Hypertension in renal failure

Hypertension

in Renal Failure

Abstract.-Hypertension is a common component of the morbidity associated with renal failure. The mechanisms that contribute to high blood pressure are reviewed in this section. Also covered are therapies to reduce hypertension, the treatment goals of those therapies, and the outcomes of antihypertensive therapy on kidney function in patients with renal failure. Various antihypertensive agents are specifically addressed, and a treatment paradigm is presented for combination antihypertensive drug therapy, which is usually necessary in the antihypertensive therapy of patients with renal failure.

Introduction Renal parenchymal disease is the most common secondary cause of hypertension,’ occurring in approximately 3% to 5% of patients with high blood pressure. When hypertension is associated with renal failure. the kidney is considered both “victim” and “villain.“’ Renal failure has long been recognized as a consequence of hypertension, and irrespective of the etiology of the renal disease, high blood pressure accelerates the time course of progressive renal impairment. Paradoxically, the kidneys possess the unique opportunity to (1) directly adjust the body sodium volume, (2) contribute a variety of vasoconstricting and vasodilating humors to the circulation, and (3) increase activity within the sympathetic nervous system, and thus they play a dominant role in the longterm regulation of blood pressure, even when these very processes contribute to a progressive decrease in renal function. Moreover, virtually all of the non-renal consequences of hypertension, such as severe hypertensive retinopathy. heart disease (including coronary artery disease, DM.

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congestive heart failure, and left ventricular hypertrophy), and stroke, are more common in hypertensive patients with renal failure. This segment will focus on hypertension associated with parenchymal renal disease and will not cover the role of isolated progressive renovascular disease in the pathogenesis of renal failure (the reader is referred to several excellent reviews of this topic3p4) or diabetic nephropathy, which is covered elsewhere in this issue.

Background Hypertension is the second most common reason stated as the cause of end-stage renal disease (ESRD),5 accounting for approximately 30% of new patients initiating dialysis, with diabetes (in which hypertension is usually present) ranking first. Whereas several categories of renal failure, such as polycystic kidney disease or glomerulonephritis, have had a stable incidence over the last decade, the number of patients reaching ESRD with hypertension, diabetes, or both continues to increase at a rate of approximately 9% per year.5 During the course of renal failure, the incidence of hypertension climbs proportionately with degree of renal insufficiency. In the recently completed Modification of Diet in Renal Disease (MDRD) Study during the early phase of renal failure (with a glomerular filtration rate of 83 mL/min/1.73m2) the incidence of hypertension was 66%, whereas in more severe renal failure (with a glomerular filtration rate of 12 mL/min/l .73m2) the incidence rose to 95%.6 Conversely, in participants screened for the Hypertension Detection and Follow-up Program, the likelihood of having an increased serum creatinine concentration was approximately three times higher in the highest stratum (diastolic blood pressure 2115 mm Hg) compared with the lowest stratum (diastolic blood pressure 90 to 104 mm Hg).7 Data such as these underscore the close relationship between declining renal function and high blood pressure. Different forms of renal parenchymal disease vary in hypertension incidence, although this variation in incidence becomes less prominent as the degree of renal failure progresses. In tubulointerstitial types of renal failure, the incidence of hypertension is less common early in the course of renal disease when renal salt wasting may be present than in other forms of renal failure. Patients with chronic glomerular diseases are more likely to be hypertensive than those with tubulointerstitial patterns of renal failure, and in those in whom hypertension (alone) is thought to be the cause of renal failure, increased blood pressures are almost uniformly demonstrated. 244

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TABLE

1. Mechanisms

by which

hypertension

contributes

to the development

and

progression

of renal

failure Promotion Growth

of vascular factor

impaired

hypertrophy

activation

glomerular

k

vessel

and

mesangial

nephrosclerosis proliferation

autoregulation

through

with increased

The Role of Hypertension

pressure

overload

F glomerulosclerosis glomerular

capillary

pressure

in Renal Failure

The large-scale clinical trials of hypertension conducted over the last 30 years have focused primarily on the role of antihypertensive drug therapy in the natural history of cerebrovascular and coronary artery disease. Unfortunately, the benefits of hypertension control (and other risk factors) in the declining incidence of stroke and heart disease have not been as manifest in renal failure. Whereas stroke and heart attack occurrences have shown a significant decline in the past three decades, the incidence of renal failure continues to increase and has shown no sign of achieving a plateau, let alone a reduction in occurrence. Several elements concurrent with hypertension have emerged as cofactors in the likelihood of renal failure developing. These include older age, male gender, African American race, lower socioeconomic class, and the systolic, more so than the diastolic, blood pressure.h.*p’O Although these are largely “non-modifiable” risks (except for blood pressure), appreciation of their presence and their role in the risk of the development or worsening of renal function in hypertensive patients should add to the aggressiveness with which practitioners treat elevated blood pressures. The mechanisms by which hypertension promotes or hastens the course of renal failure are outlined in Table 1. The data from the Multiple Risk Factor Intervention Trial indicate that the risk of renal failure associated with hypertension is continuous, so that increasing levels of blood pressure (as staged by the fifth Report of the Joint National Committee for the Detection, Evaluation, and Treatment of High Blood Pressure [JNC V]“) were associated with increasing likelihoods of renal failure.” A recent review covering the relationship between blood pressure and renal failure may be consulted for further information.”

The Role of Renal Failure in Hypertension The pivotal role of the kidneys in the maintenance of extracellular tluid volume and the elaboration of a variety of vasoactive compounds makes them well suited to participate in hemodynamic regulation. As renal function declines, the ability of the kidneys to preserve extracellular volume, DM.

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NEPHRON1 LOSS

FIG.

1. interplay

I\

of factors

\

I’-

that link renal

failure

and blood

pressure;

arrows

indicate

general

direc-

tion of effects.

suppress or metabolize vasoconstricting humors such as endothelin, and produce vasodilating factors such as nitric oxide becomes progressively impaired, thus escalating the tendency towards blood pressure elevation. In addition, the MDRD study identified body mass index (measured as weight in kilograms divided by height in meters squared; kg/m2), African American race, and increasing age as elements that potentiate the height of the blood pressure at any level of renal function.6 The MDRD Study’s identification of African American race as a potentiating element mirrors the general finding that virtually all forms of renal disease (except for polycystic kidney disease) occur more frequently and progress more rapidly in African American patients. In the past, the attribution of elevated blood pressure as the sole cause of renal failure was confounded by concern that hypertensive patients with renal failure could have had subtle forms of glomerular or tubulointerstitial disease that went undetected because biopsies were infrequent. This presented a problem with diagnostic accuracy, especially in African American patients because high blood pressure as a cause of renal failure is listed much more commonly in African American patients than in white patients.5 This idea was challenged by the recent findings of the African American Study of Kidney Disease (AASK), in which nondiabetic African American participants with either absent or low-grade proteinuria, no evidence of an immune complex disease, and renal failure underwent renal biopsy. In 38 of 39 246

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TABLE 2. Mechanisms

by which

renal

failure

contributes

to the development

and maintenance

of

hypertension Activation Sodium

of the renin-ongiotensin retention

Increased

sympathetic

Abnormal

vasoactive

parathyroid

hormone)

Diminished

vasodilator

TABLE 3. Unilateral Solitary

Kidney

Ask Upmork

system

(extrocellulor nervous peptide

system

forms

expansion)

activity

metabolism

production

[resulting

Anomaly

fluid volume

(medullolipin,

of parenchymal from congenital

(congenital

through

renal

(e.g , increases

birth

afferent

endothelin,

fibers insulin resistance,

nitric oxide)

renal disease

segmental

sympathetic

in plasma

defect,

associated trauma,

with hypertension

or surgery)

hypoplasia)

Renal Tuberculosis Reflux

Nephropothy

Unilateral

and Chronic

Renin Secretion

Pyelonephritis

(Juxtaglomerular

tumor,

Wilms’

tumor,

Adenocarcinoma-rarely)

Renal Infarction Obstructive Radiation

Uropathy Nephl-itis

Adenocorcinoma

patients, the histologic picture was one of arteriosclerosis and arteriolosclerosis, indicating that in the appropriate clinical circumstances. hypertensive nephropathy is a significant cause of renal failure.‘j The mechanisms by which renal failure contributes to elevated blood pressures are outlined in Table 2. A recent review has examined in greatel detail the role of parenchymal renal disease in maintaining elevated blood pressure. I4 The interplay between renal failure and blood pressure is shown in Figure I.

Hypertension

Associated

with Unilateral

Renal Disease

In most cases of hypertension associated with renal disease the parenchyma of both kidneys are involved. However, as shown in Table 3, several unilateral renal disorders are associated with hypertension. These disorders may arise from bacterial infection. neoplasia. or structural alterations that may be congenital or acquired in origin. They are often discovered when patients undergo evaluations for complaints of flank pain, hematuria, or when they have palpable abdominal masses. In some cases they may be found incidentally by an imaging procedure performed for an unrelated complaint. The possibility of curing hypertension by unilateral nephrectomy when one of these conditions is found varies considerably. In some cases (such as Wilms’ tumor and renal adenocarcinoma), surgery is necessary to UNDM,

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trol the malignant disease and is indicated for non-hemodynamic reasons. In others, such as the rare juxtaglomerular apparatus tumor, surgical excision can be curative.15 In patients with scarred kidneys (such as those with reflux nephropathy), blood pressure does not often fall significantly after surgery. I6 However, when these patients with unilateral renal scarring are young, with a shorter duration of hypertension, and when their diseased kidney contributes less than a quarter of the overall renal function, they are more likely to benefit from surgery.t7 Patients with unilateral renal agenesis appear to be at greater risk for hypertension or hypertension in conjunction with focal glomerulosclerosis and renal failure compared with the general population.‘8,‘9 In contrast, in nearly 500 patients who underwent unilateral nephrectomy for kidney donation, the incidence of hypertension was approximately 9% after an average follow-up of 8 years, 2o although kidney donor follow-up studies of longer duration (>12 years) show an incidence of high blood pressure that is nearer to 50%.*‘,** When nephrectomy is considered in the treatment of patients with unilateral renal disease, the decision to proceed with removing the diseased renal tissue in the interest of controlling blood pressure should be tempered by these considerations: 1. The patient may still have essential hypertension (especially if they are older and/or have a positive family history of hypertension) 2. The amount of residual function in the diseased kidney 3. The possibility of occult disease in the remaining “healthy” kidney 4. The difficulty in controlling the blood pressure 5. The tolerability of the antihypertensive regimen, when medical therapy alone is used

Treatment

of Hypertension

in Renal Failure

In contrast to the data testifying to the value of reducing blood pressure in the prevention of stroke, heart failure, and coronary artery disease, less is known about the role of blood pressure reduction in preventing or slowing the progression of renal disease in patients who have renal failure and to what level blood pressure should be reduced. Furthermore, the specific benefits associated with the use of any one class of antihypertensive agents over another class are unclear. Retrospective studies suggest that treatment of hypertension can preserve renal function or at least reduce the rate at which renal failure progresses. However, renal failure has many origins, and antihypertensive therapy may not confer equivalent benefit in all forms of chronic renal failure. 248

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Because no single class of agents has been shown to be clearly superior to any other, treatment recommendations have been generic and limited only to encouraging blood pressure reduction. There is little evidence supporting the value of most non-pharmacologic methods (such as weight loss, exercise, and alcohol intake) in the treatment of hypertension in renal failure. However, because 50% to 90% of patients with hypertension and renal impairment demonstrate salt sensitivity in their blood pressure. there is a good basis on which to recommend a diet restricted to less than 2300 mg of sodium per day, consistent with the sodium intake recommendations for essential hypertension.” Special consideration has recently been given to the use of angiotensin-converting enzyme (ACE) inhibitors in the hypertension associated with renal failure. Encouragement for this class of agents was sparked by the successful slowing of the rate of renal failure progression in type I diabetes with the use of the ACE inhibitor captopril.” A recent international study also confirmed a positive beneficial effect of ACE inhibition (using benazepril) on the progression of renal failure because of a variety of causes.24 Therefore it appears that an ACE inhibitor could reasonably be tried in the management of hypertension in renal failure. However, clinicians may be reluctant to use this class of medication because of concerns over causing a worsening of renal failure or inducing hyperkalemia. Interestingly, these problems are not common occurrences. A rapid elevation in creatinine after the initiation of an ACE inhibitor should prompt a search for bilateral renal arterial disease, which represents a potentially treatable cause of progressive renal failure.‘.‘-” The concern for hyperkalemia exists because ACE inhibitors can reduce aldosterone secretion and interfere with potassium excretion. However, in a recent study of non-diabetic patients with elevated creatinines. ACE inhibition tended to cause less than a 0.5 mEq/L rise in potassium in the 300 patients who received the ACE inhibitor benazepril, with only five participants withdrawn because of hyperkalemia (with three of 2X3 participants in the placebo group who did not receive benazepril also withdrawn because of hyperkalemia).‘” Diuretic therapy is frequently necessary in the treatment of hypertension associated with renal failure. Diuretics have an additive antihypertensive effect when incorporated into a regimen with virtually any other antihypertensive drug. The frequent retention of salt in renal failure and the high incidence of salt sensitivity are further reasons to add or initiate therapy with a diuretic. Thiazide diuretics typically become ineffective at reducing blood pressure when the serum creatinine is more than 2 mg/dL: consequently. DM,

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DIURETICS cc

REGULATION

CALCIUM

ANTAGONISTS

VASODILATORS FIG. 2. Square dividing blood third] agent for blood pressure

pressure control into four maior systems. control, choose on agent from o separate

ple, if CI diuretic was started, when Angiotensin side), or an alpha,-blocker

adding (from

When choosing a second (or side of the square. For exam-

a second agent use on ACE-inhibitor (from the Renin the Sympathetic Nervous System side) instead of anoth-

er diuretic.

loop acting diuretics (generally given at least twice a day except for torasemide, which is given once daily) are necessary to treat hypertension. Calcium channel antagonists have been studied in the treatment of hypertension in patients with renal failure.26 In general they are potent antihypertensives and are often effective when other classes of antihypertensive drugs have not been. Disagreement exists about whether all calcium channel antagonists should be considered as a single antihypertensive class, or whether differences (for example in albumin excretion) between the different subclasses of calcium channel antagonists should be taken into consideration when deciding which agent to use. Jn a study comparing the dihyrdropyridine calcium antagonist nifedipine to captopril, nifedipine performed as well as captopril in slowing the rate of renal decline during the three years of the study, although there was a tendency in the third year for more participants in the nifedipine group to go on to end-stage renal disease. 26 Currently no one class of calcium antagonist is favored more than another, and at least at the present time antihypertensive effectiveness is the primary basis on which to choose one agent or another. Treatment of hypertension in renal failure often requires multiple agents. In the MDRD study the average number of medications taken by the patients randomized to the mean arterial blood pressure goal of 92 mm Hg (corresponding to a value of 125/75 mm Hg) was two. Combination antihypertensive therapy is more successful when agents are chosen with complementary (as opposed to overlapping) mechanisms of action. The simple schema (depicted in Fig. 2) that divides blood pressure regulation into four basic areas are used 250

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to successfully treat hypertension, and, when multiple agents are used. antihypertensive agents are chosen from different sides of this “treatment square.” It is usually not necessary, and sometimes unwise, to use a potassiumsparing diuretic (amiloride, triamterene, or spironolactone) or to empirically prescribe a potassium supplement in the treatment regimen of hypertensive patients with renal failure because serious hyperkalemia may result. Two recent reviews provide more information regarding specific effects of antihypertensive drug classes on renal hemodynamics and renal function.z7.‘x

Goal Blood Pressure During Therapy Renal Failure

of Hypertension

in

It is unclear at this time what the best blood pressure level is for a patient with renal failure. The Working Group Report on Chronic Renal Failure recommended a blood pressure of 13OBS mm Hg.* It is possible that this goal should be even lower for African American patients or patients with proteinuria greater than 1 gm/24 hours.” In the MDRD study. the lower blood pressure group fared better, though the mean arterial pressure was only 6 mm Hg lower than the usual blood pressure goal (the original goals had been a mean arterial pressure of 107 mm Hg in one group and 92 mm Hg in another), arguing for a treatment goal of 92 mm Hg mean arterial pressure corresponding to a value of 12Y75 mm Hg.‘9 Despite the recognition of hypertension as a primary pathogenic factor in target organ damage, recent epidemiologic evidence indicates that only half of patients with elevated blood pressures receive antihypertensive medications. Remarkably, of those who are treated with drug therapy, only half achieve blood pressure values below the 140/90 mm Hg goal endorsed by JNC V.“’

Summary High blood pressure is an important and modifiable risk factor in the progression of renal failure. Most patients with renal failure have hypertension, and although knowledge of the processes that initiate and maintain the gradual loss of renal function is still incomplete, empiric data suggest that lowering blood pressure (by any means) will slow the rate of decline in renal function. The finding of a high incidence of salt sensitivity and the well-recognized tendency of patients with renal failure to retain sodium argues strongly for both a dietary restriction of sodium intake and the use of a diuretic in the hypertension prescription. The encouraging data on ACE inhibition and calcium channel antagonism also justify the empiric use of these classes of agents as well. The present studies suggest DM.

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a greater benefit on the course of progressive renal failure when proteinuria (>l gm/24 hours) is present, and less benefit when polycystic kidney disease is present. Whereas recent data from the MDRD study argue for a mean blood pressure of 92 mm Hg (corresponding to an office blood pressure of approximately 125/75 mm Hg) for a treatment to be deemed beneficial, it is suggested that the blood pressure achieved by therapy be at least less than 130/85 mm Hg.

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