However, the Work Group acknowledges the lack of RCTs that chapter 1 www.kidney-international.org speci cally address whether and how best to treat BP pro les identi ed by out-of-of ce BP measurements. HBPM also has the advantage of empowering individuals to take ownership of their medical care, hence promoting adherence to therapy. Research recommendations There are several areas in which more research is needed speci cally for the CKD population:  Identify if procedures for standardized BP measurement can be simpli ed, such as using a shorter rest period (e.g., 1 or 2 minutes) or a shorter interval between BP measure- ments (e.g., 15 or 30 seconds).  Compare standardized unattended versus standardized attended AOBP in routine clinical practice.  Determine the optimal interval for repeating ABPM and HBPM among individuals not taking and taking antihy- pertensive medications.  Determine the proportion of CKD patients with white- coat hypertension, masked hypertension, the white-coat effect, and masked uncontrolled hypertension using a BP threshold of 120 mm Hg instead of 140 mm Hg, and whether these phenotypes are associated with increased risk for CV disease.  Assess the cost-effectiveness of ABPM and HBPM, sepa- rately, for identifying white-coat hypertension, masked hypertension, the white-coat effect, and masked uncon- trolled hypertension.  Conduct RCTs comparing treatment based on ABPM or HBPM versus standardized of ce BP measurements. Treatment based on ABPM or HBPM includes not treating patients with white-coat hypertension, not intensifying treatment for the white-coat effect, treatment of masked hypertension, and intensifying treatment for masked un- controlled hypertension.


Treatment based on ABPM or HBPM includes not treating patients with white-coat hypertension, not intensifying treatment for the white-coat effect, treatment of masked hypertension, and intensifying treatment for masked un- controlled hypertension. www.kidney-international.org chapter 1 Chapter 2: Lifestyle interventions for lowering blood pressure in patients with CKD not receiving dialysis 2.1 Sodium intake Recommendation 2.1.1: We suggest targeting a sodium intake <2 g of sodium per day (or <90 mmol of sodium per day, or <5 g of sodium chloride per day) in patients with high BP and CKD (2C). This recommendation places a relatively high value on data from both the CKD population and the general population demon- strating that reductions in dietary sodium intake induce short- term reductions in BP and other evidence suggesting that these bene ts will reduce the need for antihypertensive medications. The Work Group placed lower value on the limited available data evaluating the effects of dietary sodium intake on clinical outcomes, including kidney failure, mortality, and CV disease endpoints in CKD patients. The recommendation is weak ac- cording to GRADE because of the low-quality evidence sup- porting the bene ts of low-sodium intake speci cally in the hypertensive CKD population; yet, many well-informed patients would agree to follow the guidance. This represents a change from the recommendation (1C) in the 2012 guideline based on the opinion of the current Work Group members, but it is consistent with the KDIGO 2020 Guideline for the Management of Patients with Diabetes and CKD. Key information Balance of bene ts and harms. In most populations worldwide, estimated average sodium intake is much higher than the proposed target of sodium intake <2 g (<90 mmol) per day for the general population.


In most populations worldwide, estimated average sodium intake is much higher than the proposed target of sodium intake <2 g (<90 mmol) per day for the general population. Recent meta-analyses of RCTs in non-CKD populations demonstrate a graded bene t in both BP and CV disease risk reduction with reductions in sodium intake. Importantly, even more- modest reductions in sodium intake that did not reach the <2 g per day target were associated with these Indeed, achieved mean sodium intake typically was in the 3.0 3.5 g/d range, and the low target of <2 g/d was reached in few participants. In CKD populations, this recommendation is driven by short-term studies of moderate- quality evidence evaluating SBP and DBP, but not CV events, as endpoints. It is unknown whether sodium intakes far below 2 g per day are safe or not. The Work Group notes that there are instances in which recommendations in the general population may not apply to the CKD population. For example, rarely, CKD patients may have salt-wasting kidney disease in which case this recom- mendation may not apply. In some instances, salt substitutes are used for the purpose of maintaining food-taste prefer- ences in people practicing dietary sodium restriction. These substitutes often replace sodium with potassium salts. Clinical trials of potassium-containing salt substitutes systematically exclude patients with CKD, so bene ts and harms of potassium-containing salt substitutes in CKD are not avail- able. Potassium-containing salt substitutes differ from foods rich in potassium, as such foods may have other health bene ts, thus extrapolating data from potassium intake in the diet may not be informative to potassium-containing salt substitutes.


Potassium-containing salt substitutes differ from foods rich in potassium, as such foods may have other health bene ts, thus extrapolating data from potassium intake in the diet may not be informative to potassium-containing salt substitutes. Although there is still controversy about the risk bene t ratio of potassium intake, observational studies often found that a higher potassium intake may be associated with a lower risk for all-cause death, CV disease, and CV death. However, at advanced stages of CKD (G4 and G5), a high potassium intake may be associated with higher risk.44 46 The Work Group suggests caution in using potassium-containing salt substitutes in CKD populations, especially in those with advanced CKD, hyporeninemic hypoaldosteronism, or hyperkalemia from other causes until more data on the safety and ef cacy of their use in CKD become available (see Practice Point 2.1.2). Quality of evidence. The Cochrane systematic reviews upda- ted for this guideline found low-to-moderate-quality evidence demonstrating that dietary sodium reduction results in short- term reductions in BP in CKD populations.47,48 This was evident for both SBP and DBP in CKD without diabetes (moderate; Supplementary Table S549 58 ); Type 1 diabetes (T1D) and CKD (low; Supplementary Table S659 63 ); Type 2 diabetes (T2D) and CKD (low; Supplementary Table S764 69 ); and diabetes and severely increased albuminuria (low; Supplementary Tables S8 and S9,63,66,68,69 ). These data were considered in the context of a substantial body of evidence con rming short-term bene ts in SBP and DBP reduction in the general population.


These data were considered in the context of a substantial body of evidence con rming short-term bene ts in SBP and DBP reduction in the general population. In the general population, the magnitude of BP lowering may be greater in persons with high BP, which is more prevalent in CKD patients.43 There is also moderate strength of evidence from sys- tematic reviews that lowering of sodium intake reduces CV disease in the general population.43 The systematic review conducted for this guideline found no RCT data evaluating the effects of dietary sodium reduction on clinical outcomes, including kidney failure (formerly known as end-stage kidney disease [ESKD]), CV disease, or mortality in CKD pop- ulations. However, the Work Group agrees that there is no reason to believe that the epidemiologic ndings in the gen- eral population would be different in CKD populations. chapter 2 www.kidney-international.org Further, persons with CKD frequently take angiotensin- converting enzyme inhibitors (ACEi) or angiotensin II re- ceptor blockers (ARB) compared to non-RASi therapy, and the kidney and CV bene ts of these medications may be enhanced if accompanied by a low-sodium diet compared to a Values and preferences. This recommendation places a relatively high value on the bene ts of using a non- pharmacologic method to lower BP and minimize additional medications. The recommendation places a relatively high value on data from the general population, demonstrating that reductions in dietary sodium intake induce short-term reductions in BP, and other evidence suggests that these bene ts likely extend to people with CKD. The Work Group placed lower value on the limited available data evaluating the effects of dietary sodium reduction on clinical outcomes, including kidney failure, mortality, and CV disease endpoints in CKD patients.


The Work Group placed lower value on the limited available data evaluating the effects of dietary sodium reduction on clinical outcomes, including kidney failure, mortality, and CV disease endpoints in CKD patients. The Work Group also considered the secondary bene ts of dietary sodium reduction in reducing pill burden and medication-related side effects. However, in the judgment of the Work Group, some individuals may prefer additional medications to the burden and decreased palatability of foods when following a low-sodium diet. Although forti ed salt is an important treatment for iodine de ciency in some countries, the Work Group judged that the bene ts of implementing this recommendation in CKD patients likely outweigh its risks. The recommendation is weak because, in controlled trials, only a minority of patients reached a target intake of <2 g (<90 mmol) of sodium per day, and effects on important clinical outcomes in CKD are uncertain. However, the Work Group believes that the bene ts of the recommendation likely exceed the harms and that many well-informed patients would try to follow the advice. Resource use and costs. Processed foods are generally higher in salt and often are less expensive than fresh food alterna- tives. Yet, a higher sodium intake associated with processed foods is likely to necessitate additional antihypertensive medications, greater pill burden, and associated healthcare costs. The Work Group also recognizes that, although feasible, following a low-sodium diet is challenging in many Western food environments. However, this recommendation may not only bene t individual patients, but also may in uence public health interventions and policymakers to consider targeting reductions of sodium in the food supply.


However, this recommendation may not only bene t individual patients, but also may in uence public health interventions and policymakers to consider targeting reductions of sodium in the food supply. Although this may require buy-in from key stakeholders, policy changes, and investment of public health resources, the Work Group believes that the health bene ts of such changes are also likely to be experienced by a wider population than those with CKD alone. Considerations for implementation. This recommendation places high value on evidence linking short-term changes in sodium intake with reductions in BP in CKD populations, and extrapolation of long-term bene ts from the general population. Although there is limited evidence from RCTs about the long-term bene ts or harms of sodium reduction in CKD populations per se, the Work Group agrees, with few exceptions, that there is little evidence or likelihood that health bene ts observed in the general population should not apply to CKD patients. On the contrary, there is reason to believe that the health bene ts of dietary sodium reduction may be particularly bene cial in CKD patients. Persons with CKD are commonly hypertensive, and systematic reviews have suggested that the magnitude of BP reduction for a given degree of reduction in dietary sodium intake is magni ed in hypertensive individuals, particularly if usual sodium intake is high.43 CKD populations also have high risk of CV disease and may therefore have a greater absolute risk reduction of such events with dietary sodium reduction, if the relative bene ts in the general population are indeed applicable to CKD.


Persons with CKD are commonly hypertensive, and systematic reviews have suggested that the magnitude of BP reduction for a given degree of reduction in dietary sodium intake is magni ed in hypertensive individuals, particularly if usual sodium intake is high.43 CKD populations also have high risk of CV disease and may therefore have a greater absolute risk reduction of such events with dietary sodium reduction, if the relative bene ts in the general population are indeed applicable to CKD. Finally, ACEi and ARBs are commonly used in CKD patients, and post hoc analyses of RCTs demonstrate that low-sodium intake may enhance the effects of these medications on kidney and CV outcomes.70 The Work Group agrees that decreasing dietary sodium intake is likely to also be appropriate in children with CKD, albeit with modi ed targets. Speci c targets are not available from prior studies for children with CKD, but the Work Group believes that adjusting the <2 g (<90 mmol) daily target for body weight in children would be reasonable.71 The Work Group considered the speci c target of sodium intake of <2 g (<90 mmol) daily and found no evidence showing different health bene ts or harms at different sodium intake targets in CKD populations per se. Existing interven- tion studies targeting BP in CKD populations typically targeted <2 g or <2.3 g daily in the low-sodium arms, which are similar to targets recommended for the general popula- Therefore, the present guideline was created in the absence of data suggesting superiority or inferiority of other targets in CKD populations. Further, for concordance across guidelines from various organizations that might facilitate policy decisions, Work Group members agree a target of <2.0 g per day should be recommended for CKD populations.


Further, for concordance across guidelines from various organizations that might facilitate policy decisions, Work Group members agree a target of <2.0 g per day should be recommended for CKD populations. Rationale This recommendation places a relatively higher value on studies in CKD populations demonstrating that short-term dietary sodium reduction interventions lower BP, and consistency with ndings of similar interventions in the general population. The recommendation also places a higher value on dietary sodium- reduction strategies as a readily available, non-pharmacologic intervention to lower BP in CKD populations. Relatively lower value was placed on the challenges in following a low-sodium diet in many current food environments. This recommenda- tion is made despite low-to-moderate-quality evidence in CKD populations per se, especially for hard clinical endpoints, because in the judgment of the Work Group, relative bene ts of efforts to lower dietary sodium intake will outweigh risks and healthcare costs in most patients. Although there is a lack of RCT data on use of potassium- containing salt substitutes in CKD populations, Work Group members are concerned about the risk of hyperkalemia that www.kidney-international.org chapter 2 these salt substitutes may pose to persons with advanced CKD, as well as observational data suggesting that higher dietary potassium intake may be associated with increased risk of CVand kidney outcomes in CKD populations.45,46 The Work Group acknowledges that there is also evidence to the contrary in people at high CV risk in the general popula- Therefore, the present recommendation for sodium reduction refers to dietary sodium reduction without substi- tution with potassium until further studies can discern risks and bene ts of salt-substitution strategies speci cally in CKD. Practice Point 2.1.1: Dietary sodium restriction is usually not appropriate for patients with sodium-wasting nephropathy.


Practice Point 2.1.1: Dietary sodium restriction is usually not appropriate for patients with sodium-wasting nephropathy. Practice Point 2.1.2: The Dietary Approaches to Stop Hy- pertension (DASH)-type diet or use of salt substitutes that are rich in potassium may not be appropriate for patients with advanced CKD or those with hyporeninemic hypo- aldosteronism or other causes of impaired potassium excretion because of the potential for hyperkalemia. (For Rationale of above practice points, please see text of 2.2 Physical activity Recommendation 2.2.1: We suggest that patients with high BP and CKD be advised to undertake moderate-intensity physical activity for a cumula- tive duration of at least 150 minutes per week, or to a level compatible with their cardiovascular and physical tolerance (2C). This recommendation places a relatively higher value on evi- dence suggesting that physical activity lowers BP, improves quality of life, and improves CV health in CKD patients. The recommendation places lower value on the time investment required for physical activity and the potential for physical ac- tivity to cause adverse events in CKD patients. The recom- mendation is weak according to GRADE because of the low quality of evidence supporting the bene ts of physical activity, speci cally in hypertensive CKD populations. Key information Balance of bene ts and harms. The recommendation is driven by low-quality evidence demonstrating that physical activity may decrease BP and body weight and improve quality of life in CKD patients. The recommendation was also supported by the larger body of evidence in the general population, demonstrating the BP-lowering and other health bene ts of regular physical activity. The Work Group recognizes a higher prevalence of comorbidity and frailty in CKD compared to the general population and is uncertain about whether regular physical activity increases or decreases adverse events.


The Work Group recognizes a higher prevalence of comorbidity and frailty in CKD compared to the general population and is uncertain about whether regular physical activity increases or decreases adverse events. Nonetheless, the Work Group believes that most CKD patients would bene t from regular physical activity. Quality of evidence. Intervention studies and systematic re- views in the general population have rmly established the effects of regular physical activity on BP lowering, improved strengthening, physical tness, lower body weight, and lower risks of dysglycemia and diabetes. In populations with CKD, however, the evidence is much more limited. Our systematic review in CKD populations found low-quality evidence from 1 study conducted over 12 months showing that physical activity may improve SBP and DBP, and low-quality evidence from the same study showing that physical activity may improve eGFR These ndings, however, were inconsistent with other studies suggesting little or no differences.76 82 The updated Cochrane systematic review nds that physical activity decreases weight and improves the mental components of quality of life in CKD.83 patients from 6 studies, the systematic review found very low-quality evidence supporting the association of physical activity with increased study-reported adverse events (including pain, kidney infection, hypotension, dizziness, etc.), an important consideration given the high burden of comorbidity and frailty in CKD populations (Supplementary ). Observational data also show a dose response relationship between greater levels of physical activity and lower risk of mortality in CKD patients.84 Overall, the available literature did not allow differentiation between resistive and aerobic physical activity, or between supervised and unsupervised physical activity programs, leading to uncertainty about the critical elements of physical activity interventions in CKD populations. Nevertheless, it was the opinion of the Work Group that recommendations for the general population are likely to apply in CKD. Values and preferences.


Nevertheless, it was the opinion of the Work Group that recommendations for the general population are likely to apply in CKD. Values and preferences. This recommendation places a relatively high value on physical activity as a nonpharmacologic intervention, with substantial evidence for BP lowering, im- provements in dysglycemia, and other CV and health bene ts in the general population. The high prevalence of hypertension, dysglycemia, and CV disease in CKD populations suggests that the absolute bene t of physical activity may be especially high in people with CKD if the established relative bene ts in the general population are indeed applicable to CKD. The higher potential for bene t is possibly offset by the high prevalence of comorbidity and frailty in CKD populations, which might limit the level of physical activity CKD patients can achieve and in- crease the risk of adverse events. However, the data on critical outcomes are not available, and those for other health bene ts and risks are limited in CKD populations, leading to a weak recommendation. The Work Group recognizes that some patients may have limited ability to exercise due to severe cardiorespiratory ill- nesses and physical or cognitive limitations, and may not be able to achieve physical activity levels recommended for the general population. In such individuals, targets can be indi- vidualized by patients and healthcare providers. The Work Group judged that most patients would bene t from efforts to perform physical activity regularly, even if not achieving the targets set for the general population. Patients in whom chapter 2 www.kidney-international.org physical activity is less feasible due to comorbidity may be less inclined to follow the recommendation, as with those who place a lower potential value on the uncertain bene ts asso- ciated with physical activity. Resource use and costs.


Patients in whom chapter 2 www.kidney-international.org physical activity is less feasible due to comorbidity may be less inclined to follow the recommendation, as with those who place a lower potential value on the uncertain bene ts asso- ciated with physical activity. Resource use and costs. Although a formal cost bene t analysis has not been performed, the Work Group judged that encouraging physical activity is likely to be a good use of resources. Some individuals may choose to perform physical activity in structured environments such as a gymnasium with guidance and supervision from exercise professionals, which could incur costs. However, simple and widely available recreational and leisure-time activities are likely to lead to health bene ts for CKD patients as well. Considerations for implementation. Moderate physical ac- tivity may include recreational and leisure-time activities such as walking and cycling, household chores, and playing sports in the context of daily family and community life. Some patients with musculoskeletal limitations, frailty, high risks of falls, cognitive impairment, or severe cardiorespiratory disease may not be able to achieve physical activity targets set for the general population, but efforts to increase physical activity levels to modi ed targets, in the Work Group s opinion, are likely to translate to health bene ts nonetheless. The speci c type, frequency, duration, and intensity of physical activity that maximizes health bene ts in CKD patients are unknown. However, the Work Group found no reason to believe that interventions with proven health bene ts in the general population would not also provide health bene ts in CKD populations. Rationale There are limited data in CKD populations on the risks and bene ts of physical activity interventions. The quality of evi- dence is low or very low.


The quality of evi- dence is low or very low. Nonetheless, short-term studies suggest that physical activity interventions lower BP, decrease weight, and improve the mental aspects of quality of life. These data are consistent with a substantial body of evidence demonstrating that physical activity improves BP, dysglycemia, cardiopulmonary tness, physical function, and mood in the general population. Prevalence of hypertension and diabetes, and risk of CV disease are extremely high in CKD populations, suggesting that the absolute bene t of physical activity in- terventions may be enhanced in CKD if the relative bene ts are equivalent to those observed in the general population. Exer- cise programs have also been shown to improve health out- comes in other chronic disease conditions, including CV disease and chronic obstructive pulmonary disease. These factors led the Work Group to believe that physical activity is likely to be bene cial in CKD populations as well, despite the low-quality direct evidence currently available. There are limited data on the optimal type or intensity of physical activity in CKD populations. The Work Group reviewed physical activity targets set forth by the World Health Organization (WHO)71 and the recently released AHA/ACC lifestyle guidelines for primary prevention of CV These targets were not developed to speci cally address physical activity in populations with chronic diseases; however, the Work Group believes there is no evidence or plausibility to suggest that these recommendations are not applicable to CKD patients. The Work Group also consulted with the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD. In an effort to align guidelines, the target set forth by the AHA/ACC guidelines of moderate- intensity physical activity for a cumulative duration of at least 150 minutes per week was adopted.


In an effort to align guidelines, the target set forth by the AHA/ACC guidelines of moderate- intensity physical activity for a cumulative duration of at least 150 minutes per week was adopted. This target is applicable to hypertensive CKD patients if their healthcare providers consider that the individual patient s comorbidities and exercise tolerance allow it. For others, the degree of physical activity should be individualized according to their cognitive, CV, and physical tolerance, and adjusted, as these limitations change over time. Practice Point 2.2.1: Consider the cardiorespiratory tness status, physical limitations, cognitive function, and risk of falls when deciding on the implementation and intensity of physical activity interventions in individual patients. Practice Point 2.2.2: The form and intensity of physical activity should be considered and modi ed as necessary in individual patients. There may still be important health bene ts even if physical activity falls below targets pro- posed for the general population. (For Rationale of above practice points, please see text of 2.3 Other lifestyle interventions The Work Group recognizes that several other lifestyle in- terventions, including weight loss among those who are overweight or obese, reducing alcohol consumption among those who drink heavily, and adopting a heart-healthy diet pattern have been demonstrated in RCTs to lower BP in the general population. These lifestyle interventions may also have BP-lowering bene ts in patients with CKD, and it may be reasonable to consider them when they can be applied safely and without side effects. Insuf cient data on the risks or bene ts of these interventions on BP in CKD populations per se precluded speci c recommendations in this guideline.


Insuf cient data on the risks or bene ts of these interventions on BP in CKD populations per se precluded speci c recommendations in this guideline. Research recommendations  Conduct clinical trials evaluating different dietary sodium reduction strategies for prevention of clinical endpoints of critical importance for CKD populations, including kidney failure, CV disease, and mortality.  There are inconsistencies among the studies examining the relationship of dietary sodium intake with health outcomes in persons with diabetes.45,46,85 Additional research is required to investigate the consistency of effects of dietary sodium changes on health bene ts and harms across different causes and severities of CKD.  It is unknown if there is a minimum dietary sodium level in CKD below which health risks are increased. Most of these www.kidney-international.org chapter 2 data derive from studies evaluating sodium intake using spot urine sodium measurements. There is current con- troversy about the accuracy of assessing sodium intake us- ing random spot urine specimens, and potential increased risk of adverse health outcomes at the low- sodium intake range when assessed by this method.86 Additional research is required in both sodium-intake assessment methodology in CKD, and to evaluate the health impacts of very low-sodium intakes in CKD populations.  Recent small, single-center clinical trials evaluating chronic oral sodium bicarbonate supplementation versus placebo have not found changes in BP.87 89 These ndings raise the possibility that the anion associated with sodium intake may in uence the BP response. Future research is required to determine if relationships of sodium intake with BP are in uenced by the accompanying anion.  In the general population, potassium-containing salt sub- stitutes have been demonstrated to lower BP.


In the general population, potassium-containing salt sub- stitutes have been demonstrated to lower BP. Persons with CKD have been systematically excluded from clinical trials evaluating potassium-based salt substitutes, and some, albeit not all, observational data in CKD populations demonstrate that higher potassium intake is associated with higher risk of CKD progression and CV disease. Whether using potassium-containing salt substitutes may have health bene ts or unique risks when applied to CKD populations requires future study.  Persons of African ancestry are disproportionately repre- sented in CKD populations. Prior systematic reviews sug- gest that reductions in sodium intake may result in larger reductions in BP in persons of African and Asian ancestry, compared to Caucasians.90 Whether such racial differences can also be found in CKD populations is uncertain and should be evaluated in future studies.  There is a paucity of data on factors that could identify individual CKD patients who have the greatest or least BP bene t from physical activity interventions, and also those that are at greater risk for harm. Identi cation of these factors and algorithms to tailor physical activity intensity and supervision to individual CKD patients is needed.  Iodine supplements are added to salt in some countries. Future studies are required to determine whether restricting sodium intake in CKD populations may contribute to iodine de ciency in these settings. chapter 2 www.kidney-international.org Chapter 3: Blood pressure management in patients with CKD, with or without diabetes, not receiving dialysis 3.1 Blood pressure targets Recommendation 3.1.1: We suggest that adults with high BP and CKD be treated with a target systolic blood pressure (SBP) of <120 mm Hg, when toler- ated, using standardized of ce BP measurement (2B).


chapter 2 www.kidney-international.org Chapter 3: Blood pressure management in patients with CKD, with or without diabetes, not receiving dialysis 3.1 Blood pressure targets Recommendation 3.1.1: We suggest that adults with high BP and CKD be treated with a target systolic blood pressure (SBP) of <120 mm Hg, when toler- ated, using standardized of ce BP measurement (2B). The recommendation is based on a single high-quality RCTwith important bene ts in the study cohort that included a sub- stantial number of CKD patients, even though the recommen- dation is considered weak by GRADE standards. This recommendation assumes that standardized of ce BP measure- ment has been taken according to Recommendation 1.1. The recommendation suggests that the majority of people would want the recommended course of action, but some, particularly in the subgroups mentioned below, may not, because adjusting BP-lowering therapy to achieve this target SBP causes potential bene ts and harms that may vary with comorbidities, severity of CKD, existing treatment burden, and the presence of white- coat or masked hypertension. The statement is weak because it is based primarily on a subgroup from 1 RCT; however, the subgroup was prespeci ed from a very high-quality trial. This recommendation does not apply to patients with CKD who have a kidney transplant; this guideline does not apply to those receiving dialysis. Key information Balance of bene ts and harms. There is evidence that tar- geting SBP to <120 mm Hg, when measured under stan- dardized conditions, reduces CV events and all-cause mortality in CKD (Supplementary Table S1191 93 ). In most people with high BP, including the frail and elderly, these bene ts appear to outweigh the risks of harm (e.g., hypotension and acute kidney injury [AKI]).


In most people with high BP, including the frail and elderly, these bene ts appear to outweigh the risks of harm (e.g., hypotension and acute kidney injury [AKI]). However, empirical evidence demonstrating how individuals would weigh these bene ts and harms is lacking. These bene ts extend to patients with or without CKD. Still, there is less certainty that the bene ts outweigh the harms with the following scenarios:  CKD G4 and G5: For people with a lower GFR, there is less certainty around the bene t of lower BP target and po- tential risk of harm, compared to people with higher GFRs.  Diabetes: The bene ts of intensive BP lowering are less certain among patients with concomitant diabetes and CKD, compared to patients with CKD without diabetes.  Individuals with SBP of 120 129 mm Hg: Observational data suggest that individuals with SBP of 120 129 mm Hg are at higher CV risk than those with SBP <120 mm Hg.94 Lowering the SBP from 120 129 mm Hg to <120 mm Hg may therefore be bene cial hypothetically. However, RCTs in CKD targeting SBP <120 mm Hg have not included individuals with SBP of 120 129 mm Hg. Therefore, the recommendation of lowering SBP from 120 129 mm Hg to <120 mm Hg by pharmacologic or non-pharmacologic means is tentative.  People with very low baseline DBP (e.g., <50 mm Hg), particularly in the presence of coronary artery disease: In theory, it is possible that intensive BP lowering will increase the risk of myocardial infarction (MI) in this subgroup because coronary perfusion depends on DBP. However, in SPRINT, the subgroup with the lowest DBP at baseline had similar CV and survival bene ts from intensive SBP reduction as those with higher baseline DBP.


However, in SPRINT, the subgroup with the lowest DBP at baseline had similar CV and survival bene ts from intensive SBP reduction as those with higher baseline DBP.  Etiology of CKD: There is no evidence that CV bene ts of a lower target BP in CKD varies with its etiology. However, kidney bene ts in autosomal dominant polycystic kidney disease may be greater with an SBP of 95 110 mm Hg than  Proteinuria: Proteinuria may no longer be an effect modi- er of BP target with an SBP target of <120 mm Hg.  Older age: The ratio of bene ts to harms of intensive BP reduction in CKD patients at the upper spectrum of age (e.g., >90 years old) is less certain, although people with a mean age of 83  3 years seemed to derive CV, survival, and  Younger age: The ratio of bene ts to harms of intensive BP reduction in people at the younger spectrum of age (e.g., <50 years old), who may have low absolute risks of CV disease and all-cause death, is less certain.  The very frail and those residing in a nursing home: Frailty did not appear to modify the bene cial effects of intensive SBP lowering.  White-coat hypertension: If of ce BP, even when measured under standardized conditions, is higher than daytime ambulatory or home BP, the risks of additional BP- lowering treatment to achieve of ce BP <120 mm Hg may be higher, with less certainty of bene ts. Nonetheless, it should be noted that patients with white-coat hyperten- sion were not excluded in SPRINT and other major outcome trials.


Nonetheless, it should be noted that patients with white-coat hyperten- sion were not excluded in SPRINT and other major outcome trials. www.kidney-international.org chapter 3  Severe hypertension, such as SBP $180 mm Hg on no or 1 antihypertensive drug, or $150 mm Hg on >4 antihyper- tensive drugs, because such patients were not included in SPRINT. Uncertainty in risk bene t ratios in the various scenarios above does not necessarily imply that intensive SBP lowering is not warranted. It only re ects the lack of RCT data to support or refute the ratios. If the patient cannot tolerate SBP <120 mm Hg despite a slow, gradual decrease in SBP over months, efforts should be made to maintain SBP <130 mm Hg, <140 mm Hg, or an even higher tolerated SBP goal. Individualization based on trial and error prevails, as in many aspects of medical practice. The importance of standardized BP measurement when applying this guideline cannot be overemphasized. Routine, non-standardized of ce BP mea- surements often, but not invariably, overestimate BP compared to measurements under standardized conditions (Chapter 1). Importantly, the extent to which routine mea- surements overestimate or underestimate standardized of ce BP is highly variable between and within patients; therefore, no correction factor can be used to convert routine BP to standardized BP measurement by calculation. The use of routine measurements to adjust BP-lowering therapy confers a serious risk of overtreatment and sometimes undertreat- ment. It should be emphasized that the most important aspect of standardized BP measurement is preparation prior to the measurement and not the equipment used (Chapter 1). Heterogeneity in primary outcomes among various RCTs.


It should be emphasized that the most important aspect of standardized BP measurement is preparation prior to the measurement and not the equipment used (Chapter 1). Heterogeneity in primary outcomes among various RCTs. It should be noted that the medium-sized trials that exclusively enrolled CKD patients and examined target BP levels, such as the Modi cation of Diet in Renal Disease (MDRD) trial,97 the African American Study of Kidney Disease and Hypertension and the Blood-Pressure Control for Renoprotection in Patients with Non-diabetic Chronic had used kidney events as the primary outcomes and had relatively few non-kidney events during the trial. In contrast, the larger trials that did not exclusively enroll CKD patients, such as the Systolic Hypertension in the Elderly Program (SHEP) trial,100 the Secondary Prevention of Small Subcortical Strokes (SPS3) the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,92 and the Systolic Blood Pressure Intervention Trial (SPRINT),93 used CV events as the primary outcomes and had relatively few kidney events, although there might be a sizeable number of CKD patients in the latter trials. These dichotomies and the heterogeneity in the characteristics of the study cohorts create challenges in data synthesis to provide an evidence base for practice recommendations in CKD. Cardiovascular outcomes. General population. In the general population, there is extensive evidence that the reduction in the risk of CV events is proportional to the SBP reduction achieved, with the absolute bene ts being greater in those with higher baseline risk of CV disease, and with no differ- ence in proportional risk reductions across groups de ned according to higher or lower baseline SBP.102 106 The meta- analysis of 21 RCTs by Xie et al.


In the general population, there is extensive evidence that the reduction in the risk of CV events is proportional to the SBP reduction achieved, with the absolute bene ts being greater in those with higher baseline risk of CV disease, and with no differ- ence in proportional risk reductions across groups de ned according to higher or lower baseline SBP.102 106 The meta- analysis of 21 RCTs by Xie et al. concluded that the absolute bene ts of lowering SBP were greater and the number-needed-to-treat was smaller in trials where all enrolled patients had vascular disease, diabetes, or kidney In this meta-analysis, on-treatment BP averaged 133/76 mm Hg on intensive treatment and 140/81 mm Hg on less-intensive treatment. Outcomes in patients with and without albuminuria at baseline were not reported separately. SPRINT provides further evidence that intensive SBP lowering reduces CV events and death in those at high CV risk.


SPRINT provides further evidence that intensive SBP lowering reduces CV events and death in those at high CV risk. Those bene ts targeting SBP <120 mm Hg compared to <140 mm Hg in SPRINT extended to CKD, the elderly, and those with frailty.91,107 In a prespeci ed analysis, the bene ts of targeting SBP <120 mm Hg in SPRINT included a signi cant reduction in the combined endpoint of probable dementia and mild cognitive impairment, with no interaction with baseline CKD.108 Secondary analyses further suggest that the bene cial effect of intensive BP lowering on the incidence of mild cognitive impairment per se may extend to those with and those who are aged 80 years or older.96 A recent meta-analysis of 74 RCTs with broader inclusion criteria than those discussed above102,105,106 concluded that the effect of BP lowering differed by baseline BP with no clear effect on death or CV disease in participants with no prior coronary heart disease and SBP <140 mm Hg at baseline.109 This nding has been used by some guideline groups, such as the National Institute for Health and Care Excellence (NICE) in the United Kingdom, to justify a more conservative approach to BP-lowering therapy than that advocated in the present guideline. However, the inclusion of large numbers of trials comparing antihypertensive drugs versus placebo, not lower versus higher BP target, and importantly, those in which BP measurement technique was less precisely speci ed makes drawing conclusions challenging.109 Adults with CKD. A meta-analysis from the Blood Pressure Lowering Treatment Trialists Collaboration, which included trials of antihypertensive drugs versus placebo and trials of different BP targets, found that the proportional reduction in CV events with more intensive BP treatment was independent of the presence or absence of CKD.110 In their meta-analysis, Ettehad et al.


A meta-analysis from the Blood Pressure Lowering Treatment Trialists Collaboration, which included trials of antihypertensive drugs versus placebo and trials of different BP targets, found that the proportional reduction in CV events with more intensive BP treatment was independent of the presence or absence of CKD.110 In their meta-analysis, Ettehad et al. also reported a risk reduction for CVevents with intensive BP lowering in those with CKD, but the size of the risk reduction was less than that in those without CKD.105 SPRINT intentionally included a CKD subgroup a priori and examined an SBP target of <120 mm Hg, as recom- mended in the present guideline, versus <140 mm Hg. In the primary analysis of the entire cohort of 9361 participants, SPRINT demonstrated bene ts for the primary CV outcome (hazard ratio [HR]: 0.75; 95% con dence interval [CI]: 0.64 0.89) and for all-cause death (HR: 0.73; 95% CI: 0.60 0.90) across all subgroups with no heterogeneity, including those with or without CKD de ned as eGFR 20 to <60 ml/min per , with proteinuria <1 g/d.91,93 Indeed, in the sub- group with CKD (median albumin-creatinine ratio [ACR]: ), the CV bene t chapter 3 www.kidney-international.org missed signi cance of P < 0.05 (HR: 0.81; 95% CI: 0.63 1.05), while the mortality bene t was nominally signi cant. That said, SPRINT was not powered for subgroup analyses, especially given that it ended early because of the substantial CV disease and mortality bene t. It should be noted that large RCTs with major clinical outcomes are rarely powered for a speci c subgroup, even for age or sex. Trial results should be interpreted for the entire study cohort, with effect modi ca- tion by factors de ning subgroups examined in secondary analysis.


Trial results should be interpreted for the entire study cohort, with effect modi ca- tion by factors de ning subgroups examined in secondary analysis. Such effect modi cation was not noticed for CKD in SPRINT. Regardless, SPRINT is the largest trial testing 2 BP targets in CKD with approximately 2600 CKD patients. Although SPRINT excluded patients with diabetes, polycystic kidney disease, or proteinuria $1 g/d, those with glomeru- lonephritis not taking immunosuppressive medications were not excluded. Three other trials comparing different BP targets, powered for kidney outcomes as primary outcomes, generated far too few CV events or death outcomes (MDRD, AASK, REIN-2). However, a meta-analysis by Malhotra et al., examining death as an outcome exclusively in the CKD subgroups of the large hypertension treatment RCTs, also found a bene t of lower target BP.111 Older adults with or without CKD. There are meta-analyses and systematic reviews based on the general population of older adults, including patients with CKD, addressing the impact of lower BP targets. Garrison et al. analyzed RCTs conducted in hypertensive adults aged 65 years or older and reported outcomes for higher SBP (150 160 mm Hg) or DBP (95 105 mm Hg), compared to a lower treatment target SPRINT was excluded from this analysis because its lower target was lower than the inclusion criteria of the meta-analysis. Its inclusion may have changed the results of the meta-analysis. Based on this meta-analysis, there was insuf cient evidence to determine whether a lower SBP target provides meaningful differences in bene ts or harms to older adults. However, there are very few major trials and relatively few events in this meta-analysis. In contrast, Bavishi et al.


However, there are very few major trials and relatively few events in this meta-analysis. In contrast, Bavishi et al. included RCTs in a meta-analysis comparing intensive versus standard or less-intensive BP control in older adults ($65 years) and provided long-term CV and safety outcomes.113 SPRINT met the inclusion criteria for this review. There were reductions in major CV events, CV mortality, and heart failure (HF), but a possible increase in AKI and serious adverse events. No analysis of the older population with CKD was described in these studies. There is only one large study analyzing the effects of lower BP targets in CKD patients older than 75 years. A post hoc analysis of that speci c subgroup in SPRINT showed that the low BP target (SBP <120 mm Hg) reduced the primary CV outcome (HR: 0.64; 95% CI: 0.45 0.92), all-cause death (HR: 0.64; 95% CI: 0.43 0.96), and the composite of primary CV disease outcome or all-cause death (HR: 0.66; 95% CI: 0.49 There was no description of potential harm of achieving lower targets in this subgroup of older adults with CKD, although the risk bene t ratio in the entire CKD cohort and in the entire subcohort older than 75 years in SPRINT was favorable. Even in the age group 80 years and older, subgroup analysis in SPRINT showed that intensive BP lowering decreased the risk of CV events (HR: 0.66; 95% CI: Adults with diabetes and CKD. Among patients with concomitant diabetes and CKD, the bene ts of intensive BP lowering are less certain than those with CKD without dia- betes. All previous studies in diabetes with and without CKD have favored more, instead of less, intensive BP reduction ). In their meta-analysis, Ettehad et al.


All previous studies in diabetes with and without CKD have favored more, instead of less, intensive BP reduction ). In their meta-analysis, Ettehad et al. reported that the reduction in major CV events remained proportional to the BP reduc- tion achieved among trial participants with diabetes, but that the proportional risk reductions were smaller than the re- ductions in those without diabetes.105 In contrast, in the meta-analysis of intensive versus less-intensive BP-lowering therapy among patients with CKD, Malhotra et al. found no evidence of heterogeneity in bene cial effects on mortality with respect to the presence or absence of diabetes.111 Brunstr m et al. conducted a systematic review and meta- analysis of RCTs that included at least 100 patients with diabetes, and found that BP reduction decreased MI, stroke, CV mortality, ESKD, and all-cause mortality if baseline SBP was >150 mm Hg; there was decreased MI, HF, and all-cause mortality if baseline SBP was 140 to 150 mm Hg, but para- doxically, increased CV mortality was observed if baseline SBP was <140 mm Hg.118 Two major caveats should be noted regarding these meta- analyses in diabetes. First, these meta-analyses differ sub- stantially from each other in their respective inclusion criteria. Brunstr m et al. and Ettehad et al. included RCTs that compared antihypertensives to placebo, and different BP targets. Ettehad et al. included RCTs of head-to-head com- parisons of antihypertensive agents to examine the effect of 10 mm Hg reduction in SBP on clinical outcomes. Second, none of the trials conducted prior to ACCORD and SPRINT examined an SBP target as low as <120 mm Hg. Nonetheless, they collectively suggest that SBP lowering decreases the CV event rate and perhaps mortality and kidney outcomes.


Nonetheless, they collectively suggest that SBP lowering decreases the CV event rate and perhaps mortality and kidney outcomes. The ACCORD trial that enrolled exclusively patients with diabetes did not show a difference in the prespeci ed primary endpoint of composite CV events between the intensive SBP target (<120 mm Hg) and standard SBP target (<140 mm Hg), but it did demonstrate a signi cant reduction in stroke (HR: 0.59; 95% CI: 0.39 0.89), a prespeci ed sec- ondary outcome, with intensive SBP lowering.92 However, ACCORD included few patients with CKD, as patients with serum creatinine >1.5 mg/dl (132 mmol/l) were excluded, and those with CKD were mostly proteinuric with well-preserved Therefore, there is little direct evidence from ACCORD alone to guide a recommendation for patients with diabetes and CKD. Nonetheless, there was no statistical interaction between CKD and intensive BP lowering on the reduction in stroke risk.119 www.kidney-international.org chapter 3 In contrast to ACCORD, SPRINT included a substantial number (n 2646) of participants with CKD. Although SPRINTspeci cally excluded patients with diabetes, 42% (n 3898) of the cohort had prediabetes, de ned as baseline fasting serum glucose >100 mg/dl [5.6 mmol/l]. A post hoc analysis of SPRINT comparing participants with and without prediabetes found that the CV and survival bene ts of intensive SBP reduction (<120 mm Hg) were similar in the 2 subgroups.120 Other secondary analyses of ACCORD data further suggest that intensive SBP lowering is bene cial. A combined post hoc analysis of SPRINT and ACCORD suggested similar CV bene ts of intensive BP-lowering therapy in the presence or absence of diabetes.121 ACCORD was not only a BP trial, but it also employed a rather complex study design.


A combined post hoc analysis of SPRINT and ACCORD suggested similar CV bene ts of intensive BP-lowering therapy in the presence or absence of diabetes.121 ACCORD was not only a BP trial, but it also employed a rather complex study design. The partici- pants were randomized rst to intensive versus less-intensive glycemic control, and then either to intensive versus less- intensive BP control or to the addition of feno brate versus placebo on a background of a statin. The trial of glycemic control was terminated early because of higher all-cause mortality with intensive glycemic control.92 This adverse ef- fect of intensive glycemic control was also demonstrated in the CKD subgroup of ACCORD.119 The ACCORD BP trial reported no statistical interaction between glycemic control and BP control on prespeci ed primary and secondary CV outcomes. However, a more detailed combined analysis of data from ACCORD and SPRINT found that the bene cial effects of intensive SBP control (with both trials targeting <120 mm Hg) on combined CV endpoints and on all-cause mortality were similar in the standard glycemia arm of ACCORD and in SPRINT.122,123 In contrast, intensive SBP control increased CV death, HF, and MI in the intensive glycemia arm.


However, a more detailed combined analysis of data from ACCORD and SPRINT found that the bene cial effects of intensive SBP control (with both trials targeting <120 mm Hg) on combined CV endpoints and on all-cause mortality were similar in the standard glycemia arm of ACCORD and in SPRINT.122,123 In contrast, intensive SBP control increased CV death, HF, and MI in the intensive glycemia arm. These interactions lessened after discontinua- tion of the glycemic intervention.122 In another post hoc analysis among ACCORD participants in the standard gly- cemia arm who had additional CV risk factors that would have met the SPRINT inclusion criteria, intensive BP control provided CV bene ts similar to those seen in SPRINT.124 Similarly, a pooled analysis of individual patient data from 4983 patients with CKD from AASK, MDRD, ACCORD, and SPRINT found a non-signi cant trend to decreased mortality with intensive BP-lowering therapy, but a statistically signif- icant reduction in mortality in a subgroup with eGFR <60 who were not assigned to intensive gly- Collectively, these aforementioned post hoc analyses support the notion that intensive BP control im- proves clinical outcomes even in patients with diabetes and CKD, but glycemic control modulates the effects of intensive BP control on CV outcomes. This evidence is indirect, hence diminishing the certainty of the bene ts and strength of recommendation of targeting SBP <120 mm Hg. Low diastolic blood pressure.


This evidence is indirect, hence diminishing the certainty of the bene ts and strength of recommendation of targeting SBP <120 mm Hg. Low diastolic blood pressure. Numerous observational including those that examine data from RCTs in a post hoc observational manner,128 although not all studies, have suggested a J-shaped curve with very low DBP being associated with an increased risk of CVevents, particularly MI among patients with pre-existing coronary artery disease.94 The validity of these observations is supported by biological plausibility, as low DBP in the setting of coronary stenosis could lead to impaired subendocardial blood ow during diastole. However, this association is heavily confounded, as patients with very low DBP inherently have high CV risks. Beddhu et al. recently showed that in SPRINT participants, baseline DBP indeed bore a U-shaped relationship with mor- tality. However, the CV-protective bene ts of intensive SBP lowering were independent of baseline DBP, including the lowest DBP quintile at baseline with a mean DBP of 61  Whether this bene cial effect of SBP lowering persists at even lower DBP levels (e.g., <45 mm Hg) cannot be determined from these data. Kidney outcomes. Rate of decline in GFR. The effects of intensive BP lowering on GFR are often complicated by an exaggerated early acute GFR decline that is also seen with inhibitors of the renin-angiotensin system (RAS) and the sodium glucose cotransporter-2 (SGLT2) system. This acute eGFR decrease with BP lowering may be mediated, at least in part, by intrarenal hemodynamic changes.


This acute eGFR decrease with BP lowering may be mediated, at least in part, by intrarenal hemodynamic changes. This hypothesis is supported by the following observations: (i) Single-nephron GFR decreases when glomerular blood ow rate drops below the level that can be sustained by (ii) Urinary excretion of various tubular biomarkers during intensive SBP treatment in SPRINT was not indicative of (iii) Albuminuria during follow-up was lower, instead of higher, in the intensive SBP arm than in the standard SBP treatment arm in SPRINT. Similar observations have been reported in ACCORD participants.133 Nonetheless, the overall rate of decline of eGFR was higher rather than lower on intensive treatment in SPRINT in both and non-CKD subgroups,134 In both ACCORD and SPRINT, participants assigned to intensive BP target also developed more incident CKD during follow-up than those assigned to standard BP target.128,134 There was no difference in the rate of doubling of serum creatinine between intensive and standard SBP treatment in SPRINT, but the small number of these discrete events pre- cludes rm conclusions. The difference in the rate of decline of eGFR in SPRINT after the initial 6 months was small (0.47 /yr in the intensive and standard arms, respectively). If this slope persisted long-term, it would take 20 years to cause a 3 ml/min per 1.73 m2 difference in eGFR between intensive and standard SBP treatment. Taking both the bene cial effect on albuminuria and the adverse effect on eGFR into account, the long-term effects of intensive SBP lowering on the kidney cannot be determined from these relatively short-term, on-treatment observations. Progression to kidney failure and effect modi cation by proteinuria. Prior to SPRINT, the largest RCTs addressing the effects of intensive BP control in CKD were MDRD,97 The primary outcome of these 3 trials was progression of kidney disease.


Prior to SPRINT, the largest RCTs addressing the effects of intensive BP control in CKD were MDRD,97 The primary outcome of these 3 trials was progression of kidney disease. During the trial phase, when the chapter 3 www.kidney-international.org participants were under their respective randomized in- terventions, none of these trials showed bene ts or harms on kidney function by intensive BP lowering in the primary analysis of the entire cohort. A caveat of MDRD and AASK is that both trials targeted mean arterial BP (MAP, calculated as DBP 1/3  pulse pressure), rather than SBP or DBP. The lower target was a MAP of <92 mm Hg (equivalent, for example, to 125/75 mm Hg, 140/68 mm Hg, 160/58 mm Hg, or many other combinations of SBPs and DBPs), whereas the higher target was a MAPof <107 mm Hg (equivalent to 140/90 mm Hg, 125/98 mm Hg, etc.). Further, the MAP targets varied in MDRD, depending on the age of the patients.136 A meta-analysis in 2011 conducted by the ERT of the KDIGO 2012 BP guideline found only these 3 studies (MDRD, AASK, and REIN-2) pertinent to the discussion of whether a lower BP target reduced the risk of progression to kidney failure in the presence of proteinuria. They concluded that the evidence was inconclusive.137 Similarly, the current ERT review found no effect modi cation according to the presence of proteinuria (Supplementary Table S1297 ).


They concluded that the evidence was inconclusive.137 Similarly, the current ERT review found no effect modi cation according to the presence of proteinuria (Supplementary Table S1297 ). The evidence that intensive BP reduction reduces the risk of progression to kidney failure is derived mainly from a prede ned subgroup analysis of MDRD (only 54 pa- tients with proteinuria >3 g/d, but large effect size)97,139 and long-term post-treatment follow-up from MDRD138 and A more recent meta-analysis of 11 RCTs of lower versus higher BP goals found that intensive BP reduction was associated with a reduction in kidney failure events (de ned as the composite of doubling of serum creatinine and a >50% reduction in eGFR or ESKD), with effect modi cation by Intensive BP control reduced the risk of kidney failure only among those with baseline proteinuria, de ned as a protein creatinine ratio (PCR) >220 mg/g (22 mg/mmol). The MDRD and AASK studies were major con- tributors to this evidence base. The REIN-2 study compared a higher DBP target of <90 mm Hg with a lower BP target of <130/80 mm Hg by adding felodipine to baseline ramipril therapy in patients with protei- nuric CKD (mean eGFR and proteinuria approximately 35 ml/ min and 3 g/d, respectively) without diabetes.99 no bene t of intensi ed BP control over a mean follow-up of approximately 19 months. However, the study was underpow- ered with a total of only 338 participants and had very small differences in achieved SBP and DBP of only 4 mm Hg and 2 mm Hg, respectively, during the intervention phase. The effects of intensive SBP lowering with target <120 mm Hg are only available in ACCORD and SPRINT.


The effects of intensive SBP lowering with target <120 mm Hg are only available in ACCORD and SPRINT. In ACCORD, which had few CKD patients, there was no dif- ference in progression to ESKD between intensive (59 cases/ 2362 patients) and standard (58 cases/2371 patients) SBP groups. SPRINT excluded patients with proteinuria >1 g/d, and the baseline median ACR was only 13 mg/g (1.3 mg/ mmol) in the CKD subgroup. ESKD events were rare in SPRINT, with a total of only 16 cases in 9361 patients. No reliable conclusions can therefore be reached on the effects of an SBP target <120 mm Hg on progression to kidney failure in patients with CKD from ACCORD or SPRINT (Supplementary Table S1191 93 ). Previous guidelines, including the KDIGO 2012 BP guide- line, recommended more aggressive BP lowering for patients with albuminuria than for those without albuminuria.141 These recommendations were based largely on the subgroup ndings of the MDRD,97 as described above, and in the pedi- atric population, the ESCAPE trial (Chapter 5).142 With the adoption of an SBP target <120 mm Hg for all patients with CKD in the present revised guideline based on the evidence for CV and survival bene ts, separate targets for patients with and without albuminuria are no longer required. There is no evi- dence supporting an even lower target (e.g., <110 mm Hg) for patients with severely increased proteinuria. Mortality. The ERT found 5 RCTs examining the effects of intensive versus less-intensive BP control on mortality in patients with CKD without diabetes (Supplementary ).


The ERT found 5 RCTs examining the effects of intensive versus less-intensive BP control on mortality in patients with CKD without diabetes (Supplementary ). Over a mean follow-up of 3.23 years of the 9351 participants in these 5 studies, 84 deaths per 1000 participants were seen in the standard BP control arm, and 66 per 1000 participants in the intensive BP control arm (18 fewer deaths per 1000; 95% CI: 26 fewer 8 fewer deaths per 1000 participants). Secondary analyses of the MDRD and AASK cohorts using administrative databases have also suggested long-term survival bene ts from a lower MAP target.144,145 The mortality rates were low in these studies, and the conclusions can only be interpreted as hypothesis-generating. When results of studies in patients with CKD without dia- betes are combined with those in patients with diabetes and CKD, the effect of intensive BP lowering on all-cause mortality was attenuated. In 9 studies with 13,367 participants and a mean of 3 years of follow-up, intensive BP targets, compared with higher BP targets, resulted in 23 fewer deaths per 1000 patients, but the 95% CI indicated 49 fewer to 33 more deaths per 1000 (Supplementary Table S1391,92,97 99,116,135,138,143,146 148 ). A recent individual patient-level meta-analysis of 18 trials comprising 15,294 patients with CKD (de ned as an ) found that intensive BP lowering resulted in a signi cantly lower risk of mortality compared to less-intensive BP lowering; this bene t was consistent across multiple subgroups.111 This meta-analysis included RCTs that compared a range of target BPs, but it also included trials comparing antihypertensive agents with placebo or no treatment.


A recent individual patient-level meta-analysis of 18 trials comprising 15,294 patients with CKD (de ned as an ) found that intensive BP lowering resulted in a signi cantly lower risk of mortality compared to less-intensive BP lowering; this bene t was consistent across multiple subgroups.111 This meta-analysis included RCTs that compared a range of target BPs, but it also included trials comparing antihypertensive agents with placebo or no treatment. Evidence of the effects of an SBP target of <120 mm Hg versus <140 mm Hg in patients with CKD without diabetes is available only from SPRINT.91 There were 53 deaths per 1000 participants in the standard BP control arm, and 40 deaths per 1000 participants in the intensive BP control arm, resulting in a statistically signi cant difference of 13 fewer per 1000 participants; Supplementary Table S1191,93 ) This dif- ference is also evident when the CKD subgroups in both ACCORD (comprised all patients with diabetes) and SPRINT (comprised no patients with diabetes) are combined. www.kidney-international.org chapter 3 Adverse effects. Some practitioners may be concerned about adverse events associated with the low SBP target. Although the Work Group cautions about these possibilities, regardless of the level of SBP, age, and comorbidities, the available evidence shows that the SBP target of <120 mm Hg is generally safe. In a patient with severe carotid stenosis, an SBP <120 mm Hg may be insuf cient to maintain cerebral perfusion, and even an SBP of 150 mm Hg may be insuf cient. Diligence in monitoring the patient and taking the appropriate actions of adjusting BP, administration of anticoagulants, or surgical correction of the stenosis may be necessary.


Diligence in monitoring the patient and taking the appropriate actions of adjusting BP, administration of anticoagulants, or surgical correction of the stenosis may be necessary. Such scenarios do not refute the notion that an SBP target <120 mm Hg in most adults is bene cial and not associated with increased signi cant adverse events. Clinical events. Within the CKD subgroup, SPRINT reported no signi cant difference in serious adverse events, and in adverse events associated with hypotension, postural hypo- tension, syncope, bradycardia, and injurious falls between the intensive (<120 mm Hg SBP) and standard (<140 mm Hg SBP) BP arms. Among the participants aged $75 years or even $80 years at baseline, of which approximately 44% and 50%, respectively, had an eGFR <60 ml/min per 1.73 m2 , the risk pro le for clinical adverse events with intensive BP lowering was also quite favorable.96,107 There were no differ- ences in serious adverse events and injurious falls between the intensive and standard BP arms. In SPRINT, standing BP was measured at prespeci ed visits.149 Intensive BP lowering reduced, rather than increased, the risk of orthostatic hypo- tension. Further, orthostatic hypotension was not associated with a higher risk of CV disease events, falls, or syncope.93 However, it is reasonable to consider a change in medica- tions or less-intensive therapy if the patient is symptomatic or BP is excessively low (e.g., SBP <100 mm Hg). Electrolyte abnormalities. Within the CKD subgroup, SPRINT reported no signi cant difference in adverse events associated with hyponatremia or hypernatremia between standard and intensive BP arms. However, there were increased risks for hy- pokalemia (HR: 1.87; 95% CI: 1.02 3.43) and hyperkalemia (HR: 1.36; 95% CI: 1.01 1.82), presumablybecause of the greater use of antihypertensive medications in the intensive BP arm. Acute kidney injury.


However, there were increased risks for hy- pokalemia (HR: 1.87; 95% CI: 1.02 3.43) and hyperkalemia (HR: 1.36; 95% CI: 1.01 1.82), presumablybecause of the greater use of antihypertensive medications in the intensive BP arm. Acute kidney injury. In the entire ACCORD cohort and SPRINT cohort (and in the SPRINT CKD subgroup), there were higher rates of AKI in the intensive SBP arms, although most of these were AKI Stage 1 and showed full recovery.150 The biomarker data described above suggest that at least some of the fall in eGFR seen with intensive BP treatment could be due to intrarenal hemodynamic changes rather than structural dam- age. In a post hoc analysis of SPRINT, there was a signi cant interaction between baseline eGFR and SBP lowering, such that patients with a baseline eGFR <45 ml/min per 1.73 m2 had an increased risk of AKI in the intensive BP arm but no reduction in the primary CVoutcome.151 Hence, the risk bene t ratio for kidney outcomes in the intensive SBP arm may not be as favorable in this subgroup as in the subgroup with higher baseline eGFR. However, caution should be used in interpreting these non-prespeci ed post hoc ndings in relatively small subgroups. In 2 other post hoc analyses of SPRINT, the respective risks of AKI were marginally increased with the intensive BP target in people $75 years old (HR: 1.41; 95% CI: 0.98 2.04) and increased in people $80 years old (HR: 2.12; 95% CI: 1.37 3.26). These data collectively suggest that inten- sive BP lowering increased the risk of AKI in people with moderate CKD and advanced age, but the episodes were rather infrequent, affecting less than 4% of SPRINT participants and tended to be mild and reversible (Supplementary Polypharmacy.


These data collectively suggest that inten- sive BP lowering increased the risk of AKI in people with moderate CKD and advanced age, but the episodes were rather infrequent, affecting less than 4% of SPRINT participants and tended to be mild and reversible (Supplementary Polypharmacy. Most participants in SPRINTwere taking 1 or 2 BP-lowering therapies before randomization. The bene ts of intensive SBP lowering are unclear among patients who require 4 or more BP-lowering medications to achieve SBP <120 mm Hg. In a post hoc analysis of the SPRINT database, the number of additional BP-lowering medications was an independent pre- dictor of poorer survival.152 However, the requirement for multiple medications to achieve SBP <120 mm Hg may re ect the patient s underlying characteristics and does not imply that intensive SBP lowering is not bene cial. Indeed, in another study using the SPRINT database and more advanced statistical tech- niques that account for confounding by indication, the addition of a new antihypertensive drug class led to signi cant reductions in SBP and major CV event rates but no difference in serious adverse events. These incremental effects appeared to be consistent regardless of the level of baseline drug use.153 Hence, at present, there is no clear evidence that people who require multiple medications to achieve an SBP of <120 mm Hg would have an unfavorable risk bene t ratio. Nonetheless, poly- pharmacy also adds to treatment burden and is often associated with reduced adherence, which may be attenuated by the use of single-pill combinations. Quality of evidence. The evidence on the effects of intensive BP lowering, namely the <120 mm Hg SBP target, on critical clinical outcomes such as CV events and all-cause mortality is considered to be moderate due to study limitations, while the effect on kidney failure is weak.


The evidence on the effects of intensive BP lowering, namely the <120 mm Hg SBP target, on critical clinical outcomes such as CV events and all-cause mortality is considered to be moderate due to study limitations, while the effect on kidney failure is weak. For CV events and all-cause mortality, the evidence is primarily derived from SPRINT, in which the sample size was large, the effects of intensive BP lowering on clinical outcomes were strong, and there was no heterogeneity in the effects between the CKD and non-CKD subgroups. Results from the subgroup analysis of ACCORD, as well as the joint analysis of the ACCORD and SPRINT data, lend further support, although there were relatively few participants with CKD in ACCORD (Supplementary Table S1191 93 ). TherenoprotectiveeffectsofBPlowering inCKDareprimarily derived from MDRD and AASK trials. The evidence is considered tobeoflowqualityduetostudylimitationsandinconsistency.The effects were seen in only the proteinuric subgroups, and in the case of AASK, the effects were seen only during the long-term post-trial follow-up (Supplementary Table S1297 99,135,138 and Supplementary Table S1391,92,95,97 99,135,138,143,146 148 ). Further, SPRINTshowed a short-term acute decline in eGFR and no long- term bene cial effect on eGFR with intensive SBP lowering. Therefore, collectively, these studies did not show convincingly that intensive BP lowering is renoprotective. chapter 3 www.kidney-international.org Values and preferences. The Work Group places high value on decreasing the risks of CV events and all-cause mortality by intensive SBP lowering, although the renoprotective effects are more tenuous. The reduction in the absolute risk of all-cause mortality in the CKD subgroup in SPRINT was 0.6% per year (1.61% and 2.21% in the intensive and standard SBP group, respectively). If this trend continues linearly, the risk reduction would be substantial over 20 or 30 years.


If this trend continues linearly, the risk reduction would be substantial over 20 or 30 years. The Work Group also places higher value on increased pill burden, more clinic visits, electrolyte abnormalities, hypo- tension, syncope, injurious falls, and AKI that may be caused by targeting an SBP <120 mm Hg. However, intensive SBP lowering in CKD patients did not cause more serious adverse events, orthostatic hypotension, syncope, or injurious falls than targeting SBP <140 mm Hg in SPRINT. The Work Group places lower values on the higher risks of mild AKI, hyperkalemia, and hypokalemia seen in the intensive SBP lowering in CKD patients because they are largely mild, transient, and manageable. We found no informative studies of how patients with CKD would balance these potential bene ts with potential harms. The adoption of an SBP target <120 mm Hg is an ideal topic for shared decision-making between individual pa- tients and clinicians. There is likely to be marked variability in how individual patients weigh and value the potential bene ts and harms of intensive BP control. This may vary with age, culture, number of drugs (both BP-lowering and other drugs), and other factors. Decision aids to support shared decision-making are available on the online version of this guideline (see link to MAGICapp at https://kdigo.org/ guidelines/blood-pressure-in-ckd/). These aids are based on the evidence syntheses compiled by the ERT that were used to develop the guideline and can be used online or to generate printable summaries of the evidence relating to each decision (e.g., differences in absolute mortality or in AKI per 1000 patients with standard vs. intensive SBP target). Resource use and costs. The implications for resource uti- lization for standardized of ce BP measurement, as recom- mended in this guideline, are discussed in Chapter 1.


The implications for resource uti- lization for standardized of ce BP measurement, as recom- mended in this guideline, are discussed in Chapter 1. Costs of additional antihypertensive drugs are relatively small in view of the bene ts; however, there may be additional costs for monitoring. The Work Group does not consider that resource implications would have signi cant impact on the recom- mendation. Indeed, economic analysis using SPRINT data suggest that intensive SBP treatment is cost-effective.154 Nonetheless, it is possible that there will be dif culties in implementing these recommendations in countries in which resources are limited; in those settings, it is probably more important to ensure that all eligible patients have at least reasonable BP control (e.g., SBP <140 mm Hg) than to focus efforts on achieving intensive BP control in a smaller fraction of the population. Considerations for implementation. Although there is strong evidence that home BP measurements are predictive of long- term adverse clinical outcomes, no adequately powered trial for guiding antihypertensive medication based on home BP targets has been reported. Nonetheless, HBPM may help to improve patient motivation and adherence to treatment and can also be used to identify patients with masked hypertension, masked uncontrolled hypertension, white- coat hypertension, and the white-coat effect as an adjunct for diagnosis and potential management of BP (see Chapter 1). The use of standardized of ce measurements for BP management may require additional equipment, clinic space, time, training, and/or change in culture, habits, or policies (see Chapter 1). Practitioners would bene t from under- standing the guidelines and the underlying data and rationale, and can tailor the target and treatment strategy for individual patients according to overall health conditions, response and tolerability to SBP lowering, as well as their preferences. Shared decision-making with individual patients is essential.


Practitioners would bene t from under- standing the guidelines and the underlying data and rationale, and can tailor the target and treatment strategy for individual patients according to overall health conditions, response and tolerability to SBP lowering, as well as their preferences. Shared decision-making with individual patients is essential. The practitioners should provide general information and individualized considerations of the pros and cons of the treatment option and explain that the evidence for intensive SBP targets is more certain in some groups (e.g., those who would have been eligible for SPRINT) and less certain in others (e.g., people with diabetes, advanced CKD with , older adults aged >90 years, and those with severe hypertension [e.g., SBP >180 mm Hg or >150 mm Hg on >4 antihypertensive drugs]). As worded, the recommendation states that clinicians should target an SBP <120 mm Hg. In practice, adoption of this recommendation in a population of patients with CKD will result in a median SBP around 120 mm Hg, meaning that 50% of patients will have SBP >120 mm Hg at any one time. A more stringent recommendation would be that all patients should achieve an SBP <120 mm Hg. This would require an even lower target or threshold for intervention. However, adoption of this more stringent recommendation would go beyond the available evidence. SPRINT targeted an SBP <120 mm Hg; the mean achieved SBP was 121.4 mm Hg.


SPRINT targeted an SBP <120 mm Hg; the mean achieved SBP was 121.4 mm Hg. Rationale This recommendation replaces the target recommendations from Chapters 3 and 4 of the KDIGO 2012 recommenda- tion on BP management in CKD.141 The most important differences are: (i) the adoption of standardized of ce measurement as the preferred technique; (ii) the adoption of a lower SBP target (<120 mm Hg); and (iii) the adoption of the same SBP target irrespective of the presence or absence of proteinuria, diabetes, or older age. The current guideline also speci es only an SBP target and not a DBP target (see below). The recommendation of standardized of ce measurement is crucial because this technique was used in large RCTs with clinically important outcomes, and values obtained using other techniques cannot be readily translated to values obtained using standardized of ce measurement. If BP is not measured using the standardized technique, the SBP target goal does not apply. The adoption of a lower SBP www.kidney-international.org chapter 3 target for patients with CKD without diabetes is based largely on the CV and survival bene ts in the CKD sub- group in SPRINT, although subgroup analysis and long- term follow-up in the MDRD and AASK studies also sug- gest kidney bene ts at BP levels that may be similar to the lower BP goal in SPRINT. The KDIGO 2012 guideline reversed previous recom- mendations from other organizations that called for more- aggressive BP-lowering therapies among CKD patients with diabetes, largely because ACCORD-BP failed to demonstrate statistically signi cant bene ts for the primary CV endpoint in the intensive BP-lowering arm.


The KDIGO 2012 guideline reversed previous recom- mendations from other organizations that called for more- aggressive BP-lowering therapies among CKD patients with diabetes, largely because ACCORD-BP failed to demonstrate statistically signi cant bene ts for the primary CV endpoint in the intensive BP-lowering arm. Since then, SPRINT and further analyses of ACCORD, together with combined ana- lyses of these 2 trials, have supported the conclusion that intensive BP-lowering therapy might well confer similar bene ts among patients with diabetes and CKD as in patients with CKD alone. However, the quality of evidence for BP target among CKD patients with concomitant diabetes is low, especially among those with advanced CKD. The recommendation of SBP <120 mm Hg is classi ed as weak (in the dichotomous classi cation of strong and weak in GRADE), raising concerns that clinicians and patients may decide to ignore the guidance and opt for less-intensive treatment. The Work Group debated whether to provide a strong recommendation for an SBP target of at least <140 mm Hg for all patients with CKD, together with separate recommendations for lower SBP (<120 mm Hg) targets in speci ed subgroups. This more complex alternative was eventually rejected, on the basis that it would probably persuade clinicians to continue to adopt an SBP target of <140 mm Hg for all CKD patients, thus denying many patients the potential advantages of tighter control. A strong recommendation implies that most patients and caregivers would want the recommended course of action, whereas a weak recommendation states that the majority of people would want the recommended course of action, but some would not. Regardless of the strength of recommendations, but especially for weak recommendations, clinicians should understand the nature and rationale of the recommendations and engage in shared decision-making with the patients, as discussed above.


Regardless of the strength of recommendations, but especially for weak recommendations, clinicians should understand the nature and rationale of the recommendations and engage in shared decision-making with the patients, as discussed above. Diastolic blood pressure as a target. The Work Group chose not to provide a target for DBP alongside the targeted SBP <120 mm Hg, although other guidelines often advocate targets for both SBP and DBP. The reasons for this decision are two-fold. First, for young patients with diastolic hypertension, it is essential to target DBP. Indeed, a number of earlier trials in the general population (e.g., ALLHAT) had explicit DBP as an inclusion criterion. However, wide pulse pressure, which is common in CKD implies that achievement of SBP <120 mm Hg will almost certainly result in DBP <70 mm Hg in the great majority of patients, making the provision of a separate DBP target redundant.141,155,156 Second, literature on RCTs targeting DBP with clinical outcomes is scarce, especially in the CKD population. Both MDRD and AASK studies employed a target MAP of <92 mm Hg, instead of an SBP and a DBP target, in the intensive BP arm, which is often considered equivalent to 125/75 mm Hg, but it is also gures, depending on the pulse pressure. As discussed earlier, these studies suggest that this intensive MAP target may provide renoprotective effects in proteinuric patients. Hence, it seems reasonable to target DBP of young patients with CKD and diastolic hypertension to <80 mm Hg, in addition to an SBP target <120 mm Hg. However, the Work Group is hesitant to recommend a DBP target because of the lack of evidence. Comparison with ACC/AHA guideline.


However, the Work Group is hesitant to recommend a DBP target because of the lack of evidence. Comparison with ACC/AHA guideline. The Work Group dis- cussed extensively the 2017 ACC/AHA guideline that offered a target of <130/<80 mm Hg for patients with CKD and analyzed the reasons provided in that guideline for this more conservative target, although the SBP target of <130 mm Hg is still more aggressive than those proposed by the European Society of Cardiology (ESC)/European Society of Hyperten- sion (ESH) (target: 130-139 mm Hg) and by NICE (target: One of the reasons was a concern that clinicians might apply the target to routine of ce BP readings. The KDIGO Work Group shares this concern but takes the view that patients should not be penalized for suboptimal clinical practice. One should not rely on routine of ce BP to adjust BP-lowering therapy. It should be noted that Hypertension Canada recommends an SBP target of <120 mm Hg using standardize BP measurement,159 consistent with the present guideline. The ACC/AHA guideline provides a table of equivalent BP values among standardized of ce, home, daytime ambulatory, night-time ambulatory, and 24-hour ambulatory measure- ments. These equivalents were established using an outcome- based approach that determines the BP threshold with each measurement technique that is associated with similar long- term outcomes in study populations.160 However, differ- ences in BP values obtained using different measurement techniques vary greatly among individual persons and even within a given individual over time. Thus, for any given in- dividual patient, the KDIGO Work Group found no evidence that one can reliably estimate the BP that would be obtained under standardized of ce conditions from measurements taken in any other settings.


Thus, for any given in- dividual patient, the KDIGO Work Group found no evidence that one can reliably estimate the BP that would be obtained under standardized of ce conditions from measurements taken in any other settings. As a result, the Work Group decided that the best evidence-based approach is to use standardized of ce BP for management (see Chapter 1). Practice Point 3.1.1: It is potentially hazardous to apply the recommended SBP target of <120 mm Hg to BP mea- surements obtained in a non-standardized manner. Non-standardized BP measurements frequently yield values that are substantially higher, but sometimes lower, than standardized measurements, in an unpredictable manner for individual patients. Basing BP-lowering therapy decisions on non-standardized BP measurements therefore often risks overtreatment and sometimes undertreatment. In these situ- ations, the risk bene t ratio of BP therapy may not be favorable. chapter 3 www.kidney-international.org Practice Point 3.1.2: Clinicians can reasonably offer less intensive BP-lowering therapy in patients with very limited life expectancy or symptomatic postural hypotension. Individualization based on patient characteristics and preferences with an understanding of the literature, including caveats, is important for proper BP goals and therapy. Research recommendations  Information is needed on how patient values and prefer- ences in uence decisions related to BP-lowering therapy. This would be an ideal topic for the Standardised Outcomes in Nephrology (SONG) initiative.  Conduct adequately powered RCTs to examine the effects of intensive BP control among patients with CKD: (i) with concomitant diabetes; (ii) with concomitant severely increased proteinuria (>1 g/d); or (iii) with very low GFR ). ACCORD included only small numbers of patients with CKD, most of whom quali ed for CKD because of albuminuria, and it is therefore uninfor- mative for patients with CKD G3 G5. On the other hand, SPRINT explicitly excluded patients with diabetes.


On the other hand, SPRINT explicitly excluded patients with diabetes.  In some Asian countries, stroke is more common than cardiac diseases as the cause of CV deaths. Whether intensive SBP control has similar, greater, or less CV- protective effects in the Asian CKD population is unclear and may require con rmation.  Although there is strong evidence that ambulatory or home BP measurements are better predictors of adverse outcomes than of ce BP, all large RCTs on BP targets in adults employed standardized of ce BP. RCTs targeting home or ambulatory BP measurements are needed.  SGLT2 inhibitors have major CV, kidney, and survival bene ts among patients with CKD. In addition to reducing BP, they cause an early, acute fall in GFR, a pattern that is also observed in intensive SBP lowering. The effects of these drugs, in combination with intensive BP-lowering therapy on CV outcomes, all-cause mortality, cognition, as well as acute and chronic changes in kidney function, require further examination.  There is a strong need for implementation research on locally acceptable strategies to increase adherence to guideline-based BP-lowering treatment (e.g., polypills). 3.2 Treatment with antihypertensive drugs, including RAS inhibitors (RASi) This section makes recommendations on which medications to use for treatment of high BP in patients with CKD, with and without diabetes, with and without albuminuria. The recom- mendations presented in this section governing initiation of RASi apply only to CKD G1 G4 since there is currently no RCT evidence on the use of these agents in CKD G5. The bene ts and harms of initiation, continuation, or discontinuation of RASi in CKD G5 have not been tested in RCTs. The evidence review included an assessment of subgroups based on the amount of albuminuria (A1 [ACR <30 mg/g or 3 mg/mmol], mg/mmol], respectively).


The evidence review included an assessment of subgroups based on the amount of albuminuria (A1 [ACR <30 mg/g or 3 mg/mmol], mg/mmol], respectively). The outcomes evaluated, where available, include all-cause mortality; CV outcomes, such as MI, stroke, and HF; and kidney outcomes, such as kidney failure (ESKD) and doubling of serum creatinine, as well as adverse effects including AKI and hyperkalemia. There are no well-powered trials examining CV outcomes or survival comparing various antihypertensive classes with each other or with placebo in people with high BP and CKD, although there was a CKD subgroup analysis in the ALLHAT A few such trials examined kidney outcomes. For example, AASK and IDNT, which enrolled only patients with high BP, were powered for kidney outcomes and compared the antihypertensive drug classes ACEi/ARB, beta-blockers, and calcium channel blockers (CCBs) while treating to target BP. ACEi/ARB demonstrated a slower decline in kidney function in AASK for those with hypertensive nephrosclerosis and in IDNT for those with diabetes and kidney disease with severely increased albuminuria.98,162 A fair number of trials examined RASi as agents used to reduce kidney disease progression in people with and without high BP, and/or with and without diabetes. Similarly, at least 3 large trials (HOPE,163 ) examined ACEi as CV protective agents in people with and without high BP and included a minority with CKD. Lowering of BP was explicitly not the aim of those trials.


Lowering of BP was explicitly not the aim of those trials. Kidney disease pro- gression was reduced with RASi compared to placebo or other antihypertensive agents with a suggestion of effect modi ca- tion by urine protein excretion.166 RASi also reduced CV outcomes as compared to placebo in high-risk populations, particularly in subgroups with CKD,166,167 independent of the presence or absence of high BP.165,167,168 That said, there is limited evidence to use speci c antihy- pertensive agents to treat high BP to target in CKD, and almost no evidence comparing antihypertensive combination therapies in CKD from outcome trials. Many people with CKD and BP of at least 20 mm Hg above the target will need combinations of several antihypertensive drugs. Starting antihypertensive ther- apy in such people with antihypertensive drug combinations is suggested. There are, however, no RCTs comparing different drug combinations in CKD, as there are no RCTs on antihy- pertensive classes other than RASi, beta-blockers, and CCBs. A recent network meta-analysis by Xie et al., including 119 RCTs (n 64,768), examined the bene ts of treating with RASi compared to placebo or active therapy in patients with CKD for kidney and CVoutcomes and included studies with and without diabetes and albuminuria (A1 A3). The results demonstrated improved precision with narrower con dence intervals than smaller meta-analyses reported below.169 Both ACEi and ARBs reduced the risk of kidney failure (de ned as a composite of any of the following: doubling of serum creatinine, 50% decline in GFR, or ESKD) by 39% and 30%, respectively, compared to placebo with high certainty; and 35% and 25%, respectively, against active controls with moderate certainty.


The results demonstrated improved precision with narrower con dence intervals than smaller meta-analyses reported below.169 Both ACEi and ARBs reduced the risk of kidney failure (de ned as a composite of any of the following: doubling of serum creatinine, 50% decline in GFR, or ESKD) by 39% and 30%, respectively, compared to placebo with high certainty; and 35% and 25%, respectively, against active controls with moderate certainty. Although both ACEi and ARB reduced major CV events to the same degree compared to placebo (18% for ACEi and 24% for ARB), ACEi, www.kidney-international.org chapter 3 compared to ARBs, were consistently associated with higher probabilities of reducing kidney failure and CV death. ACEi, but not ARB, reduced the odds of all-cause death compared to active control. Results of the network analysis were not sub- divided by diabetes or albuminuria status. Therefore, any antihypertensive treatment algorithm in CKD beyond monotherapy depends on expert opinion, pathophysiologic or pharmacodynamic considerations, extrapolation from ndings in primary hypertension in the absence of CKD, and small studies in CKD with surrogate outcomes, namely change in BP over the short term or meta- analyses of underpowered studies. In people with high BP and CKD, and mildly or moder- ately increased albuminuria (A1 or A2), there is limited evi- dence on CV or kidney outcomes from RCTs comparing speci c antihypertensive drugs to placebo or active compar- ators. There are, however, data from RCTs speci cally in those with severely increased albuminuria (A3), statistically pow- ered for kidney outcomes comparing speci c antihypertensive drugs to placebo or active comparators.


There are, however, data from RCTs speci cally in those with severely increased albuminuria (A3), statistically pow- ered for kidney outcomes comparing speci c antihypertensive drugs to placebo or active comparators. Those trials included people with and without high BP, apart from a few studies that excluded people with normal BP.98,162 There are also secondary analyses of subgroups based on level of albumin- , comparing speci c antihypertensive drugs to placebo or to active com- parators from CV and kidney outcome trials. In RCTs of primary hypertension examining the effect of antihypertensive drugs on CV outcomes that included partici- pants with CKD, CV bene ts have been most consistent with ACEi, ARBs, thiazide-like diuretics, and CCBs. The data are less consistent with beta-blockers, which have been inferior to these above classes in some but not all trials and in many meta- analyses. However, beta-blockers are often indicated for spe- ci c conditions, such as angina pectoris, post-MI, and systolic heart failure with reduced ejection fraction (HFrEF). For CV disease prevention in those with high BP, unless there is a strong indication for 1 speci c class, it seems reasonable to begin with 1 or more drugs among ACEi or ARB, CCB, and thiazide-like diuretic. Non-dihydropyridine CCBs have the apparent addi- tional bene t of reducing proteinuria.170 If a 3-drug combina- tion of RASi, CCB, and diuretic at recommended doses is not adequate to control BP, additional therapy including a mineralocorticoid-receptor antagonist (MRA), long-acting alpha antagonist, or beta-blocker can be used, as well as dihy- dralazine, hydralazine, minoxidil, or centrally acting agents.171 Higher BP due to uid overload is common in CKD; therefore, diuretics are, in general, logical agents at appropriate dose to lower high BP, with or without the concomitant use of RASi.


Non-dihydropyridine CCBs have the apparent addi- tional bene t of reducing proteinuria.170 If a 3-drug combina- tion of RASi, CCB, and diuretic at recommended doses is not adequate to control BP, additional therapy including a mineralocorticoid-receptor antagonist (MRA), long-acting alpha antagonist, or beta-blocker can be used, as well as dihy- dralazine, hydralazine, minoxidil, or centrally acting agents.171 Higher BP due to uid overload is common in CKD; therefore, diuretics are, in general, logical agents at appropriate dose to lower high BP, with or without the concomitant use of RASi. Outcome data in primary hypertension favor chlortha- lidone and indapamide over hydrochlorothiazide,2 although this has been questioned and there is an ongoing trial.172 174 Thiazide diuretics lose ef cacy in diuresis and BP lowering as GFR worsens, but several, including chlorthalidone, metola- zone, and indapamide appear to remain effective at . Loop diuretics are often effective at lower GFRs (i.e., <30 ml/min per 1.73 m2 ). When combined with a loop diuretic, thiazides are particularly effective in inducing diuresis, but they often lead to hypokalemia and hy- There are no data on clinical outcomes with loop diuretics in the treatment of high BP with or without CKD.


When combined with a loop diuretic, thiazides are particularly effective in inducing diuresis, but they often lead to hypokalemia and hy- There are no data on clinical outcomes with loop diuretics in the treatment of high BP with or without CKD. The most common side effects of each antihypertensive drug class for patients with CKD include: for both ACEi and ARBs, hyperkalemia as well as AKI, the latter when com- pounded by volume depletion or renal artery stenosis; for diuretics, hypokalemia; for dihydropyridine CCBs, edema; for non-dihydropyridine CCBs, constipation and bradyar- rhythmias when used in conjunction with beta-blockers; cough with ACEi; fatigue and limited exercise tolerance with beta-blockers; somnolence or dry mouth with central alpha- agonists; rebound hypertension if clonidine is stopped suddenly without taper; dizziness with alpha-blockers; hyper- kalemia with MRA; headache with hydralazine; and edema and hirsutism with minoxidil, to name some examples. The SPRINT research algorithm for BP management is presented in Figure 5 with slight modi cations of the foot- notes. Clinicians should use this as a reference and modify it as they see t. More detailed descriptions and recommenda- tions about the use of antihypertensive drugs, various drug combinations, potential advantages, or adverse effects is beyond the scope of this guideline; readers are referred to standard textbooks and guidelines. Recommendation 3.2.1: We recommend starting renin-angiotensin-system inhibitors (RASi) (angio- tensin-converting enzyme inhibitor [ACEi] or angiotensin II receptor blocker [ARB]) for people with high BP, CKD, and severely increased albu- minuria (G1 G4, A3) without diabetes (1B). This recommendation is strong according to GRADE, based on 3 moderate-quality RCTs with important bene ts in CKD pa- tients. The recommendation suggests that the majority of people would want the recommended course of action.