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Blood pressure management in patients on hemodialysis.

OBJECTIVES

After reading this article, the reader will be able to:

1. Describe possible pathophysiological mechanisms of hypertension in patients on hemodialysis.

2. Identify potential treatment targets for hypertension in patients receiving hemodialysis.

3. Explain non-pharmacological methods for reducing blood pressure in patients on hemodialysis.

4. Compare pharmacological agents for the treatment of hypertension in the setting of hemodialysis.

INTRODUCTION

Hypertension is present in 50% to 90% of patients on hemodialysis (Santos & Peixoto, 2008). Results from randomized controlled trials suggest that in hypertensive patients undergoing hemodialysis, blood pressure lowering therapies are associated with a lower risk of cardiovascular events and mortality (Heerspink et al., 2009). However, the optimal blood pressure target and preferred antihypertensive agent have yet to be prospectively defined. This article will review a stepwise approach to the management of hypertension in patients on hemodialysis. Nonpharmacological methods for reducing blood pressure such as individualization of the dialysate sodium prescription and reduction in target weight will be highlighted. Recommendations for the use of various pharmacological agents for the treatment of hypertension will be provided based on their safety and efficacy in hemodialysis.

PATHOPHYSIOLOGY

There are four principal mechanisms of hypertension in patients on hemodialysis. Expanded extracellular fluid volume and increased total body sodium due to a reduction in sodium excretion is arguably the most important mechanism. Volume overload results in higher blood pressures through increased cardiac output and systemic vascular resistance (Salem, 1995). Activation of the sympathetic nervous system through activation of chemoreceptors in abnormal kidneys is a second contributing mechanism to hypertension in patients receiving dialysis. Finally, activation of the renin angiotensin-aldosterone (RAAS) system and increased arterial stiffness are two other mechanisms of hypertension in patients receiving hemodialysis. When blood volume is low (i.e. during ultrafiltration) the kidneys activate the RAAS. Activation of the RAAS occurs through the conversion of angiotensin I to angiotensin II via angiotensin converting enzyme (ACE). Angiotensin II (ATII) then binds to receptors in the kidneys, arterioles and on the pituitary gland. Binding of ATII results in increased blood pressure through several different mechanisms. Specifically, ATII causes increased sympathetic activity, sodium reabsorption and water retention, and arteriolar vasoconstriction. Arterial stiffness can result from calcification of arterial walls or nitric oxide deficiency that may in turn result in endothelial dysfunction and increased blood pressure (Agarwal, 2005). Various non-pharmacological and pharmacological treatments used in the management of hypertension work to counteract these mechanisms of hypertension and will be discussed in further detail.

RATIONALE FOR TREATMENT

In the general population there is overwhelming evidence from prospective randomized trials demonstrating the cardiovascular benefits associated with lowering blood pressure to less than 140/90 mmHg in hypertensive individuals (Heerspink et al., 2009). In patients receiving hemodialysis, controversy exists regarding the benefits of blood pressure reduction and antihypertensive therapies with respect to cardiovascular outcomes. Observational studies suggest that lower blood pressures or a reduction in blood pressure over time are associated with increased mortality. In contrast, randomized controlled trials suggest cardiovascular benefits with antihypertensive therapy; however, these trials are statistically underpowered (Agarwal & Sinha, 2009). Two systematic reviews and meta-analyses have demonstrated that antihypertensive therapy and a reduction in systolic blood pressure are associated with a reduction in cardiovascular events, all-cause mortality, and cardiovascular mortality (Agarwal & Sinha, 2009; Heerspink et al., 2009).

TREATMENT TARGETS

A j-shaped curve exists in patients receiving dialysis such that both lower and higher blood pressures are associated with increased mortality. Patient level systolic blood pressure data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) indicates systolic blood pressures less than 130 mmHg are associated with increased mortality, potentially due to excessive blood pressure reductions during dialysis (Robinson, 2012). A target range of 130-159 mmHg systolic blood pressure has been suggested as optimal in the setting of hemodialysis (Robinson, 2012). This target is consistent with previous 2002 National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI)[TM] guidelines that recommended a pre-dialysis blood pressure of less than 140/90 mmHg and a post dialysis blood pressure of less

than 130/80 mmHg. Currently the Kidney Disease Improving Global Outcomes (KDIGO) guideline does not recommend a specific blood pressure target for patients on hemodialysis. A randomized controlled trial in hypertensive patients receiving hemodialysis that compares specific blood pressure targets and their respective effects on all-cause mortality and cardiovascular events is required before evidence-based blood pressure targets can be elucidated (Jindal et al., 2006).

A study conducted by Agarwal et al. suggests that intradialytic blood pressure measurements are more accurate and better reflect ambulatory blood pressure than either pre-dialysis or post-dialysis blood pressure measurements. Specifically, they determined that the mid-week median blood pressure during dialysis provides 80% sensitivity and specificity for hypertension as defined by a 44-hour ambulatory blood pressure of greater than 135/85 mmHg (2008). The mid-week median BP is considered an excellent surrogate marker for ambulatory blood pressure values. Examining the median, mid-week, intradialytic blood pressure over several weeks is recommended in order to determine a patient's blood pressure trend. The trend could then be used to determine blood pressure management strategies in patients receiving hemodialysis.

NON-PHARMACOLOGIC MANAGEMENT OF HYPERTENSION IN HEMODIALYSIS PATIENTS

There are two main ways to reduce blood pressure in hypertensive hemodialysis patients that do not involve the use of medications. These methods are extremely effective and represent a rational first step to blood pressure reduction prior to the initiation of pharmacotherapy. They are:

1. Establish an appropriate dry weight.

This intervention is regarded as the first and most important step in achieving normotension in patients on hemodialysis (Santos & Peixoto, 2008). The Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP) study demonstrated that in long-term hypertensive patients on hemodialysis, reduction of post dialysis dry weight by 1 kg at 8 weeks was associated with a 6.6 mmHg reduction in systolic blood pressure when compared to the control group. Despite an increased incidence of intradialytic hypotension, there were no negative effects seen on quality of life surveys administered as part of the study. The authors concluded that decreasing dry weight is a simple, efficacious and well-tolerated intervention that improves blood pressure control in hypertensive patients receiving hemodialysis (Agarwal, Alborzi, Satyan, & Light, 2009).

2. Individualize the dialysate sodium prescription.

The amount of sodium in the dialysate should match or be lower than the patient's pre-hemodialysis serum sodium concentration. Higher dialysate sodium prescriptions may result in relative hypernatremia if the post hemodialysis sodium concentration is higher than the pre hemodialysis sodium concentration. Relative hypernatremia results in increased thirst, higher interdialytic weight gain, and increased blood pressure. Therefore, individualization of the dialysate sodium prescription has been shown to reduce thirst, significantly decrease interdialytic weight gain, and reduce systolic blood pressure in hypertensive patients (as defined by BP >150/85 mmHg) by 15.7/6.5 mmHg (Santos & Peixoto, 2008).

Should non-pharmacological management fail to produce the desired degree of blood pressure reduction, pharmacologic management should then be introduced. A combination of both non-pharmacologic and pharmacologic management strategies has an increased potential to reduce blood pressure more than either strategy alone. Combination strategies work together targeting different mechanisms of the underlying pathophysiology of hypertension to allow for maximal blood pressure lowering effects.

PHARMACOLOGIC MANAGEMENT OF HYPERTENSION IN DIALYSIS PATIENTS

Several classes of antihypertensive agents have been evaluated for efficacy and safety in the management of hypertension in patients receiving hemodialysis. Specifically, angiotensin II receptor blockers (ARBs), angiotensin-converting

enzyme inhibitors (ACEIs), beta-blockers (BBs) and calcium channel blockers (CCBs) have been studied in controlled clinical trials to assess their relative blood pressure lowering effects with respect to cardiac outcomes. One meta-analysis including eight randomized controlled trials demonstrated that patients treated with antihypertensive agents--specifically ARBs, ACEIs, BBs or CCBs--had a weighted mean reduction in systolic and diastolic blood pressure of 4.5 mmHg and 2.3 mmHg respectively when compared with patients who received no antihypertensive therapy (Heerspink et al., 2009). Moreover, blood pressure lowering therapy was associated with a significant reduction in the risk of cardiovascular events (RR 0.71, 95% CI 0.55 to 0.92; p=0.009), all-cause mortality (RR 0.80, 95% CI 0.66 to 0.96; p=0.014) and cardiovascular mortality (RR 0.71, 95% CI 0.50 to 0.99; p=0.044) when compared with no antihypertensive therapy. It has been suggested that a randomized controlled trial comparing specific antihypertensive agents to one another is required to determine if one agent demonstrates superior efficacy with respect to cardiovascular outcomes in patients on hemodialysis with hypertension (Jindal et al., 2006). Practically speaking, the choice of antihypertensive agent should be individualized based on specific patient comorbidities. For example, patients who have a previous history of myocardial infarction (MI) or heart failure would preferentially be prescribed ACE inhibitors and beta-blockers. A review of each class of antihypertensive agent that has been evaluated in clinical trials is presented in Table 1.

CONCLUSION

In summary, hypertension is common in patients receiving hemodialysis. Untreated hypertension can lead to increased morbidity and mortality. The median blood pressure reading from the mid-week hemodialysis session correlates most closely with ambulatory blood pressure measurements. This value should be used to decide on an appropriate patient-specific management strategy. Both non-pharmacological and pharmacological therapies have been demonstrated to decrease blood pressure in patients on hemodialysis. Non-pharmacological methods such as reduction in dry weight and individualization of the sodium dialysate prescription represent effective means of reducing blood pressure in patients receiving dialysis. Once non-pharmacological strategies have been optimized, agents listed in Table 1 may be considered to further reduce blood pressure in hypertensive patients. The choice of antihypertensive should be individualized based on patient comorbidities.

CONTINUING EDUCATION STUDY QUESTIONS

CONTACT HOUR: 2.0 HRS

Blood pressure management in patients on hemodialysis.

By Stephanie Lynch and Marisa Battistella

1. Approximately what proportion of patients receiving hemodialysis has hypertension?

a) 10-30%

b) 50-90%

c) 50-80%

d) 60-90%

2. Which of the following mechanisms cause hypertension in patients receiving hemodialysis?

a) Activation of the sympathetic nervous system

b) Activation of the RAAS system

c) Reduction in sodium secretion by the kidneys resulting in fluid and sodium retention

d) All of the above

3. Which blood pressure value should be targeted in patients receiving hemodialysis?

a) The pre-dialysis blood pressure

b) The post-dialysis blood pressure

c) The median mid-week intradialytic blood pressure

d) The mean mid-week intradialytic blood pressure

4. What is the current blood pressure target recommended by KDIGO for patients with hypertension on hemodialysis?

a) Pre dialysis blood pressure of less than 140/90 mmHg

b) Post dialysis blood pressure of less than 130/80 mmHg

c) Median mid-week intradialytic blood pressure of less than 140/90 mmHg

d) No specific target is recommended by KDIGO

5. Individualization of the dialysate sodium prescription means to:

a) Match the pre-dialysis sodium concentration to the amount of sodium present in the dialysate

b) Match the post-dialysis sodium concentration to the amount of sodium present in the dialysate

c) Give a standard dialysate sodium prescription to all patients regardless of the predialysis sodium concentration

d) Give a higher dialysate sodium prescription than the patient's pre-dialysis sodium concentration

6. Despite non-pharmacological management, your patient's blood pressure remains unacceptably high at 165/95 mmHg. Which of the following strategies would be the most appropriate next step?

a) Change from an individualized to a standardized dialysate sodium prescription

b) Increase the target weight

c) Introduce pharmacological management while continuing with non-pharmacological management

d) Discontinue nonpharmacological management and start combination pharmacological management using two antihypertensive agents

7. Which classes of antihypertensive agents have been studied in randomized trials examining patients with hypertension on hemodialysis?

a) ACE inhibitors

b) Beta-blockers

c) Calcium channel blockers

d) All of the above

8. Which class of antihypertensive is associated with the greatest blood pressure lowering effect?

a) Angiotensin receptor blockers

b) ACE inhibitors

c) Beta-blockers

d) Calcium channel blockers

9. Beta-blockers are associated with which cluster of adverse effects?

a) Hyperkalemia, dry cough, dizziness

b) Vivid dreams, insomnia, cold extremities

c) Hyperkalemia, headache, dizziness

d) Peripheral edema, headache, dizziness

10. Which class of antihypertensive is not recommended for both the treatment of hypertension and the management of heart failure?

a) Angiotensin receptor blockers

b) ACE inhibitors

c) Beta-blockers

d) Calcium channel blockers

CONTINUING EDUCATION STUDY ANSWER FORM

CE: 2.0 HRS CONTINUING EDUCATION

Blood pressure management in patients on hemodialysis.

By Stephanie Lynch and Marisa Battistella

Volume 24 Number 3

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CANNT member? [] Yes [] No Expiration date of card -- REFERENCES

Agarwal, R. (2003). Systolic hypertension in hemodialysis patients. Seminars in Dialysis, 16(3), 208-213.

Agarwal, R. (2010). Blood pressure and mortality among hemodialysis patients. Hypertension, 55, 762-768.

Agarwal, R., Sinha, A.D. (2009). Cardiovascular protection with antihypertensive drugs in dialysis patients. A systematic review and meta-analysis. Hypertension, 53, 860-866.

Agarwal, R., Metiku, T., Tegegne, G.G., Light, R.P., Bunaye, Z., Bekele, DM., et al. (2008). Diagnosing hypertension by intradialytic blood pressure recordings. Clinical Journal of the American Society of Nephrology, 3, 1364-1372.

Agarwal, R., Alborzi, P., Satyan, S., Light, R.P. (2009). Dry-weight reduction in hypertensive hemodialysis patients (DRIP): A randomized, controlled trial. Hypertension, 53, 500-507.

Agarwal, R. (2005). Hypertension in chronic kidney disease and dialysis: Pathophysiology and management. Cardiology Clinics, 23, 237-248.

Agarwal, R. (2006). Management of hypertension in hemodialysis patients. Hemodialysis International, 10, 241-248.

Aronoff, G.R., Bennett, W.M., Berns, J.S., Brier, M.E., Kasbekar, N., Mueller, B.A., et al. (2007). Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th Edition, Philadelphia, PA: American College of Physicians.

Canadian Pharmacists Association (2011). ACE Inhibitors: CPhA Monograph. In Electronic Compendium of Pharmaceuticals and Specialties. Retrieved from https://www.e-therapeutics.ca

Canadian Pharmacists Association (2014). Beta-adrenergic Blocking Agents: CPhA Monograph. In Electronic Compendium of Pharmaceuticals and Specialties. Retrieved from https:// www.e-therapeutics.ca

Canadian Pharmacists Association (2011). Calcium Channel Blockers: CPhA Monograph. In Electronic Compendium of Pharmaceuticals and Specialties. Retrieved from https:// www.e-therapeutics.ca

Foley, R.N., & Agarwal, R. (2007). Hypertension is harmful to dialysis patients and should be controlled. Seminars in Dialysis, 1-4.

Heerspink, H.J.L, Ninomiya, T., Zoungas, S., de Seeuw, D., Grobbee, D.E., Jardine, M.J., et al. (2009). Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: A systematic review and meta-analysis of randomized controlled trials. Lancet, 373, 1009-1015.

Jindal, K., Chan, C.T., Deziel, C., Hirsch, D., Soroka, S.D., Tonelli, M. (2006). Management of blood pressure in hemodialysis patients. Journal of the American Society of Nephrology, 17, S1-S27.

Robinson, B.M., Tong, L., Zhang, J., Wolfe, R.A., Goodkin, D.A., Greenwood, R.N., ... & Port, F.K. (2012). Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney International 82, 570-580. doi:10.1038/ki.2012.136

Salem, M.M. (1995). Hypertension in the hemodialysis population: A survey of 649 patients. American Journal of Kidney Diseases, 26(5): 461-468.

Santos, S.F.F., & Peixoto, A.J. (2008). Revisiting the dialysate sodium prescription as a tool for better blood pressure and interdialytic weight gain management in hemodialysis patients. Clinical Journal of the American Society of Nephrology, 3(2), 522-530.

Stephanie Lynch, BScPharm, PharmD student, Leslie Dan Faculty of Pharmacy, University of Toronto

Marisa Battistella, BScPharm, PharmD, ACPR, Pharmacy Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Clinical PharmacistNephrology, University Health Network

Email: marisa.battistella@uhn.ca
Table 1: Antihypertensive agents for the treatment of hypertension
in patients receiving hemodialysis

Class and Agent   Dose in Dialysis           Common Adverse Effects

ACE Inhibitors:   10-40 mg PO q12-24 Hours   Hyperkalemia, dizziness,
Fosinopril        5-10 mg PO Once Daily      headache, taste
Ramipril          Dose after hemodialysis    disturbance, dry cough,
                                             hypotension, rash

ARBs:             16-32 mg PO Once Daily     Hyperkalemia, dizziness,
Candesartan       20-80 mg PO Once Daily     headache, hypotension
Telmisartan       No dose adjustment
                  required in hemodialysis

Beta-blockers:    6.25-25 mg PO q 12-24      Vivid dreams, insomnia,
Carvedilol        Hours                      bradycardia, fatigue,
                  No dose adjustment         cold extremities,
                  required in hemodialysis   reduced exercise
                                             tolerance

Calcium Channel   2.5-10 mg PO Once Daily    Dizziness, headache,
Blockers:         Does not require           flushing, palpitations,
Amlodipine        supplemental dosing        peripheral edema
                  after dialysis

Class and Agent   Place in Therapy

ACE Inhibitors:   Preferred in patients with previous MI, heart
Fosinopril        failure, residual renal function or left
Ramipril          ventricular hypertrophy.

ARBs:             Preferred in patients with heart failure, left
Candesartan       ventricular hypertrophy or those unable to
Telmisartan       tolerate an ACE inhibitor due to dry cough.

Beta-blockers:    Preferred in patients with previous MI or heart
Carvedilol        failure. Provides the greatest blood pressure
                  lowering effects.

Calcium Channel   Preferred in patients with left ventricular
Blockers:         hypertrophy or diastolic dysfunction.
Amlodipine
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Title Annotation:CONTINUING EDUCATION SERIES: CONTACT HOUR: 2.0 HRS
Author:Lynch, Stephanie; Battistella, Marisa
Publication:CANNT Journal
Article Type:Report
Geographic Code:1CANA
Date:Jul 1, 2014
Words:2998
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