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HTN in HD patient
INTRODUCTION
 There are several major issues to consider
when approaching hypertension in dialysis
patients:
 What is the pathogenesis of the elevation in blood
pressure (BP)?
 How is hypertension best defined?
 What are the target blood pressure goals?
 How should the hypertension be treated?
EPIDEMIOLOGY
 Hypertension is a common finding in dialysis
patients.
 Over 50 to 60 percent of hemodialysis patients (up
to 85 percent in some reports) and nearly 30 percent
peritoneal dialysis patients are hypertensive.
 These values are lower than the 80 percent incidence
of hypertension at the initiation of dialysis,
 due largely to better volume control in most patients.
EPIDEMIOLOGY
 Since poorly controlled hypertensive
hemodialysis patients are more likely to have
 large interdialytic and excessive weight gains,
 persistent hypertension often reflects volume
control that remains imperfect despite the
initiation of dialysis.
Cardiovascular risk
 The relationship between hypertension and
cardiovascular mortality in patients with endstage renal disease is complicated because of
 the high prevalence of comorbid conditions and
 underlying vascular pathology.
 Enhanced mortality has also been reported
among prevalent dialysis patients with the
lowest blood pressures who were followed for
short periods.
Cardiovascular risk
 In a cohort study of 40,933 hemodialysis
patients followed for a 15 month period,
 the hazard ratio for all cause death for a
predialysis systolic blood pressure <110 mmHg
was 1.60, while
 the ratio for a predialysis diastolic blood pressures
<50 mmHg was 2.00.

Kalantar-Zadeh K; Kilpatrick RD; McAllister CJ; Greenland S; Kopple JD
Hypertension 2005 Apr;45(4):811-7. Epub 2005 Feb 7.
Cardiovascular risk
 A second cohort study of 16,939 patients found that
a low systolic blood pressure (<120 mmHg) was
associated with
 an increased mortality with follow-up of one to two years ;
by comparison, an increased mortality after three years
was observed in those with systolic blood pressures greater
than 150 mmHg.

Stidley CA; Hunt WC; Tentori F; Schmidt D; Rohrscheib M; Paine S;
Bedrick EJ; Meyer KB; Johnson HK; Zager PG
J Am Soc Nephrol. 2006 Feb;17(2):513-20. Epub 2006 Jan 5.
Cardiovascular risk
 Enhanced mortality among those with lower
blood pressures may be a result of
 myocardial dysfunction,
 extensive comorbid conditions, and/or
 poor nutrition.
Cardiovascular risk
 Retrospective study
 2,770 patients on PD therapy at 180 days
from start of renal replacement therapy in
England and Wales between 1997 and 2004.
 greater blood pressure levels were protective
against mortality at one year among all
patients.

Udayaraj UP; Steenkamp R; Caskey FJ; Rogers C; Nitsch D; Ansell D;
Tomson CR
Am J Kidney Dis. 2009 Jan;53(1):70-8. Epub 2008 Nov 22.
Cardiovascular risk
 A retrospective study of over 44,000 dialysis
patients found that an increased pulse pressure
directly
 increased the risk of mortality at one year follow-up,
even after adjustment for the systolic blood pressure
alone.

Klassen PS; Lowrie EG; Reddan DN; DeLong ER; Coladonato JA; Szczech
LA; Lazarus JM; Owen WF Jr
JAMA 2002 Mar 27;287(12):1548-55.
Cardiovascular risk
 A higher mortality may be due to
 the presence of left ventricular hypertrophy (on
ECG or echocardiography), which is associated
with increases in the incidence of
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heart failure,
ventricular arrhythmias,
death following myocardial infarction,
sudden cardiac death,
aortic root dilation, and
a cerebrovascular event.
Cardiovascular risk
 Some evidence suggests that partial
regression of hypertrophy due to adequate
hypertensive therapy lowers the risk of
mortality among dialysis patients

London GM; Pannier B; Guerin AP; Blacher J; Marchais SJ; Darne B;
Metivier F; Adda H; Safar ME
J Am Soc Nephrol 2001 Dec;12(12):2759-67.
Cardiovascular risk
 There are conflicting data concerning a possible loss
of the usual diurnal variation in BP in end-stage renal
disease.
 To the degree that some patients may have a
diminution of the expected decline in BP during the
night (or even nocturnal hypertension),
 it may be erroneous to conclude that a "borderline"
daytime blood pressure is actually lower the rest of the day.
Cardiovascular risk
 This loss of dipping, termed nocturnal
hypertension, is associated with an increased
risk of adverse cardiovascular outcomes.
 Liu M; Takahashi H; Morita Y; Maruyama S; Mizuno M; Yuzawa Y;
Watanabe M; Toriyama T; Kawahara H; Matsuo S
Nephrol Dial Transplant 2003 Mar;18(3):563-9.
PATHOGENESIS
 The etiology of hypertension in end-stage
renal disease is multifactorial,
 Sodium and volume excess due to diminished
sodium excretory capacity.
 Activation of the renin-angiotensin-aldosterone
system due to primary vascular disease or to
regional ischemia induced by scarring.
 Increased activity of the sympathetic nervous
system.
PATHOGENESIS
 An increase in endothelium-derived
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vasoconstrictors (such as endothelin) or
a reduction in endothelium-derived vasodilators
(such as nitric oxide).
The administration of erythropoietin.
An increase in intracellular calcium induced by
parathyroid hormone excess.
 The rise in cell calcium in vascular smooth muscle
cells can then induce vasoconstriction.
Calcification of the arterial tree.
Preexistent essential hypertension.
Volume overload
 Volume expansion is perhaps the major factor in the
development of hypertension in dialyzed patients.
 It leads to an elevation in BP via
 the combination of a rise in cardiac output and
 an inappropriately high systemic vascular resistance.
Volume overload
 Regardless of the mechanism, removal of the excess
sodium and attainment of "dry weight" can result in
 the normalization of BP in more than 60 percent of
hemodialysis-dependent patients and
 nearly all patients undergoing peritoneal dialysis.
 The degree of extracellular volume expansion may
be insufficient to induce edema; thus,
 the absence of edema does not exclude hypervolemia.
Increased sympathetic activity
 The mechanism by which this occurs is unclear,
 but the afferent signal may arise within the kidney,
since sympathetic activation is not seen in anephric
patients.
Increased sympathetic activity
 It has therefore been proposed that activation
of chemoreceptors within the kidney by uremic
metabolites may play an important role.
 Activation of these chemoreceptors leads to a
neural reflex that traverses afferent pathways to the
central nervous system,
 resulting in increased efferent sympathetic tone.
Altered endothelial cell
function
 An intriguing concept regarding the
pathogenesis of hypertension in end-stage
renal disease is abnormal endothelial release of
hemodynamically active compounds.
 As an example, elevated plasma levels of the
potent vasoconstrictor endothelin-1 have been
found in uremic subjects.
Altered endothelial cell
function
 The concentration of other endothelin
isoforms also may be increased, but only
endothelin-1 has been linked to high BP.
 It should be appreciated, however, that these
observations do not prove a cause and effect
relationship.
Altered endothelial cell
function
 The endothelium also produces vasodilators, such as
prostacyclin and nitric oxide (NO or endotheliumderived relaxing factor).
 NO is a synthetic product of L-arginine in endothelial cells
and is a potent vasodilator.
 There is evidence that uremic plasma contains a
higher level of an endogenous compound —
asymmetrical dimethylarginine (an inhibitor of NO
synthesis).
 This observations raises the possibility that NO
deficiency may contribute to the development of
hypertension in end-stage renal disease.
Erythropoietin
 An increase in BP of 10 mmHg or more may
occur in patients with renal failure who are
treated with erythropoietin.
 The risk is greatest in those with rapid
correction of severe anemia and with
preexistent hypertension.
METHOD OF BLOOD PRESSURE
MEASUREMENT
 A reliance upon immediate predialysis and/or
postdialysis BP measurements alone to detect
hypertension in patients undergoing hemodialysis
may be misleading.
 The predialysis systolic BP may overestimate the
mean interdialytic SBP by 10 mmHg,
 while the postdialysis systolic BP may underestimate the
mean systolic BP by 7 mmHg.
 Some studies, however, have suggested that the
postdialysis BP may be more reflective of
interdialytic BP.
METHOD OF BLOOD PRESSURE
MEASUREMENT
 Continuous monitoring is therefore
warranted in patients suspected of poor
control (such as those with large interdialytic
weight gain) .
 The results with ambulatory blood pressure
monitoring appear to be relatively
reproducible.
METHOD OF BLOOD PRESSURE
MEASUREMENT
 Ambulatory BP monitoring may also be
useful in determining the "systolic load,"
which is the amount of time the systolic
pressure exceeds 140 mmHg during the day .
 This load may be an important factor in the
development of left ventricular hypertrophy.
METHOD OF BLOOD PRESSURE
MEASUREMENT
 The ambulatory BP is also associated with
significant prognostic value.
 Interdialytic hypertension does not appear to be
a problem with the nocturnal hemodialysis
regimens of long, slow dialysis.
 Home blood pressure monitoring may also
improve hypertension detection and prognostic
value.
METHOD OF BLOOD PRESSURE
MEASUREMENT
 In one study, the finding of an average systolic BP
greater than 150 mmHg at home was more accurate
than conventional blood pressure monitoring in
helping diagnose hypertension (as determined by
ambulatory BP).
 Agarwal, R, Andersen, MJ, Bishu, K, Saha, C. Home blood
pressure monitoring improves the diagnosis of
hypertension in hemodialysis patients.
Kidney Int 2006; 69:900.
METHOD OF BLOOD PRESSURE
MEASUREMENT
 The best prognosis was observed with a
home measurement of a systolic blood
pressure of 125 to 145 mmHg.
 Alborzi, P, Patel, N, Agarwal, R. Home blood pressures are of
greater prognostic value than hemodialysis unit recordings.
Clin J Am Soc Nephrol 2007; 2:1228.
OPTIMAL BLOOD PRESSURE
 No randomized prospective studies evaluating
the target blood pressure in dialysis patients.
 In general, the targeting of exact blood
pressure goals (whether to a specific level or
below a certain value) should ideally be set
individually based upon
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the patient's cardiac and neurologic status,
comorbid conditions,
age,
other clinical factors.
OPTIMAL BLOOD PRESSURE
 For some dialysis patients, goal BP levels be a
predialysis value of below 140/90 mmHg and a
postdialysis value of below 130/80 mmHg.
 If clinical characteristics permit, a "normal" BP,
defined as a mean ambulatory BP <135/85
mmHg during the day and <120/80 mmHg by
night, is a reasonable target goal.
OPTIMAL BLOOD PRESSURE
 However, controversy exists over the blood
pressure target; some investigators have
postulated that excessively low systemic
pressures leads to enhanced mortality (a socalled J- or U-shaped curve).
OPTIMAL BLOOD PRESSURE
 A report of nearly 4500 hemodialysis patients
found a significantly increased adjusted
mortality risk among patients with a low
predialysis systolic pressure (<110 mmHg);
risk was also increased in patients with high
postdialysis diastolic (>110 mmHg) and
systolic pressures (>180 mmHg)

Port FK; Hulbert-Shearon TE; Wolfe RA; Bloembergen WE; Golper TA;
Agodoa LY; Young EW
Am J Kidney Dis 1999 Mar;33(3):507-17.
OPTIMAL BLOOD PRESSURE
 In an observational study of 56,338 and 69,590
incident and prevalent hemodialysis patients,
respectively, a markedly increased risk of death was
noted among those with systolic blood pressures
less than 120 mmHg versus those with systolic blood
pressures between 160 and 180 mmHg (hazard ratio
of 2.63 to 3.68 based upon different statistical
adjustments).

The epidemiology of systolic blood pressure and death risk in hemodialysis
patients. AULi Z; Lacson E Jr; Lowrie EG; Ofsthun NJ; Kuhlmann MK; Lazarus JM;
Levin NW
Am J Kidney Dis. 2006 Oct;48(4):606-15.
OPTIMAL BLOOD PRESSURE
 A retrospective analysis of 13,792 incident
hemodialysis patients evaluated the
correlation between survival and achieving
K/DOQI clinical practice guidelines for
multiple parameters.
 Tentori, F, Hunt, WC, Rohrscheib, M, et al. Which targets in
clinical practice guidelines are associated with improved survival
in a large dialysis organization?.
J Am Soc Nephrol 2007; 18:2377
OPTIMAL BLOOD PRESSURE
 An increased mortality was associated
with achieving the goal predialysis
blood pressure of less than 140/90
mmHg (1.90, 95% CI 1.73-2.10).
 Tentori F; Hunt WC; Rohrscheib M; Zhu M; Stidley CA; Servilla K;
Miskulin D; Meyer KB; Bedrick EJ; Johnson HK; Zager PG
J Am Soc Nephrol. 2007 Aug;18(8):2377-84. Epub 2007 Jul 18.
OPTIMAL BLOOD PRESSURE
 Whether these results are due to a direct
effect of a relatively low blood pressure or to
an associated comorbid condition is unclear.
 In summary, the target goals should generally
be realized based upon individual patient
characteristics.
 In some younger patients, the target BP may
even be set as low as 120/80 mmHg.
TREATMENT
 Control of volume status
 Control of volume status can either normalize the BP
or make the hypertension easier to control in the great
majority of dialysis patients.
 Avoidance of large weight gains in the interdialytic
period is clearly desirable.
 Patients should adhere to a restricted salt diet (750 to
1000 mg of sodium/day), which also helps decrease
thirst.
 However, patient compliance is often suboptimal.
TREATMENT
 The exact definition of dry weight remains uncertain, but
multiple definitions have been advanced.
 As examples, dry weight has been defined clinically as
that weight at which:
 Either the BP has normalized or symptoms of
hypovolemia appear, not merely the absence of
edema.
 The seated BP is optimized, and symptomatic
orthostatic hypotension and clinical fluid overload are
not present postdialysis.
 At the end of dialysis, the patient remains
normotensive until the next dialysis without
antihypertensive medication.
TREATMENT
 Two other factors may limit the degree of fluid
removal by predisposing to episodes of
hypotension (and therefore the need for volume
replacement) during the hemodialysis
procedure:
 antihypertensive drugs; and
 rapid fluid removal required by shorter dialysis times.
 Thus, tapering drug therapy and gradual fluid
removal may be beneficial in patients in whom
hypotension during dialysis prevents the
attainment of dry weight and a normal BP.
TREATMENT
 Dialysate sodium prescriptions are relatively
higher than that observed in most dialysis
patients, leading to decreased sodium loss
during dialysis and mild increases in serum
sodium values post-dialysis.
 This results in volume overload and increased
thirst, thereby increased blood pressure.
 To help avoid these, some advocate an
individualized approach to the dialysate sodium
prescription.
TREATMENT
 Prolonged and/or more frequent hemodialysis
 Nocturnal hemodialysis, is also associated with
excellent blood pressure control.
 Patients in a large dialysis center in Tassin, France and
some home hemodialysis patients undergo long, slow
hemodialysis in which the standard regimen is eight
hours, three times per week.
 This regimen is associated with the maintenance of
normotension without medications in almost all patients.
.
TREATMENT
 Other factors may also contribute, such as more
complete control of uremia
 which may decrease afferent renal nerve activity and
efferent sympathetic activation.
Antihypertensive medications
 Therapy with antihypertensive drugs is primarily
indicated in the 25 to 30 percent of dialysis
patients in whom hypertension persists despite
seemingly adequate volume control.
 Some evidence suggests that the administration
of such agents may provide significant clinical
benefits, including improved mortality.
Antihypertensive medications
 A 2009 systematic review and meta-analysis of eight
randomised controlled trials (three with and five
without hypertensive patients) that enrolled 1679
dialysis patients found that lowering blood pressure
with antihypertensive therapy was
 associated with decreased risks of cardiovascular events
(RR of 0.71, 95% CI 0.55-0.92),
 all cause mortality (RR 0.80, 0.66-0.96) and
 cardiovascular mortality (0.71, 0.50-0.99).
 Heerspink, HJ, Ninomiya, T, Zoungas, S, et al.
Lancet 2009; 373:1009.
Antihypertensive medications
 There were no studies that compared the
efficacy of different antihypertensive agents;
the relative effects of ARBs, ACE inhibitors,
beta blockers, and calcium blockers were
largely compared with placebo or
conventional therapy.
Antihypertensive medications
 It generally appears that renin-angiotensin-
system blockers, beta blockers, and calciumchannel blockers provide similar efficacy in
dialysis patients.
 Thus, the type of antihypertensive therapy
chosen is dictated in part by coexistent
diseases.
Calcium channel blockers
 Both effective and well tolerated in dialysis patients,
 even in those who are volume expanded.
 The only randomized prospective study found that
amlodipine, compared with placebo, improved overall
mortality among hypertensive dialysis patients.
 Particularly useful in patients with left ventricular
hypertrophy and diastolic dysfunction.
 Calcium channel blockers do not require supplementary
postdialysis dosing.
ACE inhibitors
 ACE inhibitors are well tolerated and are particularly
effective in patients with
 heart failure due to systolic dysfunction and
 in many patients after an acute myocardial infarction.
 The 2006 K/DOQI guidelines also suggest that these
agents and/or angiotensin II receptor blockers are
preferred in dialysis patients with significant residual
renal function.

K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations 2006
Updates Hemodialysis adequacy Peritoneal Dialysis Adequacy Vascular Access.
Am J Kidney Dis 2006; 48(Suppl 1):S1.
ACE inhibitors
 ACE inhibitors are also associated with more
rapid regression of left ventricular hypertrophy.
 A randomized prospective study found no
survival benefit with fosinopril among
hemodialysis patients with left ventricular
hypertrophy.

Zannad, F, Kessler, M, Lehert, P, et al.
Kidney Int 2006; 70:1318.
ACE inhibitors
 A possible mortality benefit was shown in an
observational study in which hypertensive
dialysis patients were administered
antihypertensive regimens with or without ACE
inhibitors (60 and 66 patients, respectively) at
the discretion of the physician.
 Efrati, S, Zaidenstein, R, Dishy, V, et al. ACE inhibitors and survival
of hemodialysis patients. Am J Kidney Dis 2002; 40:1023.
ACE inhibitors
 Unique side effects in end-stage renal disease:
 they can interfere with the action of erythropoietin;
and
 they can trigger an anaphylactoid reaction (possibly
mediated by kinins) in patients dialyzed with an AN69
dialyzer.
ACE inhibitors
 The effect of ACE inhibitors on erythropoiesis
has been best described in renal transplant
recipients with erythrocytosis.
 This can occur by reducing the secretion or
interfering with the action of EPO, including
those receiving EPO supplementation .
 hyperkalemia among chronic hemodialysis
patients treated with an ACE inhibitor .
ARBs
 Limited experience with these drugs in ESRD.
 In one open-label trial, 360 hypertensive dialysis patients
were randomly assigned to an ARB or no ARB.
 After multivariate adjustment, ARBs significantly reduced fatal
and nonfatal cardiovascular disease events (hazard ratio 0.5, 95%
CI 0.33-0.79).
 The most common adverse event was heart failure (fatal and
nonfatal), with ARBs lowering the rate by one-half.

Suzuki, H, Kanno, Y, Sugahara, S, et al.
Am J Kidney Dis 2008; 52:501.
Beta blockers
 Beta blockers are particularly indicated in patients who
have had
 a recent myocardial infarction.
 heart failure due to systolic dysfunction.
 Potential side effects include
 central nervous system depression (an effect that may be more
prominent with lipid-soluble drugs that cross the blood-brain
barrier),
 hyperkalemia (particularly with non-selective beta blockers),
 bradycardia, and
 possible exacerbation of heart failure.
 Should be used cautiously in patients also taking a
calcium channel blocker, since there are often additive
negative chronotropic and inotropic actions.
Central sympathetic agonists
 The central sympathetic agonists, such as
methyldopa and clonidine, are used less
frequently because of their adverse effects
involving the central nervous system.
 Some physicians have found clonidine
patches to be effective and well tolerated,
but this is not a universal finding.
Reduced dialysate sodium
concentration
 A randomized crossover study, evaluated
 the antihypertensive effects of a programmed
decrease in sodium dialysate concentration from 155
to 135 meq/L (the last half hour was held constant at
135 meq/L) compared with the standard stable sodium
dialysate concentration of 140 meq/L.
 Postdialysis blood pressure (133/69 to 126/66, p<0.05),
postdialysis standing blood pressure, and drug usage
were all reduced when patients were dialyzed with a
variable sodium prescription.
 Flanigan, MJ, Khairullah, QT, Lim, VS.
Am J Kidney Dis 1997; 29:383.
Refractory hypertension
 Some dialysis patients are resistant to both
volume control and antihypertensive
medications.
 Factors to be considered in this setting are
 concurrent use of a medication that can raise the BP
(such as nonsteroidal antiinflammatory drugs),
 renovascular hypertension, noncompliance to medical
regimen, and
 expanding cyst size in polycystic kidney disease.
 If a treatable cause cannot be found, minoxidil
may be effective in reducing the BP.
Refractory hypertension
 Chronically noncompliant hypertensive patients who
refuse to take medications at home may benefit by
 the administration of long-acting antihypertensive
medications in the dialysis unit.
 This was shown in a single center study of 16 patients in
whom such a regimen (consisting of some combination
of lisinopril, amlodipine, and/or transdermal clonidine
based upon patient clinical characteristics) lowered the
predialysis systolic and diastolic blood pressures by 15
and 12 mmHg, respectively.

Ross, EA, Pittman, TB, Koo, LC. Strategy for the treatment of
noncomliant hypertensive hemodialysis patients. Int J Artif Organs 2002;
25:1061.
Refractory hypertension
 Switching to Peritoneal dialysis.
 Nearly all peritoneal dialysis patients can become
normotensive with strict adherence to volume control.

Gunal, AI, Duman, S, Ozkahya, M, et al.
Am J Kidney Dis 2001; 37:588
 The efficacy of peritoneal dialysis in controlling blood
pressure in refractory patients is related to
 its smoother volume removal and
 its more consistent maintenance of dry weight.
Refractory hypertension
 Bilateral nephrectomy may be considered in the
rare noncompliant individual with lifethreatening hypertension unable to be
controlled with any dialysis modality.
 Bilateral nephrectomy is now largely abandoned,
but was infrequently used for blood pressure
control when potent antihypertensive agents
were not yet widely available.