Introduction

Patients with chronic kidney disease (CKD) often have inadequately controlled hypertension (Lee et al., 2017), the presence of which is associated with more rapid progression of CKD and cardiovascular complications (Wan et al., 2019; Kim et al., 2020). As such, novel treatments are required to better control blood pressure and improve health outcomes in CKD. Remote ischemic conditioning (RIC) using transient limb ischemia/reperfusion has been shown to protect the kidney and microvasculature in experimental and clinical studies. Daily episodes of RIC (termed chronic RIC [CRIC]) applied for 1 to 12 months have been shown to lower systemic blood pressure (SBP), prevent stroke, and reduce post-myocardial infarction left ventricular remodeling in experimental and clinical studies (Wei et al., 2011; Meng et al., 2012; Jones et al., 2014; Chong et al., 2019). In addition, CRIC applied daily for 28 days has been shown to reduce SBP in patients with chronic ischemic heart failure (Pryds et al., 2017). Whether CRIC can reduce SBP in hypertensive patients with CKD is not known. The primary objective of the ERIC-BP-CKD study was to assess the feasibility and efficacy of CRIC administered for 28 days on lowering SBP in patients with CKD and hypertension when compared to sham. The secondary objectives were to measure central aortic systolic pressures, proteinuria, and kidney function.

Materials and methods

This was a proof-of-concept, single-center, randomized, controlled, double-blinded trial (NCT03236350). Ethics approval was granted by the SingHealth Centralized Institutional Review Board (Reference 2016-2966). Study inclusion criteria included: participants aged ≥ 21 years with CKD stages 1 to 4; stable treatment for hypertension; and automated office blood pressure (Agarwal, 2017) (AOBP) systolic blood pressure (SBP) >140mmHg. Average AOBP readings were measured after patients had rested alone for 5 minutes, followed by a fully automated sequence of two readings over 5-minutes. Exclusion criteria included: polycystic kidney disease; atrial fibrillation; peripheral arterial disease of the arms, long-acting sulphonylurea, nicorandil, or anticoagulation treatment. Eligible participants were randomized to receive either CRIC treatment (comprising four 5-minute inflations/deflation of CellAegis autoRIC® device on the upper arm) or control (comprising four 5-minute sham inflations and deflations of CellAegis autoRIC® device on the upper arm) performed daily for 28 days. The control sham device provides the same sound and vibration as the active CellAegis autoRIC® device but with no inflation of the cuff. Adherence to CRIC based on completed days and treatment cycles were automatically captured by the autoRIC® device. Demographics and clinical data were collected at baseline, whereas serum creatinine (including calculated eGFR CKD-EPI), spot urine protein-creatinine ratio (UPCR), and serum inflammatory biomarkers were measured at baseline and on day 28. AOBP readings (Omron® HEM-907), central aortic systolic pressures (CASP) BPro® Intro(Williams et al., 2011) were measured at baseline, day 28 and day 42 (2 weeks after stopping CRIC or sham). Anti-hypertensives were not adjusted throughout the study period and no specific lifestyle modification advice was given.

     Statistical analysis was performed using Stata version 16 (StataCorp, Texas). Categorical variables were presented as proportions and continuous variables summarized as medians with interquartile ranges (IQR). Baseline characteristics were compared using Pearson chi-square test or Fisher’s exact test for categorical variables and Mann-Whitney U test for non-normally distributed continuous variables. Our primary analysis compared changes in SBP between the CRIC and control groups using the intention to treat approach for all randomly assigned participants. Wilcoxon signed rank test was used to compare between two time-points and Wilcoxon rank-sum test was used to compare between control and treatment groups. Generalized Estimation Equations (GEE) were used to compare control and treatment groups over time. All analyses were two-tailed and p < 0.05 was considered statistically significant.

Results

Sixteen patients were screened with 6 screen failures due to AOBP criteria. Ten patients were recruited with 6 patients randomised to CRIC and four to control. One participant in the CRIC group withdrew consent after randomization. Baseline demographic and clinical characteristics are shown in Table 1. Adherence to treatment was excellent with completion of CRIC or sham control in 96% and 93% of participants, respectively.

Table 1. Baseline characteristics of study participants

AOBP, automated office blood pressure; BMI, body mass index; CASP, central aortic systolic pressure; CKD, chronic kidney disease; CVA, cerebrovascular accident; DBP, diastolic blood pressure; IHD, ischemic heart disease; MAP, mean arterial pressure; SBP, systolic blood pressure; UPCR, urine protein-creatinine ratio.

  There were no differences in AOBP SBP or CASP between CRIC and control after either 28 or 42 days (Table 2). However, in the CRIC group, AOBP diastolic blood pressure (DBP) and mean arterial pressure (MAP) were significantly decreased after 28 days when compared to control, and AOBP MAP remained significantly lower after 42 days. In addition, GEE analysis of AOBP DBP comparing CRIC and control groups showed significant differences over time. Differences over time were not observed for GEE analyses of AOBP SBP and MAP. There were also no differences in spot UPCR, serum creatinine, eGFR CKD-EPI or inflammatory biomarkers (interleukin-1α, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor- α) between CRIC and control groups at 28 days. No adverse events were detected in this study.

Table 2. Comparisons over time between CRIC and Control groups

AOBP, automated office blood pressure; CASP, central aortic systolic pressure; CKD; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.^aDay 28 vs. Baseline; ^bDay 42 vs. Baseline; ^cDay 42 vs. Day 28; **P = < 0.05

Discussion

In this proof-of-concept study, CRIC did not improve SBP control when compared to control treatment after 28 days, although there were significant reductions in DBP and MAP as measured via AOBP. The significance of this is uncertain in view of the small sample size. The lowest DBP was 60.0mmHg in the CRIC group (median baseline 74.5mmHg) after 28 days, which should not pose a safety issue considering that coronary artery filling is only affected at DBP levels <55mmHg. The overall reduction in MAP and DBP with CRIC warrants further investigation to understand if blood vessel compliance or cardiac output was temporarily altered. Interestingly, at day 42 (14 days after completion of CRIC), the MAP remained low signifying a potential legacy effect of CRIC. In addition, although RIC has anti-inflammatory benefits in vivo in animal models (Pearce et al., 2021), serum inflammatory biomarkers were not significantly different in our small cohort of patients. A larger study population would be necessary to validate these findings and confirm safety issues in terms of the observed reduction in DBP with CRIC.

Sources of Funding

This study was funded by the SingHealth Foundation research fund (SHF/CTG059/2016). DJH is supported by the Duke-NUS Signature Research Programme funded by the Ministry of Health, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017), Centre Grant (CGAug16M006), and Collaborative Centre Grant scheme (NMRC/CGAug16C006). This article is based upon work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology).

Disclosure

All authors declare no potential conflict of interest that might be relevant to the contents of this article.