The optimum survival was associated with the ranges of diastolic BP between 70 79mm Hg and systolic BP between 130- In another smaller study (n 331) of mortality with 2 year follow-up in elderly hospitalized subjects 470 years with vascular disease or hypertension, the longest survival was observed when diastolic BP was in the range 71 80mm Hg, with a pronounced increase in risk with diastolic BP r60mmHg.410 Further evidence to discourage aggressive reduction in BP in high risk groups comes from secondary analyses of outcomes associated with achieved BPs in the context of large RCTs. Such analyses are retrospective in nature and the trials themselves have not specifically recruited (and often excluded) patients with reduced GFR, so they cannot be used to formulate a guideline for a lower BP target in the context of CKD. One example of such a study is a retrospective analysis of the active treatment group of the SHEP trial. In this study, 4736 subjects aged Z60 years with a systolic BP 4160mmHg and diastolic o90mmHg were randomized to placebo or BP reduction with chlorthalidone with or without atenolol to reduce systolic BP. Perhaps surprisingly, a low diastolic BP on treatment was associated with an increased risk of stroke, coronary heart disease and CVD.41 Likewise in INVEST, a multi-national RCT comparing verapamil sustained-release and atenolol-based treatment in 22,576 patients with hypertension and CAD, BP control and outcomes were equivalent between the groups, but the risk of the primary outcome (all-cause death, non-fatal myocardial infarction and non-fatal stroke) progressively increased with a BP lower than 119/84mmHg, although taken alone, stroke risk did not increase with lower BP. After adjustment for multiple variables the relationship between low diastolic BP and primary outcome Further analysis of the above association including only the 2699 patients with peripheral artery disease also showed a J-shaped relationship, such that the primary outcome occurred least frequently at a systolic BP of 135-145mmHg and a diastolic BP of 60-90mmHg, with the effect most strongly related to Stratifying patients into those aged o60, 60 to o70, 70 to o80 and Z80 years and plotting survival versus diastolic BP produced a pronounced J-curve effect with a HR nadir at 75mmHg up to 80 years, then 70mmHg for subjects 480 years. For systolic BP the HR nadir increased with increasing age: 115mmHg up to 70 years, 135mmHg for In ONTARGET involving 25,588 patients with athero- sclerotic disease or diabetes with organ damage, a J-shaped relationship between on-treatment systolic BP (nadir around 130 mm Hg) and all outcomes except stroke was observed in a Data from IDNT showed that a systolic BP below 120 mmHg was associated with an increased risk of cardiovascular deaths and congestive heart failure, but not myocardial infarction in hypertensive type 2 diabetics.228 Finally, in the ACCORD study, while targeting a systolic BP of o120 mm Hg rather than o140 mm Hg did not reduce cardiovascular outcomes, serious adverse events occurred in 3.3% of the lower BP group compared with 1.3% (po0.001) in the higher BP target group indicating the potential penalty paid for aggressive BP reduction.159 In CKD ND patients, there is observational evidence from two community-based longitudinal studies including 1549 subjects with CKD 3-4. In one study, a J-shaped relationship between stroke and systolic BP was observed, with lowest stroke risk in the range of systolic BP between 120 and 129 mm Hg, and higher risk above and below this.158 A cohort study of 860 US veterans (comprising mainly men) with CKD (GFR o60 and a subset with GFR o30 ml/min/ ) showed greater mortality when systolic BP was o133 mm Hg or diastolic BP o65 mm Hg, although it appeared that the association might not be causal but instead related to atherosclerotic CVD as a co-morbidity.413 In summary, with respect to a lowest BP target, most of the relevant evidence is observational, derived from retro- spective analyses, and nearly all involves non-CKD popula- tions. No studies to date have specifically tested a strategy of reducing blood-pressure-lowering drug treatment if the BP falls below a certain limit. We anticipate that there would be major practical difficulties in implementing such a practice, particularly in patients with reduced conduit artery com- pliance and consequent increased pulse pressure (in whom a lower limit for diastolic BP might entail accepting an systolic BP much higher than the current targets). Although the available evidence is enough to support our guideline statements advising caution in those with co-morbidity, we do not consider it is robust enough to allow us to specify a lower limit for either systolic BP or diastolic BP, even though other organizations have done so.396 Although inferences can be drawn when treatment-related BP is too low, especially in patients with diabetes, the elderly and those with CVD, we are left without a lowest BP target. The NIH funded SPRINT trial currently recruiting patients in the US may clarify this issue. It will randomize over 7500 patients with systolic BP to targets of o140mmHg or o120mmHg, deliberately including approximately 1750 patients over 75, and followed for cardiovascular, cognitive and kidney end points over a period of 9 years, commencing 2010.171,172 8.3: SHOULD A REDUCTION IN ALBUMINURIA BE A TARGET FOR TREATMENT WITH AGENTS THAT MODIFY BP? As outlined elsewhere in this Guideline, RAAS intervention is effective in not only lowering BP but also protecting individual patients with CKD from further decline in kidney function. Although the BP-lowering effect of RAAS inhibi- tion contributes to renoprotection, a component of the protective effect may be independent of the effect on BP. Thus, to achieve maximum renoprotection using a RAAS inhibitor, the clinician might consider monitoring the reduction in urine albumin excretion (an off target effect). This is particularly important in macroalbuminuric and microalbuminuric hypertensive subjects with type 2 diabetes, in whom the BP response to RAAS inhibitors may be discordant with the anti-albuminuric response.414,415 Studies in such patients indicate that those in whom urine albumin was lowered without significant lowering of BP gained some renoprotection, whereas patients who did not have urine albumin lowered in spite of BP-lowering did not have Thus, albuminuria may be an independent factor in renoprotection. In a prospective study supporting this concept, Hou et al.416 detected nearly 50% additional renoprotection with a dose of a RAAS inhibitor titrated to maximally reduce urine albumin levels as compared to a standard dose used for the BP lowering effect. There have been no RCTs assessing hard renal or cardio- vascular outcomes, in which patients have been randomized to different targets of urinary albumin excretion irrespective of BP. 8.4: SHOULD RAAS INHIBITION BE MAXIMIZED IN CKD PATIENTS? Accepting that RAAS inhibitors may be used to both lower BP and urine albumin excretion, options are available to optimize the albuminuria lowering effect of these agents. For example, it is well recognized that co-administration of a low-sodium or the addition of a diuretic63,66,419 enhances the effect of both ACE-Is and ARBs on lowering urine albumin excretion. Such therapeutic combinations make good sense and are unlikely to be associated with harmful side effects. Whether more aggressive blockade of the RAAS using supramaximal doses of ACE-Is or ARBs is beneficial is less certain. Recently, Burgess et al.420 showed that increasing the dose of candesartan well beyond the guideline-recommended dose for BP-lowering resulted in further reduction of the urine albumin levels. The substantial evidence suggesting that RAAS inhibition using ACE-Is or ARBs has renoprotective effects when these agents are used individually has led to the hypothesis that combining the two classes of agents, or adding an aldosterone antagonist or a DRI, may provide additional benefit. Interest in this approach has been increased by the evidence that individuals treated with ACE-Is may have aldosterone breakthrough 89 with angiotensin I to angiotensin II conversion occurring via other and by the fact that there may be other active receptors for angiotensin II422 that may have a range of roles. A number of moderate-sized studies, mostly in patients with diabetes, have demonstrated that proteinuria levels may be further lowered by combining ACE-Is and ARBs than by using each agent alone.423 Aldosterone antagonists may substantially lower proteinuria when used on top of ACE-Is Similarly when the DRI, aliskiren, was added to proteinuria was reduced. The optimism generated by these findings has recently been seriously dampened. The ONTARGET trial did not demonstrate any cardiovascular benefit for dual RAAS blockade (with the ACE-I ramipril and the ARB telmisartan), in a population at high risk of CVD, but did suggest an increased risk of major renal outcomes with dual RAAS blockade.281 This finding has been questioned for a range of reasons, and it has been suggested that the result may have been different if the population included a greater number of patients with CKD.425 The ALTITUDE trial randomized type 2 diabetic partici- pants to receive either aliskiren or matching placebo on top of an ACE-I or ARB113 and included a large number of diabetic individuals with CKD.426 Although the results have not been published at the time of writing this Guideline, the trial was recently stopped early due to a low likelihood of ever demonstrating benefit and a suggestion of an increased risk of some adverse outcomes, including non-fatal stroke, renal complications, hyperkalemia and hypotension,427 resulting in the US FDA counselling against this practice.114 As a result, any benefits of combined blockade of the RAAS for clinically important renal outcomes currently remain unproven, and the safety issues should be taken into account prior to using this therapeutic approach. 8.5: SHOULD ACE-IS AND ARBS BE DISCONTINUED IN CKD 5 BECAUSE THEY COMPROMISE RESIDUAL KIDNEY FUNCTION? It has long been recognized that commencing ACE-Is and ARBs can lead to an acute reduction in GFR that may be reversed if the dose is reduced or if the drug is discontinued. This phenomenon has been observed in the context of RCTs such as the RENAAL trial. In a post hoc analysis of this study, an initial fall in GFR was found to predict better long-term Such acute changes in GFR are likely to reflect the hemodynamic changes that accompany initiation of RAAS blockade.88,428 However, since a reduction in GFR is not usually considered beneficial, observers have recently questioned the value of commencing or continuing BP- lowering regimens based on an ACE-I or ARB in elderly patients with advanced CKD and have specifically suggested that use of such agents in CKD 4 5 patients may compromise residual kidney function or even accelerate its rate of decline in both diabetic429 and non-diabetic patients.430 This opinion is based on uncontrolled observations and is contrary to the observations made from the RENAAL RCT in patients approaching renal replacement therapy.431 For example in one such observational study, discontinuation of ACE-Is and ARBs in 52 patients with CKD 4 5 was followed by a greater than 25% increase in the GFR in 61.5% of patients, and a greater than 50% increase in 36.5% of An RCT that specifically randomized patients with advanced CKD to benzapril or placebo did not support The study reported that 112 predominantly CKD 4 patients with a mean GFR of 26 ml/min/1.73 m2 receiving benzapril had a lower risk of doubling of SCr, kidney failure, or death compared with the same number of patients receiving placebo. A small study of 60 peritoneal dialysis patients showed better preservation of residual kidney function among patients randomized to ramipril as com- pared to no treatment.432 Thus, the current evidence does not support the discontinuing ACE-Is and ARBs in patients with advanced CKD in an effort to preserve residual kidney function, although hyperkalemia or hypotension may be a specific reason for discontinuation in some patients. 8.6: ETHNICITY, RACE, AND GENES In this Guideline, the individualization of BP control is emphasized, yet specific advice to tailor therapy according to ethnicity, race, or genetic influences is not available. In lieu of such advice, we have drawn on RCTs specific to various racial and ethnic populations: African-American, Chinese, Japa- nese, Pakistani, and European whites (sometimes from a single country). We have generalized the observations derived from these ethnicity- or race-specific RCTs to management advice applicable to all ethnic and racial groups. However, there is good reason but not good evidence to believe that ethnicity, race, and genotype influence elevated BP and CKD, with familial aggregation and ethnic racial disparities in both conditions. Currently, it is difficult to disentangle ethnic - racial disparities from social, economic, and environmental disparities. The evidence for ethnic or racial influence on CKD is mainly epidemiological. The incidence of kidney failure requiring dialysis is higher in a wide variety of non-white groups (African-American, Asian, Native American, Native Australian, and Pacific Islander) than in white groups of European heritage in North America, Europe, and the Hypertension is also more common, develops earlier in life, and manifests with a higher average BP among African-Americans than whites in the Although profound environmental and socioeconomic issues are clearly involved, information is gradually being gathered that enlightens us about some of the links among genetics, high BP and kidney disease in the African-American Genetic variance in the non-muscle myosin heavy chain 9 gene (MYH9) was reported to be partly responsible for progressive kidney disease in hypertensive This might provide a rationale for lower BP targets in hypertensive African-Americans than other racial groups,439 especially in African-Americans with genetic variation in the MYH9 gene. More recently, polymorphisms in the apolipoprotein L-1 gene (APOL1), which is located immediately upstream to MYH9, has been implicated in this process, with the APOLI G1 and G2 alleles associating with focal segmental glomerulosclerosis in Intriguingly, these variants seem to confer resistance to Trypanosoma brucei rhodesiense, which may explain the persistence of this seemingly otherwise disadvantageous gene in West Africans, but this hypothesis does not clarify the association between APOL1 and focal segmental glomerulosclerosis. Epidemiological evidence is suggestive of many other ethnic racial differences among individuals with CKD. In addition to the differences in the prevalence of types of kidney diseases in different groups, there appear to be differences in the rates of CKD progression, in the effects of BP control on CKD progression, in BP responses to various antihypertensive regimens, and in cardiovascular risk asso- ciated with a particular BP level. Outlining this evidence is beyond the scope of this Guideline, but clearly the scientific community is currently only scratching the surface of the links among BP, CKD, race, ethnicity, genes, and epigenetics. In the future evidence may become available regarding how to modify BP control in CKD according to an individual s genetic profile, or ethnic or racial background. In the meantime, we must pay greater attention to socioeconomic and environmental issues related to ethnicity or race, which are more immediately amenable to modification. 8.7: BARRIERS TO IMPLEMENTATION Although several guidelines on BP management in CKD have been published, BP management in CKD patients is often suboptimal and audit studies suggest that the target readings are not achieved in many patients.441 The reasons why it is challenging to implement recommendations and to achieve target BP in CKD (and other) patient populations are multiple and complex, but are likely to include the issues listed below. Because of these uncertainties we cannot suggest that the recommended BP targets in this Guideline should be used as performance measures in the management of CKD patients. The credibility of the guideline is questioned. Not all clinicians agree with the currently recommended BP targets, at least not for all of their patients. The evidence supporting current BP targets in CKD has been challenged, reinforcing However, surveys have shown that less stringent BP targets, such as 160/90 mm Hg, are also not The BP targets recommended in this guideline are higher than those in some previous publications and it remains to be seen whether this will result in a higher proportion of CKD patients achieving them. The trial data are not directly relevant to a real world setting. There are few systematically collected data to support the notion that BP control cannot be achieved in most patients. However several important issues need to be considered when extrapolating from clinical trials to a real world setting. Firstly, patients recruited into RCTs are selected for characteristics that increase the likelihood of BP control. These include a lack of co-morbidities, an absence of previous adverse reactions to the BP-modifying agents used in the trial, good BP control during a run-in or washout period and high motivation, reflected by the patients willingness to enroll. Secondly, patients partici- pating in trials are often micro-managed in specialized clinics, where frequent reinforcement and pill-counting increases the likelihood of adherence to the drug regimen. Thirdly, patients who drop out because of drug-related side effects or non- adherence are usually accounted for in intention-to-treat analyses and the overall proportion of dropouts is not often reported (although may be 10% or more of the recruited population). Finally, although the mean achieved BP is often close to the intended target, the SD of the reported BP measurements is often large, suggesting that the recorded values in many patients are well above the mean and hence well above the target.22 Only rarely is the actual number of patients not achieving the target BP reported. Taken together, these factors indicate that the proportion of patients with CKD in whom BP cannot be controlled to a specified target may be much higher than indicated by the data derived from RCTs. Patients do not adhere to the treatment. The reasons why patients do or do not adhere to medical advice are believed to depend in part on cost benefit analysis by the patients themselves. This is particularly relevant to the use of BP- modifying drugs that do not provide immediately perceivable improvement in quality of life or relief of symptoms, yet have immediately observable negative effects in terms of expense and inconvenience, even if there are no adverse side effects. The literature contains many reports of poor adherence to BP-modifying drug regimens and suboptimal BP control in CKD patients is known to be associated with poor adherence BP fluctuates. In a usual clinical setting, if a BP target is set, a clinician will gradually increase the number of drugs prescribed to a given patient until this target is achieved. The regimen will not then be altered again unless several BP readings are above (sometimes well above) that target. Because BP fluctuates, there is a good chance that a proportion of the subsequent BP readings will inevitably be above a previously achieved target. One way to circumvent this problem is to set a threshold level for treatment that is lower than the desired target. This strategy has been used in several health care recommendations, including the WHO nutrition goals and the 1997 NKF Dialysis Outcomes Quality Initiative Hemodialysis Adequacy guideline. As previously stated and in line with several previous guidelines on BP management in CKD, we have set the same values for the threshold for treatment and desired target systolic and diastolic levels. We emphasize the value of checking for consistency by using repeated BP measurements to direct therapy and believe that this strategy will improve target attainment. BP is measured infrequently. Traditionally, BP control is audited by measuring the BP in a patient or a group of patients on just one occasion. In an individual patient, the BP can be better assessed by means of repeated clinical measurements over a period of time or by more sophisticated techniques such as home self-measurement of BP or ABPM. Evaluating guideline implementation in a group of patients is difficult, as repeated or more sophisti- cated measurements are not possible in everyone. We have insufficient knowledge of what proportion of patients at any one time will have a BP level above the target value, even when guidelines have been closely followed and adherence has been high. In a post hoc analysis of a large RCTof essential hypertension, a single elevated office BP reading in a patient with previously well controlled BP was unlikely to indicate a persistent loss of BP control, but rather reflect day-to-day 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. Methods for guideline development AIM The overall aim of this project was to develop an evidence- based CPG for the use of BP-lowering agents in individuals with CKD. The guideline consists of recommendation statements, rationale, and a summary of systematically generated evidence on relevant pre-defined clinical topics. OVERVIEW OF PROCESS The development process for the KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease included the following steps: K Appointing Work Group members and the 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 December 2010 and for public review in July 2011. K Publishing the final version of the guideline. The Work Group, KDIGO Co-Chairs, ERT, and KDIGO support staff met for three 2-day meetings for training in the guideline development process, topic discussion, and consensus development. 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 endocrinol- ogy. 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, a project coordinator and manager, and a research assistant. The ERT instructed and advised Work Group members in all steps of literature review, critical literature appraisal, and guideline development. The Work Group and the ERT collaborated closely throughout the project. Defining scope and topics The Work Group Co-Chairs first defined the overall scope and goals of the guideline and then drafted a preliminary list of topics and key clinical questions. The Work Group and ERT further developed and refined each topic and specified screening criteria, literature search strategies, and data extraction forms (Table 5). Given the lack of robust evidence, the Work Group decided not to make guideline recommendations for patients with kidney failure (CKD 5D). The Work Group decided instead to refer readers to the KDIGO Controversies Conference paper on this topic.4 Establishing the process for guideline development The ERT performed 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. Throughout the project, the ERT offered suggestions for guideline development and led discussions on systematic review, literature searches, data extraction, assessment of quality and applicability of articles, evidence synthesis, grading of evidence and guideline recommendations, and consensus development. The Work Group took the primary role of writing the recommendation statements and rationale and retained final responsibility for their content. The Work Group Co-Chairs prepared the first draft of the scope of work document as a series of open-ended questions to be considered by Work Group members. At their first 2-day meeting, members added further questions until the methods for guideline development http://www.kidney-international.org & 2012 KDIGO initial working document included all topics of interest to the Work Group. The inclusive, combined set of questions formed the basis for the deliberation and discussion that followed. The Work Group strove to ensure that all topics deemed clinically relevant and worthy of review were identified and addressed. 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 criteria are presented in Table 5. Ranking of outcomes The Work Group ranked outcomes of interest on the basis of their importance for informing clinical decision making (Table 6). Doubling of SCr level or halving of GFR was upgraded from high to critical importance in studies where (or the SCr was 42 mg/dl [4177 mmol/l]), given the known adverse con- sequences of advanced CKD. Literature searches and article selection The Work Group sought to build on the evidence base from the previous KDOQI Clinical Practice Guidelines on Hyper- tension and Antihypertensive Agents in Chronic Kidney Disease.1 As the first search for the KDOQI guideline was conducted in Table 5 | Systematic review topics and screening criteriaa Diet or lifestyle modification Population CKD ND: CKD 1 5, non-dialysis, adults and children, with or without hypertension, any type of CKD Intervention Salt restriction, weight loss, diet, exercise Comparator Active or control Outcome Blood pressure, mortality, clinical cardiovascular events, kidney function (categorical or continuous), proteinuria or urine protein level (categorical or continuous), quality of life, adverse events Study design RCTs with parallel-group design; cross-over trials Minimum duration of follow-up 6 weeks for blood pressure, 3 months for proteinuria, 1 year for other outcomes Minimum N of subjects Z50 per arm Blood pressure targets Population CKD ND: CKD 1 5, non-dialysis, adults or children, with or without hypertension, any type of CKDa but organized by K DKD (DM and CKD) K Non-DKD K CKD in the kidney-transplant recipient (CKD T) Intervention Lower or low BP target Comparator Higher or usual BP target Outcome Mortality, clinical cardiovascular events, kidney function (categorical or continuous), proteinuria or urine protein level (categorical or continuous), quality of life, adverse events Study design RCTs with parallel-group design Minimum duration of follow-up 3 months for proteinuria, 1 year for other outcomes Minimum N of Subjects Z50 per arm Agents Population CKD ND: CKD 1 5, non-dialysis, adults or children, with or without hypertension, any type of CKDa but organized by K DKD (DM and CKD) K Non-DKD K CKD in the kidney-transplant recipient (CKD T) Intervention Any anti-hypertensive agent (single or in combination, any dose) as well as specific searches for ACE-I, ARB, aldosterone antagonist, beta-blocker, calcium-channel blocker, diuretic Comparator Active or placebo Outcomes Mortality, clinical cardiovascular events, kidney function (categorical or continuous), proteinuria or urine protein level (categorical or continuous), quality of life, adverse events Study design RCTs with parallel-group design Minimum duration of follow-up 3 months for proteinuria, 1 year for other outcomes Minimum N of Subjects Z50 per arm ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BP, blood pressure; CKD, chronic kidney disease; CKD ND, non-dialysis-dependent CKD; CKD T, non dialysis-dependent CKD with a kidney transplant; DKD, diabetic kidney disease; DM, diabetes mellitus; N, number; RCTs, randomized controlled trials. a Includes CKD subgroups from general population studies (not exclusively in CKD patients). Table 6 | Hierarchy of outcomes Hierarchya Outcomesb Critical importance Mortality, cardiovascular mortality, cardiovascular events, kidney failure, composite including clinical events High importance Doubling of SCr or halving of GFR, proteinuria (categorical) Moderate importance Kidney function (continuous), urine protein level (continuous) Importance dependent on severity Adverse events: drug discontinuation or dose decrease, hyperkalemia, early rise of SCr or decrease of GFR GFR, glomerular filtration rate; SCr, serum creatinine. a Doubling of SCr or halving of GFR is of critical importance in those studies with or SCr 42 mg/dl (177 mmol/l). b The lists are not meant to reflect outcome ranking for other areas of kidney disease management. The Work Group acknowledges that not all clinicians, patients or families, or societies would rank all outcomes the same. methods for guideline development Table 7 | Relevant systematic reviews and meta-analyses Title Reference Databases and cut-off dates of literature search Use in Work Group deliberation Topic 1. Low sodium diet or lifestyle modification and change in BP Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials Dickinson et al.53 Cochrane CENTRAL MEDLINE Embase References used to check and supplement reference list of ERT systematic review Systematic review of long term effects of advice to reduce dietary salt in adults Hooper et al.62 Cochrane CENTRAL MEDLINE Embase CAB abstracts CVRCT registry SIGLE Further search on sodium restriction and BP: Cochrane CENTRAL MEDLINE Embase Up to July 2002 References used to check and supplement reference list of ERT systematic review Topic 2. BP target and kidney outcomes Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient level meta-analysis Jafar et al.96 MEDLINE References used to check and supplement reference list of ERT systematic review Topic 3. ACE-I or ARB on CVD and CKD progression RAS blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis Balamuthusamy et al.97 OVID MEDLINE Embase References used to check and supplement reference list of ERT systematic review Angiotensin receptor blockers as anti-hypertensive treatment for patients with diabetes mellitus: meta-analysis of controlled double-blind randomized trials Siebenhofer et al.450 Cochrane CENTRAL MEDLINE Embase Cochrane Controlled Trials Register PubMed DARE NHSEED HTA References used to check and supplement reference list of ERT systematic review Topic 4. ACE-I or ARB on CKD progression Effect of inhibitors of the renin-angiotensin system and other anti-hypertensive drugs on renal outcomes: systematic review and meta-analysis Casas et al.451 Cochrane CENTRAL MEDLINE Embase References used to check and supplement reference list of ERT systematic review Topic 5. ACE-I on CKD progression in CKD without DM Angiotensin-converting enzyme inhibitors and progression of non-diabetic renal disease. A meta-analysis of patient-level data Jafar et al.141 MEDLINE References used to check and supplement reference list of ERT systematic review Topic 6. Anti-hypertensive agents in kidney-transplant recipients Anti-hypertensives for kidney-transplant recipients: Systematic review and meta-analysis of randomized controlled trials Cross et al.301 Cochrane Renal Group Specialized Register Cochrane CENTRAL MEDLINE Embase Up to July 1, 2008 References used to check and supplement reference list of ERT systematic review ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; ERT, evidence review team; RAS, renin angiotensin system. Table 8 | Literature yield Studies included in summary tables Intervention Abstracts identified Articles retrieved Studies with data extracted DKD Non-DKD Transplant General population studies in summary tables Summary tables Agents DKD, diabetic kidney disease. methods for guideline development July 2002, the search for the current KDIGO Guideline included publications since January 2002. Search strategies were developed by the ERT with input from the Work Group. The text words or medical subject headings (MeSH) that were included are provided in the Supplementary Appendix 1 online. Non-human studies and those focusing on dialysis, pregnancy, neonates, malignant hypertension, acute kidney injury, or drug pharmacology were excluded. The MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were searched by the ERT to capture all RCTs on the use of BP-lowering agents in CKD. The first search was conducted in November 2009 and was subsequently updated in April and August of 2010; the final update was done in January 2011. Additional focused searches were conducted to identify RCTs evaluating lifestyle interventions of salt restriction, weight loss, and diet and exercise in CKD and to look for reviews of adverse effects of anti-hypertensive agents. The ERTrelied on Work Group members to identify large, general population RCTs reporting on subgroup analyses based on CKD, GFR, or proteinuria status. Additional pertinent articles were added from the reference lists of JNC 7 and relevant meta-analyses and systematic reviews (Table 7). The search yield was also supplemented by articles provided by Work Group members through February 2012. A total of 10, 657 citations were initially screened. Journal articles reporting original data, meta-analyses, and systematic reviews were selected for evidence review. 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 get solicited, selected, reviewed, and edited compared to peer-reviewed publications. Post hoc analyses were also excluded, however, after discussion with the Work Group, it was decided that exception would be made for post-trial observational follow-up reports from RCTs looking at BP targets as BP interventions may take longer time to influence outcomes. These studies were downgraded one level to designate that they are of lesser quality than the original RCT. 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 the ERT. The ERT, in consultation with the Work Group, designed forms to capture data on design, methodology, sample characteristics, interventions, comparators, outcomes, results, and limita- tions 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 (Table 9). Studies included in the evidence base for the KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease1 were also incorporated if they fulfilled the inclusion criteria for the current KDIGO Guideline. Summary tables contain outcomes of interest, relevant population characteristics, description of intervention and comparator, results, and quality grading for each outcome. Categorical and continuous outcomes were summarized separately. Studies done exclusively in patients of a single race or ethnicity and studies reporting effect modifications by baseline urine protein level were annotated. Studies were also Table 9 | Work products for BP guideline* Topic Summary table of RCTs Evidence profile Diet or lifestyle modification Exercise + (single study) BP targets in CKD without DM BP target in adults + + (3 studies) BP target in children + (single study) Adverse events of target RCTs + a Agents in CKD without DM, non-transplant ACE-I or ARB versus CCB + + (7 studies) ACE-I or ARB versus placebo + + (6 studies) High-dose ACE-I versus low-dose ACE-I + + (2 studies) ACE-I versus ARB + + (3 studies) ACE-I versus beta-blocker + (single study) High-dose ARB versus low-dose ARB + + (3 studies) (ACE-I + CCB) versus ACE-I + (single study) (ACE-I + CCB) versus CCB + (single study) Beta-blocker versus CCB + (single study) CCB versus CCB + (single study) Central-acting agent versus CCB + (single study) Adverse events of agent RCTs + a Agents in CKD with DM, non-transplant Aldosterone antagonist versus placebo + (single study) ACE-I or ARB versus CCB + + (7 studies) ACE-I or ARB versus placebo + + (9 studies) ACE-I versus ARB + + (3 studies) ARB versus ARB + + (3 studies) CCB versus placebo + (single study) Direct renin inhibitor versus placebo + (single study) Endothelin antagonist versus endothelin antagonist + (single study) Endothelin antagonist versus placebo + (single study) Adverse events of agents in RCTs + a Agents in CKD in kidney transplant recipient ACE-I versus ARB + (single study) ARB versus placebo + (single study) ACE-I versus CCB + + (2 studies) CCB versus placebo + + (3 studies) Adverse events of agent RCTs + a CKD subgroups from general population studies BP target + (1 study) ACE-I + diuretic versus placebo in DM + (4 studies) ACE-I or ARB versus control + (5 studies) ACE + ARB or ARB versus ACE-I + (1 study) ARB versus CCB + (1 study) CCB versus control + (2 studies) ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BP, blood pressure; CCB, calcium-channel blocker; CKD, chronic kidney disease; DM, diabetes mellitus; RCTs, randomized controlled trials; +, work product is indicated for the topic of interest; , work product is not indicated for the topic of interest. a Included in evidence profile for other outcomes. methods for guideline development categorized by baseline proteinuria status in summary tables for the CKD with diabetes mellitus topic. For studies not exclusively examining CKD population, only those reporting analysis by CKD subgroups were tabulated. Studies including both diabetes mellitus and non-diabetes mellitus populations were included in summary tables for the CKD without diabetes mellitus topic unless results of subgroup analysis by diabetes mellitus status was provided. Work Group members proofed all summary table data and quality assessments. Summary tables are available at www.kdigo.org. 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 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 the 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. Evidence profiles were also not created for studies that did not exclusively examine CKD population. Each evidence profile was initially con- structed 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. 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). Variations of this system have been used in most KDOQI and all KDIGO guidelines and have been recommended for the US Agency for Healthcare Research and Quality Evidence-based Practice Center program.444 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 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 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 exclude possible significant biases. Poor methods, incomplete data, reporting errors. Prospective or retrospective. RCT, randomized controlled trial. 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 Other 1 level if sparse or imprecise datac 1 level if high probability of reporting bias 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 Very Low = Any estimate of effect is very uncertain 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;157 accessed http://www.nature.com/ki/journal/v70/n12/pdf/5001875a.pdf. methods for guideline development 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 Grading of Recom- mendations Assessment, Development and Evaluation 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.445 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 in either arm or a CI spanning a range 41) or sparse (only 1 study or total No500), or if there was thought to be a high likelihood of bias. 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). 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 Table 14 | KDIGO nomenclature and description for grading recommendations Implications Grade* Patients Clinicians Policy 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. Costs (resource allocation) The higher the costs of an intervention that is, the more resources consumed the less likely a strong recommendation is warranted. 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 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. methods for guideline development Table 16 | Existing major guidelines and recommendations on hypertension and anti-hypertensive agents in CKD Year Group Target CKD population Recommended BP goal (mm Hg) Recommended preferred anti-hypertensive agent(s) 2003 Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure143 Stage 3 CKD, macroalbuminuria, kidney-transplant recipients o130/80 CKD 3 or macroalbuminuria: ACE-I or ARB in combination with a diuretic Kidney-transplant recipients: No particular class of agents superior 2003 World Health Organization/International Society of Hyper- tension Statement on Management of Hypertension243 http://www.who.int/cardiovascular_diseases/guidelines/ hypertension_guidelines.pdf Type 1 DM with nephropathy Type 2 DM with nephropathy Non-diabetic nephropathy o130/80 Type 1 DM with nephropathy: ACE-I Type 2 DM with nephropathy: ARB Non-diabetic nephropathy: ACE-I 2003 European Society of Hypertension European Society of Cardiology Guidelines for the Management of Arterial DM, CKD o130/80 (if urine protein 41 g/d is present, lower target to lower protein if possible) CKD: Diuretic Type 1 DM with nephropathy: ACE-I Type 2 DM with nephropathy: ARB Non-diabetic nephropathy: ACE-I Proteinuria: ACE-I or ARB 2006 Caring for Australasians with Renal Impairment (CARI) Guidelines: Prevention of Progression of Kidney Disease http://www.cari.org.au/ckd_prevent_list_published.php DM, CKD CKD in general: if urine protein 41 g/d if urine protein 0.25 1 g/d if urine protein o0.25 g/d DKD: o130/85 for patients 450 years of age o120/70 75 for those o50 years of age Non-DKD: Regimens including ACE-I more effective than those not including ACE-I in slowing CKD progression in non-DKD Combination therapy of ACE-I and ARB slows progression of non-DKD more effectively than either single agent ACE-I more effective than beta-blockers and dihydropyridine CCB in slowing progression of CKD Beta-blockers more effective than dihydro- pyridine CCB in slowing CKD progression, especially in the presence of proteinuria DKD: ACE-I for all patients with diabetes and hypertension ACE-I for all patients with diabetes and microalbuminuria or overt nephropathy, independent of BP and GFR ARB provides specific renoprotection in diabetic nephropathy, beyond their anti-hypertensive benefit There is insufficient evidence that ACE-I and ARB combination are of additive specific benefit in diabetic nephropathy, beyond additional anti-hypertensive benefit 2008 Canadian Society of Nephrology Guidelines on Management of CKD238 DM, CKD o130/80 Non-DKD: ACE-I or ARB should be included in the regimen if urine ACR 430 mg/mmol ACE-I, ARB, thiazides, long-acting CCB, or beta- blockers (for patients older than 60 years) should be included in the regimen if urine ACR o30 mg/mmol (o300 mg/g) DKD: ACE-I or ARB should be included in the regimen 2009 Reappraisal of European Guidelines on Hypertension Management: a European Society of Hypertension Task Force Document353 DM, CKD Initiate treatment for systolic BP 4130 and diastolic ACE-I or ARB, but combination therapy with other agents most likely needed to control BP 2009 Japanese Society of Hypertension Guidelines for the Management of Hypertension452 For those with urine protein ACE-I or ARB should be the first choice of therapy and dose should be titrated by urinary albumin excretion (o30 mg/g for diabetic nephropathy and o300 mg/g for glomerulonephritis) For diuretics, thiazides should be used if GFR , and loop diuretics should Table 16 continued on following page methods for guideline development 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. 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. 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, 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 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 recom- mendation statements and grades are followed by a brief background with relevant definitions of terms and then the rationale starting with a chain of logic, which consists of declarative sentences summarizing the key points of the Table 16 | Continued Year Group Target CKD population Recommended BP goal (mm Hg) Recommended preferred anti-hypertensive agent(s) 2011 The Renal Association (UK) CKD Guidelines396 http://www.renal.org/Clinical/GuidelinesSection/ Detection-Monitoring-and-Care-of-Patients-with-CKD.aspx CKD For the majority, systolic BP: o140 mm Hg (target range 120 139 mm Hg) and diastolic BP: o90 mm Hg for the majority ACE-I or ARB For those with DM or proteinuria X1g/24 h, systolic BP: o130 mm Hg (target range 120 129 mm Hg) and diastolic BP: o80 mm Hg unless the risks are considered to outweigh the potential benefits Antihypertensive therapy should be individualized and lowering the systolic blood pressure to o120 mm Hg should be avoided 2012 Canadian Hypertension Education Program Recommendations http://www.hypertension.ca/chep-recommendations Non-DKD and DKD CKD in general: o140/90 Non-DKD: ACE-I or ARB (if ACE-I intolerant) as a first choice agent if urine ACR 430 mg/mmol (4300 mg/g) or urine protein 4500 mg/24 h DKD: For patients with persistent microalbuminuria (urine ACR 42 mg/mmol [420 mg/g] in men and 42.8 mg/mmol [428 mg/g] in women), ACE-I or or ARB is recommended as initial therapy DM with microalbuminuria or overt nephropathy o130/80 ACE-I or ARB should be considered for patients with microalbuminaria or macroalbuminaria. If ACE-I or ARB is not tolerated, then diuretics, CCBs, and beta- blockers should be considered ACE-I, angiotensin-converting enzyme inhibitor; ACR, albumin/creatinine ratio; ARB, angiotensin-receptor blocker; BP, blood pressure; CCB, calcium-channel blocker; CKD, chronic kidney disease; DKD, diabetic kidney disease; DM, diabetes mellitus; GFR, glomerular filtration rate. methods for guideline development Table 17 | The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines Topic Description Discussed in KDIGO Management of Blood Pressure in Chronic Kidney Disease Guideline 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 blood pressure and the use of anti-hypertensive agents in adults and children with CKD ND, including those with kidney transplants. 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 clinical practice guideline is intended to assist the practitioner caring for patients with non-dialysis CKD and hypertension 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. Providers: Nephrologists (adult and pediatric), Internists, and Pediatricians. Patients: Adults and children with CKD at risk for hypertension. Policy Makers: Those in related health fields. 5. Target population Describe the patient population eligible for guideline recommendations and list any exclusion criteria. Adults and children with CKD, not on dialysis; kidney transplant recipients. 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, 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 anti-hypertensive agents or to different BP targets, 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 January 2011 and supplemented by articles identified by Work Group members through February 2012. 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 at the 2010 KDIGO Board of Directors meeting and external public review in July 2011. 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. There is no date set for updating. The need for updating of the guideline will depend on the publication of new evidence that would change the quality of the evidence or the estimates for the benefits and harms. Results from registered ongoing studies and other publications will be reviewed periodically to evaluate their potential to impact on the recommendations in this guideline. Table 17 continued on following page methods for guideline development evidence base and the judgments supporting the recommen- dation. This is followed by a narrative in support of the rationale. In relevant sections, research recommendations suggest future research to resolve current uncertainties. Comparison with other guidelines We tabulated recommendations from other key English- language guidelines pertinent to the use of blood-pressure lowering agents in individuals with CKD (Table 16). This served to inform topic selection and scope. Also, after recommendations had been drafted, the Work Group reviewed them in the context of the existing guideline recommendations to avoid unnecessary or unwarranted discrepancies. Limitations of approach Although the literature searches were intended to be comprehensive, they were not exhaustive. 