Hypertension in kidney disease

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Hypertension in kidney disease

Authors
Norman M Kaplan, MD
Burton D Rose, MD

Section Editor
George L Bakris, MD

Deputy Editor
Alice M Sheridan, MD

Last literature review version 18.2: May 2010 | This topic last updated: June 17, 2010
PATHOGENESIS Hypertension is a frequent finding in both acute and chronic kidney disease,
particularly with glomerular or vascular disorders [1]. However, the incidence of hypertension and
its pathogenesis vary with the type of renal disease and its duration.
Acute glomerular disease Patients with acute glomerular disease, such as poststreptococcal
glomerulonephritis or membranous nephropathy, tend to be volume expanded and edematous
due to sodium retention [2]. As a result, the elevation in blood pressure is primarily due to fluid
overload, leading to suppression of the renin-angiotensin system and enhanced release of atrial
natriuretic peptide [3]. Although these changes are most prominent with advanced disease, the
incidence of hypertension is increased even in patients with a normal serum creatinine
concentration [4]. Both a familial predisposition to hypertension and subclinical volume expansion
are thought to be important in this setting.
Experimental studies of the nephrotic syndrome or glomerulonephritis suggest that sodium
retention in these disorders is due to increased reabsorption in the collecting tubules [5], which is
also the site of action of atrial natriuretic peptide and the related renal hormone urodilatin. (See
"Natriuretic hormones: Atrial peptides and ouabain-like hormone".)
Two different abnormalities in collecting tubule function have been identified in glomerular
disease, both of which could increase sodium reabsorption:
Relative resistance to atrial natriuretic peptide, due at least in part to more rapid degradation
of the second messenger cyclic GMP (guanosine monophosphate) by the enzyme
phosphodiesterase [4]. Infusion of a phosphodiesterase inhibitor largely reverses this defect and
restores the normal natriuretic response to volume expansion.
Increased activity of the Na-K-ATPase pump in the cortical collecting tubule but not other
nephron segments [6]. This pump provides the energy for active sodium transport by pumping
reabsorbed sodium out the cell into the peritubular capillary.
How these changes might be induced by the nephrotic syndrome or glomerulonephritis is not
clear.
Vascular disease Hypertension is also common in acute vascular diseases, such as vasculitis
or scleroderma. In these settings, however, the elevation in blood pressure results from
ischemia-induced activation of the renin-angiotensin system rather than volume expansion [7].
This difference in mechanism between glomerular and vascular disease may be of diagnostic
importance. A patient presenting with acute renal failure, hypertension, and red cells and red cell
casts in the urine sediment almost certainly has either glomerulonephritis or vasculitis. The
absence of edema in this setting would point strongly toward a primary vascular disease.
Chronic kidney disease Hypertension is present in approximately 80 to 85 percent of
patients with chronic kidney disease [8]. The prevalence of hypertension increases linearly as the
glomerular filtration rate falls and, as in patients without renal disease, is increased in patients

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with higher body weight and in blacks. Data from the Modification of Diet in Renal Disease Study,
for example, showed that the prevalence of hypertension rose progressively from 65 to 95
percent as the glomerular filtration rate fell from 85 to 15 mL/min per 1.73 m2 [8].
One or more of the following factors may contribute in the individual patient:
Sodium retention is generally of primary importance, even though the degree of extracellular
volume expansion may be insufficient to induce edema.
Increased activity of the renin-angiotensin system (probably due to regional ischemia induced
by scarring) is often responsible for at least part of the hypertension that persists after the
restoration of normovolemia.
Enhanced activity of the sympathetic nervous system has been demonstrated in patients with
chronic kidney disease [9,10]. The afferent signal may arise in part within the failing kidneys,
since it is not seen in patients who have undergone bilateral nephrectomy.
Secondary hyperparathyroidism raises the intracellular calcium concentration, which can lead
to vasoconstriction and hypertension [11]. (See "Pathogenesis of renal osteodystrophy".)
Lowering parathyroid hormone secretion by the chronic administration of an active vitamin
D analog can reduce both intracellular calcium and the systemic blood pressure.
Hypertension may occur or be exacerbated in patients with advanced chronic kidney disease
treated with erythropoietin; this effect is in part related to the degree of elevation in the
hematocrit. (See "Hypertension following erythropoietin in chronic kidney disease".)
Impaired nitric oxide synthesis and endothelium-mediated vasodilatation has been
demonstrated in patients with uremia [12-14]. Although the mechanisms are unclear, potential
explanations include reduced nitric oxide availability due to a state of increased oxidative stress,
or cofactor deficiency-induced uncoupling of nitric oxide synthase.
In addition to these factors that can raise the mean arterial pressure, two other factors may be
important:
Patients with end-stage renal disease are more likely to have an increase in pulse pressure
and isolated systolic hypertension [15]. Why this occurs is incompletely understood but increased
aortic stiffness appears to play an important role.
Patients with chronic kidney disease may not demonstrate the normal nocturnal decline in
blood pressure (called "nondippers"), a possible risk factor for hypertensive complications [16].
(See "Ambulatory blood pressure monitoring and white coat hypertension in adults".)
High-normal blood pressure The preceding observations apply to patients with overt
hypertension. However, elevations in blood pressure within the normal range also occur in
patients with chronic glomerular disease and may be clinically significant. One report evaluated
19 patients with chronic IgA nephropathy who were "normotensive" as determined by casual
blood pressure determinations [17]. When compared to matched healthy controls, the patients
with chronic glomerulonephritis had higher ambulatory blood pressures that were still within the
normal range. The patients also had a relative increase in left ventricular thickness on
echocardiography (again within the normal range), suggesting that the rise in blood pressure was
sufficient to induce early end-organ damage.
TREATMENT In view of the differences in pathogenesis, the treatment of hypertension varies
with the type of renal disease that is present.
Acute glomerular or vascular disease The hypertension in acute glomerular disease with
edema typically resolves after fluid removal with diuretics or, if necessary, dialysis. In
comparison, lowering angiotensin II formation with an angiotensin converting enzyme (ACE)
inhibitor is the treatment of choice in patients with vasculitis or scleroderma [18]. It is of interest,

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however, that ACE inhibitors may also be effective in the low renin hypertension associated with
acute glomerulonephritis [19]. This response may reflect activation of tissue renin-angiotensin
systems, such as that in the kidney, vascular endothelium, and adrenal gland. (See
"Renin-angiotensin system inhibition in the treatment of hypertension".)
Chronic kidney disease Treatment of even mild hypertension is important in patients with
chronic kidney disease (CKD) to protect against both progressive renal failure and cardiovascular
disease, the rate of which is increased with even mild to moderate CKD. (See "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease" and "Chronic kidney disease and
coronary heart disease", section on 'Blood pressure control'.)
Goal blood pressure JNC 7 and the K/DOQI Clinical Practice Guidelines on hypertension
and antihypertensive agents in chronic kidney disease recommended a goal blood pressure of less
than 130/80 mmHg [20,21]. The data supporting this goal primarily comes from studies of
patients excreting more than 1000 mg of protein per day. It is not clear if this goal applies to
patients with patients excreting less than 500 to 1000 mg/day. These issues are discussed in
detail elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney
disease", section on 'Importance of proteinuria in predicting response' and "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease", section on 'Nonproteinuric
chronic kidney disease'.)
In addition to blood pressure control, specific goals related to a reduction in urinary protein
excretion have been formulated to slow the rate of progression of proteinuric CKD. More
aggressive goals may be warranted in patients with a spot urine total protein-to-creatinine ratio
1000 mg/g (which represents protein excretion of greater than 1000 mg/day). (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)
Choice of therapy Attainment of a blood pressure below 130/80 mmHg in patients with
CKD typically requires three or more drugs [22]. The regimen should include:
An ACE inhibitor or angiotensin II receptor blocker (ARB) to slow the rate of progression of
proteinuric chronic kidney disease.
A diuretic for fluid control. As mentioned above, overt or subclinical (ie, nonedematous)
volume expansion contributes to the elevation in blood pressure in most forms of chronic kidney
disease. Thus, diuretics should be pushed until the blood pressure goal is reached or the patient
has attained "dry weight" which, in the presence of persistent hypertension, is defined as the
weight at which further fluid loss leads to symptoms (fatigue, orthostatic hypotension) or to
decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea
nitrogen and/or serum creatinine concentration.
When a diuretic is given to treat hypertension or edema in a patient with advanced renal disease,
a loop diuretic is generally used [23]. The thiazide diuretics in conventional dosage become less
effective as monotherapy when the glomerular filtration rate falls below 30 mL/min. They do,
however, produce an additive effect when administered with a loop diuretic for refractory edema.
When a thiazide given, we prefer chlorthalidone to hydrochlorothiazide. (See "Treatment of
refractory edema in adults" and "Choice of therapy in essential hypertension: Recommendations",
section on 'Chlorthalidone versus hydrochlorothiazide'.)
The third drug should be probably be a calcium channel blocker, but the optimal choice of
calcium channel blocker has not been defined and may vary with the degree of proteinuria:
- Among patients with proteinuria (more than 500 to 1000 mg/day), we suggest a
nondihydropyridine (diltiazem or verapamil) because these drugs can significantly reduce protein
excretion, a marker for slowing of disease progression. In contrast, dihydropyridines have little or
no effect on the rate of protein excretion [24].

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(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease",

Comparison to other agents).
- Among patients without significant proteinuria (less than 500 mg/day), there is no evidence
that administration of proteinuria-lowering drugs slows the rate of disease progression. However,
when given in combination with the ACE inhibitor benazepril in the ACCOMPLISH trial, the
long-acting dihydropyridine amlodipine was, despite equivalent blood pressure control, associated
with significant reductions in cardiovascular mortality and morbidity and a modest slowing of the
rate of loss of glomerular filtration compared to benazepril plus hydrochlorothiazide [25,26]. A
limitation to these findings is that ACCOMPLISH was not a trial of CKD, which was present in only
9.5 percent of patients. Nevertheless, we suggest use of a long-acting dihydropyridine as
third-line therapy in these patients.
(See "Choice of therapy in essential hypertension: Recommendations", section on 'ACCOMPLISH
trial'.)
Other antihypertensive drugs can be used as necessary in patients with chronic kidney
disease. (See "Treatment of resistant hypertension".)
- An aldosterone antagonist (spironolactone and eplerenone) is an effective fourth-line agent
for the treatment of resistant hypertension in general and in patients with CKD. The magnitude of
this effect was examined in a study of 46 patients with a mean estimated glomerular filtration
rate (eGFR) of 5716 mL/min per 1.73 m2 and hypertension that was not controlled with three
mechanistically complementary drugs, including a diuretic and angiotensin inhibitor [27]. The
mean fall in systolic pressure was 14.7 mmHg. The main adverse effects were more than a 30
percent decline in eGFR when goal blood pressure was achieved, which occurred in 39 percent of
patients, and hyperkalemia, which occurred in 17 percent. Risk factors of hyperkalemia were a
baseline eGFR 45 mL/min in patients with a serum potassium above 4.5 meq/L. and a fall in
eGFR of more than 30 percent after therapy.
- The potent vasodilator minoxidil is generally reserved for refractory hypertension, with
sodium retention, worsening edema, and hirsutism being the major side effects [28].
Angiotensin inhibition and prevention of disease progression ACE inhibitors and
angiotensin II receptor blockers (ARBs) slow the rate of progression of proteinuric CKD compared
to other antihypertensive drugs [29]. (See "Antihypertensive therapy and progression of
nondiabetic chronic kidney disease", section on 'Effect on progressive chronic kidney disease'.)
Adverse effects Two potential complications of ACE inhibitor or ARB therapy in patients
with CKD are an initial fall in glomerular filtration rate and the development of hyperkalemia:
An initial fall in glomerular filtration rate resulting in an elevation in serum creatinine is due to
the associated reduction in glomerular capillary pressure. The rise in serum creatinine typically
occurs early during dose titration. Late acute increases in serum creatinine (as opposed to
gradual increases due to disease progression) can occur if diuretics are started or the dose is
increased or if some other renal insult is superimposed, such as a nonsteroidal antiinflammatory
drug [30].
An elevation in serum creatinine of as much as 30 to 35 percent above baseline that stabilizes
within the first two to four months of therapy is considered acceptable and NOT a reason to
discontinue therapy with these drugs [21,30]. A review of 12 randomized trials of CKD
progression found that patients with a limited early acute increase in serum creatinine after
initiation of ACE inhibitors were more likely to have long-term preservation of kidney function
[30].
Hyperkalemia due to removal of the angiotensin II-mediated stimulus to the release of
aldosterone is most likely to occur in patients in whom the plasma potassium concentration is

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elevated or in the high normal range prior to therapy. Management of this issue is discussed
separately. (See "Treatment and prevention of hyperkalemia".)
A transient rise in the plasma potassium concentration may also occur with beta blockers, since
the beta-2-receptors help to drive potassium into the cells. This effect is most prominent with the
nonselective agents such as propranolol and is much less likely to occur with the beta-1-selective
agents such as metoprolol. (See "Sympathetic activity and potassium balance".)
African-American patients The ability of three different antihypertensive agents (ramipril,
metoprolol, and amlodipine) to slow progressive renal dysfunction among hypertensive
African-American patients with renal disease was evaluated in a randomized trial, the African
American Study of Kidney Disease and Hypertension (AASK) [31]. Enrollees were also assigned to
one of two blood pressure goals, 125/75 or 140/90 mmHg. There were two major findings:
ramipril was associated with better renal outcomes; and more aggressive blood pressure lowering
was of little benefit, except for a trend toward improved outcomes in patients with significant
proteinuria. (See "Clinical features and treatment of hypertensive nephrosclerosis".)
Maintenance dialysis The major therapeutic goal in hypertensive dialysis patients is gradual
fluid removal to attain "dry weight." (see "Hypertension in dialysis patients").
[32]
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