Epidemiology, Pathophysiology, and Clinical Perspectives of Intradialytic Hypertension

Patients on hemodialysis (HD) are faced with numerous associated complications, including cardiac arrhythmias, dialysis disequilibrium syndrome, reactions to the HD membrane, air embolism, bleeding, and intradialytic blood pressure (BP) variations, among others. Concerning the latter, intradialytic hypertension (IDHYPER) is a frequently encountered phenomenon that lacks a standardized definition and therapeutic approach, mandating additional research. In this review article, we aimed to showcase the current landscape concerning the epidemiology, pathophysiology, clinical correlates, and therapeutic options in IDHYPER.

Several definitions of IDHYPER have been proposed. According to the latest Kidney Disease: Improving Global Outcomes (KDIGO) suggested definition, a systolic BP rise >10 mm Hg from pre- to post-dialysis in the hypertensive range in at least four out of six consecutive HD treatments [1]. A 10 mm Hg increase in systolic BP with HD was used by Inrig et al. [2] to define IDHYPER. Other studies have opted not to use cutoffs and instead defined IDHYPER based on higher BP at the end of multiple HD sessions [3, 4], or in cases of hypertension that is resistant to ultrafiltration, occurring during or immediately after the session [5]. Therefore, it becomes evident that IDHYPER definition is still a matter of debate. Common risk factors for increased occurrence of IDHYPER are the older age, small intradialytic weight gains, lower serum albumin and pre-dialysis blood urea nitrogen levels, and the use of antihypertensive medications [6]. Crucially, IDHYPER may also present in patients without hypertension [6].

IDHYPER has a rather complex pathophysiology and the exact mechanisms can vary between patients. It can result from increased cardiac output, augmented total peripheral resistance, or fluid overload. Beginning with the latter, it is believed to be a key contributor to IDHYPER, as many patients do not appear to have acute extracellular volume expansion and are falsely prescribed less ultrafiltration than other patients. IDHYPER has been associated with extracellular fluid excess [7], and a post-dialysis body weight decrease is able to correct the intradialytic BP rise [3, 4]. As recently shown by McAdams et al. [8], post-HD extracellular volume divided by patient weight was associated with mean ambulatory BP in HD patients with IDHYPER.

The role of endothelin-1 (ET-1) and endothelial dysfunction has long been suggested as causal in the pathogenesis of IDHYPER, possibly due to the increased total peripheral resistance and vasoconstriction. Teng et al. [9] found that abnormally high ET-1 and the ET-1-to-nitric oxide (NO) ratio were characteristic findings in patients with IDHYPER. ET-1 levels were elevated in subjects with IDHYPER in the study of Li et al. [10] and were also correlated with mean arterial pressure. Furthermore, in a study of 769 HD patients, baseline ET-1 levels were associated with both baseline systolic BP and the risk of developing IDHYPER (odds ratio: 1.21, 95% CI: 1.10–1.34) [11]. A genetic susceptibility could also be present, since a study on an Egyptian HD patient population found that the pre-pro-endothelin gene polymorphism A(8002)G could account for the elevated ET-1 levels and, thus, greater risk of IDHYPER development [12]. Low blood zinc levels may contribute to IDHYPER, as suggested by the study of Liu et al. [13] in 144 HD patients (odds ratio: 0.43, 95% CI: 0.30–0.64). As a result, hypozincemia could activate the hypoxia-inducible factor-1/ET-1 pathway, resulting in increased secretion of ET-1 and migration of endothelial cells [14]. Ultimately, deficiency in endothelial NO production is evident [15].

The removal of excess fluid from the body can lead to a decrease in intravascular volume, resulting in central translocation of blood toward the heart, stimulation of the sympathetic nervous system, and enhanced release of catecholamines, such as adrenaline and noradrenaline, which can increase heart rate, myocardial contractility, and cardiac output. An increase in cardiac output can result in an increase in BP if the peripheral vascular resistance remains constant. Patients with IDHYPER may also exhibit excessive stimulation of the renin-angiotensin-aldosterone system that could be associated with intravascular volume depletion, resembling a model of renovascular hypertension. Despite the presence of end-stage renal disease, activation of the renin-angiotensin-aldosterone system and renin secretion occur even in the lowest glomerular filtration rate ranges. The subsequent release of aldosterone, which can increase sodium and water reabsorption in the kidneys, leads to an increase in blood volume and BP.

Sodium is the main electrolyte that is associated with IDHYPER. Large salt intake in HD patients contributes to a modified endothelium metabolism with a decreased NO and an increased asymmetrical dimethylarginine production [16]. Despite the hypothesized link between the sodium overload and endothelial dysfunction leading to IDHYPER, it should be noted that the changes in intradialytic BP with low dialysate sodium do not relate to lower ET-1 levels, according to the study of Inrig et al. [17]. Moving to potassium, whose lower serum levels can have a direct vasoconstrictor effect, the role of dialysate potassium in intradialytic BP is uncertain. Notably, hypokalemia induced by a low-potassium dialysate may cause rebound hypertension after HD. Finally, and with regards to calcium, an acute increase in ionized calcium levels augments myocardial contractility, cardiac output, and may ameliorate hemodynamic instability during HD [18]. A high-calcium dialysate has also been noted to decrease arterial compliance and increase arterial stiffness [19]. However, patients have shown IDHYPER using standard calcium dialysate, questioning its role in IDHYPER.

IDHYPER represents a frequent finding among patients on regular HD, with several research efforts being conducted in this field, as shown in Table 1. According to a recent study conducted in a single HD center in Pakistan, the prevalence of IDHYPER was 16% using the KDIGO IDHYPER definition, and this finding was more common in the elderly and those on antihypertensive medication [20]. A lower rate of IDHYPER (5% of sessions) was found in a cohort of HD patients in Eritrea [21]. Concerning the USA patient population, in a large cohort of 1,748 incident HD patients, the prevalence of IDHYPER was estimated at 12.2% [22]. In the blood pressure in dialysis clinical trial, 8.8% of the participants exhibited IDHYPER [23]. Data concerning IDHYPER in European populations is scarce, with a Greek two-center study of 76 HD patients reporting an IDHYPER prevalence of 19.7% [24]. In a South African population of 190 chronic HD patients, the investigators noted an increased IDHYPER prevalence of 28.4% [25].

Concerning risk factors, patient-related variables, older age, and small interdialytic weight gains may predispose to a greater risk of developing IDHYPER [6, 26]. We should also mention that several blood markers have been associated with IDHYPER, including low serum albumin, folate, magnesium, and pre-HD blood urea nitrogen [6, 26, 27]. Moving to HD-related factors, the performance of HD sessions in late AM or late PM was related to an augmented risk of IDHYPER [28]. Finally, patients who receive iron sucrose supplementation may be exposed to IDHYPER, according to a recent study [29].

As far as the clinical implications of IDHYPER are concerned, it could relate to impaired ambulatory central BP and pulse wave velocity, which are poor prognostic factors for mortality in HD [30]. Moreover, Shamir et al. [23] found that IDHYPER was associated with left ventricular mass index since every 1 mm rise in Δ systolic BP during HD was associated with 0.2 g/m² increase in left ventricular mass index in adjusted models. Other correlates of IDHYPER include chronic malnutrition, inflammation, and metabolic acidosis, as suggested by Raikou et al. [24].

It should be stated that the association between IDHYPER and ambulatory BP measurements in the interdialytic period is controversial, with recent studies producing conflicting results [31, 32]. However, average interdialytic BP readings could be reliable prognostic indicators of major adverse cardiovascular events, similarly to ambulatory BP, as shown in an analysis of 242 HD patients by Iatridi et al. [33].

Regarding the association of IDHYPER with mortality, it appears that the highest mortality risk is detected when IDHYPER is defined as any BP increase from pre- to post-HD (hazard ratio: 1.32, 95% confidence interval: 1.05–1.66) in a study of 3,198 HD patients [34]. We should mention that the researchers found a significant interaction with age between 45 and 70 years old and the lack of peripheral vascular disease [34]. The age-adjusted mortality risk was 2.9-fold higher in the presence of IDHYPER, according to a study of 73 HD patients [35]. Based on a prospective study of 120 HD patients who were followed up for 12 months, IDHYPER was associated with considerably higher rates of nonaccess-related hospitalization and mortality [36]. It is crucial to note that the frequency of IDHYPER episodes is an aggravating factor since individuals with IDHYPER in >67% of HD exposure had higher risk of mortality and hospitalization [37].

As IDHYPER represents a common finding in patients with HD, research has also focused on the possible ways of managing this phenomenon. Below, we discuss the current concepts in the pharmacologic options, management of volume overload, and the available efficacious alterations of HD-related parameters that may aid in lowering the rates of IDHYPER, as depicted in Figure 1.

Regarding antihypertensive agents, and b-blockers in particular, carvedilol produced greater reductions in pre-HD, intradialytic, and post-HD BP measurements when compared to metoprolol in a prospective study of 48 young HD subjects [38]. As sympathetic overdrive could be a core pathophysiologic mechanism of IDHYPER, b-blockers may be superior to a renin-angiotensin system blocker, as shown by a randomized, cross-over study of 38 patients with IDHYPER treated with nebivolol and irbesartan [39]. Additionally, nebivolol could similarly reduce post-HD and 24-h central systolic BP and pulse wave velocity [40]. The L/N-type calcium channel blocker, cilnidipine, has also been tried in the setting of IDHYPER, since it may affect sympathetic nervous system function. Although the reduction of systolic BP in patients with IDHYPER did not reach statistical significance [41], it remains an option that could be employed on an individualized basis. It should be stressed that angiotensin receptor blockers and calcium channel blockers are not removed by dialysis. Several angiotensin-converting enzyme inhibitors (captopril, enalapril, lisinopril, perindopril, ramipril) and b-blockers (atenolol, metoprolol, nadolol) are significantly removed by dialysis, whereas others are not (fosinopril, propranolol, pindolol, esmolol, bisoprolol, carvedilol, acebutolol).

When considering the pharmacologic options in IDHYPER, one should take into account the available evidence of antihypertensive agents in patients with chronic HD. For nondialyzable drugs, carvedilol, losartan, valsartan, candesartan, and amlodipine have led to lower rates of major adverse cardiovascular events in several studies [42‒45]. Additionally, spironolactone, a mineralocorticoid receptor antagonist was superior to placebo or no additional treatment in HD patients [46, 47]. Thus, when a substantial rise in BP occurs in the course of dialysis, in the majority of cases, a nondialyzable b-blocker (carvedilol, nebivolol) in combination with a nondialyzable renin-angiotensin system blocker (losartan, valsartan, candesartan) could be the first choice even in combination, followed by the administration of a calcium channel blocker (amlodipine) if the issue persists.

Perhaps the most important factor in the management of IDHYPER is the reduction of dry weight. The exact definition of dry weight remains a matter of debate, with multiple proposed definitions. The lowest tolerated post-HD weight at which there are minimal signs and symptoms of hypovolemia and hypervolemia may represent the most optimal definition [48]. Dry weight reduction should be gradual over days to weeks, with a goal of 200–500 mL per session. It is considered a simple, efficacious, and well-tolerated maneuver to improve BP control in hypertensive HD patients [49]. A previous study has shown that ultrafiltration volume is negatively associated with post-HD systolic BP [50]. Thrice-weekly sessions of at least 4 h duration may improve volume and BP control [51]. Performance of more frequent HD sessions was also shown to produce significant reductions in pre- and post-HD systolic BP compared to thrice-weekly sessions in the randomized controlled Frequent Hemodialysis Network Trials [52]. Additionally, altering the HD schedule to nocturnal sessions has been previously proven effective in reducing systolic BP according to a randomized clinical trial [53], but additional evidence is needed.

Precise assessment of dry weight that may lead to BP control is a challenging task. Loutradis et al. [54] also found ameliorated intradialytic BP regulation with the use of lung ultrasound-guided dry weight reduction in a randomized controlled trial of 71 clinically euvolemic HD patients. A small-scale study found such an effect to be only valid for IDHYPER patients presenting with increased pre-HD BP levels [55]. One could also use the intradialytic BP slopes as a measure of extracellular volume status and guide the management of HD patients accordingly [56]. The addition of left ventricular volume evaluation provides incremental predictive information to the extracellular volume/total body weight ratio for IDHYPER, as seen in the study of Ren et al. [57].

Several pitfalls should be acknowledged in attempting to reduce the patient’s dry weight in clinical practice. To begin with, the inability to accurately assess the dry weight represents the primary reason for inappropriate therapy. Clinical evaluation should be ideally corroborated with objective assessments such as lung ultrasonography or echocardiographic assessment of the inferior vena cava. Clinical inertia also plays an important role, as the feared risk of hypovolemic symptoms (hypotension, cramps, nausea, vomiting) may prevent the needed extracellular volume reduction. Moreover, physicians caring for HD patients should avoid easy measures of intradialytic hypotension treatment, which frequently include avoidance of further ultrafiltration, administration of hypertonic sodium and high-sodium dialysate, and ultimately premature termination of the session. Finally, patients should be instructed regarding dietary sodium (<4 g of sodium chloride per day) and fluid restriction, and their adherence should be strictly monitored. Avoiding sodium-containing or sodium-exchanging drugs could be an option that can be employed on a case-by-case basis.

Despite the importance of volume overload management, an association of intravascular volume depletion through excessive ultrafiltration with IDHYPER has been speculated due to pathophysiologic mechanisms mentioned above. This scenario has not been adequately explored in clinical studies, with the study of Kandarini et al. [58] highlighting that the vast majority of patients with IDHYPER exhibited excessive ultrafiltration (≥3L) sessions. However, the lack of data on patient hydration, either clinical or objective, precludes an accurate interpretation of those findings. Therefore, more research is needed to further understand the importance of excessive ultrafiltration in the development of IDHYPER.

Therapeutic interventions targeting HD-related factors may also be beneficial. According to a study of 50 HD patients, the use of low dialysate sodium led to ameliorated post-HD BP and lesser odds of developing IDHYPER when compared to standard dialysate sodium [59]. Similar findings were replicated in a prospective study of 40 HD patients [60]. Despite such beneficial effects of low dialysate sodium, a previously reported systematic review and meta-analysis has highlighted the potential deleterious effects of such practice, including ID hypotension and cramps [61]. Moving to isothermic HD, cooling of the dialysate to the patient’s body temperature resulted in significant improvement of BP metrics in patients with IDHYPER [62]. However, a previous systematic review and meta-analysis had suggested that reduced temperature HD led to an increase in mean arterial pressure of 12 mm Hg [63]. In all, it becomes clear that the benefit of such HD setting modifications has not been confirmed in randomized clinical trials and can only be cautiously employed on a case-by-case basis.

IDHYPER, a paradoxical increase in BP that is seen in approximately 15% of patients on regular HD, is a phenomenon with complex pathophysiology that involves endothelial dysfunction, volume overload, sympathetic nervous system, renin-angiotensin-aldosterone system, and electrolyte alterations. Although many definitions have been used in the conducted studies, it becomes apparent that IDHYPER is associated with cardiovascular sequelae and a higher risk of mortality. The field of its management remains obscure, with the reduction of excess extracellular volume being of primordial importance. Pharmacologic options are also available, with b-blockers and angiotensin receptor blockers being preferred in this setting.

The authors have no conflicts of interest to declare.

This work received no external funding.

P.T. and A.V. contributed to the design, drafted the work, and gave the final approval of the version to be published. R.K. contributed to the conception, revised the work critically, and gave the final approval of the version to be published.