Alpha-blockers reduce the symptoms of benign prostatic hyperplasia, which may be a co-morbidity to consider in older men with CKD. In general, alpha-blockers are not considered a first-line choice because of the common side effects of postural hypotension, tachycardia and headache. They should be commenced at a low dosage to avoid a first-dose hypotensive reaction. Drug combinations. There are few data available about alpha-blocker combinations with other BP lowering drugs. Vasodilatation can lead to peripheral edema, so diuretics are commonly combined with alpha-blockers, although the efficacy of this maneuver has not been studied. Alternatively, a non-selective beta-blocker can be used. Direct vasodilators Hydralazine and minoxidil both act by directly causing vascular smooth-muscle relaxation and hence vasodilatation. There have been no important changes to our understanding of these drugs since the publication of the KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensives Agents in Chronic Kidney Disease in 2004.1 Dose considerations in CKD patients. Hydralazine and minoxidil do not require dose adjustment in patients with impaired kidney function.4 Indications for direct vasodilators. Hydralazine has little value in the management of chronically elevated BP in CKD, although it is sometimes used as a parenteral hypotensive agent. Minoxidil is generally used in patients with very resistant hypertension and thus may be helpful in patients with CKD. However, its side effects (e.g., severe fluid retention, headache, tachycardia, hirsutism, and pericardial effusion) limit its use to the most resistant cases. Drug combinations. Because of the side effects of fluid retention and tachycardia, direct vasodilators (especially minoxidil) are usually combined with a beta-blocker and loop diuretic. RESEARCH RECOMMENDATIONS K Salt restriction appears to be a very promising method of reducing BP and the risk of progressive kidney disease and cardiovascular events. Therefore, large scale RCTs assessing the impact of this intervention on these patient- level outcomes are required. Patients with CKD should be included in these trials, given the potential for differences in the risks and benefits of reduced salt intake in these individuals. K RCTs should be undertaken to evaluate the benefit of weight loss at different stages of CKD. K RCTs should be undertaken in CKD with and without elevated albumin excretion levels comparing various combinations of RAAS blocking drugs. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contri- butor, copyright holder, or advertiser concerned. Accord- ingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. Chapter 3: Blood pressure management in CKD ND patients without diabetes mellitus INTRODUCTION This chapter addresses the management of BP in adult CKD patients (specifically non-dialysis-dependent CKD [CKD ND]) without diabetes mellitus. There is overlap with BP management in the elderly (defined as persons 465 years of age or as persons with CKD and aging-related co-morbid conditions). In the elderly in particular and to a lesser extent in younger CKD patients, these co-morbid conditions may require modifications in the approach to BP management. In this chapter we consider two primary adverse outcomes related to high BP: progression of kidney disease and development of CVD.137,138 The data are sufficient to provide recommendations on BP targets139 and the use of ACE-Is or ARBs, although there is evidence of heterogeneity in both areas according to the urine albumin level.96,140 142 We therefore divided the target populations on the basis of urine albumin level. We did not find sufficient data to suggest any differences according to CKD stage, so our recommendations are not stage-specific. It is not possible to recommend specific regimens or BP targets for all the various causes of CKD. Although there are strong observational data, there is no evidence from RCTs to indicate that the treatment approach should differ substantially for the patient with glomerular disease and high urine albumin levels compared to the patient with severe renovascular disease. Although we would have preferred to give a target range (lowest to highest) for BP rather than a single target for highest acceptable BP, there are insufficient data based on RCTs to recommend a target for lowest BP level. The recommendations and suggestions in this chapter therefore emphasize an approach based on highest acceptable BP and severity of albuminuria, but the interventions should be implemented cautiously and with subsequent surveillance for adverse effects. We also recognize that BP agents other than those recommended or suggested below, such as diuretics, may be necessary for BP control, especially as CKD progresses and volume retention becomes more of an issue. However, few RCTs addressing hard cardiovascular or kidney outcomes have randomized patients to a diuretic versus another agent on top of an ACE-I or ARB. Therefore, in contrast to the we do not provide a guideline statement regarding diuretic use as a preferred second-line agent. The use of diuretics and other BP agents are discussed in more detail below and in Chapter 2. 3.1: We recommend that non-diabetic adults with CKD ND and urine albumin excretion o30 mg per 24 hours (or equivalent*) whose office BP is consistently 4140 mm Hg systolic or 490 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r140mmHg systolic and r90 mm Hg *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 High BP is a risk factor for CVD and development and progression of CKD. K Lowering BP in the general population reduces cardio- vascular risk. K Lowering BP in CKD patients reduces the rate of CKD progression. K CKD is a major risk factor for CVD. Most recent BP guidelines have suggested a target BP of o140/90 mm Hg for all individuals who are not at high risk This is based on several lines of evidence, including observational data suggesting that high BP is a risk factor for CVD,144 observational data suggesting that high BP is a risk factor for development and progression of RCTs of BP agents in the general population showing a benefit of a lower target BP,149,150 and RCTs in the general population demonstrating that the treatment of BP reduces CVD outcomes.151 Several previous guidelines for kidney disease have recommended a BP target of o130/80 mm Hg for all patients with CKD, irrespective of the level of urine protein.1,143 These recommendations are primarily based on observational data in the general population showing that the presence of CKD, irrespective of the level of urine protein, is associated with high risk of CVD.152,153 In addition, data from the MDRD study, which randomized patients to a mean arterial pressure (MAP) of o92 mm Hg (equivalent to 125/75 mm Hg) versus 107 mm Hg (equivalent to 140/90 mm Hg) showed that tight BP control reduced progression of kidney disease in patients with41 g of urine protein per 24 hours.142 http://www.kidney-international.org chapter 3 & 2012 KDIGO Since the publication of previous guidelines, several events have resulted in more caution about advocating a BP target of r130/80 mm Hg in CKD patients without albuminuria. RCTs in CKD populations have shown that data from the general population cannot necessarily be extrapolated to the Moreover, particularly in RCTs related to anemia, the RCT findings may be inconsistent with are now requiring more rigorous data, in particular from RCTs, as a basis for recommendations. Several manuscripts have re- cently emphasized that tight BP control may have adverse particularly in the elderly and those with CAD and low diastolic BP.40 Furthermore, less tight control (i.e., control involving the use of fewer drugs) may improve adherence and reduce costs of treatment, a benefit particu- larly relevant in resource-poor environments. Finally, several recent RCTs have not shown a benefit of lower BP targets in patients without proteinuria. For instance, the African American Study of Kidney Disease and Hypertension (AASK) randomized participants to treat- ment to a MAP of either r92 mmHg or 102 to 107 mm Hg.140 During the long-term follow-up of participants, there was a benefit associated with the lower BP target among patients with a urine protein/creatinine ratio (PCR) of 4220 mg/g (422 mg/mmol), but not among those with a PCR r220mg/ g (r22 mg/mmol). In fact, in some analyses, there was a trend toward worse outcomes in those targeted to low BP when the urine PCR was r220 mg/g (r22 mg/mmol). Similarly, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) no benefit was found with regard to the primary composite outcome with a systolic BP target o120 mmHg versus a target of o140 mmHg. We therefore propose that targets currently recom- mended in the general population be extrapolated to those with CKD who do not have elevated urinary albumin or protein levels. Results of subgroup analyses of CKD patients included in RCTs assessing target BPs are consistent with the primary results of these trials160 (Supplementary Table 1 online). This move towards a more conservative target is consistent with other guidelines.161 We have graded this recommendation as 1B, given that this BP target is currently considered the standard of care for the general population. 3.2: We suggest that non-diabetic adults with CKD ND and urine albumin excretion of 30 to 300 mg per 24 hours (or equivalent*) whose office BP is con- sistently 4130 mm Hg systolic or 480 mm Hg dia- stolic 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 Urine albumin level of 30 to 300 mg per 24 hours (microalbuminuria) is a risk factor for CVD and CKD progression. K RCTs suggest that a BP r130/80 mm Hg may reduce progression of CKD. Patients with microalbuminuria are at high risk for progres- sion of CKD as well as development of CVD.18,153,162165 RCT data suggest that BP control is particularly important in CKD patients with high urine albumin levels. Short-term follow-up data from the MDRD study142 showed an interaction of BP target with level of urine protein, with a definitive benefit for kidney outcomes in patients with 41 g of urine protein per 24 hours and GFR (in MDRD Study A), with a trend toward a benefit with lower protein levels. Long-term follow-up showed a benefit of a low target BP and no interaction with the urine protein level, suggesting that the benefit may extend to all protein levels. In subgroup analyses, the benefit was statistically significant in those with urine protein excretion of 40.3 g per 24 hours166 (H Tighiouart, personal communication). However, there may have been insufficient statistical power to detect the interaction; hence, the risk reduction may have been greater in those with higher urine protein levels. Long-term follow- up data from the MDRD study also showed a benefit with regard to kidney outcomes with a lower target BP in specific groups, such as patients with polycystic kidney disease and non-glomerular diseases, that frequently have low urine albumin levels. Long-term follow-up in the AASK study demonstrated a benefit of lower target BPs in patients with It is unclear whether this PCR cutoff can be translated into an albumin-level cutoff, as this conversion is likely to be dependent on the type of kidney disease, and the ratio of glomerular albuminuria to tubular proteinuria. In the Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) study,14 a lower BP target was of benefit in reducing the risk of kidney outcomes, particularly in children with higher urine protein levels (P 0.06 for interaction of treatment target with urine protein level). There have been no BP target trials involving CKD patients focused on hard CVD outcomes. Subgroup analyses from the Hypertension Optimal Treatment (HOT) did not show a benefit for CVD outcomes in association with a lower diastolic BP target in CKD patients, although the statistical power to detect a difference was limited (n 470 for those with a creatinine level 41.5 mg/dl [133 mmol/l]). Furthermore, albuminuria data were not available. Because patients with CKD and microalbuminuria are at high risk, and given that the evidence does not support using different BP targets in non-diabetics and diabetics (see Chapter 4), the Work Group suggests a BP target of r130/80 mm Hg. This ensures consistency among recommendations between persons with diabetes and those without diabetes and facilitates implementation into clinical practice. 3.3: We suggest that non-diabetic adults with CKD ND and urine albumin excretion 4300 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. (2C) *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 Albuminuria is a major risk factor for CVD and CKD progression. K RCTs show that BP r130/80 mm Hg may reduce progression of CKD in patients with urine albumin excretion 4300 mg per 24 hours ( macroalbuminuria ). Patients with macroalbuminuria are at very high risk for both progression of CKD and development of CVD.18,162,163 Observational data suggest that hypertension is a risk factor for CVD and progression of CKD in patients with macro- As noted above, short-term follow-up data from the MDRD study142 showed an interaction of BP target with the level of urine protein, with a definitive benefit in patients with a urine protein level 41 g per 24 hours (in Study A) and a trend toward a benefit with lower protein levels; long-term follow-up data showed a benefit of a lower target BP. In subgroup analyses, a benefit was noted in patients with urine protein excretion 40.3 g per 24 hours166 (H. Tighiouart, personal communication). 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. 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. 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. 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). 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. 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. 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). 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. 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. 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 [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. 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 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. 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. 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). 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. 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. 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. 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). 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. 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. 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., 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 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. 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., 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. 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. 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. 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. 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. 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. 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. 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. 