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Blood pressure targets in CKD 2021: the never-ending guidelines debacle

ABSTRACT In 2021, two updated clinical guidelines were published, providing guidance on blood pressure (BP) targets for people with chronic kidney disease (CKD). Kidney Disease: Improving Global Outcomes (KDIGO) updated its 2012 Clinical Practice Guideline for the Management of BP in CKD. Different systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets for CKD (<130/80 and <140/90 mmHg, respectively, for people with a urinary albumin: creatinine ratio >30 mg/g or without pathological albuminuria) were replaced by a single number: an SBP target of <120 mmHg is suggested, when tolerated. This represents a major decrease in the SBP target and the abandonment of DBP targets. The European Society of Cardiology (ESC) also published a 2021 Clinical Guideline on Cardiovascular Disease Prevention in Clinical Practice that updates a prior 2016 guideline on prevention and the 2018 ESC/European Society of Hypertension Clinical Practice Guidelines for the Management of Arterial Hypertension. The 2021 ESC guideline was endorsed by 12 European scientific societies. The recommended office BP targets for people with CKD are <140–130 mmHg SBP (lower SBP is acceptable if tolerated) and <80 mmHg DBP. The question is: What should the practicing physician do now: treat hypertension in people with CKD to an SBP target of <120 mmHg or to a target of <140–130 mmHg? Major guideline bodies are aware of the activities of other major players. There is an urgent need for guideline bodies to establish communication channels, search consensus on major issues that impact the health of hundreds of millions of people worldwide and end individualism in guidelines generation.

in the next decades. However, major guideline bodies do not agree on BP targets for CKD [6,7]. Thus a situation that in 2019 was termed chaotic in the pages of CKJ will persist into the new decade [8]. While there might be justification for guidelines generated at different points in time examining different evidence to suggest/recommend different BP targets, there is little justification for two guidelines published over the span of 5 months using exactly the same evidence to provide highly divergent recommendations.
In 2021, two major guidelines updated prior (dating from 2012 and 2018, respectively) recommendations for BP targets for people with CKD: the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease [6] and the European Society of Cardiology (ESC) 2021 Clinical Guideline on Cardiovascular Disease Prevention in Clinical Practice [7]. Both new guidelines provide a simplified message that will favour uptake and implementation. Unfortunately, the suggested/recommended systolic blood pressure (SBP) targets were off by up to 20 mmHg. This creates confusion and will hinder implementation. There is an urgent need to reach consensus on such basic issues as the BP targets for hundreds of millions of people with CKD.

FROM KDIGO 2012 TO KDIGO 2021 CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF BLOOD PRESSURE IN CKD
The 2012 KDIGO guideline had a relatively complex set of BP targets based on the presence or absence of diabetes or pathological albuminuria [i.e. urinary albumin: creatinine ratio (UACR) > 30 mg/g] for adults with CKD not on dialysis (Fig. 1A) [9]: • Recommendation: non-diabetic, UACR <30 mg/g; office SBP target ≤140 mmHg, DBP ≤90 mmHg (1B).
That is, for KDIGO 2012, a BP of 140/90 mmHg was adequate for patients with non-diabetic, normoalbuminuric CKD. There was no recommendation for patients on dialysis, while transplant patients had the same target as patients with pathological albuminuria [9].
The 2021 KDIGO guideline has a simpler message: 'We suggest that adults with high BP and CKD be treated with a target SBP of <120 mmHg, when tolerated, using standardized office BP measurement (2B)' (Fig. 1B) [6]. Additionally, it provides guidance on how to measure office BP ( Table 1). The suggestion is based on the Systolic Blood Pressure Intervention Trial (SPRINT) [10]. SPRINT randomly assigned participants to an SBP target of <120 mmHg or <140 mmHg. Patients with an estimated glomerular filtration rate <20 mL/min/1.73 m 2 , 24-h urine protein excretion >1 g, on dialysis or kidney transplant recipients were excluded. In the subgroup of patients with CKD, the achieved BP at 1 year was 123.3 ± 0.4/66.9 ± 0.3 mmHg versus 136.9 ± 0.4/73.8 ± 0.3 mmHg [11]. In patients with CKD, after a median follow-up of 3.3 years, the hazard ratio for the primary composite cardiovascular outcome was 0.81 [95% confidence interval (CI) 0.63-1.05] and for all-cause death it was 0.72 (95% CI 0.53-0.99), but patients with an SBP target of <120 mmHg lost GFR at a 47% faster rate (-0.47 versus -0.32 mL/min/1.73 m 2 /year; P < 0.03). SPRINT measured BP in a standardized manner (Table 1). However, in SPRINT, there were four different groups of patients with regard to the presence of the doctor or study personnel during rest or during the actual BP readings (attended versus unattended BP) [12], a factor that can directly influence the levels of measured BP [13]. These four groups displayed no homogeneity with regard to the primary study outcome, a fact that makes the interpretation of the SPRINT results quite difficult.  [12], a factor that can directly influence the levels of measured BP [13]. These four groups displayed no homogeneity with regard to the primary study outcome, a fact that makes interpretation of the SPRINT results quite difficult. Patients with eGFR <20 mL/min/1.73 m 2 , 24-h urine protein excretion >1 g, on dialysis or kidney transplant recipients were excluded from SPRINT.  Table 2).
The 2018 ESC/ESH guidelines contained a complex set of suggestions to determine whether to start therapy for hypertension, based on age [13]. Thus patients with CKD >80 years of age would not start pharmacological therapy for hypertension until their SBP was ≥160 mmHg or DBP ≥90 mmHg. In contrast, in younger patients, the threshold to start therapy was 140/90 mmHg. However, once therapy was started, the target was the same for adult CKD patients of all ages: 130-139 mmHg SBP and 70-79 mmHg DBP (Fig. 1A). The CKD target was higher than that for younger (18−65 years) people in the general population or for diabetics, in whom the target was 120-129 mmHg SBP, with a remark that it should not be <120 mmHg. This discrepancy in the target BP for patients with CKD versus those with diabetes or individuals from the general population was not supported by any kind of observational or clinical trial evidence. ESC 2021 decreases differential SBP thresholds at which to initiate therapy based on age but still recommends a higher SBP target (130-139 mmHg) in adults with CKD of any age (Fig. 1B) than in younger people in the general population or in diabetics (120-130 mmHg if <70 years of age and 130-139 mmHg for those ≥70 years of age) [7]. A more subtle change to the 2018 document deemed a lower SBP acceptable in CKD, if tolerated. Additionally, the DBP target is universally <80 mmHg for all treated patients, independent of any associated comorbidity. The proposed BP assessment method is similar to that proposed by KDIGO 2021 (Table 1), ruling out that methodological differences explain the different BP targets.
ESC 2021 does not provide the rationale for target BP values in people with CKD and does not mention the SPRINT subanalysis of participants with CKD or the 2021 KDIGO guideline on BP and CKD, although it does cite other KDIGO guidelines on lipids and diabetes, one of which was accessed in June 2021 [7]. However, it does explain changes from the prior 2016 ESC prevention and 2018 ESC/ESH hypertension guidelines in the cut-off for identifying who is 'older' (from 65 to 70 years for reasons of consistency with other parts of the current guidelines), in BP targets for the elderly (based on the SPRINT subanalysis of people ≥75 years of age and others) and the rationale for BP targets for people with lower extremity artery disease [13][14][15].

FUTURE DIRECTIONS
In conclusion, it is highly disappointing that two reference guideline bodies drastically disagree, without a detailed rationale, on guidance on such basic and universal items as BP targets for the 850 million people with CKD (Box 1) [16][17][18]. Strong bidirectional and/or multidirectional communication channels should be established between guideline bodies to prevent the future occurrence of such blatant discrepancies. The individualism that has presided over guidelines generation should become a thing of the past. In a worst-case scenario, guideline bodies should agree to disagree in a common document in which each guideline body explains the rationale for their choice of BP targets that may result from assigning different weights to different aspects of the evidence or impact that may range from emphasizing safety or efficacy, cost or implementation aspects, among others. These considerations should be clearly stated in the common document, helping national scientific societies, healthcare providers and payers and individual physicians to draw their own conclusions. Otherwise, we run the risk of compromising implementation, given the doubts raised by such different targets, and providing ammunition for guidelines and science skeptics. In a best-case scenario, consensus is reached on a single BP target. This may be facilitated by a body of experts in the field of hypertension in CKD representing and shared by different societies (Fig. 2). • Not really. Standardized office BP measurement is the recommended method for evaluating BP in both (Table 1).

Box 1. Key questions and answers
Does the most recent guideline (ESC 2021) acknowledge the guidelines published earlier in the same year (KDIGO) and discuss why they do not agree on the same BP targets?
Does the European guideline offer some explanation as to why the BP targets recommended by European scientific societies should differ from those suggested for the global population of people with CKD by KDIGO?
• No. In the 2021 ESC guidelines, there is no discussion on the evidence for BP targets in CKD.

FIGURE 2:
Proposal to limit the disagreement between clinical practice guidelines on BP targets for people with CKD. A shared group of experts who have an expertise in both hypertension and in CKD may represent the different societies/guideline bodies. These experts would be identified and selected based on internal rules by each guideline body and may undergo turnover as per these rules. The rules of engagement of this committee of experts may be decided in the future, e.g. whether consensus would be needed between all experts for a specific guideline from a single guideline body, but at least the integrated discussion between experts representing different guideline bodies would contribute to reach consensus between guidelines that limits the most egregious disagreements, or at least, to provide a rationale for choosing certain BP targets and not others.