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 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. 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. 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. 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. 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. 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. This recom- mendation does not apply to patients with CKD who are receiving dialysis or have a kidney transplant. Key information Balance of bene ts and harms. Kidney bene ts of RASi in CKD without diabetes and severely increased proteinuria were demonstrated in the Ramipril Ef cacy In Nephropathy (REIN) study which compared ramipril to placebo to assess the effect of RASi on CKD progression independent of BP lowering. The Gruppo Italiano di Studi Epidemiologici in Nefologia (GISEN; [REIN Stratum-2]) study of 166 patients with proteinuria $3 g per 24 hours was stopped early due to ef cacy of ramipril in slowing eGFR decline.176 The monthly decline in GFR was signi cantly lower in the ramipril group (0.88 ml/min) than the placebo group (0.53 ml/min). The composite of doubling of serum creatinine or ESKD was reached in 18 versus 40 partici- pants (ramipril vs. placebo, P 0.02).176 In the REIN Stratum-1 of 186 patients with proteinuria of >1 to <3 g/d, the decline in GFR was not different, but ESKD events were less with ramipril chapter 3 www.kidney-international.org The Angiotensin-Converting Enzyme Inhibitors and Kidney Protection (AIPRI) trial compared benazepril to placebo in pa- tients with CKD mostly without diabetes to assess its effect on CKD progression (doubling of serum creatinine or ESKD as the primary outcome). Benazepril also caused a 53% reduction of the A meta-analysis of these 2 trials found a 49% decrease (RR: 0.51; 95% CI: 0.38 0.69) in the composite outcome, ESKD and a doubling of serum creati- nine with 769 participants (Supplementary Table S15).177,178 CV bene t from ACEi in these 3 aforementioned studies was assessed by meta-analysis, with the addition of the study by Hou et al.179 A reduction of CV events of 42% was found ). There are several meta-analyses reporting greater bene ts of ACEi or ARBs on kidney outcomes with increasing albuminuria, as for example, from Jafar et al.166,180 The Renoprotection of Optimal Antiproteinuric Doses (ROAD) study directly compared benazepril (ACEi) to los- artan (ARB) in 360 patients with CKD without diabetes and mean proteinuria of 1.4 2.0 g/d.181 No differences were found in kidney outcomes (primary outcome) or CV events between the 2 classes of RASi. Many of the above trials examined RASi versus placebo in people on background antihypertensive therapy. Few trials also tested active comparators to RASi (e.g., AASK, IDNT). There is sparse evidence of the effect of antihypertensive agents other than RASi on clinical outcomes in the setting of CKD with high BP and severely increased proteinuria, with the exception of AASK and IDNT. A number of smaller trials assessed changes Start here: At randomization visit, begin with 2- or 3-drug therapy* using a combination of a thiazide-type** diuretic, and/or an ACEI or ARB (but not both) and/or a CCB Include -blocker or other agents as appropriate for compelling indication Monitor as designated through follow-up Is SBP 120 mm Hg this visit? Is DBP 100 mm Hg at this visit or is DBP 90 mm Hg on last 2 visits? Is this a milepost visit? Yes Yes Yes No No No You must: (a) Add therapy not already in use and (b) See participant monthly until SBP <120 mm Hg You must: (a) Titrate or add therapy not already in use and (b) See participant monthly until SBP <120 mm Hg You must: Titrate or add therapy not already in use Continue therapy Figure 5 | SPRINT research treatment algorithm for the intensive group (goal SBP <120 mm Hg). From The New England Journal of Medicine, the SPRINT Research Group, A Randomized Trial of Intensive Versus Standard Blood-Pressure Control, Volume 373, Pages 2103 2116, Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.93 *May begin with a single agent for participants aged $75 years with SBP <140 mm Hg on 0 1 medications at study entry. A second medication should be added at the 1-month visit if participant is asymptomatic and SBP $ 130 mm Hg. **May use loop diuretic for participants with advanced CKD. Unless side effects warrant change in therapy. Consider adding a fth antihypertensive medication. Or until clinical decision made that therapy should not be increased further. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial. www.kidney-international.org chapter 3 in proteinuria. Whether those changes translate to changes in hard outcomes is uncertain. In particular, we have no RCT evidence that, for example, targeting a proteinuria of <1 g compared to >2 g leads to fewer hard kidney or CVoutcomes. Due to the imprecision in the studies from a low number of events, beta-blockers (Supplementary Table S18182,183 ) and CCBs (Supplementary Table S19184 186 ) were found to have little or no difference compared to placebo or RASi for the CV and kidney outcomes (ESKD, doubling of serum creatinine, GFR decline) in patients with CKD with and without diabetes and severely increased levels of albuminuria. Only RASi has been extensively studied in appropriately powered trials. There was only 1 relevant direct renin inhibitor study, comparing aliskiren to the ARB losartan in patients without diabetes and varying levels of albuminuria, and there were no events in either arm (Supplementary Table S20187 ). Quality of evidence. The overall quality of the evidence comparing ACEi or ARB with placebo or standard of care in patients with CKD and severely increased albuminuria without diabetes is moderate. The quality of the evidence was down- graded because of study limitations, such as small numbers of events, inadequate reporting of sequence generation, and allo- cation concealment (Supplementary Table S15176 179,188,188a,189 and Supplementary Table S16190,191 ). For studies of ACEi versus placebo or standard of care, some outcomes (ESKD, doubling of serum creatinine, and CV events) exhibited moderate quality of the evidence, downgraded because of study limitations (Supplementary ). The quality of evidence for other antihypertensive thera- pies in the population of CKD patients without diabetes and severely increased albuminuria was lower than the evidence for RASi, as it has only been examined in a limited number of RCTs for MRA of rather short duration and powered for surrogate outcomes (Supplementary Table S17192 195 ). Values and preferences. The presence of severely increased albuminuria and CKD is associated with a higher prevalence of CV disease, progressive CKD, and attendant loss of quality In the opinion of the Work Group, most well- informed patients with CKD and severely increased albu- minuria would place emphasis on preventing CV outcomes in addition to preventing CKD progression. Resource use and costs. The risks, bene ts, resource use, and costs of RASi therapy should be considered when treating patients with CKD. The costs of generic RASi medication are generally low. However, the use of RASi in patients with CKD G1 G4 with A3, especially those with G4, necessitates patient education (e.g., when to pause RASi), repeat lab testing, vigilance to prevent hyperkalemia and AKI due to volume depletion and other events, as well as repeat visits to restart RASi if it has been stopped during a hospitalization. On the other hand, there is moderate evidence for RASi treatment with the goal of preventing progressive loss of kidney function, which likely justi es the additional costs and visits required for monitoring. Considerations for implementation. There is insuf cient in- formation to differentiate between men and women for this recommendation, and insuf cient evidence that there are different outcomes by race. Rationale We make this recommendation for RASi because the bene ts of kidney and CV protection outweigh the potential adverse risks; therefore, most well-informed patients with CKD not on dialysis with severely increased albuminuria but without diabetes will opt for treatment with RASi. We feel that pa- tients put a large value on the cardio- and renoprotective bene ts of RASi and are willing to tolerate its potential harms, including hyperkalemia and AKI. These side effects, however, may lead to higher healthcare costs from additional visits and laboratory testing. Favors ACEi Favors placebo Study or subgroup Albuminuria/proteinuria Events Total Events Total Weight M H, random, 95% CI ACEi Placebo/ no treatment Risk ratio M H, random, 95% CI Risk ratio Subtotal (95% CI) Total events Test for overall effect: Z = 2.26 (P = 0.02) Figure 6 | Cardiovascular events in patients with CKD G3 G4, A3 without diabetes. Meta-analysis was conducted by the Cochrane Kidney and Transplant Evidence Review Team as part of the guideline evidence review. GISEN reported data from the REIN Stratum-2 group (baseline proteinuria $3 g/24 h), in contrast to REIN Stratum-1 (baseline proteinuria 1-3 g/24 h). A3, severely increased albuminuria; ACEi, angiotensin- converting enzyme inhibitor; AIPRI, Angiotensin-Converting Enzyme Inhibitors and Kidney Protection; CI, con dence interval; CKD, chronic kidney disease; events, number of events; GISEN, Gruppo Italiano di Studi Epidemiologici in Nefologia; M-H, Mantel-Haenszel; REIN, Blood- Pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease; total, number of participants. chapter 3 www.kidney-international.org Recommendation 3.2.2: We suggest starting RASi (ACEi or ARB) for people with high BP, CKD, and moderately increased albuminuria (G1 G4, A2) without diabetes (2C). This recommendation is weak according to GRADE, based on limited evidence from RCTs of suf cient duration to evaluate kidney protection. However, the Work Group judged that most well-informed patients would value the cardio- and renoprotective bene ts of RASi over potential harms from AKI or hyperkalemia. Key information Balance of bene ts and harms. The HOPE study,163 one of the largest RASi studies, found in a prespeci ed subgroup analysis of those with CKD and normal-to-moderately increased albuminuria (creatinine clearance <65 ml/min, estimated by the Cockcroft Gault formula; n 3394; mean follow-up 4.5 years) that ACEi versus placebo reduced the risk for all-cause mortality It should be noted that approximately one-third of patients in the HOPE study had diabetes, and only half had high BP. In the overall HOPE study, the CV bene ts of ramipril versus placebo were also present in those with moderately increased There were no studies speci cally evaluating the effect of RASi on slowing kidney disease progression in patients with CKD without diabetes and A2; therefore, HOPE provides the best guide for this subpopulation. Cinotti et al. examined the role of lisinopril on progression of kidney disease assessed by inulin clearance in 131 patients without diabetic nephropathy The mean baseline proteinuria perday was 506 mg, thusincluding A2and A3,and progression to dialysis or ESKD was reduced by 66% but with very wide 95% con dence intervals (HR: 0.34; 95% CI: 0.01 7.92). The TRANSCEND study compared telmisartan to placebo in high-risk patients with and without high BP. It reported a bene t of the ARB on the composite of doubling of serum creatinine or ESKD in those with moderately increased albuminuria, but detrimental kidney effects in those with normal or mildly increased albuminuria (P for interaction 0.006).198 Limitations of subgroup data on ter- tiary outcomes with low event numbers apply. There is sparse evidence for agents other than RASi used as initial therapy for high BP in people with CKD and moderately increased albuminuria (A2) without diabetes. In the AASK trial (mean PCR approximately 0.33 g/g [33 mg/mmol]), meto- prolol and amlodipine were not signi cantly different from ramipril for the few CV events that occurred, but they were inferior to ramipril for clinical kidney outcomes for which the trial was powered.98 For MRAs, there were 3 RCTs with a total of 1426 par- ticipants mainly from HF, not hypertension, trials with de ned CKD subgroups. Patients had varying levels of albu- With relatively few events for the individual there was a 29% risk reduction (HR: 0.71; 95% CI: 0.58 0.87) for the composite outcome of CV events and CV mortality based on data from 1 study with 912 CKD participants and a mean follow-up of 21 months (Supplementary Table S17192 195 ). Quality of evidence. The overall quality of the evidence for kidney outcomes comparing ACEi or ARB with placebo or standard of care in patients with CKD and moderately increased albuminuria without diabetes is low, due to imprecision because of a lack of data. The quality of the ev- idence for CV outcomes in patients with A2 without diabetes was rated as low. HOPE provided indirect evidence, as only two-thirds of the population had no diabetes. Values and preferences. In the opinion of the Work Group, many well-informed patients would place more emphasis on the potential for preventing CKD progression. Resource use and costs. When treating patients with CKD (G1 G4, A2) where the indication for ACEi or ARB therapy is not strong, consideration should be given to the clinical impact on the patient and the costs of starting RASi, including additional clinic visits and the need for additional lab testing Considerations for implementation. There is insuf cient in- formation to differentiate between men and women for this recommendation. However, data from ALLHAT demon- strated that ACEi as initial therapy for high BP in patients of African origin was inferior to chlorthalidone for stroke and combined CV outcomes.199 ALLHAT did not measure urine protein or albumin. Rationale We make this recommendation, albeit weak, because the CV bene ts appear to outweigh the potential adverse risks; there- fore, many well-informed patients with CKD not on dialysis with moderately increased albuminuria but without diabetes will opt for treatment with RASi. We feel that patients would put a large value on the CV bene ts of RASi and are willing to tolerate its potential harms, including hyperkalemia and AKI. These side effects, however, may lead to higher healthcare costs from additional visits and laboratory testing. Recommendation 3.2.3: We recommend starting RASi (ACEi or ARB) for people with high BP, CKD, and moderately-to-severely increased albuminuria (G1 G4, A2 and A3) with diabetes (1B). This is a strong recommendation based on evidence from RCTs of suf cient duration to evaluate kidney protection in patients with diabetes and CKD. This recommendation places a relatively higher value on preventing long-term progression of CKD and a relatively lower value on the risks of AKI or hyperkalemia, which are often transient. Where data are available, analyses by albuminuria subgroup are provided. Key information Balance of bene ts and harms. The 2 main studies demon- strating kidney bene t from RASi independent of BP control in diabetes were the three-arm IDNT162 and the two-arm www.kidney-international.org chapter 3 studies where ARB was compared with placebo200 or with placebo and with CCB in a double-blinded manner.162 IDNT excluded participants with normal BP; RENAAL included those with and without high BP. Both studies included only participants with severely increased albuminuria. Irbesartan in the IDNT study resulted in a 20% (RR: 0.80; 95% CI: 0.66 0.97) risk reduction in the primary composite endpoint (doubling of serum creatinine, ESKD, death from any cause) versus placebo and a 23% reduction versus amlodipine (RR: 0.77; 95% CI: 0.63 0.93); while losartan in the RENAAL study caused a 16% (RR: 0.84; 95% CI: 0.72 0.98) reduction in the composite outcome of death, dialysis, and doubling of serum creatinine compared to placebo. These studies demonstrated that RASi therapy improved the composite outcome in patients with diabetes, signi cant albuminuria (IDNT: 2.9 g/d proteinuria, baseline serum creatinine of 1.67 mg/dl [148 mmol/l]; RENAAL: albumin creatinine ratio 1237 mg/g [124 mg/mmol], baseline serum creatinine 1.9 g/dl [168 mmol/l]), and G3 G4, A3. Further, the RENAAL study demonstrated that in patients who have already doubled their serum creatinine during the study, remaining on RASi therapy signi cantly delayed the onset of dialysis by a mean of 6 months. In the IDNT study, hyperkalemia necessitating a stop in therapy occurred in only 2% of patients with RASi, versus 0.5% of patients in the other arms. Overall, serious adverse events were actually lower in the RASi group than in the control group. Therefore, in those with diabetes and CKD G3 G4, A3, there is strong evidence supporting the treatment with RASi because of their renoprotective effects. Data for people with diabetes and CKD G1 G3, A2 comes from the Micro-HOPE study, in which people with diabetes, moderately increased albuminuria, and higher CV risks had improved CV outcomes when randomized to ACEi therapy compared to placebo.201 Speci cally, for the composite outcome of MI, stroke, and CV death, there was a relative risk reduction with diabetes from the Micro-HOPE study, with a mean follow- up of 4.5 years. Kidney bene t in this group was largely limited to reducing progression from moderately increased albumin- uria to severely increased albuminuria. Only 18 cases in total developed ESKD 10 on ramipril and 8 on placebo.163 In the Micro-HOPE study, baseline serum creatinine was 1.06 mg/dl (94 mmol/l), and 474 (14%) of 3238 people progressed to a serum creatinine level of $1.4 mg/dl (124 mmol/l) over the 4.5 years (231 on ramipril and 243 on placebo).202 In a meta-analysis performed by the ERT, we found that, for patients with diabetes (including patients with and without albuminuria [A1, A2, and A3]), ACEi compared to placebo or standard of care did not reduce the risk for all-cause mortality, up of 32 months (Supplementary Table S21163,203 223 ). The absolute difference was 26 fewer events per 1000 (95% CI: 57 fewer 20 more) and was not statistically signi cant. The risk of doubling of serum creatinine was reduced by 30% (RR: with a mean follow-up of 32 months and an absolute difference was not statistically signi cant.163,207,213,215,221,222 However, in patients with severely increased albuminuria, ACEi reduced doubling of serum creatinine by 42% (RR: 0.58; 95% CI: 0.37 ACEi also reduces albuminuria in the CKD population with diabetes. The risk of progression from moderately increased albuminuria to severely increased albuminuria decreased by from 17 studies with a mean follow-up of 34 months and an absolute difference of 123 fewer events per 1000 patients (95% Compared to placebo or standard of care in 8 studies of 4106 participants, ARBs did not show a difference in all-cause mortality in patients with diabetes and CKD (RR: 0.99; 95% CI: 0.85 1.16). Similarly, there was no bene t in CV mor- tality, MI, HF, stroke, or CV bene t in diabetes and CKD. There was a kidney bene t with a reduction of doubling of serum creatinine of 16% (RR: 0.84; 95% CI: 0.72 0.98) based on 3280 patients from 4 studies with a mean follow-up of 34 months (Supplementary Table S22162,200,234,235 ). There were no differences between ACEi and ARB for the discrete outcomes of all-cause mortality, CV mortality, MI, stroke, HF, and kidney function in people with diabetes and albuminuric or non-albuminuric CKD subpopulations (Supplementary Table S23217,236 239 ). When compared to placebo or standard of care, ACEi improves CVoutcomes, but for ARB, there is no improvement. Studies comparing ACEi to ARB in patients with CKD and diabetes may have had an insuf cient number of patients to nd a difference. There has been little evidence to support the use of other agents such as MRA, beta-blockers, and CCBs as the initial therapy in patients with diabetes and albuminuria for CV or kidney protection beyond albuminuria reduction. For MRA compared to placebo, there were 3 small short-term studies powered for changes in albuminuria (Supplementary ). Albuminuria was lowered by MRA; however, in a meta-analysis by the ERT, there was no bene- cial effect in RCTs on all-cause mortality, MI, and stroke, and very few events to determine the effect on kidney out- comes. However, those trials were not powered for CV or kidney outcomes. Similarly, meta-analysis showed no evi- dence of bene ts on CV or kidney outcomes for beta-blockers (Supplementary Table S25242 249 ) and CCBs (Supplementary ) compared to placebo or standard of care. However, the studies were not properly powered for kidney or CV outcomes. The importance of diuretic therapy for lowering BP is suggested by the ADVANCE study comparing treatment with a combination of an ACEi plus diuretic (perindopril plus inda- pamide) to usual care without a thiazide-type diuretic in 11,140 people aged $55 years with diabetes, CV risk, or increased albuminuria (A2 or A3) over a mean of 4.3 years.257 The main outcomes were death from CV disease, non-fatal stroke or non-fatal MI, and new or worsening kidney or dia- betic eye disease. The relative risk of a major macrovascular or chapter 3 www.kidney-international.org microvascular event was reduced by 9% (HR: 0.91; 95% CI: 0.83 1.00); the relative risk of death from CV disease was reduced by 18% (HR: 0.82; 95% CI: 0.68 0.98); and death from any cause was reduced by 14% (HR: 0.86; 95% CI: 0.75 0.98). These improvements in clinical outcomes were associ- ated with a fall in BP of SBP 5.3/DBP 2.1 mm Hg in patients with CKD G1 or G2, and SBP 4.5/DBP 1.8 mm Hg in patients with CKD G3 G5. There was no effect modi cation by the presence of baseline albuminuria. It should be noted that in the ADVANCE study, 49% of the placebo group were already treated with RASi at baseline, which further increased to 73% by the end of the study, while 25% were on diuretics at baseline, which decreased to 21% in the placebo group at the nal visit. This nding suggests that the bene ts seen in ADVANCE might have been due to the addition of the diuretic and/or greater BP lowering in the active treatment group. There is emerging evidence that MRA have bene cial effects on clinical kidney outcomes. The FIDELIO-DKD study, an RCT of 5734 participants, demonstrated that nerenone, a nonsteroidal MRA, on the background of an ACEi or ARB in patients with diabetes, CKD, and albuminuria reduced the risk of composite primary endpoint of GFR decline, kidney failure, or renal death when added to standard of care.258 Finerenone also reduced the risk of CV events. However, its effect on SBP lowering was modest (2 3 mm Hg), and there was a higher risk of hyperkalemia-related events. At the writing of this guideline, nerenone has not been approved for clinical use. The trial was published after the evidence review cut-off for the guideline but will be assessed in future updates. Quality of evidence. The ERT updated a Cochrane system- atic review on antihypertensive therapies in patients with diabetes and CKD, A2 and A3.259 The overall quality of the evidence was rated as moderate, as the studies examining the use of RASi therapy exhibited study limitations with unclear allocation concealment for critical and important outcomes. The quality of the evidence was lower for CV outcomes, owing to there being fewer events and inconsistent reporting of these outcomes in trials (Supplementary Tables S21 S30). In the ADVANCE study of patients with CKD G1 G3, A2, the quality of evidence is low according to GRADE.260 The quality of the evidence was downgraded due to serious risk of bias, with unclear allocation concealment, and imprecision, as the bene cial results of diuretics were seen only in the CKD subgroups, when the results were negative in the entire cohort (Supplementary Table S27). The best evidence for renoprotective effects of RASi therapy independent of BP control in patients with diabetes, CKD G3 G4, and severely increased albuminuria comes from the with its active comparator arm, and from the trial. For CV outcomes, the Micro-HOPE study provides the best evidence for patients with moderately There are no RCTs in those with moderately increased albuminuria (A2) powered for hard kid- ney outcomes. Published meta-analyses for patients with dia- betes, hypertension, and CKD provided mixed results. One found a reduction of all-cause mortality, CV mortality, and major CV events in 32,827 people with diabetes treated with ACEi, but this was not found in 23,867 patients treated with A meta-analysis comparing RASi to other antihyper- tensive medications, excluding placebo-controlled trials, in people with diabetes, did not nd CVoutcome improvement.262 There was also no improvement in kidney failure, but the vast majority of included studies enrolled people with normal urine albumin or did not measure albumin at all. These meta-analyses included patients with diabetes and CKD G1 and G2, A1 A3, and G3 and G4, A1 A3, respectively. It is likely that including the low-risk and high-risk groups together led to the lack of statis- tical signi cance for CV outcomes. Although it is tempting to extrapolate the bene cial CV effects of RASi to all people with diabetes, in the absence of high BP, CVrisks, and lower GFR (G3 and G4, A2 and A3), the evidence is weak at best. For treatment with RASi, there is, therefore, a gradation of evidence from strong in the CKD subpopulation with low eGFR and severely increased albuminuria, to weak or absent in the subpopulation with normal eGFR without albuminuria. Values and preferences. In the opinion of the Work Group, this recommendation for people with diabetes and CKD with severely increased albuminuria places higher value on the ability of RASi to prevent CV and CKD events, such as doubling of serum creatinine and dialysis. It places less value on the risks of hyperkalemia and AKI. Resource use and costs. The costs of the RASi medications are probably low in most countries. However, adding RASi to patients with diabetes and severely increased albuminuria will require more laboratory testing and visits to healthcare pro- viders, especially in those with low GFR. It will also likely lead to greater incidence of hyperkalemia and AKI hence the asso- ciated costs of monitoring and treating these complications. Considerations for implementation. There is insuf cient in- formation to differentiate between men and women for this recommendation, and there is insuf cient evidence that there are different outcomes by race. Rationale We issue a strong (1B) recommendation for treatment with ACEi or ARB for patients with diabetes, increased albuminuria, and normal-to-low GFR (G1 G4; A2 or A3), because their desirable bene ts in kidney and CV protection outweigh the adverse risks associated with therapy. Nonetheless, these side effects, such as hyperkalemia and rises in serum creatinine, may lead to highercosts from additional visits and laboratory testing. Practice Point 3.2.1: It may be reasonable to treat people with high BP, CKD, and no albuminuria, with or without diabetes, with RASi (ACEi or ARB). Patients with CKD, high BP, and no albuminuria are at lower risk of CKD progression. In this subpopulation, existing evi- dence does not demonstrate clear clinical bene ts of RASi for CKD progression, and other antihypertensive agents are as appropriate for BP management. However, we feel that some patients would put a large value on the CV protection from RASi and would be willing to tolerate the potential harms, particularly patients with higher GFR and a relatively low risk of harm. www.kidney-international.org chapter 3 The HOPE study, one of the largest RASi studies, reported CV bene ts with an ACEi versus placebo in people at high CV risk with or without high BP.163 In a prespeci ed CKD sub- group (CrCl <65 ml/min by the Cockcroft-Gault formula) of 3394 patients with no or mildly increased albuminuria (approximately one-third of whom had diabetes), ACEi reduced the risk for all-cause mortality by 20% (HR: 0.80; during a mean follow-up of 4.5 years.167 In the overall HOPE study, 3577 patients had diabetes, and 2437 of them (roughly two-thirds) did not have albuminuria.163 The PEACE sub- study in those with CKD con rmed this notion.165 Practice Point 3.2.2: RASi (ACEi or ARB) should be administered using the highest approved dose that is tolerated to achieve the bene ts described because the proven bene ts were achieved in trials using these doses. The Work Group judged that a large majority of physicians would be comfortable initiating RAS blockade treatment and titrating it to the maximum dose approved by regulatory agencies and tolerated by the patient because of its bene ts in kidney protection, their familiarity with this drug, and its good safety pro le. The bene ts from RASi administered in less than maximally recommended doses are less certain. However, if for whatever reason (e.g., hyperkalemia) the patient cannot tolerate the maximum dose, a smaller dose may still be reasonable. It should be noted that the maximum dose of RASi allowed by the regulatory agency varies by country, and the practitioners are advised to follow their respective national guidance. Practice Point 3.2.3: Changes in BP, serum creatinine, and serum potassium should be checked within 2 4 weeks of initiation or increase in the dose of a RASi, depending on the current GFR and serum potassium. ACEi and ARBs are potent antihypertensive agents that counteract the vasoconstrictive effects of angiotensin II. Moreover, blocking the action of angiotensin II causes selec- tively greater vasodilatation of the efferent arterioles of the glomeruli, resulting in a decline of the intraglomerular ltra- tion pressure, and not unexpectedly, a decrease in the GFR and a rise in the serum creatinine. In addition, RAS blockade in- hibits the action of aldosterone, resulting in a greater pro- pensity for hyperkalemia. In patients at risk for hyperkalemia, measuring serum potassium before and at 1 2 weeks after initiation of RASi is recommended, based on expert opinion.44 An increase in serum creatinine level, if it occurs, will typically happen during the rst 2 weeks of treatment initiation, and it should stabilize within 2 4 weeks in the setting of normal so- dium and uid intake.263 Therefore, patients should be monitored for symptomatic hypotension, hyperkalemia, and serum creatinine within 2 4 weeks after initiating or changing the dose of the drug, with the time interval depending on baseline BP, serum creatinine, and serum potassium. A shorter time interval is indicated if the baseline serum creatinine is high, or serum potassium is already high-normal, or there is a history of hyperkalemia or an acute rise in serum creatinine with BP lowering or RASi. Practice Point 3.2.4: Hyperkalemia associated with use of RASi can often be managed by measures to reduce the serum potassium levels rather than decreasing the dose or stopping RASi. In observational cohorts, hyperkalemia is often associated with a subsequent reduction in dose or discontinuation of Pseudo-hyperkalemia needs to be rst ruled out. Then, there are multiple measures that can be taken to mitigate the hyperkalemia.44 Improvement in potassium control could lead to increased use of RASi in patients with an evidence-based indication. Strategies to control chronic hyperkalemia include dietary potassium restriction; discon- tinuation of potassium supplements, certain salt substitutes, and hyperkalemic drugs; adding potassium-wasting diuretics, and oral potassium binders.44 In CKD patients receiving RASi who develop hyperkalemia, the latter can be controlled with newer oral potassium binders in many patients, with the ef- fect that RASi can be continued at the recommended Whether the latter therapeutic strategy improves CV or kidney outcomes is being examined in RCTs, such as the ongoing DIAMOND trial (NCT03888066). Side effects of the newer potassium binders are reported to be moderate. Practice Point 3.2.5: Continue ACEi or ARB therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation of treatment or an increase in dose. This practice point reiterates a common expert opinion and may be a reasonable option for many patients treated with RASi. However, there is not a single trial that compared meaningful clinical outcomes in patients who were continuing versus dis- continuing versus reducing the dose of RASi upon a fast increase in serum creatinine by 10%, 20%, 30%, 40%, etc. Observational data relating acute changes in serum creatinine shortly after RASi initiation to subsequent long-term outcomes are equivocal An increase of <30% in serum creatinine from the baseline value does not mandate a dosage decrease or discontinuation of RASi, as long as the serum creatinine increase is not associated with other complications, such as hyperkalemia and uid retention. Practice Point 3.2.6: Consider reducing the dose or dis- continuing ACEi or ARB in the setting of either symp- tomatic hypotension or uncontrolled hyperkalemia despite medical treatment, or to reduce uremic symptoms while treating kidney failure (estimated glomerular ltration rate ). The dose of ACEi or ARBs should be reduced or dis- continued in patients with hyperkalemia after other measures have failed to achieve a normal serum potassium level. In general, similar efforts should be made to discontinue other concurrent BP medications before attempting to reduce the dose of ACEi or ARBs in patients who experience symp- tomatic hypotension and has a speci c indication for RASi, chapter 3 www.kidney-international.org such as severely increased albuminuria or heart failure. Which BP medication to discontinue or which ones to retain would depend on the relative indication of each medication. When these drugs are used in patients with eGFR <30 ml/ , close monitoring of serum potassium is required. On the other hand, withholding these drugs solely on the basis of the level of kidney function will unnecessarily deprive many patients of the CV bene ts, and perhaps even protection of the residual kidney function, that they otherwise would have received, particularly when measures could be undertaken to mitigate the risk of hyperkalemia.179,271 However, in patients with advanced CKD who are experi- encing uremic symptoms or uncontrolled hyperkalemia, it is reasonable to discontinue ACEi and ARB temporarily to allow time for kidney replacement therapy preparation.272 Practice Point 3.2.7: Mineralocorticoid receptor antagonists are effective for management of refractory hypertension but may cause hyperkalemia or a reversible decline in kidney function, particularly among patients with low eGFR. The steroidal MRAs spironolactone and eplerenone have, in small and short-term studies, been found to reduce BP in resistant hypertension (de ned as uncontrolled hypertension on 3 antihypertensive agents including a diuretic) in a popu- lation that included CKD and non-CKD171,273 and to lower albuminuria in patients with diabetes and elevated urinary Side effects, particularly hyperkalemia and decline in kidney function,274 are however a concern when added to background therapy with an ACEi, ARB, or diuretic, particularly among patients with eGFR <45 ml/min per 1.73 Thus, MRAs should not be used in patients with high risk of hyperkalemia (e.g., hypoaldosteronism or type 4 renal tubular acidosis). Results from the AMBER trial showed that in patients with resistant hypertension and advanced CKD (25 ), concomitant use of the oral po- tassium binder patiromer compared with placebo allowed a larger proportion of patients using spironolactone at 12 A recent trial, FIDELIO, examining the impact of the nonsteroidal MRA nerenone showed kidney protection; however, the effect on BP was modest and the risk of hyperkalemia-related events was increased.258 Research recommendations  RASi in patients with CKD G3 G4, A1 and A2 with or without diabetes have not been adequately studied. Future studies should examine if RASi, in the presence or absence of other renoprotective agents such as SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, provide kidney, CV, and survival bene ts to this important subgroup.  There are insuf cient data on the role of diuretics as rst- line therapy for the treatment of high BP in patients with CKD. It would be helpful to clarify the role of diuretics as initial therapy in this population. 3.3 Role of dual therapy with RASi RASi have been shown to both lower BP and slow the pro- gression of certain types of kidney diseases independently of BP control. The strongest data come from studies of patients with CKD and diabetes with albuminuria, in which therapy with ACEi or ARB has shown improvement of kidney outcomes and potentially CV outcomes, as discussed above in Section 3.2. Some investigators have advocated the use of dual therapy with ACEi, ARB, and/or aliskiren to enhance the antiproteinuric and renoprotective effects. However, compared to monotherapy with ACEi or ARB, dual RASi therapy appears to cause more adverse effects, including hyperkalemia and AKI, that may outweigh any potential CV or kidney bene t. Recommendation 3.3.1: We recommend avoiding any combination of ACEi, ARB, and direct renin in- hibitor (DRI) therapy in patients with CKD, with or without diabetes (1B). This is a strong recommendation based on evidence from RCTs of suf cient duration to evaluate kidney and CV protection. There is growing evidence that dual RAS blockade with an ACEi, ARB, or DRI does not lead to long term CVorkidney bene t despite lowering proteinuria in the short term, but it leads to an increased risk of harm from hyperkalemia and AKI. This recommendation places a higher value on preventing harm from hyperkalemia and AKI than on lowering proteinuria. The combination of ACEi or ARB with MRA was bene cial in 1 large outcome trial; thus, our recom- mendations on combination therapy do not apply in this scenario. Key information Balance of bene ts and harms. In patients with CKD with and without diabetes, a large network meta-analysis compared dual blockade to monotherapy and included 17,750 participants. Two of these studies excluded participants with There was no signi cant difference in all-cause mortality from dual blockade versus monotherapy in 7 studies of 16,862 patients with a mean follow-up of 3.4 years. There was also no difference in progression to ESKD and no improvement of CV events based on 7 studies of 16,507 patients with a mean follow-up of 40 months. On the other hand, a traditional pair-wise meta-analysis performed by the ERT demonstrated harm for dual blockade compared to monotherapy. In studies of patients with CKD with and without diabetes, dual blockade compared to mon- otherapy caused a slightly higher risk of all-cause mortality of borderline signi cance (HR: 1.09; 95% CI: 1.00 1.20) based on data from 10,615 patients in 4 studies with a mean follow-up of and (Supplementary Table S31). Importantly, in studies of patients with CKD with or without diabetes, there was evidence that dual therapy increased the incidence of AKI by 40% (RR: 1.60; 95% CI: 1.26 2.04), compared to monotherapy, based on data from 6139 patients in with a mean follow-up of 39 months (Supplementary Table S31). Combining data for patients who have both CKD and diabetes (and excluding those without diabetes) from 3 large RCTs, there was no bene t in all-cause mortality; there were www.kidney-international.org chapter 3 9% fewer deaths with monotherapy RASi compared to dual RASi therapy (RR: 0.92; 95% CI: 0.84 1.01) based on data from 10,486 patients with a mean follow-up of 52 months ). There was a marginal reduction of 20% (RR: 0.80; 95% CI: 0.65 1.00) in doubling of serum creatinine by dual therapy, compared to monotherapy, during the study of 10,486 pa- tients from 3 studies with a mean follow-up of 37 months and ONTARGET ). However, the lower con dence interval reaches the null, indicating high uncertainty. The data analysis of the meta-analysis cited above is echoed by the individual large RCTs, including ONTARGET, VA-NEPHRON D, ALTITUDE, and ORIENT. Although dual therapy with ACEi and ARB (or DRI in ALTITUDE) moderately reduces albuminuria and BP compared to monotherapy with either drug, dual therapy does not confer important clinical kidney or CV bene ts, and it causes more hyperkalemia and AKI. Quality of evidence. The overall quality of the evidence for harm was moderate. The network meta-analysis that compared dual RASi with mono RASi exhibited moderate quality of the evidence because of concerns regarding inconsistency for all- cause mortality and CV events and serious imprecision for ESKD due to wide CIs that indicated appreciable bene ts and harms (Supplementary Table S32).169 The ERT review (including Cochrane reviews that were updated259,281 ) rated the quality of evidence to be moderate for studies that compared dual with mono RASi because of study limitations, with unclear reporting for Cochrane risk of bias282 domains, random sequence generation, and allocation concealment (Supplementary Table S31234,277 279,283,284 ). The ERT updated a Cochrane review protocol on the addition of aliskiren to RASi therapy with mono RASi.285 The quality of the evidence was moderate for most outcomes (Supplementary Table S29286 291 ). For CV mortality, ESKD, moderately increased albuminuria, and doubling of serum creatinine, the quality of the evidence was downgraded because of serious imprecision due to only 1 study reporting these outcomes, and all-cause mortality was downgraded due to wide con dence intervals that indicate appreciable bene ts and harms. Finally, for the serious adverse events, the quality of the evidence was downgraded to moderate because of study limitations (unclear random sequence generation, allocation concealment, and a lack of blinding of outcome assessors). Values and preferences. In the opinion of the Work Group, this recommendation places a higher importance on preventing hyperkalemia and AKI than on the bene ts in reduction of albuminuria. The signi cance of these bene cial effects on albuminuria is unclear, in view of the absence of effects in GFR, at least during the follow-up period of the trials. Although some bene t has been found for dual therapy in HF, this has not been con rmed so far in patients with CKD with or without diabetes. The Work Group believes that patients and providers would want to avoid hyperkalemia and AKI because of the associated downstream risks as well as the need for more frequent laboratory tests, of ce and emergency department visits, additional short-term therapies, and adjustment in diet. Resource use and costs. Resource utilization and costs in- crease, instead of decrease, by instituting dual RASi therapy compared to monotherapy. Considerations for implementation. Given that dual RASi therapy decreases proteinuria, practitioners might be tempted to institute dual therapy to treat very high levels of albuminuria in selected patients, even recognizing the risks of hyperkalemia There is, unfortunately, no RCT data on safety or kidney ef cacy of dual therapy in patients with very elevated There is a report that dedicated clinics for remission of progression of kidney disease are superior to There is insuf cient information to differentiate between men and women for this recommenda- tion, and there remains insuf cient evidence that there are different outcomes by race or age. In summary, dual therapy should be discouraged for patients with CKD with or without diabetes, with or without albuminuria. Rationale The belief that dual therapies of RASi are bene cial, compared to monotherapies, stemmed only from the improvement in albuminuria with dual therapy. Addition of an MRA to ACEi or ARB. Limited data have shown that the addition of an MRA, such as spironolactone, epler- enone, or nerenone, to an ACEi or ARB for renoprotection in patients with diabetes and kidney disease resulted in a reduc- tion of albuminuria but a higher risk of hyperkalemia. Beyond albuminuria, no adequately powered study examining GFR and kidney failure outcomes has been completed with spi- ronolactone or eplerenone.295 However, the recent FIDELIO trial showed kidney and cardiovascular protection by ner- enone despite its modest effect on SBP (2 3 mm Hg lower) and a higher incidence of hyperkalemia-related events.258 Results of the FIGARO cardiovascular trial, which is also testing nerenone on the background of an ACEi or ARB in patients with diabetes and kidney disease, are forthcoming. Research recommendations  The bene ts of dual versus monotherapy on major kidney outcomes in people with CKD without diabetes and severely increased proteinuria (e.g., >2 3 g/d) have not been well studied. Future trials should examine this important sub- group, while curtailing the risks of hyperkalemia and AKI.  Conduct studies examining the addition of endothelin blockers or GLP-1 receptor agonists to concomitant RASi monotherapy for potential kidney bene ts in the advanced CKD (G4 G5) population and the nonproteinuric CKD populations.  In the era of personalized medicine, research should be directed to identify individuals who will bene t or experience harm from these combinations in all CKD populations. chapter 3 www.kidney-international.org Chapter 4: Blood pressure management in kidney transplant recipients (CKD G1T G5T) This chapter makes recommendations for BP management in adult (age $18 years) kidney transplant recipients (CKD G1T G5T). The evidence review for this chapter included an update of a previous Cochrane review296 in addition to a new search of the Cochrane Kidney and Transplant Registry for all RCTs. The term high BP is used throughout the document for BP above the target. For kidney transplant recipients, the target is SBP <130 mm Hg/DBP <80 mm Hg. Practice Point 4.1: Treat adult kidney transplant recipients with high BP to a target BP of <130 mm Hg systolic and <80 mm Hg diastolic using standardized of ce BP measurement (see Recommendation 1.1). This practice point is identical to the original recom- mendation put forward in the KDIGO 2012 Clinical Practice Guideline for the Management of Blood Pressure in Chronic The target is also consistent with the rec- ommended target of <130/80 mm Hg as de ned in the KDIGO Clinical Practice Guideline for the Care of Kidney There are no completed RCTs in kidney transplant re- cipients that have tested different BP targets on clinically important outcomes such as graft survival, CV events, or mortality. There is only 1 RCT on intensi ed BP control in kidney transplant recipients that compared to standard blood pressure (MAP between 50th and 99th percentiles) versus intensi ed BP control (MAP <50th percentile), and it did not report on any clinical outcomes.298 The Work Group judged that a target of <130 mm Hg systolic, using standardized of ce measurement, remained a reasonable goal for kidney transplant recipients. A higher target SBP, such as 140 mm Hg, was in the opinion of the Work Group too high given the preponderance of evidence from RCTs demonstrating survival and CV bene ts of tar- geting SBP <130 mm Hg in the general population.299 301 In contrast, the Work Group judged that a lower SBP goal, such as 120 mm Hg (see Recommendation 3.1.1), may not be appropriate for kidney transplant recipients without further data on the risks and bene ts of targeting this level of BP in this population. This concern for the lower SBP goal of <120 mm Hg partly stems from observations from the SPRINT trial showing that, compared to the standard arm (SBP target <140 mm Hg), patients in the intensive BP arm had modestly higher rates of eGFR decline within the 3-year follow-up of the trial,91,302 AKI (albeit mild in in- and incident CKD,134 which may be of concern to kidney transplant recipients and clinicians (see Values and preferences below). It is conceivable that kidney trans- plant patients with a solitary, denervated kidney could be at an even higher risk for such adverse events with intensive BP lowering, although this has not been substantiated by clinical data. Data from RCTs involving kidney transplant recipients will be needed to provide a clearer pro le of the true risks and bene ts of a SPRINT-like goal in this population. Similar to the non-transplant CKD population (Recom- mendation 1.2), ABPM or HBPM may be used to comple- ment standardized of ce BP readings for the diagnosis and management of high BP in the kidney transplant population. As with the general population, classi cation of BP status using out-of-of ce BP is often different from classi cation using standardized of ce BP in kidney transplant recipients; the complementary use of out-of-of ce BP measurements may lead to more appropriate therapeutic decisions.303,304 Again, it should be noted that there have been no completed RCTs targeting different BP values using either of ce BP readings or out-of-of ce BP readings in the kidney transplant population. Recommendation 4.1: We recommend that a dihy- dropyridine calcium channel blocker (CCB) or an ARB be used as the rst-line antihypertensive agent in adult kidney transplant recipients (1C). This recommendation places a relatively higher value on pre- venting kidney allograft loss and a relatively lower value on the risk of a possible medication-related side effect. This recom- mendation is strong because in the judgment of the Work Group, the potential prevention of transplant failure outweighs potential risks of burden associated with its implementation. The Work Group also judged that all or nearly all well-informed transplant patients would choose to receive a CCB or an ARB given the potential bene t. Key information Balance of bene ts and harms. This recommendation relies heavily on the importance of preventing graft loss to kidney transplant recipients and clinicians.305,306 The evidence re- view, including both hypertensive and normotensive www.kidney-international.org chapter 4 patients, has found that, compared to placebo, CCB use caused a mean 26% reduction in graft loss (RR: 0.74; 95% [Santos AF, Keitel E, Bittar A, et al., eds. Long-term re- sults of diltiazem use associated to cyclosporin in renal transplantation {abstract}. XIXth International Congress of the Transplantation Society; August 25 30, 2002; Miami, FL, USA]). This evidence is derived from a meta-analysis of 22 RCTs involving 1745 patients conducted by the ERT for this guideline. These 22 trials, however, evaluated both dihy- dropyridine CCBs (e.g., amlodipine, nifedipine) and non- dihydropyridine CCBs (e.g., diltiazem, verapamil). From a pharmacologic perspective, non-dihydropyridine and dihy- dropyridine CCBs are very different medications with distinct effects and adverse effects and should not be com- bined in a meta-analysis. When these medication classes were examined separately, only the dihydropyridine CCB group caused a 38% reduction in graft loss (RR: 0.62; 95% CI: 0.43 0.90) over a mean of 25 months compared to placebo (Figure 7307 326 ). This evidence was derived from 8 RCTs involving 926 participants followed for a mean of 25 In contrast, the reduction in graft loss caused by the non-dihydropyridine CCB group was not statistically signi cant (RR: 0.91; 95% CI: 0.61 1.34) compared to placebo (Figure 7307 326 ). The evidence review has also found that ARB use compared to placebo caused a 65% reduction in graft loss (RR: 0.35; 95% CI: 0.15 0.84; Supplementary Table S34). This evidence was derived from 3 RCTs involving 786 participants followed for a mean of 37 months.327 329 The evidence review found no bene t of CCB or ARB use on all-cause mortality or CV events such as MI or stroke. Dihydropyridine CCB use, but not ARB use, however, caused a lower serum creatinine concentration (mean difference: lower) and a higher GFR (mean difference: 5.27 ml/min Less with CCB Less with placebo M H, Random, 95% CI Risk ratio Study or subgroup Events Total Events Total Weight M H, Random, 95% CI CCB Placebo/no treatment Risk ratio Chen 2013a CyP+ Chen 2013a CyP Subtotal (95% CI) Non-dihydropyridine Not estimable Not estimable Not estimable Not estimable Total (95% CI) Total events Test for overall effect: Z = 2.20 (P = 0.03) Test for subgroup differences: 2 Total events Test for overall effect: Z = 0.49 (P = 0.62) Van den Dorpel 1994 Van Riemsdijk 2000 Subtotal (95% CI) Dihydropyridine Total events Test for overall effect: Z = 2.54 (P = 0.01) Figure 7 | CCB versus placebo/no treatment for the outcome of graft loss. Meta-analysis was conducted by the Cochrane Kidney and Transplant Evidence Review Team as part of the guideline evidence review. *Includes patients both with and without high blood pressure. CCB, calcium channel blocker; CI, con dence interval; CyP, cytochrome P450 3A5 polymorphism; M-H, Mantel-Haenszel. chapter 4 www.kidney-international.org higher; 95% CI: 2.79 higher 7.74 higher) compared to pla- cebo over a mean follow-up of 15.3 months (Supplementary ). The tradeoff or harms with these interventions include well-known adverse events for both dihydropyridine CCB ) and ARB (e.g., anemia, acute decline in kidney function, hyperkalemia336 ). The evidence review found that, compared to placebo or no treatment, ACEi, alpha-blockers, beta-blockers, and MRAs had no signi cant effect on mortality, graft loss, or CV events (Supplementary Table S35,332,337 349 Supplementary Table S36,350 Supplementary Table S37,351 Supplementary Table S38352 ). With regard to ACEi there was trial evidence showing that these agents were effective at reducing BP and proteinuria in kidney transplant recipients (Supplementary Table S35). However, there was no signi - cant effect of ACEi on all-cause mortality or graft loss, and their use was associated with a signi cant increase in adverse events in the kidney transplant population, including angioedema, cough, hyperkalemia, and anemia (Supplementary Table S35). Quality of evidence. The ERT updated a Cochrane sys- and evaluated the quality of the evidence based on RCTs only (Supplementary Tables S33 S39). 