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 trans- plant 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) dis- orders 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