Long-term fol- low-up data from AASK also showed a benefit of a lower target BP in patients with PCR 4220 mg/g (422 mg/ and the ESCAPE trial14 showed a benefit in the entire population with a borderline interaction of treatment target and urine protein level. In summary, we believe there is sufficient evidence to suggest a BP target of r130/80 mm Hg for kidney protection in those with macroalbuminuria. We have graded this suggestion 2C, for the following reasons. The reported benefits in the AASK and the MDRD study are based on post hoc and subgroup analyses. Furthermore, in both the MDRD study and AASK, MAP was targeted rather than systolic and diastolic BP, and a specific MAP may translate into different systolic and diastolic BP, depending on the individual patient. Additionally, in the MDRD study, a higher MAP was targeted in patients over the age of 60 years.169 The Ramipril Efficacy in Nephropathy 2 (REIN-2) study did not show a benefit of tight BP control, although admittedly this was a short-term study with relatively few outcomes and it is unclear whether the use of a dihydropyridine calcium-channel blocker (felodipine) in the low-target arm may have confounded (See Supplementary Tables 2 4 online). We also do not believe that this recommendation should in any way hinder trials from randomizing patients with CKD and urine protein excretion o1 g per 24 hours to various BP targets, as there is sufficient equipoise and uncertainty to endorse these trials. One such trial that will evaluate this question is Systolic Blood Pressure Intervention Trial (SPRINT) which is funded by National Institutes of Health (NIH).171,172 It will evaluate cardiovascular and kidney outcomes in patients randomized to a systolic BP of o140 mm Hg versus o120 mm Hg.


One such trial that will evaluate this question is Systolic Blood Pressure Intervention Trial (SPRINT) which is funded by National Institutes of Health (NIH).171,172 It will evaluate cardiovascular and kidney outcomes in patients randomized to a systolic BP of o140 mm Hg versus o120 mm Hg. There is a CKD component for patients with GFR 20 60 ml/min/ . Patients with diabetes and those with 24-hour urine protein excretion of 41 g per 24 hours are excluded from this study. 3.4: We suggest that an ARB or ACE-I be 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) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Urine albumin excretion of 30 to 300 mg per 24 hours (microalbuminuria) is a risk factor for CVD and CKD progression. K ACE-Is and ARBs have been shown to reduce urine albumin levels. K RCTs suggest that ACE-Is or ARBs may help reduce progression of CKD and possibly CVD in patients with urine albumin excretion of 30 to 300 mg per 24 hours. As mentioned above, patients with microalbuminuria are at high risk for both progression of CKD and development of Here, we describe the trial data which either focused on kidney disease or CVD outcomes. Some trials focused on both.173176 Kidney disease. In AASK, a study of patients with a PCR o220 mg/g (o22 mg/mmol), the ACE-I ramipril decreased the urine protein level.


In AASK, a study of patients with a PCR o220 mg/g (o22 mg/mmol), the ACE-I ramipril decreased the urine protein level. It remains to be determined whether this translates into a clinically important benefit.177 In post hoc analyses of the Heart Outcomes Prevention Evaluation (HOPE), which was an RCT involving patients with diabetes or vascular disease and at least one other CVD risk factor, ramipril prevented progression of proteinuria or develop- ment of new-onset microalbuminuria, independent of In a post hoc analysis of Candesartan Antihypertensive Survival Evaluation in Japan (CASE J), which was an RCT comparing the ARB candesartan with the calcium-channel blocker amlodipine,178 candesartan reduced progression of CKD 4 (see Supplementary Table 5 online). In subgroup analyses of the Telmisartan Randomized Assess- ment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND), an RCT that included patients with vascular disease or diabetes, in patients with microalbumi- nuria (defined as an ACR 43.4 mg/mol [434 mg/g]), the ARB telmisartan decreased the risk of the composite kidney outcome (doubling of SCr level, dialysis, or death) in comparison with placebo.179 There was an interaction whereby telmisartan benefited patients with microalbumi- nuria but was associated with harm in those without microalbuminuria (P 0.006 for interaction). Finally, in patients with diabetes, ACE-Is and ARBs have been shown to prevent the development of macroalbuminuria in subjects and we have not found evidence of substantive differences between diabetics and non-diabetics with respect to either BP target or agent. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a large RCT examining the effects of the ACE-I lisinopril, the thiazide chlorthalidone, and the dihydropyridine calcium-channel blocker amlodipine in individuals 455 years of age with hypertension and at least one other CVD risk factor.


The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a large RCT examining the effects of the ACE-I lisinopril, the thiazide chlorthalidone, and the dihydropyridine calcium-channel blocker amlodipine in individuals 455 years of age with hypertension and at least one other CVD risk factor. Lisinopril did not show a benefit for doubling of creatinine or kidney failure when compared with chlorthalidone in the entire cohort or among patients with CKD at baseline175 (see Supplementary Table 6 online). ALLHAT, however, did not permit the use of an ACE-I with a diuretic a combination that is frequently required in clinical practice to achieve adequate BP control.182184 In addition, the diuretic arm in ALLHAT achieved better BP control making comparison of agents more difficult to interpret. Unfortunately, albuminuria or proteinuria status was not measured in the enrolled subjects, but assuming that ALLHAT was consistent with other trials of high-risk individuals recruited from the general population (e.g., HOPE or TRANSCEND), the median level of proteinuria was most likely below the microalbuminuria cutoff. CVD. There have been few RCTs of BP agents that have focused on CVD outcomes in CKD patients without diabetes mellitus (Supplementary Tables 7 32 online). Most of the data are taken from subgroup analyses of patients with CKD from general population studies (Supplementary Tables 1, 5 6, 33 36 online).


Most of the data are taken from subgroup analyses of patients with CKD from general population studies (Supplementary Tables 1, 5 6, 33 36 online). HOPE showed a benefit for CVD outcomes in patients randomized to ramipril.185 This benefit extended to those with a creatinine level 41.4 mg/dl (124 mmol/l) or a creatinine clearance o65 ml/min (1.1 ml/ sec) in non-diabetic individuals,173 as well as those with In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), which included patients with a history of cerebrovascular disease, the ACE- I perindopril, as compared with placebo, decreased the rate of recurrent stroke in those with CKD.186 Although the level of urine albumin was not specified in PROGRESS, it seems reasonable to assume that CVD protection would extend to those with microalbuminuria. In patients with stable coronary disease in the Prevention of Events with Angio- tensin-Converting Enzyme Inhibitor Therapy (PEACE) trial, the ACE-I trandolapril, as compared with placebo, reduced mortality in those with a GFR o60 ml/min/1.73 m2 , although trandolapril did not have a benefit in those with However, the effect of trandolapril therapy on outcomes was not significantly modified by the level of albuminuria.188 In the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), there was no modification of benefit by level of kidney function, and perindopril (versus placebo) decreased the risk of the primary composite end point of cardiovascular death, non- fatal myocardial infarction, or resuscitated cardiac arrest in as well as those ALLHAT, however, did not show a benefit of lisinopril over chlorthalidone with respect to CVD outcomes in the subgroup of patients with The Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) included CKD patients with urine albumin levels of 15 mg to 300 mg per 24 hours.


In patients with stable coronary disease in the Prevention of Events with Angio- tensin-Converting Enzyme Inhibitor Therapy (PEACE) trial, the ACE-I trandolapril, as compared with placebo, reduced mortality in those with a GFR o60 ml/min/1.73 m2 , although trandolapril did not have a benefit in those with However, the effect of trandolapril therapy on outcomes was not significantly modified by the level of albuminuria.188 In the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), there was no modification of benefit by level of kidney function, and perindopril (versus placebo) decreased the risk of the primary composite end point of cardiovascular death, non- fatal myocardial infarction, or resuscitated cardiac arrest in as well as those ALLHAT, however, did not show a benefit of lisinopril over chlorthalidone with respect to CVD outcomes in the subgroup of patients with The Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) included CKD patients with urine albumin levels of 15 mg to 300 mg per 24 hours. Patients were randomized to the ACE-I fosinopril or placebo. Fosinopril decreased albumin excretion by 26% and showed a trend toward reducing the risk of CVD outcomes (hazard ratio [HR] versus placebo 0.60; 95% CI Similarly, in the CASE J trial, candesartan reduced the rate of CVD outcomes, as compared with amlodipine, in CKD 4 patients178 (Supplementary Table 5 online). The Work Group suggests ACE-Is or ARBs as the preferred class of BP-modifying agent in CKD patients with microalbuminuria. This recommendation is based on observational data and subgroup and post hoc analyses, hence the grade of 2D.


This recommendation is based on observational data and subgroup and post hoc analyses, hence the grade of 2D. 3.5: We recommend that an ARB or ACE-I be used in non-diabetic adults with CKD ND and urine albumin excretion 4300 mg per 24 hours (or equivalent*) in whom treatment with BP-lowering drugs is indicated. (1B) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Urine albumin excretion 4300 mg per 24 hours ( macroalbuminuria ) is a risk factor for CVD and for CKD progression. K In RCTs involving patients with CKD and urine albumin excretion 4300 mg per 24 hours, ARBs or ACE-Is reduce the risks of hard outcomes such as the doubling of SCr level, kidney failure, or death. Patients with macroalbuminuria are at very high risk for both progression of CKD and development of CVD.18,162,163 Kidney disease. Several trials have demonstrated a benefit, in patients with macroalbuminuria, of ACE-Is or ARBs over either placebo or other agents, in reducing the risk of macroalbuminuria, doubling of creatinine levels, and devel- opment of kidney failure (See Supplementary Tables 7 12 online). These trials include RCTs in patients with CKD of various causes, primarily glomerulonephritis,191 African-Americans and patients with advanced CKD (a A meta-analysis of in- dividual patient data from 11 RCTs compared antihyperten- sive regimens including ACE-Is to regimens without ACE-Is in 1860 patients with predominantly non-diabetic CKD. In adjusted analyses, ACE-Is were associated with a HR of 0.69 for kidney failure (95% CI 0.51 0.94) and 0.70 for the combined outcome of doubling of the baseline SCr concentration or kidney failure (95% CI 0.55 0.88).


In adjusted analyses, ACE-Is were associated with a HR of 0.69 for kidney failure (95% CI 0.51 0.94) and 0.70 for the combined outcome of doubling of the baseline SCr concentration or kidney failure (95% CI 0.55 0.88). Patients with greater urinary protein excretion at baseline benefited more from ACE-I therapy (P 0.03 for kidney failure and P 0.001 for the combined outcome).141 The Work Group did not find heterogeneity with regard to the benefit of ACE-Is according to CKD stage; therefore, the guideline statements are not divided on this basis. Further- more, few RCTs with hard CVD or kidney-disease outcomes randomized patients to a diuretic or another agent in addition to an ACE-I or ARB; therefore, we have not included any guideline statements to support this practice. In fact, one RCT in individuals predominantly without CKD showed that the risk of doubling of the creatinine level was higher with an ACE-I hydrochlorothiazide combination than The clinical importance of this end point remains to be determined,193 as it may reflect a reversible hemodynamic effect. Finally, there is only limited quality evidence evaluating either differences in ACE-I versus ARB, or comparison of ACE-I plus ARB versus either ACE-I or ARB with regard to hard clinical outcomes (Supplemen- tary Tables 13 15 online). CVD. Only a few RCTs of BP agents have focused on CVD outcomes in subjects with CKD (Supplementary Tables 7 32 online); therefore, most of the data are from subgroup analyses of CKD patients from general population studies.


Only a few RCTs of BP agents have focused on CVD outcomes in subjects with CKD (Supplementary Tables 7 32 online); therefore, most of the data are from subgroup analyses of CKD patients from general population studies. Several analyses have shown a benefit of ACE-Is or ARBs over placebo or another agent, and although most of these studies were performed in patients with urine albumin levels below the macroalbuminuria cutoff, there is no obvious reason why the benefit would not extend to individuals with macroalbuminuria (Supplementary Tables 7 12 online). In summary, the data in support of the use of ACE-Is or ARBs are reasonably strong for preventing progression of CKD and less so for CVD protection. Notably, they show no harm of either class of drugs with regard to CVD. Taken together, the data on both drug classes support a grade 1B recommendation for ACE-Is or ARBs as a preferred agent in CKD patients with albumin excretion 4300 mg per 24 hours or its equivalent. RESEARCH RECOMMENDATIONS K Large RCTs of BP targets are needed in CKD patients without diabetes (stratified by GFR and albuminuria) that are powered for clinical outcomes including kidney failure, CVD events and mortality. K Large RCTs of BP agents are needed in CKD patients without diabetes (stratified by GFR and albuminuria) that are powered for clinical outcomes including kidney failure, CVD events and mortality. K Subgroup analyses in new, large-scale RCTs as described above by specific causes of CKD are needed. K Studies are needed to examine how intermediate out- comes for CKD and CVD (i.e., doubling of creatinine level, change in urine protein level, and development or regression of left ventricular hypertrophy) track with clinical outcomes to assess their validity as prognostic tools and possible surrogate outcomes going forward.


, doubling of creatinine level, change in urine protein level, and development or regression of left ventricular hypertrophy) track with clinical outcomes to assess their validity as prognostic tools and possible surrogate outcomes going forward. K Development of prediction tools for clinical outcomes in patients with CKD and testing in clinical trials for exploration of treatment heterogeneity are encouraged. K Development of prediction tools for the adverse out- comes of ACE-Is and ARBs is encouraged. K Cost-effectiveness analyses of lower BP targets in CKD patients without diabetes as stratified by GFR and albuminuria should be conducted. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contri- butor, copyright holder, or advertiser concerned. Accord- ingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplementary Table 1. General population RCTs comparing BP targets in CKD subgroups. Supplementary Table 2. Evidence profile of RCTs examining the effect of blood pressure target in patients with CKD without DM. Supplementary Table 3. RCTs examining the effect of blood pressure targets in patients with CKD without DM [categorical outcomes]. Supplementary Table 4.


RCTs examining the effect of blood pressure targets in patients with CKD without DM [categorical outcomes]. Supplementary Table 4. RCTs examining the effect of blood pressure targets in patients with CKD without DM [continuous outcomes]. Supplementary Table 5. General population RCTs comparing ARB versus CCB in CKD subgroups with and without DM. Supplementary Table 6. General population RCTs comparing ACEI or ARB versus control (active or placebo) in CKD subgroups with and without DM. Supplementary Table 7. Evidence profile of RCTs examining the effect of ACEI or ARB versus placebo in patients with CKD without DM. Supplementary Table 8. RCTs examining the effect of ACEI or ARB versus placebo in patients with CKD without DM [categorical outcomes]. Supplementary Table 9. RCTs examining the effect of ACEI or ARB versus placebo in patients with CKD without DM [continuous outcomes]. Supplementary Table 10. Evidence profile of RCTs examining the effect of ACEI or ARB versus CCB in patients with CKD without DM. Supplementary Table 11. RCTs examining the effect of ACEI or ARB versus CCB in patients with CKD without DM [categorical outcomes]. Supplementary Table 12. RCTs examining the effect of ACEI or ARB versus CCB in patients with CKD without DM [continuous outcomes]. Supplementary Table 13. Evidence profile of RCTs examining the effect of ACEI versus ARB in patients with CKD without DM. Supplementary Table 14. RCTs examining the effect of ACEI versus ARB in patient with CKD without DM [categorical outcomes]. Supplementary Table 15. RCTs examining the effect of ACEI versus ARB in patient with CKD without DM [continuous outcomes]. Supplementary Table 16. Evidence profile of RCTs examining the effect of high versus low dose ACEI in patients with CKD without DM. Supplementary Table 17.


Evidence profile of RCTs examining the effect of high versus low dose ACEI in patients with CKD without DM. Supplementary Table 17. RCTs examining the effect of high dose ACEI versus low dose ACEI in patient with CKD without DM [categorical outcomes]. Supplementary Table 18. RCTs examining the effect of high dose ACEI versus low dose ACEI in patient with CKD without DM [continuous outcomes]. Supplementary Table 19. Evidence profile of RCTs examining the effect of high versus low dose ARB in patients with CKD without DM. Supplementary Table 20. RCTs examining the effect of high dose ARB versus low dose ARB in patient with CKD without DM [categorical outcomes]. Supplementary Table 21. RCTs examining the effect of high dose ARB versus low dose ARB in patient with CKD without DM [continuous outcomes]. Supplementary Table 22. RCTs examining the effect of ACEI versus b-blocker in patients with CKD without DM [categorical outcomes]. Supplementary Table 23. RCTs examining the effect of ACEI versus b-blocker in patients with CKD without DM [continuous outcomes]. Supplementary Table 24. RCTs examining the effect of ACEI CCB versus ACEI in patients with CKD without DM [categorical outcomes]. Supplementary Table 25. RCTs examining the effect of ACEI CCB versus ACEI in patients with CKD without DM [continuous outcomes]. Supplementary Table 26. RCTs examining the effect of ACEI CCB versus CCB in patients with CKD without DM [categorical outcomes]. Supplementary Table 27. RCTs examining the effect of ACE CCB versus CCB in patients with CKD without DM [continuous outcomes]. Supplementary Table 28. RCTs examining the effect of CCB versus CCB in patients with CKD without DM [categorical outcomes]. Supplementary Table 29. RCTs examining the effect of CCB versus CCB in patients with CKD without DM [categorical outcomes]. Supplementary Table 30.


RCTs examining the effect of CCB versus CCB in patients with CKD without DM [categorical outcomes]. Supplementary Table 30. RCTs examining the effect of b-blocker versus CCB in patients with CKD without DM [categorical outcomes]. Supplementary Table 31. RCTs examining the effect of b-blocker versus CCB in patients with CKD without DM [continuous outcomes]. Supplementary Table 32. RCTs examining the effect of central-acting agent versus CCB in patients with CKD without DM [continuous outcomes]. Supplementary Table 33. General population RCTs comparing ACEI diuretic versus placebo in CKD with DM subgroups [categorical outcomes]. Supplementary Table 34. General population RCTs comparing ACEI diuretic versus placebo in CKD with DM subgroups [continuous outcomes]. Supplementary Table 35. General population RCTs comparing ARB or (ACE ARB) versus ACE in CKD subgroups with and without DM. Supplementary Table 36. General population RCTs comparing CCB versus active control in CKD subgroups with and without DM. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/bp.php Chapter 4: Blood pressure management in CKD ND patients with diabetes mellitus INTRODUCTION This chapter addresses the management of BP in adult CKD patients (specifically non-dialysis-dependent CKD [CKD ND]) with diabetes mellitus. Previous guidelines1,30 have used the term diabetic nephropathy or diabetic kidney disease. This Work Group decided to use the term diabetes with CKD in recognition of the fact that many patients who have co-existing diabetes and CKD do not undergo kidney biopsy and may have other forms of kidney damage with or without the changes that characterize diabetes. Examples of alternative pathologies include nephroangiosclerosis, atheromatous embolism, atherosclerotic renal artery disease, or glomerulonephritis.


Examples of alternative pathologies include nephroangiosclerosis, atheromatous embolism, atherosclerotic renal artery disease, or glomerulonephritis. In addition, there is evidence that the classic histological features of diabetic nephropathy can on occasion be found in patients who do not have a high urine Also, progressive loss of excretory kidney function has been observed in the absence of progression from microalbuminuria to overt proteinuria in some patients Observational studies in the general population provide strong evidence of a linear relationship between BP and risk of cardiovascular events.21 A large number of RCTs have also shown that drugs that reduce BP also reduce the risk of subsequent cardiovascular events.198 The benefits of BP reduction observed in clinical trials involving high-risk patients have also been shown to be consistent across a range of baseline BP levels in recent, large meta-ana- In addition, baseline BP levels have been shown to be a powerful determinant of the subsequent risk of kidney failure in large population-based studies from around the Diabetes increases the risk of CVD by a factor of two to three at every level of systolic BP,201 and this risk is further potentiated by the presence of CKD.


In addition, there is evidence that the classic histological features of diabetic nephropathy can on occasion be found in patients who do not have a high urine Also, progressive loss of excretory kidney function has been observed in the absence of progression from microalbuminuria to overt proteinuria in some patients Observational studies in the general population provide strong evidence of a linear relationship between BP and risk of cardiovascular events.21 A large number of RCTs have also shown that drugs that reduce BP also reduce the risk of subsequent cardiovascular events.198 The benefits of BP reduction observed in clinical trials involving high-risk patients have also been shown to be consistent across a range of baseline BP levels in recent, large meta-ana- In addition, baseline BP levels have been shown to be a powerful determinant of the subsequent risk of kidney failure in large population-based studies from around the Diabetes increases the risk of CVD by a factor of two to three at every level of systolic BP,201 and this risk is further potentiated by the presence of CKD. In addition, type 2 diabetes is a leading cause of CKD, accounting for 30 to 50% of new cases of kidney failure in the industrialized world.202 Microalbuminuria is one of the earliest detectable manifesta- tions of kidney disease in patients with diabetes, with a prevalence of 25% after 10 years of diabetes and an annual rate of progression to overt nephropathy of approximately The risk of incident and progressive microalbumin- uria is highly associated with BP levels.204 Progression of retinopathy is also closely associated with high BP.205 208 It is therefore important that the clinician is provided with clear, evidence-based recommendations on the use of BP-lowering drugs in the management of patients with diabetes and CKD.


In addition, type 2 diabetes is a leading cause of CKD, accounting for 30 to 50% of new cases of kidney failure in the industrialized world.202 Microalbuminuria is one of the earliest detectable manifesta- tions of kidney disease in patients with diabetes, with a prevalence of 25% after 10 years of diabetes and an annual rate of progression to overt nephropathy of approximately The risk of incident and progressive microalbumin- uria is highly associated with BP levels.204 Progression of retinopathy is also closely associated with high BP.205 208 It is therefore important that the clinician is provided with clear, evidence-based recommendations on the use of BP-lowering drugs in the management of patients with diabetes and CKD. This management should also include interventions for multiple risk factors, which have been shown to improve outcomes in patients with diabetes.209 211 The Work Group recognizes that the benefits of BP reduction in patients with diabetes and CKD may include reductions of the risks of progressive loss of kidney function, CVD and progression of diabetic retinopathy. We also took into account the fact that the effects of BP reduction may differ among outcomes; for instance, a lower achieved BP may be associated with an increased risk of one outcome but a reduced risk of another. These recommendations are not stratified by CKD stage as there are remarkably few studies in which the effect of BP- lowering therapy has been reported according to CKD stage. The Work Group could find no evidence that the balance of benefits and harms of BP-lowering therapy, or specific types of therapy, varied with the GFR other than the known risks of hyperkalemia, particularly with agents that directly interfere with renin angiotensin aldosterone system (see Chapter 2).


The Work Group could find no evidence that the balance of benefits and harms of BP-lowering therapy, or specific types of therapy, varied with the GFR other than the known risks of hyperkalemia, particularly with agents that directly interfere with renin angiotensin aldosterone system (see Chapter 2). 4.1: We recommend that adults with diabetes and CKD ND with urine albumin excretion o30 mg per 24 hours (or equivalent*) whose office BP is consistently 4140 mmHg systolic or 490mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r140 mmHg systolic and r90 mmHg *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K RCTs that have examined various BP targets or compared active treatment with placebo, along with observation studies, have been consistent in suggesting that lowering BP so that it is consistently o140/90 mm Hg will prevent major cardiovascular events. Lowering BP to these levels is also likely to reduce the risk of progressive CKD. K The evidence for the benefit of further lowering of the BP target is mixed, with modest cardiovascular benefits in patients with diabetes partly offset by increases in the risk of serious adverse effects in trials, and inconsistency in results among observational studies using clinical trial datasets. http://www.kidney-international.org chapter 4 & 2012 KDIGO Recommendation 4.1 applies to diabetic patients with CKD, , and normal albumin excretion (normoalbuminuria) prior to the use of BP- lowering drugs such as ACE-Is or ARBs.


http://www.kidney-international.org chapter 4 & 2012 KDIGO Recommendation 4.1 applies to diabetic patients with CKD, , and normal albumin excretion (normoalbuminuria) prior to the use of BP- lowering drugs such as ACE-Is or ARBs. Several studies have shown that this is not a rare occurrence in patients with type For example, in the National Health and Nutrition Examination Survey (NHANES), 36% of adults with type 2 diabetes and a GFR o60 ml/min/1.73 m2 had normal urine albumin levels.195 A population-based study in Japan found 262 of 3297 people (7.9%) with type 2 had a normal AER. The diabetic patients with CKD but a normal AER were older and included a higher proportion of women and patients with hypertension, hyperlipidemia, and CVD but fewer smokers, compared with the diabetic patients with a normal AER and preserved GFR.217 A long-term follow-up study of participants with type 1 diabetes in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complica- tions (DCCT/EDIC) study showed that 24% of those had an AER o30 mg per 24 hours at all previous evaluations,218 indicating that normoalbuminuric CKD is also an important entity in type 1 diabetes. RCTs. The Work Group could not identify any RCTs in which patients with CKD and normoalbuminuric diabetes had been randomized to various BP targets. Several trials have been completed in broader populations with diabetes, some of whom had CKD at study entry. These are summarized here. In the United Kingdom Prospective Diabetes Study patients with diabetes, a minority of whom also had nephropathy, were randomized to BP o150/ 85 mm Hg or o180/105 mm Hg. Tighter BP control was associated with a reduction in risk of diabetes-related death, stroke, and progression of retinopathy.


Tighter BP control was associated with a reduction in risk of diabetes-related death, stroke, and progression of retinopathy. recruited 18,790 adults with diastolic BP between 100 and 115 mm Hg and randomized them to one of three diastolic BP targets: r90, r85, and r80 mm Hg. Among the 1501 subjects with diabetes (a relatively small proportion, suggesting under-representation of diabetics), the risk of major cardiovascular events in the group targeted to a diastolic BP r80 mm Hg was half that of the group targeted to 90 mm Hg. Baseline data on cardiovascular risk factors were not provided for the diabetic subgroup, leading some commentators to speculate whether this result was due to imbalance between the groups rather than to a genuine treatment effect. No data were given on urinary albumin excretion in the diabetic subgroup. The Appropriate Blood Pressure Control in Diabetes (ABCD) study was a 5-year prospective RCT comparing intensive and moderate BP control in patients with diabetes.221 The hypertensive arm comprised diabetic patients with a diastolic BP 490 mmHg randomized to a diastolic BP target of 75 mmHg or 80 to 89 mmHg. Patients assigned to the lower BP target were also randomized to receive either nisoldipine or enalapril.


Patients assigned to the lower BP target were also randomized to receive either nisoldipine or enalapril. This arm of the trial was terminated early because of a significantly higher incidence of myocardial infarction (a pre- specified secondary end point) in the nisoldipine group.222 At 5 years of follow-up, there was no difference in the rate of pre- specified kidney outcomes or cardiovascular outcomes between the group targeted to 75 mm Hg and the group targeted to 80 to 89 mmHg but a significantly lower incidence of death in the The normotensive arm in the ABCD study comprised diabetic patients (around 30% of whom had CKD, as defined on the basis of albumin excretion) with a baseline BP o140/ 90 mm Hg who were randomized to placebo or active treatment (and in that group, further randomized to either enalapril or nisoldipine) titrated to reduce the diastolic BP to 10 mm Hg below baseline.223 As compared with less- intensive treatment, intensive treatment (to the lower BP target) was not associated with any difference in the change in creatinine clearance over the study period but was associated with lower risks of progression from normo- albuminuria to microalbuminuria and from microalbumin- uria to overt proteinuria, as well as a reduced risk of stroke and of progression of retinopathy. The inclusion criteria for the normotensive arm of ABCD prevents reliable extra- polation of this finding to patients whose baseline BP is 4140/90 mm Hg. The ACCORD study159 randomized 4733 patients with diabetes and high cardiovascular risk to a systolic BP target o140 mm Hg or o120 mm Hg. A total of 39% of patients had an elevated urinary AER. There was no difference between the two groups in the primary composite end point (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death).


There was no difference between the two groups in the primary composite end point (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death). However, the lower systolic BP target was associated with a significant reduction in the risk of stroke (62 events with o140 mm Hg target vs. 36 events with o120 mm Hg target, P 0.01), a pre-specified second- ary end point, but also with a significant increase in rate of serious adverse events (30 events vs. 77 events, respectively; As compared with the group targeted to o140 mm Hg, the group targeted to o120 mm Hg had higher rates of hyperkalemia and elevations in SCr level. The mean GFR was significantly lower in the intensive-therapy (lower-target) group than in the standard-therapy group at the last visit. There were significantly more instances of a single GFR in the intensive-therapy group than in the standard-therapy group (99 events vs. 52 events, respectively; Po0.001), but the proportion of participants with more than one GFR reading o30 ml/ was similar in the two groups (38% vs. 32%, respectively; P 0.46). The frequency of macroalbuminuria at the final visit was significantly lower with intensive therapy than with standard therapy, and there was no between-group difference in the frequency of kidney failure or initiation of dialysis (in 58 patients vs. 59 patients, P 0.93).159 The ACCORD trial also showed that intensive glycemic control and combination lipid-lowering treatment, but not intensive BP control, was associated with a reduction in the rate of progression of retinopathy.224 Observational studies.


The frequency of macroalbuminuria at the final visit was significantly lower with intensive therapy than with standard therapy, and there was no between-group difference in the frequency of kidney failure or initiation of dialysis (in 58 patients vs. 59 patients, P 0.93).159 The ACCORD trial also showed that intensive glycemic control and combination lipid-lowering treatment, but not intensive BP control, was associated with a reduction in the rate of progression of retinopathy.224 Observational studies. There have been several large observational studies of patients with diabetes, CKD, or both, most of which found a lower risk of cardiovascular or kidney outcomes in people with lower BP.148,225 These studies have been cited by many previous guidelines and used to support a BP target of o130/80 mm Hg for patients with CKD or diabetes. However, none of these studies prove causality and it is equally possible that higher BP, whether occurring before initiation of BP-lowering treatment or after, is simply a marker for more severe disease, which in turn has a poorer prognosis.22 Among patients screened for the Multiple Risk Factor Intervention (MRFIT) trial, there was a strong, graded, positive relationship between baseline BP and subsequent risk of kidney failure; the association was weaker among older men, blacks, and men with diabetes.148 In the diabetic subgroup of MRFIT participants,201 the risk of cardiovascular death increased to a greater degree with increasing risk factors, including systolic BP, than in the non-diabetic subgroup. A strong association between baseline BP and subsequent risk of kidney failure was also demonstrated in an Okinawan After adjustment for age and BMI, there was a significant, positive association between systolic BP and the risk of diabetic kidney failure, with a relationship also demonstrated for diastolic BP in women only.


A strong association between baseline BP and subsequent risk of kidney failure was also demonstrated in an Okinawan After adjustment for age and BMI, there was a significant, positive association between systolic BP and the risk of diabetic kidney failure, with a relationship also demonstrated for diastolic BP in women only. The Pittsburg Epidemiology of Diabetes Complications reported on 589 patients with childhood- onset diabetes. A graded association between baseline BP and subsequent risk of major events was found. Data from the Cardiovascular Health Study and the Atherosclerosis Risk In Communities study158 showed that among participants with CKD, there was a J-shaped relationship between systolic BP and risk of stroke, with a higher risk of stroke with a systolic BP o120 mm Hg; this relationship was not seen in those without CKD. Post hoc analyses of RCTs. Post hoc analyses of several large RCTs have indicated various relationships between achieved BP and outcomes. A post hoc analysis of achieved BP and outcome in the Irbesartan Diabetic Nephropathy Trial (IDNT)228 indicated that systolic BP o120 mm Hg was associated with an increased (rather than decreased) risk of cardiovascular events. A post hoc analysis of UKPDS 36,229 irrespective of treatment allocation, revealed a significant association between higher systolic BP and higher risk of clinical complications over a systolic BP range of 115 to 170 mm Hg. The International Verapamil SR Trandolapril (INVEST) study recruited patients with hypertension and CAD and compared the effects of verapamil and atenolol. Trandolapril, hydrochlorothiazide, or both were added to achieve either a BP o140/90mm Hg or a BP of o130/85mm Hg in patients with diabetes or kidney impairment.230 In an analysis of achieved BP among participants with diabetes (irrespective of their rando- mized treatment assignments), those who achieved tight BP control (i.e.


Trandolapril, hydrochlorothiazide, or both were added to achieve either a BP o140/90mm Hg or a BP of o130/85mm Hg in patients with diabetes or kidney impairment.230 In an analysis of achieved BP among participants with diabetes (irrespective of their rando- mized treatment assignments), those who achieved tight BP control (i.e., a systolic BP o130mm Hg) had similar rates of cardiovascular outcomes, and higher rates of death, than those with usual BP control (i.e., systolic BP, 130 to 140mm Hg). Both groups had better outcomes than did a third group with poor BP control (i.e., systolic BP 4140 mm Hg). The increased risk of mortality in the tight-control group persisted during an extended follow-up period.231 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (AD- VANCE) collaborative group showed that the addition of perindopril plus indapamide to current therapy used in patients with type 2 diabetes and high cardiovascular risk reduced the rate of major or microvascular events.232 In a secondary analysis, kidney events (mostly measures of appearance or worsening of urinary AER) were less frequent with a lower achieved BP at the follow-up visit.233 The absolute risk reductions for cardiovascular and kidney end points associated with active treatment (irrespective of BP) were greater among patients with CKD 3 5 than among patients with CKD 1 2.234 Interpretation.


The increased risk of mortality in the tight-control group persisted during an extended follow-up period.231 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (AD- VANCE) collaborative group showed that the addition of perindopril plus indapamide to current therapy used in patients with type 2 diabetes and high cardiovascular risk reduced the rate of major or microvascular events.232 In a secondary analysis, kidney events (mostly measures of appearance or worsening of urinary AER) were less frequent with a lower achieved BP at the follow-up visit.233 The absolute risk reductions for cardiovascular and kidney end points associated with active treatment (irrespective of BP) were greater among patients with CKD 3 5 than among patients with CKD 1 2.234 Interpretation. The Work Group believed that the data for reducing usual systolic BP to r140 mm Hg and diastolic BP to r90 mm Hg were strong, on the basis of the data presented above, as well as the clear relationship between BP levels and the risk of cardiovascular and kidney out- comes consistently noted in observational studies in both the and in patients with diabetes with a systolic BP 4140 mm Hg and a diastolic BP Further support is provided by reports from a number of clinical trials or trial subgroups demonstrat- ing that BP-lowering therapy prevents cardiovascular and kidney events in patients with diabetes, most of whom had BP levels 4140/90 mm Hg at trial entry.183,219,221,223,232 There are few data for individuals with diabetes and CKD, but those that are available have reported broadly consistent findings.234 The Work Group does not believe that the evidence is sufficiently strong to support a lower target BP level for all patients with diabetes and CKD. Some support for lower BP targets is provided by the ACCORD and ABCD trials population.


Some support for lower BP targets is provided by the ACCORD and ABCD trials population. However in ACCORD, these benefits must be balanced against the increased risk of adverse events. As a result, it was felt that the risk-to-benefit ratio is likely to be unfavorable for at least some groups of individuals with diabetes and CKD. These include patients with diabetes and non-albuminuric CKD, who may be likely to have additional co-morbidities; the elderly, who are prone to falls; patients with marked systolic hypertension; and those with severe autonomic neuropathy. Such patients may have been under- represented in the RCTs and observational studies. A target BP of r140 systolic and r90 mm Hg diastolic may appear to require less aggressive therapy than the targets recommended in some other guidelines for patients with diabetes. However, whether this is true depends on how targets are interpreted by clinicians. There is extensive evidence from routine clinical practice that many patients do not achieve the targets set in guidelines; instead, achieved values often have a normal distribution around the target.22 This distribution of values is the reason for the wording we have chosen for the recommendation statements: that BP be consistently below a given level. For instance, to account for random fluctuations in resting office BP over time, the intervention threshold needs to be significantly o130 mm Hg to achieve a systolic BP consistently o130 mm Hg. The Work Group, therefore, is confident that most individuals with diabetes and CKD should have their usual BP lowered to be consistently r140/90 mm Hg (hence the grade of 1B for recommendation 4.1), and that targets lower than r140/90 mm Hg could be considered on an individual basis for patients believed to be more likely to benefit than to be harmed by the treatment (e.g.


The Work Group, therefore, is confident that most individuals with diabetes and CKD should have their usual BP lowered to be consistently r140/90 mm Hg (hence the grade of 1B for recommendation 4.1), and that targets lower than r140/90 mm Hg could be considered on an individual basis for patients believed to be more likely to benefit than to be harmed by the treatment (e.g., patients not already on several BP-lowering agents, younger individuals, or persons at high risk of stroke). Overall, the evidence supporting the statement that systolic BP should be lowered to r140 mm Hg is at least level B. However, the evidence supporting the implication that systolic BP needs to be lowered further, for instance to r130 mm Hg, is weaker. This grading should not, therefore, be taken to imply that no further research is required on the question of lower BP targets in this group. Comparison with current guidelines. Recommendation 4.1 is consistent with recommendations made by numerous international and national guidelines for the general popula- all of which agree on a treatment goal of r140/ 90 mm Hg on the grounds that BP-lowering drugs reduce the risk of all-cause and cardiovascular mortality in people whose BP is 4140/90 mmHg. There is no reason to expect that patients with diabetes and CKD are less likely to have a benefit. Although there is observational evidence that the risk of CVD is higher among diabetic patients than non-diabetic patients at any given BP, these findings do not, in the absence of RCT evidence, support a recommendation that BP should be lowered further than is recommended in diabetic patients.


Although there is observational evidence that the risk of CVD is higher among diabetic patients than non-diabetic patients at any given BP, these findings do not, in the absence of RCT evidence, support a recommendation that BP should be lowered further than is recommended in diabetic patients. The Work Group is aware that this recommendation appears more conservative than the recommendations of some other international and national guidelines that recommend a BP target r130/80 mm Hg for patients with diabetes and CKD.1,9,30,237 240,243,245 247 However, there is insufficient high-quality evidence from RCTs to support a lower target for patients with diabetes and CKD (which we ) who do not have an increased urinary AER. All other guidelines have relied on observational evidence to support a lower systolic BP threshold for patients with diabetes. The Work Group did not consider the evidence from the HOT220 trials strong enough to justify a recommendation to lower the target diastolic BP to r80 mm Hg. The Work Group analyzed the evidence base for the existing guidelines carefully to ensure that the apparent departure from accepted wisdom was justified. Few existing guidelines specify how patients with normoalbuminuric CKD and diabetes should be treated with BP-lowering drugs, with the majority advising a BP target of r130/80 mmHg for all patients with diabetes, irrespective of GFR or albuminuria. Although the grades (and grading system) of these recommendations vary, all supporting statements acknowledge that the evidence is largely observational. For instance, many guidelines refer back to JNC 7,9 which qualified the recommendation with the caveat, although available data are somewhat sparse to justify the low target level of 130/80 mmHg y.


For instance, many guidelines refer back to JNC 7,9 which qualified the recommendation with the caveat, although available data are somewhat sparse to justify the low target level of 130/80 mmHg y. The JNC 7 goes on to cite the American Diabetes Association guidelines245 and the supporting literature analysis,235 which rely on the HOT for justification of the 80 mmHg diastolic BP and on Systolic Hypertension in the Elderly Program and Systolic Hypertension in Europe (Syst-Eur) (both studies of the general population) for the 140 mmHg systolic BP target. Finally, the JNC 7 states that Epidemiological studies indicate that there is a benefit to reducing systolic BP still further to 130 mm Hg or below , citing two references, UKPDS 36229 and a study from Allegheny County that contains no data on BP.249 We have not made recommendations about the choice of the BP-lowering drug to be used in patients with CKD and diabetes who do not have elevated rates of urinary albumin excretion. Although there is some evidence that inhibitors of the renin angiotensin system might prevent an increase in particularly in the presence of higher and might also reduce cardiovascular risk, such studies have not been performed in patients with reduced GFR but normal urinary albumin excretion. In such patients, the balance of risks and benefits of the use of ACE-Is or ARBs may well differ from the balance of their use for primary prevention of diabetic kidney disease. Considerations. Most interpretations of the observational evidence predict that achieved BPs below a target of r140/ 90 mm Hg in patients with CKD and diabetes would be associated with additional benefit in the prevention of both progressive kidney disease and cardiovascular events. However, no RCTs have demonstrated such a benefit.


Most interpretations of the observational evidence predict that achieved BPs below a target of r140/ 90 mm Hg in patients with CKD and diabetes would be associated with additional benefit in the prevention of both progressive kidney disease and cardiovascular events. However, no RCTs have demonstrated such a benefit. It remains possible that clinical harm could be done, at least in some subgroups, by attempting to reach lower BPs. Achieving lower BPs would require multiple drug treatments in the majority of patients with CKD and diabetes, particularly those with high pulse pressures. This has implications both for adherence and for the cost of treatment, of which the latter is particularly important in resource-poor settings. 4.2: We suggest that adults with diabetes and CKD ND with urine albumin excretion 430 mg per 24 hours (or equivalent*) whose office BP is consistently 4130 mm Hg systolic or 480 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r130 mm Hg systolic and r80 mm Hg diastolic. (2D) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Observational studies show that the level of urine albumin predicts the risk of adverse cardiovascular and kidney outcomes. K BP lowering reduces the rate of urinary albumin excretion, which may in turn lead to a reduced risk of both kidney and cardiovascular events, although this has not been shown in RCTs. RCTs.


K BP lowering reduces the rate of urinary albumin excretion, which may in turn lead to a reduced risk of both kidney and cardiovascular events, although this has not been shown in RCTs. RCTs. The Work Group found only one RCT, from the Steno Diabetes Centre in Copenhagen (Intensified Multi- factorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria [Steno-2 study]) in which diabetic patients with high urine albumin were selected and randomized to two BP targets.209,211,253 In the Steno-2 study, 160 adults with microalbuminuria and type 2 diabetes were randomized to intensive multifactorial intervention or to conventional therapy. The intensive-care arm received ACE-I or ARB irrespective of BP and had a BP target that was initially 140/85 mm Hg but was reduced to 130/80 mm Hg during the study, as compared to o160/95 mm Hg which was subsequently reduced to o135/85 mm Hg in the conven- tional arm. However, intensive intervention also included dietary advice, exercise, lipid-lowering treatment, help with smoking cessation, vitamin supplementation, aspirin, and intensified glycemic control. This intensive therapy was shown to be associated with a reduced risk of CVD, nephropathy, retinopathy, and autonomic neuropathy. The improvements seen in the intensive-therapy group were mostly in BP and the lipid profile, with only minor differences between the two groups in glycemic control and no differences in smoking, exercise measures, or body Observational evidence.


The improvements seen in the intensive-therapy group were mostly in BP and the lipid profile, with only minor differences between the two groups in glycemic control and no differences in smoking, exercise measures, or body Observational evidence. There is strong observational evidence of an association between higher BP and an increased risk of worsening kidney function.148,201,225,254,255 Diabetic patients with microalbuminuria are at increased risk of both and progressive kidney disease as compared to diabetic patients with normal albumin excretion.256 258 Reduction of the rate of urinary albumin excretion during treatment is associated with a better kidney and cardiovascular However, these associations do not prove causation, and it remains possible, albeit highly unlikely, that patients in whom the rate of urine albumin excretion declines, either spontaneously or in response to treatment, have intrinsically less severe disease than those in whom no remission occurs. RCTs examining the effects of targeting certain levels of urine albumin on clinically relevant end points are needed before it can be concluded that treatment to reduce the rate of urinary albumin excretion will improve prognosis. The Work Group therefore felt that benefits of targeting lower BP levels were likely to be greater for individuals with micro- or macroalbuminuria, so a target BP of r130/ 80 mm Hg is suggested; however, stronger evidence is required in this population, hence the grade of 2D. 4.3: We suggest that an ARB or ACE-I be used in adults with diabetes and CKD ND with urine albumin excretion of *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Patients with diabetes and microalbuminuria are at increased risk of kidney failure and cardiovascular events.


RATIONALE K Patients with diabetes and microalbuminuria are at increased risk of kidney failure and cardiovascular events. K ACE-Is and ARBs reduce the level of urine albumin in patients with diabetes and microalbuminuria at baseline, but data regarding the effects on kidney failure or cardiovascular outcomes are limited. Microalbuminuria is much more common than frank proteinuria or albuminuria in patients with diabetes, but it is also associated with an increased risk of kidney and cardiovascular events. Several trials have shown a benefit of ACE-Is or ARBs over placebo in patients with microalbumi- nuria, irrespective of pre-treatment BP (See Supplementary All of these trials studied the effects of treatment on surrogate outcomes, most commonly the transition to overt proteinuria; none demonstrate conclu- sively that these improvements are associated with a reduction in hard end points in this population, although this may be the result of low event rates, inadequate statistical power, and short follow-up times. The Work Group believes that ACE-Is and ARBs should be the preferred classes of BP-lowering agent used in patients with diabetes and microalbuminuria, although the relatively weak available evidence is reflected in the poor grade assigned to this guideline statement (2D). We have not made statements about prevention of microalbuminuria as this topic will be addressed in the forthcoming KDOQI Diabetes guideline update.268 4.4: We recommend that an ARB or ACE-I be used in adults with diabetes and CKD ND with urine albumin excretion 4300mg per 24 hours (or equivalent*). (1B) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1.


(1B) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Patients with diabetes and high levels of urine albumin are at a particularly high risk of adverse cardiovascular and kidney outcomes. K There is strong evidence from RCTs conducted in patients with diabetes and CKD demonstrating that ACE-Is and ARBs protect against kidney failure and increases in albumin levels. Individuals with elevated levels of urinary albumin or protein and diabetes have some of the highest rates of cardiovascular events and kidney failure of any group with CKD. For example, in IDNT and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, the annual risk of the kidney and cardio- vascular end points all approached 10%.182,184,259 261 RCTs. Several RCTs have provided high-quality evidence, both in type 1 diabetes269 that ARBs and ACE-Is reduce the risk of kidney outcomes270 as compared to placebo or a dihydropyridine calcium-channel although no clear effect on cardiovascular out- comes has been established (possibly due to inadequate power) (see Supplementary Tables 37 42 online). How- ever, applicability of study findings to the entire CKD and diabetes population is somewhat limited, because major studies have excluded patients with clinically significant CVD. There is high-quality evidence from trials of high-risk individuals from the general population showing that ARBs and ACE-Is improve cardiovascular outcomes,185,271 276 including in patients with diabetes.277,278 But these studies did not focus on patients with clinically significant albuminuria. In contrast, there was no benefit of ACE-Is as compared to diuretic therapy in the CKD and diabetic subgroups in ALLHAT,279 although, again, few of the study patients were likely to have had frank albuminuria.


In contrast, there was no benefit of ACE-Is as compared to diuretic therapy in the CKD and diabetic subgroups in ALLHAT,279 although, again, few of the study patients were likely to have had frank albuminuria. Moreover, ALLHAT showed clear BP differences in favor of diuretic therapy over ACE-Is, making the comparison between the two groups somewhat difficult. As the RCT data in this population is strong and consistent, the level of evidence is high (see Supplementary Table 37 online). The decision on the grade of this recommendation statement (1B) was made by a majority vote. The minority of Work Group members supported an evidence grade of A. The choice between an ACE-I and an ARB in CKD patients is controversial. In general, the evidence for kidney outcomes that supports the use of ACE-Is is older and applies largely to type 1 diabetes, whereas the evidence supporting the use of ARB comes from more recent trials in type 2 diabetes. For cardiovascular protection in patients with diabetes, the evidence largely points to ACE-Is. The available data are consistent, suggesting the effects of both classes of agents are likely to be similar. Cost and availability may be an important consideration in some countries. However, extra- polations within and between drug classes must be made with care: within-class effects on hard outcomes may differ substantially and may depend on the dose, making extrapolation to other drug classes problematic. A 2004 meta-analysis concluded that there was insufficient evidence on the relative effects of ACE-Is versus ARBs on survival.280 We were unable to find trials directly comparing ACE-Is and ARBs in patients with diabetes and albuminuria.


A 2004 meta-analysis concluded that there was insufficient evidence on the relative effects of ACE-Is versus ARBs on survival.280 We were unable to find trials directly comparing ACE-Is and ARBs in patients with diabetes and albuminuria. No clear difference between the effects of the two classes of drugs was found in the large Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint (ONTARGET) trial involving people at high cardiovascular risk, including subgroups with diabetes or CKD.281,282 However, this study was not powered to make this comparison, so a real difference remains possible. The data are even more scarce regarding the effects of other drug classes on outcomes in patients with diabetes and proteinuria. In IDNT, patients with proteinuria were rando- mized to irbesartan, amlodipine, or placebo. Amlodipine did not significantly affect the risk of kidney or cardiovascular events as compared to placebo and was clearly inferior to irbesartan for the prevention of kidney outcomes.184 Aldoster- one antagonists can reduce the risk of proteinuria in non- diabetic CKD patients109,283 and in patients with diabetic but adequately powered studies are lacking. In the opinion of the Work Group, ACE-Is and ARBs are likely to be similarly effective in improving outcomes in patients with diabetes and proteinuria. Practitioners should therefore base prescribing decisions on the evidence available for each class, the risk of side effects, and cost considerations. RESEARCH RECOMMENDATIONS K Prospective RCTs of a risk-based approach to the reduction of cardiovascular risk and kidney end points are encouraged. K Studies comparing various BP intervention thresholds and targets among patients with diabetes, with or without an increased urinary AER, and with or without a reduced GFR are needed. K Studies in which drug dose is titrated on the basis of the urine albumin level (or change in GFR) are needed.


K Studies in which drug dose is titrated on the basis of the urine albumin level (or change in GFR) are needed. K Studies on the effects of non-dihydropyridine calcium- channel blockers on long-term outcomes are needed. K Prospective studies of add-on therapy (consisting of thiazides, aldosterone antagonists, or DRIs) and reduc- tion of sodium chloride intake on the effects of ACE-Is or ARBs in patients with diabetes and CKD are encouraged. K Prospective studies of the combination of ACE-Is and ARBs in patients with diabetes and CKD are encouraged. K Prospective studies of different target BP levels stratified by GFR are encouraged. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contribu- tor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplementary Table 37. Evidence profile of RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM. Supplementary Table 38. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM [categorical outcomes]. Supplementary Table 39.


RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM [categorical outcomes]. Supplementary Table 39. RCTs examining the effect of ACEI or ARB vs. placebo in patient with CKD and DM [continuous outcomes]. Supplementary Table 40. Evidence profile of RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM. Supplementary Table 41. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 42. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 43. Evidence profile of RCTs examining the effect of ACEI vs. ARB in patients with Type 2 DKD. Supplementary Table 44. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 45. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 46. Evidence profile of RCTs examining the effect of ARB vs. ARB in patients with CKD and DM. Supplementary Table 47. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 48. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 49. RCTs examining the effect of DRI ARB vs. placebo ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 50. RCTs examining the effect of dihydropyridine CCB vs. placebo in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 51.


RCTs examining the effect of dihydropyridine CCB vs. placebo in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 51. RCTs examining the effect of aldosterone antagonist ACEI vs. placebo ACEI in patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 52. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [categorical outcomes]. Supplementary Table 53. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [continuous outcomes]. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/bp.php Chapter 5: Blood pressure management in kidney transplant recipients (CKD T) INTRODUCTION This chapter addresses the management of BP in adults with non dialysis-dependent CKD who have received a kidney transplant (CKD T). There is insufficient evidence to make recommendations specific to children with a kidney transplant. 5.1: We suggest that adult kidney transplant recipients whose office BP is consistently 4130 mm Hg systolic or 480 mm Hg diastolic be treated to maintain a BP that is consistently r130 mm Hg systolic and r80 mm Hg diastolic, irrespective of the level of urine albumin excretion. (2D) RATIONALE In adult kidney transplant recipients we consider two primary outcomes from the standpoint of BP: graft function and CVD.


(2D) RATIONALE In adult kidney transplant recipients we consider two primary outcomes from the standpoint of BP: graft function and CVD. High BP is well recognized as an important risk factor for both decline in graft function and develop- ment of CVD.153,284 288 Increased levels of both systolic and diastolic BP are associated with worse graft survival over a 7-year period after transplantation,289 and maintaining a systolic BP o140 mm Hg at 3 years after transplantation is associated with improved graft survival and reduced cardiovascular mortality at 10 years.290 Similarly, high BP is associated with an increased risk of graft loss and all-cause Although no RCT defines BP targets in adult kidney transplant recipients for clinically important end points such as graft survival, cardiovascular events, or all-cause mortality, our suggestion is that the BP target should not deviate from the recommended target of r130/80 mm Hg as defined in the recent KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients,292 since there have been no recent data to contradict this recommendation. Although the European Best Practice Guidelines for Renal Transplantation 2002 recommended a target BP r125/ 75 mm Hg in proteinuric patients, there is no evidence to differentiate BP target based on albumin excretion in renal Because adult CKD T patients are at high risk for both graft loss and development of CVD,284 288 we favor a target of r130/80 mm Hg rather than a target of r140/90 mm Hg. We recognize that this recommendation is based on observational data and have therefore given it a grade of 2D. 5.2: 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.


5.2: 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) RATIONALE BP-lowering agents are prescribed in 70 to 90% of kidney transplant recipients, according to both registry reports and There are many considerations in choosing anti- hypertensive drugs for use in adult kidney transplant recipients. These include side effects that are also seen in the general population, side effects particular to kidney transplant patients (e.g.


These include side effects that are also seen in the general population, side effects particular to kidney transplant patients (e.g., increased propensity to hyperkalemia or anemia with ACE-Is or ARBs), level of urine albumin, degree of hemodynamic stability and the associated potential to alter graft perfusion (especially in a period soon after transplanta- tion), co-morbid conditions that may indicate or preclude certain agents, interactions with immunosuppressive medica- tions or other medications unique to patients with kidney transplant patients, and long-term impact on graft function, CVD, and all-cause mortality.296 Because of these considera- tions and the absence of large trials with clinically important outcomes, there is marked variability in the prescription of cardioprotective medications after transplantation.294 Short-term RCTs (of duration r2 years) suggest a beneficial effect of calcium-channel blockers, as compared with either placebo or ACE-Is, with regard to level of kidney In addition, a recent meta-analysis of RCTs indicated that the use of calcium-channel blockers, versus placebo or no treatment (plus additional agents in either arm, as needed) was associated with a 25% lower rate of graft loss (relative risk [RR] 0.75; 95% CI 0.57 0.99) and higher These findings prompted the Canadian Society of Transplantation and Canadian Society of Nephrology to question the recommen- dation from the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients to use any class of antihypertensive agent after kidney transplantation.292,302 Most transplantation centers prefer to use dihydropyridine calcium-channel blockers for initial therapy after transplan- tation, since these agents dilate afferent arterioles and counteract the vasoconstrictive effect of CNIs298,303 (Supple- mentary Tables 54 59 online). However, non-dihydropy- ridines might interfere with the metabolism and excretion of chapter 5 http://www.kidney-international.org & 2012 KDIGO the CNIs cyclosporine and tacrolimus, as well as the mTOR inhibitors sirolimus and everolimus.


However, non-dihydropy- ridines might interfere with the metabolism and excretion of chapter 5 http://www.kidney-international.org & 2012 KDIGO the CNIs cyclosporine and tacrolimus, as well as the mTOR inhibitors sirolimus and everolimus. When renal transplant recipients are prescribed non-dihydropyridine calcium- channel blockers, careful monitoring of CNIs and mTOR inhibitors blood levels is required if drugs or dosages are changed. ACE-Is and ARBs are known to have acute hemodynamic effects, resulting in an increase in SCr level, and are therefore frequently avoided within the first 3 to 4 months after transplantation, when acute rejection is a strong possibility, and an increase in creatinine level can be difficult to Side effects of ACE-Is and ARBs when used soon after transplantation include increased creatinine levels, hyperkalemia, and anemia. One study showed that although 44% of patients were receiving ACE-Is or ARBs at the time of transplantation, the proportion dropped to 12% at 1 month and subsequently increased to 24% at 6 months.294 In the longer term, especially in kidney-transplant patients with persistent albuminuria, ARBs and ACE-Is should be considered. Two analyses of registry data have been published, with one showing a benefit and the other no benefit with the use of ACE-Is or ARBs for graft and patient Small trials have examined various agents to lower BP in kidney-transplant patients. One examined losartan, captopril, and amlodipine and noted no change in BP or kidney function between baseline and end of follow-up. ACE-Is and ARBs did, however, reduce the risk of proteinuria, as compared with a calcium-channel blocker308 (Supplementary Table 60 online). The Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) was an RCT of candesartan The primary outcome was all-cause mortality, cardiovascular morbidity, or graft failure.


The Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) was an RCT of candesartan The primary outcome was all-cause mortality, cardiovascular morbidity, or graft failure. Enroll- ment of 700 patients was planned, but unfortunately, the study was terminated prematurely due to lower-than- expected event rates after enrollment of 502 participants because only 26 events took place in the 20 months of follow- up (with no difference in frequency between the two arms), whereas 210 events had been predicted over 3 years. Although there was slightly better BP control in the active group versus the control group (mean BP, 131/80 mm Hg vs. 137/ 83 mm Hg, respectively), the relatively tight BP control in both arms might have contributed to the low event rate. The protein excretion rate decreased in the ARB arm and increased in the placebo arm, but this difference may have been influenced by the different achieved BP levels (Supple- mentary Tables 61 62 online). A large Canadian RCT of ramipril versus placebo is It will enroll 528 kidney-transplant patients who underwent transplantation 46 months previously, have protein excretion of 40.2 g per 24 hours, and have a GFR . Outcomes will include doubling of SCr level, kidney failure, and death. Because no large studies with clinically important out- comes have been completed, we have chosen to follow the recommendations of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients292 and to provide an ungraded statement. RESEARCH RECOMMENDATIONS RCTs are needed to determine: K The optimal target BP for adult patients with kidney transplants with a focus on clinically important outcomes such as graft survival, CVD, and mortality.


RESEARCH RECOMMENDATIONS RCTs are needed to determine: K The optimal target BP for adult patients with kidney transplants with a focus on clinically important outcomes such as graft survival, CVD, and mortality. K The effects of ACE-Is and ARBs versus placebo, ACE-Is and ARBs versus calcium-channel blockers, and calcium- channel blockers versus placebo regarding long-term graft survival, CVD, and patient survival. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contri- butor, copyright holder, or advertiser concerned. Accord- ingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplementary Table 54. Evidence profile of RCTs examining the effect of ACEI or ARB vs. CCB in transplant recipients without DM. Supplementary Table 55. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [categorical outcomes]. Supplementary Table 56. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [continuous outcomes]. Supplementary Table 57. Evidence profile of RCTs examining the effect of CCB vs. placebo in transplant recipients without DM. Supplementary Table 58.


Evidence profile of RCTs examining the effect of CCB vs. placebo in transplant recipients without DM. Supplementary Table 58. RCTs examining the effect of CCB vs. placebo in transplant recipients [categorical outcome]. Supplementary Table 59. RCTs examining the effect of CCB vs. placebo in transplant recipients without DM [continuous outcome]. Supplementary Table 60. RCTs examining the effect of ACE vs. ARB in hypertensive transplant recipients without DM [continuous out- comes]. Supplementary Table 61. RCTs examining the effect of ARB vs. placebo in transplant recipients [categorical outcome]. Supplementary Table 62. RCTs examining the effect of ARB vs. placebo in transplant recipients without DM [continuous outcome]. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/bp.php Chapter 6: Blood pressure management in children with CKD ND INTRODUCTION This chapter addresses the management of BP in children (defined as 18 years or younger, although chronological age does not necessarily parallel biological or social development). Children with non-dialysis-dependent CKD (CKD ND) differ from adults in the etiologies of CKD, definition of hyperten- sion, and CKD associated co-morbidities. As cardiovascular end points such as myocardial infarction, stroke, or cardio- vascular death are rare, effects of high BP and its treatment on kidney outcomes (e.g., lowering of GFR, initiation of dialysis, or transplantation) and target-organ damage are relevant end points in studies of children with CKD, although in the longer-term, CVD has a more important role. Elevated BP and high BP are common in children with CKD, but RCTs of various treatment agents or targets are scarce. Observational studies and registry data311 315 demon- strate that more than half of children with CKD have high BP based upon a casual BP reading.


Observational studies and registry data311 315 demon- strate that more than half of children with CKD have high BP based upon a casual BP reading. Observational data also suggest that hypertensive children with CKD progress to kidney failure significantly faster than normotensive children In studies of young adults with kidney failure whose kidney disease began in childhood, the risk of cardiovascular death is extremely high.316,317 Sudden cardiac death is the main cause of cardiac death in these In light of the high prevalence and substantial morbidity associated with elevated BP in children with CKD, we systematically reviewed the existing literature and previously published guideline statements regarding the management of elevated BP in this vulnerable population. As RCTs are considered to provide the strongest evidence for CPGs, we reviewed RCTs with kidney and cardiovascular outcomes in which children with CKD was the study population. We supplemented this limited RCT evidence with information obtained from case series, cohort studies, and previous guideline statements on BP in healthy children and children with CKD. We further described the evidence base in detail in the narrative following each recommendation statement. The strict evidence-based approach of formulating recommendations may have resulted in statements that do not include some commonly accepted treatment practices in children. The rationale for this approach is that we do not wish to provide guideline recommendations and discourage research in areas where evidence is weak. The research recommendations listed at the end of the chapter illustrate areas where more evidence is needed. BACKGROUND Definitions. For this Guideline, the age range for children is defined as from birth through 18 years.


For this Guideline, the age range for children is defined as from birth through 18 years. The preferred method of BP measurement in children is auscultation, and reference tables for BP percentiles for age, sex, and height can be accessed at the National Heart, Lung, and Blood Institute s Fourth Report on the Diagnosis, Evaluation, and Treatment of High BP in Children and Adolescents at http://www.nhlbi. Throughout this guideline when we refer to thresholds or targets for BP therapy, we are referring to manual, auscultatory measurements of both systolic and diastolic BP unless otherwise specified. Correct BP measurement requires a cuff that is appropriate to the size of the child s upper arm and elevated BP must be confirmed on repeated visits. In deciding on treatment, unless severe hypertension is present, an individual s BP level should be determined as an average of multiple BP measurements taken over weeks Current recommendations suggest that measurements obtained by oscillometric devices that exceed the 90th percentile for age, sex, and height should be repeated by auscultation.319 Detailed descriptions of appropriate BP measurement techniques in children and the strengths and limitations of various BP measure- ment methods in children with CKD have been detailed previously in the KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease, Guideline 13: Special Considerations in Although there is insufficient trial evidence to recommend the use of ABPM in this Guideline, by virtue of frequent measurement and recording, ABPM allows the practitioner to compute the mean BP during the day, night, and over 24 hours, as well as to assess the time in which BP exceeds the upper limit of the normal range (i.e., the BP load).


In deciding on treatment, unless severe hypertension is present, an individual s BP level should be determined as an average of multiple BP measurements taken over weeks Current recommendations suggest that measurements obtained by oscillometric devices that exceed the 90th percentile for age, sex, and height should be repeated by auscultation.319 Detailed descriptions of appropriate BP measurement techniques in children and the strengths and limitations of various BP measure- ment methods in children with CKD have been detailed previously in the KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease, Guideline 13: Special Considerations in Although there is insufficient trial evidence to recommend the use of ABPM in this Guideline, by virtue of frequent measurement and recording, ABPM allows the practitioner to compute the mean BP during the day, night, and over 24 hours, as well as to assess the time in which BP exceeds the upper limit of the normal range (i.e., the BP load). A number of reviews and guidelines suggest that in children with CKD, ABPM is a particularly useful tool to assess BP patterns.320 322 In children, ABPM can be particularly useful, as a significant number of patients have masked hypertension and would not be recognized as having hypertension based on the outpatient measurements only. A few studies using ABPM in patients with CKD suggest that it may give a better measure of overall BP and better indicate risk for kidney disease progression than office BP measurement.12,77,323 In fact, the only large RCT of BP control in children with CKD used ABPM as the method for BP assessment.14 Further research may elucidate chapter 6 http://www.kidney-international.org & 2012 KDIGO that future guidelines for therapy should be based on ABPM, rather than office based measures that are commonly used today.


A few studies using ABPM in patients with CKD suggest that it may give a better measure of overall BP and better indicate risk for kidney disease progression than office BP measurement.12,77,323 In fact, the only large RCT of BP control in children with CKD used ABPM as the method for BP assessment.14 Further research may elucidate chapter 6 http://www.kidney-international.org & 2012 KDIGO that future guidelines for therapy should be based on ABPM, rather than office based measures that are commonly used today. We have not recommended ABPM targets in this Guideline as ABPM is currently expensive and not readily available as routine clinical care in many settings. 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) RATIONALE CVD has long been recognized as a substantial cause of late morbidity and mortality in individuals with onset of CKD The majority of children with CKD are and a substantial proportion show evidence of target-organ damage associated with both masked and confirmed hypertension in a dose dependent fashion.325 However, few RCTs directly comparing thresholds for initiation of BP treatment (vs. no treatment) or targets of BP treatment to prevent or reverse target-organ damage have ever been performed in children with CKD. Observational studies of healthy children suggest that persistent elevations in BP are associated with significant late sequelae.


Observational studies of healthy children suggest that persistent elevations in BP are associated with significant late sequelae. In cross-sectional studies, elevated BP is associated with evidence of target-organ damage, including left ventricular hypertrophy and increased carotid intimal medial In longitudinal analysis from the Bogalusa Heart Study, high systolic or diastolic BP was associated with an increased risk of developing kidney failure during long-term and high childhood BP was an independent predictor of increased ankle brachial pulse wave velocity in Persistently elevated BP in the young has been associated with decreased measures of carotid artery In healthy children, in the absence of long-term data linking specific BP levels with adverse cardiovascular or kidney events, hypertension is defined on the basis of a population-based distribution. Specifically, hypertension is defined as average systolic BP or diastolic BP that is greater than or equal to the percentile for sex, age, and height on three or more In healthy children, the goal of anti-hypertensive treatment is reduction of the BP to below the 95th percentile, unless concurrent conditions are present. CKD is considered such a concurrent condition. In children with CKD, according to the Fourth Report on the Diagnosis, Evaluation, and Treat- ment of High BP in Children and Adolescents, the BP should be lowered to below the 90th percentile (http://www.nhlbi.nih. The rationale for this approach is similar to the recommended treatment of hypertension in adults with additional cardiovascular risk factors or co-morbid conditions. A number of expert panels have reviewed the existing literature and made similar recommendations.


A number of expert panels have reviewed the existing literature and made similar recommendations. The National High Blood Pressure Education Program Working Group on High BP in Children and Adolescents has recommended initiating pharmacologic therapy for BP above the 90th percentile if a compelling indication such as CKD is In 2004, the NKF KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease1 recommended that the target BP in children with CKD should be lower than the 90th percentile for normal values adjusted for age, sex, and height or o130/ 80 mm Hg, whichever is lower. Similarly, the Cardiovascular Risk Reduction in High-Risk Pediatric Patients report330 listed children with CKD or kidney failure as a pediatric population at high risk for CVD, for which a target BP below percentile for age, sex, and height is suggested. According to that consensus statement, CKD is considered a coronary heart disease equivalent for which the treatment recommendations are similar to those in secondary preven- tion guidelines for adults with established coronary disease. Among children with CKD, observational data have shown that those with hypertension (i.e.


Among children with CKD, observational data have shown that those with hypertension (i.e., BP above the 95th percentile) have a more rapid decline in estimated GFR than those without hypertension.313,331 In a study by the European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood, children with a systolic BP 4120 mm Hg had a significantly faster decline in GFR.332 In children who have received a kidney transplant, hyperten- sion is a strong predictor of accelerated GFR decline333 and Preliminary data from the ongoing observa- tional Chronic Kidney Disease in Children (CKiD) study show that, among 425 children with repeated measures of GFR, having systolic BP above the 90th percentile for age, sex, and height is associated with faster progression of CKD as compared with lower BP.336 In this cohort, the annualized percent change in GFR among those with systolic BP above with systolic BP between the 50th percentiles and 2.5 (95% CI 8.9 3.9) in those with systolic BP below the percentile. In the ESCAPE trial (described in detail in the next section), the kidney survival rate was 66% during follow-up among those with systolic BP below the 90th percentile but only 41% among those with systolic BP above percentile (P 0.0002). In ESCAPE, a diastolic BP below the 90th percentile was associated with a kidney survival rate of 67%, compared to 28% among those with diastolic BP above the 90th (F. Schaefer and E. Wuhl, personal communication). On the basis of the RCT evidence, observational data, and other guidelines, the Work Group graded this recommendation as 1C. The quality of evidence was graded as C because the RCT evidence is limited to inferred evidence from one trial.


The quality of evidence was graded as C because the RCT evidence is limited to inferred evidence from one trial. 6.2: We suggest that in children with CKD ND (parti- cularly 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) RATIONALE The evidence for this recommendation comes largely from the which showed a benefit in slowing CKD progression by targeting 24-hour MAP by ABPM to less than percentile for age, height and sex. Secondary analysis of the data suggested the effect was stronger in proteinuric children with CKD. (See Supplementary Tables 63 64 online). Based largely on the ESCAPE results, the European Society of Hypertension guidelines recently recommended that in children with CKD, BP targets should be below the 50th percentile in the presence of proteinuria and below the 75th percentile in the absence of proteinuria.337 In the European Society of Hypertension guidelines, the rationale for choosing percentile as a threshold in children with CKD without proteinuria is based on a re-analysis of ESCAPE results, examining kidney outcomes according to achieved 24-hour mean BP level. Since the 75th percentile was not an original targeted intervention in the ESCAPE trial, and the trial was not powered to detect differences by levels of proteinuria in recruited subjects, we have not made a separate specific recommendation distinguishing between the presence and absence of proteinuria for target BP levels for children with CKD, but this is an important area for future study. Our guideline includes a statement of caution in aggressively pursuing low BP targets in children with CKD.


Our guideline includes a statement of caution in aggressively pursuing low BP targets in children with CKD. We recognize that children are particularly susceptible to intercurrent illnesses, gastroenteritis and dehydration, and aggressive use of BP lowering medications in polyuric and dehydrated patients can lead to hypotension and alterations in renal perfusion. Clinicians who prescribe anti-hypertensive medications, particularly ACE-Is and ARBs in children need to be aware of the risk of drug toxicity in children susceptible to intravascular dehydration. Clinicians should consider discontinuing the drugs in the presence of acute diarrhea.338 Additionally we recognize that reaching a target of less than percentile BP may be quite difficult in some children with CKD. The risks of polypharmacy have to be weighed against the potential benefits of achieving lowered BP. In the ESCAPE trial,14 468 hypertensive children with a 24-hour MAP above the 95th percentile for age, sex, and height, and a GFR (based on the Schwartz formula) of , received ramipril at a fixed dose of /day and were randomized to target a 24-hour MAP, measured by means of ABPM, of either between the 50th and percentile or below the 50th percentile. Additional anti- hypertensive agents, except for other antagonists of the RAAS, were added at the discretion of the local provider to achieve the target BP. In this study the largest prospective RCT of BP therapy in children with CKD to date fixed-dose ramipril and a lower therapeutic BP target (MAP below the 50th percentile for age, sex, and height by ABPM delayed the progression to kidney failure. There were no differences in the frequency or types of adverse events between the intensified and conven- tional BP target arms in the trial. In subsequent stratified analyses, the effects were more pronounced in children with glomerulopathy and kidney hypodysplasia or dysplasia.


In subsequent stratified analyses, the effects were more pronounced in children with glomerulopathy and kidney hypodysplasia or dysplasia. There was no evidence of improved outcomes in individuals with hereditary nephropathies or other congenital causes of kidney disease other than aplasia or dysplasia, although there were relatively few individuals in these subgroups. Additionally, in stratified analyses, the efficacy of the intensified BP control intervention was most marked in children with a urine PCR of 4150 mg/g (415 mg/mmol) (see supplement of Wuhl ). Data presented at the American Society of Nephrology 2010 annual meeting from the observational CKiD study336 also shows slower progression of decline in kidney function in individuals with auscultatory manual BP below the 50th percentile for age, sex, and height as compared to individuals with BP between the 50th percentile and those with BP above the 90th percentile. BP in this study is measured according to a standard protocol at annual study visits with an aneroid device. BP targets in children with CKD should be individualized on the basis of susceptibility to hypotension. Many causes of childhood CKD include diagnoses associated with salt and water losses in the urine. As such, the risk of hypotension associated with aggressive BP control should temper the ramping-up of BP-lowering medication to reach a low BP target. 6.3: 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 RATIONALE This recommendation is based on published experience with these agents in children with hypertension, showing the drugs to be safe and effective in lowering BP and to confer a benefit for slowing CKD and reducing urine protein levels in adults with CKD.


6.3: 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 RATIONALE This recommendation is based on published experience with these agents in children with hypertension, showing the drugs to be safe and effective in lowering BP and to confer a benefit for slowing CKD and reducing urine protein levels in adults with CKD. However in teenage girls, pregnancy testing and the use of birth control prior to and during ACE-I/ARB therapy need to be considered. Additionally, as mentioned above, discontinuing these agents during episodes of diarrheal illness and dehydration should be considered.338 ACE-Is or ARBs should be the preferred choice in treating proteinuric CKD (see Chapters 3 and 4). Multiple studies in adults with CKD have shown renoprotection with the use of ACE-Is or ARBs. RAAS antagonists preserve kidney function not only by lowering BP but also by means of anti-proteinuric, anti-fibrotic, and anti-inflammatory properties. In the ESCAPE trial described above, on the basis of previous research in adults, the children in both arms of the intervention received a fixed, maximum dose of the ACE-I ramipril.323 Further BP lowering was achieved through the addition of other medica- tions at the discretion of the local provider. Others have recommended ACE-Is or ARBs as first-line agents in treating children with CKD and high BP,339 particularly in those with proteinuria.340 The recently released European Society of Hypertension guidelines337 assert that it is reasonable to recommend agents blocking the renin angiotensin system as first choice in proteinuric, and also in non-proteinuric patients with CKD. How- ever, limited direct evidence from clinical trials is available with which to assess the efficacy of RAAS in children with CKD.