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 ) The Diabetes Atherosclerosis Intervention Study (DAIS)92 and the FIELD study93 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 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 chapter 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 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-albumin- 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 0.002). Importantly, only 5% (519 of 9795) of the randomized participants had a baseline , so only 117 cardiovascular events occurred in this subgroup. The significant treatment effects presented for those with eGFR below 60 ml/min/ (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 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 (1.19 vs. per year; But the inaccuracy of eGFR above 60 ml/min/ 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 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 Again, 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/ . Ultimately too few participants with eGFR o60 ml/ 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. Suggested Audit Criteria Given the lack of evidence to support this recommendation, no audit criteria are suggested. KEY POINTS 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. RESEARCH RECOMMENDATIONS 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-in- duced 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. 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 contri- butor, copyright holder, or advertiser concerned. Accord- ingly, 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. Chapter 6: Triglyceride-lowering treatment in children 6.1: In children with CKD (including those treated with chronic dialysis or kidney transplantation) and hyper- triglyceridemia, we suggest that therapeutic lifestyle changes be advised. (2D) RATIONALE Non-pharmacological treatment of high triglycerides TLC includes dietary modification, weight reduction, increased physical activity, reducing alcohol intake, and treatment of hyperglycemia (if present). As for adults, the evidence that TLC will reduce serum TG levels and/or improve clinical outcomes is weak. Nonetheless, in the opi- nion of the Work Group, it is reasonable to advise children with high fasting levels of serum TGs (45.65 mmol/l [4500 mg/dl]) to adopt TLC based on similar considerations as mentioned in Guideline 5.1. Dietary changes that may reduce serum TGs include a very low-fat diet (o15% total calories), medium-chain TGs, and fish oils to replace some long-chain TGs. Dietary modification should be used judi- ciously, if at all, in children who are malnourished. Input from a social worker may be helpful if there are concerns that the patient or his/her parents are unable to safely implement TLC. Pharmacological treatment of high triglycerides: effects on risk of pancreatitis 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 The safety and efficacy of lowering TGs with fibrates and niacin have not been established in adolescents; studies have been of extremely short duration and with very small sample sizes.100 102 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 but the longer-term benefits, harms, and tolerability of such treatment is unclear. Therefore, pharmacological treatment of hypertriglycer- idemia 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 apolipo- protein C-II deficiency. Suggested Audit Criteria 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. KEY POINTS 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. RESEARCH RECOMMENDATIONS 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. 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. chapter 6 http://www.kidney-international.org & 2013 KDIGO Methods for guideline development AIM The overall aim of this project was to develop an evidence- based CPG for the management of dyslipidemia and CKD. The guideline consists of recommendation statements, ratio- nales, and a summary of systematically generated evidence on relevant pre-defined clinical topics. The general guideline development method is described at http://www.kdigo.org/ home/guidelines/development as well as below. OVERVIEW OF PROCESS The development process for the KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease included the following steps: K Appointing Work Group members and the evidence review team (ERT) K Discussing process, methods, and results K Developing and refining topics K Identifying populations, interventions or predictors, and outcomes of interest K Selecting topics for systematic evidence review K Standardizing quality assessment methodology K Developing and implementing literature search strategies K Screening abstracts and retrieving full-text articles on the basis of pre-defined eligibility criteria K Creating data extraction forms K Extracting data and performing critical appraisal of the literature K Grading the methodology and outcomes in individual studies K Tabulating data from individual studies into summary tables K Grading quality of evidence for each outcome across studies, and assessing the overall quality of evidence across outcomes with the aid of evidence profiles K Grading the strength of recommendations on the basis of the quality of evidence and other considerations K Finalizing guideline recommendations and supporting rationales K Sending the guideline draft for peer review to the KDIGO Board of Directors in August 2012 and for public review in November 2012 K Editing the guideline K Publishing the final version of the guideline The Work Group Co-Chairs, KDIGO Co-Chairs and ERT met for a two-day meeting to go over the guideline develop- ment 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 endocrino- logy. 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 evidence- based 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 perform- ing 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. http://www.kidney-international.org methods for guideline development & 2013 KDIGO Table 6 | 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. 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, 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 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 Population General population Intervention Any statin Comparator Other agent or placebo Outcomes Change in LDL-C Design Systematic review or meta-analysis, 2006-2011 Minimum duration of follow-up NA Minimum N of subjects NA 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 Abbreviations: AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NA, not applicable; RCT, randomized controlled trial; SCr, serum creatinine; TC, total cholesterol; TG, triglyceride. methods for guideline development 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 Searches and Article Selection Systematic search strategies were developed by the ERT with input from the Work Group Co-Chairs. Modules were created for RCTs, kidney disease, dyslipidemia, and lipid- lowering 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 con- ducted 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. For selection of studies, all members of ERT indepen- dently 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, compara- tors, 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 interven- tion and comparator, results, and quality grading for each outcome. Categorical outcomes and continuous lipid out- comes 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. Table 7 | Hierarchy of outcomes 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 Table 8 | Literature yield for RCTs* Studies included in Summary Tables Intervention Abstracts identified Articles retrieved Studies with data extracted Statin vs. Placebo Atorvastatin vs. Placebo, kidney transplant recipients Statin vs. Lifestyle Statin vs. Placebo, ADPKD Atorvastatin 80 mg vs. Low vs. Moderate Protein Diet Ezetimibe vs. Placebo Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; RCT, randomized controlled trial. *Counts not listed for the four other topics for various reasons: no RCTs were found for frequency of testing and existing systematic reviews were used for change in LDL-C by statin and drug interactions. methods for guideline development Evidence Profiles 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 trans- parent. 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 Each 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 Table 9 | Work products for the guideline* Topic Summary table of RCTs Evidence profile Lipid-lowering agents or diet/lifestyle modification Atorvastatin vs. atorvastatin + (single study) Ezetimibe vs. placebo (simvastatin+ezetimibe vs. simvastatin) + (single study) Statin vs. placebo in ADPKD + (single study) Statin vs. placebo in CKD + + (8 studies) Statin vs. usual care + (single study) Low vs. moderate protein diet + (single study) Statin + ezetimibe vs. placebo + (single study) Statin vs. placebo in kidney transplant recipients + + (2 studies) Statin vs. lifestyle in kidney transplant recipients + + (2 studies) Statin vs. placebo in children + (single study) Statin vs. placebo in CKD with dialysis + + (2 studies) Exercise vs. control + (single study) Drug interactions (update of Tables 32 37 in KDOQI 2003 guideline) Drug interactions + (single pre-existing systematic review) Adverse events from statin+fibrate therapy Any adverse event + (no evidence profiles prepared re adverse events) Serious adverse event + (no evidence profiles prepared re adverse events) Treatment-related adverse event + (no evidence profiles prepared re adverse events) Discontinuation due to adverse event + (no evidence profiles prepared re adverse events) Increased ALT or AST + (no evidence profiles prepared re adverse events) Increased creatine kinase + (no evidence profiles prepared re adverse events) Increased SCr + (no evidence profiles prepared re adverse events) Rhabdomyolysis + (no evidence profiles prepared re adverse events) Other adverse event + (no evidence profiles prepared re adverse events) Frequency of lipids testing Frequency of lipids testing (0 studies) Change in LDL-C by statin Change in LDL-C by statin + (single pre-existing systematic review) Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; LDL-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; SCr, serum creatinine. Coding: +: work product is indicated for the topic of interest; : work product is not indicated for the topic of interest. General population studies with a CKD subgroup are included. Table 10 | 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. Abbreviation: RCT, randomized controlled trial. methods for guideline development consistency, clarity, thoroughness and precision, etc.). Each reported outcome was then evaluated and given an individual grade depending on the quality of reporting and methodo- logical 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 GRADE108 110 and facili- tated 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 recom- mendations 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 Grading 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. 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 or 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 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 Table 11 | GRADE system for grading quality of evidence Step 1: Starting grade for quality of evidence based on study design Step 2: Reduce grade Step 3: Raise grade Final grade for quality of evidence and definition Randomized trials = High Observational study = Low Study quality 1 level if serious limitations 2 levels if very serious limitations Consistency 1 level if important inconsistency Directness 1 level if some uncertainty 2 levels if major uncertainty Strength of association +1 level if stronga , no plausible confounders +2 levels if very strongb , no major threats to validity Other +1 level if evidence of a dose response gradient +1 level if all residual plausible confounders would have reduced the observed effect High = Further research is unlikely to change confidence in the estimate of the effect Moderate = Further research is likely to have an important impact on confidence in the estimate of effect, and may change the estimate Low = Further research is very likely to have an important impact on confidence in the estimate, and may change the estimate Any other evidence = Very Low Other 1 level if sparse or imprecise datac 1 level if high probability of reporting bias Very Low = Any estimate of effect is very uncertain Abbreviation: GRADE, Grading of Recommendations Assessment, Development and Evaluation. a Strong evidence of association is defined as significant relative risk of 42 (o0.5) based on consistent evidence from two or more observational studies, with no plausible confounders. b Very strong evidence of association is defined as significant relative risk of 45 (o0.2) based on direct evidence with no major threats to validity. c Sparse if there is only one study or if total N o500. Imprecise if there is a low event rate (0 or 1 event) in either arm or confidence interval spanning a range 41. Adapted by permission from Macmillan Publishers Ltd: Kidney International. Uhlig K, Macleod A, Craig J et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 70: 2058 2065;110 accessed http:// methods for guideline development 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. Quality of the main study: A. Good B. Fair C. Poor Is CKD subgroup defined by kidney function or proteinuria measured at baseline? If yes, do not downgrade for subgroup. If no, reject or downgrade for subgroup by 1 or 2 levels based on the risk of bias. Is CKD subgroup pre-specified before secondary analysis? If no, is the standard definition of CKD , or the presence of proteinuria) used? If yes, do not downgrade for subgroup. If yes, do not downgrade for subgroup. If no, downgrade the quality for subgroup by 1 level. Are baseline characteristics by intervention and comparator groups provided in CKD subgroup? If yes, are there differences between groups? If no, do not downgrade for subgroup. If yes, downgrade by one level if differences are likely to have influenced results. Do not downgrade, if, on the judgment of the reviewer, differences are unlikely to have influenced results, or are properly accounted for in the analysis. If no, downgrade the quality for subgroup by 1 level. Final study quality for sub-group: A. Good (not downgraded) B. Fair (downgraded by 1 level) C. Poor (downgraded by 2 levels) Figure 3 | Grading the quality of CKD subgroups of non-CKD trials. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. methods for guideline development 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 recommenda- tion includes an explicit link between the quality of the Table 12 | Final grade for overall quality of evidence Grade Quality of 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 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. K For non statistically significant benefit or harm, report as possible benefit [or harm] of drug X. K In instances where studies are inconsistent, report as possible benefit [or harm] of drug X. K No difference can only be reported if a study is not imprecise. K Insufficient evidence is reported if imprecision is a factor. Table 14 | KDIGO nomenclature and description for grading recommendations Implications Grade* Patients Clinicians Policy-makers 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. 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. 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. methods for guideline development Table 16 | The Conference on Guideline Standardization (COGS)112 checklist for reporting clinical practice guidelines Topic Description Discussed in KDIGO Clinical Practice Guideline for Lipid 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. 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. 6. Developer Identify the organization(s) responsible for guideline development and the names/credentials/potential conflicts of interest of individuals involved in the guideline s development. Organization: KDIGO Names/credentials/potential conflicts of interest of individuals involved in the guideline s development are disclosed in the Biographic and Disclosure Information. 7. Funding source/ sponsor Identify the funding source/sponsor and describe its role in developing and/or reporting the guideline. Disclose potential conflict of interest. KDIGO is supported by the following consortium of sponsors: Abbott, Amgen, Bayer Schering Pharma, Belo Foundation, Bristol-Myers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole Food Company, Fresenius Medical Care, Genzyme, Hoffmann-LaRoche, International Society of Nephrology, JC Penney, Kyowa Hakko Kirin, NATCO The Organization for Transplant Professionals, NKF-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical, Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma, and Wyeth. No funding is accepted for the development or reporting of specific guidelines. All stakeholders could participate in open review. 8. Evidence collection Describe the methods used to search the scientific literature, including the range of dates and databases searched, and criteria applied to filter the retrieved evidence. Topics were triaged either to a) systematic review, b) systematic search followed by narrative summary, or c) narrative summary. For systematic reviews on treatment with different lipid-lowering agents or lifestyle modifications, we searched for RCTs in MEDLINE, Cochrane Central Registry for trials, and Cochrane database of systematic reviews. Screening criteria are outlined in the Methods for Guideline Development chapter. The search was updated through August 2011 and supplemented by articles identified by Work Group members through June 2013. We also searched for pertinent existing guidelines and systematic reviews. grading criteria 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. 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. methods for guideline development available evidence and the strength of that recommendation. However, Table 15 shows that the strength of a recommenda- tion 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 includ- ing 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 state- ments 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 conclu- sion of each chapter. Limitations of Approach Although the literature searches were intended to be comprehensive, they were not exhaustive. MEDLINE was Table 16 | Continued Topic Description Discussed in KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease 13. Definitions Define unfamiliar terms and those critical to correct application of the guideline that might be subject to misinterpretation. Abbreviations and Acronyms. tions 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. 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. 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. Abbreviations: CKD, chronic kidney disease; CPG, clinical practice guideline; CVD, cardiovascular disease; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HDL-C, high-density lipoprotein cholesterol; KDIGO, Kidney Disease: Improving Global Outcomes; LDC-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; TC, total cholesterol; TG, triglyceride. methods for guideline development 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) the Conference on Guideline Standardization and the Institute of Medicine s recent Standards for Systematic Reviews113 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. SUPPLEMENTARY MATERIAL Supplemental Appendix 1: Online search strategies. Supplemental Appendix 2: Concurrence with Institute of Medicine standards for systematic reviews and for guidelines. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/home/guidelines/lipids methods for guideline development Biographic and disclosure information Marcello A Tonelli, MD, SM, FRCPC (Work Group Co-Chair), received an MD from the University of Western Ontario, specialist certification in nephrology (FRCPC) at Dalhousie University, and an SM in epidemio- logy from Harvard University. He is a nephrologist and Associate Professor at the University of Alberta. He serves as Associate Editor of American Journal of Kidney Diseases, the Cochrane Renal Group and the Journal of Nephrology, and is a member of the Editorial Board for Journal of the American Society of Nephrology. Dr. Tonelli is the President of the Canadian Society of Nephrology, a Councillor of the International Society of Nephrology and a past member of the Minister s Expert Committee for Drug Evaluation for the Province of Alberta. In March 2010, Dr. Tonelli was named the chair of the Canadian Task Force for Preventive Health Care, a national panel of experts that will make recommen- dations about preventive health services to Canada s more than 36,000 family physicians. Dr. Tonelli holds a Health Scholar award from the Alberta Heritage Foundation for Medical Research (AHFMR) and a Canada Research Chair in the optimal care of people with CKD. He is a founding member of the Alberta Kidney Disease Network and co-leader of the AHFMR Interdisciplinary Chronic Disease Collaboration (ICDC) research team. Since 2005, Dr. Tonelli has been the co-leader of a joint initiative between the University of Alberta and the Hospital Civil de Guadalajara, aimed at prevention of kidney failure among the poor of Jalisco, Mexico. Consultant: Merck (honorarium donated to charity) Speaker: Merck (honorarium donated to charity) Christoph Wanner, MD (Work Group Co-Chair), is Head of Nephrology, Department of Medicine at University of Wu rzburg, where he also obtained his MD. He then trained in Internal Medi- cine and subsequently Nephrology, in Freiburg, Germany. Dr Wanner has maintained an active research interest in the role of lipids in progression of kidney disease, having participated in two major trials conducted in this area: 4D and SHARP. His research also includes the elucidation of the inflammatory response syndrome in diabetic nephropathy, CKD and ESRD; pathogenesis and treatment for Fabry disease; and identification of risk factors for CKD progression and CVD in large study cohorts. Dr. Wanner has authored over 400 publications, including serving presently as Editor-in-Chief of Journal of Renal Nutrition and editorial board member for Clinical Nephrology, Current Opinion in Nephrology & Hyper- tension, Kidney International, and Nephrology Dialysis Trans- plantation. He is also President of the International Society of Renal Nutrition and Metabolism and Chairman of ERA-EDTA Renal Registry. In recognition of his contributions to nephrology, he was awarded the International Distinguished Medal from the US NKF in 2007 and nominated as honorary member of the Polish Society of Nephrology in 2011. In 2012 he obtained a doctor honoris causa from the Charles University of Prague. Advisory Board: Boehringer Ingelheim; Keryx; Reata Consultant: AMAG; Baxter; Boehringer Ingelheim; Reata Development of Educational Materials: Mitsubishi Grant/Research Support: Genzyme* Speaker: Abbott; Amgen; Astellas; AstraZeneca; Bristol- Myers Squibb; Fresenius Medical Care; Genzyme; Merck Sharp & Dohme; Mitsubishi; Roche *monies paid to institution Alan Cass, MBBS, FRACP, PhD, is Director of the Menzies School of Health Research in Darwin, Australia and previously served as Senior Director, Renal and Metabolic Division, The George Institute for Global Health in Sydney, Australia. Dr Cass completed his nephrology training and PhD studies at the University of Sydney where he investigated the social determinants of ESRD. His current research encompasses the use of rigorous quantitative and qualitative methods to foster the development, implementation and evaluation of strate- gies to address the growing burden of CKD. He also conducts primary care intervention research aiming to reduce barriers to necessary care for Indigenous Australians and enhance access to renal services in remote areas, thereby improving their health outcomes. Dr Cass is President-Elect for the Australian and New Zealand Society of Nephrology (ANZSN), a member of the Executive of the Australasian Kidney Trials Network and International Society of Nephrol- http://www.kidney-international.org biographic and disclosure information & 2013 KDIGO ogy (ISN) CKD Policy Task Force. An author of over 150 publications, he recently received the 2012 NSW Aboriginal Health Award for Closing the Gap through Excellence in Chronic Care, and the 2013 T J Neale Award for Outstanding Contribution to Nephrological Science from ANZSN. Advisory Board: Abbott; Merck Consultant: Baxter Expert Testimony: Merck Grant/Research Support: Amgen;* Baxter;* Merck;* Novartis* Speaker: Fresenius Medical Care *monies paid to institution Amit X Garg, MD, FRCPC, FACP, PhD, is a Professor of Medicine, Epidemiology and Biostatistics at the University of Western Ontario. He practices nephro- logy at the London Health Sciences Centre and cares for patients with CKD, acute kidney injury (AKI) and individuals wishing to donate a kidney to a loved one. Dr. Garg conducts clinical and health services research to improve health outcomes for patients with kidney diseases including those receiving dialysis or a kidney transplant. He also aims to improve the efficiency by which renal care is delivered. He currently holds a Clinician Scientist Award from the Canadian Institutes of Health Research. He is the current Director of the London Kidney Clinical Research Unit and Scientific Director of the Institute for Clinical Evaluative Sciences at Western Facility. Dr Garg reported no relevant financial relationships Hallvard Holdaas, MD, PhD, is senior consultant in Nephrology at Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Norway, where he also received his training in transplant medicine. His primary research interests are immunosuppression, dyslipidemia, and CVD in renal transplant recipients. He was the PI in the ALERT trial (fluvastatin) and co-PI in the AURORA and SHARP trials. Dr Holdaas is a member of numerous professional organizations including American Society of Nephrology, American Society of Transplantation, European Dialysis and Transplant Associa- tion and European Society for Organ Transplantation. He has published more than 170 original articles, reviews and book chapters in the fields of nephrology, dialysis and transplantation. Speaker: Abbott; Astellas; AstraZeneca; Novartis Alan G Jardine, MBChB, MD, FRCP, graduated in Physiology (1981) and Medicine (1984) from the University of Glasgow. He undertook postgraduate research training as a Clinical Training Fellow in the MRC Blood Pressure Unit, where he pursued studies on the phy- siology, pharmacology and therapeutic potential of natriuretic peptides. He trained initially in Endocrinology and subsequently Nephrology, in Glasgow and Aberdeen, UK. Since 1994 he has been on the staff of the University of Glasgow, where he has been Professor of Renal Medicine since 2006. He has pursued a variety of research themes that center on accelerated vascular disease and long- term adverse outcomes in patients with renal disease and transplantation, their pathophysiological and genetic deter- minants, and their management. His current research combines laboratory work, clinical research and clinical trials, and he is the leader of the Renal Research Group in the BHF Glasgow Cardiovascular Research Centre. Since 2010 he has been the Head of the Undergraduate Medical School in Glasgow. He is a member of the Council of the European Society for Transplantation. Consultant: Abbott; Novartis; Pfizer;* Opsona* Development of Educational Materials: Pfizer* Expert Testimony: Commission on Human Medicines (UK); European Medicines Agency; US Food and Drug Adminis- tration Speaker: Astellas; Bristol-Myers Squibb; Genzyme (Sanofi); Merck Sharp & Dohme; Pfizer* *monies paid to institution Lixin Jiang, MD, PhD, is the Director for National Cardiovascular Bio-bank Centre, Co-Director for China Oxford Centre for International Health Research, and Deputy Director for Center of Dyslipidemia and Cardiovascular Disease of Fuwai Hospital. She is also Editor-in-Chief for The Lancet Chinese Edition, Editorial Board Member for the journal Circulation: Cardiovascular Quality and Out- comes and a Doctoral mentor at Chinese Academy of Medical Sciences and Peking Union Medical College. Dr. Jiang obtained her medical degree from the Chinese Academy of Medical Sciences and Peking Union Medical College. Her main research interests involve large RCTs, epidemiological studies, pharmacogenomics studies and outcomes research. She serves as the Executive Member in the Young and Middle-Aged Scholar Committee of Stroke Screening and Prevention, National Health and Family Planning Commission of China, and the Advisory Expert on the Panel on Cardiovascular Disease, Committee of Experts on Rational Drug Use, National Health and Family Planning Commission of China. biographic and disclosure information As the Steering Committee member and site PI in China, Dr. Jiang has successfully run several international large- scale clinical trials including: ISCHEMIA, HPS3/TIMI55: TRACER, and INTER-HEART. Moreover, she is the PI of four national key research projects funded by Chinese government, including China Patient-centered Evaluative Assessment of Cardiac Events (China PEACE) (2012 2014), The Study on Hereditary Susceptibility to Statin-related Myopathy (2011 2015), Establishment of the Bio-bank of Chinese Cardiovascular & Cerebro- vascular Disease (2011 2015), and China PEACE-stent (2013 2014). Dr. Jiang started her international collaboration with the Oxford University in the 1980 s and since then she has been cooperating with different top research institu- tions worldwide. Presently, her collaborative partners include Oxford University, Yale University, NHLBI, NIH, University of Edinburgh, Duke University, Merck Research Laboratories, etc. Through years of research operation, Dr. Jiang has set up a reliable and stable national coopera- tion network of over 200 hospitals within 31 provinces in China. Her achievements in the field of evidence-based medicine have attracted international recognition and acclaim. Sir Richard Peto, Co-Director of Clinical Trials Service Unit and Epidemiological Studies Unit at Oxford University, once said that she has been a whirlwind force for evidence and The Lancet commented that she is at the heart of China s evidence base. Dr Jiang reported no relevant financial relationships Florian Kronenberg, MD, received his MD from the University of Innsbruck, Austria. After specializing in Medical Genetics he worked two years each at the University of Utah, Salt Lake City, USA and the Institute of Epidemiology at the Helmholtz Center, Munich, Germany. In 2004, he became Full Professor for Genetic Epidemiology at the Innsbruck Medical University where he presently heads the Department of Medical Genetics, Molecular and Clinical Pharmacology. Dr. Kronenberg served as PI in several studies on genetic risk factors for atherosclerosis and biomarkers for the progression of CKD including the Mild to Moderate Kidney Disease Study00 (MMKD). He served as a workgroup member of the NKF K/DOQI Guidelines on Cardiovascular Disease in Dialysis Patients and is Associate Editor of Atherosclerosis and Academic Editor of PLoS One. Advisory Board: Genzyme, Keryx Speaker: Amgen; Genzyme Rulan S Parekh, MD, MS, FRCP(C), FASN, is a Clinician Scientist and Associate Professor of Medicine and Paediatrics at the University of Toronto, The Hospital for Sick Children and University Health Net- work. The focus of Dr. Parekh s research is to study risk factors both clinically and genetically leading to progression of CKD and CVD. She has published over 80 peer reviewed manuscripts and book chapters, and has mentored over 25 postdoctoral fellows and students. She leads the NIH-NIDDK sponsored Predictors in Arrhythmic and Cardiovascular Disease in End Stage Renal Disease (PACE) , a new cohort study in dialysis patients to identify risk factors for sudden cardiac death. She is currently the chair of the American Kidney Fund Clinical Scientist Committee and on the Board of Trustees of the American Kidney Fund. She has recently been inducted into the American Society of Clinical Investigation and Society for Pediatric Research and has received awards for Advising, Teaching and Mentoring Award from the Johns Hopkins Bloomberg School of Public Health. She is presently an Associate Editor for BMC Nephrology and on the editorial board of the Clinical Journal of the American Society of Nephrology. Trustee: American Kidney Fund (no compensation) Grant/Research Support: Physician Services Inc* *monies paid to institution Tetsuo Shoji, MD, PhD, is affiliated with the Department of Geriatrics and Vascular Medicine, Osaka City Univer- sity Graduate School of Medicine, Osaka, Japan. He studied medicine in the medical school of Osaka City University and then worked at the Second Department of Internal Medicine, Osaka City University Hospital. 