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The Challenges of Blood Pressure Control in Hemodialysis Patients
Introduction
Hypertension is a risk factor for chronic kidney disease (CKD) that increases in prevalence as CKD progresses, and it is nearly universal in patients with kidney failure. The hemodialysis (HD) procedure itself induces hemodynamic changes throughout the course of treatment that warrant routine pre-, post-, and intradialytic blood pressure (BP) monitoring for safety purposes. Consequently, this generates an abundance of highly variable data between and within patients that make interpretation of cardiovascular and mortality risk as well as decisions on management very challenging. Compared to the general adult population and even patients with CKD, evidence-based guidelines for both BP targets and even specific pharmacologic antihypertensive therapy are lacking in HD patients. The purpose of this chapter is to present the unique challenges associated with the diagnosis and management of hypertension in HD patients. This includes emphasis on the role of extracellular volume (ECV) overload in this population, the significance of intradialytic and interdialytic BP changes, and discussion related to the pharmacologic treatment of hypertension in HD patients. While uncertainty exists for specific guidelines in many circumstances, this chapter provides some strategies for how to address frequently occurring situations that are independently associated with harm and other important considerations for managing hypertension in HD patients. The primary focus of the chapter is on the majority of HD patients that receive standard thrice-weekly in-center HD.
Pathophysiology of Hypertension in Hemodialysis Patients
Hypertension is present in approximately 30%–50% of the general population, but its prevalence is disproportionately higher in patients with CKD and greater with each incremental stage of CKD. Among patients with kidney failure, nearly 90% have hypertension (defined by systolic BP > 140 mm Hg or use of an antihypertensive drug) with little difference in distribution between varying demographics based on age, sex, race, or ethnicity. There are numerous mechanisms that contribute to the high prevalence of hypertension in this population ( Table 44.1 ), and the unifying result is that they act to increase cardiac output, vascular resistance, or both. The overlap of many of these mechanisms may also explain why it is difficult to manage hypertension by targeting a specific individual process alone. ECV overload is a critical factor in hypertension in HD patients, so for the sake of this chapter, we will consider it separately after reviewing other mechanisms that are not related to ECV overload.
Table 44.1
Mechanisms Contributing to Hypertension in Hemodialysis Patients
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Factors Not Related to Extracellular Volume Overload
Sympathetic nervous system hyperactivity has been proposed to be one important mechanism contributing to hypertension in patients with kidney failure. This is based on the higher rate of postganglionic sympathetic-nerve discharge from the peroneal nerve observed in kidney failure patients compared to controls. It is of interest that a kidney transplant does not necessarily reduce sympathetic nervous system activity, but nephrectomy does. This suggests that the primary stimulus for the increased activity is likely not related to uremic toxins but rather signaling from the native kidneys. While adrenergic receptor blockers are not considered first-line therapies for patients in the general population, there is interest in how some of these agents might be particularly beneficial in HD patients (see later section on “Pharmacologic Antihypertensive Use”).
Increased activity of the renin-angiotensin system (RAS) is another factor proposed to be responsible for hypertension in HD patients. Failing kidneys can still secrete renin even in the context of impaired glomerular filtration rate, and individuals with advanced kidney disease have inappropriately elevated levels of RAS activity given the relative degree of ECV overload. Before the era of targeted pharmacologic RAS inhibition, there was evidence that (1) at least a subset of hypertensive HD patients had hypertension that was strongly associated with circulating levels of RAS mediators, including renin and angiotensin II, and (2) there was a strong correlation between reductions in these mediators and BP following bilateral nephrectomy. Inhibitors of the RAS system are first-line agents in the general population and remain frequently prescribed for HD patients, although the specific long-term benefits in this population are less clear (see later section on “Pharmacologic Antihypertensive Use”).
While the RAS mediator angiotensin II can induce vasoconstrictive effects by binding to receptors on vascular smooth muscle cells, vascular tone is further influenced by endothelial cell-derived mediators, including the vasoconstrictors endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA). ET-1 is released from endothelial cells, while ADMA is an endogenous inhibitor of nitric oxide synthase and can interfere with nitric oxide-induced vasodilatation. There is limited direct evidence of the hypertensive effects of these mediators in HD patients, but there is evidence that ADMA is significantly elevated in kidney failure patients and associated with higher cardiovascular events and mortality in this population. In addition to the worsening of endothelial cell function that may occur in HD patients as a comorbidity, there is also concern that the commonly prescribed erythropoietin stimulating agents may contribute to hypertension by increasing release of ET-1.
A separate concern related on the vascular biology of kidney failure patients is the potentially irreversible effects to blood vessels that can result from bone mineral disease. The combined calcium-phosphorus product has been associated with higher mean arterial pressure in HD patients. Hyperphosphatemia can contribute to vascular medial calcifications, and vascular calcification of various arterial beds is exacerbated by exposure to exogenous calcium through either the dialysate or calcium-containing phosphorus binders. There are likely multiple mechanisms to explain these associations, but poorly controlled renal osteodystrophy, in general, is likely yet another contributing factor to hypertension in HD patients.
Finally, an HD patient’s response to various pharmacologic antihypertensives may vary greatly compared to those with normal or less severely impaired kidney function. In addition to consideration of the kidney clearance of medications that may vary, one must consider the dialyzability of the individual drugs, which can even vary within the same drug class. As with other toxins and medications, the dialyzability will depend upon factors related to molecular weight, protein binding, and water solubility. In short, either excessive or insufficient levels may result due to severely impaired glomerular filtration rate and the thrice-weekly dialysis schedule itself.
Extracellular Volume Overload
ECV overload is one factor that is particularly important and unique in the kidney failure population because these patients have lost most, if not all, ability to excrete sodium and water naturally through the kidneys. These circumstances predispose dialysis patients to ECV overload and make them largely reliant on the dialysis procedure to treat it. The patients go through phases of acute ECV expansion during each interdialytic period, and they can develop chronic extracellular overload if the appropriate target weight is either not identified correctly or is not able to be achieved due to limitations of fluid removal during dialysis.
The initial increase in BP from acute ECV expansion is likely due to increased cardiac output, but persistence of the volume expanded state can ultimately sustain high BP through a delayed increase in vascular resistance. In prevalent HD patients, the overall BP burden between dialysis treatments is more strongly associated with chronic ECV overload than it is with the acute interdialytic weight gains. Gradual dry weight lowering reduces both intradialytic BP and ambulatory BP as further support to the critical importance of controlling volume in order to control BP.
While ECV overload and hypertension can frequently coexist, it is important to acknowledge the independent effect of ECV overload on outcomes. Using either biomarker such as brain natriuretic peptide or bioimpedance spectroscopy to define ECV overload, there is evidence that patients who are more volume overloaded have higher mortality risk compared to patients who are more euvolemic. For any given range of systolic BP, the presence of ECV overload is associated with higher mortality risk. Because of this independent association, the lack of evidence-based guidelines supporting a specific BP target (discussed in detail later), and the influence of ECV management on intra- and interdialytic blood patterns, it is advisable to emphasize cautious but persistent optimization of ECV in HD patients to help stabilize BP and possibly improve outcomes in general.
Blood Pressure Targets in Hemodialysis Patients
Although hypertension becomes more prevalent as kidney disease progresses in patients, the management strategies for patients with and without advanced CKD are not exactly the same. There is evidence of a linear relationship between mortality and systolic BP in the general population, but there has consistently been shown to be a U-shaped curve that defines the relationship between BP measured before or after dialysis with mortality in HD patients. The Systolic Blood Pressure Reduction Intervention Trial identified the superiority of a target systolic BP < 120 mm Hg compared to 140 mm Hg among individuals with hypertension and at least one additional cardiovascular risk factor using the primary composite outcome of multiple individual cardiovascular endpoints and death from any cause. There were no kidney failure patients in this trial, but 28% had CKD. There were no differences between the two study arms in the occurrence of the primary endpoint among the CKD subgroup, but subsequent analysis identified that intensive BP lowering reduced mortality in the CKD participants. The current recommendation from the American Heart Association for patients with CKD is to target a BP of 130/80 mm Hg. Presently, there is no such trial with conclusive evidence of an ideal BP target in HD patients. The Blood Pressure in Dialysis (BP in HD) Trial was a pilot study investigating the effects of targeting a pre-HD systolic BP of 110–140 mm Hg compared to standard control (155–165 mm Hg) that found no difference in cardiovascular endpoints but increased risk of access thrombosis, hospitalization, and hypotension in the intensive group. While this study fails to identify an ideal target for predialysis BP, its results may not necessarily be generalizable for strategies that target post-HD BP targets. The current existing guidelines from the Kidney Disease Outcomes Quality Initiative recommend targeting a predialysis BP of 140/90 mm Hg or a postdialysis BP of 130/80 mm Hg. These recommendations likely stemmed from observational data that incremental increases in BP above these thresholds are associated with a higher risk for de novo congestive heart failure or coronary artery disease.
These recommended targets can be challenging to achieve, and they also fail to address the larger context of BP in this patient population with regard to the frequent BP changes that occur both during and between HD treatments. There are peridialytic and intradialytic BP patterns/behaviors that are now recognized as being associated with greater underlying cardiovascular risk and poor general prognosis. Several large epidemiologic studies show a U-shaped curve for the association between change in BP from pre- to post-HD and mortality, demonstrating a poor prognosis from large decreases in BP or any increase in BP from pre- to post-HD. Independent of these peridialytic measurements, the frequent occurrence of intradialytic hypotension during the treatment is also associated with higher mortality. So even when pre or postdialysis BP targets are achieved, the presence of intradialytic hypotension or intradialytic hypertension should alert clinicians that the patient has high-risk features that warrant consideration of modifying the management. Attempts should also be made to ascertain BP outside the dialysis unit with ambulatory BP monitoring or intermittent home BP measurements as these provide superior prognostic information regarding mortality and end-organ damage compared to pre and postdialysis measurements. If measurements from outside the dialysis unit are not available for review, one can increase the accuracy of predicting the ambulatory BP by considering the average of all intradialytic and peridialytic BP measurements.
We will discuss these specific challenges in BP management in HD patients in greater detail following a brief discussion on the “typical” response to an HD treatment.
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