Treatment of hypertension represents a major area of intervention for cardiovascular risk reduction in dialysis patients.

I. DEFINITION AND MEASUREMENT. Blood pressure (BP) is commonly measured across hemodialysis, but peridialytic measurements do not adequately reflect the BP burden. Indeed, measurements made immediately before dialysis overestimate the underlying average BP, and the reverse is true for postdialysis BP. Thus outof-office BP monitoring is the preferable method for diagnosing and monitoring BP in hemodialysis patients. Both home and 24-hour ambulatory BP monitoring (ABPM) can be applied, but ABPM is rarely used in a routine chronic hemodialysis setting unless some unusual problem with BP is suspected. Estimates based on home BP are more reproducible than pre- and postdialysis BP, and associate with ABPM better than peridialytic measurements (Agarwal, 2012). Furthermore, home measurements reflect target organ (left ventricular hypertrophy [LVH]) and cardiovascular prognosis better than pre- and postdialysis measurements (Agarwal, 2009). Two daily home measurements, one in the morning and the other before the night sleep, taken the day after a midweek dialysis session, averaged over 4 weeks are considered adequate for the diagnosis of hypertension (Agarwal, 2009). The frequency of measurements should be higher when BP lability is noted. Midweek median intradialytic BP is a more sensitive indicator of the prevailing BP burden (i.e., average ABPM) than predialysis or postdialysis BP and may be applied when home measurements are not feasible (Agarwal and Light, 2010). When ABPM is done, the period of monitoring should ideally cover the whole interdialytic interval (44 hours with a 3-perweek schedule, beginning after the midweek session). Although long sessions of ABPM are generally poorly tolerated, ABPM can give some information regarding the nocturnal BP profile, which is frequently altered in dialysis patients, but effective means of correcting lack of nocturnal BP dipping in this population have not been determined.

The definition of hypertension (Table 33.1) depends on the method of measurement (average home BP: >135/85 mm
Hg; ABPM: >130/80 mm Hg; midweek median intradialysis BP: >140/90 mm Hg). Average home BP >135/85 mm Hg is considered a valid threshold for the definition of hypertension in patients on both hemodialysis and peritoneal dialysis. High visit-to-visit BP variability is common in end-stage kidney disease (ESKD) patients and is a strong predictor of mortality (Rossignol, 2012). Methods of reducing BP variability in this population have not been systematically evaluated.

II. PATHOPHYSIOLOGY

A. Extracellular volume expansion and sodium retention remains the main cause of hypertension. A relationship between chronic volume expansion and mortality is well established (Wizemann, 2009). There is an association between ECF volume expansion and diastolic dysfunction in dialysis patients (Joseph, 2006), and it is not always clear to what extent volume overload is a cause rather than a marker for severe cardiac disease. Recent attention has been called to nonosmotic accumulation of sodium in the subcutaneous space and in other organs. Nonosmotic accumulation of sodium in the muscles has been found in human hypertension (Kopp, 2013), and a similar finding was documented over 30 years ago in dialysis patients (Montanari, 1978). The consequences of nonosmotic sodium accumulation in various tissues are not fully known, but elevated sodium stores may impact inflammatory and cardiac fibrotic processes
via vascular endothelial growth factor C (Mallamaci, 2008; Machnik, 2010) and other mechanisms.

B. Inappropriately high vascular tone. Sodium accumulation in arterial smooth muscle cells may contribute to increased vascular stiffness. Sleep apnea, a condition characterized by high sympathetic activity, is exceedingly common in dialysis patients, and associates with vasoconstriction and nocturnal hypertension. Sympathetic overactivity triggered by afferent signals originating in diseased kidneys can cause secondary activation of the renin-angiotensin system, and this may play an important role in the high peripheral vascular resistance seen in ESKD. In fact, there are reports of BP and sympathetic activity both falling dramatically after bilateral nephrectomy (Converse, 1992) in dialysis patients, and radiofrequency ablation of renal sympathetic nerve fibers produces similar effects (Schlaich, 2013). Asymmetric dimethyl-arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is elevated in dialysis patients, and high levels associate with elevated sympathetic nervous system activity (Mallamaci, 2004).

C. Hypertension and left ventricular hypertrophy. The usual reasons for treating hypertension are to reduce the risk of stroke and cardiovascular events. One popular surrogate outcome for cardiovascular events and mortality is the presence of left ventricular hypertrophy, and many studies looking at reduction of fluid overload and/or antihypertensive treatment of dialysis patients have focused on change in left ventricular mass. It is important to realize that substantial left ventricular hypertrophy can be present in dialysis patients even at normal levels of BP (Mominadam, 2008), and that when one is optimizing extracellular fluid status, one is doing it not only to control BP, but also aiming at optimizing cardiac structure and function.

III. TREATMENT

A. Prevention

1. Sodium and fluid restriction. Most fluid intake is driven by salt ingestion, and nutritional recommendations are discussed in Chapter 31. Patients should be encouraged to restrict sodium chloride ingestion to 5 g per day (2 g or 87 mmol sodium). Another source of sodium is diffusive gain from dialysis solution when the dialysate sodium is greater than the predialysis plasma level. Many units tend to use the same dialysate sodium level for all dialysis patients, regardless of their predialysis sodium, while patients’ predialysis sodium levels may range from 130 to 145 mmol/L. Use of a dialysate sodium higher than that of plasma can improve hemodynamic tolerance to fluid subtraction but increases thirst and fluid intake postdialysis. This results in an increased interdialytic weight gain, which then requires a higher ultrafiltration rate during the next dialysis. Some nephrologists favor use of “sodium profiling,” where, with the aid of an advanced dialysis machine, one can begin
the dialysis session with a sodium level higher than the patient’s plasma level, and then progressively reduce dialysate sodium during the treatment, so that dialysis ends it with a dialysate sodium below the initial plasma level. Sodium profiling can offer some of the benefits of higher sodium dialysis in terms of hemodynamic stability while minimizing the interdialytic weight gain effect, but only if the time-averaged dialysate sodium level during the session does not exceed the initial plasma level.

Preliminary data suggest that lowering dialysate sodium unitwide (from 140 to 137 mM) may reduce interdialytic weight gain as well as fluid-related hospitalization rate (Lacson, 2011).

2. Longer and/or more frequent dialysis sessions. These are discussed in Chapter 16. Frequent dialysis schedules and long, nocturnal dialysis may substantially improve BP control in hypertensive dialysis patients and revert LVH. Apart from frequency, increasing the length of a dialysis session allows for a slower ultrafiltration rate, and increases the time available to finish dialysis at the desired postdialysis weight.

B. Correction of salt and fluid overload

1. Clinical assessment of dry weight. Ideally, a dialysis treatment should bring the patient back to a normal extracellular volume. In clinical practice, the “dry weight” is defined as the level below which further fluid removal would produce hypotension, muscle cramps, nausea, and vomiting. However, the occurrence of such symptoms depends on how quickly fluid is removed, on the dialysis strategy used, on the predialysis volume status, and on concomitant drug treatment (many antihypertensive drugs impair the reflex cardiovascular adjustments to volume removal).

a. Time delay in BP fall after correction of fluid overload. There may be a time delay between lowering extracellular fluid and correction of markedly elevated BP (Charra, 1998). For this reason, if BP does not reduce initially after lowering the dry weight, this does not exclude hypervolemia as a cause of the hypertension. The lag phenomenon fits well with the hypothesis that nonosmotic sodium accumulation may occur in dialysis patients. Although it may take a considerable amount of time for this sodium to be removed from various tissue spaces (this has not been well studied), it is more likely that delayed improvement in hypertension after correction of longstanding fluid excess is due to vascular remodeling.

b. Need for frequent reassessment. Dry weight and the nutritional status should be reevaluated frequently, because loss of muscle mass due to malnutrition or to intercurrent illness can result in fluid overload. For example, when a patient returns to the dialysis unit after a hospitalization, the previously determined level of “dry
weight” will almost always need to be reset to a lower level, due to intercurrent loss of lean body mass.

2. Technology

a. Bioimpedance analysis (BIA). The assessment of dry weight is based on subjective clinical assessment. Tracking optimal dry weight by the usual clinical criteria (presence of edema, jugular venous distension, lung râles) may be difficult. Furthermore, edema may not be detectable until the interstitial volume has risen by about one-third above normal (e.g., about 5 L). Multifrequency bioimpedance spectroscopy has now emerged as a reliable method to measure body fluids. The Body Composition Monitor (BCM, Fresenius Medical Care, Germany) is one such device that has been well validated in dialysis patients (Moissl, 2006). The application of a BCM-based treatment policy aimed at minimizing fluid overload has been used to control hypertension in a dialysis setting (Moissl, 2013). In a randomized controlled trial, a BCM-guided fluid management approach led to clear-cut improvement in left ventricular mass index and vascular stiffness (Hur, 2013). However, no evidence has been produced so far that use of BCM-guided “dry weight” increases survival or reduces fluid-related hospitalization.

b. Other methods. Continuous recording of hematocrit during dialysis (Crit-line Monitor) is considered a useful method, but a clinical trial testing the hypothesis that the systematic use of this device would improve clinical outcomes found higher, rather than lower, nonvascular and vascular access-related hospitalizations and mortality as compared with conventional monitoring (Reddan, 2005). Ultrasonography of the inferior vena cava diameter or the measurement of the diameter of the left atrium are both sensitive to volume changes but do not reflect interdialytic BP (Agarwal, 2011) and are therefore of limited value for assessing dry weight. Serum levels of brain natriuretic peptide (BNP) largely reflect left ventricular mass (Zoccali, 2001) and are unsuitable for volume monitoring (Agarwal, 2013). Pulmonary congestion can be detected and monitored by an easy to apply, reliable ultrasound technique that can be performed with virtually all ultrasound machines and probes (Mallamaci, 2010). Lung congestion is a strong predictor of death and cardiovascular events (Zoccali, 2013). Use of lung ultrasonography to help establish dry weight in dialysis patients with heart disease is attractive in theory, but its ability to improve hard outcomes such as hospitalization or mortality has not been tested.

C. Common clinical problems

1. Excessive ultrafiltration. Overzealous ultrafiltration may precipitate severe hypotension and disastrous cardiovascular consequences such as myocardial or cerebral infarction
and mesenteric ischemia. Frequent intradialytic hypotensive episodes are associated with increased mortality, although it is not clear whether this association is causal in nature (Shoji, 2004). Intradialytic hypotension is also associated with “myocardial stunning” (manifesting as cardiac wall motion abnormalities) and with subtle ischemic changes to brain white matter linked to mood and cognition (Selby, 2014

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