2013 KDIGO慢性肾病血脂管理临床实践指南

指南心血管内科· 血脂管理 · 2013

KDIGO Board Members

Authors

Keywords

Parameter Conventional unit Conversion factor SI units Cholesterol (total, HDL-C, LDL-C) mg/dl 0.0259 mmol/l Creatinine (serum, plasma) mg/dl 88.4 mmol/l Triglycerides (serum) mg/dl 0.0113 mmol/l Abbreviations: HDL-C, high-density lipoprotein cholesterol, LDL-C, low-density lipoprotein cholesterol. Note: Conventional unit Â conversion factor ¼ SI unit cholesterol, chronic kidney disease, clinical practice guideline, dyslipidemia, evidence-based recommendation, KDIGO, systematic review, triglycerides CITATION CI, confidence interval, CKD, chronic kidney disease, eGFR, estimated glomerular filtration rate, MI, myocardial infarction

# CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO

CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO

Abstract

CKD is defined as abnormalities of kidney structure or function, present for 43 months, with implications for health. CKD is classified based on Cause, GFR category (G1-G5), and Albuminuria category (A1-A3), abbreviated as CGA.

We are confident that the true effect lies close to that of the estimate of the effect.

B Moderate

The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

C Low

The true effect may be substantially different from the estimate of the effect.

D Very low

The estimate of effect is very uncertain, and often will be far from the truth.

Implications

Grade* Patients Clinicians Policy-makers Level 1 'We recommend'

Most people in your situation would want the recommended course of action and only a small proportion would not.

Most patients should receive the recommended course of action.

The recommendation can be evaluated as a candidate for developing a policy or a performance measure.

Level 2 'We suggest'

The majority of people in your situation would want the recommended course of action, but many would not.

Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences.

The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.

*The additional category 'Not Graded' was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence.

The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Foreword

Kidney International Supplements (2013) 3, 260; doi:10.1038/kisup.2013. 28 It is our hope that this document will serve several useful purposes. Our primary goal is to improve patient care. We hope to accomplish this, in the short term, by helping clinicians know and better understand the evidence (or lack of evidence) that determines current practice. By providing comprehensive evidence-based recommendations, this guideline will also help define areas where evidence is lacking and research is needed. Helping to define a research agenda is an often neglected, but very important, function of clinical practice guideline development. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and the strength of recommendations. In all, there were 3 (27.3%) recommendations in this guideline for which the overall quality of evidence was graded 'A,' whereas 2 (18.2%) were graded 'B,' 4 (36.4%) were graded 'C,' and 2 (18.2%) were graded 'D.' Although there are reasons other than quality of evidence to make a grade 1 or 2 recommendation, in general, there is a correlation between the quality of overall evidence and the strength of the recommendation. Thus, there were 4 (36.4%) recommendations graded '1' and 7 (63.6%) graded '2.' There was 1 (9.1%) recommendation graded '1A,' 1 (9.1%) was '1B,' 2 (18.2%) were '1C,' and no '1D' recommendations. There were 2 (18.2%) recommendations graded '2A,' 1 (9.1%) were '2B,' 2 (18.2%) were '2C,' and 2 (18.2%) were '2D.' There were 2 (15.4%) statements that were not graded. Some argue that recommendations should not be made when evidence is weak. However, clinicians still need to make decisions in their daily practice, and they often ask, ''What do the experts do in this setting?'' We opted to give guidance, rather than remain silent. These recommendations are often rated with a low strength of recommendation and a low quality of evidence, or were not graded. It is important for the users of this guideline to be cognizant of this (see Notice). In every case these recommendations are meant to be a place for clinicians to start, not stop, their inquiries into specific management questions pertinent to the patients they see in daily practice.

Quick summary of the KDIGO recommendations for lipid-lowering treatment in adults with CKD (a) Rule out remediable causes of secondary dyslipidemia. (b) Establish the indication of treatment (YES or NO) and select agent and dose. (c) Treat according to a ''fire-and-forget'' strategy: do not measure LDL-C unless the results would alter management.

Upon first presentation to establish the diagnosis of CKD, the nephrologist will obtain a full lipid profile as part of routine care. In case of referral and to confirm the CKD diagnosis, a full lipid profile may already be available. Results of the lipid profile should be used together with other clinical data to rule out remediable causes of secondary dyslipidemia. If excluded, the nephrologist will establish whether statin treatment is indicated (YES or NO) based on underlying cardiovascular risk. If the level of risk suggests that statin treatment is indicated, she/he will select a dose of a statin (Table 4 ) that is available in her/his country and has been tested for safety in people with CKD.

Contemporary practice and other clinical practice guidelines emphasize the use of targets for LDL-C (e.g., 1.8 or 2.6 mmol/l [70 or 100 mg/dl]), which require repeated measurements of LDL-C and treatment escalation with higher doses of statin or initiation of combination lipid-lowering therapy (''treat-to-target'' strategy) when the LDL-C target is not met. The KDIGO Work Group does not recommend the treat-totarget strategy because it has never been proven beneficial in any clinical trial. In addition, higher doses of statins have not been proven to be safe in the setting of CKD. Therefore, the Work Group recommends a ''fire-and-forget'' strategy for patients with CKD (see Rationale for Recommendation 1.2). Physicians may choose to perform follow-up measurement of lipid levels in patients for whom these measurements are judged to favorably influence adherence to treatment or other processes of care.

Introduction: The case for updating and context

Kidney International Supplements (2013) 3, 266-267; doi:10.1038/kisup.2013. 32 In 2003, the US-based KDOQI (Kidney Disease Outcomes Quality Initiative) group published Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease (CKD). In the absence of randomized controlled trials (RCTs), ATP III Guidelines (Adult Treatment Panel III) were considered to be generally applicable to patients with estimated glomerular filtration rate (eGFR) Z15 ml/min/ 1.73 m 2 (GFR categories G1-G4, formerly CKD stages 1-4) with the exception that: (1) CKD was classified as a coronary heart disease (CHD) risk equivalent, (2) complications of lipid-lowering therapies may result from reduced kidney function, (3) indications for the treatment of dyslipidemias other than preventing acute cardiovascular disease (CVD) may be applicable, and (4) treatment of proteinuria might also be an effective treatment for dyslipidemias. 1 At that time the Work Group included children and adolescents with CKD (defined by the onset of puberty) in these guidelines, and recommended that they be managed in the same way as adults.

The 2003 publication anticipated that an update should be performed in about 3 In 2007 KDOQI issued Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease and included a set of guidelines on Management of Dyslipidemia in Diabetes and Chronic Kidney Disease. 2 The guidelines adopted trends in treating people with very high risk and recommended treatment to target low-density lipoprotein cholesterol (LDL-C) of o2.6 mmol/l (o100 mg/dl) for people with diabetes and eGFR categories G1-G4. The target of o1.8 mmol/l (o70 mg/dl) was considered a therapeutic option. The guidelines included the results of the 4D study, which to the surprise of many, demonstrated that lowering LDL-C with atorvastatin in hemodialysis (HD) patients with type 2 diabetes did not produce statistically significant reductions in the primary outcome measure. The study had strong impact on a recommendation for HD patients which stated that ''treatment with a statin should not be initiated in patients with type 2 diabetes on maintenance HD therapy who do not have a specific cardiovascular indication for treatment.'' Four years later, AURORA was hoped to provide clarification of whether LDL-C lowering with rosuvastatin would offer any benefit to HD patients. Like 4D, the main results of AURORA were negative. Since then, multiple hypotheses have been raised to explain these unexpected findings. A different cardiovascular pathology with vascular stiffness, calcification, structural heart disease, and sympathetic overactivity contributing to an increasing risk for cardiac arrhythmia and heart failure was deemed responsible. The results of SHARP, a very large international RCT, is highly relevant to this discussion. SHARP showed a significant decrease in major atherosclerotic events with simvastatin and ezetimibe compared with placebo in dialysis-dependent and non-dialysis-dependent patients.

The overall objective for the guideline is to advise about the management of dyslipidemia and use of cholesterollowering medications in adults and children with known CKD. Questions addressed by the guideline include how and when to assess lipid status, and how and when to prescribe lipid-lowering treatment in the target population. The target audience of the guideline includes nephrologists, primary care physicians, non-nephrology specialists (e.g., cardiologists, diabetologists, etc), clinical chemists and other practitioners caring for adults and children with CKD worldwide. The guideline is also expected to be suitable for use in public policy and other healthcare arenas. As a global guideline it is sensitive to issues related to ethnicity and geographical considerations and is written for use in different health care settings.

The Work Group included an international group of kidney specialists, diabetologists, cardiologists, epidemiologists, lipidologists and a professional evidence review team i n t r o d u c t i o n http://www.kidney-international.org & 2013 KDIGO (ERT) who provided support. Details of the methods used by the ERT are described in Methods for Guideline Development section, along with the systematic searches for areas identified by Work Group members and performed by the ERT.

Research recommendations are described to inform ongoing research agendas in the international community. The recommendations and statements created herein will serve to direct both care and research in the next decade. Several statements in this guideline have obtained a high grade according to the international system, Grading of Recommendations Assessment, Development and Evaluation (GRADE).

This document is not intended to serve as a textbook of medicine or nephrology. Unless otherwise stated, several aspects including drug dosing and interaction, especially in transplanted patients, are still valid with respect to the KDOQI 2003 guidelines.

The current guideline synthesized all of the available evidence but is largely driven by a few large RCTs and post hoc analyses of patients with CKD from statin trials of the general population. This guideline proposes a new concept in the management of dyslipidemia in CKD in the hopes of stimulating discussion, generating substantial research, and influencing public policy and laboratory practice.

The requirement for an update will be assessed in five years from the publication date or earlier if important new evidence becomes available in the interim. Such evidence might, for example, lead to changes to the recommendations or may modify information provided on the balance between benefits and harms of a particular therapeutic intervention.

i n t r o d u c t i o n Chapter 1: Assessment of lipid status in adults with CKD Kidney International Supplements (2013) 3, 268-270; doi:10.1038/kisup.2013. 33 1.1: In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplantation), we recommend evaluation with a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides). (1C)

RATIONALE

Dyslipidemia is common but not universal in people with CKD. The major determinants of dyslipidemia in CKD patients are glomerular filtration rate (GFR), the presence of diabetes mellitus, severity of proteinuria, use of immunosuppressive agents, modality of renal replacement therapy [RRT] (treatment by HD, peritoneal dialysis, or transplantation), comorbidity and nutritional status. 3 Initial evaluation of the lipid profile mainly serves to establish the diagnosis of severe hypercholesterolemia and/or hypertriglyceridemia and potentially rule out a remediable (secondary) cause if present. Major causes of secondary dyslipidemia should be considered (Table 1 ). The precise levels of serum or plasma lipids that should trigger specialist referral are not supported by evidence, but in the opinion of the Work Group, fasting triglyceride (TG) levels above 11.3 mmol/l (1000 mg/dl) or LDL-C levels above 4.9 mmol/l (190 mg/dl) should prompt consideration of (or specialist referral for) further evaluation.

Previous guidelines have emphasized the potential value of LDL-C as an indication for pharmacological treatment with lipid-lowering agents; 1 the KDIGO Work Group no longer recommends this approach (see Chapter 2.1). Isolated low high-density lipoprotein cholesterol (HDL-C) does not imply specific therapy in people with CKD; the Work Group suggests that HDL-C be measured as part of the initial lipid panel because it may help to assess overall cardiovascular risk. Measurement of lipoprotein(a) [Lp(a)] and other markers of dyslipidemia require further research before it can be routinely recommended in CKD patients.

The lipid profile should ideally be measured in the fasting state; if not feasible, nonfasting values provide useful information as well. 4 Fasting will mainly affect TG values and to a lesser extent LDL-C values as estimated from the Friedewald formula. ] [6] There is no direct evidence indicating that measurement of lipid status will improve clinical outcomes. However, such measurement is minimally invasive, relatively inexpensive, and has potential to improve the health of people with secondary dyslipidemia. In the judgment of the Work Group, patients with CKD place a high value on this potential benefit and are less concerned about the possibility of adverse events or inconvenience associated with baseline measurement of lipid levels. In the judgment of the Work Group, these considerations justify a strong recommendation despite the low quality of the available evidence.

1.2: In adults with CKD (including those treated with chronic dialysis or kidney transplantation), follow-up measurement of lipid levels is not required for the majority of patients. (Not Graded)

Prior guidelines have emphasized treatment escalation to achieve specific LDL-C targets by increasing the dose of statin and/or combination therapy. 1, 7 Given the lack of data to support this approach in populations with and without CKD, 8 the substantial within-person variability in LDL-C measurements 9 and the potential for medication-related toxicity, this approach is no longer recommended for CKD populations (see guideline 2). Since higher cardiovascular risk and not elevated LDL-C is now the primary indication to initiate or adjust lipid-lowering treatment in CKD patients, follow-up monitoring of LDL-C (after an initial measurement) may not be required for many patients -especially given normal variability in LDL-C over time, which reduces the clinical utility of followup measurements. 10 n the judgment of the Work Group, follow-up measurement of lipid levels should be reserved for instances where the results would alter management. Potential reasons to measure LDL-C (or the lipid profile) in people with CKD after their initial presentation might include: assessment of adherence to statin treatment; change in RRT modality or concern about the presence of new secondary causes of dyslipidemia (Table 1 ); or to assess 10-year cardiovascular risk in patients aged o50 years and not currently receiving a statin (because knowledge of LDL-C in this case might suggest that a statin was required -see Recommendation 2.2).

In the judgment of the Work Group, it is unnecessary to measure LDL-C in situations where the results would not (or likely would not) change management. For example, patients already receiving a statin (or in whom statin treatment is clearly indicated/not indicated based on changes in their cardiovascular risk profile or clinical status) would not require follow-up LDL-C measurements because the results would not alter treatment. Similarly, since the association between LDL-C and adverse clinical outcomes is weaker in people with CKD than in the general population, the value of measuring LDL-C to assess prognosis is uncertain.

Since low HDL-C and elevated apolipoprotein B (apoB) or non-HDL-C associated with excess risk of future cardiovascular events, 11 clinicians might choose to measure these parameters in patients not receiving a statin but in whom estimated cardiovascular risk is close to the threshold for initiating statin treatment. Put differently, clinicians could choose to measure HDL-C, apoB and/or non HDL-C if the finding of these tests would influence their decision to prescribe statin treatment.

Few data document how frequently CKD patients develop severely elevated fasting TGs 411.3 mmol/l (41000 mg/dl). Since clinical experience suggests that this event is rare, routine measurement of fasting TG levels is not recommended. However, clinicians may consider following serum TG levels in patients with known severe hypertriglyceridemia.

The ideal frequency of follow-up of LDL-C, HDL-C and serum TGs is unknown. Since any benefits of lipid-lowering treatment are likely to accrue over years rather than months or weeks, the Work Group suggests that cardiovascular risk be assessed annually in most patients with CKD. However, more frequent (or less frequent) follow-up measurements may be appropriate based on the clinical status of the patient.

There is no direct evidence that routine follow-up of lipid levels improves clinical outcomes or adherence to lipidlowering therapy. In fact, evidence indicates that random within-patient variation in serum cholesterol levels is substantial ( ± 0.8 mmol/l [31 mg/dl] for total cholesterol [TC] ) and therefore that such follow-up measurements may not reliably indicate good or poor compliance. 10 However, some patients may prefer to know their lipid levels during follow-up, or may respond favorably to such knowledge (for example, with better adherence to recommended statin use). In the judgment of the Work Group, these considerations favor an ungraded statement. Physicians may choose to perform follow-up measurement of lipid levels in patients for whom these measurements are judged to favorably influence processes of care.

Considerations for International Settings

If resources are limited, priority should be given to prescribing statins to patients at risk based on clinical criteria, rather than to measuring lipid profiles at baseline or in follow-up. In the opinion of the Work Group, the frequency of pancreatitis due to severe hypertriglyceridemia among CKD patients is sufficiently low that measuring fasting TG levels can be omitted in low-resource settings. Conversely, in settings where documentation of hypercholesterolemia is required to justify prescription of statins (e.g., Japan), more liberal or more frequent measurement of serum lipids may be necessary.

Suggested Audit Criteria

K Proportion of adults who had a lipid profile measured within 1 month of referral.

K Frequency of specialist referral for further evaluation of abnormal lipid abnormalities (e.g., fasting TG levels above 11.3 mmol/l (1000 mg/dl) or LDL-C levels above 4.9 mmol/l (190 mg/dl)).

KEY POINTS

K Dyslipidemia is common in people with CKD but LDL-C does not reliably discriminate between those at low or high risk of cardiovascular events.

K Clinicians should measure the lipid profile at initial presentation with CKD. Follow-up of the lipid profile or LDL-C is not required unless the results would change management. Examples of patients in whom knowledge of LDL-C might change management are given in Table 2 .

RESEARCH RECOMMENDATIONS

Future studies should:

K Assess the clinical effectiveness and economic merits of interventions to improve adherence to these recommendations, particularly those which are level 1. This includes better understanding of physician and patient barriers to guideline adoption and the contribution of polypharmacy.

K Examine secular trends in adherence to recommendations in this clinical practice guideline (CPG) and any secular changes in patient outcomes.

K Confirm real practice safety of statin use (outside of restrictive eligibility criteria used in RCTs). Specifically the frequency and severity of clinically relevant statindrug interactions should be studied in this population to improve the safety of statin prescribing.

K Assess the cost implications of less frequent or avoidance of cholesterol measurements, and confirm that less frequent measurements do not adversely affect the clinical benefits of treatment (compared to more frequent measurements). K Investigate whether the association between serum TGs and risk varies meaningfully as a function of fasting status.

K Investigate the independent association between Lp(a), apoB and cardiovascular outcomes in large prospective studies of people with CKD. It should further be investigated whether knowledge of high Lp(a), non-HDL-C, and/or apoB values has any influence on the management of other risk factors and whether this has an influence on outcomes.

DISCLAIMER

While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer's own published literature.

INTRODUCTION

Therapeutic lifestyle measures to reduce serum cholesterol levels have been broadly recommended by prior guidelines. 1, 12 Although clinically appealing, such measures typically reduce serum cholesterol to only a small extent, and have not been shown to improve clinical outcomes (Supplemental Tables 1-5 online). The Work Group therefore chose to focus the recommendations for treatment on pharmacological interventions. However, it is important to note that many of these measures may improve general health (independent of any effect on lipid levels). The primary rationale for pharmacological cholesterollowering treatment is to reduce morbidity and mortality from atherosclerosis. Although limited clinical data support a link between treatment of dyslipidemia and better renal outcomes, 13 more recent trials have not confirmed this hypothesis. 14 lthough several different medications lower LDL-C, only regimens including a statin (including statin/ezetimibe) have been convincingly shown to reduce the risk of adverse cardiovascular events in CKD populations. Therefore, the recommended approach for pharmacological cholesterollowering treatment in CKD focuses on the use of statins (with or without ezetimibe) in people at risk of future cardiovascular events. BACKGROUND LDL-C is not suitable for identifying CKD patients who should receive pharmacological cholesterol-lowering treatment LDL-C is strongly and independently associated with risk of atherosclerotic events in the general population; 15 knowledge of this association facilitated the discovery that statins reduce coronary risk. Initially, statin use was limited to those with substantially elevated LDL-C (44.5 mmol/l [4174 mg/dl]), but subsequent work indicated that the relative risk (RR) reduction associated with statin use is relatively constant across a broad range of baseline LDL-C levels, suggesting that absolute benefit from statin treatment is proportional to baseline coronary risk rather than baseline LDL-C.

Associations between LDL-C and coronary artery disease in dialysis patients. 7] [18] [19] This paradoxical association between cholesterol and outcomes appears to be due to effect modification by protein energy wasting, inflammation and malnutrition, 20, 21 which are all common in kidney failure and are themselves associated with a high risk of adverse outcomes. Put differently, patients with one of more of these three conditions are more likely to also have low cholesterol, which confounds the apparent association between cholesterol and the risk of cardiovascular death. Although cardiovascular risk is increased in dialysis patients with higher LDL-C and TC, elevated cholesterol seems unsuitable as the criterion for statin prescription in patients with kidney failure because it will fail to identify those with low cholesterol -who are also at high risk.

Associations between LDL-C and coronary artery disease in CKD patients with eGFR Z15 ml/min/1.73 m 2 . As eGFR declines, the magnitude of the excess risk associated with increased LDL-C decreases. For instance, the hazard ratio [HR] (95% confidence interval [CI] ) of incident myocardial infarction (MI) associated with LDL-C 44.9 mmol/l [4190 mg/dl] (as compared to 2.6-3.39 mmol/l [100-131 mg/dl] ) is 3.01 (2.46-3.69), 2.30 (2.00-2.65) and 2.06 (1.59-2.67) for people with eGFR of Z90, 60-89.9 and 15-59.9 ml/min/1.73 m 2 , respectively. Figure 1 shows the relation between LDL-C and the risk of hospitalization for MI for selected values of baseline eGFR.

The figure shows that the relation between LDL-C and the risk of MI appears linear at LDL-C above 2.6 mmol/l (100 mg/dl). The HR (95% CI) of MI associated with each 1 mmol/l (39 mg/dl) increase in LDL-C above 2.6 mmol/l (100 mg/dl) is 1.48 (1.43-1.54), 1.33 (1.27-1.40), 1.26 (1.18-1.35), 1.20 (1.09-1.30) and 1.13 (1.01-1.27) among people with eGFR of 90, 60, 45, 30 and 15 ml/min/1.73 m 2 , respectively. The weaker and potentially misleading association between LDL-C and coronary risk among those with lower levels of kidney function (a group who is at the highest absolute risk) argue against its use for identifying CKD patients who should receive pharmacological cholesterollowering treatment.

Which CKD patients should receive pharmacological cholesterol-lowering treatment?

To maximize the ratio of benefits to harms and costs, contemporary clinical practice emphasizes three potential determinants of the decision to prescribe lipid-lowering treatment in people with normal kidney function: baseline coronary risk; case-fatality rate following MI; and evidence that lipid-lowering treatment is beneficial. 23 aseline coronary risk. The 10-year incidence risk of coronary death or non-fatal MI (numerically equivalent to the rate of such events per 1000 patient-years) is often used as the benchmark for assessing future coronary risk; the risk in patients with prior MI (in whom the rate of new MI is 20 per 1000 patient-years) is generally considered as sufficiently high to clearly warrant ongoing statin treatment. 12 5] [26] There is no consensus on the level of future coronary risk that is sufficient to justify statin treatment, but in the judgment of the Work Group rates of coronary death or non-fatal MI o10 per 1000 patient-years are unlikely to be broadly accepted as an indication for treatment. The rate of coronary death or incident MI among patients with CKD (defined by eGFR 15-59.9 ml/min/1.73 m 2 or with heavy proteinuria) is similar to or higher than those with diabetes (with or without CKD). 27 However, the risk associated with CKD is age-dependent. For example, the rate of coronary death or incident MI among CKD patients aged 450 years (both men and women) is consistently greater than 10 per 1000 patient-years, even in those without diabetes or prior MI) (Figure 2 ; Table 3 ). In contrast, the rate of coronary death or incident MI among CKD patients aged r50 years is low in those without diabetes or prior MI (Figure 2 ) -although it is higher than in otherwise comparable people without CKD. Further inspection of the absolute risks indicate that participants aged 40-50 years have average rates of CHD death or incident MI that are consistently less than 10 per 1000 patient-years.

Case-fatality rate following myocardial infarction. Multiple studies demonstrate that the risk of death following MI is increased among people with CKD, as compared to otherwise comparable people with normal kidney function. 27 The absolute risk of death is especially high in patients treated with chronic dialysis. 28 idence that pharmacological cholesterol-lowering treatment is beneficial. The evidence supporting the clinical benefits of statin treatment in adults (alone or in combination with ezetimibe) differs substantially by severity of CKD. This evidence is presented in Supplemental Tables 6-18 online and summarized below.

Collectively, available evidence argues against the use of LDL-C to identify CKD patients who should receive cholesterol-lowering treatment and suggests focusing instead on two factors: the absolute risk of coronary events, and the evidence that such treatment is beneficial. This is the approach taken in the recommendations that follow. 0] [31] This suggests that a concerted attempt will be required to identify and treat CKD patients that are likely to benefit from lipid-lowering therapy.

How should the dose of pharmacological cholesterollowering treatment be determined in CKD patients? Guidelines for the general population recommend that (among patients receiving statin treatment), the dose of statin is titrated to achieve the target level of LDL-C, which in turn is determined by each patient's presumed coronary risk. 12 This approach is widely accepted, although it has never been shown to lead to clinical benefit in a RCT. Instead, existing randomized trials have compared statin and placebo, or compared higher and lower doses of statin (regardless of achieved LDL-C). Taken together, these trials suggest that higher statin doses produce greater clinical benefits, but at the expense of an increased risk of adverse events.

CKD patients are at high risk of medication-related adverse events, perhaps because of the reduced renal excretion, frequent polypharmacy and high prevalence of comorbidity in this population. Therefore, reduced doses of statins are generally recommended for patients with advanced CKD. The SHARP trial addressed this issue by using lower dose simvastatin (20 mg/day) and adding ezetimibe (10 mg/day) to achieve an average LDL-C reduction of about 0.83 mmol/l (32 mg/dl), during a 4.9-year period of treatment. 14 ubgroup analysis of the TNT trial reported that atorvastatin 80 mg/day reduced major cardiovascular events 32 Serious adverse events and treatment discontinuation were increased in the high dose statin group for both people with and without CKD; the RRs of these adverse events were numerically higher in people with CKD as compared to those without, but no significance testing was performed. However, TNT participants were pretreated with 10 mg of atorvastatin during the run-in phase, and therefore were preselected for atorvastatin tolerance. In addition, the mean eGFR among TNT participants with CKD was approximately 53 ml/min/1.73 m 2 , and patients with heavy proteinuria were excluded. Therefore, whether these findings apply to the broader population of people with CKD is uncertain.

Given the potential for toxicity with higher doses of statins and the relative lack of safety data, the Work Group suggests that prescription of statins in people with eGFR o60 ml/ min/1.73 m 2 or RRT should be based on regimens and doses that have been shown to be beneficial in randomized trials done specifically in this population (Table 4 ). Patients with progressive renal dysfunction who are tolerating an alternative regimen do not necessarily need to be switched to a regimen described in Table 4 , although dose reduction may be prudent in patients with severe kidney dysfunction who are receiving very aggressive regimens. Given less concern about drug toxicity in the setting of better kidney function, patients with eGFR Z60 ml/min/1.73 m 2 (and no history of kidney transplantation) may be treated with any statin regimen that is approved for use in the general population. In the judgment of the Work Group, existing evidence does not support a specific on-treatment LDL-C target and thus adjusting the dose of statin regimens based on LDL-C levels is not required.

Safety data from large clinical trials suggest that the excess risk of adverse events associated with these regimens is similar among people with and without CKD. In the judgment of the Work Group, these considerations suggest that measurement of creatine kinase (CK) or liver enzyme assays is not required in asymptomatic patients.

Certain medications and grapefruit juice increase blood levels of statins (Supplemental Tables 19, 20 online). If such medications are required in patients who are otherwise good candidates for statin treatment, physicians may consider one of two strategies. For medications that will be required only for short periods (such as an antibiotic), the statin could be temporarily discontinued. For medications that will be required for more than a few days, a switch to an alternative statin or reducing the statin dose could be considered to reduce the risk of drug toxicity. Patients with CKD appear to be at increased risk of adverse events when statins and fibrates are used in combination (Supplemental Tables 21-28 online). For this reason, the Work Group recommends that fibrates not be used concomitantly with statins in patients with CKD. As mentioned earlier, given that evidence of clinical benefit is greater for statins than for fibrates, the Work Group recommends that statins be prescribed in preference to fibrates when clinicians are trying to choose between the two classes of medication.

Statins are contraindicated in pregnant or breast-feeding females; in people with active liver disease; and in people with transaminase levels that are three times or more the upper limit of normal. There is no evidence that the risk of liver dysfunction differs in people with CKD, as compared to those without. Regardless of CKD severity, the Work Group recommends that baseline levels of transaminases be measured before initiating statin treatment. Routine followup measurements of transaminases are not recommended, given the low frequency of abnormalities among people without abnormal values at baseline. 33 Similarly, the Work Group does not recommend measurement of CK levels at baseline or during follow-up, unless the patient develops symptoms suggestive of myopathy.

2.1.1:

In adults aged Z50 years with eGFR o60 ml/min/ 1.73 m 2 but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ ezetimibe combination. (1A)

Data on the effects of statins and statin/ezetimibe combination in non-dialysis dependent adults with eGFR o60 ml/ min/1.73 m 2 are presented in Supplemental Tables 6-10, 15-17 online. The SHARP trial included 9270 participants with CKD (mean eGFR of 27 ml/min/1.73 m 2 ) to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 5 years. 14 Thirty-three percent of participants (n ¼ 3023) were receiving dialysis at randomization and 23% (n ¼ 2094) had diabetes. Statin plus ezetimibe therapy led to a significant 17% reduction in the relative hazard of the primary outcome of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo (HR 0.83; 95% CI 0.74-0.94), driven by significant reductions in non-hemorrhagic stroke and coronary revascularization. Among the 6247 patients with CKD not treated by dialysis at randomization, treatment with simvastatin plus ezetimibe did not reduce the risk of progression to end-stage renal disease (ESRD) requiring RRT. The risk of serious adverse events was similar in participants assigned to treatment and to control. These data are supported by post hoc analyses of randomized trials of statin vs. placebo that focus on the subset of participants with CKD at baseline. In general, these analyses suggest that statins reduce the RR of cardiovascular events to a similar extent among patients with and without CKD but that the absolute benefit of treatment is larger in the former due to their higher baseline risk. 34 In addition, the risk of adverse events associated with statin treatment appeared similar in participants with and without CKD. However, most of the participants with CKD in these analyses had eGFR 45-59.9 ml/min/1.73 m 2 and very few had eGFR o30 ml/min/1.73 m 2 .

Since the absolute risk in people who are non-dialysisdependent with eGFR o60 ml/min/1.73 m 2 aged Z50 years is consistently greater than 10 per 1000 patient-years, in the judgment of the Work Group, knowledge of LDL-C is not required to gauge average coronary risk in this population. Although multivariable prediction instruments might yield more precise estimates of risk for individuals, the Work Group judged that the increased simplicity of an age-based approach was defensible for patients aged Z50 years based on the data presented above and would enhance uptake of the guideline.

There is no evidence that ezetimibe monotherapy will improve clinically relevant outcomes in patients with or without CKD. Therefore, ezetimibe monotherapy is not recommended.

The combination of findings from SHARP, post hoc analyses of randomized trials from the general population (focusing on the subset with CKD), and the large body of evidence from the general population trials collectively provide a strong rationale for this recommendation. In the judgment of the Work Group, these data warrant a strong recommendation.

2.1.2:

In adults aged Z50 years with CKD and eGFR Z60 ml/min/1.73 m 2 (GFR categories G1-G2) we recommend treatment with a statin. (1B)

The risk of future coronary events in patients aged Z50 years with CKD is markedly increased, as compared to those without CKD, and the rate of coronary death or non-fatal MI in this population exceeds 10 per 1000 patient-years even in the absence of prior MI or diabetes (Table 3 ). Most patients with CKD and eGFR Z60 ml/min/1.73 m 2 have proteinuria and slightly reduced or normal eGFR; many such patients would have been included but not recognized in randomized trials of statins done in the general population, since many such trials did not assess proteinuria at baseline. On the other hand, this population was explicitly excluded from participation in SHARP, for which the primary inclusion criterion was elevated serum creatinine [SCr] (hence, reduced eGFR).

Existing data suggest that the relative benefit of statin treatment is not influenced by the presence of albuminuria: CARDS 35 and the Cholesterol and Recurrent Events (CARE) trial 36 both tested for an interaction between the presence of albuminuria and the effect of statin treatment on cardiovascular events. Both found no significant interaction (p ¼ 0.7 and p ¼ 0.59, respectively), suggesting that the benefit of statins is similar in people with and without albuminuria.

A randomized trial of pravastatin 40 mg daily vs. placebo in CKD patients with preserved GFR (i.e., eGFR categories G1-G2) but microalbuminuria found no significant risk reduction associated with pravastatin treatment on the risk of cardiovascular events (RR 0.87; 95% CI 0.49-1.57), 37 lthough the number of events was small (n ¼ 47). A post hoc analysis of CARE participants with slightly more events (n ¼ 60) found a significant reduction in the risk of the primary outcome (CHD death or non-fatal MI) among the subset of CKD patients with eGFR categories G1-G2 (HR of pravastatin vs. placebo 0.48; 95% CI 0.28-0.83).

Given these data, the high cardiovascular risk among people with CKD and eGFR categories G1-G2, the large body of evidence supporting the efficacy of statins in the general population, and the lack of an a priori reason why statins would be less effective in the presence of proteinuria (i.e., the lack of justification for a new trial done specifically in people with CKD and eGFR categories G1-G2), the Work Group judged that a strong recommendation was appropriate. 2 ). In the judgment of the Work Group, this rate is sufficiently high to warrant statin treatment. Similarly, some CKD patients aged 18-50 years may not have diabetes or prior vascular disease but yet have multiple cardiovascular risk factors that substantially increase their risk of future coronary events. In the judgment of the Work Group, an estimated 10-year incidence of coronary death or non-fatal MI is sufficiently high to warrant statin treatment. Since unequivocally elevated LDL-C does appear to confer an increased risk of coronary events in people with CKD (although to a lesser extent than in the general population), increased LDL-C levels should be considered when estimating coronary risk in CKD patients aged o50 years. The 10-year incidence of coronary death or non-fatal MI may be estimated using any validated risk prediction tool such as the Framingham risk score, 38 SCORE, 39 PROCAM, 40 ASSIGN, 41 or the QRISK2. 42 Overall, these instruments tend to overestimate future coronary risk and usually incorporate information on LDL-C. However, since most do not explicitly consider the presence of CKD, which would be expected to increase coronary risk for any given set of traditional cardiovascular risk factors, such overestimation should be less pronounced in CKD populations.

Patients whose 10-year risk of coronary death or non-fatal MI is o10% could choose to receive statin treatment if they placed relatively more value on a small absolute reduction in the risk of cardiovascular events, and relatively less value on minimizing the risks of polypharmacy and drug toxicity. On the other hand, patients valuing the potential benefits of statin treatment to a lesser extent than the potential harms might choose not to receive statin treatment even if their 10-year risk of coronary death or non-fatal MI is 410%. In this international double-blind randomized trial, 2776 HD patients were assigned to receive rosuvastatin 10 mg daily or placebo, and followed for a median of 3.8 years. 44 This international double-blind randomized trial assigned 9270 participants Z40 years old with CKD to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 4.9 years. 14 Thirty-three percent of the patients (n ¼ 3023) were receiving maintenance dialysis at randomization. The remaining 6247 CKD patients had a mean eGFR of 27 ml/min/1.73 m 2 . Mean reduction in LDL-C among the treatment group was 0.83 mmol/l (32 mg/dl), compared to placebo. Statin plus ezetimibe therapy was associated with a significant 17% RR reduction of the primary outcome of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo (HR 0.83; 95% CI 0.74-0.94). SHARP indicated that risk for the primary outcome of major atherosclerotic events other than death was reduced by simvastatin/ezetimibe among a wide range of patients with CKD. Combination treatment did not significantly reduce the risk of the primary outcome in the subgroup of over 3000 patients treated with dialysis at baseline. A systematic review pooling data from all available randomized trials done in CKD populations reported significant heterogeneity between dialysis and non-dialysis patients for the benefit of statins on major cardiovascular events (HR for dialysis 0.96; 95% CI 0.88-1.03; HR for nondialysis 0.76; 95% CI 0.72-0.79; p for heterogeneity o0.001). 34 When findings from SHARP, 4D and AURORA are considered together, the clinical benefit of statins (alone or in combination with ezetimibe) in prevalent dialysis patients is uncertain. Another meta-analysis in essence confirmed the results, although the data were analyzed in a different manner. 45 Even if statins truly do prevent cardiovascular events in prevalent dialysis patients, it is clear that the magnitude of any relative reduction in risk is substantially 276 Kidney International Supplements (2013) 3, 271-279 c h a p t e r 2 smaller than in earlier stages of CKD. 34 However, if this speculative benefit among dialysis patients is confirmed in future studies, the absolute benefit might be comparable to that in people with less severe CKD, due to the higher event rate among dialysis patients. 46 he smaller RR reduction noted in SHARP could be due to lower compliance to study drug in the subgroup of dialysis patients. Dialysis patients showed on average a 0.60 mmol/l (23 mg/dl) LDL-C reduction in comparison to the nondialysis CKD group which outlined a 0.96 mmol/l (37 mg/dl) LDL-C decrease.

In summary, these data suggest that despite the exceedingly high cardiovascular risk in dialysis patients, it is uncertain whether statin regimens lead to clinical benefit in this population. Therefore, in the judgment of the Work Group, initiation of statin treatment is not recommended for most prevalent HD patients. However, patients might reasonably choose statin treatment if they are interested in a relatively small, uncertain reduction in cardiovascular events. Since very high LDL-C might increase the likelihood of benefit from statin in a dialysis patient, 47 patients who meet this criterion may be more inclined to receive a statin, recognizing that the benefit remains uncertain. Other factors that might influence a patient's decision to receive statin could include recent MI or greater life expectancy (both favoring treatment), and more severe comorbidity or higher current pill burden (both favoring non-treatment).

2.3.2:

In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued. (2C) RATIONALE SHARP, 4D and AURORA do not directly address the question of whether statins should be discontinued in patients initiating dialysis, who may be systematically different from prevalent dialysis patients. However, 2141 (34%) of SHARP patients without kidney failure at baseline commenced dialysis during the trial and were analyzed in the non-dialysis group -in which overall benefit was observed. 14 n the judgment of the Work Group, it is reasonable to continue statins in patients who are already receiving them at the time of dialysis initiation, recognizing that the magnitude of clinical benefit may be lower than in patients with non-dialysis-dependent CKD. Physicians should consider periodically reviewing the clinical status of dialysis patients and revisiting the decision to prescribe statins as required.

Given the lack of direct evidence that statin treatment is beneficial in dialysis patients, this recommendation is graded as weak. Discontinuation of statin or statin/ezetimibe may be warranted in patients who place a relatively low value on a small potential relative reduction in cardiovascular events, and a relatively high value on the risks of polypharmacy and drug toxicity.

2.4:

In adult kidney transplant recipients, we suggest treatment with a statin. (2B)

The risk of future coronary events in kidney transplant recipients is markedly elevated: data from the placebo arm of the ALERT trial suggest that the rate of cardiovascular death or non-fatal MI is approximately 21.5 per 1000 patientyears. 48 Data on the rate of non-fatal MI by age are not available for kidney transplant recipients, but a populationbased study from Australia and New Zealand suggests that the rate of cardiovascular death alone is approximately 5 per 1000 patient-years even among those aged 25-44 years. 49 ata on the effect of statins in adult kidney transplant recipients are presented in Supplemental Tables 29-31 online. ALERT examined the effect of statin therapy on cardiovascular risk reduction in 2102 patients aged 30-75 years with functioning kidney transplants who were followed for 5-6 years. Fluvastatin therapy (40-80 mg/day) led to a nonsignificant 17% reduction in the primary outcome of coronary death or non-fatal MI, compared to placebo (RR 0.83; 95% CI 0.64-1.06). However, fluvastatin led to a significant 35% relative reduction in the risk of cardiac death or definite nonfatal MI (HR 0.65; 95% CI 0.48-0.88), 48 and an unblinded extension study found that randomization to fluvastatin was associated with a significant reduction in the original primary outcome after 6.7 years of follow-up. In the judgment of the Work Group, the apparent benefits observed in ALERT are consistent with the effects of statins in the general population, and suggest that statins are beneficial in patients with a functioning kidney transplant. However, the nominal lack of statistical significance in the primary analysis and the existence of a single randomized trial favor a weak recommendation.

The age at which statin treatment should begin in kidney transplant recipients is uncertain: the risk of coronary events is age-dependent, and ALERT did not enroll participants younger than 30 years, However, ESRD treated by kidney transplantation is a chronic disease, with cardiovascular risk expected to increase over time even in the presence of optimal graft function. In the judgment of the Work Group, these considerations warrant treatment in all adult kidney transplant recipients. However, younger patients (for example, those o30 years and without traditional cardiovascular risk factors) could choose not to receive statin treatment if they placed relatively less value on a small absolute reduction in the risk of cardiovascular events, and relatively more value on minimizing the risks of polypharmacy and drug toxicity.

In some Asian countries, doses of statins tend to be lower than those used in Western countries, due to concern about drug toxicity and clinical trial data indicating that such doses safely reduce LDL-C 50, 51 and improve clinical outcomes. 52, 53 Therefore, physicians practicing in such countries may choose to prescribe lower doses than recommended in Table 4 . c h a p t e r 2 Suggested Audit Criteria K One year before and after the publication of this guideline, assess the proportion of non-dialysis-dependent adults aged Z50 years with eGFR o60 ml/min/1.73 m 2 that receive treatment with a statin or statin/ezetimibe combination.

K One year before and after the publication of this guideline, assess the proportion of adults aged Z50 years with CKD and eGFR 460 ml/min/1.73 m 2 that receive treatment with a statin.

K One year before and after the publication of this guideline, assess the proportion of adult kidney transplant recipients that receive treatment with a statin.

K One year before and after the publication of this guideline, assess the prevalence of statin use among non-dialysis-dependent adults aged 18-49 years with CKD and at least one of the following risk factors: known coronary disease (MI or coronary revascularization), diabetes mellitus, previous ischemic stroke, or predicted 10-year risk of CHD death/non-fatal MI 410%.

K Coronary risk is sufficiently high to justify prescription of statins in people aged Z50 with non-dialysis-dependent CKD or a kidney transplant.

K Coronary risk in people aged o50 years with non-dialysisdependent CKD is lower, but the presence of additional cardiovascular risk factors may increase risk to justify statin prescription. Given the evidence that treatment with statins improve vascular outcomes in this population, such treatment is suggested for patients aged o50 years with non-dialysis-dependent CKD and known vascular disease (prior MI, coronary revascularization or stroke), diabetes, or other risk factors that increase the 10-year risk of coronary death or non-fatal MI (as estimated using a validated risk calculator) to 410%.

K Patients with dialysis-dependent CKD should not be initiated on statin or statin/ezetimibe treatment, given the lack of evidence that such treatment is beneficial. However, statin or statin/ezetimibe treatment should not necessarily be discontinued among existing users when dialysis treatment is initiated.

K Physicians should be alert to the possibility of toxicity resulting from substances that increase blood levels of statins (e.g., grapefruit juice, certain medications).

K An extended observational study should be undertaken of the SHARP study cohort to determine whether the reduction in major atherosclerotic events resulting from 5 years of LDL-C lowering persists in the long-term, and whether LDL-C lowering significantly delays renal disease progression in people with non-dialysis-dependent CKD and eGFR o60 ml/min/1.73 m 2 .

K Given that the majority of early CKD is managed in primary care, audits of pharmacological cholesterollowering treatment should be undertaken in this setting.

K Data from the AURORA, 4D and SHARP studies (dialysis cohort) should be pooled to undertake individual patient data meta-analysis to more comprehensively assess the benefits and risks of cholesterol-lowering treatment in people with dialysis-dependent CKD.

Young adults with eGFR o15 ml/min/1.73 m 2 have at least 10-fold higher risk for CVD mortality compared to the general population. 54 Many recent studies document the prevalence of CVD risk factors in children with CKD. However, due to limited follow-up, few studies demonstrate the association of dyslipidemia with clinical CVD events in adolescents or young adults, especially in the setting of CKD. In the general pediatric population, lipid levels in childhood are predictive of future lipid levels and subsequent cardiovascular events. 55 The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study shows that initial fatty streaks seen in adolescents with normal kidney function develop into atheromatous plaques in young adults. 56 Over 50% of children 10-14 years old had early fatty streaks, and 8% had fibrous plaques, thus confirming that atherosclerosis begins in childhood. 56 8] [59] Moreover, this atherosclerotic process is likely accelerated in nephrotic syndrome, proteinuric states and chronic kidney disease due to abnormal lipid metabolism and other atherogenic risk factors, thus putting children and adolescents at risk for developing CVD as they age into adulthood. In the Bogalusa Heart Study, body mass index, LDL-C, and systolic blood pressure were associated with atherosclerotic disease of the aorta and coronary vessels of children. 56, 57 Recent studies of subclinical atherosclerotic CVD in children with familial hypercholesterolemia found an increase in intimal medial thickness of the aorta and carotid arteries compared to that of healthy young children. 60 Thus, atherosclerotic disease appears to begin in childhood, and dyslipidemia in children may play an important role in the early pathogenesis of atherosclerosis.

In children with CKD, the relationship between dyslipidemias and subsequent atherosclerotic clinical events is not known due to short follow-up in observational studies or clinical trials. Recently, the Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement from the American Heart Association Expert Panel on Population and Prevention Science stated that CVD prevention in many chronic pediatric conditions was warranted given the high risk of developing disease as adults. 61 he recent National Institutes of Health Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents in 2011 addressed specific questions of screening for dyslipidemias in children and adolescents and also treatment of dyslipidemias. 7 holesterol and its metabolism are important in children as cholesterol is the basis of cell membranes, myelin formation, subcellular organelles and steroid hormones which are all key for natural growth and development. Based on growth and development, lipid levels vary depending on age, puberty, and gender. 62 Lipid levels are very low at birth and increase during the first year of life [mean TC of 3.9 mmol/ l (150 mg/dl), LDL-C 2.6 mmol/l (100 mg/dl), and HDL-C 1.4 mmol/l (55 mg/dl)] where they remain fairly constant till age 12 and are slightly lower in girls than boys. During puberty, there is a decrease in TC, LDL-C, and a slight decrease in HDL-C in boys. After puberty, TC and LDL-C increase to adult levels in boys and girls. Boys continue to have a slightly lower HDL-C than girls. Due to these variations in levels, former guidelines used the 95th percentile for age and gender to determine the upper limit of acceptable values. More recently, age-and gender-specific curves for lipoproteins linked to CVD risk over 15-20 years 55, 58 have been used instead. A simplified and more practical approach has been to define acceptable, borderline high and high lipid concentration for children and adolescents based on these curves 7 (see Table 5 ).

Many studies document the prevalence of dyslipidemias among children with CKD and ESRD. 63, 64 As in adults, the pattern of dyslipidemias in children with CKD is greatly influenced by the underlying pathogenesis and duration of CKD, severity of proteinuria, and treatment. 63, 64 Due to this variability, the prevalence of hypercholesterolemia ranges from 39% to 65% in children with CKD. Among 391 children from the North American observational cohort study, CKiD (Chronic Kidney Disease in Children), TG and non-HDL-C levels increased as the measured GFR declined in this cross sectional study population. 63 Conversely, HDL-C was lower for those with a lower GFR. Factors that impacted TG, HDL-C and non-HDL-C levels were primarily GFR, significant proteinuria and obesity by multivariate analyses. 63 Over half the population had no evidence of dyslipidemias and of the remainder, 25% had a single abnormal lipid level, and the other 25% had at least 2 abnormal lipid levels. 63 The most c h a p t e r 3 http://www.kidney-international.org & 2013 KDIGO common abnormality was hypertriglyceridemia. 63 The frequency of these abnormalities suggests that clinicians should measure lipid levels at baseline in children with CKD to screen for underlying secondary causes of dyslipidemia.

As for adults, there is no direct evidence indicating that measurement of lipid status will improve clinical outcomes. However, such measurement is minimally invasive, relatively inexpensive, and has potential to improve the health of people with secondary dyslipidemia. In the judgment of the Work Group, children with CKD (and their families) place a high value on this potential benefit and are less concerned about the possibility of adverse events or inconvenience associated with baseline measurement of lipid levels. In the judgment of the Work Group, these considerations justify a strong recommendation despite the low quality of the available evidence.

3.2:

In children with CKD (including those treated with chronic dialysis or kidney transplantation), we suggest annual follow-up measurement of fasting lipid levels.

(Not Graded)

Few data document how frequently the clinical lipid status changes in children with CKD, although it is clear that abnormal levels (once documented) are likely to persist. Unlike adults, growth and development in children have potential to influence lipid levels over time. Therefore, the Work Group recommends that fasting lipid levels be followed in children with CKD to screen for underlying secondary causes of dyslipidemia.

The ideal frequency of follow-up for fasting levels of LDL-C, HDL-C and serum TGs is unknown. These levels could be assessed annually in most children with CKD.

However, more frequent (or less frequent) follow-up measurements may be appropriate based on the clinical status of the patient, and the potential for such follow-up measurements to influence management. 65 Possible changes in management in response to such measurements could include therapeutic lifestyle measures (see Recommendation 6.1) or statin regimens for children with very high LDL-C levels (see Recommendation 4.1).

Similar to those for Chapter 1.

K Dyslipidemia is common in children with CKD. K All children with CKD should be screened for dyslipidemias at presentation.

K Because growth and development as well as modality switches may influence lipid metabolism, lipids could be regularly evaluated during follow-up and when children initiate dialysis or receive a kidney transplant.

RESEARCH RECOMMENDATION

K Future studies should be conducted to determine the prevalence of dyslipidemias among children initiating dialysis or receiving a kidney transplant.

While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. reatment for dyslipidemia in children should first include nutrition and dietary counseling, and address obesity with weight loss regimens if necessary. 8] [69] [70] Diets, however, should be used judiciously, or not at all, in children who are malnourished. Secondary causes of dyslipidemias should also be treated first (Table 1 ). Therapeutic lifestyle changes (TLC) should be adopted among all children with CKD.

Statin therapy has been shown to reduce LDL-C in children and adolescents ages 8-18 years with no adverse effects on growth, development or sexual maturation reported. 7 However, the follow-up time of the studies was quite variable and safety data in children with CKD are very limited. Data on the benefits of treating LDL-C in children aged o10 years are extremely limited, and chiefly include patients with severe familial hypercholesterolemia or cardiac allografts. In the US, statins are approved for use among adolescent boys and post-menarchal girls ages 10-18 years (age 8 and older for pravastatin) for treatment of elevated LDL-C among those with familial dyslipidemias, family history of premature heart disease and 2 or more cardiovascular risk factors. 7 2] [73] [74] The trials demonstrate that statins lower LDL-C over 7 months to 5 years. No randomized trials have studied clinically relevant outcomes such as cardiovascular events or mortality.

There have been 13 statin trials in 1683 children with dyslipidemias and normal kidney function. 6] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] There were only two studies that studied statins in combination with a second drug such as colestipol or ezetimibe. 81, 85 his is a weak recommendation that reflects the lack of evidence for benefit and safety associated with long-term use. As for all weak recommendations, practitioners should consider the clinical circumstances and the patient's preferences when considering an individual patient. The Work Group further suggests that the patient's age could also be considered when applying this recommendation.

Due to the very limited available data, the Work Group does not recommend the use of statins in children with CKD aged o10 years. Patients (boys aged 410 years and postmenarchal girls, together with their parents) with severely elevated LDL-C who place a higher value on the potential for preventing cardiovascular events and are less concerned about adverse events from statin use might be candidates for statin use -especially those with multiple additional risk factors such as family history of premature coronary disease, diabetes, hypertension, smoking and ESRD.

If a statin is prescribed, the Work Group suggests the lowest dose available. There are no data on the appropriate target for LDL-C in children (with or without CKD), extremely limited long-term safety data in pediatric CKD populations, and no dose escalation studies in children with CKD to confirm the safety of higher statin doses even over the short term.

Given the lack of evidence for the benefit and safety of combination therapy with bile acid resins, colestipol and ezetimibe in pediatric CKD populations, the Work Group does not recommend the use of such multi-drug regimens even in children with severely elevated LDL-C.

K Determine the number of children treated with statins (and statin type) and other lipid-lowering therapies by CKD severity.

K Document the number of children with intolerance and/ or non-compliance to statins or other lipid-lowering treatment.

K Document the number of children that receive statin therapy for primary prevention.

K TLC should be recommended to all children with CKD and dyslipidemia.

K Statins are not recommended for children with CKD and dyslipidemia.

available evidence and the strength of that recommendation. However, Table 15 shows that the strength of a recommendation is determined not only by the quality of the evidence but also by other, often complex judgments regarding the size of the net medical benefit (potential risks versus benefit), values, and preferences, and costs. Formal decision analyses including cost analysis were not conducted.

Ungraded statements. This category was designed to allow the Work Group to issue general advice. Typically an ungraded statement meets the following criteria: it provides guidance based on common sense, it provides reminders of the obvious, and it is not sufficiently specific to allow for application of evidence to the issue and therefore it is not based on systematic evidence review. Common examples include recommendations about frequency of testing, referral to specialists, and routine medical care. We strove to minimize the use of ungraded recommendations.

This grading scheme, with two levels for the strength of a recommendation together with four levels of grading the quality of the evidence, as well as the option of an ungraded statement for general guidance, was adopted by the KDIGO Board in December 2008. The Work Group took on the primary role of writing the recommendations and rationale statements and retained final responsibility for the content of the guideline statements and the accompanying narrative. The ERT reviewed draft recommendations and grades for consistency with the conclusions of the evidence review.

Format for guideline recommendations. Each chapter contains one or more specific recommendations. Within each recommendation, the strength of recommendation is indicated as level 1 or level 2 and the quality of the supporting evidence is shown as A, B, C, or D. The recommendation statements and grades are followed by the rationale text summarizing the key points of the evidence base and the judgments supporting the recommendation. In relevant sections, considerations of the guideline statements in international settings and suggested audit criteria are also provided where applicable. Important key points and research recommendations suggesting future research to resolve current uncertainties are also outlined at the conclusion of each chapter.

Limitations of Approach

Although the literature searches were intended to be comprehensive, they were not exhaustive. MEDLINE was Abbreviations and Acronyms.

14. Recommendations and rationale

State the recommended action precisely and the specific circumstances under which to perform it. Justify each recommendation by describing the linkage between the recommendation and its supporting evidence. Indicate the quality of evidence and the recommendation strength, based on the criteria described in Topic 9.

Each guideline chapter contains recommendations for lipid management in CKD patients. Each recommendation builds on a supporting rationale with evidence tables if available. The strength of the recommendation and the quality of evidence are provided in parenthesis within each recommendation.

15. Potential benefits and harms

Describe anticipated benefits and potential risks associated with implementation of guideline recommendations.

The benefits and harm for each comparison of interventions are provided in summary tables and summarized in evidence profiles. The estimated balance between potential benefits and harm was considered when formulating the recommendations.

16. Patient preferences

Describe the role of patient preferences when a recommendation involves a substantial element of personal choice or values.

Recommendations that are level 2 or ''discretionary'' indicate a greater need to help each patient arrive at a management decision consistent with her or his values and preferences. 17. Algorithm Provide (when appropriate) a graphical description of the stages and decisions in clinical care described by the guideline.

No overall algorithm.

18. Implementation considerations

Describe anticipated barriers to application of the recommendations. Provide reference to any auxiliary documents for providers or patients that are intended to facilitate implementation. Suggest review criteria for measuring changes in care when the guideline is implemented.

These recommendations are intended for a global audience. Review criteria were not suggested because implementation with prioritization and development of review criteria have to proceed locally. Furthermore, most recommendations are discretionary, requiring substantial discussion among stakeholders before they can be adopted as review criteria. Suggested audit criteria were provided to assess impact of guideline after publication. Research recommendations were also outlined to address current gaps in the evidence base. the only database searched. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. However, any important studies known to domain experts that were missed by the electronic literature searches were added to retrieved articles and reviewed by the Work Group.

Review of Guideline Development Process

Several tools and checklists have been developed to assess the quality of the methodological process for systematic review and guideline development. These include the Appraisal of Guidelines for Research and Evaluation (AGREE 2) criteria, 111 the Conference on Guideline Standardization (COGS) checklist, 112 and the Institute of Medicine's recent

Standards for Systematic Reviews 113 and Clinical Practice Guidelines We Can Trust. 114 Table 16 and Supplemental Appendix 2 online show, respectively, the criteria which correspond to the COGS checklist and the Institute of Medicine standards, and how each one of them is addressed in this guideline.

Dr Balk reported no relevant financial relationships

Amy Earley, BS, is a project coordinator at the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She is key in coordinating the guideline development activities within the ERT, especially in the development of the evidence reports for all guidelines. Ms Earley also heads the actual evidence review, which includes running searches, screening, data extraction, drafting of tables and methods sections, proofing of guideline drafts, and critical literature appraisals. She participates in the conduct of research projects at the Center and actively collaborates with other members of the Center on independent research topics and manuscript submissions.

Ms Earley reported no relevant financial relationships

Shana Haynes, MS, DHSc, is a research assistant at the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She participates in all aspects of evidence review and guideline development. She screens abstracts and articles, extracts data, and assists in the drafting and editing of evidence tables. Dr Haynes also assists in the development of clinical practice guidelines and conducts systematic reviews and critical literature appraisals.

Dr Haynes reported no relevant financial relationships

Jenny Lamont, MS, is a project manager and medical writer at the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She participates in all aspects of evidence review and guideline development, assists in the preparation of talks and manuscripts, and edits KDIGO draft guidelines currently in progress.

Ms Lamont reported no relevant financial relationships.

A special debt of gratitude is owed to the KDIGO Co-Chairs, Bertram Kasiske and David Wheeler, and the KDIGO Board for their invaluable guidance throughout the development of this guideline. In particular, we thank the ERT members: Ashish Upadhyay, Ethan Balk, Amy Earley, Shana Haynes, and Jenny Lamont for their substantial contribution to the rigorous assessment of the available evidence. We are also especially grateful to the Work Group members for their expertise throughout the entire process of literature review, data extraction, meeting participation, the critical writing and editing of the statements and rationale, which made the publication of this guideline possible. The generous gift of their time and dedication is greatly appreciated. Finally, and on behalf of the Work Group, we gratefully acknowledge the careful assessment of the draft guideline by 268 external reviewers. The Work Group considered all of the valuable comments made and, where appropriate, suggested changes were incorporated into the final publication. No  In some circumstances, a GDG may not be able to perform its work without members who have COIs, such as relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the CPG.

Marcello

True for KDIGO

 Members with COIs should represent not more than a minority of the GDG. No  The chair or cochairs should not be a person(s) with COI.

No  Funders should have no role in CPG development. Yes 3.

Guideline Development Group Composition 3.1

The GDG should be multidisciplinary and balanced, comprising a variety of methodological experts and clinicians, and populations expected to be affected by the CPG. Yes When systematic reviews are conducted specifically to inform particular guidelines, the GDG and systematic review team should interact regarding the scope, approach, and output of both processes.

Yes

5.

Establishing Evidence Foundations for and Rating Strength of Recommendations 5.1

For each recommendation, the following should be provided:  An explanation of the reasoning underlying the recommendation, including Yes  a clear description of potential benefits and harms; Yes  a summary of relevant available evidence (and evidentiary gaps), description of the quality (including applicability), quantity (including completeness), and consistency of the aggregate available evidence;

IOM Standards for Developing Trustworthy Clinical Practice Guidelines

Part of KDIGO Process?  an explanation of the part played by values, opinion, theory, and clinical experience in deriving the recommendation.

 A rating of the level of confidence in (certainty regarding) the evidence underpinning the recommendation Yes  A rating of the strength of the recommendation in light of the preceding bullets Yes  A description and explanation of any differences of opinion regarding the recommendation Yes Literature should be monitored regularly following CPG publication to identify the emergence of new, potentially relevant evidence and to evaluate the continued validity of the CPG.

Planned after publication 8. 3 CPGs should be updated when new evidence suggests the need for modification of clinically important recommendations. For example, a CPG should be updated if new evidence shows that a recommended intervention causes previously unknown substantial harm; that a new intervention is significantly superior to a previously recommended intervention from an efficacy or harms perspective; or that a recommendation can be applied to new populations.

Planned after publication

Supplemental Table 1

-10 (-17, 2) 0.012 Fair 2 Estimated from graph 3 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group". 4 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group". 5 Estimated from graph 6 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group". 7 Estimated from graph 8 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group". 9 Estimated from graph 10 Estimated from graph 11 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group".

4 y ( 3 y) 127 (212) 124 (211) 113 (111) -12 (-13) 1 (

Supplemental Table 8 40 34 Mild chronic renal insufficiency is defined as eGFR < 75 mL/min/1.73m 2 ( < 1.25 mL/s) or creatinine clearance < 75 mL/min (1.25 mL/s) 35 Study is graded "Good" however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 36 Study is graded "Fair" due to the fact that baseline characteristics by intervention were not provided in the CKD subgroup. Consider downgrading again in EP due to not being able to find interaction results. 37 Mild chronic renal insufficiency is defined as creatinine clearance < 75 mL/min 38 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. 39 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. Study is graded "Good", however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P > 0.1) for all interaction tests. Mild chronic renal insufficiency is defined as eGFR < 60 mL/min/1.73m 2 Study is graded "Good" however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 7 Estimated from figure 80 Estimated from graph 81 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group". 82 Estimated from graph 83 Study is graded "Good" however consider downgrading in EP due to the fact that "there was no significant interaction of baseline eGFR and treatment group". (905)

No limitations

No important inconsistencies 88 NS Good 85 Mean absolute difference adjusted for baseline differences 86 Mean absolute difference adjusted for baseline differences 87 Mean absolute difference adjusted for baseline differences 88 Mean absolute difference adjusted for baseline differences Supplemental NS Good 91 Calculated by ERT for all outcome other than primary outcome of major CV event 92 Calculated by ERT for all outcome other than primary outcome of major CV event 93 Estimated from figure 94 Death from CHD, nonfatal non-procedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke. 95 Death from CHD, nonfatal non-procedure-related MI, or resuscitation after cardiac arrest.

|Table 6.|Systematic review topics and screening criteria| |---|---|

|Table 7.|Hierarchy of outcomes|

|Table 8.|Literature yield for RCTs|

|Medical Conditions|| |---|---|

|Nephrotic syndrome|Excessive alcohol consumption|

|Hypothyroidism|Liver disease|

|Diabetes||

|Medications||

|13-cis-retinoic acid|Androgens|

|Anticonvulsants|Oral contraceptives|

|Highly active anti-retroviral therapy|Corticosteroids|

|Diuretics|Cyclosporine|

|Beta-blockers|Sirolimus|

|Reproduced from National Kidney Foundation. K/DOQI Clinical Practice Guidelines||

|for Managing Dyslipidemias in Chronic Kidney Disease. Am J Kidney Dis 41(Suppl 3):||

|S38, 2003 with permission from the National Kidney Foundation; 1 accessed http://||

|www.kidney.org/professionals/kdoqi/guidelines_dyslipidemia/pdf/ajkd_dyslipidemia_||

|gls.pdf||

|Already receiving|| |---|---|

|statin?|Would measuring cholesterol level change management?|

|||c h a p t e r 2| |---|---|---|

|Overall|Male|Female|

|||eGFR G3a-G5, including patients on| |---|---|---|

|Statin|eGFR G1-G2|dialysis or with a kidney transplant|

|Lovastatin|GP|nd|

|Fluvastatin|GP|80 1|

|Atorvastatin|GP|20 2|

|Rosuvastatin|GP|10 3|

|Simvastatin/Ezetmibe|GP|20/10 4|

|Pravastatin|GP|40|

|Simvastatin|GP|40|

|Pitavastatin|GP|2|

|All statins may not be available in all countries. Lower doses than those used in|All statins may not be available in all countries. Lower doses than those used in|All statins may not be available in all countries. Lower doses than those used in|

|major trials of statins in CKD populations may be appropriate in Asian countries.|major trials of statins in CKD populations may be appropriate in Asian countries.|major trials of statins in CKD populations may be appropriate in Asian countries.|

|Note that rosuvastatin 40 mg daily is not recommended for use in CKD 1-2 non-|Note that rosuvastatin 40 mg daily is not recommended for use in CKD 1-2 non-|Note that rosuvastatin 40 mg daily is not recommended for use in CKD 1-2 non-|

|transplant patients, as it may increase the risk of adverse renal events. Cyclosporin|transplant patients, as it may increase the risk of adverse renal events. Cyclosporin|transplant patients, as it may increase the risk of adverse renal events. Cyclosporin|

|inhibits the metabolism of certain statins resulting in higher blood levels.|inhibits the metabolism of certain statins resulting in higher blood levels.|inhibits the metabolism of certain statins resulting in higher blood levels.|

|Data based on 1 ALERT, 2 4D, 3 AURORA,|||

||||c h a p t e r 3| |---|---|---|---|

|Category|Acceptable Borderline High (75%) High (95%)|||

|Total Cholesterol o4.4 (o170) LDL-C o2.8 (o110) Non-HDL-C o3.1 (o120)|4.4-5.2 (170-199) 2.8-3.3 (110-129) 3.1-3.7 (120-144)|45.2 (X200) X3.4 (Z130) X3.8 (Z145)||

|Comparator|Active or control| |---|---|

|Outcome|Categorical: All-cause mortality, cardiovascular mortality, clinical cardiovascular events, ESRD, graft failure, doubling|

||of SCr, halving of GFR|

||Continuous: changes in TC, LDL-C, or HDL-C or TGs|

|Study design|RCTs with parallel-group design; systematic reviews, CKD-subgroup analyses of general population RCTs if no|

||evidence of selection bias and of sufficient size|

|Minimum duration of follow-up|4 weeks for continuous lipid outcomes; 1 year for clinical outcomes; if general population study, 1 year|

|Minimum N of Subjects Z100 per arm for adults, Drug interactions (update of Tables 32-37 in KDOQI 2003 guideline)||

|Population|General population|

|Intervention|Any statin and any other drug|

|Comparator|NA|

|Outcomes|Change in bioavailability of statin|

|Design|Systematic reviews|

|Minimum duration of follow-up|NA|

|Minimum N of subjects|NA|

|Change in LDL-C level by statin||

|Intervention|Any statin|

|Comparator|Other agent or placebo|

|Outcomes|Change in LDL-C|

|Design|Systematic review or meta-analysis, 2006-2011|

|Adverse events from statin+fibrate therapy|Adverse events from statin+fibrate therapy|

|Population|General population (typically focused on familial hypercholesterolemia or mixed dyslipidemia)|

|Intervention|Any statin or statins + any fibrate or fibrates|

|Comparator|Statin or statins alone (also captured data vs. fibrate alone or placebo)|

|Outcomes|Any adverse event, any serious adverse event, discontinuation owing to drug, AKI, cancer, rhabdomyolysis,|

||myalgia, increased creatine kinase, increased creatinine, increased ALT or AST, any other specified; in children, also|

||measures of growth, development, cognitive function|

|Design|Any|

|Minimum duration of follow-up|Any|

|Minimum N of Subjects|Any|

|Frequency of lipids testing||

|Population|Any|

|Intervention|Any regimen with variable timing of measurement: e.g., more vs. less testing, some vs. no testing|

|Comparator|Active or placebo|

|Outcomes|Measures of compliance, cardiovascular outcomes, mortality|

|Design|RCTs or systematic reviews|

|Minimum duration of follow-up|6 months|

|Minimum N of subjects|Z50 per arm|

|Hierarchy|Outcome| |---|---|

|Critical importance|Mortality, cardiovascular mortality, cardiovascular|

||or cerebrovascular events, ESRD, graft failure|

|High importance|Doubling of SCr or halving of GFR|

|Moderate importance|Change in TC, LDL-C, or HDL-C or TGs|

|Importance dependent on severity|Adverse events|

|Abbreviations: ESRD, end-stage renal disease; GFR, glomerular filtration rate; HDL-C,||

|high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SCr,||

|serum creatinine; TC, total cholesterol; TG, triglyceride||

|Studies included in Summary Tables| |---|

|Topic| |---|

|Step 1: Starting grade for|||| |---|---|---|---|

|quality of evidence based on|||Final grade for quality of evidence|

||À1 level if serious limitations|+1 level if strong a , no|change confidence in the estimate of|

||À2 levels if very serious limitations|plausible confounders|the effect|

|||+2 levels if very strong b ,||

||Consistency|no major threats to validity||

||À1 level if important inconsistency||Moderate = Further research is likely to|

|||Other|have an important impact on|

||À1 level if some uncertainty|dose-response gradient|and may change the estimate|

||À2 levels if major uncertainty|||

|||+1 level if all residual|Low = Further research is very likely to|

|||plausible confounders|have an important impact on|

|||would have reduced the|confidence in the estimate, and may|

|||observed effect|change the estimate|

|Any other evidence = Very Low|Other||Very Low = Any estimate of effect is|

||À1 level if sparse or imprecise data c||very uncertain|

||À1 level if high probability of|||

||reporting bias|||

||Quality of|| |---|---|---|

|Grade|Evidence Meaning||

|A|High|We are confident that the true effect lies close to|

|||that of the estimate of the effect.|

|B|Moderate The true effect is likely to be close to the estimate||

|||of the effect, but there is a possibility that it is|

|||substantially different.|

|C|Low|The true effect may be substantially different from|

|||the estimate of the effect.|

|D|Very low||

|Implications| |---|

|||Discussed in KDIGO Clinical Practice Guideline for Lipid| |---|---|---|

|Topic|Description|Management in Chronic Kidney Disease|

|1. Overview material|Provide a structured abstract that includes the guideline's||

||release date, status (original, revised, updated), and print||

||and electronic sources.||

|13. Definitions|Define unfamiliar terms and those critical to correct||

||application of the guideline that might be subject to||

||misinterpretation.||

|Consultant: Amgen; Astellas; Baxter; Merck Sharp &| |---|

|Dohme; Otsuka; Vifor|

|Grant/Research Support: Abbott;* AstraZeneca;* Genzyme*|

|Speaker: Abbott; Amgen; Astellas; Fresenius Medical Care;|

|Genzyme; Otsuka; Shire|

|*monies paid to institution|

|EVIDENCE REVIEW TEAM|

|a c k n o w l e d g m e n t s|http://www.kidney-international.org|http://www.kidney-international.org|http://www.kidney-international.org| |---|---|---|---|

||||& 2013 KDIGO|

|A Tonelli, MD, SM, FRCPC Christoph Wanner, MD Work Group Co-Chairs Part of Part of APPENDIX 2: CONCURRENCE WITH INSTITUTE OF MEDICINE STANDARDS FOR SYSTEMATIC REVIEWS AND FOR GUIDELINES IOM Standards for Systematic Reviews Part of KDIGO Process? 2.1 Establish a team with appropriate expertise and experience to conduct the systematic review Yes 2.1.1 Include expertise in the pertinent clinical content areas Yes 2.1.2 Include expertise in systematic review methods Yes 2.1.3 Include expertise in searching for relevant evidence Yes 2.1.4 Include expertise in quantitative methods Yes 2.1.5 Include other expertise as appropriate Yes 2.2 Manage bias and conflict of interest (COI) of the team conducting the systematic review Yes 2.2.1 Require each team member to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.2.2 Exclude individuals with a clear financial conflict Yes 2.2.3 Exclude individuals whose professional or intellectual bias would diminish the credibility of the review in the eyes of the intended users Not explicitly 2.3 Ensure user and stakeholder input as the review is designed and conducted Yes 2.3.1 Protect the independence of the review team to make the final decisions about the design, analysis, and reporting of the review Yes 2.4 Manage bias and COI for individuals providing input into the systematic review Yes 2.4.1 Require individuals to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.4.2 Exclude input from individuals whose COI or bias would diminish the credibility of the review in the eyes of the intended users No 2.5 Formulate the topic for the systematic review Yes 2.5.1 Confirm the need for a new review Yes 2.5.2 Develop an analytic framework that clearly lays out the chain of logic that links the health intervention to the outcomes of interest and defines the key clinical questions to be addressed by the systematic review No 2.5.3 Use a standard format to articulate each clinical question of interest No IOM Standards for Systematic Reviews KDIGO Process? 2.6.10 Yes 2.6.11 Describe the proposed timetable for conducting the review Yes 2.7 Submit the protocol for peer review IOM Standards for Systematic Reviews KDIGO Part of KDIGO Process? 3.5.3 Use standard data extraction forms developed for the specific SR Process? Yes 3.5.4 Pilot-test the data extraction forms and process 1. Establishing Transparency Yes 3.6 Critically appraise each study Yes 1.1 The processes by which a CPG is developed and funded should be detailed explicitly and publicly Yes accessible. No 2.7.1 Provide a public comment period for the protocol and publicly report on disposition of comments 3.6.1 Systematically assess the risk of bias, using predefined criteria Yes 2. Management of Conflict of Interest (COI) Yes No 2.8 Make the final protocol publicly available, and add any amendments to the protocol in a timely fashion No 3.1 Conduct a comprehensive systematic search for evidence Yes 3.1.1 Work with a librarian or other information specialist trained in performing systematic reviews to plan the search strategy No 3.1.2 Design the search strategy to address each key research question Yes 3.1.3 Use an independent librarian or other information specialist to peer review the search strategy No 3.1.4 Search bibliographic databases Yes 3.1.5 Search citation indexes No 3.1.6 Search literature cited by eligible studies No 3.1.7 Update the search at intervals appropriate to the pace of generation of new information for the research question being addressed Yes 3.1.8 Search subject-specific databases if other databases are unlikely to provide all relevant evidence 3.6.2 Assess the relevance of the study's populations, interventions, and outcome measures Yes 3.6.3 Assess the fidelity of the implementation of interventions Yes 4.1 Use a prespecified method to evaluate the body of evidence 2.1 Prior to selection of the guideline development group (GDG), individuals being considered for Yes membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG: Yes 4.1.1 For each outcome, systematically assess the following characteristics of the body of evidence: Risk of Yes  Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, Yes (not intellectual) bias; Consistency; Precision; Directness; Reporting bias 4.1.2 For bodies of evidence that include observational research, also systematically assess the following institutional, and patient-public activities pertinent to the potential scope of the CPG. Yes 2.2 Disclosure of COIs within GDG: characteristics for each outcome: Dose-response association; Plausible confounding that would change the observed effect; Strength of association 4.1.3 For each outcome specified in the protocol, use consistent language to characterize the level of confidence in the estimates of the effect of an intervention  Reported, not discussed Yes 4.2 Conduct a qualitative synthesis No  Each panel member should explain how his or her COI could influence the CPG development process or specific recommendations. Yes 4.2.1 Describe the clinical and methodological characteristics of the included studies, including their size, inclusion or exclusion of important subgroups, timeliness, and other relevant factors 2.3 Divestment Yes  Not explicitly N/A 3.1.9 Search regional bibliographic databases if other databases are unlikely to provide all relevant evidence 4.2.2 Describe the strengths and limitations of individual studies and patterns across studies Yes N/A 3.2 Take action to address potentially biased reporting of research results No 3.2.1 Search grey-literature databases, clinical trial registries, and other sources of unpublished information 3.2.2 Invite researchers to clarify information about study eligibility, study characteristics, and risk of bias No 3.2.3 Invite all study sponsors and researchers to submit unpublished data, including unreported outcomes, for possible inclusion in the systematic review 3.2.4 Handsearch selected journals and conference abstracts 3.2.5 Conduct a web search 3.2.6 Search for studies reported in languages other than English if appropriate Yes 3.3 Screen and select studies Yes 3.3.1 Include or exclude studies based on the protocol's prespecified criteria Yes 3.3.2 Use observational studies in addition to randomized clinical trials to evaluate harms of interventions No 4.4 If conducting a meta-analysis, then do the following:  Assess the sensitivity of conclusions to changes in the protocol, assumptions  Accompany all estimates with measures of statistical uncertainty  Address the heterogeneity among study effects  Use expert methodologists to develop, execute, and peer review the meta-analyses N/A No 4.3.1 Explain why a pooled estimate might be useful to decision makers No No 4.3 Decide if, in addition to a qualitative analysis, the systematic review will include a quantitative analysis (meta-analysis) No No 4.2.5 Discuss the relevance of individual studies to the populations, comparisons, cointerventions, settings, and outcomes or measures of interest No about studies No 4.2.3 Describe, in plain terms, how flaws in the design or execution of the study (or groups of studies) could No 2.4 Exclusions bias the results, explaining the reasoning behind these judgments 4.2.4 Describe the relationships between the characteristics of the individual studies and their reported findings and patterns across studies No  Whenever possible GDG members should not have COI.|A Tonelli, MD, SM, FRCPC Christoph Wanner, MD Work Group Co-Chairs Part of Part of APPENDIX 2: CONCURRENCE WITH INSTITUTE OF MEDICINE STANDARDS FOR SYSTEMATIC REVIEWS AND FOR GUIDELINES IOM Standards for Systematic Reviews Part of KDIGO Process? 2.1 Establish a team with appropriate expertise and experience to conduct the systematic review Yes 2.1.1 Include expertise in the pertinent clinical content areas Yes 2.1.2 Include expertise in systematic review methods Yes 2.1.3 Include expertise in searching for relevant evidence Yes 2.1.4 Include expertise in quantitative methods Yes 2.1.5 Include other expertise as appropriate Yes 2.2 Manage bias and conflict of interest (COI) of the team conducting the systematic review Yes 2.2.1 Require each team member to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.2.2 Exclude individuals with a clear financial conflict Yes 2.2.3 Exclude individuals whose professional or intellectual bias would diminish the credibility of the review in the eyes of the intended users Not explicitly 2.3 Ensure user and stakeholder input as the review is designed and conducted Yes 2.3.1 Protect the independence of the review team to make the final decisions about the design, analysis, and reporting of the review Yes 2.4 Manage bias and COI for individuals providing input into the systematic review Yes 2.4.1 Require individuals to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.4.2 Exclude input from individuals whose COI or bias would diminish the credibility of the review in the eyes of the intended users No 2.5 Formulate the topic for the systematic review Yes 2.5.1 Confirm the need for a new review Yes 2.5.2 Develop an analytic framework that clearly lays out the chain of logic that links the health intervention to the outcomes of interest and defines the key clinical questions to be addressed by the systematic review No 2.5.3 Use a standard format to articulate each clinical question of interest No IOM Standards for Systematic Reviews KDIGO Process? 2.6.10 Yes 2.6.11 Describe the proposed timetable for conducting the review Yes 2.7 Submit the protocol for peer review IOM Standards for Systematic Reviews KDIGO Part of KDIGO Process? 3.5.3 Use standard data extraction forms developed for the specific SR Process? Yes 3.5.4 Pilot-test the data extraction forms and process 1. Establishing Transparency Yes 3.6 Critically appraise each study Yes 1.1 The processes by which a CPG is developed and funded should be detailed explicitly and publicly Yes accessible. No 2.7.1 Provide a public comment period for the protocol and publicly report on disposition of comments 3.6.1 Systematically assess the risk of bias, using predefined criteria Yes 2. Management of Conflict of Interest (COI) Yes No 2.8 Make the final protocol publicly available, and add any amendments to the protocol in a timely fashion No 3.1 Conduct a comprehensive systematic search for evidence Yes 3.1.1 Work with a librarian or other information specialist trained in performing systematic reviews to plan the search strategy No 3.1.2 Design the search strategy to address each key research question Yes 3.1.3 Use an independent librarian or other information specialist to peer review the search strategy No 3.1.4 Search bibliographic databases Yes 3.1.5 Search citation indexes No 3.1.6 Search literature cited by eligible studies No 3.1.7 Update the search at intervals appropriate to the pace of generation of new information for the research question being addressed Yes 3.1.8 Search subject-specific databases if other databases are unlikely to provide all relevant evidence 3.6.2 Assess the relevance of the study's populations, interventions, and outcome measures Yes 3.6.3 Assess the fidelity of the implementation of interventions Yes 4.1 Use a prespecified method to evaluate the body of evidence 2.1 Prior to selection of the guideline development group (GDG), individuals being considered for Yes membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG: Yes 4.1.1 For each outcome, systematically assess the following characteristics of the body of evidence: Risk of Yes  Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, Yes (not intellectual) bias; Consistency; Precision; Directness; Reporting bias 4.1.2 For bodies of evidence that include observational research, also systematically assess the following institutional, and patient-public activities pertinent to the potential scope of the CPG. Yes 2.2 Disclosure of COIs within GDG: characteristics for each outcome: Dose-response association; Plausible confounding that would change the observed effect; Strength of association 4.1.3 For each outcome specified in the protocol, use consistent language to characterize the level of confidence in the estimates of the effect of an intervention  Reported, not discussed Yes 4.2 Conduct a qualitative synthesis No  Each panel member should explain how his or her COI could influence the CPG development process or specific recommendations. Yes 4.2.1 Describe the clinical and methodological characteristics of the included studies, including their size, inclusion or exclusion of important subgroups, timeliness, and other relevant factors 2.3 Divestment Yes  Not explicitly N/A 3.1.9 Search regional bibliographic databases if other databases are unlikely to provide all relevant evidence 4.2.2 Describe the strengths and limitations of individual studies and patterns across studies Yes N/A 3.2 Take action to address potentially biased reporting of research results No 3.2.1 Search grey-literature databases, clinical trial registries, and other sources of unpublished information 3.2.2 Invite researchers to clarify information about study eligibility, study characteristics, and risk of bias No 3.2.3 Invite all study sponsors and researchers to submit unpublished data, including unreported outcomes, for possible inclusion in the systematic review 3.2.4 Handsearch selected journals and conference abstracts 3.2.5 Conduct a web search 3.2.6 Search for studies reported in languages other than English if appropriate Yes 3.3 Screen and select studies Yes 3.3.1 Include or exclude studies based on the protocol's prespecified criteria Yes 3.3.2 Use observational studies in addition to randomized clinical trials to evaluate harms of interventions No 4.4 If conducting a meta-analysis, then do the following:  Assess the sensitivity of conclusions to changes in the protocol, assumptions  Accompany all estimates with measures of statistical uncertainty  Address the heterogeneity among study effects  Use expert methodologists to develop, execute, and peer review the meta-analyses N/A No 4.3.1 Explain why a pooled estimate might be useful to decision makers No No 4.3 Decide if, in addition to a qualitative analysis, the systematic review will include a quantitative analysis (meta-analysis) No No 4.2.5 Discuss the relevance of individual studies to the populations, comparisons, cointerventions, settings, and outcomes or measures of interest No about studies No 4.2.3 Describe, in plain terms, how flaws in the design or execution of the study (or groups of studies) could No 2.4 Exclusions bias the results, explaining the reasoning behind these judgments 4.2.4 Describe the relationships between the characteristics of the individual studies and their reported findings and patterns across studies No  Whenever possible GDG members should not have COI.|A Tonelli, MD, SM, FRCPC Christoph Wanner, MD Work Group Co-Chairs Part of Part of APPENDIX 2: CONCURRENCE WITH INSTITUTE OF MEDICINE STANDARDS FOR SYSTEMATIC REVIEWS AND FOR GUIDELINES IOM Standards for Systematic Reviews Part of KDIGO Process? 2.1 Establish a team with appropriate expertise and experience to conduct the systematic review Yes 2.1.1 Include expertise in the pertinent clinical content areas Yes 2.1.2 Include expertise in systematic review methods Yes 2.1.3 Include expertise in searching for relevant evidence Yes 2.1.4 Include expertise in quantitative methods Yes 2.1.5 Include other expertise as appropriate Yes 2.2 Manage bias and conflict of interest (COI) of the team conducting the systematic review Yes 2.2.1 Require each team member to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.2.2 Exclude individuals with a clear financial conflict Yes 2.2.3 Exclude individuals whose professional or intellectual bias would diminish the credibility of the review in the eyes of the intended users Not explicitly 2.3 Ensure user and stakeholder input as the review is designed and conducted Yes 2.3.1 Protect the independence of the review team to make the final decisions about the design, analysis, and reporting of the review Yes 2.4 Manage bias and COI for individuals providing input into the systematic review Yes 2.4.1 Require individuals to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.4.2 Exclude input from individuals whose COI or bias would diminish the credibility of the review in the eyes of the intended users No 2.5 Formulate the topic for the systematic review Yes 2.5.1 Confirm the need for a new review Yes 2.5.2 Develop an analytic framework that clearly lays out the chain of logic that links the health intervention to the outcomes of interest and defines the key clinical questions to be addressed by the systematic review No 2.5.3 Use a standard format to articulate each clinical question of interest No IOM Standards for Systematic Reviews KDIGO Process? 2.6.10 Yes 2.6.11 Describe the proposed timetable for conducting the review Yes 2.7 Submit the protocol for peer review IOM Standards for Systematic Reviews KDIGO Part of KDIGO Process? 3.5.3 Use standard data extraction forms developed for the specific SR Process? Yes 3.5.4 Pilot-test the data extraction forms and process 1. Establishing Transparency Yes 3.6 Critically appraise each study Yes 1.1 The processes by which a CPG is developed and funded should be detailed explicitly and publicly Yes accessible. No 2.7.1 Provide a public comment period for the protocol and publicly report on disposition of comments 3.6.1 Systematically assess the risk of bias, using predefined criteria Yes 2. Management of Conflict of Interest (COI) Yes No 2.8 Make the final protocol publicly available, and add any amendments to the protocol in a timely fashion No 3.1 Conduct a comprehensive systematic search for evidence Yes 3.1.1 Work with a librarian or other information specialist trained in performing systematic reviews to plan the search strategy No 3.1.2 Design the search strategy to address each key research question Yes 3.1.3 Use an independent librarian or other information specialist to peer review the search strategy No 3.1.4 Search bibliographic databases Yes 3.1.5 Search citation indexes No 3.1.6 Search literature cited by eligible studies No 3.1.7 Update the search at intervals appropriate to the pace of generation of new information for the research question being addressed Yes 3.1.8 Search subject-specific databases if other databases are unlikely to provide all relevant evidence 3.6.2 Assess the relevance of the study's populations, interventions, and outcome measures Yes 3.6.3 Assess the fidelity of the implementation of interventions Yes 4.1 Use a prespecified method to evaluate the body of evidence 2.1 Prior to selection of the guideline development group (GDG), individuals being considered for Yes membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG: Yes 4.1.1 For each outcome, systematically assess the following characteristics of the body of evidence: Risk of Yes  Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, Yes (not intellectual) bias; Consistency; Precision; Directness; Reporting bias 4.1.2 For bodies of evidence that include observational research, also systematically assess the following institutional, and patient-public activities pertinent to the potential scope of the CPG. Yes 2.2 Disclosure of COIs within GDG: characteristics for each outcome: Dose-response association; Plausible confounding that would change the observed effect; Strength of association 4.1.3 For each outcome specified in the protocol, use consistent language to characterize the level of confidence in the estimates of the effect of an intervention  Reported, not discussed Yes 4.2 Conduct a qualitative synthesis No  Each panel member should explain how his or her COI could influence the CPG development process or specific recommendations. Yes 4.2.1 Describe the clinical and methodological characteristics of the included studies, including their size, inclusion or exclusion of important subgroups, timeliness, and other relevant factors 2.3 Divestment Yes  Not explicitly N/A 3.1.9 Search regional bibliographic databases if other databases are unlikely to provide all relevant evidence 4.2.2 Describe the strengths and limitations of individual studies and patterns across studies Yes N/A 3.2 Take action to address potentially biased reporting of research results No 3.2.1 Search grey-literature databases, clinical trial registries, and other sources of unpublished information 3.2.2 Invite researchers to clarify information about study eligibility, study characteristics, and risk of bias No 3.2.3 Invite all study sponsors and researchers to submit unpublished data, including unreported outcomes, for possible inclusion in the systematic review 3.2.4 Handsearch selected journals and conference abstracts 3.2.5 Conduct a web search 3.2.6 Search for studies reported in languages other than English if appropriate Yes 3.3 Screen and select studies Yes 3.3.1 Include or exclude studies based on the protocol's prespecified criteria Yes 3.3.2 Use observational studies in addition to randomized clinical trials to evaluate harms of interventions No 4.4 If conducting a meta-analysis, then do the following:  Assess the sensitivity of conclusions to changes in the protocol, assumptions  Accompany all estimates with measures of statistical uncertainty  Address the heterogeneity among study effects  Use expert methodologists to develop, execute, and peer review the meta-analyses N/A No 4.3.1 Explain why a pooled estimate might be useful to decision makers No No 4.3 Decide if, in addition to a qualitative analysis, the systematic review will include a quantitative analysis (meta-analysis) No No 4.2.5 Discuss the relevance of individual studies to the populations, comparisons, cointerventions, settings, and outcomes or measures of interest No about studies No 4.2.3 Describe, in plain terms, how flaws in the design or execution of the study (or groups of studies) could No 2.4 Exclusions bias the results, explaining the reasoning behind these judgments 4.2.4 Describe the relationships between the characteristics of the individual studies and their reported findings and patterns across studies No  Whenever possible GDG members should not have COI.|A Tonelli, MD, SM, FRCPC Christoph Wanner, MD Work Group Co-Chairs Part of Part of APPENDIX 2: CONCURRENCE WITH INSTITUTE OF MEDICINE STANDARDS FOR SYSTEMATIC REVIEWS AND FOR GUIDELINES IOM Standards for Systematic Reviews Part of KDIGO Process? 2.1 Establish a team with appropriate expertise and experience to conduct the systematic review Yes 2.1.1 Include expertise in the pertinent clinical content areas Yes 2.1.2 Include expertise in systematic review methods Yes 2.1.3 Include expertise in searching for relevant evidence Yes 2.1.4 Include expertise in quantitative methods Yes 2.1.5 Include other expertise as appropriate Yes 2.2 Manage bias and conflict of interest (COI) of the team conducting the systematic review Yes 2.2.1 Require each team member to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.2.2 Exclude individuals with a clear financial conflict Yes 2.2.3 Exclude individuals whose professional or intellectual bias would diminish the credibility of the review in the eyes of the intended users Not explicitly 2.3 Ensure user and stakeholder input as the review is designed and conducted Yes 2.3.1 Protect the independence of the review team to make the final decisions about the design, analysis, and reporting of the review Yes 2.4 Manage bias and COI for individuals providing input into the systematic review Yes 2.4.1 Require individuals to disclose potential COI and professional or intellectual bias Yes (not intellectual bias) 2.4.2 Exclude input from individuals whose COI or bias would diminish the credibility of the review in the eyes of the intended users No 2.5 Formulate the topic for the systematic review Yes 2.5.1 Confirm the need for a new review Yes 2.5.2 Develop an analytic framework that clearly lays out the chain of logic that links the health intervention to the outcomes of interest and defines the key clinical questions to be addressed by the systematic review No 2.5.3 Use a standard format to articulate each clinical question of interest No IOM Standards for Systematic Reviews KDIGO Process? 2.6.10 Yes 2.6.11 Describe the proposed timetable for conducting the review Yes 2.7 Submit the protocol for peer review IOM Standards for Systematic Reviews KDIGO Part of KDIGO Process? 3.5.3 Use standard data extraction forms developed for the specific SR Process? Yes 3.5.4 Pilot-test the data extraction forms and process 1. Establishing Transparency Yes 3.6 Critically appraise each study Yes 1.1 The processes by which a CPG is developed and funded should be detailed explicitly and publicly Yes accessible. No 2.7.1 Provide a public comment period for the protocol and publicly report on disposition of comments 3.6.1 Systematically assess the risk of bias, using predefined criteria Yes 2. Management of Conflict of Interest (COI) Yes No 2.8 Make the final protocol publicly available, and add any amendments to the protocol in a timely fashion No 3.1 Conduct a comprehensive systematic search for evidence Yes 3.1.1 Work with a librarian or other information specialist trained in performing systematic reviews to plan the search strategy No 3.1.2 Design the search strategy to address each key research question Yes 3.1.3 Use an independent librarian or other information specialist to peer review the search strategy No 3.1.4 Search bibliographic databases Yes 3.1.5 Search citation indexes No 3.1.6 Search literature cited by eligible studies No 3.1.7 Update the search at intervals appropriate to the pace of generation of new information for the research question being addressed Yes 3.1.8 Search subject-specific databases if other databases are unlikely to provide all relevant evidence 3.6.2 Assess the relevance of the study's populations, interventions, and outcome measures Yes 3.6.3 Assess the fidelity of the implementation of interventions Yes 4.1 Use a prespecified method to evaluate the body of evidence 2.1 Prior to selection of the guideline development group (GDG), individuals being considered for Yes membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG: Yes 4.1.1 For each outcome, systematically assess the following characteristics of the body of evidence: Risk of Yes  Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, Yes (not intellectual) bias; Consistency; Precision; Directness; Reporting bias 4.1.2 For bodies of evidence that include observational research, also systematically assess the following institutional, and patient-public activities pertinent to the potential scope of the CPG. Yes 2.2 Disclosure of COIs within GDG: characteristics for each outcome: Dose-response association; Plausible confounding that would change the observed effect; Strength of association 4.1.3 For each outcome specified in the protocol, use consistent language to characterize the level of confidence in the estimates of the effect of an intervention  Reported, not discussed Yes 4.2 Conduct a qualitative synthesis No  Each panel member should explain how his or her COI could influence the CPG development process or specific recommendations. Yes 4.2.1 Describe the clinical and methodological characteristics of the included studies, including their size, inclusion or exclusion of important subgroups, timeliness, and other relevant factors 2.3 Divestment Yes  Not explicitly N/A 3.1.9 Search regional bibliographic databases if other databases are unlikely to provide all relevant evidence 4.2.2 Describe the strengths and limitations of individual studies and patterns across studies Yes N/A 3.2 Take action to address potentially biased reporting of research results No 3.2.1 Search grey-literature databases, clinical trial registries, and other sources of unpublished information 3.2.2 Invite researchers to clarify information about study eligibility, study characteristics, and risk of bias No 3.2.3 Invite all study sponsors and researchers to submit unpublished data, including unreported outcomes, for possible inclusion in the systematic review 3.2.4 Handsearch selected journals and conference abstracts 3.2.5 Conduct a web search 3.2.6 Search for studies reported in languages other than English if appropriate Yes 3.3 Screen and select studies Yes 3.3.1 Include or exclude studies based on the protocol's prespecified criteria Yes 3.3.2 Use observational studies in addition to randomized clinical trials to evaluate harms of interventions No 4.4 If conducting a meta-analysis, then do the following:  Assess the sensitivity of conclusions to changes in the protocol, assumptions  Accompany all estimates with measures of statistical uncertainty  Address the heterogeneity among study effects  Use expert methodologists to develop, execute, and peer review the meta-analyses N/A No 4.3.1 Explain why a pooled estimate might be useful to decision makers No No 4.3 Decide if, in addition to a qualitative analysis, the systematic review will include a quantitative analysis (meta-analysis) No No 4.2.5 Discuss the relevance of individual studies to the populations, comparisons, cointerventions, settings, and outcomes or measures of interest No about studies No 4.2.3 Describe, in plain terms, how flaws in the design or execution of the study (or groups of studies) could No 2.4 Exclusions bias the results, explaining the reasoning behind these judgments 4.2.4 Describe the relationships between the characteristics of the individual studies and their reported findings and patterns across studies No  Whenever possible GDG members should not have COI.|

|2.5.4 3.3.3 5.1|State the rationale for each clinical question Use two or more members of the review team, working independently, to screen and select studies Prepare final report using a structured format|No No N/A||

|2.5.5 2.6 2.6.1 2.6.2 2.6.3 2.6.4 2.6.5 2.6.6 3.3.4 5.1.1 3.3.5 5.1.2 5.1.3 5.1.4 3.3.6 5.1.5 5.1.6 3.4 3.4.1 2.6.7 3.4.2 3.5 2.6.8 2.6.9 3.5.1 3.5.2|Refine each question based on user and stakeholder input Develop a systematic review protocol Describe the context and rationale for the review from both a decision-making and research perspective Describe the study screening and selection criteria (inclusion/exclusion criteria) Describe precisely which outcome measures, time points, interventions, and comparison groups will be addressed Describe the search strategy for identifying relevant evidence Describe the procedures for study selection Describe the data extraction strategy Train screeners using written documentation; test and retest screeners to improve accuracy and Include a report title consistency Use one of two strategies to select studies: (1) read all fulltext articles identified in the search or (2) Include an abstract Include an executive summary screen titles and abstracts of all articles and then read the full texts of articles identified in initial Include a summary written for the lay public screening Taking account of the risk of bias, consider using observational studies to address gaps in the Include an introduction (rationale and objectives) Include a methods section. Describe the following: evidence from randomized clinical trials on the benefits of interventions Document the search  Research protocol Provide a line-by-line description of the search strategy, including the date of every search for each database, web browser, etc.  Eligibility criteria (criteria for including and excluding studies in the systematic review)  Analytic framework and key questions Describe the process for identifying and resolving disagreement between researchers in study Document the disposition of each report identified including reasons for their exclusion if appropriate  Databases and other information sources used to identify relevant studies Manage data collection  Search strategy selection and data extraction decisions Describe the approach to critically appraising individual studies Describe the method for evaluating the body of evidence, including the quantitative and qualitative  Study selection process  Data extraction process  Methods for handling missing information synthesis strategies Link publications from the same study to avoid including data from the same study more than once  Information to be extracted from included studies|Yes Yes No Yes Yes Yes Yes N/A Yes N/A Yes (2) N/A N/A N/A No Yes No Yes Yes Yes No Yes No Yes No Yes Yes Yes Single Yes extraction Yes Yes No Yes Yes||

Future studies should be conducted to assess short-and longterm association between lipids and CVD, using surrogate outcomes such as carotid intima-media thickness and clinically relevant outcomes such as MI and stroke.

c h a p t e r 4 Although previous guidelines have suggested the use of fibric acid derivatives for preventing pancreatitis from severe hypertriglyceridemia, 1 the evidence supporting the safety and efficacy of this approach is extremely weak, especially in patients with CKD. Therefore, the Work Group no longer recommends this approach, especially since statins appear to prevent pancreatitis in people with normal or mildly elevated TGs. 88 ibric acid derivatives could be considered for the rare patients with CKD and markedly elevated fasting levels of serum TG (411.3 mmol/l [41000 mg/dl]). If such therapy is prescribed, fibric acid derivatives must be dose-adjusted for kidney function. There is limited evidence to recommend one fibric acid derivative over another in the setting of CKD and therefore any of the alternatives may be used. As mentioned in Chapter 2, concomitant therapy with both a fibric acid derivative and a statin is not recommended in patients with CKD due to the potential for toxicity. Nicotinic acid has not been well studied in advanced CKD and therefore is not recommended for treatment of severe hypertriglyceridemia, given the risk of toxicity (especially flushing and hyperglycemia).

The Work Group considered a weak recommendation against the use of fibric acid derivatives in people with CKD. However, in the judgment of the Work Group, there is insufficient evidence to recommend for or against the use of fibric acid derivatives in this population. Treatment with fibric acid derivatives might be warranted in patients who place a relatively high value on preventing pancreatitis, and a relatively low value on the risks of polypharmacy and drug toxicity.

Pharmacological treatment of high triglycerides: effects on cardiovascular risk

A meta-analysis of data from 18 randomized trials involving 45,058 participants drawn from the general population (i.e., not specific to CKD) demonstrated a modest 10% RR reduction (95% CI 0-18; p ¼ 0.048) in major cardiovascular events and a 13% RR reduction in coronary events (95% CI 7-19; p o0.0001) for fibrate therapy. But such benefits are smaller than the 20% reduction in vascular events and 10% reduction in mortality demonstrated by statins per mmol/l reduction in LDL-C. 14, 89, 90 s mentioned in Chapter 1, the dyslipidemia associated with CKD appear particularly suited to therapy with fibric acid derivatives, which alter triglyceride-rich lipoproteins more than LDL-C, the main target of statins. This observation has raised the hypothesis that fibrates might be especially effective for preventing vascular events in CKD populations.

Randomized treatment trials that examined the effect of fibrates relative to placebo in patients with diabetes and CKD are summarized below. The Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) found evidence that gemfibrozil reduces risk of major cardiovascular events (i.e., fatal CHD, nonfatal MI, and stroke) by 42% compared with placebo (RR 0.58; 95% CI 0.38-0.89) in a post hoc analysis of 297 individuals with low eGFR (GFR o75 ml/min/1.73 m 2 ) and diabetes. 91 he Diabetes Atherosclerosis Intervention Study (DAIS) 92 and the FIELD study 93 reported that fenofibrate treatment significantly lowered the risk of developing new-onset microalbuminuria compared with placebo (RR 0.87 in patients with type 2 diabetes; 95% CI 0.77-0.97). In a pooled analysis of these two trials, fenofibrate also promoted regression from microalbuminuria to normoalbuminuria (RR1.15; 95% CI 1.04-1.28; n ¼ 2260). None of the other trials of fibrate therapy in diabetes reported CVD or kidney disease outcomes for the subgroup of patients with CKD.

The FIELD study was a large randomized double-blind trial in which 9795 participants aged 50-75 years with type 2 c h a p t e r 5 http://www.kidney-international.org & 2013 KDIGO diabetes were allocated to micronized fenofibrate 200 mg daily or matching placebo, and followed for a median of 5 years. 93 Patients were eligible if there was no clear indication for, or treatment with, lipid-modifying therapy at study entry, and patients with renal impairment, defined as a plasma creatinine 4130 mmol/l (41.47 mg/dl), were excluded. There was a significant difference in the proportion of participants with progression of albuminuria, analyzed categorically to/from normo-, micro-, and macro-albuminuria (466 [9.5%] progressing and 462 [9.4%] regressing in the fenofibrate group vs. 539 [11.0%] progressing and 400 [8.2%] regressing in the placebo group; i.e., 2.6% more patients were regressing or not progressing in those allocated fenofibrate than placebo, p ¼ 0.002). Importantly, only 5% (519 of 9795) of the randomized participants had a baseline eGFR below 60 ml/min/1.73 m 2 , so only 117 cardiovascular events occurred in this subgroup. The significant treatment effects presented for those with eGFR below 60 ml/min/ 1.73 m 2 (for the outcomes of coronary revascularization, cardiovascular mortality, and total cardiovascular events) were based on too few events to be reliable. Hence, there was not good evidence that the treatment effects on vascular outcomes differed between those with and without lower baseline eGFR.

Ting and colleagues also considered whether allocation to fenofibrate affected renal function but were unable to conclusively address this issue due to lack of statistical power. 94 Another paper, which provides more detailed renal analyses from FIELD, suggested that after excluding the 10-12 mmol/l (0.11-0.14 mg/dl) step-rise in creatinine on commencing fenofibrate, allocation to fenofibrate was in fact associated with a slower rate of change in eGFR (À1.19 vs. À2.03, absolute difference B1 ml/min/1.73 m 2 per year; p o0.001). 95 But the inaccuracy of eGFR above 60 ml/min/ 1.73 m 2 and the use of surrogate outcomes such as rate of change in eGFR and albuminuria remain important caveats. Furthermore, allocation to fenofibrate was also associated with an increased risk of doubling of plasma creatinine (148 [3.0%] vs. 90 [1.8%] , p o0.001), which cannot simply be explained by the small step-rise in creatinine.

ACCORD Lipid, the other large randomized trial which investigated the effect of fibrates in type 2 diabetic patients, assessed the addition of fenofibrate 160 mg daily to simvastatin 10-40 mg daily (dose modified over time in response to changing guidelines) in 5518 participants. 96 gain, this study excluded patients with impaired kidney function, creatinine 4133 mmol/l (41.5 mg/dl), such that only 141 participants had baseline eGFR below 50 ml/min/ 1.73 m 2 . Ultimately too few participants with eGFR o60 ml/ min/1.73 m 2 were included in either FIELD or ACCORD Lipid to provide reliable information on either the safety or efficacy of fenofibrate in this group.

A recent large observational study in patients aged Z66 years demonstrated a clear association between new prescriptions for fibric acid derivatives and increased SCr levels, as well as a small increase in the risk of hospitalization and nephrologist consultation. 97 These findings contribute to the uncertainty that fibric acid derivatives would yield net clinical benefit in people with CKD.

For these reasons, use of fibric acid derivatives to reduce cardiovascular risk is not recommended in patients with CKD.

Given the lack of evidence to support this recommendation, no audit criteria are suggested.

K TLC should be recommended to adults with CKD and hypertriglyceridemia.

K Fibric acid derivatives are not recommended to prevent pancreatitis or reduce cardiovascular risk in adults with CKD and hypertriglyceridemia.

K There are currently no published randomized trials of fibric acid derivatives in CKD populations and too few participants with CKD were included in previous trials to provide reliable information. Other agents, such as niacin and the cholesteryl ester transfer protein inhibitor anacetrapib are currently being investigated in clinical trials in the general population and deserve investigation in CKD patients.

K CKD registries should report hypertriglyceridemia-induced pancreatitis to identify true incidence.

K Studies should be conducted to confirm that pancreatitis due to TG levels above 11.3 mmol/l (1000 mg/dl) is infrequent in HD patients.

c h a p t e r 5 Although previous guidelines have suggested the use of fibric acid derivatives for preventing pancreatitis from severe hypertriglyceridemia, the evidence supporting the safety and efficacy of this approach is extremely weak -especially in children with CKD. Therefore, the Work Group no longer recommends this approach.

Evidence that very high TGs can cause pancreatitis in children comes from case reports and small series of patients with familial dyslipidemias. 98, 99 1] [102] There have been 4 trials of fish oil completed in children with glomerular causes of CKD and one trial among children on dialysis; fish oil appears to lower serum TGs after as little as 12 weeks of therapy, [103] [104] [105] [106] but the longer-term benefits, harms, and tolerability of such treatment is unclear.

Therefore, pharmacological treatment of hypertriglyceridemia is not recommended in children with CKD. This is a weak recommendation that reflects the lack of evidence on clinical benefit and safety. Treatment could be considered in children with very severely increased hypertriglyceridemia (411.3 mmol/l [41000 mg/dl]); such children should be referred to a pediatric lipid specialist for management and to rule out familial hypertriglyceridemia or rare, inherited disorders such as lipoprotein lipase deficiency or apolipoprotein C-II deficiency.

K Audit the number of pediatric CKD patients treated with TLC, diet, and weight loss for lowering TGs.

K Audit the number of pediatric CKD patients treated with pharmacological TG-lowering therapy.

K Record the number of pediatric CKD patients with drug intolerance and/or non-compliance.

K TLC should be recommended to children with CKD and hypertriglyceridemia.

K Fibric acid derivatives are not recommended to prevent pancreatitis or reduce cardiovascular risk in children with CKD and hypertriglyceridemia.

Future studies should be conducted to:

K Determine prevalence of hypertriglyceridemia in pediatric kidney transplant recipients.

K Determine the effect of diet and weight loss in lowering TG among pediatric CKD patients.

While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. The Work Group Co-Chairs, KDIGO Co-Chairs and ERT met for a two-day meeting to go over the guideline development process, evidence review topics, and systematic review findings. Following this, the Work Group, KDIGO Co-Chairs and KDIGO support staff met held a two-day meeting to revisit the available evidence, formulate recommendation statements, deliberate on rationale for recommendations, and to develop consensus.

Commissioning of Work Group and ERT

The KDIGO Co-Chairs appointed the Work Group Co-Chairs, who then assembled the Work Group of domain experts, including individuals with expertise in internal medicine, adult and pediatric nephrology, cardiology, hypertension, pharmacology, epidemiology, and endocrinology. The Tufts Center for Kidney Disease Guideline Development and Implementation at Tufts Medical Center in Boston, Massachusetts, USA, was contracted to conduct systematic evidence review and provide expertise in guideline development methodology. The ERT consisted of physician-methodologists with expertise in nephrology and evidencebased clinical practice guideline development, a project coordinator, a research assistant, and a project manager/ medical writer.

Defining Scope and Topics

The Work Group Co-Chairs and the ERT defined the overall scope and goals of the guideline (including a list of critical and important outcomes) and then drafted a preliminary list of topics and key clinical questions. They also reviewed the topics in the KDOQI guideline, 1 which the ERT also had helped to develop. The Work Group and ERT further developed and refined each topic and specified screening criteria, literature search strategies, and data extraction forms (Table 6 ).

Establishing the Process for Guideline Development

The ERT performed systematic literature searches and organized abstract and article screening. The ERT also coordinated the methodological and analytical processes, and defined and standardized the methodology for performing literature searches, data extraction, and summarizing the evidence. The Work Group took the primary role of writing the recommendation statements and rationales and retained final responsibility for their content. The Work Group Co-Chairs and the ERT prepared the first draft of the scope of work document as a series of open-ended questions to be considered by Work Group members.

Formulating Questions of Interest

Questions of interest were formulated according to the PICODD (Population, Intervention, Comparator, Outcome, study Design and Duration of follow-up) criteria. Details of the PICODD criteria are presented in Table 6 .

Ranking of Outcomes

The Work Group ranked outcomes of interest on the basis of their importance for informing clinical decision making (Table 7 ). Mortality, cardiovascular mortality, cardiovascular or cerebrovascular events, ESRD, and graft failure were considered to be of critical importance; doubling of SCr and halving of GFR, high importance; and change in TC, LDL-C, or HDL-C or TG, moderate importance. The importance of adverse events was considered to depend on the event severity.

Literature For selection of studies, all members of ERT independently and manually screened the abstracts using the computerized screening program Abstrackr. To establish relevance and consensus among reviewers, the entire team screened and achieved consensus on an initial batch of 500 abstracts. A total of 11,337 citations were initially screened. Journal articles reporting original data, meta-analyses, and systematic reviews were selected for evidence review, based on a priori criteria for eligible evidence. Editorials, letters, abstracts, unpublished reports, and articles published in non-peer-reviewed journals were not included. The Work Group also decided to exclude publications from journal supplements because of potential differences in the process of how they are solicited, selected, reviewed, and edited compared to peer-reviewed publications. The overall search yield along with the number of abstracts identified and articles reviewed for each topic are presented in Table 8 .

Data Extraction

Data extraction was done by an ERT member. Although no duplicate extraction was independently performed, data from each study was examined by another reviewer to confirm accuracy. The ERT, in consultation with the Work Group Co-Chairs, designed forms to capture data on design, methodology, sample characteristics, interventions, comparators, outcomes, results, and limitations of individual studies. Methodology and outcomes were also systematically graded (see the section on grading below) and recorded during the data extraction process.

Summary Tables

Summary tables were developed for each comparison of interest. Summary tables contain outcomes of interest, relevant population characteristics, description of intervention and comparator, results, and quality grading for each outcome. Categorical outcomes and continuous lipid outcomes were tabulated separately. For studies not exclusively examining CKD populations, only those reporting analysis by CKD subgroups were tabulated.

Work Group members proofed all summary table data and quality assessments. Summary tables are available at http://www.kdigo.org/home/guidelines/lipids. Evidence profiles were constructed to assess the quality and record quality grades and descriptions of effect for each outcome across studies, as well as the quality of overall evidence and description of net benefits or harms of the intervention or comparator across all outcomes. These profiles aim to make the evidence synthesis process transparent. Decisions in the evidence profiles were based on data from the primary studies listed in corresponding summary tables and on judgments of the ERT and Work Group. When the body of evidence for a particular comparison of interest consisted of only one study, the summary table provided the final level of synthesis and an evidence profile was not generated. Each evidence profile was initially constructed by the ERT and then reviewed, edited, and approved by the Work Group. The work products created by the ERT for summarizing the evidence base are listed in Table 9 .

Grading of Quality of Evidence for Outcomes of Individual Studies

Methodological quality (internal validity) refers to the design, conduct, and reporting of outcomes of a clinical study. A previously devised three-level classification system for quality assessment was used to grade the overall study quality and quality of all relevant outcomes in the study (Table 10 ). Grading of individual studies was done by one of the reviewers, then confirmed by another, and finalized in a group meeting. Variations of this system have been used in most KDOQI and all KDIGO guidelines and have been recommended by the US Agency for Healthcare Research and Quality Evidence-based Practice Center program. 107 ach study was given an overall quality grade based on its design, methodology (randomization, allocation, blinding, definition of outcomes, appropriate use of statistical methods, etc.), conduct (dropout percentage, outcome assessment methodologies, etc.) and reporting (internal consistency, clarity, thoroughness and precision, etc.). Each reported outcome was then evaluated and given an individual grade depending on the quality of reporting and methodological issues specific to that outcome. However, the quality grade of an individual outcome could not exceed the quality grade for the overall study.

Grading the Quality of Evidence and the Strength of a Guideline Recommendation

A structured approach, based on GRADE [108] [109] [110] and facilitated by the use of evidence profiles, was used to grade the quality of the overall evidence and the strength of recommendations. For each topic, the discussion on grading of the quality of the evidence was led by the ERT, and the discussion regarding the strength of the recommendations was led by the Work Group Co-Chairs. The ''strength of a recommendation'' indicates the extent to which one can be confident that adherence to the recommendation will do more good than harm. The ''quality of a body of evidence'' refers to the extent to which our confidence in an estimate of effect is sufficient to support a particular recommendation. 109 ading the quality of evidence for each outcome across studies. Following GRADE, the quality of a body of evidence pertaining to a particular outcome of interest was initially categorized on the basis of study design. 11 ).

CKD subgroup analyses. The following criteria were devised to grade the quality of CKD-subgroup analyses of RCTs that were not specifically designed for or limited to individuals with CKD. CKD subgroups were graded only if they were of an acceptable size for the topic of interest (e.g., 50 per arm with CKD for lipid guideline). These criteria will be considered along with the assessment of whether the putative subgroup effect is plausible with regard to direction and size of effect.

For the complete set of subgroup grading criteria, see Figure 3 . Briefly, the study quality was graded according to whether the CKD subgroup defined by kidney function or proteinuria measured at baseline (rather than after the start of treatment), whether or not analyses of subgroups were pre-specified before randomization, whether or not intervention and comparator groups were balanced within the CKD subgroup. The directness of the CKD subgroup analysis was graded on the basis of whether or not the CKD subgroup results of trials that were not specifically designed for CKD were applicable to patients with CKD and also whether or not a test for interaction by baseline kidney function (or the level of proteinuria) was performed. Grading the overall quality of evidence. The quality of the overall body of evidence was then determined on the basis of the quality grades for all outcomes of interest, taking into account explicit judgments about the relative importance of each outcome. The resulting four final categories for the quality of overall evidence were: 'A', 'B' , 'C' or 'D' (Table 12 ).

Assessment of the net health benefit across all important clinical outcomes. The net health benefit was determined on the basis of the anticipated balance of benefits and harms across all clinically important outcomes (Table 13 ). The assessment of net benefit also involved the judgment of the Work Group and the ERT.

Developing the recommendations. Draft recommendation statements were developed by the Work Group Co-Chairs and Work Group members with input from all Work Group members. The health benefits, side effects, and risks associated with each recommendation were considered when formulating the guideline, as well as information on patient preferences when available. Recommendation statements were revised in a multi-step process during teleconferences and a face-to-face meeting, as well as in subsequent drafts by email. All Work Group members provided feedback on initial and final drafts of the recommendation. The final draft was sent for internal and external peer review, and was further revised by the Work Group Co-Chairs and members. All Work Group members approved the final version of the guideline.

Grading the strength of the recommendations. The strength of a recommendation is graded as level 1 or level 2. Table 14 shows the KDIGO nomenclature for grading the strength of a recommendation and the implications of each level for patients, clinicians, and policy-makers. Recommendations can be for or against doing something. Each recommendation includes an explicit link between the quality of the The estimate of effect is very uncertain, and often will be far from the truth.

Table 13 | Balance of benefits and harms

When there was evidence to determine the balance of medical benefits and harms of an intervention to a patient, conclusions were categorized as follows:

K For statistically significant benefit or harm, report as 'benefit [or harm] of drug X.' The recommendation can be evaluated as a candidate for developing a policy or a performance measure.

Level 2 'We suggest'

*The additional category 'Not Graded' was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Table 15 | Determinants of strength of recommendation

Factor Comment

Balance between desirable and undesirable effects

The larger the difference between the desirable and undesirable effects, the more likely a strong recommendation is warranted. The narrower the gradient, the more likely a weak recommendation is warranted.

Quality of the evidence

The higher the quality of evidence, the more likely a strong recommendation is warranted.

Values and preferences

The more variability in values and preferences, or the more uncertainty in values and preferences, the more likely a weak recommendation is warranted. Values and preferences were obtained from the literature where possible or were assessed in the judgment of the Work Group where robust evidence was not identified. Costs (resource allocation)

The higher the costs of an intervention-that is, the more resources consumed-the less likely a strong recommendation is warranted. Abstract and Methods for Guideline Development.

2. Focus

Describe the primary disease/condition and intervention/ service/technology that the guideline addresses. Indicate any alternative preventative, diagnostic or therapeutic interventions that were considered during development.

Management of elevated levels of TC, LDL-C, or HDL-C or TGs and lipid-lowering agents in adults and children with CKD (non-dialysis-dependent or dialysis) or a kidney transplant.

3. Goal

Describe the goal that following the guideline is expected to achieve, including the rationale for development of a guideline on this topic.

This CPG is intended to assist the practitioner caring for patients with CKD and dyslipidemia and to prevent deaths, CVD events, and progression to kidney failure while optimizing patients' quality of life.

4. User/setting

Describe the intended users of the guideline (e.g., provider types, patients) and the settings in which the guideline is intended to be used.

Target audience is practicing nephrologists and other healthcare providers for adults and children with CKD and dyslipidemia.

5. Target population

Describe the patient population eligible for guideline recommendations and list any exclusion criteria.

Adults and children with CKD and dyslipidemia. Describe the criteria used to rate the quality of evidence that supports the recommendations and the system for describing the strength of the recommendations. Recommendation strength communicates the importance of adherence to a recommendation and is based on both the quality of the evidence and the magnitude of anticipated benefits and harms.

Quality of individual studies was graded in a three-tiered grading system (see Table 10 ). Quality of evidence and strength of recommendations were graded following the GRADE approach (Tables 12 and 14 ). The Work Group could provide general guidance in unngraded statements.

10. Method for synthesizing evidence

Describe how evidence was used to create recommendations, e.g., evidence tables, meta-analysis, decision analysis.

For systematic review topics, summary tables and evidence profiles were generated. For recommendations on treatment interventions, the steps outlined by GRADE were followed.

11. Prerelease review

Describe how the guideline developer reviewed and/or tested the guidelines prior to release.

The guideline had undergone internal review by the KDIGO Board in August 2012 and external public review in November 2012. Public review comments were compiled and fed back to the Work Group, which considered comments in its revision of the guideline. 12. Update plan State whether or not there is a plan to update the guideline and, if applicable, an expiration date for this version of the guideline.

o Yes No Yes Yes Yes Single Yes extraction Yes Yes No Yes Yes||

|6.|Articulation of Recommendations|| |---|---|---|

|6.1|Recommendations should be articulated in a standardized form detailing precisely what the recommended action is, and under what circumstances it should be performed.|Yes|

|6.2|Strong recommendations should be worded so that compliance with the recommendation(s) can be evaluated.|Yes|

|7.|External Review||

|7.1|External reviewers should comprise a full spectrum of relevant stakeholders, including scientific and clinical experts, organizations (e.g., health care, specialty societies), agencies (e.g., federal|Yes|

||government), patients, and representatives of the public.||

|7.2|The authorship of external reviews submitted by individuals and/or organizations should be kept confidential unless that protection has been waived by the reviewer(s).|Yes|

|7.3|The GDG should consider all external reviewer comments…|Yes|

||…and keep a written record of the rationale for modifying or not modifying a CPG in response to reviewers' comments.|Yes|

|7.4|A draft of Yes||

|8.|Updating||

|8.1|The CPG publication date, date of pertinent systematic evidence review, and proposed date for future CPG review should be documented in the CPG.|Yes; The requirement for an update will|

|||be assessed in five years from the publication date|

|||or earlier if important new evidence becomes|

|||available in the interim|

|8.2|||

|Outcome (Units)|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled)|Baseline GFR or SCr Proteinuria|Baseline Intervention (Control)|Results (Lipids) Final Intervention (Control) Intervention ∆ (Control)|Net ∆ (95% CI)|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Lipid levels|||||||||||||||

|∆Total cholesterol, mmol/L|van Vlsteren 2005 The Netherlands 1|3 mo (3 mo)|Exercise program|Control|53 (60)|43 (43)|CKD 5HD|nd|4.6 (4.7)|4.6 (4.6)|0 (-0.1)|0.1|NS|Good|

|Supplemental|||||||||||||||

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control|No. Analyzed (Enrolled) Intervention Control|GFR|DM (%)|Baseline TC|LDL mg/dL HDL Tg|Results RR/OR/HR Intervention Events No. (%) [Control] (95% CI) 1|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Mortality|||||||||||||||||

||||||||16||||||||||

|All-cause mortality|Cianciaruso 2009 Italy 2|4 y (3 y)|Low-protein diet|Moderate-protein diet|212 (212)|211 (211)|(17) mL/min/|11 (13)|nd|125 (124)|nd|nd|23 (11%) [25 (12%)]|HR 1.12 (0.64, 1.99)|nd|Fair|

||||||||1.73 m 2||||||||||

|ESRD|Cianciaruso 2009 Italy 2|4 y (3 y)|Low-protein diet|Moderate-protein diet|212 (212)|211 (211)|(17) mL/min/|11 (13)|nd|125 (124)|nd|nd|42 (20) [41 (19)]|HR 1.00 (0.65, 1.55)|nd|Fair|

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control|No. Analyzed (Enrolled) Intervention Control|Baseline GFR|DM (%)|Baseline Intervention (Control)|Results (Lipids) Final Intervention Intervention ∆ (Control) (Control)|Net ∆ (95% CI)|P value|Quality| |---|---|---|---|---|---|---|---|---|---|---|---|

|Lipid levels||||||||||||

|||6 mo|||206|198||||||

|||(3 y)|||(212)|(211)||||||

|∆LDL, mg/dL|Cianciaruso 2009 Italy 2||Low-protein diet|Low-protein diet|Low-protein diet|Low-protein diet|Moderate-protein diet|||16 (17) mL/min/ 1.73 m 2||

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled)|GFR or SCr|DM (%)|Baseline TC|LDL (mg/dL) HDL|Tg|Results Events No. (%) RR/OR/HR Intervention [Control] (95% CI)|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|CV events|||||||||||||||||

|Focal cerebellar infarctions|Nart 2009 Turkey 3|4 y (4 y)|Fluvastatin 40 mg|NCEP diet modified Step 1|90 (90)|53 (53)|GFR 71.3 (1.43) mg/dL (69.7) mL/min SCr 1.32|nd|231 (187)|135 (99)|63 (56)|170 (139)|2 (2%) [0 (0%)]|nd|nd|Fair|

|Supplemental|||||||||||||||||

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control|No. Analyzed (Enrolled) Intervention Control GFR or SCr Baseline|DM (%)|Baseline Intervention (Control)|Results (Lipids) Final Intervention (Control) Intervention ∆ (Control)|Net ∆ (95% CI)|P value|Quality||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|∆LDL, mg/dL||1 y (4 y) 4 y (4 y)|||||||135 (99.2)|115.6 (96.2) 123.4 (101.3)|-18.9 (-3.0) -11.1 (+2.1)|-15.9 -13.2|< 0.000 < 0.000|Fair Fair|

|∆HDL, mg/dL ∆Triglycerides,|Nart 2009 Turkey 3|1 y (4 y) 4 y (4 y) 1 y (4 y)|Fluvastatin 40 mg|NCEP modified Step 1 diet|90 (90)|53 (53)|GFR 71.3 (69.7) mL/min SCr 1.32 (1.43)|nd|63 (56) 170|53.2) (49.2) 48.9 (46.1) 169.7 (143.4)|-9.7 (-6.5) -14.0 (-9.6) -0.6 (+4.7)|-3.2 -4.4 -5.3|NS NS 0.035|Fair Fair Fair|

|mg/dL||4 y (4 y)|||||mg/dL||(139)|163.0 (145.3)|-7.3 (+6.6)|-0.7|NS|Fair|

|∆Total cholesterol, mg/dL||1 y (4 y) 4 y (4 y)|||||||231.2 (187.3)|202.7 (172.7) 206.0 (177.7)|-28.5 (-14.6) -25.2 (-9.6)|-13.9 -15.6|0.00 0.00|Fair Fair|

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled)|GFR or SCr|DM (%)|Baseline TC|Baseline TC|Baseline TC|Baseline TC|Baseline TC|Baseline TC|Baseline TC|Baseline TC|Baseline TC|Baseline TC|LDL (mg/dL) HDL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Composite outcome|Composite outcome||||||||||||||||

|ESRD or Halving of GFR ESRD or 25% decline in GFR|ALLHAT (CKD subgp) Rahman 2008 Multi 4|5 y (5 y)|Pravastatin 40 mg/d|Usual care|779 (779)|778 (778)|GFR 50.8 (50.6) mL/min/1.73 m 2|32 (30)|226 (224)|147 (145)|46 (46) 2|165 (164)|52 (7) [50 (6)] 156 (20) [154 (20] )|RR 0.97 (0.66, 1.43) RR 0.98 (0.79, 1.22)|nd nd|Good 3 Good 4|

|Kidney function|||||||||||||||||

|ESRD|ALLHAT (CKD subgp) Rahman 2008 Multi 4|5 y (5 y)|Pravastatin 40 mg/d|Usual care|779 (779)|778 (778)|GFR 50.8 (50.6) mL/min/1.73 m 2|nd|226 (224)|147 (145)|46 (46) 5|165 (164)|32 (4) [31 (4)]|RR 1.05 (0.64, 1.73)|nd|Good 6|

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled)|Baseline GFR or SCr|DM (%)|Baseline Intervention (Control)|Results (Lipids) Final Intervention Intervention ∆ (Control) (Control)|Net ∆ (95% CI)|P value Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|∆Total cholesterol, mg/dL ∆HDL, mg/dL|ALLHAT (CKD subgp) Rahman 2008 Multi 4|5 y (5 y)|Pravastatin 40 mg/d|Usual care|779 (779)|778 (778)|GFR 50.8 (50.6) mL/min/1.73 m 2|32 (30)|226 (224) 46 (46) 9|178 (198) 7 56 (38) 10|-48.2 (-26.1) +10 (-8)|-22.1 18|nd nd|Good 8 Good 11|

|Outcome Outcome CKD with DM Composite outcomes Author, Year Country Ref # Author, Year Country Ref # Coronary heart disease death, nonfatal MI, CABG, or PTCA (primary) All cause mortality CARDS (CKD subgp) Colhoun, 2009 UK Ireland 6 CV events CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi 5 Coronary heart disease death, nonfatal MI, CABG, PTCA, or stroke CABG or PTCA CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Any stroke Multi 5 Coronary heart disease death or nonfatal MI Mortality All-cause mortality CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi 5 Major CV disease CARDS (CKD subgp) Calhoun, Stroke Coronary heart disease 2009 UK Ireland 6 Coronary revascularizatio n|Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment) 4 y (4 y) 5 y (5 y) 5 y (5 y) 5 y (5 y) 4 y (4 y)|Description Intervention Control Intervention Control No. Analyzed (Enrolled) Description No. Analyzed (Enrolled) Intervention Control Intervention Control Atorvastatin Placebo 482 (482) 488 (488) Pravastatin Placebo 571 (571) Pravastatin Placebo 571 (571) Pravastatin Placebo 571 (571) Atorvastatin Placebo 482 (482) 488 (488)|GFR or SCr GFR or SCr eGFR 53.5 (54.1) mL/min/1. 73 m 2 eGFR 58 ml/min/1.73 m 2 SCr 1.3 mg/dL eGFR 58 ml/min/1.73 m 2 SCr 1.3 mg/dL eGFR 58 ml/min/1.73 m 2 SCr 1.3 mg/dL eGFR 53.5 (54.1) mL/min/1. 73 m 2|DM (%) DM (%) 100 (100) 100 (100) 100 (100) 100 (100) 100 (100)|Baseline TC Baseline TC 210 (212) 213 213 213 210 (212)|LDL LDL mg/dL HDL HDL mg/dL 120 (120) 56 (56) 140 36 140 36 140 36 120 (120) 56 (56)|Tg Tg ≤600 (≤60 0) 181 181 181 ≤600 (≤60 0)|Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) RR/OR/HR Intervention (95% CI) [Control] HR 0.75 12 (0.57, 0.98) 27 (6%) [30 (6%)] HR 0.86 16 (0.51, 1.45) nd HR 0.79 13 (0.62, 1.03) HR 0.69 17 (0.47, 1.01) nd HR 1.12 18 (0.63,1.97) HR 0.84 14 (0.60, 1.18) nd HR 0.98 15 (0.69, 1.39) 25 (5%) [42 (9%)] HR 0.57 19 (0.35, 0.94) 6 (1%) [15 (3%)] HR 0.38 20 (0.15, 0.99) 18 (4%) [27 (6%)] HR 0.65 21 (0.36, 1.17) 5 (1%) [12 (2%)] HR 0.40 22 (0.14, 1.15)|P value P value < 0.05 NS NS (0.06) NS (0.06) NS NS NS 0.02 0.04 NS NS (0.07)|Quality Quality Good Fair Fair Fair Fair Fair Fair Good Good Good Good| |---|---|---|---|---|---|---|---|---|---|---|

|Outcome Outcome Outcome Outcome Outcome|Author, Year Country Ref # Author, Year Country Ref # Author, Year Country Ref # Author, Year Country Ref # Author, Year Country Ref #|Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled) Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control|Description Intervention Control Intervention Control No. Analyzed (Enrolled) Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control|GFR or SCr GFR or SCr GFR or SCr GFR or SCr GFR or SCr|DM (%) DM (%) DM (%) DM (%) DM (%)|Baseline TC Baseline TC Baseline TC Baseline TC Baseline TC|LDL mg/dL HDL LDL HDL mg/dL LDL HDL mg/dL LDL HDL mg/dL LDL HDL mg/dL|Tg Tg Tg Tg Tg|Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) RR/OR/HR Intervention [Control] (95% CI)|P value P value P value P value P value|Quality Quality Quality Quality Quality||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Nonfatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularizatio n, or confirmed CV death (primary) MI, stroke, or confirmed CV death Nonfatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularizatio n, or confirmed CV death and all-cause mortality Nonfatal MI, nonfatal stroke, Coronary heart disease death, nonfatal MI, CABG, or PTCA (primary) Coronary heart disease death, nonfatal MI, CABG, PTCA, or stroke Coronary heart disease death or nonfatal MI First primary CV event including cardiac death, nonfatal MI, resuscitated cardiac arrest, cardiac revascularizatio n or unstable angina CV mortality and hospitalization for CV morbidity All-cause mortality All-cause mortality (primary) (primary) Cardiac death or MI All cause death or MI Unstable angina, fatal and nonfatal MI, and sudden death All-cause mortality Total mortality CV Mortality Mortality All-cause mortality All-cause mortality Death from CHD or nonfatal MI (primary) Total mortality All-cause mortality Noncardiac death Cardiac death|JUPITER Ridker 2010 Multi 7 CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi 5 ALLIANCE (CKD subgp) Koren 2009 US 8 PREVEND CARE, 4S (CKD IT Asselbergs 2004 Netherlands 9 LIPID, WOSCOPS (CKD subgp) subgp) Chonchol 2007 Scandinavia Tonelli 2005 n countries 12 LIPS (CKD subgp) Lemos 2005 Multi 10 Multi 5 ALLIANCE (CKD subgp) Koren 2009 MEGA (CKD subgp) Nakamura 2009 Japan 13 AFCAPS/Te xCAPS (CKD subgp) Kendrick 2010 US 11 JUPITER Ridker 2010 Multi 7 US 8 PREVEND IT Asselbergs 2005 Netherland 9 s CARE (CKD subgp) Tonelli 2003 US & Canada 14 LIPS (CKD subgp) Lemos 2005 Multi 10 LIPS (CKD subgp) Lemos 2005 Multi 10|2 y (2 y) Median 5 y (5 y) 5 y (5 y) 4 y (4 y) 5 y (5 y) 5 y (5 y) 4 y (4 y) 5 y (5 y) 5 y (5 y) 5 y (5 y) 2 y (2 y) 4 y (4 y) 5 y (5 y) 4 y (4 y) 4 y (4 y)|Rosuvastati n Pravastain Atorvastatin Pravastatin Pravastain Simvastatin Fluvastatin Atorvastatin Pravastatin + NCEP Step 1 Diet Lovastatin Rosuvastati n Pravastatin Pravastatin Fluvastatin Fluvastatin|Placebo Placebo Usual care Placebo Placebo Placebo Placebo Usual care NCEP Step 1 Diet Placebo Placebo Placebo Placebo Placebo Placebo|1638 (1638) (4099) 4099 286 (286) 433 (433) 4099 (4099) 1143 (1143) 150 (150) 286 (286) 1462 (1462) 145 (145) 1638 (1638) 433 (433) 844 (844) 150 (150) 150 (150)|1629 (1629) 293 (293) 431 (431) 1171 (1171) 160 (160) 293 (293) 1516 (1516) 159 (159) 1629 (1629) 431 (431) 867 (867) 160 (160) 160 (160)|eGFR 56 ml/min/1. 73 m 2 eGFR 56.5 ml/min/1. 73 m 2 SCr 1.3 mg/dL eGFR 51.3 (51.1) mL/min/1. 73 m 2 GFR 65.2 SCr 91 (90) µmol/L eGFR 56.5 ml/min/1. 73 m 2 (65.2) mL/min) 34 SCr 1.15 (1.14) SCr 1.3 mg/dL SCr 1.33 mg/dL CrCl < 47 mL/min GFR 53 mg/dL eGFR 51.3 (51.1) mL/min/1. GFR 52.6 (52.5) mL/min/m 2 (53) mL/min/1. 73 m 2 SCr 1.4 (1.4) mg/dL eGFR 56 ml/min/1. 73 m 2 73 m 2 SCr 91 (90) µmol/L CrCl 61.2 (61.3) mL/min 37 Scr 61.2 (61.3) µmol/L SCr 1.33 mg/dL CrCl < 47 mL/min SCr 1.33 mL/min mg/dL CrCl CrCl < 47|0 (0) 0 (0) 30 (26) 3 (2) 0 (0) 5 (4) Total 12 30 (26) Total 19 1 (2) 0 (0) 3 (2) 13 (15) Total 12 Total 12|189 224 228 (227) 5.8 (5.8) mmol/ L 224 261 (261) 200 228 (227) 6.3 mmol/ L 224 (220) 189 5.8 (5.8) mmol/ L 209 (209) 200 200|109 153 148 (146) 4.1 (4.0) mmol /L 153 189 (189) 131 148 (146) 4.0 mmol /L 151 (151) 109 4.1 (4.0) mmol /L 138 (139) 131 131|49 38 40 (40) 1.0 (1.0) mm ol/L 38 46 (46) 39 40 (40) 1.5 mm ol/L 39 (39) 49 1.0 (1.0) mm ol/L 41 (41) 39 39|130 161 200 (207) 1.4 (1.3) mmol 161 131 (134) /L 150 200 (207) 1.5 mmol /L 177 (168) 130 1.4 (1.3) mmol 149 (149) /L 150 150|40 (2%) [71 (4%)] 24 (2%) [40 (3%)] 64 (4%) [114 (7%)] nd 78 (27%) [105 (36%)] 22 (5%) [25 (6%)] nd Total 246 (11%) 7 (5%) [13 (8%)] 7 (5%) [13 (8%)] 47 (16%) 16 (1%) [34 (2%)] [59 (20%)] 5 (3.4%) 17 (7.5%) 34 (2%) [61 (4%)] 6 (1%) [4 (1%)] 89 (11%) [126 (15%)] 86 (10%) [111 (13%)] 3 (2%) [3 (2%)] 0 (0%) [0 (0%)] 3 (2%) [3 (2%)]|HR 0.55 (0.38, 0.82) HR 0.59 (0.36, 0.99) HR 0.55 (0.41, 0.75) HR 0.77 23 (0.68, 0.87) HR 0.80 24 (0.71, 0.90) HR 0.85 25 (0.73, 1.00) HR 0.72 (0.54, 0.97) HR 0.87 (0.49, 1.57) HR 0.97 29 (0.82, 1.15) HR 0.69 (0.54, 0.89) RR 0.57 (0.24, 1.40) RR 0.57 (0.24, 1.40) RR 0.82 (0.58, HR 0.49 (0.27, 0.89) 1.15) 30 RR 0.32 (0.10, 1.11) HR 0.56 (0.37, 0.85) RR 1.49 (0.42-5.25) 31 HR 0.72 38 (0.55, 0.95) HR 0.81 39 (0.61, 1.08) RR 1.07 (0.22, 5.20) --RR 1.07 (0.22, 5.20)|0.002 0.04 0.0001 < 0.05 < 0.05 0.05 0.02 NS NS nd NS NS NS 0.02 NS (0.06) 0.005 NS 0.02 NS NS nd NS|Good Good Good Fair Fair Fair Fair Fair Fair Good 35 Fair 26 Fair 27 Fair Fair 36 Good 28 Good Fair Good Good Fair 32 Fair 33 Fair|

|hospital stay requiring|||||||||||||||||

|for unstable hospitalization|||||||||||||||||

|angina, arterial revascularizatio n, or confirmed CV death and Nonfatal MI or cardiac death|||||||||||||69 (4%) [127 (8%)] 32 (11%) [54 (18%)]|HR 0.53 (0.40, 0.71) HR 0.55 (0.35, 0.85)|1 < 0.000 0.008|Good Fair|

|all-cause|||||||||||||||||

|mortality and|||||||||||||||||

|venous|||||||||||||||||

|thromboemboli|||||||||||||||||

|sm|||||||||||||||||

|Outcome Outcome Outcome Outcome|Author, Year Country Ref # Author, Year Country Ref # Author, Year Country Ref # Author, Year Country Ref #|Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment) Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled) Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control|Description Intervention Control Intervention Control No. Analyzed (Enrolled) Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control Description No. Analyzed (Enrolled) Intervention Control Intervention Control|GFR or SCr GFR or SCr GFR or SCr GFR or SCr|DM (%) DM (%) DM (%) DM (%)|Baseline TC Baseline TC Baseline TC Baseline TC|LDL mg/dL HDL LDL HDL mg/dL LDL HDL mg/dL LDL HDL mg/dL|Tg Tg Tg Tg|Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) Intervention [Control] RR/OR/HR (95% CI) Results Events No. (%) RR/OR/HR Intervention [Control] (95% CI)|P value P value P value P value|Quality Quality Quality Quality||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Major coronary event in subgroup with CrCl 60-75 mL/min Major coronary event in subgroup with CrCl 50-75 mL/min Major coronary event in subgroup with CrCl ≤60 mL/min Major coronary event in subgroup with CrCl ≤50 mL/min CABG or PTCA Any stroke Nonfatal MI eGFR ≤60 ml/min/1.73m 2 in patients with Non-fatal MI mild CKD Coronary revascularizatio n ↓≥25% CG-eGFR in patients with mild CKD Stroke Cardiac death CV events ↓eGFR ≥25% Fatal and non fatal CV events Fatal and non fatal MI Major coronary events eGFR in patients with mild CKD failure in patients with Acute renal ↓≥25% MDRD-Doubling of SCr Stroke Kidney function ↓GFR≥25%|CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi 5 2007 Scandinavia n countries 12 ALLIANCE (CKD subgp) Koren 2009 US 8 PREVEND IT Asselbergs 2005 Netherlands AFCAPS/Te xCAPS (CKD subgp) 9 Kendrick AFCAPS/Te xCAPS (CKD subgp) Kendrick 2010 US 11 4S (CKD subgp) Chonchol LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi 15 CARE, JUPITER Ridker 2010 Multi 7 n countries 16 MEGA (CKD subgp) Nakamura 2009 Japan 13 2010 US 11 4S (CKD subgp) Huskey 2009 Scandinavia|5 y (5 y) 5 y (5 y) 4 y (4 y) 5 y (5 y) 5 y (5 y) 5 y (5 y) 5 y (5 y) Median 2 y (2 y) 5 y (5 y) 6 y (6 y)|Pravastain Atorvastatin Pravastatin Lovastatin Lovastatin Simvastatin Pravastain Rosuvastati n Pravastatin + NCEP Step 1 Diet Simvastatin|Placebo Usual care Placebo Placebo Placebo Placebo Placebo Placebo NCEP Step 1 Diet Placebo|524 (524) 719 (719) 320 (320) 125 (125) 286 (286) < 6479 (4099) 4099 ( < 6479) 433 (433) 145 (145) 145 (145) 1143 (1143) (6479) 6479 1638 (1638) 1462 (1462) 199 (199)|518 (518) 736 (736) 349 (349) 131 (131) 293 (293) < 6364 ( < 6364) 431 (431) 159 (159) 159 (159) 1171 (1171) (6364) 6364 1629 (1629) 1516 (1516) 210 (210)|CrCl 60-75 mL/min CrCl 50-75 mL/min CrCl ≤60 mL/min CrCl ≤50 mL/min eGFR 56.5 ml/min/1. 73 m 2 SCr 1.3 mg/dL SCr 1.15 (1.14) mg/dL nd eGFR 51.3 (51.1) mL/min/1. 73 m 2 GFR 53 SCr 91 (90) µmol/L (53) mL/min/1. 73 m 2 SCr 1.4 (1.4) GFR 53 (53) mL/min/1. 73 m 2 SCr 1.4 (1.4) mg/dL (65.2) mL/min) 55 SCr 1.08 (1.08) mg/dL m 2 mL/min/1.73 eGFR 73.8 (73.8) GFR 65.2 eGFR 56 ml/min/1. 73 m 2 mg/dL GFR 52.6 (52.5) mL/min/m 2 GFR 55 (55) mL/min/1. 73 m 261|0 (0) 6 (6) 30 (26) 3 (2) 1 (2) 1 (2) 5 (4) (6) 6 0 (0) Total 19 4 (1)|224 nd 228 (227) 5.8 (5.8) mmol /L 224 (220) 224 (220) 261 (261) (236) 236 189 6.3 mm ol/L 265 (265 )|153 nd 148 (146) 4.1 (4.0) mmol/ L 151 (151) 151 (151) 189 (189) (163) 163 109 4.0 mmol/L 192 (191)|38 nd 40 (40) 1.0 (1.0) mm ol/L 39 (39) 39 (39) 46 (46) (40) 40 49 1.5 mm ol/L 47 (48)|161 nd 200 (207) 1.4 (1.3) mmol /L 177 (168) 177 (168) 131 (134) (158) 160 130 1.5 mmol /L 133 (134)|103 (20%) [143 (28%)] 140 (20%) [207 (28%)] 68 (21%) [91 (26%)] 31 (25%) [27 (21%)] nd nd nd (27%) [nd [29%)] 17 (6%) [29 (10%)] nd nd (9%) [nd (10%)] 11 (4%) [12 (4%)] 18 (4%) [21 (5%)] 4% [3%] 17 (6%) [27 (9%)] 8 (6%) [21 (13%)] 2 (1%) [6 (4%)] Total (24%) nd (0.2%) [nd [0.5%)] nd (10%) [nd (11%)] [0 (0%)] 3 (0.2%) 8 (1%) [29 (2%)] 5 (3%) [13 (6%)]|Unadjusted absolute reduction in cumulative incidence 7.9 Unadjusted absolute reduction in cumulative incidence 8.6 Unadjusted absolute reduction in cumulative incidence 4.8 --HR 0.72 48 (0.61, 0.86) HR 0.96 49 (0.71, 1.30) HR 0.65 (0.55, 0.78) RR 0.95 (0.90, 1.00) HR 0.54 (0.30, 0.99) HR 0.62 (0.49, 0.77) RR 0.88 (0.78, 0.91) RR 0.94 (0.42, 2.09) 50 RR 0.65 nd nd (0.36,1.16) 51 RR 0.39 (0.16, 0.93) RR 0.10 (0.01, 1.32) HR 0.67 (0.56, 0.79) (0.22, 0.78) RR 0.42 (0.85, 1.03) RR 0.94 nd HR 0.27 (0.12, 0.59) OR 0.21 (0.05, 0.94)|nd nd nd nd < 0.05 NS nd NS (0.06) NS nd 0.03 NS nd NS NS 0.03 52 NS (0.08) nd 0.006 NS nd 0.01 0.04|Good Good Good Good Fair Good 57 Fair Fair Good 58 Fair Fair Fair Fair Good 60 Fair Good 53 Fair Fair Good 56 Good Good 54 Fair 59 Good 62|

|mild CKD|||||||||||||||||

|Outcome (Units)|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention No. Analyzed (Enrolled) Control|Baseline GFR or SCr DM (%)|Baseline Intervention (Control)|Results (Lipids) Final Intervention (Control) Intervention ∆ (Control)|Net ∆ (95% CI)|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|∆Total cholesterol, mg/dL|AFCAPS/Tex||||||GFR 53 (53)||224 (220)|nd|-20% (+1.5%)|-18.5%|nd|Good 68|

|∆HDL, mg/dL ∆LDL, mg/dL|CAPS (CKD subgp) Kendrick 2010 US 11|5 y (5 y)|Lovastatin|Placebo|145 (145)|159 (159)|mL/min/ 1.73 m 2 SCr 1.4 (1.4)|1 (2)|39 (39) 151 (151)|nd nd|+7.4% (+1.1%) -27% (+1.9%)|+6.3% -25.1%|nd nd|Good 69 Good 70|

|∆Triglycerides, mg/dL|||||||mg/dL||177 (168)|nd|-15% (+4.2%)|-10.8%|nd|Good 71|

|∆Total cholesterol, mg/dL ∆HDL, mg/dL ∆LDL, mg/dL ∆Triglycerides, mg/dL|4S (CKD subgp) Chonchol 2007 Scandinavian countries 12|5 y (5 y)|Simvastatin|Placebo|1143 (1143)|1171 (1171)|GFR 65.2 (65.2) mL/min) 72 SCr 1.15 (1.14) mg/dL|5 (4)|261 (261) 46 (46) 189 (189) 131 (134)|233 (261) 52 (43) 151 (186) 115 (136)|-28% (0%) +6% (-3%) -38% (+2%) -16% (+2%)|-28% +3% -36% -14%|nd nd nd nd|Good 73 Good 74 Good 75 Good 76|

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled)|GFR or SCr|DM (%)|Baseline TC|LDL mg/dL|HDL|Tg|Results Events No. (%) RR/OR/HR Intervention [Control] (95% CI)|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Dialysis with DM||||||||||||||||||

|Composite outcomes|Composite outcomes|||||||||||||||||

|Composite of||||||||||||||||||

|cardiac death, nonfatal MI, or stroke|4D Wanner 2005 Germany 18|4 y (2 y)||619 (619)|636 (636)|||218 (220)|125 (127)|36 (36)|261 (267)|226 (37%) [243 (38%)]|RR 0.92 (0.77, 1.10)|NS|Good|||

|(primary)||||||||||||||||||

|cardiac death,||||||||||||||||||

|nonfatal MI, or stroke for CRP||||316 (316)||||||126|||60 [50]|HR 1.19 (0.81,1.76)|NS|Fair||

|quartile 1 (≤2.3||||||||||||||||||

|mg/L)||||||||||||||||||

|nonfatal MI, or stroke for CRP||||310 (310)||||||128|||50 [56]|HR 0.75 (0.50, 1.10)|NS|Fair||

|quartile 2||||||||||||||||||

|( > 2.3-≤5 mg/L) Composite of|||Atorvastatin|Placebo||CKD 5HD|100 (100)|||||||||||

|cardiac death, nonfatal MI, or stroke for CRP|4D Krane 2008 Germany 19|4 y (2 y)||312 (312)||||nd||126||nd|nd|52 [78]|HR 0.79 (0.55, 1.13)|NS|Fair|

glyceride s, mg/dL|||||||||167 (188)|135 (171)|-32 (-17)|-16|||

|Outcome|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control No. Analyzed (Enrolled)|GFR or SCr (units)|DM (%)|Baseline TC LDL (mmol/L) HDL|Tg|Results Events No. (%) Intervention [Control]|RR/OR/HR (95% CI)|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Death from any cancer|||||||||||||150 (3%) [128 (3%)]|RR 1.17 (0.92, 1.48)|nd|Good|

|Death from renal causes|||||||||||||164 (4%) [173 (4%)]|RR 0.95 (0.76, 1.17)|nd|Good|

|Death from respiratory causes|||||||||||||124 (3%) [100 (2%)]|RR 1.24 (0.95,1.61)|nd|Good|

|Death from GI causes|||||||||||||72 (2%) [70 (2%)]|RR 1.03 (0.74, 1.42)|nd|Good|

|Death from|||||||||||||||||

|other medical causes Death from trauma or fracture|SHARP 2011 Multi 24|5 y (4 y)|Simvastatin 20 mg/d + ezetimibe 10 mg/d|Placebo|4650 (4650)|4620 (4620)|GFR 27 (27) mL/min/ 1.73 m 2|23 (23)|4.88 (4.90)|2.77 (2.78)|1.12 (1.11)|2.31 (2.34)|124 (3%) [119 (3%)] 34 (1%) [22 (1%)]|RR 1.04 (0.81, 1.34) RR 1.53 (0.91, 2.59)|nd nd|Good Good|

|Any nonvascular death|||||||||||||668 (14%) [612 (13%)]|RR 1.09 (0.98, 1.21)|NS|Good|

|Sudden death|||||||||||||50 (1%) [55 (1%)]|RR 0.91 (0.62, 1.33)|nd|Good|

|Death for reasons unclear|||||||||||||63 (1%) [60 (1%)]|RR 1.05 (0.74, 1.49)|nd|Good|

|Death from unknown causes|||||||||||||113 (2%) [115 (3%)]|RR 0.98 (0.76, 1.27)|NS|Good|

|CV mortality|||||||||||||||||

|CHD death|SHARP 2011 Multi 24|5 y (4 y)|Simvastatin 20 mg/d +|Placebo|4650 (4650)|4620 (4620)|GFR 27 (27)|23 (23)|4.88 (4.90)|2.77 (2.78)|1.12 (1.11)|2.31 (2.34)|91 (2%) [90 (2%)]|RR 1.01 (0.75, 1.35)|NS|Good|

|Outcome|Author, Year Country Ref #|Duration Outcome measure-ment (Treatment)|Description Intervention Control|No. Analyzed (Enrolled) Intervention Control|eGFR|DM (%)|Baseline TC|LDL mg/dL|HDL|Tg|Results* Events No. (%) RR/HR 92 Intervention [Control] (95% CI)|P value 91|Quality|||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|All-cause mortality|TNT Shepherd 2008 Multi 25 TNT Shepherd 2008 Multi 26|Median 5 y (5 y)|80-mg Atorvastatin|10-mg Atorvastatin|273 (273) 1602 (1602)|273 (273) 1505 (1505)|51.5 (50.7) mL/min/ 1.73 m 2 53.0 (52.8) mL/min/ 1.73 m 2|100 (100) 17 (18)|176.1 (178.0) 175.9 (175.9)|95.5 (97.0) 96.3 (96.5)|44.9 (45.2) 48.0 (47.6)|181.6 (180.2) 159.2 (159.8)|33 (12%) [32 (12%)] 112 (7%) [113 (8%)]|RR 1.03 (0.65, 1.63) HR 0.95 1.2) 93 (0.70,|NS NS|Good Good|

|Major CV|||||||||||||||||

|event|||||||||||||||||

|(primary) 94|||||||||||||||||

|Reference #| |---|

|Study Year Country Ref #|Population|Duration Outcome measurement (Treatment)|Description Intervention Control|Description Intervention Control|Description Intervention Control|Description Intervention Control|Description Intervention Control|No analyzed (Enrolled) Intervention Control|Baseline GFR or SCr|% with DM|Definition|Results No. (%) Intervention [Control]| |---|---|---|---|---|---|---|---|---|---|---|---|---|

|||||Atorvastatin,|||||||||

|Yang 2009 New Zealand 53 [Post hoc analysis of 3 RCTs]|Adults with mixed dyslipidemia|Median 12 wk (Median 12 wk)|Fenofibric + low dose atorvastatin, rosuvastatin, or simvastatin|rosuvastatin, or simvastatin Fenofibric acid|1895 (1911)|nd|19-26|CK 5x or 10xULN|0-2% [0-2%] 0-2% [0%]|----|nd nd||

|Wiklund 1993 Sweden & Finland 46|Adults with hypercholest erolemia|12 wk (12 wk)|Pravastatin + gemfibrozil|Placebo Pravastatin Gemfibrozil|75 (75)|73 (73) 70 (70) 72 (72)|nd|nd|CK increased to 4x baseline at least once|4 (5%) [1 (1%)] 4 (5%) [1 (1%)] 4 (5%) [2 (3%)]|3.89 (0.45, 34.01) 3.73 (0.43, 32.60) 1.92 (0.36, 10.16)|nd nd nd|

||||5 mg rosuvastatin + fenofibric acid||118 (118)|||22 (16)||0 (0%) [0 (0%)]|--|nd|

||||10mg rosuvastatin + fenofibric acid|Simvastatin|119 (119)|119 (119)||19 (16)|CK > 5x ULN|0 (0%) [0 (0%)]|--|nd|

|Roth 2010 US 47|Adults with hypercholest erolemia and hypertriglyce ridemia|12 wk (8 wk)|20 mg rosuvastatin + fenofibric acid 5 mg rosuvastatin + fenofibric acid||118 (118) 118 (118)||nd|23 (16) 22 (16)||2 (2%) [0 (0%)] 0 (0%) [0 (0%)]|----|nd nd|

||||10mg rosuvastatin + fenofibric acid||119 (119)|119 (119)||19 (16)|CK > 10x ULN|0 (0%) [0 (0%)]|--|nd|

||||20 mg rosuvastatin + fenofibric acid||118 (118)|||23 (16)||1 (1%) [0 (0%)]|--|nd|

|DM|TC|LDL|HDL|Tg|Events No. (%)|RR/OR/HR| |---|---|---|---|---|---|---|

|(%)||(mmol/L)|||Intervention [Control]|(95% CI)|

Supplemental

Acknowledgments

TABLES Secondary causes of dyslipidemias

Examples of situations in which measuring cholesterol level might or might not change the management implied by Recommendation 1.2

Rate of coronary death or non-fatal MI (by age and eGFR)

Recommended doses of statins in adults with CKD

Plasma lipid concentrations for children and adolescents

Work products for the guideline

Classification of study quality

GRADE system for grading quality of evidence

Final grade for overall quality of evidence

Balance of benefits and harms

KDIGO nomenclature and description for grading recommendations

Determinants of strength of recommendation

The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines

Secondary causes of dyslipidemias

Rate of coronary death or non-fatal MI (by age and eGFR)Rate (95% CI) of coronary death or non-fatal MI (per 1000 patient-years)

Recommended doses (mg/d) of statins in adults with CKD

Plasma lipid concentrations for children and adolescents 7 Values given are in mmol/l (mg/dl). Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children. Non-HDL-C values from the Bogalusa Heart Study are equivalent to the NCEP Pediatric Panel cut points for LDL-C.

Systematic review topics and screening criteria Lipid-lowering agents Population Adults and children with CKD of any severity, with or without dyslipidemia and diabetes; kidney transplant recipients; CKD subgroups in large studies of the general population Intervention Z1 lipid-lowering agent (typically statin, niacin, colestipol, or cholestyramine). Excluded dietary supplements, phosphate binders, apheresis, stanols, and sterols. Z25 per arm for children; if general population study, Z500 per arm for adults or Z100 per arm for children in full study Diet or lifestyle modification Population Adults and children with CKD of any severity, with or without dyslipidemia and diabetes; kidney transplant recipients; CKD subgroups in large studies of the general population Intervention Weight loss, special diet, or exercise; also structured care vs. usual care Comparator Different diet or lifestyle modification or agent or placebo Outcome Categorical: All-cause mortality, cardiovascular mortality, clinical cardiovascular events, ESRD, graft failure, doubling of SCr, halving of GFR Continuous: changes in TC, LDL-C, or HDL-C or TGs Design RCTs with parallel-group design; systematic reviews, CKD-subgroup analyses of general population RCTs if no evidence of selection bias and of sufficient size Minimum duration of follow-up 4 weeks for continuous lipid outcomes; 1 year for clinical outcomes; if general population study, 1 year Minimum N of subjects Z25 per arm

Searches and Article SelectionSystematic search strategies were developed by the ERT with input from the Work Group Co-Chairs. Modules were created for RCTs, kidney disease, dyslipidemia, and lipidlowering agents. For the primary search, search terms were limited to the year 2000 and later to capture trials that would affect current clinical practice and because the KDOQI dyslipidemia guideline covered through 2000. Five new topics were added to the KDOQI systematic review for studies in the general population: effect of diet or lifestyle modification; an update of drug interactions with statins and fibrates; changes in LDL-C levels associated with various statins; adverse events from statin and fibrate use; and frequency of lipid-level testing. These searches were not restricted to 2000 and later. The text words or medical subject headings (MeSH) that were included are provided in the Supplemental Appendix 1. In addition, the ERT searched for existing relevant systematic reviews. The final searches were conducted in August 2011. The ERT searched MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The ERT also relied on Work Group members to identify large, general population RCTs reporting on CKD subgroups. The search yield was also supplemented by articles provided by Work Group members through June 2013.

Hierarchy of outcomes

Literature yield for RCTs*

Work products for the guideline*

Classification of study quality Good quality Low risk of bias and no obvious reporting errors; complete reporting of data. Must be prospective. If study of intervention, must be RCT. Fair quality Moderate risk of bias, but problems with study or paper are unlikely to cause major bias. If study of intervention, must be prospective. Poor quality High risk of bias or cannot rule out possible significant biases. Poor methods, incomplete data, reporting errors. Prospective or retrospective.

For questions of interventions, the initial quality grade was 'High' if the body of evidence consisted of RCTs, 'Low' if it consisted of observational studies, and 'Very Low' if it consisted of studies of other study designs. For questions of interventions, the Work Group decided to use only RCTs. The grade for the quality of evidence for each intervention-outcome pair was then lowered if there were serious limitations to the methodological quality of the aggregate of studies, if there were important inconsistencies in the results across studies, if there was uncertainty about the directness of evidence including limited applicability of the findings to the population of interest, if the data were imprecise (a low event rate [0 or 1 event] in either arm or a CI spanning a range 41) or sparse (only 1 study o r total N o500), or if there was thought to be a high likelihood of bias. Once consensus is reached in a group meeting, the final grade for the quality of the evidence for an intervention-outcome pair could be one of the following four grades: 'High', 'Moderate' , 'Low' or 'Very Low' (Table

112 Conference on Guideline Standardization (COGS)112checklist for reporting clinical practice guidelines

Continued

Ashish Upadhyay, MD, is Assistant Professor, Renal Section and Associate Director, Internal Medicine Residency Program at Boston University School of Medicine, Boston, MA, USA. Dr Upadhyay was previously Assistant Professor at Tufts University School of Medicine and staff physician in the William B Schwartz, MD, Division of Nephrology at Tufts Medical Center. He joined the ERT in July 2009 and served as the Assistant Project Director for the KDIGO Management of Blood Pressure in CKD and Anemia in CKD Guidelines. In the role as lead project director for this guideline, Dr Upadhyay coordinated and assisted in the collection, evaluation, grading, and synthesis of evidence, and played a critical role in the revisions of the final evidence report. He also provided methodological guidance and training of Work Group members on topic refinement, key question formulation, data extraction, study assessment, evidence grading, and recommendation formulation. Dr Upadhyay's past research involved studying kidney disease epidemiology in the Framingham Heart Study. He has published in areas ranging from arterial stiffness in CKD and inflammation in kidney disease to dialysis complications and epidemiology of hyponatremia. Dr Upadhyay reported no relevant financial relationships Ethan M Balk, MD, MPH, is Director, Evidence-based Medicine at the Tufts Center for Kidney Disease Guideline Development and Implementation, in Boston, MA, USA, Associate Director of the Tufts Evidence-based Practice Center, and Associate Professor of Medicine at Tufts University School of Medicine. Dr Balk graduated from Tufts University School of Medicine and completed a fellowship in Clinical Care Research. As Program Director for this guideline, he played a role in providing methodological expertise in the guideline development process and assisted in the collection, evaluation, grading, and synthesis of evidence and the revisions of the final evidence report. Dr Balk also provided methodological guidance and training of Work Group members regarding topic refinement, key question formulation, data extraction, study assessment, evidence grading, and recommendation formulation. His primary research interests are evidence-based medicine, systematic review, clinical practice guideline development, and critical literature appraisal.

Describe and justify any planned analyses of differential treatment effects according to patient subgroups, how an intervention is delivered, or how an outcome is measured At a minimum, use two or more researchers, working independently, to extract quantitative and other critical data from each study. For other types of data, one individual could extract the data while the second individual independently checks for accuracy and completeness. Establish a fair procedure for resolving discrepancies-do not simply give final decision-making power to the senior reviewer All COI of each GDG member should be reported and discussed by the prospective development group prior to the onset of his or her work. Members of the GDG should divest themselves of financial investments they or their family members have in, and not participate in marketing activities or advisory boards of, entities whose interests could be affected by CPG recommendations.

the CPG at the external review stage or immediately following it (i.e., prior to the final draft) should be made available to the general public for comment. Reasonable notice of impending publication should be provided to interested public stakeholders.

Results are for adjusted analysis if provided. If unadjusted results are different please annotate.

Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB

40Study graded "Fair" due to unbalance in baseline characteristics. No info on treatment vs. placebo among the 310 renal impairment patients. Consider downgrading further in EP due to being unable to locate interaction results.

SUPPLEMENTARY MATERIAL

Supplemental Table 1 64 Estimated from figure 65 Estimated from figure 66 Results of ∆ in total cholesterol from baseline to 3 months, 1 year, 2 years and 3 years was also statistically significant. 67 nes 2010 US 49 Adults with mixed dyslipidemia 16 These data are exploratory and merely show that it is easier to detect a significant reduction in some subgroups than in others. However, the overlapping 95% confidence intervals and negative interaction analysis indicate that there is no significance when individual subgroups (e.g. men and women) are compared with one another. The failure to achieve statistical significance in some subgroups is likely to reflect the low number of events and the low overall power of the study.

References

|quartile 3 ( > 5-||||||||||||||||||

|≤12.4 mg/L)||||||||||||||||||

|nonfatal MI, or stroke for CRP||||311 (311)||||||122|||62 [57]|HR 1.06 (0.73, 1.54)|NS|Fair||

|quartile 4||||||||||||||||||

|( > 12.4 mg/L)||||||||||||||||||

|Primary||||||||||||||||||

|outcome in 2 nd and 3 rd CRP quartiles||||622 (622)||||||nd|||nd|HR 0.85 (0.65, 1.10)|NS|Fair||

|combined||||||||||||||||||

|Outcome (Units)|Author, Year Country Ref #|Duration Outcome measurement (Treatment)|Description Intervention Control Intervention Control GFR or SCr No. Analyzed (Enrolled) Baseline|DM (%)|Baseline Intervention (Control)|Results (Lipids) Final Intervention (Control) Intervention ∆ (Control)|Net ∆ (95% CI)|P value|Quality|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Dialysis with DM|||||||||||||||

|∆LDL, mg/dL|4D Wanner 2005 Germany 18|4 wk (2 y) 5 y (2 y)|Atorvastatin|Placebo|619 (619) 44 (619)|636 (636) 37 (636)|CKD 5HD|100 (100)|125 (127)|72 (120) 70 79 (92)|-53 (-7) -55 (-35)|-46 -20|nd nd|Fair Fair|

|∆LDL, mmo/L ∆Total cholesterol, mmol/L|AURORA Holdaas subgp with DM 2011 21 Multi|3 mo (2 y)|Rosuvastatin|Placebo|388 (388|343 (343)|CKD 5HD|100|2.51 (2.43) 4.49 (4.35)|1.41 (2.43) 3.29 (nd)|-1.1 (0) -1.2 (nd)|-1.1 nd|nd nd|Good Fair|

|Dialysis without DM|||||||||||||||

|∆LDL, mg/dL|||||||||100 (99)|58 (97.1)|-42 (-1.9)|-43.9|< 0.001|Good|

|∆Total cholesterol, mg/dL ∆Triglycerides, mg/dL|AURORA Fellstrom 2009 Multi 20|Median 4y (2 y)|Rosuvastatin|Placebo|1389 (1391)|1384 (1385)|CKD 5HD|21 (18)|176 (174) 157 (154)|129 (173) 131 (155.8)|-47 (-1) -26 (+1.8)|-48 -24.2|< 0.001 < 0.001|Good Good|

|∆HDL, mg/dL|||||||||45 (45)|46.2 (44.6)|+1.2 (+0.4)|1.6|0.045|Good|

|∆LDL, mg/dL|||||||||147 (145)|98 (135) 80|-48.5 (-9.5)|-39|nd|Good 81|

|∆Triglycerides,|||||||||165|129|||||

|mg/dL|||||||||(164)|(165) 82|||||

|None (0)|Moderate|Possible benefit from statins for patients with DM|Critical| |---|---|---|---|

t from statins for patients with DM|Critical| |---|---|---|---|

||Author,|Duration|Description|No. Analyzed (Enrolled)|||Baseline||||Results|||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Outcome|Year Country Ref #|Outcome measurement (Treatment)|Intervention|Control|Intervention Control|GFR or SCr|DM (%)|TC|LDL (mg/dL) HDL|Tg|Events No. (%) Intervention [Control]|RR/OR/HR (95% CI)|P value|Qualit y|||

|Death|UK-HARP II Landray 2006 UK 23|6 mo (6 mo)|Simvastatin 20 mg/d Ezetimibe 10mg/d|Simvastatin 20 mg/d|102 (102)|101 (101)|GFR 26.1 (29.7) mL/min/1.73 m 2|12 (10)|198 (195)|121 (117)|40 (40)|167 (188)|3 (2%) [0 (0%)]|nd|nd|Good|

|ESRD|UK-HARP II Landray 2006 UK 23|6 mo (6 mo)|Simvastatin 20 mg/d Ezetimibe 10mg/d|Simvastatin 20 mg/d|102 (102)|101 (101)|GFR 26.1 (29.7) mL/min/1.73 m 2|12 (10)|198 (195)|121 (117)|40 (40)|167 (188)|14 (14%) [14 (14%)]|RR 0.99 1.97) 84 (0.50,|NS|Good|

||Author,|Duration|Description|No. Analyzed (Enrolled)|Baseline|||Results (Lipids)||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

|Outcome|Year Country Ref #|Outcome measurement (Treatment)|Intervention|Control|Intervention Control|GFR or SCr|DM (%)|Baseline Intervention (Control)|Final Intervention (Control)|∆ Intervention (Control)|Net ∆ (95% CI)|P value Quality|||

|∆Total cholesterol, mg/dL|||||||||198 (195)|139 (158)|-59 (-37)|-22 85|< 0.001|Good|

|∆LDL, mg/dL ∆HDL, mg/dL|UK-HARP II Landray 2006 UK 23|6 mo (6 mo)|Simvastatin 20 mg/d Ezetimibe 10mg/d|Simvastatin 20 mg/d|102 (102)|101 (101)|GFR 26.1 (29.7) mL/min/1.73 m 2|12 (10)|121 (117) 40 (40)|72 (86) 40 (39)|-49 (-31) 0 (-1)|-18 86 1 87|< 0.001 NS|Good Good|

|∆Triglyceride s, mg/dL|||||||||167 (188)|135 (171)|-32 (-17)|-16|||

|Composite outcomes|||||||||||||||||

||||Simvastatin||||GFR 27||||||||||

|ESRD or death|SHARP 2011 Multi 24|5 y (4 y)|20 mg/d + ezetimibe 10|Placebo|4650 (4650)|4620 (4620)|(27) mL/min/|23 (23)|4.88 (4.90)|2.77 (2.78)|1.12 (1.11)|2.31 (2.34)|1477 (47%) [1513 (48%)]|RR 0.97 (0.90, 1.04)|NS|Good|

||||mg/d||||1.73 m 2||||||||||

|All-cause mortality|||||||||||||1142 (25%) [1115 (24%)]|RR 1.02 (0.94, 1.11)|NS|Good|

引用 / 出处

2013 KDIGO慢性肾病血脂管理临床实践指南. 2013.