphorus (mg) <1 <1* * Plant sterol content 1.7 g stanol esters 1.7 g stanol esters 1.65 g soybean 1.65 g soybean extract extract Comments Cook, bake or fry Can be used in cooking; Contains 35% contains 60% soybean and canola soybean and canola oils aOne serving (15 g) of margarines (331). Benecol1and Benecol Light1 are registered trademarks of Neil Consumer Health-Care, (Fort Washington, PA), a division of Johnson & Johnson (http://www.benecol.com). Take Control1 and Take Control Light1 are registered trademarks of Unilever Bestfoods, Engelwood Cliffs, NJ (http://www.takecontrol.com).*Insignificant amount.

42 American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 Clinical practice guidelines for managing dyslipidemias in kidney transplant patients

Table 30: Contents of some commercially available cereals high in fiber (332) Serving Fiber K P Product size (g) (mg) (mg) Cereals All Bran1 113.4 g 10 310 300 Post Bran Flakes1 151.2 g 6 180 150 Cheerios1 151.2 g 3 90 100 Quaker Crunchy Bran1 170 g 5 56 36 Fiber One1 113.4 g 13 230 150 Common Sense Oat Bran1 113.4 g 4 120 150 General Mills Raisin Bran1 170 g 3 220 150 Kellogg’s Raisin Bran1 226.8 g 8.2 350 200 Post Raisin Bran1 226.8 g 8 380 250 General Mills Wheaties1 226.8 g 3 110 100 Quaker Old Fashioned Oatmeal1 113.4 g dry 3.7 143 183 Ralston Oatmeal1 170 g cooked 4.6 116 110 Fruit Apple, raw, skin on Medium 3.7 159 10 Blackberries, raw 113.4 g 3.8 141 15 Orange, navel, raw 1 fruit 3.1 233 25 Peaches, canned in water 226.8 g 3.2 242 24 Pear, canned in water p 226.8 g 4.0 129 17 Raspberries, raw 113.4 g 4.2 94 8 Vegetables Broccoli, boileda 113.4 g 2.3 228 4.6 Brussels sprouts, boiled 113.4 g 2 247 44 Carrots, sliced, boiled 113.4 g 2.6 177 23 Corn, boiled 113.4 g 2.3 204 84 Mixed vegetables, frozen 113.4 g 4 154 46 Green peas, frozen, boiled 113.4 g 4.4 134 72 Spinach, boileda 113.4 g 2.2 419 150 Bread Pumpernickel 1 slice 2.1 67 57 American rye 1 slice 1.9 53 40 Whole wheat 1 slice 1.9 71 64 aMay 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 Bran1, Common Sense Oat Bran1, and Kellogg’s Raisin Bran1, Kellogg USA Inc, Battle Creek, MI; Post Bran Flakes1and Post Raisin Bran1, Kraft Foods Inc., Northfield, IL; Cheerios1, Fiber One1, General Mills Raisin Bran1, and Wheaties1, General Mills, Minneapolis, MN; Quaker Crunchy Bran1and Quaker Old Fashioned Oatmeal1, Quaker Oats Company, Chicago, IL; Ralston Oatmeal1, Ralston Foods, a division of Ralcorp, St. Louis, MO. K, potassium; P, phosphorus

Gamble, Cincinnati, OH). It should be mixed with insert before use to ensure that it contains low amounts 236.58 mL of fluid per dose, which may be difficult due of potassium, sodium, and magnesium. Unifiber1 (Niche to strict fluid restrictions in the dialysis patient. Magne- Pharmaceuticals, Inc., Roanoke, TX, USA) contains pow- sium may also be an excipient in some psyllium products, dered cellulose, corn syrup solids and xanthan gum, and and those should be avoided. Sugar-free products are can easily be blended into applesauce, Cream of Wheat, or available for use in diabetics. Psyllium is also made 88.72 mL of apple juice or water to provide 3 g of natural generically, and it is imperative to review the product fiber. These products do not interfere with the absorption of

Table 31: The electrolyte content of some commonly used fiber supplements Product Fiber (g) kCal Na (mg) K (mg) P (mg) Metamucil1 3 g per dose — — 30 mg per dose — MetamucilWafers1 3 g per 2 wafers — — 60 mg per dose — Unifiber1 1 tbsp (3 g) 4 0 0 0 Hyfiber1 1 tbsp (3 g) 14 15 12 — Metamucil1and Metamucil Wafers1 are registered trademarks of Procter and Gamble, Cincinnati, OH; Unifiber1 is a registered trademark of Niche Pharmaceuticals, Inc., Roanoke, TX; Hyfiber1 is a registered trademark of National Nutrition Lancaster, PA. kCal, kilocalories; tbsp, tablespoon; K, potassium; P, phosphorus

American Journal of Transplantation 2004; 4 (Suppl. 7): 13–53 43 National Kidney Foundation medications or vitamins. Constipation is a chronic problem 14. Kunz K, Petitjean P, Lisri M et al. Cardiovascular morbidity and for dialysis patients who are restricted in the actual amount endothelial dysfunction in chronic haemodialysis patients: is of fiber and fluid they can consume. Osmotic agents such as homocyst (e) ine the missing link? Nephrol Dial Transplant 1999; Polyethylene Glycol 3350, NF Powder, e.g. Miralax1 17 g 14: 1934–1942. 15. Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM. Serum p.o (Braintree Laboratories, Braintree, MA, USA) or other total homocysteine and cardiovascular disease occurrence in products, may be needed to relieve constipation. chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11: 134–137. 16. Mallamaci F, Zoccali C, Tripepi G et al. 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