There is a continuous relationship between increased blood pressure (BP) and cardiovascular (CV) morbidity and mortality, although in elderly hypertensive patients this relationship is less pronounced and is influenced by other factors.1–4 BP exhibits specific characteristics in older individuals, who show increased arterial stiffness that induces greater elevations in systolic blood pressure (SBP) and pulse pressure, as well as a reduction in diastolic blood pressure (DBP), along with more pronounced BP fluctuations.5,6 BP varies in response to physical factors, such as changes in body position.7,8 Orthostatic hypotension (OH) is defined as a sustained reduction in BP upon standing and is common in older adults due to the aging process itself, as well as dysautonomia. OH is considered a complex process that may reflect different regulatory mechanisms throughout the entire CV system. From a physiological standpoint, these mechanisms involve sympathetic nervous system activation and the activity of the aortic and carotid baroreflexes across the entire CV system, as well as arterial distensibility. In the elderly, these factors may be impaired and contribute to BP fluctuations that result in intermittent ischemia, episodes of increased afterload, and repeated mechanical stress on the endothelium, which subsequently leads to organ damage.6,9,10 The aim of the present study was to evaluate the association of orthostatic BP changes with the presence of hypertension-mediated organ damage (HMOD) at the cardiac, renal, and vascular levels in a group of elderly patients with essential arterial hypertension (HTN) and preserved functional status.

We observed a very high percentage of overall HMOD (145 patients, 92.9%), affecting one organ (32%), two organs (34%), or three organs (26%). A total of 75 patients (48%) had kidney disease (12% with increased UAE only, 21% with reduced eGFR only, and 15% with both), 74 (47%) had LVH, and 126 (81%) had elevated aPWV.

A wide distribution of orthostatic SBP changes was recorded, with BP delta values ranging from -51 to 64 mmHg and a median of 2 mmHg (IQR: 22.7 mmHg). For DBP, values ranged from -40 to 29 mmHg with a median of −1 mmHg (IQR: 13 mmHg) (Fig. 1). OH, as conventionally defined, was present in 33 patients (21%), of whom 12 (36%) met the criteria for SBP, 16 (49%) for DBP, and 5 (15%) for both. Table 1 shows the differences in clinical parameters between patients with and without OH. A higher percentage of patients with OH had dyslipidemia and a history of CV events compared with those without OH. Regarding antihypertensive treatment, calcium channel blockers were the most frequently used drugs and, as expected, patients treated with alpha-blockers had OH more frequently. All patients with OH showed HMOD involvement: in 9 (27%) one organ was affected, in 14 (42%) two organs, and in 10 (30%) all three organs. In addition, patients with OH showed significantly higher ambulatory SBP measurements, both peripheral and central, including 24-h, daytime, and nighttime values. Peripheral office SBP values were similar between groups (Fig. 2).

Fig. 1.

Box plot of orthostatic SBP and DBP delta values.

Δ-DBP: diastolic blood pressure delta; Δ-SBP: systolic blood pressure delta.

Fig. 2.

Differences in brachial and aortic SBP estimates between patients with and without orthostatic hypotension.

* p < 0.05 for between-group comparison.

OH: orthostatic hypotension; SBP: systolic blood pressure.

We found no significant difference in HMOD-defining parameters between patients with and without OH after adjusting for covariates. However, there was a trend toward lower eGFR in patients with OH compared with those without OH.

As mentioned above, standing-induced BP changes measured as a continuous variable showed a wide distribution. Therefore, HMOD was compared between patients with changes above and below the median of this distribution. No association with cardiac or vascular HMOD was found. However, when analyzing BP reduction and renal HMOD as a categorical variable defined by eGFR < 60 mL/min/1.73 m2, 41.9% of patients in the group with orthostatic SBP decrease above the median had organ damage, compared with 30.8% of patients with SBP decrease below the median. Similar results were observed for orthostatic DBP changes, with 45.6% versus 28.7% (Fig. 3). These differences were statistically significant for both SBP and DBP after adjusting for age, office BP, and alpha-blocker treatment (p < 0.05) (Table 2).

Fig. 3.

Differences in the presence of renal HMOD defined by eGFR between patients with orthostatic SBP and DBP delta values below (group 1) and above (group 2) the median.

* p < 0.05 for between-group comparison.

Δ-DBP: diastolic blood pressure delta; Δ-SBP: systolic blood pressure delta; eGFR: estimated glomerular filtration rate; HMOD: hypertension-mediated organ damage.

According to HMOD defined by UAE ≥ 30 mg/g of creatinine, 36.6% of patients with an orthostatic DBP decrease above the median had organ damage, compared with 19.3% of patients with an orthostatic DBP decrease below the median (Fig. 4). This association remained statistically significant after adjustment for the above-mentioned covariates (p < 0.05) (Table 3). No such association was observed for orthostatic SBP changes (Fig. 4).

Fig. 4.

Differences in the presence of renal HMOD defined by UAE between patients with orthostatic SBP and DBP delta values below (group 1) and above (group 2) the median.

* p < 0.05 for between-group comparison.

Δ-DBP: diastolic blood pressure delta; Δ-SBP: systolic blood pressure delta; UAE: urinary albumin excretion; HMOD: hypertension-mediated organ damage.

Since a relationship was found between orthostatic BP decrease and renal HMOD defined by its categorical variables, its relationship with eGFR and UAE as quantitative markers of damage was also assessed. It was observed that, for both SBP and DBP, patients with an orthostatic BP reduction above the median had lower eGFR values. Regarding SBP reduction, group 1 showed an eGFR of 68 ± 17.4 mL/min/1.73 m2 versus an eGFR of 61.7 ± 17.5 mL/min/1.73 m2 in group 2 (p = 0.02). Similarly, for DBP, eGFR was 68.3 ± 14.8 mL/min/1.73 m2 in group 1 and 61 ± 19.9 mL/min/1.73 m2 in group 2 (p = 0.01). Regarding the BP delta and increased UAE as a continuous variable, no significant differences were observed for SBP; however, for the DBP delta, values were 7 mg/g (IQR: 14) in group 1 and 14 mg/g (IQR: 64) in group 2, with a trend toward statistical significance (p = 0.07). These results were maintained after adjustment for age, office BP, and alpha-blocker treatment.

The present study shows that a more pronounced orthostatic BP reduction is associated with renal damage, particularly with lower eGFR, in our population of functionally preserved elderly hypertensive patients. However, orthostatic BP reduction was not associated with cardiac or vascular HMOD. Furthermore, conventionally defined OH was not significantly associated with HMOD, including renal impairment.

Previous reports have shown that the prevalence of OH is highly variable, ranging from 6% to 50%, depending on age (meta-analyses show a prevalence of up to 24% in those older than 65 years), clinical comorbidities (higher frequency is observed in patients with autonomic neurodegenerative diseases, diabetes, or HTN), and the use of certain drugs (antidepressants, diuretics, vasodilators, or adrenergic antagonists).16,17 In our functionally preserved elderly hypertensive population, 21% of patients had OH, with a higher prevalence among those with a history of CV events, dyslipidemia, and alpha-blocker use, consistent with previous reports.18 We also observed, as expected, that patients with OH had higher central and peripheral SBP values.

Regarding the conventional definition of OH, there is great heterogeneity among different clinical guidelines regarding the timing of measurement after standing.9,19,20 In most studies, OH assessment has been based on the classic definition (a sustained reduction in SBP of at least 20 mmHg or in DBP of at least 10 mmHg within 3 min of standing after the patient has been in the supine position for at least 5 min). However, beyond the lack of consensus in its definition, this measurement may not capture the full pathophysiological spectrum of the phenomenon, such as earlier- or later-onset BP drops, or those of lesser magnitude. In this context, some authors have proposed analyzing OH as a continuous variable.21,22 Furthermore, BP drops upon standing have been described as being associated with HMOD even when they do not meet the classic diagnostic criteria for OH, which has given rise to the concept of "orthostatic hypotensive stress".22 This term postulates that organ damage results from hypoperfusion and hypoxia secondary to repeated BP decreases throughout the day. In this regard, 24-h ABPM allows the detection of BP drops that are not captured by conventional OH diagnostic criteria.

In our study, since the patient distribution based on the classic OH definition was heterogeneous, we also analyzed BP changes as a continuous variable. Using the median as a cutoff, with a value close to 0 mmHg, allowed a more homogeneous group distribution, improved statistical power, and simplified interpretation by creating a clear distinction between patients with a positive BP change upon standing and those without one.

Our results show that functionally preserved elderly hypertensive patients with a more pronounced orthostatic BP reduction more frequently present renal HMOD, and that this association is independent of office BP, age, and alpha-blocker treatment. Frailty was also not considered a confounding factor due to the previously mentioned inclusion criteria, in which functional and cognitive assessment was performed using the Barthel index and the Pfeiffer test, respectively. Our results are consistent with those of other cross-sectional studies that have shown a higher prevalence of reduced eGFR in the presence of OH.23 Since this is a cross-sectional study, we cannot establish causality; however, other prospective studies have supported the association between OH and renal impairment in middle-aged populations, with OH found before the development of chronic kidney disease (CKD).22,24,25 Conventionally defined OH was not associated with renal impairment in our study, possibly due to the low proportion of patients meeting the classic OH criteria.

To our knowledge, only one other observational study has separately investigated the effects of orthostatic SBP and DBP changes on renal HMOD, defined not only by eGFR but also by proteinuria.22 However, Ko et al.22 found an association between eGFR-based renal damage and BP reduction, but not with proteinuria. It is important to note that proteinuria in their study was defined qualitatively using dipsticks. In contrast, our study measured UAE quantitatively using the albumin-to-creatinine ratio, which provides greater sensitivity and specificity. Additionally, UAE was determined as the average of two independent samples, as described above.

Regarding the other organs analyzed, although a higher percentage of patients with OH had a history of CV events compared with the group without OH, we found no association with cardiac HMOD. Similarly, no association was observed with vascular damage according to aPWV. This is probably due to the very high prevalence of vascular damage in this elderly population.

The mechanisms by which orthostatic BP reduction may promote renal damage are diverse: 1) decreased renal blood flow that would cause renal hypoperfusion and ischemia, with consequent reduction in oxygen and nutrient supply; 2) activation of the renin–angiotensin–aldosterone system and other vasoactive pathways, which may exacerbate renal inflammation and fibrosis; and 3) autonomic dysfunction, which could affect innervation of the renal microcirculation.10,26 On the other hand, we cannot rule out the possibility that sympathetic nervous system abnormalities associated with renal damage contribute to orthostatic BP changes.

Our study has several limitations. First, its cross-sectional nature allows the description of associations but does not permit exploration of the predictive value of OH in the development, progression, or regression of renal HMOD. Second, our relatively small sample size could limit the generalizability of the findings. Third, we did not study neuroendocrine mechanisms that could contribute to impaired orthostatic homeostasis and/or trigger the activation of other biological effectors capable of inducing HMOD. Fourth, patients tend to have more symptoms upon waking, and morning orthostatic measurements are more sensitive for detecting OH. In our study, orthostatic BP was measured in the office and not at home.

In conclusion, functionally preserved elderly hypertensive patients who experience more pronounced BP decreases upon standing present greater renal damage compared with those without such decreases. These findings reinforce the importance of routine orthostatic BP assessment in clinical practice to identify hemodynamic changes associated with standing, which may contribute to orthostatic hypotensive stress and potential renal damage.

Research idea: AdlS and PFL; study design: AdlS, ARG, and PFL; data acquisition: AO, CC, FC, NA, PA, PC, and SV; data analysis/interpretation: AdlS, ARG, and PFL; statistical analysis: AdlS and ARG. Each author contributed important intellectual content during manuscript writing or revision and accepts responsibility for the work as a whole, ensuring that issues related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

This work was funded by a grant from the Spanish Society of Nephrology: "Research Grants in Nephrology" (Fundación SENEFRO, Sociedad Española de Nefrología), awarded to Patricia Fernández-Llama.