Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for the management of blood pressure in CKD.

CSN Commentary Canadian Society of Nephrology Commentary on the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD Marcel Ruzicka, MD, PhD, FRCPC,1 Robert R. Quinn, MD, PhD, FRCPC,2,3 Phil McFarlane, MD, PhD, FRCPC,4 Brenda Hemmelgarn, MD, PhD, FRCPC,2,3 G.V. Ramesh Prasad, MBBS, MSc, FRCPC,4 Janusz Feber, MD, FRCPC,5 Gihad Nesrallah, MD, MSc, FRCPC,6,7 Martin MacKinnon, MD, FRCPC,8 Navdeep Tangri, MD, PhD, FRCPC,9 Brendan McCormick, MD, FRCPC,1 Sheldon Tobe, MD, MSc, FRCPC,10 Tom D. Blydt-Hansen, MD, FRCPC,11 and Swapnil Hiremath, MD, MPH1 The KDIGO (Kidney Disease: Improving Global Outcomes) 2012 clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) provides the structural and evidence base for the Canadian Society of Nephrology (CSN) commentary on this guideline’s relevancy and application to the Canadian health care system. While in general agreement, we provide commentary on 13 of the 21 KDIGO guideline statements. Specifically, we agreed that nonpharmacological interventions should play a significant role in the management of hypertension in patients with CKD. We also agreed that the approach to the management of hypertension in elderly patients with CKD should be individualized and take into account comorbid conditions to avoid adverse outcomes from excessive BP lowering. In contrast to KDIGO, the CSN Work Group believes there is insufficient evidence to target a lower BP for nondiabetic CKD patients based on the presence and severity of albuminuria. The CSN Work Group concurs with the Canadian Hypertension Education Program (CHEP) recommendation of a target BP for all non–dialysis-dependent CKD patients without diabetes of #140 mm Hg systolic and #90 mm Hg diastolic. Similarly, it is our position that in diabetic patients with CKD and normal urinary albumin excretion, raising the threshold for treatment from ,130 mm Hg systolic BP to ,140 mm Hg systolic BP could increase stroke risk and the risk of worsening kidney disease. The CSN Work Group concurs with the CHEP and the Canadian Diabetic Association recommendation for diabetic patients with CKD with or without albuminuria to continue to be treated to a BP target similar to that of the overall diabetes population, aiming for BP levels , 130/80 mm Hg. Consistent with this, the CSN Work Group endorses a BP target of ,130/80 mm Hg for diabetic patients with a kidney transplant. Finally, in the absence of evidence for a lower BP target, the CSN Work Group concurs with the CHEP recommendation to target BP , 140/90 mm Hg for nondiabetic patients with a kidney transplant. Am J Kidney Dis. 63(6):869-887. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Hypertension; chronic kidney disease (CKD); Kidney Disease: Improving Global Outcomes (KDIGO); Canadian Society of Nephrology (CSN); commentary; clinical practice guideline.

A

dverse vascular outcomes are the leading cause of morbidity and mortality among patients with chronic kidney disease (CKD). Hypertension is highly prevalent among patients with CKD at all stages and is a modifiable risk factor for adverse vascular events. Over the last several decades, guidelines for management of hypertension in the general population, as well as in patients with CKD, have been developed

by different national professional organizations. These guidelines make recommendations regarding diagnosis and treatment of hypertension. Specifically, they provide guidance regarding when treatment of hypertension should be initiated, the target blood pressure (BP) for a given risk profile, which BP-lowering drugs should be used, and in what order.

From the 1Division of Nephrology, University of Ottawa, Ottawa, Ontario; Departments of 2Medicine and 3Community Health Sciences, University of Calgary, Calgary, Alberta; 4Division of Nephrology, St. Michael’s Hospital, University of Toronto, Toronto; 5Division of Nephrology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa; 6The Li Ka Shing Knowledge Institute, Keenan Research Centre, St. Michael’s Hospital, University of Toronto; 7Division of Nephrology, Humber River Regional Hospital, Toronto, Ontario; 8 Division of Nephrology, Saint John Regional Hospital, Saint John, New Brunswick; 9Division of Nephrology, Seven Oaks General Hospital, University of Manitoba, Winnipeg, Manitoba;

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Am J Kidney Dis. 2014;63(6):869-887

Division of Nephrology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario; and 11Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba. Originally published online April 10, 2014. Address correspondence to Marcel Ruzicka, MD, PhD, FRCPC, Division of Nephrology, University of Ottawa, The Ottawa HospitalRiverside Campus, 1967 Riverside, Suite 5-21, Ottawa, Ontario, Canada K1H 7W9. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.03.003 869

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The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for the management of BP in CKD was based upon a systematic literature search conducted in January 2011 and updated through February 2012.1 KDIGO used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system to rate the quality of evidence and strength of recommendations.2 KDIGO found that the quality of evidence was suboptimal for several of the recommendations. Thus, none of the recommendations had overall quality of evidence rated A, 4 (23.5%) were graded B, 3 (17.7%) were graded C, and the majority of recommendations (10; 58.8%) were graded D. Guideline statements were also evaluated on the strength of recommendation. In all, 8 (47.1%) recommendations were graded 1 (ie, “We recommend”) and 9 (52.9%) were graded 2 (ie, “We suggest”). There were 4 (19.1%) statements which were not graded, where opinion-based recommendations were provided with little or no evidence. The KDIGO Work Group emphasizes that these recommendations are “meant to be a place for clinicians to start, not stop, their inquiries into specific management questions pertinent to the patients they see in daily practice.”1(p338) They further emphasize that these guideline statements are “designed to provide information and assist decision making,”1(p337) not to define a standard of care or an exclusive course of management policy. The purpose of this commentary is to review the evidence supporting the KDIGO recommendations for BP management in non–dialysis-dependent CKD (NDD-CKD) patients, as well as to highlight and discuss differences between KDIGO recommendations and Canadian recommendations by the Canadian Hypertension Education Program (CHEP),3 the Canadian Society of Nephrology (CSN),4 and the Canadian Diabetes Association (CDA).5 The CHEP annually updates guidelines on the diagnosis and management of hypertension in Canada3; CHEP recommendations for the diagnosis and treatment of hypertension in patients with CKD are harmonized with recommendations by the CDA and CSN.4,5 Our Work Group was diverse, consisting of pediatric and adult nephrologists practicing in the community and in academic settings. The CSN Hypertension Work Group recognizes and applauds the work done by the KDIGO Work Group to generate their guideline statements. While there is general agreement between the CHEP, CSN Work Group, CDA, and the KDIGO Work Group on the quality of the available evidence, differences in recommendations between KDIGO and the CSN Work Group relate to interpretation of inconclusive or lacking evidence and the applicability of some 870

recommendations in the Canadian health care system. The KDIGO Work Group and the CSN Commentary Work Group differ on the quality of evidence required to make a recommendation regarding pharmacological management of elevated BP specifically. KDIGO elected to make ungraded recommendations when an intervention was widely accepted in practice and included observational data if randomized controlled trial (RCT) data were considered inadequate. It is the general practice of the CHEP, and endorsed by this CSN Commentary Work Group, to include treatment recommendations only when evidence from RCTs or meta-analyses of RCT data are available. The KDIGO BP guideline and this commentary apply to all NDD-CKD patients and kidney transplant recipients. A specific part of the guideline also addresses BP management in children with NDD-CKD. This commentary is relevant to Canadian adult and pediatric nephrologists, general internists, primary care physicians, and nursing and pharmacy specialists who care for patients with CKD.

REVIEW AND APPROVAL PROCESS FOR CSN COMMENTARIES The development and review of this commentary were consistent with the CSN process set out for the development of clinical practice guidelines. The CSN Clinical Practice Guidelines Committee determined that this commentary was a priority, and a Chair was selected to guide the commentary process. Individual members were selected based on their interest and expertise, taking into consideration relevant conflicts of interest. Commentary development took place during the first 9 months of 2013. The AGREE (Appraisal of Guidelines Research and Evaluation) II instrument was used to evaluate overall guideline quality.6 All guideline statements were independently reviewed and ranked as “concur,” “do not concur,” and “concur, with comments” by each member of the Work Group. The Work Group discussed all guideline statements and reviewed in detail those rated as “do not concur” or “concur, with comments.” Final decisions regarding rating “concur,” “concur, with comments,” or “do not concur” were based on majority vote when we did not have unanimous agreement. This commentary is based on discussions that occurred during several teleconferences and reflect the consensus of the Work Group. All authors approved the final text of the commentary. The commentary was also reviewed by an external review committee established through the CSN Clinical Practice Guidelines Committee. The reviews were considered and responded to, with incorporation of further revisions, before ratification by the CSN Clinical Practice Guidelines Committee. Am J Kidney Dis. 2014;63(6):869-887

CSN Commentary on KDIGO BP Management Guideline 2012

STRUCTURE OF THIS COMMENTARY This commentary does not seek to discuss all KDIGO recommendation statements; rather, it was our intent to focus the commentary on recommendations that were rated by the Work Group as “do not concur” or “concur, with comments” and when implications in the Canadian health care setting were controversial or required discussion. The KDIGO recommendation statements are numbered as in the original and are presented as numbered text within horizontal rules. All recommendations, including those reproduced in the tables, are quoted directly from the KDIGO guideline, and all material is reproduced with permission of KDIGO. Commentary and implications relevant to Canadian health care for selected recommendations are provided in the text when appropriate.

ASSESSMENT OF GUIDELINE QUALITY Five members of the CSN Work Group independently completed the AGREE II instrument6 for the KDIGO management of BP in CKD clinical practice guideline. Overall, the guideline was thought to be of good quality (average score, 6.25/7) and all members agreed that they would recommend the guideline for use, albeit with some modifications. Several areas for improvement in the guideline were identified, including better representation of views and preferences of the target populations and the inclusion of methods, facilitators, and barriers for implication of these guideline recommendations into clinical practice. A summary of the AGREE II instrument scores is provided in Table 1.

OVERVIEW OF KDIGO RECOMMENDATION STATEMENTS The first chapter of the KDIGO document highlights several important concepts relevant to the interpretation of recommendations that are consistent with the approach taken by the CSN Commentary Work Group and CHEP. The KDIGO Work Group based recommendations on targeted BP levels rather than a hybrid of targeted and achieved levels, which is the method used by the CHEP and the CSN Commentary Work Group. Outcomes of interest included kidney disease progression (change in kidney function as measured by estimated glomerular filtration rate [eGFR], kidney failure requiring renal replacement therapy, or death due to kidney failure) and cardiovascular events. Finally, while the KDIGO Work Group indicated that measurements obtained from ambulatory BP monitoring (ABPM) are a better predictor of outcomes, they also acknowledged that much of the existing literature is based on office BP measurements and focused on them for the purpose of making recommendations. Am J Kidney Dis. 2014;63(6):869-887

LIFESTYLE MODIFICATION AND PHARMACOLOGICAL TREATMENTS FOR LOWERING BP An overview of the CSN Work Group’s appraisal of the KDIGO recommendation statements concerning lifestyle and pharmacological treatments for lowering BP in patients with NDD-CKD is provided in Table 2; the rest of this section focuses on guideline recommendations that the Work Group thought merited comment. Assessment for Postural Hypotension 2.2 Inquire about postural dizziness and check for postural hypotension regularly when treating CKD patients with BP-lowering drugs (Not Graded)

Commentary KDIGO notes that patients with CKD are prone to postural hypotension due to underlying autonomic neuropathy associated with CKD and diabetic CKD. Furthermore, as patients with CKD frequently require 3 or more BP-lowering drugs, including vasodilators and sympatholytic agents, to reach the target BP, pharmacological therapy may predispose them to symptomatic postural hypotension. As such, they recommend that symptoms of postural hypotension should be elicited and that BP should be regularly checked supine, seated, and standing, especially after change in antihypertensive therapy. The CSN Work Group believes that while symptomatic postural hypotension is important and should prompt a re-evaluation of antihypertensive therapy, the utility of routinely screening for asymptomatic postural hypotension is not known. Although postural hypotension (presumably as a result of autonomic neuropathy and/or drug therapy) is strongly associated with an increased risk of mortality in epidemiologic studies,7 it has never been shown that altering antihypertensive therapy to reduce asymptomatic postural hypotension or to achieve a target standing BP is of benefit. The CSN Work Group believes that at this time, there is insufficient evidence to recommend routine postural BP monitoring in asymptomatic patients with CKD. Implications Within Canadian Health Care The CSN Work Group endorses regular inquiry about symptoms of postural hypotension in patients with CKD. The CSN Work Group also endorses that in symptomatic patients, supine, seated, and standing BPs are checked regularly, and especially after a change in the BP-lowering regimen. Based on convention, the patient should stand for up to 3 minutes to observe for a fall in BP before postural hypotension can be excluded.8 The 24-hour 871

Ruzicka et al Table 1. Summary of AGREE II Scores for CSN Commentary on KDIGO Clinical Practice Guideline for the Management of BP in CKD Item

AGREE II Ratinga

The overall objective(s) of the guideline is (are) specifically described. The health question(s) covered by the guideline is (are) specifically described. The population (patients, public, etc) to whom the guideline is meant to apply is specifically described.

7 7 7

Domain

Scope and purpose

Stakeholder involvement The guideline development group includes individuals from all the relevant professional groups. The views and preferences of the target population (patients, public, etc) have been sought. The target users of the guideline are clearly defined.

4.25

Rigor of development

Systematic methods were used to search for evidence. The criteria for selecting the evidence are clearly described. The strength and limitations of the body of evidence are clearly described. The methods for formulating the recommendations are clearly described. The health benefits, side effects, and risks have been considered in formulating the recommendations. There is an explicit link between the recommendations and the supporting evidence. The guideline has been externally reviewed by experts prior to its publication. A procedure for updating the guideline is provided.

5.5 4.75 5.5 6 6.5

Clarity of presentation

The recommendations are specific and unambiguous. The different options for management of the condition of health issue are clearly presented. Key recommendations are easily identifiable.

5.75 5.75

Applicability

The guideline describes facilitators and barriers to its application. The guideline provides advice and/or tools on how the recommendations can be put into practice. The potential resource implications of applying the recommendations have been considered. The guideline presents monitoring and/or auditing criteria.

3 3

Editorial independence

The views of the funding body have not influenced the content of the guideline. Competing interests of the guideline development group members have been recorded and addressed.

6.5 7

Overall guideline assessment

Rate the quality of this guideline. I would recommend this guideline for use.

2.25 5.75

5.5 6.5 3

5.75

3 2

6.25 Yes, with modifications

Abbreviations: AGREE, Appraisal of Guidelines Research and Evaluation; BP, blood pressure; CKD, chronic kidney disease; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. a 1 (strongly disagree) to 7 (strongly agree).

ABPM is another important tool to consider for those who report symptoms suggestive of postural hypotension but have no findings of seated or postural hypotension in the office. The CSN Work Group highlights the importance of further research on relevance of postural changes in BP and related adverse outcomes in treated hypertensive patients with CKD. Lifestyle Modification: Healthy Weight 2.3

Encourage lifestyle modification in patients with CKD to lower BP and improve long-term cardiovascular and other outcomes: 2.3.1 We recommend achieving or maintaining a healthy weight (BMI 20 to 25). (1D)

Commentary The CSN Work Group supports the KDIGO recommendation on maintaining a healthy weight and 872

recognized the evidence for a strong relationship between BP and body mass index (BMI) and a nonlinear (J curve) relationship between BMI and all-cause mortality in the general population9 and a potentially paradoxical relationship between BMI and survival in patients on dialysis.10 In addition, the limited data on the effect of weight loss interventions on reducing BP in the general population was recognized. However, the Work Group also thought that alternative measures of obesity, such as waist-tohip ratio, should also be considered as modifiable lifestyle risk factors since observational data suggest that waist-to-hip ratio may be more strongly correlated with cardiovascular outcomes than BMI in the CKD population.11,12 In addition, Canada’s urban population comprises individuals from multiple ethnicities, and as such, cutoffs for BMI derived from predominantly Caucasian cohorts may not apply. In particular, studies have Am J Kidney Dis. 2014;63(6):869-887

CSN Commentary on KDIGO BP Management Guideline 2012 Table 2. Lifestyle and Pharmacological Treatments for Lowering BP in Non–Dialysis-Dependent CKD Patients No.

KDIGO Recommendation Statement

CSN Work Group Rating

2.1

Individualize BP targets and agents according to age, co-existent cardiovascular disease and other comorbidities, risk of progression of CKD, presence or absence of retinopathy (in CKD patients with diabetes) and tolerance of treatment. (Not Graded)

Concur

2.2

Inquire about postural dizziness and check for postural hypotension regularly when treating CKD patients with BP-lowering drugs. (Not Graded)

Concur, with comments

2.3.1

We recommend achieving or maintaining a healthy weight (BMI 20 to 25). (1D)


2.3.2

We recommend lowering salt intake to ,90 mmol (,2 g) per day of sodium (corresponding to 5 g of sodium chloride), unless contraindicated. (1C)


2.3.3

We recommend undertaking an exercise program compatible with cardiovascular health and tolerance, aiming for at least 30 minutes 5 times per week. (1D)


2.3.4

We suggest limiting alcohol intake to no more than two standard drinks per day for men and no more than one standard drink for women. (2D)

Concur

Abbreviations: BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. Reproduced with permission of KDIGO from the KDIGO BP guideline.1

shown that BMI cutoffs as low as 21 kg/m2 may be associated with an increased risk of impaired glucose tolerance in Canadians of South Asian and Chinese descent.13,14 The Work Group would recommend that physicians consider lower cutoffs of BMI as appropriate for Canadians of Asian descent. Implications Within Canadian Health Care CSN Work Group endorses KDIGO recommendation regarding healthy weight in patients with CKD. CSN Work Group recommends waist-to-hip ratio as a further parameter in the assessment of obesity, with particular relevance for adverse cardiovascular outcomes, and recommends that physicians take into account the diversity of Canada’s urban population. This may be consideration of lower BMI cutoffs as appropriate for Canadians of Asian descent.13,14 Am J Kidney Dis. 2014;63(6):869-887

Lifestyle Modification: Salt Intake 2.3.2 We recommend lowering salt intake to , 90 mmol (, 2 g) per day of sodium (corresponding to 5 g of sodium chloride), unless contraindicated. (1C)

Commentary The CSN Work Group supports the KDIGO recommendation on lowering salt intake to ,2 g/d of sodium (corresponding to 5 g of sodium chloride) with the aim of achieving lower BP in hypertensive CKD patients. Since the publication of the KDIGO guideline, the World Health Organization has also published a guideline on salt intake using the GRADE framework2 that incorporates a systematic review.15 It reports a similar estimate of a reduction in systolic BP of 3.4 mm Hg and diastolic BP of 1.5 mm Hg with a dietary reduction of 1.7 g/d or w45% from baseline (mean baseline sodium intake was 3.8 g/d).15 Moreover, in a pooled estimate of 2 trials comparing an intake . 2 g/d versus , 2 g/d, the reductions in BP were 3.5 and 1.8 mm Hg in systolic and diastolic BP, respectively. It should be noted, however, that the participants enrolled in most of these trials received an intensive education program for reduction in salt intake, including actual provision of low-sodium food for the trial period in some trials.16 These data are from the general population and not from the CKD population, but there is no reason to suspect that similar reductions in BP will not be observed since alterations in sodium handling are likely to contribute substantially to elevated BP levels in this population.17 Two small randomized trials published recently, conducted in patients with GFRs , 60 mL/min/1.73 m2, demonstrate a significant reduction in BP after a reduction in salt intake.18,19 Interventions that are efficacious in clinical trials do not always translate well in routine clinical practice.20,21 This may be due to costs, limited availability of the intervention, or challenges with implementation. These issues are even more critical for lifestyle modifications, where provision of the interventions similar to that in a trial, such as a supervised high-intensity aerobic exercise program or actual low-salt meals, would entail significant health care resources beyond those available within the existing infrastructure. Implications Within Canadian Health Care CSN Work Group endorses further research to assess the availability and efficacy of dietary counselling programs for patients with CKD and hypertension in Canada.

Lifestyle Modification: Exercise 2.3.3 We recommend undertaking an exercise program compatible with cardiovascular health and tolerance, aiming for at least 30 minutes 5 times per week. (1D)

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Ruzicka et al Table 3. BP Management in Non–Dialysis-Dependent CKD Patients Without Diabetes Mellitus

No.



3.1 We recommend that non-diabetic adults Concur with CKD ND and urine albumin excretion , 30 mg per 24 hours (or equivalent) whose office BP is consistently . 140 mm Hg systolic or . 90 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently # 140 mm Hg systolic and #90 mm Hg diastolic. (1B) 3.2 We suggest that non-diabetic adults with Do not concur CKD ND and urine albumin excretion 30 to 300 mg per 24 hours (or equivalent) whose office BP is consistently . 130 mm Hg systolic or . 80 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently # 130 mm Hg systolic and #80 mm Hg diastolic. (2D) 3.3 We suggest that non-diabetic adults with CKD ND and urine albumin excretion . 300 mg per 24 hours (or equivalent) whose office BP is consistently . 130 mm Hg systolic or .80 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently # 130 mm Hg systolic and #80 mm Hg diastolic. (2C)

Do not concur

Concur, with 3.4 We suggest that an ARB or ACE-I be comments used in non-diabetic adults with CKD ND and urine albumin excretion of 30 to 300 mg per 24 hours (or equivalent) in whom treatment with BP-lowering drugs is indicated. (2D) 3.5 We recommend that an ARB or ACE-I be Concur, with comments used in non-diabetic adults with CKD ND and urine albumin excretion . 300 mg per 24 hours (or equivalent) in whom treatment with BP-lowering drugs is indicated. (1B) Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BP, blood pressure; CKD ND, non–dialysis-dependent chronic kidney disease; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. Reproduced with permission of KDIGO from the KDIGO BP guideline.1

Commentary The CSN Work Group supports the KDIGO recommendation on undertaking an exercise program compatible with cardiovascular health and tolerance. There is evidence from the general population, based on a systematic review of 21 trials which reported that a supervised program of aerobic exercise of 30-60 minutes 5 times per week can reduce systolic BP by a pooled estimate of 4.6 mm Hg and diastolic BP by 2.6 mm Hg.22 A second systematic review examined 874

the effects of exercise (including cardiovascular training, mixed cardiovascular and resistance training, resistance-only training, and yoga) in CKD patients specifically and reported BP outcomes.23 The review reports a similar overall reduction in BP (mean difference, 6.1 mm Hg in systolic from 9 trials and 2.3 mm Hg in diastolic from 11 trials) as the previous review conducted in the general population.23 However, in subgroup analyses, the effects on both systolic and diastolic BP were significant in the pooled analysis of trials when exercise training was supervised (and was not significant in trials when it was unsupervised) and in trials with high-intensity exercise training (and not significant in trials with low-intensity exercise).23 These subgroup analyses should be interpreted with caution given the small number of trials and patients involved. Both these reviews showed significant heterogeneity and possibility of bias due to small study effect24 and thus the true effect of exercise on BP is likely to be somewhat smaller. Implications Within Canadian Health Care CSN Work Group endorses further research to assess the availability and efficacy of exercise programs for patients with CKD and hypertension in Canada.

BP MANAGEMENT IN NDD-CKD PATIENTS WITHOUT DIABETES Table 3 provides an overview of the CSN Work Group’s assessment of the KDIGO guideline recommendations concerning management of BP in NDDCKD patients without diabetes mellitus. BP Treatment Targets 3.1 We recommend that non-diabetic adults with CKD ND and urine albumin excretion , 30 mg per 24 hours (or equivalent) whose office BP is consistently . 140 mm Hg systolic or .90 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently # 140 mm Hg systolic and #90 mm Hg diastolic. (1B) 3.2 We suggest that non-diabetic adults with CKD ND and urine albumin excretion 30 to 300 mg per 24 hours (or equivalent) whose office BP is consistently . 130 mm Hg systolic or .80 mm Hg diastolic be treated with BPlowering drugs to maintain a BP that is consistently #130 mm Hg systolic and #80 mm Hg diastolic. (2D) 3.3 We suggest that non-diabetic adults with CKD ND and urine albumin excretion . 300 mg per 24 hours (or equivalent) whose office BP is consistently .130 mm Hg systolic or .80 mm Hg diastolic be treated with BPlowering drugs to maintain a BP that is consistently #130 mm Hg systolic and #80 mm Hg diastolic. (2C)

Commentary The CSN Work Group evaluated evidence to support graded targets for BP in nondiabetic CKD according to urinary albumin excretion, as CSN and CHEP recommend a target BP of #140 mm Hg Am J Kidney Dis. 2014;63(6):869-887


systolic and #90 mm Hg diastolic for all individuals with NDD-CKD without diabetes, regardless of presence or amount of urinary albumin excretion.3,4 There are 4 relevant studies referenced by the KDIGO guideline which formed the basis for their recommendations regarding target BP: the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), the REIN-2 (Blood Pressure Control for Renoprotection in Patients With Non-Diabetic Chronic Renal Disease) trial, and the ESCAPE (Effect of Strict Blood Pressure Control and ACE [angiotensin-converting enzyme] Inhibition on the Progression of CRF in Pediatric Patients) trial.25-28 The first 3 studies will be discussed in detail in this commentary as they also formed the basis on which the CHEP and CSN Work Group based their target BP recommendations, which are in contrast to KDIGO.26-28 The ESCAPE trial was conducted in a pediatric population and its relevance to the adult population is limited.25 The MDRD Study randomized patients with CKD and reduced GFR to a usual-BP target (MAP [mean arterial pressure] of 107 mm Hg; w140/90 mm Hg) or a low-BP target (MAP of 92 mm Hg if #60 years of age, or 98 mm Hg if .60 years of age; w125/ 75 mm Hg and w130/80 mm Hg, respectively). There was no difference in slope of decline in GFR or the secondary outcomes of kidney failure, death, a composite of kidney failure and death, or cardiovascular events. Long-term follow-up of the MDRD Study cohort suggested that individuals originally randomized to the low-BP target had a lower risk of kidney failure. Unfortunately, no data were available about the therapy that the patients received following the trial or the targeted and achieved BPs in each group.28 In the original MDRD Study, results of subgroup analyses showed a significant interaction between the baseline level of proteinuria and the BP target to which patients were randomized (P value for interaction 5 0.02). It appeared that individuals with proteinuria with protein excretion .1 g/d benefited most from more intensive BP control.28 In a reanalysis of the trial data, the rate of GFR decline increased when the achieved MAP was . 98 mm Hg (w130/80 mm Hg) in those with proteinuria with protein excretion . 0.25 g/d. In patients with $3 g of proteinuria per day, the rate of GFR decline increased above an MAP of 92 mm Hg (w125/75 mm Hg).29 Although there was a suggestion that patients with higher degrees of proteinuria at baseline may benefit from a lower BP target, these findings should be considered hypothesis generating as they are based on post hoc subgroup analyses. These results are further limited as proteinuria categories were not Am J Kidney Dis. 2014;63(6):869-887

prespecified, randomization was not stratified on the basis of level of proteinuria, and baseline patient characteristics were not presented according to subgroup. In addition, there were no a priori power calculations done for the subgroups and the level of statistical significance was not adjusted for multiple testing. Finally, the use of ACE inhibitors was higher in the patients assigned to the low-BP target, and this may have influenced the outcomes. AASK had a 3 3 2 factorial design that randomized African American patients with nondiabetic CKD to one of 3 different classes of antihypertensive medications (ACE inhibitor, calcium channel blocker, or b-blocker) and a standard-BP goal (MAP of 102107 mm Hg) or a low-BP goal (MAP of 92 mm Hg).26 BP group assignment had no effect on the primary outcome of interest (rate of change in GFR as measured by GFR slope) or the secondary outcomes of GFR event, end-stage renal disease (ESRD), or death; GFR event or ESRD; ESRD or death; or ESRD alone. There was a 17% reduction in proteinuria in the low-BP group compared to a 7% increase in proteinuria in those randomized to the standard-BP goal. As in the MDRD Study,28 the authors noted a significant interaction between the level of baseline proteinuria and the BP groups to which patients were assigned (P 5 0.007). The interaction was interpreted to mean that individuals with higher levels of proteinuria might benefit from more intensive BP targets. However, it appeared to be driven by worse outcomes in patients with low-grade proteinuria assigned to the low-BP group. The authors went on to stratify the analysis according to baseline proteinuria and report that the effect of BP target on outcomes “was not significantly different within either the lower (baseline urinary protein-creatinine ratio # 0.22 mg/ mg) or higher (baseline urinary protein-creatinine ratio . 0.22 mg/mg) proteinuria strata”26(p2428) for the secondary clinical composite outcome (doubling of serum creatinine level, kidney failure, or death). A subsequent study presented a re-analysis of AASK and the outcomes of patients followed up beyond the end of the trial for a total of 8.8-12.2 years.30 In this study, the primary focus was on progression of CKD, defined as doubling of serum creatinine level, diagnosis of ESRD, or death (the secondary clinical outcome from the original trial). Again, there was no overall effect of BP target on outcomes, but the authors reported a significant reduction in the relative hazard of the outcome in those with a protein-creatinine ratio . 0.22 mg/mg during the trial phase (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.56-0.99) and for both phases combined (HR, 0.73; 95% CI, 0.58-0.99).30 This finding appeared to contradict the original report for reasons that are unclear, but might relate to 875

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differences in the way that data were analyzed. The study was a post hoc subgroup analysis of a secondary outcome from the original trial. Again, randomization was not stratified based on level of proteinuria, the proteinuria categories were not specified prior to the start of the trial, and the level of statistical significance was not adjusted to account for multiple testing. The results from the MDRD Study and AASK should be interpreted with caution as they are post hoc subgroup analyses of RCT data. There are a number of examples in the medical literature where subgroup analyses of RCTs have suggested clinically important heterogeneity of treatment effects that were subsequently shown to be false.31 Further, guidelines have been proposed for the design, analysis, interpretation, and reporting of subgroup analyses to encourage best practices31 and a number of these recommendations were violated in the subgroups analyses from the MDRD Study and AASK, as outlined previously. There is another consideration relevant to the post hoc analyses discussed. A paper comparing the results of analyses based on achieved BP to intention-to-treat analyses in AASK yielded important findings.32 In the intention-to-treat analyses, the authors showed that there was no difference in renal outcomes (rate of decline in GFR and the clinical composite outcome of decline in GFR, need for dialysis, transplantation, or death) in individuals assigned to the low-BP group compared to those assigned to the usual-BP group. However, when the analysis was repeated, each 10–mm Hg increase in achieved BP was associated with a 0.35–mL/min/1.73 m2 faster decline in GFR (95% CI, 0.08-0.62 mL/min/1.73 m2) and a 17% increased risk of the clinical composite outcome (95% CI, 5%-32%).32 The results of this analysis suggest that individuals who achieve lower BPs (compared to those who do not achieve lower BPs), regardless of treatment assignment, are different in meaningful ways. Hence caution should be exercised when interpreting the findings of these post hoc analyses of achieved BPs. Ultimately, the best test of the validity of subgrouptreatment effect interactions is our ability to reproduce them in clinical trials. The REIN-2 trial was designed to specifically address the benefit of more intensive BP control in individuals with proteinuric renal disease.27 REIN-2 is the only RCT to date designed to examine the impact of intensive BP control on outcomes in individuals with nondiabetic CKD and high-grade proteinuria. The REIN-2 investigators randomly assigned patients with proteinuria with protein excretion . 1 g/d to either an intensified BP target (,130/80 mm Hg) or a conventional BP target (diastolic BP , 90 mm Hg). All individuals enrolled 876

in the study received ramipril. Felodipine was added at a dose of 5-10 mg/d to achieve targets and investigators were permitted to use additional agents as necessary. Ultimately, the study was stopped at a median follow-up of 19 months due to futility. At the time that the trial was terminated, there was no significant difference in outcomes between the 2 BP groups (HR, 1.00; 95% CI, 0.61-1.64).27 The REIN-2 trial has been criticized due to the small differences in achieved BP in the 2 groups, the use of a dihydropyridine calcium channel blocker in the intensive control arm, the short duration of followup, and the fact that the small sample size limited power to rule out a clinically important difference. However, it is the only randomized trial to explicitly look at the issue of whether intensive BP control leads to better outcomes in individuals with proteinuric renal disease. Altogether, although there is a suggestion that tighter BP control in individuals with nondiabetic CKD and higher levels of proteinuria may improve outcomes, the data are of low quality and the single RCT to directly address this issue in the adult population showed no benefit. While the CSN Work Group cannot rule out a benefit of more stringent BP targets, we do not think that there is sufficient evidence to support such a recommendation in individuals with nondiabetic CKD, regardless of the level of proteinuria. Whether a lower target for BP would benefit patients with proteinuria with protein excretion .300 to 1,000 mg/d requires further study.33 Implications Within Canadian Health Care The CSN Work Group, for reasons outlined previously, believes there is insufficient evidence to target a lower BP for NDD-CKD patients based on the presence and severity of albuminuria. The CSN Work Group concurs with the CHEP recommendation of a target BP for all NDD-CKD patients of #140 mm Hg systolic and #90 mm Hg diastolic. Further research is required to determine the optimal target BP in NDD-CKD patients.

Angiotensin Receptor Blockers and ACE Inhibitors 3.4 We suggest that an ARB or ACE-I be used in nondiabetic adults with CKD ND and urine albumin excretion of 30 to 300 mg per 24 hours (or equivalent) in whom treatment with BP-lowering drug is indicated. (2D) 3.5 We recommend that an ARB or ACE-I be used in nondiabetic adults with CKD ND and urine albumin excretion . 300 mg per 24 hours (or equivalent) in whom treatment with BP-lowering drug is indicated. (1B)

Commentary CSN Work Group is largely in agreement with these recommendations. The KDIGO recommendations cite 5 relevant studies: re-analyses of the HOPE Am J Kidney Dis. 2014;63(6):869-887


(Heart Outcomes Prevention Evaluation) trial,34 the CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan) trial,35 TRANSCEND (Telmisartan Randomised Assessment Study in Subjects with Cardiovascular Disease),36 as well as the Makino et al37 study, and the IDNT (Irbesartan in Development of Nephropathy in Patients with Type 2 Diabetes) trial.38 The CSN and CHEP have historically considered the evidence for diabetic and nondiabetic CKD separately, although KDIGO argues that there is no compelling reason to treat these groups differently. In this commentary, we focus on the evidence in nondiabetic CKD and in particular on studies focusing on the renal end points identified as being of primary importance above. A meta-analysis of 11 RCTs included studies of patients with nondiabetic CKD treated with BPlowering regimens containing ACE inhibitors to those not containing ACE inhibitors.39 All trials included in the analysis targeted a BP , 140/90 mm Hg and nearly all patients were hypertensive at baseline. In their analysis, the use of an ACE inhibitor was associated with a significant reduction in the risk of progression of kidney disease as defined by doubling of serum creatinine or the need for dialysis. This effect was independent of other important covariates, including baseline BP and urinary protein excretion. Of relevance, there was no significant interaction between current urinary protein excretion and treatment allocation. In other words, there was no evidence that degree of protein excretion modified the relationship between the use of ACE inhibitors and progression of kidney disease. The results of the meta-analysis suggest that ACE inhibitors should be the antihypertensive of choice in individuals with CKD and hypertension.39 However, another analysis of the same data set suggested that baseline urinary protein excretion was an important effect modifier in that those with baseline urine protein excretion $ 500 mg/d seemed to have greater benefits with ACE-inhibitor therapy.40 Those with proteinuria , 500 mg/d at baseline appeared to receive little if any benefit compared to other antihypertensive regimens. In ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial), investigators randomized patients 55 years of age or older who had a history of atherosclerotic vascular disease or diabetes with end-organ damage to ramipril, telmisartan, or the combination of both drugs.41 The primary outcome of interest was the combined end point of dialysis, doubling of serum creatinine, or death. There was no significant difference in the primary outcome between ramipril and telmisartan alone (HR, 1.00; 95% CI, 0.92-1.09), but combination therapy increased the risk (HR, 1.09; 95% CI, 1.01-1.18; Am J Kidney Dis. 2014;63(6):869-887

P 5 0.037). In predefined subgroups defined by the presence of diabetes, hypertension, microalbuminuria, macroalbuminuria, or an eGFR , 60 mL/min/1.73 m2, the results were consistent. The ONTARGET results suggest that ACE inhibitors and angiotensin receptor blockers (ARBs) are associated with similar renal outcomes in high-risk patients.41 TRANSCEND randomized patients at high vascular risk, who were intolerant of ACE inhibitors, to telmisartan or placebo.42 No difference was observed between groups in the primary cardiovascular end point or the secondary renal end point of dialysis, doubling of serum creatinine, or death. While the KDIGO guideline does not comment on the use of ACE inhibitors in individuals with albuminuria , 30 mg/d, in a re-analysis of TRANSCEND, a significant interaction between baseline urinary albumin excretion and treatment allocation was observed (P value for interaction 5 0.006).36 Individuals without microalbuminuria had an increased risk of the renal end point, while there was no significant difference in those with urinary albumin excretion $ 30 mg/d, although the trend favored telmisartan. This was a post hoc subgroup analysis of the larger trial and as a result, suffers from the limitations detailed previously.31 It should be considered hypothesis generating. In summary, our review of the evidence suggests that ACE inhibitors appear to be associated with improved outcomes in individuals with nondiabetic CKD relative to other classes of antihypertensives. Lower quality evidence suggests that ACE inhibitors and ARBs are equivalent with respect to renal outcomes and that ARBs may be harmful in individuals with urinary albumin excretion , 30 mg/d. Implications Within Canadian Health Care The CSN Work Group concurs with the KDIGO recommendation that an ARB or ACE inhibitor be used in nondiabetic adults with NDD-CKD and urine albumin excretion . 30 mg/d.

BP MANAGEMENT IN NDD-CKD PATIENTS WITH DIABETES Table 4 provides an overview of the CSN Work Group’s appraisal of the KDIGO guideline recommendations concerning management of BP in NDDCKD patients with diabetes mellitus. BP Treatment Target in the Context of Normal Urinary Albumin Excretion 4.1 We recommend that adults with diabetes and CKD ND with urine albumin excretion , 30 mg per 24 hours (or equivalent) whose office BP is consistently . 140 mm Hg systolic or .90 mm Hg diastolic be treated with BPlowering drugs to maintain a BP that is consistently # 140 mm Hg systolic and #90 mm Hg diastolic. (1B)

877

Ruzicka et al Table 4. BP Management in Non–Dialysis-Dependent CKD Patients With Diabetes Mellitus

No.



4.1 We recommend that adults with diabetes Do not concur and CKD ND with urine albumin excretion , 30 mg per 24 hours (or equivalent) whose office BP is consistently . 140 mm Hg systolic or .90 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently #140 mm Hg systolic and #90 mm Hg diastolic. (1B) 4.2 We suggest that adults with diabetes and Concur CKD ND with urine albumin excretion . 30 mg per 24 hours (or equivalent) whose office BP is consistently . 130 mm Hg systolic or .80 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently # 130 mm Hg systolic and # 80 mm Hg diastolic. (2D) 4.3 We suggest that an ARB or ACE-I be Concur used in adults with diabetes and CKD ND with urine albumin excretion of 30 to 300 mg per 24 hours (or equivalent). (2D) 4.4 We recommend that an ARB or ACE-I be Concur used in adults with diabetes and CKD ND with urine albumin excretion . 300 mg per 24 hours (or equivalent). (1B) Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BP, blood pressure; CKD ND, non–dialysis-dependent chronic kidney disease; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. Reproduced with permission of KDIGO from the KDIGO BP guideline.1

Commentary This recommendation examines the treatment thresholds and targets for BP in people with diabetes, hypertension, and NDD-CKD with normal albuminuria. KDIGO recommends that in this group, BP be treated with antihypertensives to reduce BP to # 140/90 mm Hg. This is a significant departure from previous recommendations where this group would be targeted for a BP , 130/80 mm Hg. The rationale for this was that KDIGO could not identify RCTs that included patients with diabetes, CKD, and normoalbuminuria that randomized patients to various BP targets. However, as we discuss next, there is evidence that lowering BP to ,130/ 80 mm Hg is associated with a reduced risk of stroke and a reduced rate of progression of nephropathy in the general diabetes population,43 and that people with diabetes and hypertension without albuminuria are at a higher risk of stroke and progressive renal disease than those with diabetes who are free of 878

CKD. While KDIGO Recommendation 4.1 may be methodologically correct, it leads to an illogical situation where Canadians with diabetes are recommended to have a systolic BP # 130 mm Hg in order to reduce the risk of stroke and progressive renal disease, with the exception of a group that are at a higher risk of these outcomes (ie, diabetes and CKD without albuminuria). The presence of CKD as manifested by a low GFR is associated with a higher risk of stroke. This increased risk appears to be independent of BP level. The ARIC (Atherosclerosis Risk in Communities) Study followed up a prospective cohort of middleaged individuals for 9 years to investigate the causes of atherosclerosis.44 In an examination of 13,716 individuals free of cerebrovascular disease at baseline, it was determined that the risk of stroke was nearly double in those with CKD as defined by a creatinine clearance , 60 mL/min (HR, 1.81; 95% CI, 1.26-2.02). The mean BP in this study was 120.9 6 18.2/73.9 6 11.1 mm Hg for those with a creatinine clearance $ 60 mL/min and 119.8 6 20.8/ 70.8 6 11.5 mm Hg for those whose creatinine clearance was ,60 mL/min (P , 0.05 for differences in both systolic and diastolic BP). In PROGRESS (Perindopril Protection Against Recurrent Stroke Study), 6,105 patients were randomized to either an ACE inhibitor, an ACE inhibitor–thiazide combination, or placebo.45 Of these, 1,757 patients had CKD as defined by a creatinine clearance , 60 mL/min. In this study, the risk of stroke was w50% higher in those with CKD (crude HR, 1.49; 95% CI, 1.28-1.73; P , 0.0001). The mean BP was 149 6 20/84 6 11 mm Hg in those with a creatinine clearance , 60 mL/min and was 146 6 19/ 86 6 11 mm Hg in those whose creatinine clearance was $ 60 mL/min (P , 0.0001 for differences in both systolic and diastolic BP). In the HOPE Study, 9,297 high-cardiovascular-risk patients were randomized to either ramipril or placebo.46 Of these, 3,394 had a creatinine clearance , 65 mL/min and their risk of stroke was higher than of those with a higher level of renal function (5.2% vs 3.5%). In the HOPE Study, the mean baseline BP for those on ramipril was 138.4 6 19.7/78.9 6 10.6 mm Hg in those without renal insufficiency, and 141.3 6 20.8/78.5 6 11.4 mm Hg for those with renal insufficiency. Within the Canadian context, Bello et al47 reported on a longitudinal cohort study from Alberta of 920,985 patients followed up for a median of 35 months, examining the relationship between markers of renal disease and future cardiovascular events. For patients with normal proteinuria, the risks of stroke/transient ischemic attack for an eGFR of $60 mL/min/1.73 m2, 45-59 mL/min/1.73 m2, 30-45 mL/min/1.73 m2, and Am J Kidney Dis. 2014;63(6):869-887


15-29 mL/min/1.73 m2 were 0.58, 0.68, 0.73, and 0.83 events per 1,000 patient-years, respectively. These studies demonstrate that individuals with impaired renal function represent a group with a high risk of stroke. The presence of impaired renal function (including in those with normoalbuminuria) appears to be associated with a stroke risk that is w50% higher than in those with higher levels of renal function. The UK Prospective Diabetes Study (UKPDS) Group examined the impact of less tight BP control (,180/105 mm Hg) with tighter control (,150/ 85 mm Hg).48 The UKPDS is one of the first trials in this area, and in that era, tight control was defined less aggressively than now. However, 1,148 people with type 2 diabetes and hypertension were randomized and followed up for a median of 8.4 years, with tight BP control being associated with a 44% reduction in stroke (95% CI, 11%-65%; P 5 0.019) The ABCD (Appropriate Blood Pressure Control in Diabetes Trial) Normotensive study examined the impact of more intensive versus conventional control of BP in “normotensive” people with diabetes (diastolic BP, 80-89 mm Hg).49 The intensive arm was targeted for a reduction in diastolic BP from baseline of 10 mm Hg; 480 patients were followed up for a mean of 5.3 years. The patients generally did not have advanced kidney disease (mean starting creatinine clearance, w85 6 2 mL/min, w23% having albuminuria). The intensive-control arm achieved a mean BP during the last 4 years of follow-up of 128/75 versus 137/81 mm Hg in the control group (P , 0.0001). Intensive BP control was associated with a significant reduction in stroke (relative risk [RR], 0.30; 95% CI, 0.10-0.94; P 5 0.03). Importantly, this stroke reduction was seen in a population that was presumably at lower risk for stroke than patients with diabetes and more advanced CKD.49,50 Reboldi et al51 reported on a meta-analysis of 31 trials consisting of 73,913 patients with diabetes, examining the impact of intensive BP control on the risk of cardiovascular events. In this meta-analysis, allocation to tighter BP control significantly reduced the risk of stroke by 39% (RR, 0.61; 95% CI, 0.48-0.79; P , 0.001), and each 5–mm Hg reduction in systolic BP led to a 13% reduction of stroke (RR, 0.870; 95% CI, 0.797-0.950; P 5 0.006). A second meta-analysis reported by Bangalore et al43 examined 13 trials that studied a total of 37,736 individuals with either type 2 diabetes or impaired fasting glucose/impaired glucose tolerance. This metaanalysis demonstrated that control of systolic BP to ,130 mm Hg was associated with a halving of the risk of stroke (odds ratio [OR], 0.53; 95% CI, 0.38-0.75). Am J Kidney Dis. 2014;63(6):869-887

The recent ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial followed up 4,733 people with diabetes for a mean of 4.7 years and examined the impact of tight (systolic BP , 120 mm Hg) versus less tight (,140 mm Hg) BP control on macro- and microvascular outcomes.52 The median baseline albumin-creatinine ratio was 14.3 mg/g, just below the microalbuminuria threshold, and the mean eGFR was 91.6 6 28.8 mL/min/1.73 m2. Thus, while some patients would have had stage 3 CKD with or without albuminuria, few patients would have had more advanced CKD. While there was no difference in the primary composite cardiovascular outcome or the death rate, there was a significant reduction in the prespecified secondary end point of stroke (HR, 0.59; 95% CI, 0.39-0.89; P 5 0.01).52 This is consistent with the Reboldi et al51 and Bangalore et al43 metaanalyses, as well as the findings of the ABCD Study.49 Both diabetes and hypertension are well understood to be major risk factors for progressive kidney disease. It is beyond the scope of this article to review all the literature that verifies these as important renal risk factors; however, we will examine 2 trials as representative examples. ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) is a good example of the impact of diabetes as a renal risk factor amongst individuals with hypertension. ALLHAT tested various forms of antihypertensive drug therapy in more than 30,000 hypertensive individuals.53 In this study, ESRD was more than twice as likely to occur in people with diabetes (OR, 2.66). The impact of hypertension on the risk of ESRD among people with diabetes was examined by Hsu et al,54 who reported on the risk of ESRD due to hypertension by examining a historical cohort of 316,675 adults (29,220 with diabetes) whose health insurance was provided by Kaiser Permanente of Northern California. All these people had a GFR $ 60 mL/min/1.73 m2 and had no evidence of proteinuria or hematuria on dipstick at baseline. After more than 8 million patient-years of follow-up, a strong relationship between baseline BP and ESRD risk was identified. In those with diabetes, the risk of ESRD was 13/100,000 patient-years for patients with optimal BP, 27/100,000 patient-years for normal but not optimal BP, 40/100,000 patient-years for high normal BP, 49/100,000 patient-years for stage 1 hypertension, 44/100,00 patient-years for stage 2 hypertension, 59/100,00 patient-years for stage 3 hypertension, and 54/100,00 patient-years for stage 4 hypertension.54 These studies and many others demonstrate that people with diabetes are more likely to develop kidney disease that progresses to ESRD, and that progressively higher BPs are associated with increasing 879

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risk of ESRD amongst people with diabetes. These data would suggest that targeting an aggressive lowering of BP could potentially reduce the progression of renal disease in people with diabetes. Three trials have targeted different levels of BP control with an aim to demonstrate a reduction in progression of renal disease in people with diabetes. UKPDS 38 (described previously) found that tighter BP control was associated with a 37% reduction in microvascular end points, including progression of nephropathy (P 5 0.0092).48 Renal failure was numerically reduced, but was a rare event with wide CIs (RR, 0.58; 95% CI, 0.15-2.21). Progression to microalbuminuria was also reduced, reaching statistical significance at some time points. The RR for the development of microalbuminuria was 0.77 (95% CI, 0.55-1.09), 0.71 (95% CI, 0.51-0.99), and 0.87 (95% CI, 0.60-1.29) at 3, 6, and 9 years, respectively.48 The ABCD Normotensive Study (described previously) also found a reduction in the progression of renal disease when lower BP levels were targeted (128/75 vs 137/81 mm Hg).49 The RR of progressing from normoalbuminuria to microalbuminuria was 0.61 (P 5 0.02), and the RR of progressing from microalbuminuria to overt nephropathy was 0.49 (P 5 0.02). Finally, the ACCORD Study (described previously) again demonstrated that aggressive BP targets (systolic BP , 120 vs ,140 mm Hg) reduced the progression of renal disease.52 The development of macroalbuminuria was reduced in the aggressive-BP group (RR, 0.76; P 5 0.009). While these studies have demonstrated that achieving systolic BP levels of ,130 mm Hg are associated with a reduction in stroke and less progression of nephropathy, other outcomes have not benefited from lower BP levels. In particular, these studies do not demonstrate a benefit of aggressive BP control on the rates of myocardial infarction or overall mortality in people with diabetes. While proteinuria outcomes are reduced by aggressive BP control, there has not been any clear demonstration that rates of decline of GFR or occurrence of ESRD are also reduced. The evidence we have presented suggests that the presence of CKD raises the risk of stroke. The evidence presented would also suggest that in people with diabetes, aggressive control of BP to levels # 130/80 mm Hg is associated with a reduction in the risk of stroke. The KDIGO group is correct that people with diabetes and nonproteinuric CKD have not been specifically targeted in BP trials; however, suggesting that this higher-stroke-risk group be assigned a higher BP target than the general diabetes population is not logical. This approach could be supported if there were evidence that 880

this population would not benefit to the same extent as the general diabetes population or if there were evidence of increased toxicity of treatment in this group. Such evidence does not exist, nor is there an a priori reason to expect that this would be the case. In addition to the benefit of reduction in stroke, a lower BP target may slow progression of renal disease in people with diabetes, including those with normoalbuminuria. It is important to recognize that the population of people with diabetes is very heterogeneous, with substantial person-to-person variation in age, race, family history, body habitus, presence of cardiovascular risk factors, presence of micro- or macrovascular complications, duration of diabetes, severity of dysglycemia, etc. It will always be possible to subdivide the general diabetes population finely enough to produce subgroups that have not been specifically targeted in RCTs. Taken to an extreme, it would be possible to subdivide the diabetes population so finely that the general diabetes guidelines do not apply to any given individual with diabetes, as that individual would fall into a subtype that had not been specifically selected for study. In the case of people with diabetes, there already exists a large body of epidemiologic and clinical trial evidence regarding BP targets, and there is a general guideline to aim for a BP , 130/80 mm Hg in this population.5 In the absence of evidence for a unique BP target in a particular subgroup, the general diabetes target should be used unless there are compelling reasons to suspect that this target should not apply. This is particularly relevant for subgroups at high risk for complications that are known to be reduced by aggressive BP control. It is our position that raising the threshold for treatment from 130 mm Hg systolic BP to 140 mm Hg systolic BP could increase stroke risk and the risk of worsening kidney disease in people with diabetes and NDD-CKD without albuminuria. As the Canadian target for BP is # 130/80 mm Hg in people with diabetes,5 we recommend that patients with diabetes and NDD-CKD without albuminuria be treated to the same BP target as the general diabetes population. Implications Within Canadian Health Care We have argued that the movement of the BP target for diabetes and NDD-CKD without albuminuria to higher values may not be advisable. However, this does not imply that the Canadian guideline targets for BP in diabetes are beyond criticism. First, these guidelines have not been standardized on whether clinical trials should be evaluated based on targeted BP or achieved BP. For example, the systolic BP target of ,130 mm Hg comes primarily from the ABCD Normotensive trial.49 This study enrolled Am J Kidney Dis. 2014;63(6):869-887


individuals with a diastolic BP between 80 and 89 mm Hg and targeted a reduction of 10 mm Hg in the intervention arm. There was no targeted effect on systolic BP. The intervention arm of the study achieved a mean BP for the last 4 years of follow-up of 128 6 0.8/75 6 0.3 mm Hg. The positive effects on renal and stroke outcomes led to the adoption of a systolic BP target of ,130 mm Hg, based on the achieved systolic BP in the ABCD Normotensive Study.49 For diastolic BP, one of the strongest arguments in favor of a target of ,80 mm Hg came from the HOT (Hypertension Optimal Treatment) trial, where 18,790 people with a diastolic BP between 100 and 115 mm Hg were randomized to a diastolic BP target of #90, #85, or #80 mm Hg and followed up for an average of 3.8 years.55 Amongst the 1,501 patients with diabetes, major cardiovascular events and cardiovascular death were lower in the lowest diastolic BP group (RR for major cardiovascular events of 2.06 for #90 vs #80 mm Hg; 95% CI, 1.24-3.44; P for trend 5 0.005; RR for cardiovascular mortality of 3.0 for #90 vs #80 mm Hg; 95% CI, 1.28-7.08; P for trend 5 0.016). Unlike for systolic BP, where the achieved BP was used in establishing the target, for diastolic BP, the targeted value of #80 mm Hg was used, even though the average achieved BP was slightly higher than the target (81.1 6 5.3 mm Hg). This lack of consistency becomes even more important when critiquing trials where there were large differences between targeted and achieved BP values. For example, in the ACCORD trial, patients were randomized to a systolic BP target of either ,120 or ,140 mm Hg.52 The achieved values were 119.3 (95% CI, 118.9119.7) mm Hg in the ,120–mm Hg group and 133.5 (95% CI, 133.1-133.8) mm Hg in the ,140–mm Hg group. When considering ACCORD, the achieved and targeted systolic BPs for the ,120–mm Hg group are very similar, but this is not the case for the ,140–mm Hg group. When synthesizing the results of ACCORD, it is important to be clear whether achieved or targeted systolic BP values should be used when examining the ,140–mm Hg group. Consistent standards would be helpful in making this determination. The second major criticism of the Canadian guidelines is that there has not been a consistent definition of clinically important events. As described previously, the ,130–mm Hg systolic BP target for people with diabetes has been primarily justified using the positive effects on stroke and renal disease seen in the ABCD Normotensive Study. Rates of progression from normoalbuminuria to microalbuminuria and from microalbuminuria to overt proteinuria in the ABCD Normotensive Study, as well as stroke, were prespecified secondary outcomes. However, ACCORD was seen to be a null clinical trial by the CHEP, the Am J Kidney Dis. 2014;63(6):869-887

CDA, and CSN because of a null primary composite end point and a null effect on mortality. Yet ACCORD showed some positive effect on secondary outcomes, including stroke and renal progression, the same end points impacted by lower BP in the ABCD Normotensive Study. If prespecified secondary outcomes such as stroke and progression of renal disease are not considered important enough to justify changing a BP target based on ACCORD data, then the ABCD Normotensive Study should be discarded from consideration by guideline groups, and presumably the systolic BP target should be raised to ,140 mm Hg. However, if same secondary outcomes are important enough to impact on guideline BP targets, then ACCORD could be considered a positive trial in the same way as the ABCD Normotensive Study, and careful consideration would need to be given to dropping the systolic BP target to ,120 mm Hg, taking into account the magnitude of the benefits as well as the risks described in ACCORD. The KDIGO group has done excellent work in reviewing a large body of literature pertaining to BP targets in people with CKD and diabetes. We are in agreement with all of the KDIGO recommendations in this chapter, with the exception of 4.1. It is our recommendation that in the Canadian context, people with diabetes and CKD with or without albuminuria continue to be treated to a BP target similar to that of the overall diabetes population, aiming for BP levels , 130/80 mm Hg.

BP MANAGEMENT IN KIDNEY TRANSPLANT RECIPIENTS Table 5 provides an overview of the CSN Work Group’s assessment of the KDIGO guideline recommendations concerning management of BP in kidney transplant recipients. BP Treatment Target 5.1 We suggest that adult kidney transplant recipients whose office BP is consistently . 130 mm Hg systolic or .80 mm Hg diastolic be treated to maintain a BP that is consistently # 130 mm Hg systolic and #80 mm Hg diastolic, irrespective of the level of urine albumin excretion. (2D)

Commentary The KDIGO recommendation is based on Grade D evidence, due to a paucity of studies directly informing BP targets (and a threshold for initiating therapy) in kidney transplant recipients.55 The 2013 CHEP guidelines recommend a BP target and treatment initiation threshold of ,140/90 mm Hg for patients with nondiabetic CKD.3 This target was based on Grade B evidence in nontransplantation individuals with nondiabetic CKD. We acknowledge 881

Ruzicka et al Table 5. BP Management in Kidney Transplant Recipients CSN Work Group Rating

No.


5.1

We suggest that adult kidney transplant recipients whose office BP is consistently . 130 mm Hg systolic or .80 mm Hg diastolic be treated to maintain a BP that is consistently # 130 mm Hg systolic and # 80 mm Hg diastolic, irrespective of the level of urine albumin excretion. (2D)

Do not concur

In adult kidney transplant recipients, choose a BP-lowering agent after taking into account the time after transplantation, use of calcineurin inhibitors, presence or absence of persistent albuminuria, and other co-morbid conditions. (Not Graded)


5.2

Abbreviations: BP, blood pressure; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. Reproduced with permission of KDIGO from the KDIGO BP guideline.1

the absence of data supporting this target for kidney transplant recipients. However, applying the quality appraisal criteria proposed by the GRADE Work Group,2 we use this indirect body of evidence for the management of transplant recipients, and rate the quality of evidence down one level for indirectness. This provides overall Grade C evidence for a target of ,140/90 mm Hg in transplant recipients without diabetes. Moreover, one large observational study (N . 24,404) demonstrated that patients with systolic BP , 140 mm Hg at 3 years after transplantation had improved graft survival and cardiovascular mortality at 10 years.56 Although this study may have been prone to residual confounding related to inability to achieve lower BPs, it is the only study that has directly evaluated the effects of a specific BP target in the renal transplant population. The CSN Work Group agrees with KDIGO recommendations that proteinuria or albuminuria should not influence BP targets in persons without diabetes when there is no evidence to differentiate BP target on this basis. This is consistent with the CHEP recommendation as well.3 Many kidney transplant recipients have a burden of pre-existing diabetes mellitus, which often is the primary cause of their ESRD. In addition, kidney transplant recipients are prone to develop new-onset diabetes after transplantation for a variety of reasons. In either of these cases, we recommend a lower target BP of ,130/80 mm Hg. This is consistent with 2013 CHEP guidelines for patients with hypertension and diabetes.3 In the nontransplantation population, this treatment threshold and target is based on Grade A 882

evidence, which when applied indirectly to transplant recipients provides Grade B evidence for this target. We also propose that when a transplant recipient develops new-onset diabetes, they should be treated according to this lower target, even if diabetes is well controlled. As with the CHEP guidelines, this recommendation applies to patients with diabetes with and without proteinuria. Implications Within Canadian Health Care The CSN Work Group suggests that adult kidney transplant recipients without diabetes and with office systolic BP consistently . 140 and/or diastolic BP . 90 mm Hg receive antihypertensive therapy to achieve a systolic BP that is consistently , 140 and diastolic BP , 90 mm Hg, regardless of level of albuminuria. The CSN Work Group suggests that adult kidney transplant recipients with diabetes and with office systolic BP consistently . 130 and/or diastolic BP . 80 mm Hg receive antihypertensive therapy to achieve a systolic BP that is consistently , 130 and diastolic BP , 80 mm Hg, regardless of level of albuminuria.

Selection of a BP-Lowering Drug 5.2 In adult kidney transplant recipients, choose a BPlowering agent after taking into account the time after transplantation, use of calcineurin inhibitors, presence or absence of persistent albuminuria, and other co-morbid conditions. (Not Graded)

Commentary The CSN Work Group agrees with KDIGO that there are many nuances to the prescription of specific BP-lowering agents in kidney transplant recipients. These are well summarized in the KDIGO document and in the KDIGO clinical practice guideline for the care of kidney transplant recipients.57 The Work Group also agrees with KDIGO that more research is needed to compare the effects of, for example, ACE inhibitor versus ARB or either class versus calcium channel blockers, and calcium channel blockers versus placebo. Patients with CKD often come to transplantation with comorbid conditions for which 2013 CHEP guidelines recommend specific BP-lowering agents. These recommendations are based on moderate- to high-quality evidence (Grade A or B) in nontransplantation populations.3 Conditions for which specific agents are recommended include diabetes (ACE inhibitor or ARB; Grade A), stroke (combination of ACE inhibitor and thiazide diuretic; Grade B), coronary artery disease (ACE inhibitor, ARB, bblocker, or calcium channel blocker; Grade B), recent myocardial infarction (combination of ACE Am J Kidney Dis. 2014;63(6):869-887


inhibitor and b-blocker; Grade A), and congestive heart failure (ACE inhibitor or ARB if intolerant; bblocker, and mineralocorticoid receptor blocker; Grade A). Until clinical trials directly addressing the management of kidney transplant recipients are available, the CSN Work Group favors drug selection based on the CHEP recommendations for non– transplant recipients, again, recognizing limitations in the indirectness of the evidence (quality rating should be rated down one level) supporting this recommendation. A Canadian RCT is currently underway addressing the effects of an ACE inhibitor as compared with placebo in proteinuric kidney transplant recipients on doubling of serum creatinine level, kidney failure, and death.58 Implications Within Canadian Health Care The CSN Work Group suggests that for adult kidney transplant recipients who require treatment for hypertension, the selection of agent should be based on comorbid conditions (see text), though blockers of the renin-angiotensin system should be avoided in the immediate posttransplantation period.

BP MANAGEMENT IN CHILDREN WITH NDD-CKD Table 6 provides an overview of the CSN Work Group’s assessment of the KDIGO guideline recommendations concerning management of BP in children with NDD-CKD. Treatment Initiation 6.1 We recommend that in children with CKD ND, BPlowering treatment is started when BP is consistently above the 90th percentile for age, sex, and height. (1C)

Commentary Although this recommendation is based on only one RCT25 and a few observational studies,59-62 it can be supported for use in clinical practice in Canada. In children, the upper limit of normal BP is defined as the 95th percentile based on the distribution of BP values measured by auscultation in the normal population.63 For population screening in otherwise healthy children, BP that is consistently above the 95th percentile is regarded as significantly elevated and indicates the diagnosis of hypertension. Setting the threshold for initiating BP therapy to the 90th percentile for children with CKD is a logical step because children with CKD are already recognized as being at risk for cardiovascular disease and progression of CKD. Treatment that lowers BP is associated with a slower progression of CKD as suggested by the available studies.25,60,61 The choice of the 90th percentile as a threshold for BP therapy is further supported by the difficulties with accurate measurement of BP in children. It is not unusual to repeat a Am J Kidney Dis. 2014;63(6):869-887

Table 6. BP Management in Children With Non–DialysisDependent CKD CSN Work Group Rating

No.


6.1

We recommend that in children with CKD ND, BP-lowering treatment is started when BP is consistently above the 90th percentile for age, sex, and height. (1C)


6.2

We suggest that in children with CKD ND (particularly those with proteinuria), BP is lowered to consistently achieve systolic and diastolic readings less than or equal to the 50th percentile for age, sex, and height, unless achieving these targets is limited by signs or symptoms of hypotension. (2D) We suggest that an ARB or ACE-I be used in children with CKD ND in whom treatment with BP-lowering drugs is indicated, irrespective of the level of proteinuria. (2D)


6.3

Concur

Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BP, blood pressure; CKD ND, non–dialysis-dependent chronic kidney disease; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. Reproduced with permission of KDIGO from the KDIGO BP guideline.1

BP measurement multiple occasions during one visit and to require repeated assessments to obtain a reliable and accurate BP reading. Unfortunately, the recommendation does not address the fact that the BP is frequently measured by oscillometric automatic BP devices, which tend to overestimate both systolic and diastolic BPs and may lead to misclassification of BP status.64 The normative values are based, however, on careful auscultatory measurement.63 While oscillometric measurement of BP may be conveniently used to screen for hypertension, an elevated BP should always be confirmed by manual sphygmomanometry to establish the need for treatment and monitoring, using the normative values that were derived from and designed for auscultatory devices.63 The proposed guideline to use the 90th percentile as a threshold for starting BP-lowering treatment can be fully supported if the BP is measured or confirmed by a manual sphygmomanometer. The casual (office) BP measurement may, however, not be sufficient to diagnose all forms of hypertension in children with CKD due to a high prevalence of masked hypertension in this population.65,66 The presence of a masked hypertension, that is, an elevated BP outside the physician’s office, can be documented by ABPM or home BP monitoring, but 883

Ruzicka et al

not during the regular office visit. The diagnosis of masked hypertension therefore would be missed if using only office BP measurement. Since masked hypertension portends a similar risk for developing target-organ damage, it is important to diagnose this entity as early as possible in the course of CKD.67 In addition, children with CKD often suffer from nighttime hypertension,68 which would not be captured by home BP monitoring, but can be detected by ABPM. A smaller number of children with CKD would also have white-coat hypertension,66 that is, an elevated BP in the office but normal BP in an out-of office setting. In this situation, BP therapy may not be immediately indicated. However, close monitoring of BP is necessary as some children with white-coat hypertension may develop sustained hypertension and target-organ damage later in life.69 We therefore believe that the use of ABPM (in addition to the office BP) is important for the diagnosis of an elevated BP in children with CKD. We also believe that the advantages of ABPM to confirm hypertension diagnosis (masked, night-time, and white-coat hypertension) outweigh some disadvantages of this technique, such as the inconvenience of wearing the BP cuff over 24 hours. The use of ABPM has also become standard of practice in many if not all university centers across Canada, where the vast majority of children with CKD are treated or followed up. Implications Within Canadian Health Care We recommend that in children with NDD-CKD, BP-lowering treatment is started when the BP, measured by a mercury sphygmomanometer, is consistently above the 90th percentile for age, sex, and height. The additional use of ABPM is recommended to confirm the diagnosis of sustained hypertension, to detect masked hypertension, and rule out white-coat hypertension.

significantly slower progression of CKD as compared to children with the MAP at the 95th percentile (conventional BP control). Moreover, the type of BP may also play a role, as a child can have a higher systolic BP but normal diastolic BP or vice versa. In both instances, the child would be considered as hypertensive. The differences/ variations between systolic and diastolic BP can be circumvented by using the MAP, which combines both systolic and diastolic BP and can provide a more accurate assessment of the BP status; in part due to the fact that it is directly measured by the oscillometric ABPM device.70 The use of casual/office BP as a target BP seems to be less advantageous in children with CKD, mainly because of the masked and night-time hypertension as described previously; there is only one observational study reporting office BP as the target BP.62 When casual/office BP is used to titrate treatment, it is important that resting casual BP be measured manually by sphygmomanometer rather than oscillometric devices, so that the appropriate reference values may be used in the process. Based on available evidence in the literature, we suggest using the MAP from ABPM as the target BP in children with CKD. Implications Within Canadian Health Care We suggest that in children with NDD-CKD (and particularly in those with proteinuria), BP is lowered to consistently achieve systolic and diastolic reading less than or equal to the 50th percentile for age, sex, and height, measured by mercury sphygmomanometer, unless achieving these targets is limited by signs or symptoms of hypotension. We further suggest that monitoring should periodically include ABPM to confirm that the MAP readings are less Table 7. BP Management in Elderly Persons With Non– Dialysis-Dependent CKD

BP Treatment Target 6.2 We suggest that in children with CKD ND (particularly those with proteinuria), BP is lowered to consistently achieve systolic and diastolic readings less than or equal to the 50th percentile for age, sex, and height, unless achieving these targets is limited by signs or symptoms of hypotension. (2D)

Commentary Target BP has been a hot topic in pediatric nephrology and hypertension. As much as the lowering of BP to the 50th percentile makes clinical sense, it is supported by only one prospective randomized study.25 In this particular study, the BP was measured by 24-hour ABPM and the target BP was the 24-hour MAP. Children with the MAP at the 50th percentile (intensified BP control) achieved a 884

No.


7.1 Tailor BP treatment regimens in elderly patients with CKD ND by carefully considering age, co-morbidities and other therapies, with gradual escalation of treatment and close attention to adverse events related to BP treatment, including electrolyte disorders, acute deterioration in kidney function, orthostatic hypotension and drug side effects. (Not Graded)


Concur

Abbreviations: BP, blood pressure; CKD ND, non–dialysisdependent chronic kidney disease; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease: Improving Global Outcomes. Reproduced with permission of KDIGO from the KDIGO BP guideline.1 Am J Kidney Dis. 2014;63(6):869-887


than or equal to the target 50th percentile for age, sex, and height.

BP MANAGEMENT IN ELDERLY PERSONS WITH NDD-CKD Table 7 contains the KDIGO guideline recommendation regarding BP management in elderly persons with NDD-CKD, with which the CSN Work Group concurs.

TRANSLATING THIS COMMENTARY INTO PRACTICE IN CANADA The Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) is working with the CSN Clinical Practice Guidelines Committee to implement recommendations identified by medical leads of Canadian kidney programs. It is the expectation that the CANN-NET knowledge translation group will develop the tools and measures to assist with dissemination of the updated KDIGO clinical practice guideline for the management of BP in CKD with the Canadian context as provided in this document.

ACKNOWLEDGEMENTS Support: No financial support was required for the development of this commentary. Financial Disclosure: In the interest of transparency and full disclosure, the Appendix includes conflict-of-interest information for all members of the CSN Work Group.

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42. Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372(9644): 1174-1183. 43. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123(24):2799-2810, 2799, p following 2810. 44. Abramson JL, Jurkovitz CT, Vaccarino V, Weintraub WS, McClellan W. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int. 2003;64(2):610-615. 45. Perkovic V, Ninomiya T, Arima H, et al. Chronic kidney disease, cardiovascular events, and the effects of perindopril-based blood pressure lowering: data from the PROGRESS study. J Am Soc Nephrol. 2007;18(10):2766-2772. 46. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134(8):629-636. 47. Bello AK, Hemmelgarn B, Lloyd A, et al. Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes. Clin J Am Soc Nephrol. 2011;6(6): 1418-1426. 48. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317(7160): 703-713. 49. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61(3):1086-1097. 50. Schrier RW, Estacio RO, Mehler PS, Hiatt WR. Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trial. Nat Clin Pract Nephrol. 2007;3(8):428-438. 51. Reboldi G, Gentile G, Angeli F, Ambrosio G, Mancia G, Verdecchia P. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73, 913 patients. J Hypertens. 2011;29(7):1253-1269. 52. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585. 53. Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensinconverting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165(8):936-946. 54. Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med. 2005;165(8):923-928. 55. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118):1755-1762. 56. Opelz G, Dohler B. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant. 2005;5(11):2725-2731.

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CSN Commentary on KDIGO BP Management Guideline 2012 57. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299-311. 58. Knoll GA, Cantarovitch M, Cole E, et al. The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation—study design. Nephrol Dial Transplant. 2008;23(1):354-358. 59. Seeman T, Pohl M, Misselwitz J, John U. Angiotensin receptor blocker reduces proteinuria independently of blood pressure in children already treated with angiotensin-converting enzyme inhibitors. Kidney Blood Press Res. 2009;32(6):440-444. 60. Mitsnefes M, Ho PL, McEnery PT. Hypertension and progression of chronic renal insufficiency in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). J Am Soc Nephrol. 2003;14(10):2618-2622. 61. Flynn JT, Mitsnefes M, Pierce C, et al. Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension. 2008;52(4):631-637. 62. Furth S, Flynn JT, Pierce C, Mitsnefes M. Lower systolic BP associated with slower CKD progression in the CKiD study [abstract]. J Am Soc Nephrol. 2013;21:551A. 63. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high

blood pressure in children and adolescents. Pediatrics. 2004;114(2 suppl 4th Report):555-576. 64. Flynn JT, Pierce CB, Miller ER III, et al. Reliability of resting blood pressure measurement and classification using an oscillometric device in children with chronic kidney disease. J Pediatr. 2012;160(3):434-440 e431. 65. VanDeVoorde RG, Mitsnefes MM. Hypertension and CKD. Adv Chronic Kidney Dis. 2011;18(5):355-361. 66. Samuels J, Ng D, Flynn JT, et al. Ambulatory blood pressure patterns in children with chronic kidney disease. Hypertension. 2012;60(1):43-50. 67. Angeli F, Reboldi G, Verdecchia P. Masked hypertension: evaluation, prognosis, and treatment. Am J Hypertens. 2010;23(9): 941-948. 68. Seeman T, Palyzova D, Dusek J, Janda J. Reduced nocturnal blood pressure dip and sustained nighttime hypertension are specific markers of secondary hypertension. J Pediatr. 2005;147(3):366-371. 69. Litwin M, Niemirska A, Ruzicka M, Feber J. White coat hypertension in children: not rare and not benign? J Am Soc Hypertens. 2009;3(6):416-423. 70. Sulakova T, Feber J. Should mean arterial pressure be included in the definition of ambulatory hypertension in children? Pediatr Nephrol. 2013;28(7):1105-1112.

APPENDIX: CONFLICT OF INTEREST INFORMATION FOR CSN WORK GROUP MEMBERS Member

Marcel Ruzicka Robert Quinn

Type of Conflict of Interest

Advisory Board None

Phil McFarlane

None

Brenda Hemmelgarn

None

G.V. Ramesh Prasad

None

Janusz Feber

None

Gihad Nesrallah

None

Martin MacKinnon

None

Navdeep Tangri Brendan McCormick

Advisory Board None

Sheldon Tobe

None

Tom D. Blydt-Hansen

None

Swapnil Hiremath

None

Am J Kidney Dis. 2014;63(6):869-887

Role

Period

Sponsor

Medical Advisory

2013

Forest Laboratories, Inc

Medical Advisory

2013

Takeda Canada, Inc

887

Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management.

Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of glomerulonephritis in adults.

Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children.

KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.

KDOQI US commentary on the 2013 KDIGO Clinical Practice Guideline for Lipid Management in CKD.

Commentary on the KDIGO Clinical Practice Guideline for the management of blood pressure in chronic kidney disease.

In reply to 'A perspective from the Baltics regarding the Canadian Society of Nephrology commentary on the KDIGO Glomerulonephritis Guideline'.

A perspective from the Baltics regarding the Canadian Society of Nephrology commentary on the KDIGO Glomerulonephritis Guideline.

Canadian Society of Nephrology 2014 clinical practice guideline for timing the initiation of chronic dialysis.

KDIGO Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation statements and clinical approach to the patient.

The Canadian Society of Nephrology methods in developing and adapting clinical practice guidelines: a review.

Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents.

KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors.

Clinical practice guideline for the management of intracranial aneurysms.

Acromegaly: an endocrine society clinical practice guideline.

Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.

Summary of Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors.

Management of Bell palsy: clinical practice guideline.

Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis.

Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement.

Assessing the trustworthiness of the guideline for management of high blood pressure in adults.

Prostate cancer survivorship care guideline: American Society of Clinical Oncology Clinical Practice Guideline endorsement.

The Japanese Breast Cancer Society clinical practice guideline for epidemiology and prevention of breast cancer.

Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines.