A critical commentary on connection between changes in kidney function and recurrent stroke and dementia

The prevalence of hypertension among patients in our daily practice is steadily increasing. This trend may be attributable to contemporary lifestyle factors, as well as shifts in climate and environmental conditions. Healthcare professionals recognize that hypertension is a potentially fatal condition that can significantly impact patients' lives, potentially rendering them dependent on third-party assistance due to disability. One of the most significant challenges we encounter is the suboptimal adherence of patients, compounded by the limited time and high workload of healthcare providers. As such, any tools that assist in identifying the most vulnerable hypertensive patients and optimizing their treatment are greatly welcomed. These tools can also help in educating patients about the importance of medication adherence. Indeed, those who have experienced a previous cardiovascular event face an elevated risk of recurrence, underscoring the need for targeted interventions in this high-risk group. We read with great interest the article by Maeda and his coauthors, who bring diverse expertise from fields such as neurology, epidemiology, preventive medicine, global health, and brain research. Their international and interdisciplinary perspectives contribute to a comprehensive understanding of the problem and provide valuable insights. Article entitled 'Risk of recurrent stroke and dementia following acute stroke by changes in kidney function: results from PROGRESS' based on the retrospective analyses of using data of randomized control trial database called PROGRESS study. This was an international multicentre placebo-controlled trial of a blood pressure (BP)-lowering treatment, based on the angiotensin-converting enzyme inhibitor (ACE-I) perindopril, most often in combination with the diuretic, indapamide, in patients with a history of a cerebrovascular event. Six thousand one hundred and five patients with a history of stroke or transient ishemic attac (TIA) within the previous 5 years, and no clear indication for, or contraindication to, treatment with an ACE-I were recruited from 172 centres in 10 countries between 1995 and 1997 were included. Active treatment comprised a flexible treatment regimen based on perindopril (4 mg daily) in all participants, with the addition of indapamide (2.5 mg daily; or 2 mg daily in Japan) for patients with no specific indication for, nor contraindication to, the use of a diuretic. Retrospective data analyses offer certain advantages, such as the ability to assess large datasets efficiently and study rare outcomes using existing information. However, these analyses also present disadvantages, including potential biases in data collection, issues with data quality and completeness, and challenges in establishing causality due to the observational nature of the data. The main purpose of the published article was to investigate functional relationships between dynamic kidney function change and cardiovascular outcomes, which they achieved using spline functions and also according to the categories of percentage change in estimated glomerular filtration rate eGFR; declines of >30% (0% to ≤30% (≥−30 and <0%), and increases of ≥0 to <30%, and ≥30%. The categorization in four categories allowed them to demonstrate the U-shaped relationship between eGFR and additional risk of a major cardiovascular events, dementia, and 2-year mortality. An interesting part was pointed out that a large increase in kidney function was also associated with a high risk of mortality. The statistical analyses were conducted appropriately; however, there are multiple ways to interpret the data, which can influence the conclusions drawn. Additionally, the practical application of these findings in daily clinical practice is a crucial consideration for maximizing their usefulness. There are few points, which should be stressed not to misinterpret the results. Estimating renal function is a complex process that extends beyond plasma creatinine levels. Various formulas have been developed for daily practice, but these can sometimes lead to inaccurate assessments of renal function, especially in older populations. In this study, GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, based on serum creatinine levels measured at local laboratories during the study period (at registration, randomization, 3 months, and annually thereafter). Although patient demographic data and physical examination findings were collected, urinary protein excretion levels were not assessed. Although CKD-EPI is commonly used in clinical practice, its reliability in elderly patients may be limited, necessitating careful interpretation and consideration of additional factors. Second, we lack data on potential muscle mass loss that could result from disability and subsequently impact plasma creatinine levels. BMI may not serve as an adequate substitute for assessing muscle mass. A key point raised by the authors is the uncertainty around whether the observed increase in renal function could be due to discontinuation of renin–angiotensin system inhibitors, which may lead to an increase in eGFR and potentially elevate cardiovascular risk. Additionally, the specific impact of incorporating indapamide into the treatment regimens of the studied patients remains unclear. Moreover, a substantial body of research has established a significant association between blood pressure variability (BPV) and its impact on cognitive function and mortality. These findings suggest that effective management of BPV may contribute to the preservation of cognitive health and a reduction in mortality risk. However, this key aspect of data is absent from the data presented in the described study 1. BPV is quantified as the extent of blood pressure fluctuation and can be calculated through various methods. Recent meta-analyses have indicated that elevated BPV and diminished circadian blood pressure dipping patterns are associated with cerebral small vessel disease, independent of average blood pressure 2. These findings illuminate the connection between BPV and heightened mortality rates, as well as cognitive impairments such as dementia 3. Due to the constraints of retrospective analyses, data on BPV were unavailable, and night-time blood pressure measurements were also excluded from the study. These omissions could have impacted the findings and emphasize the necessity for interpretation of recent findings 4,5. The connection between the heart, kidney, and brain is a complex and interconnected relationship often referred to as the cardiovascular–renal–cerebral axis. These organs share common risk factors and pathological pathways, where dysfunction in one organ can significantly impact the others. The underlying mechanisms vary among individuals, with microcirculation being a critical factor that influences the health and function of each organ. Despite potential limitations, we commend the PROGRESS investigators and the authors, particularly Maeda and colleagues, for their published work. Their research demonstrates a significant association between renal function and the risk of cerebrovascular events and dementia. This highlights the crucial importance of routine kidney function monitoring in clinical practice, an aspect frequently overlooked in daily medical care. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.