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).


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).


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.


**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 ).


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.


, 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).


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.


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.


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.


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.


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.


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 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.


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 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.


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).


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.


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.


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.


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.


, 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.


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.


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.


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).


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.


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.


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 ).


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 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.


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.


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 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.


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.


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.


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 ).


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.


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). The evidence for the use of an ARB or CCB compared to placebo or no treatment is considered low quality because of a serious risk of bias (unclear randomization sequence generation and allocation concealment) and imprecision around the effect estimates. Overall, there were very few graft failure events, which introduces greater fragility in the effect estimates.


Overall, there were very few graft failure events, which introduces greater fragility in the effect estimates. For example, there were only a total of 25 graft failure outcomes among the 786 participants over a mean of 37 months of follow-up in the ARB trials. Values and preferences. Kidney transplant recipients place a high priority on allograft survival. The SONG Kidney Transplantation (SONG-Tx) group was established to deter- mine which outcomes to measure in transplant trials.305 The SONG-Tx methodology included a Delphi survey that was completed by 461 patients or caregivers and 557 health pro- fessionals from 79 countries. They also held 3 consensus conferences in which patients and caregivers partici- Kidney allograft survival was unequivocally the dominant priority for patients, caregivers, and health pro- From the patient s perspective, there was a prevailing dread of returning to dialysis, and they focused on Preventing graft loss was the top priority, even over death, as the patients were more concerned with quality than quantity of life.305 The SONG-Tx work provides strong rationale for the use of interventions that will reduce graft failure. It is the opinion of the Work Group that most well-informed transplant pa- tients would have the same values and preferences for the avoidance of graft loss, as was evident from the SONG-Tx work. Thus, we believe that nearly all well-informed trans- plant patients would accept the tradeoffs of side effects of a CCB or an ARB in exchange for the possible bene t of pro- longed graft survival. Resource use and other costs. This recommendation as- sumes that an antihypertensive agent will be started for the treatment of high BP, and the guideline is to facilitate the decision on the choice of the agent. In most countries, generic CCBs and generic ARBs are inexpensive.


In most countries, generic CCBs and generic ARBs are inexpensive. In resource-limited settings, these drugs are most likely to be available at even lower cost. Given the high nancial and human cost of graft failure, and the relatively low cost of CCB or ARB, it is likely that the initiation of a CCB or ARB would be cost-effective.353 However, a formal economic analysis evaluating different antihypertensive agents in the kidney transplantation setting has not been Considerations for implementation. High BP can be dif cult to control in kidney transplant recipients, and most patients will require more than 1 antihypertensive agent.299 301 This recommendation is for the selection of an initial antihy- pertensive agent with the understanding that other medi- cations may be required to achieve BP control. Patients with evidence of volume overload and high BP should be treated with diuretics before considering an ARB or CCB. Women trying to conceive or who are pregnant should be treated with a CCB, which is generally safe during preg- nancy and lactation, whereas ARB is contraindicated in these conditions. In kidney transplant recipients with pro- teinuria and high BP, ARB should be considered rst given the known proteinuria-lowering effects of these In the early posttransplant period, ARBs should be avoided until kidney transplant function stabilizes, as the acute negative effect of an ARB on GFR can be confused with other causes of graft dysfunction (e.g., rejection). For most other subgroups of transplant patients (e.g., elderly, diabetic), an ARB or CCB should be considered as the rst-line antihypertensive agent. Most, if not all patient subgroups, would value graft survival as a high-priority outcome. The choice of class (i.e., ARB vs. CCB) and speci c agent should be based on local availability and cost.


, ARB vs. CCB) and speci c agent should be based on local availability and cost. Rationale This recommendation places a higher value on preventing kidney allograft loss and a lower value on the risk of medication-related side effects. There are many advantages of using an ARB or CCB for high BP in kidney transplant recipients, including physician familiarity with these agents, well-known side-effect pro les, availability, and low costs. This recommendation is strong because, in the judgment of the Work Group, the potential prevention of transplant www.kidney-international.org chapter 4 failure far outweighs potential risks and burden associated with its implementation. The Work Group also judged that most transplant patients would take a CCB or an ARB given the potential bene t, and only a small proportion would not. Finally, the Work Group judged that the majority, if not all, of clinicians would be comfortable in starting a CCB or ARB due to the familiarity with these agents and their well-known safety pro les. Research recommendations Future research should include:  Adequately powered RCT to evaluate CV and kidney effects of targeting SBP <120 mm Hg versus <130 mm Hg SBP among patients with kidney transplants.  Adequately powered RCT to evaluate CV and kidney effects of ARB versus dihydropyridine CCB among patients with kidney transplants. chapter 4 www.kidney-international.org Chapter 5: Blood pressure management in children with CKD Recommendation 5.1: We suggest that in children with CKD, 24-hour mean arterial pressure (MAP) by ABPM should be lowered to 50th percentile for age, sex, and height (2C). This recommendation is weak, according to GRADE, because the potential risks for adverse events from BP lowering may vary depending on the underlying cause of CKD in children.


This recommendation is weak, according to GRADE, because the potential risks for adverse events from BP lowering may vary depending on the underlying cause of CKD in children. In particular, risks of dehydration, hypotension, and possible AKI may be greater in children with underlying urologic disease that may be associated with xed urine output despite intercurrent gastrointestinal (GI) illness and uid loss or decreased uid intake. There may also be burden due to limitations in available resources associated with BP monitoring via 24-hour ABPM. It places a high value on reduction in kidney disease progression and kidney failure and use of the same BP measurement tech- nique by ABPM as in the single RCT that forms the evidence base. It places a relatively low value on the lack of evidence demonstrating that the clinical bene ts of BP lowering extend to populations characterized by different causes of CKD, level of albuminuria, race and ethnicity, and on the costs and incon- venience associated with BP monitoring using ABPM. Key information Balance of bene ts and harms. This recommendation relies heavily on the data from a single trial (the Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CKD in Pediatric Patients [ESCAPE] trial) of 385 participants in which intensi ed BP control (targeting 24-hour MAP <50th percentile of normal children) was compared to standard BP control (targeting 24-hour MAP 50th 99th percentile of normal children; Supplementary Table S401,142,355 ). This study showed a probable bene t in slowing kidney disease progression and no greater risk of adverse events, such as hypotension or acute decrease in GFR. This study in children was not powered for, and did not demonstrate, differences in the critical outcome of all-cause mortality.


This study in children was not powered for, and did not demonstrate, differences in the critical outcome of all-cause mortality. In the ESCAPE trial, targeting the intensi ed BP control required a larger number of antihypertensive agents than the conventional target, which may be a burden for some children. Certain subgroups, those with glomerular disorders, GFR <45 ml/ , and those with PCR >1.5 g/g (150 mg/ mmol) seemed to bene t the most. Of note, based on this observation, the 2016 European Society of Hypertension guideline recommends targeting the 75th percentile of MAP of normal children in a CKD patient with no proteinuria, and the 50th percentile if an individual has proteinuria.356 This is based on a subgroup analysis of the ESCAPE data, which suggested that those children with a PCR <0.5 g/g (50 mg/ mmol) did not have a signi cant bene t from strict BP control. Therefore, the risk bene t ratio associated with this treatment strategy may differ in different subpopulations. There may be a higher risk of adverse events with aggressive BP control in individuals who are prone to become dehydrated and are at risk of AKI.


There may be a higher risk of adverse events with aggressive BP control in individuals who are prone to become dehydrated and are at risk of AKI. This is especially relevant to children with CKD and congenital anomalies of the kidney and urinary tract (CAKUT) who may be unable to concentrate urine and have a salt-losing nephropathy.357 On the other hand, there are potential CV end-organ bene ts, such as less left ventricular hypertrophy.358 The single RCT of BP control and kidney failure outcomes in the pediatric CKD population utilized 24-hour MAP as the Additionally, the AHA Scienti c Statement on pediatric ABPM currently considers ABPM as the gold stan- dard metric for the assessment of BP in children, as stronger associations have been reported between ABPM and target organ damage in children compared with clinic BP values.359 Targeting BP control by ABPM in children with CKD is also recommended by the American Academy of Pediatrics However, in clinics that do not have the capacity to provide ABPM, performance of standardized, protocol-driven manual BP measurement using an aneroid sphygmoma- nometer is a reasonable alternative. Such standardized manual BP measurement provides prognostic information similar to that provided by ABPM.360,361 Data from the Chronic Kidney Disease in Children Study (CKiD) further demonstrate that manual auscultatory clinic BPs taken in a protocol-driven setting are not inferior to ambulatory BP in the discrimination of BP-related adverse outcomes in children However, it must be emphasized that, despite their prognostic utility, RCTs targeting standardized manual BP with meaningful clinical outcomes are not available in children. Proper technique is essential for BP measurement. BP should be measured in the right arm using standard practices, similar to the method used for adults (see Figure 2 in Chapter 1).


BP should be measured in the right arm using standard practices, similar to the method used for adults (see Figure 2 in Chapter 1). The AAP 2017 Clinical Practice guidelines also provide considerable detail on correct BP measurement methods.1 When possible, in the clinic, the use of auscultatory BP is preferred, as normative BP data in children are obtained using this technique, and there are signi cant differences between values obtained by oscillometric and auscultatory measurements, with oscillometric measures being slightly www.kidney-international.org chapter 5 higher on average.1,3,362 Regardless, RCT data targeting either oscillometric or auscultatory BP measurements obtained in the clinic setting in children are lacking.363 For practical purposes, the initial BP measurement in a clinic setting may be oscillometric using a calibrated machine that has been validated for use in the pediatric population.1,3 However, conversion from oscillometric to ascultatory measurement on an individual basis is dif cult. In individuals at particularly high risk for elevated BP (e.g., those with glomerular dis- readings should then be con rmed by auscultation. Use of HBPM in children requires further study and has not been endorsed for the diagnosis of hypertension by the AAP Clinical Practice Guideline. When performed, elec- tronic upper-arm cuff monitors, which have been clinically validated in children, should be used with appropriate cuff size. Validation status for oscillometric BP devices in the pediatric age group can be checked at stridebp.org. HBPM should be performed for 7 days (not less than 3), with duplicate morning and evening measurements after 5 mi- nutes of sitting at rest and 1 minute between measurements (total of at least 12 readings per week).


HBPM should be performed for 7 days (not less than 3), with duplicate morning and evening measurements after 5 mi- nutes of sitting at rest and 1 minute between measurements (total of at least 12 readings per week). These preparations have been suggested to be useful in the initial evaluation of untreated children with suspected hypertension, and for children with treated hypertension before each follow-up visit to the healthcare provider.365 The advantages of HBPM include the ability to obtain multiple BP measure- ments outside the of ce setting, its relative ease of use, and perhaps higher acceptance by patients and families. Similar to standardized of ce BP measurements and in contrast to ABPM, however, no prospective RCTs targeting HBPM to improve clinical outcomes are available in children. Reliable factors converting standardized of ce BP to home BP or ABPM are also not available in children. Additionally, clin- ical validation of newer, more automated BP devices in children is necessary. Quality of evidence. The quality of the evidence is low for the outcomes of annual GFR loss and ESKD, as the recom- mendation of a target of <50th percentile MAP by ABPM in children was based on a single RCT with study limitations (Supplementary Table S40142 ). The quality of the evidence for the mortality outcome was very low because of study limi- tations and very serious imprecision because death is a rare event in children. Nonetheless, multiple smaller interven- tional trials and observational studies with multiple mean- ingful outcomes for children have consistently shown bene ts of BP lowering.


Nonetheless, multiple smaller interven- tional trials and observational studies with multiple mean- ingful outcomes for children have consistently shown bene ts of BP lowering. For example, observational data from CKiD, published in abstract form, suggest that MAP targets at <90th percentile are bene cial for children with either glomerular or non-glomerular causes of CKD, and lower MAP at <50th percentile may have an additional bene t.366 Therefore, a range of MAP targets, including the 50th 90th percentile, may also be considered. Values and preferences. The Work Group judged that the prevention of kidney failure and progressive kidney function loss would be of high value to nearly all well-informed patients or caregivers. Published patient-reported outcome data from the SONG Kids study reported that children with kidney disease and caregivers rated kidney function as an important outcome, whereas BP control was also rated as an important outcome by caregivers.367 In the judgment of the Work Group, most patients would value these clinical bene ts despite the inconvenience and potential risk of harms associated with aggressive BP management (e.g., multiple medications, more-frequent dosing, possible adverse events if dehydrated, and the burden of monitoring with 24-hour ABPM). Patients for whom medication burden or the burden of ABPM monitoring are particularly important concerns may be more inclined not to follow this recommendation. Resource use and costs. In the judgment of the Work Group, the potential bene ts associated with ABPM outweigh the costs and inconvenience associated with its implementa- tion. Patients and families in areas where ABPM is unavailable or less affordable will be less inclined to follow this recom- mendation and may choose to use clinic-based auscultatory BP monitoring instead. Consideration for implementation.


Patients and families in areas where ABPM is unavailable or less affordable will be less inclined to follow this recom- mendation and may choose to use clinic-based auscultatory BP monitoring instead. Consideration for implementation. There are no data that suggest differences in bene cial effects of BP lowering be- tween males and females, or children of different ethnic backgrounds or races. However, compared to nonproteinuric kidney diseases, children with proteinuria may derive more clinical bene ts from intensive BP lowering.142 Implementation of ABPM for monitoring treatment of hypertension is challenging.368 Some children have dif culty wearing the monitors and completing the full 24 hours of measurements. Monitors are not always available when needed; they require time from a parent or other adult to return the monitor to the clinic and are expensive. With this in mind, there are certain situations in which there is a low probability of nding elevated BP by ABPM. For example, individuals with clinic BP at #25th percentile are unlikely to have elevated ABPM. Individual practitioners may, therefore, consider less-frequent ABPM monitoring if this level of clinic BP is achieved.360 There are additional challenges on how these guidelines apply to children who are too young to undergo ABPM or to children <120 centimeters in height, for whom no normative ABPM data exist. Additionally, for those on ACEi or ARB, it is important for families to understand how to monitor their children to prevent complications, such as dehydration, hy- potension, and AKI. Rationale The Work Group considered the balance between bene ts and harms, evidence quality, values and preferences, as well as resource utilization in making this recommendation.


Rationale The Work Group considered the balance between bene ts and harms, evidence quality, values and preferences, as well as resource utilization in making this recommendation. Primary evidence comes from the ESCAPE trial in which children with baseline CKD with eGFR 20 80 ml/min per 1.73 m2 hour average ambulatory MAP >95th percentile were ran- domized to <50th percentile versus 50th 90th percentile of MAP in the nomogram of healthy children. Both arms received ramipril. The primary composite endpoint of 50% chapter 5 www.kidney-international.org GFR decline and ESKD favored the intensive BP arm (HR: Existing guidelines from other organizations include the 2016 ESH guidelines for management of high BP in chil- dren and adolescents, which promote the use of ausculta- tory of ce measurements and BP targets in children with CKD of <75th percentile of normal children (and <50th percentile if proteinuric). This recommendation is based on a post hoc analysis from the ESCAPE study.142 Obser- vational data on standardized auscultatory of ce moni- toring in the CKiD cohort suggest achieved of ce SBP and DBP <90th percentile offers protection against kidney function decline, compared to of ce SBP and DBP >90th percentile in children with CKD, with potential additional bene t of even lower of ce BP levels in children with non- glomerular forms of CKD.369 Additionally, observational data illustrate that higher levels of proteinuria are most strongly associated with poor BP control and worsening BP Targeting BP control by ABPM in children with CKD is also recommended by the AAP. The AAP 2017 Pediatric Hyper- tension guideline recommends that children or adolescents with both CKD and hypertension should be treated to lower 24-hour MAP to <50th percentile of the distribution of BP of healthy children, as measured using ABPM.


The AAP 2017 Pediatric Hyper- tension guideline recommends that children or adolescents with both CKD and hypertension should be treated to lower 24-hour MAP to <50th percentile of the distribution of BP of healthy children, as measured using ABPM. They further recommend that, regardless of apparent control of BP ac- cording to of ce measurements, children and adolescents with CKD and a history of hypertension should have BP assessed by ABPM at least yearly. Additionally, this guideline recommends that children and adolescents with CKD, hypertension, and proteinuria should be treated with an ACEi or ARB, largely based on observational data.1 In the ESCAPE trial, children in both arms of the trial were given a xed-dose ACEi; therefore, the effect of ACEi per se could not be delineated. Key differences between the current and prior KDIGO recommendations in children with CKD include that the prior KDIGO guideline made a recommendation for the initiation of antihypertensive medication when the of ce SBP or DBP is consistently above the 90th percentile for age, sex, and height, whereas in the current guideline, all children with CKD and MAP consistently above the 50th percentile should be treated.


Key differences between the current and prior KDIGO recommendations in children with CKD include that the prior KDIGO guideline made a recommendation for the initiation of antihypertensive medication when the of ce SBP or DBP is consistently above the 90th percentile for age, sex, and height, whereas in the current guideline, all children with CKD and MAP consistently above the 50th percentile should be treated. The use of medications is included in this update only as a practice point, as direct trial evidence supporting their use does not exist, and the prior recommendation was based on limited indirect evidence, primarily data from CKiD that showed better BP control with use of ACEi or ARB.371 Compared to standard-of-care therapy, ACEi in children with CKD did not lower BP or protect against GFR decline, although it has been reported to have a bene cial effect on proteinuria and left ventricular hypertrophy in small Practice Point 5.1: We suggest monitoring BP once a year with ABPM, and monitoring every 3 6 months with stan- dardized auscultatory of ce BP in children with CKD. Practice Point 5.2: In children with high BP and CKD, when ABPM is not available, manual auscultatory of ce BP obtained in a protocol-driven standardized setting target- ing achieved SBP <90th percentile for age, sex, and height of normal children is a reasonable approach. Practice Point 5.3: Use ACEi or ARB as rst-line therapy for high BP in children with CKD. These drugs lower pro- teinuria and are usually well tolerated, but they carry the risk of hyperkalemia and have adverse fetal risks for pregnant women.


These drugs lower pro- teinuria and are usually well tolerated, but they carry the risk of hyperkalemia and have adverse fetal risks for pregnant women. (For Rationale of above practice points, please see text of Research recommendations  Develop normative reference values for ABPM in pediatric populations that include various races and ethnicities, as differences in normative values by race or ethnicity might inform appropriate targets for BP treatment in childhood CKD.  Identify the best BP measurement technique and setting to de ne hypertension and BP targets for pediatric CKD patients.  Ascertain when antihypertensive medications should be initiated.  Conduct RCTs that de ne targets for treatment when ABPM cannot be obtained repeatedly, for example, with home-based or of ce-based auscultatory or oscillometric BP, with kidney disease progression and CVD as outcomes. www.kidney-international.org chapter 5 Methods for guideline development Aim This is an update of the KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease (CKD) published in 2012.141 In September 2017, KDIGO held a Contro- versies Conference to determine whether there was suf cient new evidence to support updating any of the guideline recommendations. It was decided that a guideline update was required.374 The objective of this project was to update the evidence-based clinical practice guideline for the management of BP in patients with CKD. The guideline development methods are described below. Overview of the process This guideline adhered to international best practice for guideline development (Appendix B: Supplementary Tables S2 and S3).375,376 This guideline has been conducted and reported in accordance with the AGREE II reporting checklist.377 The processes under- taken for the development of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in CKD are described below.


Overview of the process This guideline adhered to international best practice for guideline development (Appendix B: Supplementary Tables S2 and S3).375,376 This guideline has been conducted and reported in accordance with the AGREE II reporting checklist.377 The processes under- taken for the development of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in CKD are described below.  Appointing Work Group members and the ERT  Finalizing guideline development methodology  De ning scope and topics of the guideline  Formulating clinical questions identifying the Population, Intervention, Comparator, Outcome, Methods (PICOM)  Selecting topics for systematic evidence review and linking to existing Cochrane Kidney and Transplant systematic reviews  Developing and implementing literature search strategies  Selecting studies according to prede ned inclusion criteria  Data extraction and critical appraisal of the literature  Evidence synthesis and meta-analysis  Grading the quality of the evidence for each outcome across studies  Grading the strength of the recommendation, based on the quality of the evidence, and other considerations  Finalizing guideline recommendations and supporting rationale  Public review in January 2020  Guideline update  Finalizing and publishing the guideline The development process was followed in the majority of the guideline chapters. Some chapters, in particular Chapter 3, required an iterative process, whereby the initial evidence review deliverables were revised to re ect issues raised during the Work Group meeting in January 2019. These additional reviews and clari cations were provided to the Work Group coauthors to ensure that the draft of the Chapter re ected available evidence. Commissioning of Work Group and ERT. The KDIGO Co- Chairs appointed the Work Group Co-Chairs, who then assembled the Work Group, to include content experts in adult and pediatric nephrology, blood pressure management, epidemiology, and public health.


The KDIGO Co- Chairs appointed the Work Group Co-Chairs, who then assembled the Work Group, to include content experts in adult and pediatric nephrology, blood pressure management, epidemiology, and public health. Cochrane Kidney and Transplant was contracted to conduct systematic evidence review and provide expertise in guideline development methodology. The ERT consisted of adult and pediatric nephrologists, and methodologists with expertise in evidence synthesis, and guideline development. The ERT coordinated the methodological and analytical processes of guideline development, including literature searching, data extraction, critical appraisal, evidence synthesis and meta-analysis, grading the quality of the evidence per outcome, and grading the quality of the evidence for the recommendations. The Work Group was responsible for writing the recommendations and underlying rationale, as well as grading the strength of the recommendation. The KDIGO Co-Chairs, KDIGO Methods Chair, Work Group Co-Chairs, and the ERT had a one-day meeting in Houston, Texas, USA in February 2018 to discuss the previous guideline and the ndings from the KDIGO Controversies Conference on Blood Pressure in Chronic Kidney Disease,374 and nalize the guideline development process. Guideline topics from the previous guideline and new guideline topics were linked with appropriate clinical questions to underpin the systematic evidence review. The draft guideline topics and review topics were nalized with feedback from the Work Group. De ning scope and topics and formulating key clinical questions. The guideline Work Group, with assistance from the ERT, determined the overall scope of the guideline. A preliminary list of topics and key clinical questions was informed by the pre- vious KDIGO guideline141 and the KDIGO Controversies Confer- ence on Blood Pressure in CKD.374 Logical frameworks were developed to present a visual representation of the clinical question and facilitate discussion about the scope of the guideline.


A preliminary list of topics and key clinical questions was informed by the pre- vious KDIGO guideline141 and the KDIGO Controversies Confer- ence on Blood Pressure in CKD.374 Logical frameworks were developed to present a visual representation of the clinical question and facilitate discussion about the scope of the guideline. The majority of clinical questions for this guideline were based upon RCTs to avoid bias by design. However, for questions of critical importance, systematic reviews of the general population were included. Clinical questions adhered to the PICOM format (a list of critical and important outcomes was compiled after voting from the Work Group [Table 1]). The Work Group and the ERT further re ned the clinical questions to nalize inclusion and exclusion criteria to guide literature searching and data extraction. Clinical questions were mapped to existing Cochrane Kidney and Trans- plant systematic reviews. These systematic reviews were updated accordingly. For clinical questions that did not map with any Cochrane Kidney and Transplant systematic reviews, de novo sys- tematic reviews were undertaken. The previous guideline was reviewed to ensure all identi ed studies were included in the evi- Details of the PICOM questions and associated Cochrane Kidney and Transplant systematic reviews are provided in Table 2. All evidence reviews were conducted in accordance to the Cochrane Handbook,383 and guideline development adhered to the standards of GRADE.384 Literature searches and article selection. Searches for RCTs utilized the Cochrane Kidney and Transplant Registry of studies. The Cochrane Kidney and Transplant Registry of studies is a database of RCTs in kidney disease that is maintained by information specialists.


The Cochrane Kidney and Transplant Registry of studies is a database of RCTs in kidney disease that is maintained by information specialists. The database is populated by monthly searches of the Cochrane Central Register of Controlled Trials, weekly searches of MEDLINE methods for guideline development www.kidney-international.org OVID, yearly searches of Embase OVID, hand-searching of major kidney and transplant conference proceedings, searches of trial registries, including clinicaltrials.gov and the International Clinical Trials Register search portal. The updated search examined the medical databases MEDLINE, Cochrane Central Registry of Controlled Trials, and Embase. For review topics that matched existing Cochrane Kidney and Transplant systematic reviews, an updated search for the review using the Cochrane Kidney and Transplant Registry of studies was conducted. The Cochrane Kidney and Transplant Registry of studies was searched for clinical questions that included only RCTs and were not linked to any existing Cochrane systematic review. For clinical questions that included other study types, such as systematic reviews on non-CKD populations, the medical literature databases MED- LINE and Embase were searched. The search strategies are provided in Appendix A: Supplementary Table S1. The titles and abstracts resulting from the searches were screened by 2 ERT members who independently assessed retrieved abstracts, and if necessary, the full text, to determine which studies satis ed the inclusion criteria. Disagreement about inclusion was resolved by discussion with a third member of the ERT. A total of 6863 citations were screened. Of these, 290 RCTs, 35 reviews, and 14 observational studies were included in the evidence review (Figure 8). Data extraction. Data extraction was performed independently by 2 members of the ERT. Unclear data were clari ed by contacting the author of the study report, and any relevant data obtained in this manner were included.


Unclear data were clari ed by contacting the author of the study report, and any relevant data obtained in this manner were included. The ERT designed data extraction forms to capture data on study design, study participant characteristics, intervention and comparator characteristics, and critical and important outcomes. Any differences in extraction between mem- bers of the ERT were resolved through discussion. A third reviewer was included if consensus could not be achieved. Critical appraisal of studies. The majority of reviews undertaken were intervention reviews that included RCTs. For these reviews, the Cochrane Risk of Bias tool was used to assess individual study limitations based on the following items383 :  Was there adequate sequence generation (selection bias)?  Was allocation adequately concealed (selection bias)?  Was knowledge of the allocated interventions adequately pre- vented during the study (detection bias)?  Participants and personnel (performance bias)  Outcome assessors (detection bias)  Were incomplete outcome data adequately addressed (attrition bias)?  Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?  Was the study apparently free of other problems that could put it at risk of bias? For some topics, for which there were no RCTs in the CKD population, the ERT conducted reviews of existing systematic re- views. AMSTAR 2 was used to critically appraise systematic re- For systematic reviews of diagnostic test accuracy studies, the QUADAS-2 tool was used to assess study limitations.386 All critical appraisal was conducted independently by 2 ERT members, with disagreements regarding the risk of bias adjudications resolved by consultation with a third review author. Evidence synthesis and meta-analysis. Measures of treatment effect.


AMSTAR 2 was used to critically appraise systematic re- For systematic reviews of diagnostic test accuracy studies, the QUADAS-2 tool was used to assess study limitations.386 All critical appraisal was conducted independently by 2 ERT members, with disagreements regarding the risk of bias adjudications resolved by consultation with a third review author. Evidence synthesis and meta-analysis. Measures of treatment effect. Dichotomous outcomes (all-cause mortality, CV mortality, kidney failure, CV events [MI, stroke, HF], dementia or cognitive impairment, doubling serum creatinine, AKI, falls, fatigue, body weight, and BP) results were expressed as RR with 95% CI. When continuous scales of measurement were used to assess the effects of treatment, such as body weight, the mean difference (MD) with 95% CI was used. Data synthesis. Data were pooled using the Mantel-Haenszel random-effects model for dichotomous outcomes, and the inverse variance random-effects model for continuous outcomes. The random-effects model was chosen because it provides a conservative estimate of effect in the presence of known and Assessment of heterogeneity. Heterogeneity was assessed by visual inspection of forest plots of standardized mean effect sizes and of risk ratios, and c2 tests. A P value of <0.05 was used to denote statistical heterogeneity, and an I2 was calculated to measure the proportion of total variation in the estimates of treatment effect that was due to heterogeneity beyond chance.384 We used conventions of interpre- tation as de ned by Higgins et al. (2003).387 Assessment of publication bias. We made every attempt to minimize publication bias by including unpublished studies (for example, by searching online trial registries). To assess publication bias, we used funnel plots of the log odds ratio (effect vs. standard error of the effect size) when a suf cient number of studies were Other reasons for the asymmetry of funnel plots were considered.