Sex differences in the progression of kidney injury and risk of death in CKD patients: is different ambulatory blood pressure control the underlying cause?

In current literature, the term ‘sex’ is used to identify the biological sex, which can influence a disease pathophysiology, clinical manifestations and response to treatment, whereas the term ‘gender’ mostly refers to behaviours (e.g. lifestyle, perceived stress and nutritional habits) that modulate the expression of biological sex, and issues such as perception of disease, help-seeking behaviour and healthcare use from the individuals, as well as perceptions that influence decision making and responses by providers [1]. Sex and gender differences have a major impact on the epidemiology, aetiology, manifestations and treatment considerations of a vast number of diseases, including cardiovascular disease (CVD) and chronic kidney disease (CKD) [1–3]. When the underlying aetiology is considered, accumulated evidence suggests that there are many cases of differences between men and women in the strength of the associations between common risk factors and major outcomes. In this regard, it was previously noted that the presence of metabolic syndrome, diabetes or prolonged smoking was more strongly associated with underlying vascular injury and conferred a higher risk of cardiovascular outcomes in women than in men [2, 4]. In contrast to the above, several recent prospective studies clearly demonstrate that men with CKD display a faster decline in estimated glomerular filtration rate (eGFR) and a higher risk of end-stage kidney disease (ESKD) compared with women [5–7]. This difference may be a central factor explaining the paradoxical phenomenon of the prevalence of CKD being steadily higher in women and the institution of renal replacement therapy being more common in men [3]. Hypertension is highly prevalent in CKD patients and represents the most common modifiable risk factor for both cardiovascular events and CKD progression in these individuals [8]. Furthermore, hypertension is another typical example of a disease where significant sex and gender differences on epidemiology, pathogenesis and treatment are established [9]. On this basis, the aforementioned studies investigated whether possible differences in blood pressure (BP) between sexes could affect CKD progression to ESKD; the overall conclusion was that there is no modification on CKD progression by office BP levels, as in most cases men and women had similar office BP control [5–7]. In recent years, however, several studies have highlighted a number of advantages that ambulatory BP (ABP) monitoring (ABPM) has over office BP with regards to phenotyping and risk stratification of patients with hypertension, including those with pre-dialysis CKD. These works have uncovered important evidence regarding the high prevalence of ‘white coat’ and ‘masked’ hypertension in this population [10], the much stronger associations of ABP compared with office BP with CKD progression, cardiovascular events and mortality [11, 12], and the relation of specific components of ABP profile, such as nighttime BP or short-term BP variability, with renal and cardiovascular outcomes [11, 13, 14]. Therefore, whether sex differences in ABP profiles could promote differences in CKD progression was an interesting open question. In this issue of Nephrology Dialysis Transplantation, Minutolo et al. report the results of a prospective cohort study aiming to answer this question by examining possible sex differences in office BP and ABP control and the effect of these differences on the future risks of ESKD (chronic dialysis or pre-emptive kidney transplantation) and mortality [15]. The study included 553 men and 353 women with hypertension and CKD Stages 2–5 prior to dialysis. All patients were followed in Nephrology Outpatient clinics in Italy and underwent ABPM during a workday with their regular antihypertensive treatment. Patients were classified at goal for daytime and nighttime if their BP was <135/85 mmHg and <120/70 mmHg, respectively, and at goal for office BP if BP was ≤140/90 mmHg or ≤130/80 mmHg for patients with and without proteinuria, respectively. At baseline no difference between genders emerged for office systolic BP and diastolic BP, number of antihypertensive agents and office control rates. However, men had higher 24 h, daytime and nighttime BP compared with women, and therefore significantly lower control rates for the total 24-h period, daytime and nighttime BP [15]. The distribution of BP phenotypes was also significantly different between genders, with men having lower prevalence of controlled hypertension with both metrics and lower prevalence of white-coat effect, but higher prevalence of masked hypertension and sustained hypertension than women. As such, the adjusted odds of ABP being not at goal were significantly higher in men than women [15]. With regards to longitudinal associations, Minutolo et al. [15] have estimated the overall risks of ESKD and mortality after careful adjustment for a wide set of covariates (age, smoking, body mass index, diabetes, history of CVD, left ventricular hypertrophy, phosphate, haemoglobin, eGFR, proteinuria, number of antihypertensive drugs and use of inhibitors of renin–angiotensin system). The authors noted that the risks of both ESKD and death were higher in men than women. In further models, additional adjustment for control of office BP did not affect at all these associations, but adjustment for ABP control attenuated and rendered insignificant the previous risk differences between sexes. Looking in this issue from another perspective, in the fully adjusted model office BP control was not associated with change in the risks of ESKD or death, whereas ABP controlled practically halved the risks of both outcomes. No interaction between sex and controlled ABP on the risk of ESKD and death was found, a fact suggesting that risks driven by ABP are consistent in males and females and that the underlying factor driving the outcome differences was worse ABP in men [15]. Overall, the study by Minutolo et al. [15] is an important addition to the current literature in several ways. On one hand, it confirms previous works in the field [5–7] indicating also that office BP levels and BP control are similar in men and women with CKD, and that sex differences in CKD progression and overall mortality in these patients are independent of office BP control. On the other hand, it thoroughly depicts that ABP profile differs between sexes; men had significantly higher daytime and nighttime systolic BP by 3–4 mmHg, but this supposedly small difference in actual ABP levels translates into major differences in ABP control rates. In addition, the study reveals that phenotypes of BP differ significantly between sexes. Finally, this study shows for the first time that ABP control is a major determinant of future risks of ESKD and death in the whole population, and that worse ABP control in men is the key contributor to their higher risk of adverse outcomes. The strengths of this study include the large original sample and long follow-up contributing to a large number of accrued events (occurring at 57.4% of participants), as well as a thorough statistical analysis, employing Cox proportional hazards models adjusted for many clinical and laboratory covariates. The main limitations, also acknowledged by the authors, include the study’s observational nature and the inclusion of only Caucasian patients. The reasons for the reported differences in ABP control between men and women are not clear. For patients with essential hypertension, current evidence suggests the involvement of both sex- and gender-related factors [16–18]. Sex differences in major pathogenetic mechanisms of hypertension, including the renin–angiotensin system, the sympathetic nervous system, the endothelin system, sex hormones and the immune system, can be involved [9, 16]. Furthermore, previous studies have noted sex differences in the pharmacokinetics and pharmacodynamics of major antihypertensive classes, such as dihydropyridine calcium-channel blockers and angiotensin-receptor blockers that elicit greater BP reductions at equivalent doses [17, 18]. On the other hand, issues related not to biological sex but to patient and physician approaches to treatment promoting gender differences may be accountable [18]. One such example is the fact that thiazide diuretics are more often prescribed to women than men, possibly because treating physicians take into account other health issues, such as the beneficial effects of thiazides on bone mineral density in post-menopausal women; in this way the established benefits of thiazides on BP control may be more relevant to women [17]. Another relevant aspect is the level of adherence to drug therapy, which might differ in men and women. Poor adherence is very common in CKD patients and has been associated with poor BP control; male gender has been recognized as a determinant of poor adherence in dialysis [19] but no comparable data have been reported so far in non-dialysed CKD patients. In addition to offering a rational explanation of how different ABP controls may drive differences in outcomes between men and women with CKD, the findings of Minutolo et al. [15] add to several observations highlighting the high predictive value of ABPM in patients with CKD. In this respect, these results support existing standpoints [20] and the recent recommendations of the KDIGO 2021 Clinical Practice Guideline for the management of BP in CKD [21] suggesting that out-of-office BP measurements with ABPM or home BP monitoring should be increasingly used in CKD patients. This article was not supported by any source and represents an original effort of the authors. All authors disclose that they do not have any financial or other relationships that might lead to a conflict of interest regarding this article.