KDIGO guidelines for the management of blood pressure in chronic kidney disease: A sprint to the curve

Published:September 29, 2021DOI:https://doi.org/10.1016/j.ejim.2021.09.014

      Highlights

      • New KDIGO Guidelines recommend straight blood pressure control in renal disease.
      • Available evidence shows a J Curve effect of blood pressure control on morbimortality in kidney disease patients.
      • Intensive blood pressure control should be avoided in most chronic kidney disease patients.

      Keywords

      The KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease has been recently released [
      Kidney disease: improving global outcomes (KDIGO) Blood Pressure Work Group. KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease.
      ]. The guidelines suggest (but do not recommend) that adults with high blood pressure and chronic kidney disease (CKD) be treated with a target systolic blood pressure (SBP) of <120 mm Hg, when tolerated, using standardized office blood pressure measurement. Moreover, the guidelines state that clinicians can reasonably offer less intensive antihypertensive treatment in patients with very limited life expectancy or symptomatic postural hypotension. No recommendations on diastolic blood pressure levels are given.
      These recommendations resemble those of the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults [
      • Whelton PK
      • Carey RM
      • Aronow WS
      • Casey Jr, DE
      • Collins KJ
      • Dennison Himmelfarb C
      • et al.
      ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
      ], which were mostly based on the results of the Systolic Blood Pressure Intervention Trial (SPRINT) [
      • Wright Jr, JT
      • Williamson JD
      • Whelton PK
      • Snyder JK
      • Sink KM
      • Rocco MV
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      ]. These treatment thresholds are different from those stated in the 2018 European Society of Cardiology and the European Society of Hypertension Guidelines for the management of arterial hypertension [

      Williams B, Mancia G, Spiering W, et al.; Authors/Task Force Members. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36(10):1953-2041.

      ]: “current evidence suggests that in patients with CKD, BP should be lowered to <140/90 mmHg and towards 130/80 mmHg”. They recommended to lower SBP to a range of 130–139 mmHg, but never below 130 mmHg.
      The evidence reviewed with respect to BP targets in patients with CKD was small. They included one meta-analysis in patients with non-diabetic CKD showing that the slowest progression on CKD was obtained with a treated SBP in the range of 110 - 119 mmHg in patients with albuminuria >1 g/day. However, in the same meta-analysis, in patients with a proteinuria <1 g/day, the lowest risk of developing CKD (not CV risk) was obtained with an SBP of <140 mmHg [
      • Jafar TH
      • Stark PC
      • Schmid CH
      • Landa M
      • Maschio G
      • de Jong PE
      AIPRD Study Group
      Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensinconverting enzyme inhibition: a patient-level meta-analysis.
      ]. Another systematic review failed to demonstrate that a BP target of <130/80 mmHg improves clinical outcomes more than a target of <140/90 mmHg in non-diabetic CKD [
      • Upadhyay A
      • Earley A
      • Haynes SM
      • Uhlig K.
      Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier.
      ]. Contrariwise, in a large retrospective cohort containing 398 419 treated hypertensive patients (30% with diabetes), the nadir SBP and DBP for the lowest risk of end-stage renal disease and mortality were 137 and 71 mmHg, respectively, with a clear increase in mortality risk at SBP <120 mmHg [
      • Sim JJ
      • Shi J
      • Kovesdy CP
      • Kalantar-Zadeh K
      • Jacobsen SJ.
      Impact of achieved blood pressures on mortality risk and end-stage renal disease among a large, diverse hypertension population.
      ].
      The J curve phenomenon was originally described for diastolic BP by Stewart [
      • Stewart IM.
      Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension.
      ] in a group of hypertensive patients treated and followed for 6.25 years. At the end of the study, the incidence of myocardial infarction was five times higher in the patients with achieved diastolic BP under 90 mm Hg. This phenomenon, although still controversial, has been repeatedly described in the medical literature. An inverse relationship between diastolic pressure and adverse cardiac ischemic events (i.e., the lower the diastolic pressure the greater the risk of coronary heart disease and adverse outcomes) has been observed in numerous studies. This effect is more pronounced in patients with underlying Coronary Artery Disease (CAD) [
      • Panjrath GS
      • Chaudhari S
      • Messerli FH.
      The j-point phenomenon in aggressive therapy of hypertension: new insights.
      ]. In this regard, Böhm et al. have reported a late follow-up (median 56 months) of diabetic patients with (N = 11 487) or without diabetes (N = 19 450 enrolled in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Low BP levels (<120 or <70 mmHg) were associated with increased cardiovascular outcomes (except stroke) and death [
      • Böhm M
      • Schumacher H
      • Teo KK
      • Lonn EM
      • Mahfoud F
      • Mann JFE
      • et al.
      Cardiovascular outcomes and achieved blood pressure in patients with and without diabetes at high cardiovascular risk.
      ].
      It has been published in large reviews on the presence of J curve in patients with chronic kidney disease. Viazzi et al. [
      • Viazzi F
      • Leoncini G
      • Grassi G
      • Pontremoli R.
      Antihypertensive treatment and renal protection: is there a J-curve relationship?.
      ] identified 23 studies that had examined J curve in CKD patients. Together, large trials and real-life cohort studies indicated that below a definite BP value renal protection seems to plateau and too low levels may even be associated with a paradoxical increase in renal morbidity. Existing evidence supports a systolic target around 130 mmHg to combine both renal and CV protection and possibly lower levels in the presence of overt proteinuria. Lower BP levels may not be associated with further renal protection and possibly entail greater risk especially in patients without albuminuria. In the same way, Robles et al. [
      • Robles NR
      • Hernandez-Gallego R
      • Fici F
      • Grassi G.
      Does a blood pressure J curve exist for patients with chronic kidney disease?.
      ] examined 10 studies about blood pressure control and cardiovascular outcomes in patients with chronic kidney disease (two of them including more than 600.000 patients) that found an increase of cardiovascular mortality when SBP was below 130 mmHg. They also detected nine studies on blood pressure control and renal events in patients with CKD (including the SPRINT study) that demonstrate that a SBP <120 mmHg was deleterious and increased CKD progression. They concluded that there is no evidence that a lower BP target (<130/70 mmHg) could improve renal outcomes. Even more, the straight control of BP may induce an unintended reduction of renal function and this decrease, in turn, may increase cardiovascular risk.
      In this regard, the results of the SPRINT trial need to be discussed. [
      • Wright Jr, JT
      • Williamson JD
      • Whelton PK
      • Snyder JK
      • Sink KM
      • Rocco MV
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      ] In the randomized controlled open-label SPRINT trial 9,361 hypertensive patients (mean age: 67.9 years) were randomized to a standard treatment group with target SBP of <140 mmHg and an intensive treatment group with target SBP of <120 mmHg. Eligible patients had an increased risk of cardiovascular events, defined by one or more of the following: clinical or subclinical cardiovascular disease other than stroke; chronic kidney disease; a 10-year risk of cardiovascular disease of ≥15% based on the Framingham risk score; or age ≥75 years. Exclusion criteria included: diabetes, prior stroke, heart failure within the past six months or left ventricular ejection fraction <35%, and dementia. Systolic blood pressure throughout the 3.26 years of follow-up averaged 134.6 mmHg in the standard treatment group and 121.5 mmHg in the intensive treatment group. In the intensive treatment group death from any cause was reduced by 27%, cardiovascular death by 43% and heart failure by 38%; but the incidence of myocardial infarction, acute coronary syndrome or stroke was not different between the two treatment groups. Serious adverse events occurred in 4.7% in the intensive treatment group and in 2.5% in the standard treatment group.
      The methods, results and conclusions of the SPRINT trial have been largely discussed; therefore, we will focus on the renal aspects of this study. The incidence of kidney injury or failure (defined as ≥ 30% reduction in estimated GFR to <60 ml/min/1.73 m2) was higher in the intensive-treatment group (3.8%) than in the standard-treatment (1.1%) group without benefits in terms of avoiding CKD progression or albuminuria reduction [
      • Wright Jr, JT
      • Williamson JD
      • Whelton PK
      • Snyder JK
      • Sink KM
      • Rocco MV
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      ]. The specified subgroup analyses of outcomes in participants with baseline CKD in the SPRINT have been reported in a separate paper. Treatment effects did not differ between participants with and without CKD. The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants. After the initial 6 months, the intensive group had a 50% higher rate of decrease in eGFR (-0.47 versus -0.32 ml/min per 1.73 m2 per year, P = 0.003). The incidence of albuminuria was not significantly different between the randomized groups. Patients who received intensive treatment have a significant greater incidence of acute kidney injury and potassium disturbances, which could be related to the high dose of chlortalidone use in most of patients [
      • Cheung AK
      • Rahman M
      • Reboussin DM
      • Craven TE
      • Greene T
      • Kimmel PL
      • et al.
      SPRINT Research Group. Effects of intensive BP control in CKD.
      ]. It is important to consider the method of blood pressure measurement in the SPRINT trial. Blood pressure was defined as the average of three blood pressure measurements at each office visit with the use of a validated automatic measurement system. Some studies have shown that unattended automated office blood pressure is up to 20 mmHg lower than conventionally measured office blood pressure. Therefore, blood pressures taken in SPRINT cannot be directly compared with blood pressures in other trials [
      • Agabiti Rosei E.
      Target blood pressure for treatment: should current recommendations be changed?.
      ].
      Regarding the J curve phenomenon, a post hoc analysis focused on various subgroups of patients with different baseline systolic blood pressures and cardiovascular risks. The results suggest that those with very high baseline systolic blood pressure but otherwise at low cardiovascular risk appear to have a worse outcome with intensive blood-pressure lowering than with standard treatment. In the group with a baseline systolic pressure of ≥160 mmHg and a lower 10-year Framingham risk score (≤31.3%, median), intensive treatment resulted in an approximate threefold increased risk of death from any cause. In this subgroup of patients, there was no benefit on the primary outcome of intensive blood-pressure lowering. But there were two- to threefold increases in non-cardiovascular death, and in all-cause death [
      • Wang TD
      • et al.
      Increased all-cause mortality with intensive blood-pressure control in patients with a baseline systolic blood pressure of >160 mmHg and a Lower Framingham risk score: a cautionary note from SPRINT.
      ]. This point is particularly interesting. In another post hoc analysis of SPRINT, the participants were categorized by baseline SBP status, defined as high-SBP (≥ 140 mmHg) group versus the low-SBP (< 140 mmHg) group. Among participants with CKD, there were no significant differences of intensive blood pressure treatment in long-term dialysis and albuminuria between the low-SBP and high-SBP groups. Intensive treatment was associated with a higher incidence of adverse events, including acute kidney injury, hypotension, syncope, and bradycardia. The benefits of intensive SBP were only evident among those with SBP < 140 mmHg at baseline. For participants with higher baseline SBP, intensive treatment showed no improvement in clinical outcomes. The conclusion of the authors is that a lower targeted SBP may not be applicable to patients with considerably higher baseline SBP in SPRINT [
      • Sun X
      • Guo Y
      • Nie Z
      • Cheng J
      • Zhou H
      • Zhong X
      • et al.
      Influence of baseline systolic blood pressure on the relationship between intensive blood pressure control and cardiovascular outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT).
      ].
      A recent report analyzed outcome data of patients at high cardiovascular risk who were randomized to intensive or standard blood pressure control and achieved treated systolic blood pressure of less than 130 mm Hg in the Systolic Blood Pressure Intervention Trial (SPRINT) and Action to Control Cardiovascular Risk in Diabetes–Blood Pressure (ACCORD-BP) trial. A total of 7515 patients (4793 from SPRINT and 3722 from ACCORD-BP) were included in this analysis. The nominally lowest risk was observed at a diastolic blood pressure between 70 and 80 mmHg (and a treated systolic blood pressure less than 130 mmHg) for the primary outcome, the composite cardiovascular outcome, nonfatal myocardial infarction, and cardiovascular death. A mean diastolic blood pressure of less than 60 mmHg was associated with significantly increased risk of the primary outcome (a composite of all-cause death, nonfatal myocardial infarction, and nonfatal stroke), the composite cardiovascular outcome, nonfatal myocardial infarction, and nonfatal stroke [
      • Li J
      • Somers VK
      • Gao X
      • Chen Z
      • Ju J
      • Lin Q
      • et al.
      Evaluation of optimal diastolic blood pressure range among adults with treated systolic blood pressure less than 130 mm Hg.
      ]. Therefore, these results directly support the recommendations of the European Guidelines and show again the risk of increased cardiovascular morbimortality after blood pressure intensive treatment. It could be suggested that, in the lowest SBP cohort, the low baseline blood pressure can be a marker of a more severe illness profile. Nevertheless, the authors attempted to limit the risk of residual confounding by controlling for multiple comorbid illnesses in the adjusted Cox model.
      New recommendations provided by the KDIGO Guidelines on the management of blood pressure in CKD seem to not have well balanced the current evidence on the risk of increasing cardiovascular morbimortality in patients with renal disease. Criticism will not change a released guide, even when solidly grounded on scientific evidence; but clinicians should be aware of all available knowledge to make their own opinion. Particularly, in patients with very high SBP any attempt to sharply reduce BP should be avoided.

      Declaration of Competing Interest

      The authors declare no conflicts of interest.

      References

      1. Kidney disease: improving global outcomes (KDIGO) Blood Pressure Work Group. KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease.
        Kidney Int. 2021; 99: S1-S87
        • Whelton PK
        • Carey RM
        • Aronow WS
        • Casey Jr, DE
        • Collins KJ
        • Dennison Himmelfarb C
        • et al.
        ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
        J Am Coll Cardiol. 2017; 71 (2018 May 15): e127-e248https://doi.org/10.1016/j.jacc.2017.11.006
        • Wright Jr, JT
        • Williamson JD
        • Whelton PK
        • Snyder JK
        • Sink KM
        • Rocco MV
        • SPRINT Research Group
        A randomized trial of intensive versus standard blood-pressure control.
        N Engl J Med. 2015; 373: 2103-2116
      2. Williams B, Mancia G, Spiering W, et al.; Authors/Task Force Members. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36(10):1953-2041.

        • Jafar TH
        • Stark PC
        • Schmid CH
        • Landa M
        • Maschio G
        • de Jong PE
        • AIPRD Study Group
        Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensinconverting enzyme inhibition: a patient-level meta-analysis.
        Ann Intern Med. 2003; 139: 244-252
        • Upadhyay A
        • Earley A
        • Haynes SM
        • Uhlig K.
        Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier.
        Ann Intern Med. 2011; 154: 541-548
        • Sim JJ
        • Shi J
        • Kovesdy CP
        • Kalantar-Zadeh K
        • Jacobsen SJ.
        Impact of achieved blood pressures on mortality risk and end-stage renal disease among a large, diverse hypertension population.
        J Am Coll Cardiol. 2014; 64: 588-597
        • Stewart IM.
        Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension.
        Lancet. 1979; 1: 861-865
        • Panjrath GS
        • Chaudhari S
        • Messerli FH.
        The j-point phenomenon in aggressive therapy of hypertension: new insights.
        Curr Atheroscler Rep. 2012; 14: 124-129
        • Böhm M
        • Schumacher H
        • Teo KK
        • Lonn EM
        • Mahfoud F
        • Mann JFE
        • et al.
        Cardiovascular outcomes and achieved blood pressure in patients with and without diabetes at high cardiovascular risk.
        Eur Heart J. 2019; 40: 2032-2043
        • Viazzi F
        • Leoncini G
        • Grassi G
        • Pontremoli R.
        Antihypertensive treatment and renal protection: is there a J-curve relationship?.
        J Clin Hypertens (Greenwich). 2018; 20: 1560-1574
        • Robles NR
        • Hernandez-Gallego R
        • Fici F
        • Grassi G.
        Does a blood pressure J curve exist for patients with chronic kidney disease?.
        J Clin Hypertens (Greenwich). 2017; 19: 764-770
        • Cheung AK
        • Rahman M
        • Reboussin DM
        • Craven TE
        • Greene T
        • Kimmel PL
        • et al.
        SPRINT Research Group. Effects of intensive BP control in CKD.
        J Am Soc Nephrol. 2017; 28: 2812-2823
        • Agabiti Rosei E.
        Target blood pressure for treatment: should current recommendations be changed?.
        Hypertension. 2016; 68 (Aug): 263-265
        • Wang TD
        • et al.
        Increased all-cause mortality with intensive blood-pressure control in patients with a baseline systolic blood pressure of >160 mmHg and a Lower Framingham risk score: a cautionary note from SPRINT.
        in: European Society of Cardiology 2017 Congress. 2017 (August 28Barcelona, Spain. Abstract 3828)
        • Sun X
        • Guo Y
        • Nie Z
        • Cheng J
        • Zhou H
        • Zhong X
        • et al.
        Influence of baseline systolic blood pressure on the relationship between intensive blood pressure control and cardiovascular outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT).
        Clin Res Cardiol. 2019; 108: 273-281
        • Li J
        • Somers VK
        • Gao X
        • Chen Z
        • Ju J
        • Lin Q
        • et al.
        Evaluation of optimal diastolic blood pressure range among adults with treated systolic blood pressure less than 130 mm Hg.
        JAMA Netw Open. 2021; 4 (Feb 1PMID: 33595663; PMCID: PMC7890449)e2037554https://doi.org/10.1001/jamanetworkopen.2020.37554