Dr. Nozaina Mahmood is a Nephrology fellow at the University of Alabama at Birmingham with clinical and academic interests in chronic kidney disease, health disparities in nephrology, and evidence-based approaches to patient care.

Dr Efren Chavez Morales is an Assistant Professor in the Division of Nephrology at the University of Alabama at Birmingham. He is a board-certified hypertension specialist. His areas of interest include hypertension and hereditary kidney diseases.

The landmark SPRINT trial that intensive SBP control in hypertensive subjects with increased cardiovascular risk resulted in a reduction in major cardiovascular events and death from any cause, but patients with diabetes, advanced CKD, and high proteinuria were excluded. The BPROAD trial also demonstrated a benefit of intensive SBP in Chinese individuals with hypertension, type 2 diabetes, and increased cardiovascular risk by decreasing the rates of major cardiovascular events or death from cardiovascular causes. However, the study also excluded patients with advanced CKD and high proteinuria. The cardiovascular benefits of intensive SBP were also demonstrated in the elderly population in the STEP and SPRINT Senior trials. A post-hoc analysis of the STEP study suggests that the effects of intensive SBP lowering on cardiovascular outcomes are unaffected by baseline diastolic BP. Whether an intensive SBP is also feasible and beneficial in a population with advanced CKD has not been explored as these patients have been excluded from large hypertension clinical trials.

In a  pilot study published in AJKD, Ku et al. performed a nonblinded RCT that aimed to bridge this knowledge gap by specifically evaluating the feasibility and safety of an intensive SBP goal (<120 mm Hg) compared to a less intensive SBP goal in a cohort of 108 patients with advanced CKD (estimated glomerular filtration rate [eGFR] ≤30 ml/min/1.73m²) and hypertension. This commentary explores the study’s methodology, results, implications, and potential future directions, while also considering its real-world applicability and limitations.

Key strengths of the study:

1. Feasibility of intensive SBP control: One of the study’s most significant contributions is its demonstration that intensive SBP control in patients with advanced CKD was achievable with multiple antihypertensive medicine titrations in the first 4 months of the study, and consistently maintained until the study end. The mean duration of follow-up in the trial was 19.3 ± 15.6 (SD) months. The primary efficacy outcome was the difference in achieved clinic SBP between the two study arms from months 4 to 12. Averaged over months 4 to 12, the difference in mean SBP between the intensive and less intensive arms was significant (11.7 mm Hg in clinic measurements and 12.3 mm Hg in home readings [p<0.001]), showing that tighter BP control can be maintained over time. This is an encouraging finding, as it suggests that even patients with advanced CKD can adhere to intensive BP management strategies.
2. Use of home BP monitoring (HBPM): The study measured BP with a wireless Bluetooth-enabled HBPM that transmitted readings to providers in real-time. HBPM is a superior diagnostic method than clinic BP measurements for assessing true BP control when compared with 24-hour ambulatory BP monitoring as the reference standard. This aligns with existing evidence that HBPM results in lower white-coat and masked hypertension effects. The data of the effect of HBPM on patient’s medication adherence are mixed.
3. Reduction in hospitalization risk: Patients in the intensive SBP arm had a lower risk of all-cause hospitalization (HR: 0.52; 95% CI, 0.29-0.92), particularly for cardiovascular-related hospitalizations. Given that CKD patients are at a significantly higher risk of cardiovascular morbidity and mortality, this potential benefit is of paramount importance.
4. Comparable safety outcomes in both arms: The frequency of hospital visits related to AKI, hyperkalemia, and the composite outcome of falls or syncope were similar in both arms (Table).

Frequency of primary and other adverse event outcomes of interest within the first 12 months of randomization Table 3 from Ku et al, © National Kidney Foundation.

      5. Expanded inclusion criteria: Unlike the SPRINT trial, this study also included some diabetics (30.6%) and kidney transplant recipients (9.3%).

Potential Study Limitations:

1. Risk of progression to end-stage kidney disease (ESKD): In this study, there was a tendency towards more incident ESKD events with intensive SBP as compared with less intensive SBP at 12 months (4.5% vs 0%, p=0.2). While the number of ESKD events was low and the association was not statistically significant, it raises a crucial question: Could intensive BP lowering accelerate kidney function decline in certain patients? It has been suggested that in patients who have an impaired kidneys’ autoregulatory capacity, such as patients with advanced CKD or the elderly who tend to have more vascular arteriosclerosis, intensive BP treatment could increase the risk of AKI due to renal ischemia with subsequent chronic damage. In SPRINT, the overall rate of eGFR decline was higher rather than lower on intensive treatment in the CKD subgroup. But albuminuria was also lower in the intensive SBP arm during follow-up, and measurement of various urinary biomarkers during intensive BP treatment was not indicative of tubular damage. These findings overall suggest that the eGFR decline with BP lowering may be mediated, at least in part, by intrarenal hemodynamic changes. In the AASK and MDRD trials, a ≥20% eGFR decline following intensive BP treatment was associated with a higher risk of ESKD. Ku et al published a meta-analysis of seven trials with a pool of 5,823 participants with an eGFR <60 ml/min/1.73m² where they evaluated the effect of intensive BP control on the risk of progression to ESKD or trial-defined kidney outcomes. There were 1,080 individuals with CKD stages 4-5 included in this meta-analysis. Overall, intensive BP control was associated with a lower risk of kidney outcomes compared to usual BP, but these findings did not achieve statistical significance. However, a subgroup analysis according to baseline eGFR suggested that intensive BP control was associated with a 20% lower risk of the primary kidney outcome in those with CKD stages 4-5, but not in those with CKD stage 3. Therefore, a more nuanced, patient-specific approach may be required when implementing intensive BP control in CKD.
2. Dropout rates: The study reported a 15% dropout rate, with some participants citing medication burden or nonadherence to home BP monitoring as the main reasons to withdraw from the study. Finding the right balance between achieving optimal BP control and minimizing pill burden remains a frequent challenge in hypertension management. Many CKD patients are already on multiple medications, making adherence a significant issue. Future research should explore strategies to simplify medication regimens, such as combination therapy pills or text medication reminders, to enhance adherence.
3. Insufficient power to evaluate safety outcomes: While the study showed similar rates of AKI-related hospitalizations, falls and hyperkalemia between the two treatment arms, these risks should not be overlooked, especially in elderly patients. This study was not powered to examine the risks of adverse outcomes, which limits the ability to draw conclusions about the safety of intensive BP treatment. Larger studies with longer follow-up periods are necessary to better quantify these risks.
4. External validity: The study was conducted at a single center and had a relatively small sample size (n=108). It included large proportions of White or Asian individuals, but there were few Black or Hispanic participants (8.3% and 14%, respectively), limiting its generalizability. Additionally, non-English speakers and patients without smartphones were excluded, potentially introducing selection bias. A more diverse, multi-center trial with broader inclusion criteria is needed to validate these findings across different populations.
   

   Copyright: sfam_photo / Shutterstock

The results of this study have significant implications for clinical practice and future research. Below are key takeaways:

• Intensive SBP control in patients with advanced CKD is feasible and seemingly safe; and it has the potential benefit of decreasing all-cause and cardiovascular-related hospitalizations. However, careful monitoring is essential to mitigate risks.
• Home BP monitoring should be standardized in CKD care. The strong correlation between home and clinic SBP readings in this study underscores the importance of HBPM in CKD patients. Healthcare providers should encourage patients to use validated home BP monitors and incorporate these readings into clinical decision-making.

Future research studies should also investigate the impact of intensive BP control on long-term CKD progression, particularly in patients with advanced CKD at baseline.

This pilot study represents a crucial step toward defining optimal BP targets in advanced CKD. While intensive SBP control appears feasible and may reduce hospitalization risk, concerns remain regarding potential kidney-related adverse outcomes. A personalized, risk-stratified approach should be adopted when applying these findings to real-world clinical practice. Additionally, larger trials with diverse populations and longer follow-up duration are necessary to provide more definitive guidance. Until then, nephrologists and primary care providers should weigh the potential benefits of intensive SBP control against individual patient risks and preferences, ensuring a balanced approach to hypertension management in CKD.

–Post prepared by Nozaina Mahmood and Efren Chavez Morales

To view Ku et al, please visit AJKD.org:

Title: Intensive Home Blood Pressure Lowering in Patients With Advanced CKD
Authors: Elaine Ku, Timothy P. Copeland, Charles E. McCulloch, Divya Seth, Christopher A. Carlos, Kerry Cho, Anna Malkina, Lowell J. Lo, Raymond K. Hsu
DOI: 10.1053/j.ajkd.2024.08.010