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Blood Pressure Targets in Chronic Kidney Disease: An Update on the

Evidence
Dominique Guerrot; Jelmer K. Humalda

Curr Opin Nephrol Hypertens. 2020;29(3):327-332.

Abstract and Introduction

Abstract

Purpose of review: Hypertension is the leading modifiable cause of cardiovascular events and of mortality and is generally
considered as a direct cause of chronic kidney disease. Defining optimal blood pressure targets in patients with chronic kidney
disease is therefore of critical importance.

Recent findings: Over the recent years, results and post-hoc analyses of several important trials comparing blood pressure
targets which included patients with chronic kidney disease have been published. Although these results provide important means
to understand the consequences of high blood pressure and to improve the management of hypertension in chronic kidney
disease, they led to remarkably different interpretations and recommendations in the current guidelines.

Summary: The present review summarizes the current evidence and areas of controversy for the definition of blood pressure
targets in patients with chronic kidney disease.

Introduction

Hypertension is the leading modifiable risk factor for mortality in developed countries.[1] In patients with chronic kidney disease
(CKD), the prevalence of hypertension increases with the progression of kidney disease and is close to 90% in stage 5 CKD.[2,3]
Hypertension contributes significantly to the excess cardiovascular mortality of the CKD population and its management is an
everyday concern for the nephrologist. Although there is a clear epidemiological link between blood pressure (BP) level and
cardiovascular morbidity and mortality,[4] the BP target under treatment in hypertensive patients, including in CKD patients,
remains highly debated. The present review aims to synthesize current evidence on BP control in patients with nondialysis
nontransplanted CKD, by integrating the results of the major randomized controlled trials (RCT) and meta-analyses recently
published.

Evidence for Blood Pressure Targets to Reduce Cardiovascular Disease and Mortality in Patients
With Chronic Kidney Disease

Hypertension and kidney disease are closely linked. Regardless of the type of nephropathy, the pathophysiology of hypertension
in CKD is multifactorial and can involve excessive fluid retention, progressive arterial stiffness, activation of the sympathetic and
renal-angiotensin-aldosterone nervous systems, and disruption of circadian rhythms. On average 86% of patients with CKD have
hypertension, compared to 29% of the general population,[3,5,6] and the more the GFR decreases, the more the prevalence of
hypertension increases.[2] Multiple studies have demonstrated that hypertension is a major cause of cardiovascular mortality and
morbidity in CKD.[7–9] The management of hypertension is particularly challenging in patients with CKD and frequently requires a
combination of several drug classes and nonpharmacological interventions.[8]

In spite of the assumed benefit of BP control in CKD, interventional studies evaluating different BP targets are scarce in this
specific population. In a study of 400 000 patients treated for hypertension, compared to the group reaching a target SBP of 130
to 140 mmHg, patients between 120 and 130 mmHg experienced more dialysis and death.[10] The J-curve described in the
general population has been demonstrated in CKD as well. A large observational study conducted in 651 000 patients with CKD
(mean eGFR 50.5 mL/min/1.73m2) showed such an association between mortality and systolic and diastolic BP, with excess
mortality for DBP less than 70 mm Hg, regardless of the value of SBP (except for SBP > 180 mmHg). All-cause mortality was
highest in the CKD group with SBP more than 160 mmHg and was lowest in the group of patients with BP of 130–149/70–89
mmHg.[11] Similarly, a post-hoc analysis of the IDNT study performed in 1590 patients with diabetic nephropathy demonstrated an
increased risk of cardiovascular mortality, all-cause mortality and heart failure in association with SBP less than 120 mmHg and
DBP less than 85 mmHg under treatment.[12]

Findings From the SPRINT Trial

The main RCTs including patients with CKD are summarized in Figure 1. To date, the RCT designed to compare BP targets which
included the largest number patients with CKD is the SPRINT trial.[13] In SPRINT, 9361 patients without diabetes with an
increased cardiovascular risk were assigned to intensive BP control or standard treatment, aiming at SBP less than 120 and less

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than 140 mmHg, respectively. The trial's data safety monitoring board halted the trial after 3.26 years of the intended 5 years
follow-up because of clear benefit in the intensive-treatment arm, that reached a SBP of 121.4 mmHg achieved with on average
one additional antihypertensive drug. The intensive-treatment arm demonstrated a 25% lower risk of the composite outcome
myocardial infarction, acute coronary syndrome, stroke, acute decompensate heart failure, or cardiovascular death (hazard ratio
[HR] = 0.75; confidence interval [CI], 0.64–0.89, P < 0.001). This was mainly driven by heart failure (HR = 0.62; CI, 0.45–0.84)
and cardiovascular death. The HR for death of all causes was 0.73 (CI, 0.60–0.90, P = 0.003). A post-hoc analysis by Obi et al.
reported that intensive-treatment in participants with eGFR less than 45 ml/min/1.73 m2 did not improve the composite outcome
(HR = 0.92; CI 0.62–1.38). Actually, in SPRINT 28.2% of the participants had a baseline MDRD eGFR between 20 and 60
ml/min/1.73 m2. Cheung et al.[14,15] found that in this subgroup of patients with CKD, intensive-treatment lowered the risk of death
by 28% (HR = 0.72; CI, 0.53–0.99). Heart failure (41 vs. 52 events) and cardiovascular death (18 vs. 30 events) had the largest
difference in incidence between treatment groups, nevertheless the composite outcome did not reach significance (HR = 0.81; CI
0.63–1.05).[15] Kjeldsen et al.[16] expressed concern that increase use of diuretics and thus inadvertent treatment of heart failure
in the intensive-treatment group may have driven these results. They also pointed that SPRINT was a methodological exception
among hypertension RCTs, because BP was evaluated by automated BP measurement which yields significantly lower values
compared with manual office BP measurement.[17] This is a major point, which partly explains different interpretations and hence
different guidelines regarding BP targets, both in the general and the CKD populations following the publication of SPRINT.[18]
Moreover, SPRINT excluded patients with diabetes (and thus diabetic nephropathy) and proteinuria more than 1 g/day, polycystic
kidney disease and glomerulonephritis (about to be) treated with immunosuppressive therapy, limiting generalization to a
nephrology outpatient clinic. Of particular importance, whether the benefits observed in SPRINT apply to patients with stage four
to five CKD or albuminuria more than 1 g/g is unclear.

Figure 1.

Cardiovascular and renal outcomes of the major randomized controlled trials (RCTs) comparing blood pressure (BP) targets and
including patients with chronic kidney disease (CKD).

Findings From Other Blood Pressure Trials in Chronic Kidney Disease

Strolling away from SPRINT, a recent analysis of the AASK and MDRD trials by Ku et al. described that strict BP control was
mainly associated with lower risk of death in the eGFR below 30 ml/min/1.73 m2 subgroup.[19] The 19-year follow-up of the
MDRD study shows a long-term benefit on the risk of death from any cause, whether the patients are on dialysis or not.[20] BP
targets were defined as mean arterial pressure (MAP) less than 92 mmHg in AASK. In addition, targets varied in MDRD by age,
translating to targets of less than 125/75 mmHg in patients less than 61 years old or less than 135/80 mmHg in patients more than
61 years in intensive-treatment, versus 140/90 or 160/90 in normal control.

Notwithstanding the aforementioned uncertainty what BP should be targeted to limit cardiovascular disease in CKD, recent
publications offer valuable information on how to achieve these targets, that's is how to interpret creatinine rise or orthostatic
hypotension during treatment, how to deliver optimal treatment without increasing drugs by timing or dietary interventions. A
reduction in GFR may occur acutely after intensification or initiation of antihypertensive therapy. In the combined AASK/MDRD
dataset, Ku et al. found that a reduction in eGFR of 5–20% in the first 4 months of intensive-treatment was actually associated
with less death (HR = 0.77; CI, 0.62–0.96) in adjusted analysis compared to the usual treatment group with less than 5%
reduction. This mirrors findings in other CKD trials were acute drops after treatment intensification are associated with favorable
outcome in the long term, for example ACEi or SGLT2i.[21,22] A separate analysis of the AASK found that pursuing the intensive-
treatment BP goal did not result in more orthostatic hypotension compared to standard treatment,[23] in line with earlier findings in

[24] [13]
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patients with diabetes in ACCORD[24] and SPRINT.[13] Orthostatic hypotension itself was associated with cardiovascular disease
and all-cause mortality, and more prevalent when β blockade instead of ACEi was used.

Findings From Nonpharmacological Intervention Studies

A nonpharmaceutical intervention, changing timing instead of increasing pill count, may offer benefits as suggested by the Hygia
Chronotherapy Trial. Indeed, Hermida et al. reported that in 19 084 hypertensive patients (diagnosed with ambulatory BP
monitoring, ABPM) randomized to take their BP lowering medications at bedtime or after awakening, bedtime-treatment resulted a
45% lower risk (HR = 0.55; CI, 0.50–0.61] of reaching the composite cardiovascular endpoint during 6.3 years of follow-up.[25]
This endpoint consisted of myocardial infarction, coronary revascularization, heart failure, stroke, and cardiovascular death.
29.4% of the participants had CKD, they demonstrated similar risk reduction of bedtime-treatment compared to participants
without CKD. ABPM demonstrated lower night time SBP (114.7 vs. 118 mmHg), however without an adverse effect on day time
SBP (129.5 vs. 129.2), resulting in lower average ABPM SBP. Replication of the findings of this study in other cohorts would
further strengthen these interesting results. Sodium restriction contributes to BP and proteinuria control in patients with CKD, as
reviewed earlier.[26] Adherence is challenging. We recently published results of the SUBLIME trial, which assessed effects of a
web-based self-management intervention (including e-coaching and group meetings; Humalda et al.,[27]). In the SUBLIME
intervention group, sodium intake decreased from 188 to 148 mmol/day, and a decrease of SBP from 140 to 132 mmHg in 3
months. After 6 months of maintenance phase, SBP remained 132 mmHg, but because of a concomitant modest decrease in
sodium intake and BP in the control group (possibly Hawthorne-effect, awareness of participation in a trial influences behaviour),
the between group difference was formally not significant.

Evidence for Blood Presure Targets to Reduce Kidney Disease Progression in Patients With
Chronic Kidney Disease

Although intensive BP lowering is associated with an increase in the risk of acute GFR decline,[13,28–31] optimal management of
hypertension is recommended as a major goal for nephroprotection.[32] This largely relies on the concept of 'hypertensive
nephropathy', in which a chronic nonsevere hypertension is, per se, considered as the cause of kidney parenchymal disease.
Actually, accumulating evidence challenges this classical concept, which is key in defining whether BP targets in CKD should, or
should not, be driven by renal outcomes.

A recent study describing a long-term follow-up of 609 patients with essential hypertension without CKD at baseline showed that a
large majority (91%) of these patients did not present a significant decrease in GFR with time.[33] In the 9% patients with
decreased kidney function at follow-up, the GFR decrease did generally not follow a progressive pattern but was driven by
episodes of AKI without return to baseline, which is opposite to the pathophysiological model of hypertensive nephropathy.

If hypertension was to be a leading and 'dose-dependent' cause of CKD, then a genetically-driven increase in BP should result in
a long-term increase in the risk of CKD. A genome-wide association study defined a genetic risk score based on 29 genetic
polymorphisms individually associated with BP. As expected, this score was strongly associated with hypertension and
demonstrated clear associations with left ventricular hypertrophy, stroke, and coronary artery disease. Importantly, the score was
not associated with the onset of albuminuria or decreased kidney function.[34]

Moreover, in the concept of hypertensive nephropathy was valid, lower BP targets in hypertensive patients with normal kidney
function at baseline should reduce the onset of CKD, and lower BP targets should also limit progression of CKD in patients with
CKD (Figure 1). The MDRD study was the first RCT to analyze the consequences on GFR decline of two different BP targets.[28]
This study compared a mean BP target less than 92 mmHg (approximately 125/80 mmHg) to less than 107 mmHg (approximately
140/90 mmHg). A post-hoc analysis showed a significant interaction on the decline of GFR between the BP target and proteinuria,
with a significant benefit for proteinuria more than 3 g/day, moderate between 1 and 3 g/day, and absent less than 1 g/day. This
result motivated the recommendation of K-DOQI and JNC6 to target BP less than 125/75 mmHg in patients with CKD with
proteinuria above 1 g/day. These recommendations were secondarily withdrawn, because of doubts about the strength of the data
and in particular the fact that only post-hoc analyzes had led to these conclusions. The AASK study included African-American
patients with stage 3 and 4 CKD. It compared two BP targets (128/78 vs. 141/85 mm Hg on average), but also three different
antihypertensive classes. Patients with diabetes with proteinuria more than 2.5 g/g were excluded.[35] AASK showed no difference
between the two targets on GFR evolution at 4 years, including in a post-hoc analysis of subgroups defined by proteinuria more
than 0.22 g/g and on an extended follow-up of the study cohort.[36] However, the same group in a recent meta-analysis of MDRD
and AASK studies found that in a subpopulation of patients with CKD with proteinuria more than 0.44 g/day the more intensive BP
target was associated with a hazard ratio of 0.79 (CI, 0.63–0.91) of ESRD.[19]

The REIN-2 study compared a DBP target of less than 90 mmHg to an intensive target (<130/80 mmHg). Patients included had
nondiabetic proteinuric nephropathy. This study did not show any difference regarding the risk of ESRD.[37] The SPRINT study,
within the initial follow-up, was also negative on the evolution of eGFR.[13] In patients with normal kidney function at baseline,
intensive BP management was associated with a 3.54-fold (CI, 2.50–5.02) increase in the risk of incident CKD.[38] Magrico et al.
[39] evaluated the risk-benefit of intensive treatment in SPRINT, focusing on the balance between cardiovascular events or death
and kidney function decline. In patients without CKD larger reductions in MAP were associated with increased incidence of kidney
function decline. In a propensity score analysis, MAP reduction less than 20 mm Hg presented a number needed to treat (NNT)
(cardiovascular events or death) of 44 and a number needed to harm (NNH; kidney function decline) of 65; MAP reduction

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between 20 and less than 40 mm Hg presented an NNT of 42 and an NNH of 35; and MAP reduction more than 40 mm Hg
presented an NNT of 95 and an NNH of 16. Intensive treatment therefore appeared as less favorable when a larger reduction in
MAP from baseline was needed to attain the BP target.

Despite slight discrepancies, possibly related to the heterogeneity of populations included and of follow-up, the conclusions of
most major trials do not show a significant effect of an intensive BP target compared to a standard target in terms of renal
function. Accordingly, a meta-analysis including the nine major RCT available to date concluded that there is no significant benefit
on kidney function associated with an intensive strategy in reducing BP.[40] Furthermore, the increased prescription of renin–
angiotensin system blockers would have been expected to improve renal outcomes in the intensive treatment arms,
independently of the direct effects of BP. Overall, excluding severe hypertension, the current evidence does not support the
classical concept of hypertensive nephropathy.

What do the Guidelines Recommend?

The three major guidelines currently defining BP targets in CKD are summarized in Figure 2.

Figure 2.

Blood pressure (BP) targets in patients with chronic kidney disease (CKD) recommended by the latest KDIGO, ACC/AHA, and
ESH/ESC guidelines (31, 41, 42). Exceptions defined by ESH/ESC for age more than 80 and diabetes mellitus are not included in
the figure.

In 2017, a KDIGO conference was dedicated to reexamine the 2012 KDIGO guideline by including data from the most recent trials
published, including SPRINT and SPS3. The summary of this conference, published in 2019, suggested BP targets in CKD
should be revised, but underline the numerous areas of uncertainty in defining these targets, especially regarding applicability of
the results of SPRINT to CKD patients with significant albuminuria, eGFR less than 45 ml/min and diabetes mellitus.[41]

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Although the most recent guidelines (ACC/AHA 2017 and ESH/ESC 2018) rely on the same evidence it is remarkable that they
generated significantly different conclusions, both in the general and the CKD population.[42,43] This situation, which mainly stems
from different definitions of hypertension, identification of subpopulations, and implementation of methodological issues of the
SPRINT study in clinical practice, is dramatically confusing for clinicians.

Conclusion

In patients without albuminuria, the current evidence does not support the direct role of hypertension in the onset and the
progression of CKD. Therefore, following the publication of SPRINT, the justification of lowering BP targets in CKD relies on the
cardiovascular benefit afforded by intensive antihypertensive strategies. In order to be widely applicable, recommended BP
targets should be clear and undoubtedly supported by evidence. Variable definitions of hypertension, separation of
subpopulations, and interpretations of RCTs have led to significant differences in the major recommendations, both in the general
and the CKD populations. Although areas of uncertainty remain, unification of the guidelines for the management of BP in CKD
would be an important step towards an improved adherence of physicians and patients to consensus BP targets.

Sidebar
Key Points

Current evidence does not support the classical concept of hypertensive nephropathy.

Intensive lowering of BP reduced death in the CKD population included in the SPRINT trial.

Whether the benefits observed in the SPRINT trial apply to patients with stage 4–5 CKD or albuminuria more than 1 g/g is
unclear.

Discrepancies between current guidelines defining hypertension and BP targets in patients with CKD limit their applicability
in the clinical practice.

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Acknowledgements
None.

Financial support and sponsorship

None.

Curr Opin Nephrol Hypertens. 2020;29(3):327-332. © 2020 Lippincott Williams & Wilkins

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