Does this dialysis patient have hypertension?

The National Kidney Foundation’s Kidney Disease Outcome Quality Improvement program (KDOQI) published a guideline calling for a pre-dialysis systolic blood pressure (SBP) <140 mmHg. The evidence supporting this guideline was graded as weak since it was largely extrapolated from the general population in which a continuous reduction in cardiovascular disease (CVD) risk accompanies each mm Hg drop in SBP. Despite the continuing uncertainty surrounding the applicability of data derived from the general population to dialysis patients, the current definition of hypertension for dialysis patients is based on the KDOQI target. However, targeting a lower BP increases risk for intradialytic hypotension (IDH) and the untoward consequences of IDH (e.g., cardiac stunning). Therefore, the optimal BP target may need to be individualized. Randomized clinical trials are lacking.

Is he/she fluid overloaded?

A patient on maintenance dialysis therapy cycles from post-dialysis weight (ideally achieving a pre-determined “dry weight”) into accumulating fluid based on the balance of intake and loss from residual renal function, insensible loss (skin and gut) and of course, next dialysis treatment. This cycle of cumulative “fluid overload” is exaggerated in patients that have lost urine output treated with intermittent hemodialysis therapy and is least problematic with patients treated by continuous peritoneal dialysis with residual renal function. When fluid overload becomes symptomatic, it is a common cause of repeated hospitalization. The current definitions of “dry weight” and volume overload are vague. A patient’s estimated dry weight (EDW) is based on clinical assessment. It is usually determined by successively decreasing the post-dialysis weight until clinical symptoms or intradialytic hypotension occur. Objective measures of extracellular volume have been proposed to aid in establishing the EDW (See volume measurement and imaging section below). Of note, this is an area of active research in the absence of a true gold standard.

What tests to perform?

Blood pressure measurements

Routine dialysis unit systolic blood pressure measurements have significant limitations. The vast majority of dialysis clinics do not adhere to the American Heart Association (AHA) guidelines. Moreover, large inter and intra-patient variability has been reported, using routine dialysis unit blood pressure measurements. “Out of dialysis unit” blood pressure measures; eg, home blood pressure monitoring (HBPM) and ambulatory blood monitoring (ABPM) may be more strongly associated to clinical outcomes. However, adherence to HBPM and ABPM schedules has been noted to be poor. Furthermore, whether ABPM are the most reflective measures of a patient’s true blood pressure remains controversial. Finally, current clinical guidelines for the diagnosis and treatment of hypertension in hemodialysis patients are based on routine pre-dialysis systolic blood pressure.

Laboratory testing

Several biomarkers have been advocated as potential indicators of volume overload (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] and cylic guanosine monophosphate [cGMP]). However, all are fraught with excessive variability and poor correlation with volume status.

Volume measurement & Imaging

Since EDW is difficult to assess by physical exam, other methods have been used to guide ultrafiltration; e.g., extracellular fluid volume (ECFV) measurement by bioelectrical impedance, ultrasonic measurement of the inferior vena cava diameter and collapsibility upon inspiration, ultrasound measurement of lung water, and continuous intra-dialytic blood volume monitoring. These measures suffer from operator dependence, low accuracy and/or precision, and impracticality. Furthermore, none is sufficiently reliable to justify routine use in clinical practice.

How should patients with hypertension and fluid overload be managed?

Management of fluid overload

Dietary sodium restriction

The 2005 KDOQI Guidelines K/DOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients recommend reducing dietary sodium and ECFV as first steps in treating hypertensive dialysis patients. In the 2006 Update for Hemodialysis Adequacy, KDOQI states that “daily dietary sodium intake should not exceed 5g of sodium chloride (2.0g or 85 mmol of sodium).

Ultrafiltration

Avoidance of large interdialytic weight gains and control of ECFV facilitate blood pressure control. Ultrafiltration is an effective way to achieve EDW and lower blood pressure. Aggressive ultrafiltration may lead to regression in left ventricular mass, decreased left atrial and left ventricular systolic and diastolic pressures. Kayikiouglu et al. reported that the combination of dietary sodium restriction and ultrafiltration decreased the use antihypertensive agents and the prevalence of left ventricular hypertrophy. Given the lack of reliability of instrumental exams aimed at assessing ECFV, ultra filtration goals and EDW remain largely based on accurate physical exam and dry weight probing, in which dry weight is successively challenged to determine the lowest weight that does not precipitate intradialytic hypotension. Based on KDOQI recommendation, ultrafiltration “should be optimized with a goal to render the patient euvolemic and normotensive.”

Dialysate sodium concentration

Changes in dialysate sodium concentration may alter blood pressure. A variable dialysate sodium concentration, used judiciously, may lower antihypertensive medications requirement. A randomized crossover study demonstrated that a programmed decreased in sodium dialysate concentration from 155 to 135 mEq/L vs. a stable sodium dialysate concentration of 140 mEq/L lowered post-dialysis BP from 133/69 to 126/66 (p<0.05) and the use of antihypertensive medications. A fixed lower dialysate sodium concentration may also lower blood pressure, though this has not been consistent in all studies and the lower dialysate sodium may precipitate more intradialytic hypotension. Sodium neutral profiling may reduce intradialytic hypotension without increasing interdialytic weight gain. However, inadvertently pushing positive sodium balance by inappropriate prescribing or misuse of “sodium profiling” or using a high dialysate sodium concentration should be avoided.

Management of hypertension

Pharmacological agents commonly used in the treatment of hypertension in dialysis patients include:

Diuretics

To promote loss of sodium and water from dialysis patients, large doses of potent loop diuretics, such as furosemide, bumetanide, or torsemide can be administered. In the International Dialysis Outcomes and Practice Patterns Study (DOPPS), diuretic prescription was associated with lower interdialytic weight gain.

However, diuretic therapy is effective only when the daily urine output is at least 100 ml. Furthermore, the effectiveness of diuretic therapy may not last long over time, likely due to the loss of residual kidney function. Finally, ototoxicity should always be considered as a potential side effect of high-dose loop diuretics, especially furosemide. Therefore, periodic monitoring of urine production in patients taking diuretics should be done as most patients become anuric within several months of starting dialysis.

Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs)

Zannad et al. demonstrated that lower blood pressure in HD patients randomized to fosinopril was associated with a trend toward decreasing CVD events (RR: 0.79, 0.59-1.1, p=0.99). In a trial comparing candesartan vs. placebo, CVD events and mortality were higher in controls (45.9% vs. 16.3% and 18.9% vs. 0.0%, respectively (p<0.001)). Blood pressure changes were similar in the two groups, thus, the beneficial effects of ARBs may be independent of changes in BP. This is consistent with a prior report that the beneficial effects of ACEi in HD patients may also be independent of changes in blood pressure.

Suzuki et al. randomized 360 HD patients to either an ARB (valsartan, candesartan, or losartan) or no ARB (control). Patients were followed for 1-5 years. SBP and DBP, respectively, did not differ significantly between the two groups at 12, 24 and 36 months. For the primary endpoint, (fatal and nonfatal CVD events), event free survival was greater in the ARB vs. the control group (p=0.001). In a Cox regression analysis, adjusted for age, sex, diabetes, SBP, and center, ARB administration was associated with a reduction in fatal and nonfatal CVD events (RR -0.51, 0.33-0.79; p=0.002). Event free survival was similar in both groups. ACEi and ARBs are well tolerated and effective. ACEi are associated with regression of LVH and may reduce mortality.

However, a recent randomized clinical trial comparing lisinopril with B-Blocker found increased CV hospitalization with lisinopril which prompted early termination of the trial, though this was based on a very small number of events. None of these trials were of sufficient size or duration to adequately assess whether RAAS blockers confer benefit (or harm) independent of BP lowering.

Calcium Channel Blockers (CCBs)

The USRDS Morbidity and Mortality Wave II Study suggested that CCB use was associated a 21% lower mortality risk. Subsequently, Tepel et al. randomized hypertensive hemodialysis patients to receive amlodipine or a placebo. Baseline SBP (median and interquartile range), were similar in the CCB (140 [128-160] mmHg) and control (141 [130-160] mm Hg) groups. SBP decreased from 140 (128-160) mmHg to 130 (120-147 mm Hg) in the CCB group. There was a trend toward decreased risk for the primary end-point, AC- mortality, in the CCB group (HR: 0.65, 0.34-1.23) but this did not reached statistical significance. Risk for the secondary end-point, a composite of AC-mortality, CVD events, stroke, and peripheral vascular disease requiring surgery, was reduced in the CCB group (HR: 0.53, 0.31-0.93; p=0.03) vs. the control group. CCBs are effective and well tolerated in HD patients even when volume expanded.

Beta Adrenergic Blocking agents (beta blockers)

Cice et al. conducted a RCT in which HD patients (n=144) with dilated cardiomyopathy, were randomized to a beta-adrenergic blocking agent (carvedilol), or placebo plus standard therapy. Carvedilol administration was associated with significant attenuation of pathologic remodeling with reduced left ventricular volumes and increased left ventricular ejection fraction. There were fewer deaths in the carvedilol treated group (29.3%) vs. the control group (67.9%) (p<0.0001). Foley et al. observed a robust association between therapy with beta blockers and survival. However, use of these agents require evaluation to screen for patients with poor cardiac reserve that are prone to bradycardia.

What happens to patients with hypertension or fluid overload?

Whether the blood pressure target identified by current clinical guidelines actually contributes to improved survival of hemodialysis patients remains controversial. A recent meta-analysis concluded that decreasing SBP in HD patients lowered the number of CVD events, as well as all cause- and CVD-mortality. A RCT comparing intensive vs. standard hypertension control in HD patients is needed to assess the safety and efficacy of the KDOQI guidelines. The National Institutes of Health recently funded a pilot study (Blood Pressure in Dialysis [BID]) to assess the feasibility and safety of ‘standard (pre-dialysis systolic BP 155-165 vs. 110-140) vs. Intensive BP control in hypertensive HD patients. Separation between arms of 10 mmHg was achieved though there was an increase in hospitalizations, vascular access thrombosis and intradialytic hypotension in the intensive arm. The trial was too small (n-126 patients with 1 year follow up) to be conclusive.

Pending results of a large scale randomized clinical trial of treating to 2 levels of BP control, the available evidence indicates that many HD patients with elevated BP may experience higher rates of cardiovascular events and mortality. The exception may be in HD patients prone to intradialytic hypotension (which may be from cardiomyopathy, slow’ vascular refilling’, autonomic dysfunction, other causes) or those with recurrent vascular access thrombosis / limited vascular access options.

However, poor volume control can exacerbate hypertension and its myriad of detrimental effects on the cardiovascular system. Several studies support the association between fluid overload and all-cause and cardiovascular mortality. Fluid overload has also been associated with myocardial stunning, left ventricular hypertrophy and death. Perhaps in patients not at risk of acute hypertensive complications, it is prudent to initially determine and achieve the appropriate dry weight and fluid balance, before pharmacologic anti-hypertensive therapy is initiated or intensified.

How to utilize team care?

In order to optimally treat hypertension and fluid overload in dialysis patients, the nephrologist, nurse and renal dietitian will apply a multidisciplinary approach to optimize dialysis prescription and determine appropriate use of anti-hypertensive regimens as well as to advise and empower patients to the appropriate individualized dietary fluid and salt intake to optimize balance.

Are there clinical practice guidelines to inform decision making?

K/DOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients.
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 Updates: Hemodialysis Adequacy, Peritoneal Dialysis Adequacy and Vascular Access.

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Nephrology Hypertension

Medical Management of the Dialysis Patient: Blood Pressure and Fluid Volume Management