Systolic Blood Pressure Time in Target Range and Acute Kidney Injury in Patients With Hypertension

Abstract

BACKGROUND:

Acute kidney injury (AKI) is a serious complication of hypertension management. However, the association between systolic blood pressure (SBP) time in target range (TTR) and the risk of AKI remains unclear.

METHODS:

This is a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial). Participants were randomly assigned to intensive (<120 mm Hg) or standard (<140 mm Hg) SBP treatment arms. SBP TTR was defined as 110 to 130 mm Hg for the intensive arm and 120 to 140 mm Hg for the standard arm over 3 months. The primary outcome was incident AKI. The secondary outcome was the severity of AKI based on the modified Kidney Disease: Improving Global Outcomes criteria. Competing risk models were used to estimate the relationship between SBP TTR and AKI.

RESULTS:

Among 8985 participants, 258 developed AKI (incidence, 7.62 per 1000 person-years). Each 1-SD increase in SBP TTR was associated with a 14% lower risk of AKI (hazard ratio, 0.86 [95% CI, 0.75–0.97]; P=0.017). No significant interaction was observed between treatment assignment (P_interaction=0.930). Compared with participants with lower TTR (0%–<59%), those with higher TTR (59%–100%) had a lower risk of AKI events (hazard ratio, 0.69 [95% CI, 0.53–0.91]; P=0.008). By treatment arm, hazard ratios (95% CIs) for standard/lower versus intensive/lower, standard/higher, and intensive/higher were 1.70 (1.23–2.38; P=0.002), 0.68 (0.45–1.03; P=0.070), and 1.19 (0.81–1.75; P=0.470), respectively.

CONCLUSIONS:

Higher SBP TTR was associated with a lower risk of AKI, independent of treatment intensity, underscoring the importance of sustained blood pressure management.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

NOVELTY AND RELEVANCE.

What Is New?

Despite acute kidney injury (AKI) being a serious complication of hypertension management, optimal blood pressure (BP) control strategies for prevention remain unclear. This post hoc analysis of the SPRINT (Systolic BP Intervention Trial) investigated the relationship between systolic BP time in target range (TTR) and AKI risk in adults with hypertension.

What Is Relevant?

This study quantified the protective role of sustained BP control. Patients with higher systolic BP TTR had a lower AKI risk than those with lower TTR. Maintaining a higher systolic BP TTR was significantly associated with a lower risk of AKI, independent of treatment intensity. Notably, intensive treatment combined with high TTR provided the strongest AKI prevention.

Clinical/Pathophysiological Implications?

These findings highlight the importance of sustained and consistent BP control in reducing kidney-related complications in hypertension management.

Hypertension is a major modifiable risk factor for cardiovascular disease (CVD) and premature death worldwide.¹ Furthermore, hypertension is one of the risk factors for developing acute kidney injury (AKI), and the risk increases with elevated blood pressure (BP) levels, with severe hypertension being an independent predictor of developing AKI.² Paradoxically, acute treatment of hospitalized hypertension is associated with an increased risk of AKI during subsequent hospitalizations, regardless of the degree of BP elevation.^3,4 AKI can lead to severe morbidity as it often progresses to chronic kidney disease (CKD) and, in some cases, end-stage renal disease.^5–7 In addition, AKI is linked to an increased risk of the SPRINT (Systolic BP Intervention Trial) primary cardiovascular outcome and death from any cause.^8–11 However, participants in the intensive-treatment group were at increased risk for an AKI event.¹² Therefore, the AKI risk associated with intensive antihypertensive therapy raises public concern regarding the choice of antihypertensive strategy.

Identifying modifiable risk factors for AKI is crucial, especially in the context of intensive BP management. This helps pinpoint patients at high risk of adverse events, allowing for closer monitoring and preventive strategies. BP control is typically defined by values recorded during a single clinical visit, which is problematic because BP fluctuates over time, and the last recorded value may not accurately reflect overall BP control. Previous studies have shown that significant changes in systolic BP (SBP) are linked to the incidence of AKI across different populations.^13–15 However, assessing changes in SBP alone is flawed, especially for those undergoing antihypertensive therapy. Time in target range (TTR) for SBP is a new concept that reflects the consistency of effective BP control. This measure includes average BP values, the degree of BP variability, and the duration of well-controlled BP within the target range. This may be a more accurate metric to evaluate the impact of BP on the renal microvascular system. TTR has been shown to provide incremental value beyond average SBP for population-based hypertension quality monitoring and clinical trial-based BP interventions.¹⁶

Multiple studies have shown that SBP TTR influenced a wide range of clinical outcomes in patients with hypertension, including major adverse cardiovascular events, all-cause mortality, incident atrial fibrillation, long-term kidney outcomes, and cognitive results.^17–20 The recently released 2023 European Hypertension Management Guidelines highlight the potential value of TTR for assessing BP control and recommend that future studies incorporate time-based metrics.²¹ However, to date, no study has specifically evaluated the association between SBP TTR and the risk of AKI, which is the novel focus of our analysis. In a post hoc analysis of SPRINT, we aim to estimate the relationship between SBP TTR and AKI events and explore a more suitable BP control performance measure to prevent AKI events.

Methods

Data Availability

All data and materials have been made publicly available at the National Heart, Lung, and Blood Institute BioLINCC data repository and can be accessed at https://biolincc.nhlbi.nih.gov/home/.

Study Design

This study is a post hoc analysis of SPRINT, an open-label, randomized controlled trial conducted at 102 clinical sites across the United States and Puerto Rico. The design and findings of SPRINT have been previously published.^12,22 In brief, participants in SPRINT were randomly assigned to intensive or standard SBP treatment arms, with SBP targets of <120 and <140 mm Hg, respectively. The study was approved by the institutional review boards of all participating clinical sites, and all participants provided written informed consent.

Study Population

Participants were enrolled between November 2010 and March 2013. The inclusion criteria are given as follows: age of ≥50 years, SBP between 130 and 180 mm Hg, and an increased risk of CVD. Increased CVD risk was defined as having ≥1 of the following: clinical or subclinical CVD (excluding stroke), CKD with an estimated glomerular filtration rate (eGFR) of 20 to <60 mL/min per 1.73 m², a 10-year CVD risk of 15% or higher based on the Framingham global risk score, or age of ≥75. Major exclusion criteria included the presence of diabetes, prior stroke, fasting proteinuria >1 g/d, polycystic kidney disease, congestive heart failure (symptoms or ejection fraction <35%), dementia, or residence in a nursing home. Participants who had an incident AKI during the SBP TTR calculation period (3 months for the primary analysis and 6 months for a sensitivity analysis) were excluded from that analysis, as these windows reflect the early phase of antihypertensive management when BP control is most dynamic and clinical decisions are most frequently made.

SBP Control Measures

We defined 3 longitudinal measures of SBP control during months 0 to 3. SBP TTR was estimated by linear interpolation using the Roosendaal method, which could take the frequency and the actual values of BP measures into consideration.^18,23 The target SBP was defined as 110 to 130 mm Hg for the intensive-treatment arm and 120 to 140 mm Hg for the standard-treatment arm.^24,25 BP measurements were taken at baseline, 1, 2, and 3 months, and subsequently every 3 months, irrespective of the treatment arm assignment.

Study Outcomes

The primary outcome of this study was incident AKI, defined using modified Kidney Disease: Improving Global Outcomes criteria focused on serum creatinine levels. The secondary outcome included the severity of AKI.

Statistical Analysis

Categorical data were summarized as counts and percentages, and continuous data were presented as mean±SD for normally distributed variables and as median (interquartile range) for nonnormally distributed variables. The Student t test or the Wilcoxon rank-sum test was applied to continuous variables, and the χ² test was used for categorical variables.

We used the Fine and Gray model to estimate the relationship between SBP TTR and the occurrence of AKI, considering all-cause mortality as a competing risk. This model calculates hazard ratios (HRs) and their 95% CIs through proportional hazards regression in the context of competing risks. Models were adjusted for age, sex, and race (model 1) and further adjusted for body mass index, baseline SBP, baseline eGFR, and 10-year cardiovascular risk score (model 2). Multiple interpolation was performed for missing covariates. For exploratory subgroup analyses, SBP TTR was dichotomized at the sample median (59%) to allow balanced comparison across treatment arms. To assess whether the association between SBP TTR and AKI differed by treatment arm (intensive versus standard), we stratified all analyses accordingly and tested for effect modification by including multiplicative interaction terms between SBP TTR and treatment arm. Nonlinear associations between SBP TTR and AKI were evaluated using restricted cubic splines with 4 knots. Additional subgroup interaction analyses (by age, sex, and race) and sensitivity analyses (eg, excluding users of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers) were performed to test the robustness of our findings (details are given in the Supplemental Material).

P<0.05 was considered statistically significant. Statistical analyses were performed using R Studio, version 4.3.1 (R Foundation, Vienna, Austria).

Results

Baseline Characteristics

This study excluded 327 patients with <2 BP measurements in the first 3 months and 49 patients who experienced an AKI event within the first 3 months from the SPRINT trial. A total of 8985 patients were eligible for this study (Figure S1). The mean age of the study population was 67.9±9.3 years, with 3177 (35.4%) female and a mean SBP of 139.6±15.6 mm Hg. The overall mean eGFR was 72.0±20.1 mL/min per 1.73 m², and 2535 (28.2%) had a history of CKD. The SBP TTR and mean SBP achieved during the first 3 months for the entire study population were 56±31% and 129±11 mm Hg, respectively. Participants with SBP TTR of 0% to <59% were older, more likely to be women, and had a higher 10-year arteriosclerotic CVD risk and lower eGFR than those with SBP TTR of 59% to 100% (Table 1). However, there was no difference in the prevalence of CKD history between the 2 groups.

Table 1.

Participant Characteristics According to Systolic Blood Pressure Time in Target Range.

Overall Association Between SBP TTR and AKI Risk

As of August 20, 2015, 258 participants developed AKI, corresponding to an incidence rate of 7.62 per 1000 person-years (95% CI, 6.72–8.61; Figure 1). The cumulative incidence of AKI was higher among participants with lower SBP TTR compared with those with higher TTR (Figure 2A). Each 1-SD (31%) increase in 3-month SBP TTR was significantly associated with a reduced risk of incident AKI in both unadjusted and demographically adjusted models (Table S1). In fully adjusted models, each 1-SD increase in 3-month SBP TTR was associated with a 14% lower risk of AKI (HR, 0.86 [95% CI, 0.75–0.97]; P=0.017; Figure 1), independent of treatment arm and other covariates. Comparable results were observed using 6-month SBP TTR (HR, 0.85 [95% CI, 0.75–0.97]). In fully adjusted models, participants with higher SBP TTR (59%–100%) had a significantly lower risk of AKI compared with those with lower SBP TTR (0%–<59%; HR, 0.69 [95% CI, 0.53–0.91]; P=0.008; Table 2). Adjusted cubic spline models showed a linear inverse association between SBP TTR and AKI risk, with no evidence of nonlinearity (P_nonlinearity=0.469; Figure 3).

Figure 1.

Association of systolic blood pressure time in target range (SBP TTR) with incident acute kidney injury by treatment arm. *Incidence rate (IR) per 1000 person-years. †Hazard ratio per 1-SD (31%) increase in time in target range. Models were adjusted for age, sex, race, treatment arm, 10-year cardiovascular risk score, body mass index, estimated glomerular filtration rate, and baseline SBP.

Figure 2.

Kaplan-Meier curves for incident acute kidney injury (AKI) by median systolic blood pressure time in target range (SBP TTR) and treatment arm. Cumulative incidence of AKI is shown by median-split SBP TTR (A) and by combined categories of SBP TTR and treatment assignment (B).

Table 2.

Hazard Ratios of AKI According to the Median of TTR for SBP and Treatment Arm

Figure 3.

Restricted cubic spline analysis of acute kidney injury (AKI) risk by systolic blood pressure time in target range (SBP TTR). Hazard ratios for AKI are modeled continuously across the range of SBP TTR, with reference to the median value of 59%.

Association of SBP TTR With AKI Risk by Treatment Arm

Stratified analyses were performed to assess the association between SBP TTR and AKI risk across treatment arms. No statistically significant interaction was observed between treatment assignment and SBP TTR at either the 3- or 6-month interval (P_interaction=0.930 and 0.660, respectively). When stratified by both treatment arm and SBP TTR category, the intensive-treatment/low-SBP TTR group showed the highest cumulative incidence of AKI (Figure 2B). Compared with this group, adjusted HRs (95% CIs) were 1.70 (1.23–2.38; P=0.002) for the standard-treatment/low-SBP TTR group, 0.68 (0.45–1.03; P=0.070) for the standard/high-SBP TTR group, and 1.19 (0.81–1.75; P=0.470) for the intensive/high-SBP TTR group (Table 2).

Association Between SBP TTR and Different AKI Stages

The number of AKI stage outcomes for different SBP TTRs and treatment arms is presented in Table S2. After categorizing the AKI outcomes into stage 1 and stages 2 or 3, AKI stage 1 events occurred in 167 participants, with an incidence rate of 4.96 (95% CI, 4.23–5.77) per 1000 person-years, and stages 2 or 3 events occurred in 100 participants, with an incidence rate of 2.98 (95% CI, 2.42–3.62) per 1000 person-years, respectively (Table S3). The cumulative incidence of each AKI stage was higher in the low-SBP TTR group compared with the higher SBP TTR group (Figure S2). In the fully adjusted model, a 1-SD increase in SBP TTR was not significantly associated with AKI stage 1 (HR, 0.94 [95% CI, 0.80–1.10]; P=0.420) but was significantly associated with a 29% lower risk of incident AKI stages 2 or 3 (HR, 0.71 [95% CI, 0.58–0.87]; P<0.001; Table S3).

Sensitivity Analyses

To assess whether our findings were sensitive to different cut-point definitions, we first repeated the analyses using tertile and quartile categorizations of SBP TTR (Table S4). The associations between higher SBP TTR and lower AKI risk were consistent in direction and magnitude across both categorizations, supporting the robustness of our findings.

Sensitivity analyses yielded consistent results across various definitions and stratifications. When using a direct SBP target range to define SBP TTR, the inverse association between SBP TTR and AKI risk remained (Table S5) though the association was not statistically significant when stratified by treatment arm (Table S6). Using 6-month SBP TTR instead of 3-month SBP TTR also showed similar protective associations (Tables S7 and S8). To account for the influence of renin–angiotensin system inhibitors, analyses excluding users of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (Table S9) and subgroup analysis by drug use (Table S10) revealed no interaction effects and supported the main findings. No significant effect modification was observed across subgroups defined by age, sex, race, CKD history, or CKD (Figure S3).

Finally, to address concerns regarding imputation uncertainty, we conducted additional sensitivity analyses using Cox proportional hazards models: (1) a complete-case analysis without imputation and (2) a pooled analysis across 5 imputed data sets using Rubin’s Rules (Table S11). We also examined the extent of missing data in covariates (Table S12) and found that missingness was minimal (<1% for all variables), occurring only in the fully adjusted model (model 3). All these additional analyses produced estimates consistent in direction and magnitude with the primary Fine and Gray model, further supporting the robustness of our findings.

Discussion

To our knowledge, this is the first study to explore the relationship between SBP TTR and the occurrence of AKI. In this post hoc analysis of SPRINT, a higher SBP TTR was consistently associated with a lower risk of AKI, especially in more severe stages (stage 2 or 3). Importantly, this association remained significant after adjusting for treatment intensity and was consistent across both standard and intensive-treatment arms, with no evidence of interaction. Although intensive antihypertensive therapy increases the risk of AKI, our findings suggest that maintaining a higher SBP TTR early in treatment may mitigate this risk. Moreover, this association was not influenced by baseline SBP or renal function. These results underscore the potential value of SBP TTR as an independent and modifiable metric in BP management strategies aimed at reducing AKI risk.

Hypertension is a risk factor for developing AKI, with the risk increasing with elevated BP levels, and severe hypertension is an independent predictor of developing AKI.² Paradoxically, acute treatment of hospitalized hypertension is associated with an increased risk of AKI during subsequent hospitalization, regardless of the degree of BP elevation.^3,4 Although intensive antihypertensive therapy can provide definite cardiovascular benefits, there is an increased risk of AKI events.¹² This risk remains a stumbling block to choosing intensive antihypertensive therapy. In reality, however, the increased risk of AKI associated with intensive antihypertensive therapy compared with standard therapy is likely due to greater fluctuations in BP and the fact that patients do not stabilize their BP into the appropriate range more quickly. Our findings likewise confirm this view. Indeed, good SBP TTR is beneficial in patients with hypertension who undergo antihypertensive therapy, regardless of the target SBP. Previous studies have shown that significant changes in SBP are associated with the incidence of AKI in different populations likewise confirming this.^13–15 Recently, the composite BP control performance metric, SBP TTR, has been shown to be a useful indicator for assessing all-cause mortality, adverse cardiovascular, and cognitive outcomes.^18,19 Similarly, in nephrology, Buckley et al¹⁷ noted that higher SBP TTR was associated with a lower risk of adverse renal events among participants in the SPRINT study and the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Park et al²⁶ suggested that a BP index considering the degree of BP control may be useful in clinical practice for patients with CKD for risk stratification. Although there is a close relationship between BP and renal function, and AKI is a prerequisite for the development of CKD in most patients, our study found that better SBP TTR was associated with a lower risk of AKI and subsequent adverse events, irrespective of the antihypertensive strategy performed.

This observation is complemented in the present study, where we assessed TTR at 3 months in the primary analysis and at 6 months in the sensitivity analysis. Our findings suggest that controlling BP in the early phase after initiating antihypertensive therapy has a favorable impact on the risk of future AKI. Moreover, better BP control may offset some of the risk associated with an intensive antihypertensive strategy. Furthermore, the results provided greater prognostic insight when achieving better SBP TTR during 6 months. Certainly, SBP TTR is an important modifiable factor for future AKI events in patients with hypertension undergoing antihypertensive therapy, regardless of the chosen antihypertensive strategy. The relationship between AKI risk and cumulative duration of exposure to hypertension may be one reason for this and should be validated in a study cohort with long-term follow-up. The choice of antihypertensive medication in the occurrence of AKI is highly controversial.^27,28 However, in our sensitivity analyses, SBP TTR remained significantly associated with the development of AKI even after excluding the use of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitor drugs. In addition, there was no interaction observed between the use of these 2 classes of drugs. This suggests that the choice of antihypertensive medication does not affect the benefit of SBP TTR on the occurrence of AKI, even when concerns about medication choice conflict with SBP TTR in clinical practice.

The potential mechanisms underlying this differential effect likely relate to the distinct physiological implications of SBP TTR. While angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may lead to acute declines in eGFR by dilating efferent arterioles and lowering intraglomerular pressure, SBP TTR reflects sustained BP stability within a physiologically optimal range over time.²⁹ Renal autoregulation normally protects glomerular and tubulointerstitial tissues from hypertensive injury.^30–32 When renal autoregulation is impaired, more BP fluctuations are transmitted to the glomerulus. However, although autoregulation usually adapts to higher BPs in hypertensive models, its efficiency tends to decline over time. The degree of glomerular injury in hypertensive models is usually proportional to the degree of impairment of renal autoregulation.^33–35 Thus, ideal treatment of hypertension should reduce BP while maintaining or improving the effectiveness of renal autoregulation.^33,35–37 Ideally, the preglomerular vasculature should protect the kidneys from persistent hypertension and rapid fluctuations in BP^30,38–40 because both elevated BP and elevated pulse pressure predict hypertensive renal damage.^32,39

This study has several limitations. First, the study population was drawn from a clinical trial that implemented a highly structured BP management protocol. Such strict control limits BP variation, causing the time in the target range to converge with the average BP, potentially biasing the results toward the null. Moreover, the exposure window for TTR calculation was relatively short, with exposure limited to 3 months in the primary analysis and 6 months in the sensitivity analysis to maximize statistical power. Although this period captured most treatment adjustments, a longer duration may have provided a more comprehensive assessment of sustained BP control and its association with AKI risk. Second, because of changes in antihypertensive drug prescriptions during the follow-up period, we did not examine the effect of individual drugs and doses on the occurrence of AKIs. Nonetheless, we adjusted for baseline use of key drug classes, and the results remained consistent, partially mitigating this concern. Third, the study did not capture AKI events managed in outpatient settings, which are typically milder and less likely to require hospitalization. As a result, the incidence of AKI in our analysis may underestimate the total burden but accurately reflects clinically significant events requiring inpatient care. In addition, the trial excluded patients with prior stroke or diabetes, limiting the generalizability of the findings to the entire hypertensive population.

In conclusion, this study demonstrated that maintaining a higher SBP TTR was associated with a lower risk of AKI, independent of treatment intensity.

Perspectives

The relationship between SBP TTR and AKI has not been investigated in previous studies. Our findings demonstrate that higher SBP TTR is strongly associated with a reduced risk of incident AKI in patients with hypertension. This study suggests that achieving consistent BP control early in antihypertensive therapy may help mitigate the increased AKI risk associated with intensive treatment, highlighting the importance of sustained BP management.

Article Information

Acknowledgments

The authors appreciate the SPRINT (Systolic Blood Pressure Intervention Trial) investigators for providing public access to the study data via the National Heart, Lung, and Blood Institute BioLINCC Biologic Specimen and Data Repository.

Author Contributions

W.-H. Chen, C. Yang, K. Guan, J.-J. Li, and R.-C. Huang were involved in the conception, design, and conduct of the study and the analysis and interpretation of the results. W.-H. Chen and C. Yang wrote the first draft of the manuscript, and all authors edited, reviewed, and approved the final version of the manuscript. R.-C. Huang is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Sources of Funding

This work was partially supported by the Leading Talents Plan, Beijing Municipal Health Commission, Beijing, China (grant LJRC20240306).

Disclosures

None.