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 end-stage 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 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 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 endothelium-derived 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 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 so-called 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.

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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 calcium-channel 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 life-threatening 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.