The Kidney in Blood Pressure Regulation L. Gabriel Navar L. Lee Hamm

D

espite extensive animal and clinical experimentation, the mechanisms responsible for the normal regulation of arterial pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton and other authors [1–4]: the long-term regulation of arterial pressure is intimately linked to the ability of the kidneys to excrete sufficient sodium chloride to maintain normal sodium balance, extracellular fluid volume, and blood volume at normotensive arterial pressures. Therefore, it is not surprising that renal disease is the most common cause of secondary hypertension. Furthermore, derangements in renal function from subtle to overt are probably involved in the pathogenesis of most if not all cases of essential hypertension [5]. Evidence of generalized microvascular disease may be causative of both hypertension and progressive renal insufficiency [5,6]. The interactions are complex because the kidneys are a major target for the detrimental consequences of uncontrolled hypertension. When hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater hypertension and additional renal injury. These interactions culminate in malignant hypertension, stroke, other sequelae, and death [7]. In normal persons, an increased intake of sodium chloride leads to appropriate adjustments in the activity of various humoral, neural, and paracrine mechanisms. These mechanisms alter systemic and renal hemodynamics and increase sodium excretion without increasing arterial pressure [3,8]. Regardless of the initiating factor, decreases in sodium excretory capability in the face of normal or increased sodium intake lead to chronic increases in extracellular fluid volume and blood volume. These increases can result in hypertension. When the derangements also include increased levels of humoral or neural factors that directly cause vascular smooth muscle constriction, these effects increase peripheral vascular resistance or decrease vascular capacitance. Under these conditions the effects of subtle increases in blood volume are compounded because of increases in the blood volume relative to

CHAPTER

1

1.2

Hypertension and the Kidney

Aortic pressure, mm Hg

160

Isolated systolic hypertension (61 y)

120

Aortic blood flow, mL/s

80

A

400 0

Normotensive (56 y)

Arterial pressure, mm Hg

the capacitance, often referred to as the effective blood volume. Through the mechanism of pressure natriuresis, however, the increases in arterial pressure increase renal sodium excretion, allowing restoration of sodium balance but at the expense of persistent elevations in arterial pressure [9]. In support of this overall concept, various studies have demonstrated strong relationships between kidney disease and the incidence of hypertension. In addition, transplantation studies have shown that normotensive recipients from genetically hypertensive donors have a higher likelihood of developing hypertension after transplantation [10]. This unifying concept has helped delineate the cardinal role of the kidneys in the normal regulation of arterial pressure as well as in the pathophysiology of hypertension. Many different

B

200 180 160 140 120 100 80 60 40 20

extrinsic influences and intrarenal derangements can lead to reduced sodium excretory capability. Many factors also exist that alter cardiac output, total peripheral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial dysfunctional process that can be caused by a myriad of different conditions. These conditions range from stimulatory influences that inappropriately enhance tubular sodium reabsorption to overt renal pathology, involving severe reductions in filtering capacity by the renal glomeruli and associated marked reductions in sodium excretory capability. An understanding of the normal mechanisms regulating sodium balance and how derangements lead to altered sodium homeostasis and hypertension provides the basis for a rational approach to the treatment of hypertension.

C

A

B

PP = 72 mm Hg PP = 40 mm Hg PP = 30 mm Hg

500

600 700 800 900 Arterial volume, mL

FIGURE 1-1 Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to a specific stroke volume. The normal relationship is shown in curve A, and arrows designate the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic distensibility. These decreases lead to marked increases in PP and overall mean arterial pressure for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isolated systolic hypertension often found in elderly persons. Recordings of actual aortic pressure and flow profiles in persons with normotension and systolic hypertension are shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from Nichols et al. [12].)

HEMODYNAMIC DETERMINANTS For any vascular bed: Arterial pressure gradient Blood flow = Vascular resistance For total circulation averaged over time: Blood flow = cardiac output Therefore, Arterial pressure - right atrial pressure Cardiac output = Total peripheral resistance and: Mean arterial pressure = Cardiac output  total peripheral resistance

FIGURE 1-2 Hemodynamic determinants of arterial pressure. During the diastolic phase of the cardiac cycle, the elastic recoil characteristics of the arterial tree provide the kinetic energy that allows a continuous delivery of blood flow to the tissues. Blood flow is dependent on the arterial pressure gradient and total peripheral resistance. Under normal conditions the right atrial pressure is near zero, and thus the arterial pressure is the pressure gradient. These relationships apply for any instant in time and to timeintegrated averages when the mean pressure is used. The time-integrated average blood flow is the cardiac output that is normally 5 to 6 L/min for an adult of average weight (70 to 75 kg).

1.3

The Kidney in Blood Pressure Regulation

Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion

+

–

–

Arterial baroreflexes Atrial reflexes Renin-angiotensin-aldosterone Adrenal catecholamines Vasopressin Natriuretic peptides Endothelial factors: nitric oxide, endothelin kallikrein-kinin system Prostaglandins and other eicosanoids

Net sodium and fluid balance

ECF volume Arterial pressure Blood volume

Mean circulatory pressure

(Autoregulation)

Neurohumoral systems

Total peripheral resistance

Interstitial fluid volume

Venous return

Heart rate and contractility

Cardiac output

FIGURE 1-3 Volume determinants of arterial pressure. The two major determinants of arterial pressure, cardiac output and total peripheral resistance, are regulated by a combination of short- and long-term mechanisms. Rapidly adjusting mechanisms regulate peripheral vascular resistance, cardiovascular capacitance, and cardiac performance. These mechanisms include the neural and humoral mechanisms listed. On a long-term basis, cardiac output is determined by venous return, which is regulated primarily by the mean circulatory pressure. The mean circulatory pressure depends on blood volume and overall cardiovascular capacitance. Blood volume is closely linked to extracellular fluid (ECF) volume and sodium balance, which are dependent on the integration of net intake and net losses [13]. (Adapted from Navar [3].)

Cardiovascular capacitance

If increased

Concentrated urine: Increased free water reabsorption

6

Thirst: Increased water intake

5

+

Na+ and Cl– Quantity of Extracellular concentrations ÷ = NaCl in ECF fluid volume in ECF volume

–

If decreased NaCl losses (urine insensible)

A

Blood volume, L

Antidiuretic hormone release

NaCl intake

Decreased water intake Increased salt intake

FIGURE 1-4 A, Relationship between net sodium balance and extracellular fluid (ECF) volume. Sodium balance is intimately linked to volume balance because of powerful mechanisms that tightly regulate plasma and ECF osmolality. Sodium and its accompanying anions constitute the major contributors to ECF osmolality. The integration of sodium intake and losses establishes the net amount of sodium in the body, which is compartmentalized primarily in the ECF volume. The quotient of these two parameters (sodium and volume) determines the sodium concentration and, thus, the osmolality. Osmolality is subject to very tight regulation by vasopressin and other mechanisms. In particular, vasopressin is a very powerful regulator of plasma osmolality; however, it achieves this regulation primarily by regulating the relative solute-free water retention or excretion by the kidney [13–15]. The important point is that the osmolality is rapidly regulated by adjusting the ECF volume to the total solute present. Corrections of excesses in extracellular fluid volume involve more complex interactions that regulate the sodium excretion rate.

4 3 2

Antidiuretic hormone inhibition Dilute urine: Increased solute-free water excretion

Edema

0 10

B

15 Extracellular fluid volume, L

20

B, Relationship between the ECF volume and blood volume. Under normal conditions a consistent relationship exists between the total ECF volume and blood volume. This relationship is consistent as long as the plasma protein concentration and, thus, the colloid osmotic pressure are regulated appropriately and the microvasculature maintains its integrity in limiting protein leak into the interstitial compartment. The shaded area represents the normal operating range [13]. A chronic increase in the total quantity of sodium chloride in the body leads to a chronic increase in ECF volume, part of which is proportionately distributed to the blood volume compartment. When accumulation is excessive, disproportionate distribution to the interstitium may lead to edema. Chronic increases in blood volume increase mean circulatory pressure (see Fig. 1-3) and lead to an increase in arterial pressure. Therefore, the mechanisms regulating sodium balance are primarily responsible for the chronic regulation of arterial pressure. (Panel B adapted from Guyton and Hall [13].)

1.4

Hypertension and the Kidney

Intrarenal Mechanisms Regulating Sodium Balance Sodium excretion, normal

6 High sodium intake Normal sodium intake Low sodium intake

5

B

A

4 3

2

Elevated sodium intake

4

2 1

C

5 1

Normal sodium intake Reduced

3

0 60

80

100 120 140 160 Renal arterial pressure, mm Hg

180

200

Filtered sodium load, µmol/min/g

FIGURE 1-5 Arterial pressure and sodium excretion. In principle, sodium balance can be regulated by altering sodium intake or excretion by the kidney. However, intake is dependent on dietary preferences and usually is excessive because of the abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering urinary sodium excretion. It is therefore of major significance that, for any given set of conditions and neurohumoral environment, acute elevations in arterial pressure produce natriuresis, whereas

150 100 50

Low Normal High

0

Fractional sodium reabsorption, %

100 98 96 94 92

Fractional sodium excretion, %

8 6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg

reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pressure natriuresis serves a critical role linking arterial pressure to sodium balance. Representative relationships between arterial pressure and sodium excretion under conditions of normal, high, and low sodium intake are shown. When renal function is normal and responsive to sodium regulatory mechanisms, steady state sodium excretion rates are adjusted to match the intakes. These adjustments occur with minimal alterations in arterial pressure, as exemplified by going from point 1 on curve A to point 2 on curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by point 3 on curve C. When the regulatory mechanisms are operating appropriately, the kidneys have a large capability to rapidly adjust the slope of the pressure natriuresis relationship. In doing so, the kidneys readily handle sodium challenges with minimal long-term changes in extracellular fluid (ECF) volume or arterial pressure. In contrast, when the kidney cannot readjust its pressure natriuresis curve or when it inadequately resets the relationship, the results are sodium retention, expansion of ECF volume, and increased arterial pressure. Failure to appropriately reset the pressure natriuresis is illustrated by point 4 on curve A and point 5 on curve C. When this occurs the increased arterial pressure directly influences sodium excretion, allowing balance between intake and excretion to be reestablished but at higher arterial pressures. (Adapted from Navar [3].)

FIGURE 1-6 Intrarenal responses to changes in arterial pressure at different levels of sodium intake. The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during changes in arterial pressure, GFR, and filtered sodium load. These values do not change significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the changes in sodium excretion in response to arterial pressure alterations are due primarily to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride intake to effect the large increases in the sodium excretion rate. These responses demonstrate the importance of tubular reabsorptive mechanisms in modulating the slope of the pressure natriuresis relationship. (Adapted from Navar and Majid [9].)

The Kidney in Blood Pressure Regulation

RA

πB140/90 mm Hg) is common and almost universally observed in patients with acute glomerulonephritis (GN). Many of these patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to normal in some but not all of these patients. Overall, 39% of patients with acute renal failure develop new hypertension. IN—interstitial nephritis. (Adapted from RodriguezIturbe and coworkers [3]; with permission.)

20 10 0 Acute GN

Acute IN

FIGURE 2-6 (see Color Plate) Micrograph of an onion skin lesion from a patient with malignant hypertension.

2.4

Hypertension and the Kidney

Pathophysiology of Hypertension in Renal Disease

Increased vasoconstriction Increased adrenergic stimuli Inappropriate renin-endothelin release Increased endothelin-derived contracting factor Increased thromboxane

Decreased vasodilation Decreased prostacyclin Decreased nitric oxide

7

6

6

Intake and output of water and salt (x normal)

7

5 4

D

High intake

E s se n hyp tial erte nsio n

3 2 Normal intake

1

Low intake

0 0

50

A

B

4 3

High intake

F

ass lm na e r of ss D Lo C

E

2 Normal intake

1

Low intake

C

100 150 Arterial pressure, mm Hg

5

kid G o ld ne blat t ys

Systemic vascular resistance

Al do ste ron e-s tim ula ted

Increased contraction Increased adrenergic activation

Normal

Intake and output of water and salt (x normal)

Increased extracellular fluid volume Decreased glomerular filtration rate Impaired sodium excretion Increased renal nerve activity Ineffective natriuresis, eg, atrial natriuretic peptide resistance

A

x

Cardiac output

Normal

Blood pressure =

FIGURE 2-7 Pathophysiologic mechanisms related to hypertension in parenchymal renal disease: schematic view of candidate mechanisms. The balance between cardiac output and systemic vascular resistance determines blood pressure. Numerous studies suggest that cardiac output is normal or elevated, whereas overall extracellular fluid volume is expanded in most patients with chronic renal failure. Systemic vascular resistance is inappropriately elevated relative to cardiac output, reflecting a net shift in vascular control toward vasoconstricting mechanisms. Several mechanisms affecting vascular tone are disturbed in patients with chronic renal failure, including increased adrenergic tone and activation of the reninangiotensin system, endothelin, and vasoactive prostaglandins. An additional feature in some disorders appears to depend on reduced vasodilation, such as in impaired production of nitric oxide.

A

B H

G

0 200

FIGURE 2-8 A, The relationship between renal artery perfusion pressure and sodium excretion (which defines “pressure natriuresis”) has been the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pressures required to achieve daily sodium balance. B, Distortion of this relationship routinely occurs in patients with parenchymal renal disease, illustrated here

0

B

50

100 150 Arterial pressure, mm Hg

200

as “loss of renal mass.” Similar effects are observed in conditions with disturbed hormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (“Goldblatt” kidneys). In all of these instances, higher arterial pressures are required to maintain sodium balance.

2.5

Renal Parenchymal Disease and Hypertension

35

30

122

118

Cumulative daily sodium intake

0 Cumulative urinary sodium loss

–400 Sodium, mEq

Percentage of body weight, kg

126

40

Total blood volume, mL/cm

200 Hemodialysis

130

–800

–1200 F

S

S

M

T

W TH Days

F

S

S

Sodium losses during hemodialysis or ultrafiltration Net sodium loss

M –1600

Total net loss of sodium=1741 mEq

A

Blood pressure, mm Hg

Plasma renin activity, mg/mL/h

10.0 Uremic control subjects

5.0

F

B

180 Captopril, 25 mg

140

100

FIGURE 2-9 Sodium expansion in chronic renal failure. The degree of sodium expansion in patients with chronic renal failure can be difficult to ascertain. A, Shown are data regarding body weight, plasma renin

Blood pressure, mm Hg

Angiotensin II inhibitor, µg/kg/min 5 10 50 100 10 10 Saline infusion L40

200

150

Plasma renin Cumulative sodium balance, mEq activity, ng/mL/hr

100 200

100 0 100 50 0 0

1

11 35 38 41 Hours

65 67

S

S

M T

W TH F Days

S

S M

T

activity, and blood pressure (before and after administration of an ACE inhibitor) over 11 days of vigorous fluid ultrafiltration. Sequential steps were undertaken to achieve net negative sodium and volume losses by means of restricting sodium intake (10 mEq/d) and initiating ultrafiltration to achieve several liters of negative balance with each treatment. A negative balance of nearly 1700 mEq was required before evidence of achieving dry weight was observed, specifically a reduction of blood pressure. Measured levels of plasma renin activity gradually increased during sodium removal, and blood pressure became dependent on the renin-angiotensin system, as defined by a reduction in blood pressure after administration of the angiotensin-converting enzyme inhibitor captopril. Achieving adequate reduction of both extracellular fluid volume and sodium is essential to satisfactory control of blood pressure in patients with renal failure. B, Daily and cumulative sodium balance.

FIGURE 2-10 Interaction between sodium balance and angiotensin-dependence in malignant hypertension. Studies in a patient with renal dysfunction and accelerated hypertension during blockade of the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interaction between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin II antagonist was reversed during saline infusion with a positive sodium balance and reduction in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide], 40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and restored sensitivity to the angiotensin II antagonist. Such observations further establish the reciprocal relationship between the sodium status and activation of the renin-angiotensin system [5]. (From Brunner and coworkers [5]; with permission.)

2.6

Hypertension and the Kidney

15 s

Normal person

Hemodialysis, bilateral nephrectomy

Hemodialysis, no nephrectomy

Neurogram

Electrocardiogram 3s

A

Systolic blood pressure, mm Hg

200

Sham Renal denervated

190 180 170 160 150 140 130 120 110

NS

0

B

NS

3.0 g/d). No such relationship was evident over the duration of this trial (mean, 2.2 years) for patients with less severe proteinuria. These data emphasize the importance of blood pressure in determining disease progression in patients with proteinuric nondiabetic renal disease. No distinction was made in this study regarding the relative benefits of specific antihypertensive agents. (From Peterson and coworkers [21]; with permission.)

Slope of 1/creatinine vs time, dL/mg mo

Effects of Antihypertensive Therapy on Renal Disease Progression

–0.006 –0.008 –0.010 –0.012 0 85–90 70–85 90–96 96–113 Range of diastolic blood pressure (mm Hg) for each quartile of the population

FIGURE 2-24 Blood pressure and rate of progressive renal failure. Rates of disease progression (defined as the slope of 1/creatinine) were determined in 86 patients who reached end-stage renal disease and dialytic therapy. The rates of progression were defined between mean creatinine levels of 3.8 mg/dL (start) and 11.4 mg/dL (end) over a mean duration of 33 months [22]. Brazy and coworkers [22] demonstrated that the slope of disease progression appeared to be related to the range of achieved diastolic blood pressure during this interval. Hence, these authors argue that more intensive antihypertensive therapy may delay the need for replacement therapy in patients with end-stage renal disease. As noted in the Modification of Diet in Renal Disease trial, such benefits are most apparent in patients with proteinuria over a shorter follow-up period. (From Brazy and coworkers [22]; with permission.)

Renal Parenchymal Disease and Hypertension

CLASSES OF ANTIHYPERTENSIVE AGENTS USED IN TREATMENT OF CHRONIC RENAL DISEASE Diuretics: Thiazide class Loop diuretics Potassium-sparing agents Adrenergic inhibitors Peripheral agents, eg, guanethidine Central -agonists, eg, clonidine, methyldopa, and guanfacine -Blocking agents, eg, doxazosin -Blocking agents Combined - blocking agents, eg, labetalol Vasodilators Hydralazine Minoxidil Classes of calcium-channel blocking agents Verapamil Diltiazem Dihydropyridine Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers

50 45 40 35

Rate of change in GFR, mL/min/1.73 m2/y

Conventional Strict n=87 patients Bars=95% confidence intervals for GFR estimates

55 GFR, mL/min/1.73 m2/y

FIGURE 2-25 The current classification of agents applied for chronic treatment of hypertension as summarized in the report by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure [23]. Attention must be given to drug accumulation and limitations of individual drug efficacy as glomerular filtration rates decrease in chronic renal disease. Potassium levels may increase during administration of potassium-sparing agents and medications that inhibit the renin-angiotensin system, especially in patients with impaired renal function [24].

4

60

30

3

Mean ±SEM

2

1

0 –1 –2

25

–3 –6

A

2.13

0

6

12

18

24 30 Time, mo

36

42

48

FIGURE 2-26 Strict blood pressure control and progression of hypertensive nephrosclerosis. Whether vigorous blood pressure reduction reduces progression of early parenchymal renal disease in blacks with nephrosclerosis is not yet certain. A and B, A randomized prospective trial comparing strict (panel A) blood pressure control (defined as diastolic blood pressure [DBP] 1.5 mg/dL) as shown in the top two lines. It should be noted that calcium channel blocking drugs were excluded from this trial and the ACE inhibitor arm had somewhat lower arterial pressures during treatment. These data offer support to the concept that ACE inhibition lowers intraglomerular pressures, reduces proteinuria, and delays the progression of diabetic nephropathy by more mechanisms than can be explained by pressure reduction alone. (Data from Lewis and coworkers [27].)

2.6 Benazepril: n=583 patients; creatinine=1.5–4.0 Placebo

Benazepril: n=583 patients; creatinine=1.5–4.0 Placebo

239

2.4

117

2.4 137

262

A

2.2

2.2

2.0

2.0

0

1

Years

2

3

FIGURE 2-28 Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal disease. A and B, Shown here are serum creatinine levels from the 12-month (panel A) and 36-month (panel B) cohorts followed in the benazepril trial. In this trial, 583 patients were randomized to therapy with or without benazepril [28]. Slight reductions in the rates of increase in creatinine and of stop points in the ACE inhibitor group occurred; however, these reductions were modest. Whereas these

B

0

1

Years

2

3

data support a role for ACE inhibition, the results are considerably less convincing than are those for diabetic nephropathy. These results argue that some groups may not experience major benefit from ACE inhibition over the short term. Preliminary reports from recent studies limited to patients with proteinuria suggest that rates of progression were substantially reduced by treatment with ramipril [29]. (From Maschio and coworkers [28]; with permission.)

Renal Parenchymal Disease and Hypertension

CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997 1. Hypertension may result from renal disease that reduces functioning nephrons. 2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease. 3. Blood pressure should be controlled to ≤130/85 mm Hg (50–55 y

Women Age 20–40 y

Total occlusion common Ischemic atrophy common

Total occlusion rare Ischemic atrophy rare

Surgical intervention or angioplasty: Mediocre cure rates of the hypertension Less amenable to PTRA

Surgical intervention or angioplasty: Good cure rates of the hypertension More amenable to PTRA

FIGURE 3-8 A comparison of atherosclerotic renal artery disease and medial fibroplasia. The most common types of renal artery disease (atherosclerotic renal artery disease [ASO-RAD] and medial fibroplasia) are compared here. In general, ASO-RAD is observed in men and women older than 50 to 55 years of age, whereas medial fibroplasia is observed primarily in younger white women. Total occlusion of the renal artery and, hence, atrophy of the

3.5

FIGURE 3-7 Arteriogram and schematic diagram of intimal fibroplasia. A, Selective right renal arteriogram demonstrating a localized, highly stenotic, smooth lesion involving the distal renal artery, from intimal fibroplasia. B, Schematic diagram of intimal fibroplasia. Intimal fibroplasia occurs primarily in children and adolescents and angiographically gives the appearance of a localized, highly stenotic, smooth lesion, with poststenotic dilatation. It may occur in the proximal portion of the renal artery as well as in the mid and distal portions of the renal artery, is progressive, and is occasionally associated with dissection or renal infarction. Pathologically, idiopathic intimal fibroplasia is due to a proliferation of the intimal lining of the arterial wall. Intimal fibroplasia of the renal artery may also occur as an event secondary to atherosclerosis or as a reactive intimal fibroplasia consequent to an inciting event such as prior endarterectomy or balloon angioplasty. (Panel A from Pohl [1]; with permission.) kidney beyond the stenosis are relatively common with ASO-RAD, but ischemic atrophy of the kidney ipsilateral to the medial fibroplasia lesion is rare. Surgical intervention or pecutaneous transluminal renal angioplasty (PTRA) typically produce good cure rates for the hypertension in medial fibroplasia and these lesions are technically quite amenable to PTRA. In contrast, ASO-RAD is, technically, much less amenable to PTRA (particularly ostial lesions), and surgical intervention or PTRA produce mediocre-to-poor cure rates of the hypertension. ASO-RAD and medial fibroplasia may cause hypertension and when the hypertension is cured or markedly improved following intervention, the patient may be viewed as having “renovascular hypertension.” This sequence of events is far more likely to occur in patients with medial fibroplasia than in patients with ASO-RAD. ASO-RAD and medial fibroplasia involve both main renal arteries in approximately 30% to 40% of patients.

3.6

Hypertension and the Kidney

Pathophysiology of Renovascular Hypertension

Stenotic kidney

Contralateral kidney

Ischemia Renin

• Supressed renin • Pressure natriuresis

Angiotensin II Vasoconstriction

Aldosterone

• Intrarenal hemodynamics • Sodium retention

FIGURE 3-9 Schematic representation of renovascular hypertension. Renovascular hypertension may be defined as the secondary elevation of blood pressure produced by any of a variety of conditions that interfere with the arterial circulation to kidney tissue and cause renal ischemia. Almost always, renovascular hypertension is caused by obstruction of the renal artery or its branches, and demonstration of causality between the renal artery lesion and the hypertension is essential to this definition.

This diagram shows the classic model of two-kidney, one clip (2K,1C) Goldblatt hypertension, wherein one renal artery is constricted and the contralateral kidney is left intact. In the presence of hemodynamically sufficient unilateral renal artery stenosis, the kidney distal to the stenosis is rendered ischemic, activating the renin angiotensin system, and producing high levels of angiotensin II, causing a “vasoconstrictor” type of hypertension. Numerous studies have established the causal relationship between angiotensin II–mediated vasoconstriction and hypertension in the early phase of this experimental model. In addition, the high levels of angiotensin II stimulate the adrenal cortex to elaborate larger amounts of aldosterone such that the “stenotic kidney” demonstrates sodium retention. This secondary aldosteronism also produces hypokalemia. The degree of renal artery stenosis necessary to produce hemodynamically significant reductions in perfusion, triggering renal ischemia and activation of the renin angiotensin system, generally does not occur until a reduction of 80% or more in both lumen diameter and cross-sectional area of the renal artery takes place. Lesser degrees of renal artery constriction do not initiate this sequence of events. This model of 2K,1C Goldblatt hypertension implies that the contralateral (nonaffected) kidney is present, and that its renal artery is not hemodynamically significantly narrowed. As illustrated, the “contralateral kidney” demonstrates suppressed renin production and undergoes a pressure natriuresis, presumably because of angiotensin II–initiated vasoconstriction and sodium retention, leading to systemic elevation of blood pressure that then results in suppression of renin release and enhanced excretion of sodium (pressure natriuresis) by the “contralateral kidney.”

Renovascular Hypertension and Ischemic Nephropathy

Clip

I

Phase II

III

Blood pressure

Renin Change in blood pressure on removing clip

FIGURE 3-10 Sequential phases in two-kidney, one-clip (2K,1C) experimental renovascular hypertension. The schematic representation of renovascular hypertension depicted in Figure 3-9 is an oversimplification. In fact, the course of experimental 2K,1C hypertension may be divided into three sequential phases. In phase I, renal ischemia and activation of the renin angiotensin system are of fundamental importance, and in this early phase of experimental hypertension, the blood pressure elevation is renin- or angiotensin II–dependent. Acute administration of angiotensin II antagonists, administration of angiotensin-converting enzyme (ACE) inhibitors, removal of the renal artery stenosis (ie, removal of the clip in the experimental animal or removal of the “stenotic kidney”) promptly normalizes blood pressure. Several days after renal artery clamping, renin levels fall, but blood pressure remains elevated. This second phase of experimental 2K,1C hypertension may be viewed as a pathophysiologic transition phase that, depending on the experimental model and species, may last from a few days to several weeks. During this transition phase (phase II), salt and water retention are observed as a consequence of the effect of hypoperfusion of the stenotic kidney;

Two-kidney hypertension

Blood pressure

Renin

Volume

High

Normal

One-kidney hypertension

Blood pressure

Renin

Volume

Normal

High

3.7

augmented proximal tubular reabsorption of sodium and water and angiotensin II–induced stimulation of aldosterone secretion contribute to this sodium and water retention. In addition, the high levels of angiotensin II stimulate thirst, which further augments expansion of the extracellular fluid volume. The expanded extracellular fluid volume results in a progressive suppression of peripheral renin activity. During this transition phase, the hypertension is still responsive to removal of the unilateral renal artery stenosis, to angiotensin II blockade, or unilateral nephrectomy, although these maneuvers do not normalize the blood pressure as promptly and consistently as in the acute phase. After several weeks, a chronic phase (phase III) ensues wherein unclipping the renal artery of the experimental animal does not lower the blood pressure. This failure of “unclipping” to lower the blood pressure in this chronic phase (III) of 2K,1C hypertension is due to widespread arteriolar damage to the “contralateral kidney,” consequent to prolonged exposure to high blood pressure and high levels of angiotensin II. In this chronic phase of 2K,1C renovascular hypertension, extracellular fluid volume expansion and systemic vasoconstriction are the main pathophysiologic abnormalities. The pressure natriuresis of the “contralateral kidney” blunts the extracellular fluid volume expansion caused by the “stenotic kidney;” but as the contralateral kidney suffers vascular damage from extended exposure to elevated arterial pressure, its excretory function diminishes and extracellular fluid volume expansion persists. In this third phase of experimental 2K,1C hypertension, acute blockade of the renin angiotensin system fails to lower blood pressure. Sodium depletion may ameliorate the hypertension but does not normalize it. The clinical surrogate of phase III experimental 2K,1C hypertension is duration of hypertension. Widespread clinical experience indicates that major improvements in blood pressure control or cure of the hypertension following renal revascularization or even removal of the kidney ipsilateral to the renal artery stenosis are rarely observed in patients with a long duration (ie, >5 years) of hypertension. (Adapted from Brown and coworkers [3]; with permission.) FIGURE 3-11 Schematic representation of two types of experimental hypertension. The discussion so far of the pathophysiology of renovascular hypertension has focused on the two-kidney, one-clip model of renovascular hypertension (“two-kidney hypertension”), wherein the artery to the “contralateral kidney” is patent and the “contralateral” nonaffected kidney is present. Elevated peripheral renin activity, normal plasma volume, and hypokalemia are typically associated with the elevated arterial pressure. There is another type of “renovascular hypertension” known as “one-kidney” hypertension, wherein in the experimental model, one renal artery is constricted and the contralateral kidney is removed. Although there is an initial increase in renin release responsible for the early rise in blood pressure in “one-kidney” hypertension as in “two-kidney” hypertension, the absence of an unclipped contralateral kidney allows for sodium retention early in the course of this one-kidney, one-clip (1K,1C) model. Renin levels are suppressed to normal levels in conjunction with high blood pressure which is maintained by salt and water retention. Thus, extracellular fluid volume expansion is a prime feature of “one-kidney” hypertension.

3.8

Hypertension and the Kidney

A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (“TWO-KIDNEY HYPERTENSION”)* Unilateral atherosclerotic renal arterial disease Unilateral fibrous renal artery disease Renal artery aneurysm Arterial embolus Arteriovenous fistula (congenital and traumatic) Segmental arterial occlusion (traumatic) Pheochromocytoma compressing renal artery Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma) *Implies contralateral (nonaffected) kidney present.

B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (“ONE-KIDNEY HYPERTENSION”)* Stenosis to a solitary functioning kidney Bilateral renal arterial stenosis Aortic coarctation Vasculitis (polyarteritis nodosa and Takayasu’s arteritis) Atheroembolic disease

FIGURE 3-12 Lesions producing the syndrome of renovascular hypertension. A, Two-kidney hypertension. The most common clinical counterpart to “two-kidney” hypertension is unilateral renal artery stenosis due to either atherosclerotic or fibrous renal artery disease. Unilateral renal trauma, with development of a calcified fibrous capsule surrounding the injured kidney causing compression of the renal parenchyma, may produce renovascular hypertension; this clinical situation is analogous to the experimental Page kidney, wherein cellophane wrapping of one of two kidneys causes hypertension, which is relieved by removal of the wrapped kidney. B, One-kidney hypertension. Clinical counterparts of experimental one-kidney, one-clip (“one kidney”) hypertension include renal artery stenosis to a solitary functioning kidney, bilateral renal arterial stenosis, aortic coarctation, Takayasu’s arteritis, fulminant polyarteritis nodosa, atheroembolic renal disease, and renal artery stenosis in a transplanted kidney. In some parts of the world, eg, China and India, Takayasu’s arteritis is a frequent cause of renovascular hypertension.

*Implies total renal mass ischemic.

STEPS IN MAKING THE DIAGNOSIS OF RENOVASCULAR HYPERTENSION 1. Demonstration of renal arterial stenosis by angiography 2. Determination of pathophysiologic significance of the stenotic lesion 3. Cure of the hypertension by intervention, ie, revascularization, percutaneous transluminal angioplasty, nephrectomy

FIGURE 3-13 Steps in making the diagnosis of renovascular hypertension (RVHT). With the exception of oral contraceptive use and alcohol ingestion, RVHT is the most common cause of potentially remediable secondary hypertension. RVHT is estimated to occur with a prevalence of 1% to 15%. Some hypertension referral clinics have estimated a prevalence of RVHT as high as 15%, whereas other prevalence data suggest that less than 1% to 2% of the hypertensive population has RVHT.

Although elderly atherosclerotic hypertensive individuals often have atherosclerotic renal artery disease, their hypertension is usually essential hypertension, not RVHT. On balance, the prevalence of RVHT in the general hypertensive population is probably no more than 2% to 3%. The particular appeal of diagnosing RVHT centers around its potential curability by an interventive maneuver such as surgical revascularization, percutaneous transluminal renal angioplasty (PTRA), or renal artery stenting. Whether or not to use these interventions for the goal of improving blood pressure depends on the likelihood such intervention will improve the blood pressure. The overwhelming majority of patients with RVHT will have this syndrome because of main renal artery stenosis. Therefore, the first step in making the diagnosis of RVHT is to demonstrate renal artery stenosis by one of several imaging procedures and, eventually, by angiography. The second step in establishing the probability that the renal artery stenosis is instrumental in promoting hypertension is to determine the pathophysiologic significance of the stenotic lesion. Finally, the hypertension, presumed to be renovascular in origin, is proven to be RVHT when the elevated blood pressure is cured or markedly ameliorated by an interventive maneuver such as surgical revascularization, PTRA, renal artery stent, or nephrectomy.

Renovascular Hypertension and Ischemic Nephropathy

DIAGNOSIS OF RENAL ARTERIAL STENOSIS Clinical clues

Diagnostic tests

Age of onset of hypertension 55 y Abrupt onset of hypertension Acceleration of previously well-controlled hypertension Hypertension refractory to an appropriate three-drug regimen Accelerated retinopathy Systolic-diastolic abdominal bruit Evidence of generalized atherosclerosis obliterans Malignant hypertension Flash pulmonary edema Acute renal failure with use of angiotensin-converting enzyme inhibitors or angiotensin II receptor-blockers

Duplex ultrasonography Radionuclide renography Captopril renography Captopril provocation test Intravenous digital subtraction angiography Rapid sequence IVP Magnetic resonance angiography Spiral CT angiography CO2 angiography Conventional (contrast) angiography

FIGURE 3-14 Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some of which suggest that the stenosis is the cause of the hypertension, are listed on the left. The well-documented age of onset of hypertension in an individual under the age of 30 or over age 55 years, particularly if the hypertension is severe and requiring three antihypertensive drugs, is a strong clinical clue to renal artery stenosis and predicts that the stenosis is causing the hypertension. The patient with a long history of mild hypertension, easily controlled with one or two drugs, who, particularly in older age, develops severe and refractory hypertension, is likely to have developed atherosclerotic renal artery stenosis as a contributor to underlying

3.9

longstanding essential hypertension. Grade III hypertensive retinopathy, malignant hypertension, and flash pulmonary edema all suggest renal artery stenosis with or without renovascular hypertension. The observation of a diastolic bruit in the abdomen of a young white women suggests fibrous renal artery disease and, further, is a reliable clinical clue that the hypertension will be helped substantially by surgical renal revascularization or percutaneous transluminal renal angioplasty. The diagnostic tests listed along the right side are used mainly to detect renal artery stenosis (ie, the anatomic presence of disease). Captopril renography is also used to predict physiologic significance of the stenotic lesion. The popularity of these diagnostic tests in detecting renal artery stenosis varies from institution to institution; correlations with percent stenosis by comparative angiography are widely variable. A substantial fall in blood pressure following initiation of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker suggests RVHT. With the exception of a diastolic abdominal bruit and accelerated retinopathy, no clear-cut physical findings definitely discriminate patients with RVHT from the larger pool of patients with essential hypertension.

FIGURE 3-15 Renal duplex ultrasound for diagnosis of renal artery stenosis. Duplex ultrasound scanning of the renal arteries is a noninvasive screening test for the detection of renal artery stenosis. It combines direct visualization of the renal arteries (B-mode imaging) with measurement of various hemodynamic factors in the main renal arteries and within the kidney (Doppler), thus providing both an anatomic and functional assessment. Unlike other noninvasive screening tests (eg, captopril renography), duplex ultrasonography does not require patients to discontinue any antihypertensive medications before the test. The study should be performed while the patient is fasting. The white arrow indicates the aorta and the black arrow the left renal artery, which is stenotic. Doppler scans (bottom) measure the corresponding peak systolic velocities in the aorta and in the renal artery. The peak systolic velocity in the left renal artery was 400 cm/s, and the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renalaortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman and coworkers [4]; with permission.)

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Hypertension and the Kidney

COMPARISON OF DUPLEX ULTRASOUND WITH ARTERIOGRAPHY

Percent stenosis by ultrasound 0–59 60–99 100 Total

Percent stenosis by arteriogram 0–59

60–79

80–99

100

Total

62 1 0 63

0 31 1 32

1 67 1 69

1 0 22 23

64 99 24 187

Sensitivity, 0.98. Specificity, 0.98. Positive predictive value, 0.99. Negative predictive value, 0.97.

DETERMINATION OF PATHOPHYSIOLOGIC SIGNIFICANCE OF THE STENOTIC LESION Duration of hypertension 75% stenosis) Systolic-diastolic bruit in abdomen Renal vein renin ratio >1.5 Positive captopril provocation test or captopril renogram Abnormal rapid sequence IVP Hypokalemia

FIGURE 3-17 Determination of pathophysiologic significance of the stenotic lesion. The second step in making the diagnosis of renovascular hypertension (RVHT) is to determine the pathophysiologic significance of the stenotic lesion demonstrated by angiography. The likelihood of cure of the hypertension by an interventive maneuver is greatly enhanced when one or more of the items listed here are present. A positive captopril provocation test, abnormal rapid sequence intravenous pyelogram (IVP), or positive captopril

FIGURE 3-16 Comparison of duplex ultrasound with arteriography. A total of 102 consecutive patients with both duplex ultrasound scanning of the renal arteries and renal arteriography were prospectively studied. All patients in this study had difficult-to-control hypertension, unexplained azotemia, or associated peripheral vascular disease, giving them a high pretest likelihood of renovascular hypertension. Sixty-two of 63 arteries that showed less than 60% stenosis by formal arteriography, were identified by duplex ultrasound scanning. Twenty-two of 23 arteries with total occlusion on arteriography were correctly identified by duplex ultrasound. Thirty-one of 32 arteries with 60% to 79% stenosis using arteriography were identified as having 60% to 99% stenosis on duplex ultrasound and 67 of 69 arteries with 80% to 99% stenosis on arteriography were detected to have 60% to 99% stenosis on ultrasound. A current limitation of duplex ultrasound is the inability to consistently distinguish between more than and less than 80% stenosis (considered to be the magnitude of stenosis required for hemodynamic significance of the lesion). Nevertheless, duplex ultrasound is currently highly sensitive and specific in patients with a high likelihood of renovascular disease in detecting patients with more or less than 60% renal artery stenosis. Accessory renal arteries are difficult to identify by ultrasound and remain a limitation of this test. (Adapted from Olin and coworkers [5]; with permission.) renogram not only suggest the anatomic presence of renal artery stenosis but also imply that the stenosis is instrumental in producing the hypertension. Reductions of lumen diameter of less than 70% to 80% generally do not initiate renal ischemia or activation of the renin angiotensin system; thus, before recommending a renal revascularization procedure, severe renal artery stenosis (>75% reduction in lumen diameter) should be observed on the renal angiogram. A lateralizing renal vein renin ratio (a comparison of renin harvested from the renal vein ipsilateral to the renal artery stenosis with the renin level from renal vein of the contralateral kidney), particularly when renin production from the contralateral kidney is suppressed, suggests that an intervention on the renal artery stenosis will cure or markedly ameliorate the hypertension in about 90% of cases. Conversely, cure or marked improvement in blood pressure following renal revascularization has been reported in nearly 50% of cases in the absence of lateralizing renal vein renins. Hypokalemia, in the absence of diuretic therapy, strongly suggests that the hypertension is renovascular in origin, consequent to secondary aldosteronism. The sensitivity of an IVP in detecting unilateral RVHT is relatively poor (about 75%) and the overall sensitivity in detecting patients with bilateral renal artery disease is only about 60%. Because RVHT has a low prevalence in the general population, a negative IVP provides strong evidence (98% to 99% certainty) against RVHT.

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Renovascular Hypertension and Ischemic Nephropathy

RENIN CRITERIA FOR CAPTOPRIL TEST THAT DISTINGUISH PATIENTS WITH RVHT FROM THOSE WITH ESSENTIAL HYPERTENSION Stimulated PRA of 12 ng/mL/h or more Absolute increase in PRA of 10 ng/mL/h or more Percent increase in PRA Increase in PRA of 150% if baseline PRA >3 ng/mL/h Increase in PRA of 400% if baseline PRA 50% stenosis

109 21 189 76 76 817

38 33 39* 70† 29† 20‡

Abdominal aortic aneurysm Aorto-occlusive disease Lower extremity disease Suspected renal artery stenosis Coronary artery disease

*50% in diabetic patients. †Data from Vetrovec and coworkers [12]. ‡Data from Harding [13].

CLINICAL PRESENTATIONS OF ISCHEMIC RENAL DISEASE Acute renal failure, frequently precipitated by a reduction in blood pressure (ie, angiotensin-converting enzyme inhibitors plus diuretics) Progressive azotemia in a hypertensive patient with known renal artery stenosis treated medically Progressive azotemia in a patient (usually elderly) with refractory hypertension Unexplained progressive azotemia in an elderly patient Hypertension and azotemia in a renal transplant patient

FIGURE 3-24 Atherosclerotic renal artery stenosis in patients with generalized atherosclerosis obliterans and in patients with coronary artery disease (CAD). Atherosclerotic renal artery stenosis is common in older patients with and without hypertension simply as a consequence of generalized atherosclerosis obliterans. Approximately 40% of consecutively studied patients undergoing arteriography for routine evaluation of abdominal aortic aneurysm, aorto-occlusive disease, or lower extremity occlusive disease have associated renal artery stenosis (more than 50% unilateral renal artery stenosis) and nearly 30% of patients undergoing coronary angiography may have incidentally detected unilateral renal artery stenosis. Approximately 4% to 13% of patients with CAD or peripheral vascular disease have more than 75% bilateral renal artery stenosis. Correlations of hypercholesterolemia and cigarette smoking with renal artery atherosclerosis are not unequivocally clear, but they probably represent risk factors for renal artery atherosclerosis just as they represent risk factors for atherosclerosis in other vascular beds. (Adapted from Olin and coworkers [11]; with permission.)

FIGURE 3-25 Clinical presentations of ischemic renal disease. The clinical presentation of a patient likely to develop renal failure from atherosclerotic ischemic renal disease is that of an older (more than 50 years) individual demonstrating progressive azotemia in conjunction with antihypertensive drug therapy, risk factors for generalized atherosclerosis obliterans, known renal artery disease, refractory hypertension, and generalized atherosclerosis. Acute renal failure precipitated by a reduction in blood pressure below a “critical perfusion pressure,” and particularly with the use of angiotensin convertingenzyme inhibitors (ACEI) or angiotensin II receptor blockers plus diuretics, strongly suggests severe intrarenal ischemia from arteriolar nephrosclerosis and/or severe main renal artery stenosis. Unexplained progressive azotemia in an elderly patient with clinical signs of vascular disease with minimal proteinuria and a bland urinary sediment also suggest ischemic nephropathy. (Adapted from Jacobson [14]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy

A

FIGURE 3-26 Mild stenosis (less than 50%) due to atherosclerotic disease of the left main renal artery (panel A) that has progressed to high-grade (75% to 99%) stenosis on a later arteriogram (panel B). Underlying the concept of renal revascularization for preservation of renal function is the notion that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. The sequential angiograms in Figures 3-26 and 3-27 show angiographic progression of ASO-RAD over time. In patients demonstrating progressive renal artery stenosis by serial angiography, a decrease in kidney function as measured by serum creatinine and a decrease in ipsilateral kidney size correlate significantly with progressive occlusive disease. Patients demonstrating more than 75% stenosis of a renal artery are at highest risk for progression to complete occlusion. (From Novick [15]; with permission.)

B

A FIGURE 3-27 A, Normal right main renal artery and minimal atherosclerotic irregularity of left main renal artery on initial (1974) aortogram. B, Repeat aortography (1978) showed progression to moderate

3.15

B stenosis of the right main renal artery (arrow) and total occlusion of left main renal artery (arrow). (From Schreiber and coworkers [16]; with permission.)

3.16

Hypertension and the Kidney

CLINICAL CLUES TO BILATERAL ATHEROSCLEROTIC RENOVASCULAR DISEASE Generalized atherosclerosis obliterans Presumed renovascular hypertension Unilateral small kidney Unexplained azotemia Deterioration in renal function with BP reduction and/or ACE inhibitor therapy Flash pulmonary edema

FIGURE 3-28 Clinical clues to bilateral atherosclerotic renovascular disease. The patient at highest risk for developing renal insufficiency from renal artery stenosis (ischemic nephropathy) has sufficient arterial stenosis to threaten the entire renal functioning mass. These highrisk patients have high-grade (more than 75%) arterial stenosis to a solitary functioning kidney or high-grade (more than 75%) bilateral renal artery stenosis. Patients with two functioning kidneys with only unilateral renal artery stenosis are not at significant risk for developing renal insufficiency because the

PREDICTORS OF KIDNEY SALVAGEABILITY

Kidney size >9 cm (laminography) Function on either urogram or renal flow scan Filling of distal renal arteries (by collaterals) angiographically, with total proximal occlusion Glomerular histology on renal biopsy

FIGURE 3-29 Predictors of kidney salvageability. In evaluating patients as candidates for renal revascularization to preserve or improve renal function, some determination should be made of the

entire renal functioning mass is not threatened by large vessel occlusive disease. Clinical clues to the high-risk patient are similar to the clinical presentations of ischemic renal disease shown in Figure 3-25. Nearly 75% of adults with a unilateral small kidney have sustained this renal atrophy due to large vessel occlusive disease from atherosclerosis. One third of these patients with a unilateral small kidney have high-grade stenosis of the artery involving the contralateral normalsized kidney. Flash pulmonary edema is another clue to bilateral renovascular disease or high-grade stenosis involving a solitary functioning kidney. These patients, usually hypertensive and with documented coronary artery disease and underlying hypertensive heart disease, present with the abrupt onset of pulmonary edema. Left ventricular ejection fractions in these patients are not seriously impaired. Flash pulmonary edema is associated with atherosclerotic renal artery disease and may occur with or without severe hypertension. Renal revascularization to preserve kidney function or to prevent life-threatening flash pulmonary edema may be considered in patients with high-grade arterial stenosis to a solitary kidney or high-grade bilateral renal artery stenosis. Pecutaneous transluminal renal angioplasty (PTRA), renal artery stenting, or surgical renal revascularization may be employed. Patients with chronic total renal artery occlusion bilaterally or in a solitary functioning kidney are candidates for surgical renal revascularization, but are not candidates (from a technical standpoint) for PTRA or renal artery stents. potential for salvable renal function. Clinical clues suggesting renal viability include 1) kidney size greater than 9 cm (pole-topole length) by laminography (tomography); 2) some function of the kidney on either urogram or renal flow scan; 3) filling of distal renal arteries (by collaterals) angiographically, when the main renal artery is totally occluded proximally (see Fig. 3-30); and 4) well-preserved glomeruli with minimal interstitial scarring (see Fig. 3-31) on renal biopsy. Patients with moderately severe azotemia, eg, serum creatinine more than 3-4 mg/dL, are likely to have severe renal parenchymal scarring (see Fig. 3-32), which renders improvement in renal function following renal revascularization unlikely. Exceptions to this observation are cases of total main renal artery occlusion wherein kidney viability is maintained via collateral circulation (see Figure 3-30). A kidney biopsy may guide subsequent decision making regarding renal revascularization for the goal of improving kidney function. FIGURE 3-30 This abdominal aortogram reveals complete occlusion of the left main renal artery (panel A) with filling of the distal renal artery branches from collateral supply on delayed films (panel B). The observation of collateral circulation when the main renal artery is totally occluded proximally suggests viable renal parenchyma. (From Novick and Pohl [10]; with permission.)

A

B

Renovascular Hypertension and Ischemic Nephropathy

FIGURE 3-31 Renal biopsy of a solitary left kidney in a 67-year-old woman who had been anuric and on chronic dialysis for 9 months. The biopsy shows hypoperfused retracted glomeruli consistent with ischemia. There is no evidence of active glomerular proliferation or glomerular sclerosis. Note intact tubular basement membranes and negligible interstitial scarring. Left renal revascularization resulted in recovery of renal function and discontinuance of dialysis with improvement in serum creatinine to 2.0 mg/dL. (From Novick [15]; with permission.)

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FIGURE 3-32 Pathologic specimen of kidney beyond a main renal artery occlusion in a patient with severe bilateral renal artery stenosis and a serum creatinine of 4.5 mg/dL. The biopsy demonstrates glomerular sclerosis, tubular atrophy, and interstitial fibrosis. The magnitude of glomerular and interstitial scarring predict irreversible loss of kidney viability. (From Pohl [1]; with permission.)

FIGURE 3-33 Severe atherosclerosis involving the abdominal aorta, renal, and iliac arteries. This abdominal aortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, and subtotal occlusion of the proximal left main renal artery. Such patients are at high-risk for atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization.

FIGURE 3-34 (see Color Plate) “Purple toe” syndrome reflecting peripheral atheroembolic disease in the patient in Figure 3-33 (ragged aorta), following an abdominal aortogram.

3.18

Hypertension and the Kidney FIGURE 3-35 Pathologic specimen of kidney demonstrating atheroembolic renal disease (AERD). Microemboli of atheromatous material are readily identified by the characteristic appearance of cholesterol crystal inclusions that appear in a biconvex needle-shaped form. In routine paraffin-embedded histologic sections, the cholesterol is not seen because the methods used in preparing sections dissolve the crystals; the characteristic biconvex clefts in the glomeruli (or blood vessels) persist, allowing easy identification. Several patterns of renal failure in patients with AERD are recognized: 1) insult (eg, abdominal aortogram) leads to end-stage renal disease (ESRD) over weeks to months; 2) insult leads to chronic stable renal insufficiency; 3) multiple insults (repeated angiographic procedures) lead to a step-wise rise in serum creatinine eventuating in end-stage renal failure; and 4) insult leading to ESRD over several weeks to months with recovery of some renal function allowing for discontinuance of dialysis. FIGURE 3-36 Renal biopsy demonstrating severe arteriolar nephrosclerosis. Arteriolar nephrosclerosis is intimately associated with hypertension. The histology of the kidney in arteriolar nephrosclerosis shows considerable variation in intensity and extent of the arteriolar lesions. Thickening of the vessel wall, edema of the smooth muscle cells, hypertrophy of the smooth muscle cells, and hyaline degeneration of the vessel wall may be apparent depending on the severity of the nephrosclerosis. In addition to the vascular lesions of arteriolar nephrosclerosis there are abnormalities of glomeruli, tubules, and interstitial areas that are believed to be secondary to the ischemia that results from arteriolar insufficiency. Arteriolar nephrosclerosis is observed in patients with longstanding hypertension; the more severe the hypertension, the more severe the arteriolar nephrosclerosis. Arteriolar nephrosclerosis may also be seen in elderly normotensive individuals and is frequently observed in elderly patients with generalized atherosclerosis or essential hypertension.

Atherosclerosis

Nephrosclerosis

Atheroembolism

FIGURE 3-37 Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of nephrosclerosis (small vessel disease) or atheroembolic renal disease. Whether or not the renal insufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renal disease is difficult to determine. The term “ischemic nephropathy” is more complex than being simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASORAD, one should exclude other potential or contributing causes of renal insufficiency such as obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure.

Renovascular Hypertension and Ischemic Nephropathy 4% Miscellaneous

FIGURE 3-38 Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASORAD) has been claimed to contribute to the ESRD population. This diagram from the US Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year 1991 incident patients entered ESRD programs because of “hypertension (HBP).” No renovascular disease diagnosis is listed. Crude estimates of the percentage of patients entering ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making these estimates are both unclear and confounded by the high likelihood of coexisting arteriolar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD as a major contributor to the ESRD population is probably small on a percentage basis, occupying some portion of the ESRD diagnosis “hypertension (HBP).” For dialysis-dependent patients with ASO-RAD, predictors of recovery of renal function following renal revascularization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilateral (vs unilateral) renal artery stenosis, 2) a relatively fast rate of decline of estimated glomerular filtration rate (less than 6 months) prior to initiation of dialysis; and 3) mild-tomoderate arteriolar nephrosclerosis angiographically.

11% Other

12% CGN

5% Urology 3% Cyst

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36% DM 29% High blood pressure

Treatment of Renovascular Hypertension and Ischemic Nephropathy TREATMENT OPTIONS FOR RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Pharmacologic antihypertensive therapy PTRA Renal artery stents Surgical renal revascularization

INCREASING COMORBIDITY IN PATIENTS UNDERGOING RENOVASCULAR SURGERY Comorbidity, % Condition Angina Prior MI CHF Cerebrovascular disease Diabetes Claudication *P 1 degree, after coronary artery bypass graft surgery Nitroprusside equally efficacious in catecholaminerelated crises

Delayed onset Nasal congestion, None—not CNS sedation, recommended for of action, unpredictable bradycardia, use in hypertenhypotensive effect exacerbates pepsive crises tic ulcer disease, depression

Contraindicated in hypertensive encephalopathy, CNS catastrophe, cumulative hypotensive response

Contraindicated in hypertensive encephalopathy, CNS catastrophe

aortic dissection, atherosclerotic coronary vascular disease

Tachycardia, arrhythmias, nausea, vomiting, diarrhea, exacerbation of peptic ulcer disease Headache, angina Contraindicated in Delayed onset IV bolus: 5–10 mg over Proven efficacy of action, 20–30 min or continuand safety in ous infusion 400 µg/mL hypertensive crises unpredictable hypotensive effect solution Loading dose: of pregnancy 200–300 µg/min for 30–60 min Maintenance infusion: 50–150 µg/min Delayed onset Sedation IV of 250–500 mg None—not over 6–8 h recommended for of action, unpredictable use in hypertenhypotensive effect sive crises

IV bolus: 1–5 mg over 5 min

Fails to control BP Headache, nausea, Theoretic advanin some patients vomiting, tages over nitropalpitations, prusside in setting abdominal pain of myocardial ischemia -blockage can Nausea, vomiting, IV minibolus: Initial, 20 Continuous worsen congestive paresthesias, mg over 2 min Then monitoring not heart failure, headache, 40–80 mg over 10 min. required bronchospasm, bradycardia Maximum, 300 mg heart block

1–5 min after infusion Continuous infusion: stopped Initially, 5 µg/min Increase by 5 µg/min over 3–5 min

insufficiency and glaucoma; potentiates succinylcholine Dilates intracoronary collaterals

Comments

Discontinue if 2–3 min after infusion Continuous infusion: Precise titration of Monitoring in ICU Nausea, vomiting, required apprehension. stopped Initial, 0.5 µg/kg/min BP. Consistently thiocyanate level Thiocyanate toxic- >10 mg/dL Average, 3 µg/kg/min effective when ity with prolonged Maximum, 10 µg/kg/min other drugs fail. infusion, renal Parenteral agent insufficiency of choice for hypertensive crises Sustained Nausea, vomiting, Contraindicated in 4–24 h IV minibolus: 50–100 mg Long duration of hypotension with hyperglycemia, IV given rapidly over action. Constant aortic dissection, CNS and myocarmyocardial 5–10 min. Total dose, monitoring not cerebrovascular ischemia, uterine 150–600 mg required after ini- dial ischemic can disease, myocardial occur. Reflex sym- atony tial titration ischemia pathetic cardiac stimulation Dry mouth, blurred Tilt-bed enhances 5–10 min after infuContinuous infusion: Blocks barorecep- Parasympathetic blockade vision, urinary sion stopped Initial, 0.5 mg/min tor-mediated effect; tachyphylaxis retention, paralyt- after 24–48 h; Maximum, 5.0 mg/min sympathetic ic ileus, respiratocardiac stimulation contraindicated ry arrest in respiratory

Method of Duration of action administration

BP—blood pressure; CNS—central nervous system; CO—cardiac output; ICU—intensive care unit; IV—intravenous; SVR—systemic vascular resistance.

Reserpine

10–30 min

2–3 min

Minutes

Minutes Ganglionic blockage with venodilation and arteriolar vasodilation

Trimethaphan camsylate

Labetalol

10–15 min

1–2 min

Direct arteriolar vasodilation

Diazoxide

Minutes

Immediate

Onset of action Peak effect Instantaneous

Mechanism of action

Sodium Direct arteriolar nitroprusside vasodilation and venodilation

Drug

VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES

Hypertensive Crises

8.27

8.28

Hypertension and the Kidney

Mean arterial pressure, mm Hg

200

Uncontrolled hypertensives (n=13) Controlled hypertensives (n=9) Normotensives (n=10)

150

100 79 72 ± 74 10% ± 29% ± 12%

50

0 Baseline mean arterial pressure

Lower limit of autoregulation

45 ± 6%

46 45 ± ± 16% 12%

Lowest tolerated mean arterial pressure

FIGURE 8-35 Risks of rapid blood pressure reduction in hypertensive crises. It has been argued over the years that rapid reduction of blood pressure in the setting of hypertensive crises may have a detrimental effect on cerebral perfusion because the autoregulatory curve of cerebral blood flow is shifted upward in patients with chronic hypertension. Conversely, this upward shift protects the brain from hypertensive encephalopathy in the face of severe hypertension. However, this autoregulatory shift could be deleterious when the blood pressure is reduced acutely because the lower limit of autoregulation is shifted to a higher level of blood pressure. Theoretically, aggressive reduction of the blood pressure in chronically hypertensive patients could induce cerebral ischemia. Nonetheless, in clinical practice, moderately controlled reduction of blood pressure in patients with hypertensive crises rarely causes cerebral ischemia. This clinical observation may be explained by the fact that even though the cerebral autoregulatory curve is shifted in patients with chronic hypertension, a considerable difference still exists between the initial blood pressure at presentation and the lower limit of autoregulation. Illustrated are the differences in the lower autoregulatory threshold during blood pressure reduction with trimethaphan in patients with uncontrolled hypertension and treated hypertension, and those in the control group [53]. At least eight of the 13 patients with uncontrolled hypertension had hypertensive neuroretinopathy consistent with malignant hypertension. The control groups included nine patients with a history of severe hypertension in the past whose blood pressure was effectively controlled at the time of study and a group of 10 normotensive persons. Baseline mean arterial pressures (MAPs) in the three groups were 145 ±17 mm Hg, 116 ±18 mm Hg, and 96 ±17 mm Hg, respectively. The lower limit of blood pressure at which autoregulation failed was 113 ±17 mm Hg in persons with uncontrolled hypertension, 96 ±17mm Hg in persons with treated hypertension, and 73 ±9 mm Hg in normotensive persons. Although the absolute level at which autoregulation failed was substantially higher in patients with uncontrolled hypertension, the percentage reduction in blood pressure from the baseline level required to reach the autoregulatory threshold was similar in each group. The numbers on the bars indicate the percentage reduction from the baseline

blood pressure required to reach the autoregulatory limit. Thus, a reduction in MAP of approximately 20% to 25% was required in each group to reach the threshold. This result indicates that a considerable safety margin exists for blood pressure reduction before cerebral autoregulation of blood flow fails, even in patients with severe untreated hypertension. Moreover, symptoms of cerebral ischemia did not develop until the blood pressure was reduced substantially below the autoregulatory threshold because even in the face of reduced blood flow, cerebral metabolism can be maintained and ischemia prevented by an increase in oxygen extraction by the tissues. The lowest tolerated MAP, defined as the level at which mild symptoms of brain hypoperfusion developed (ie, yawning, nausea, and hyperventilation), was 65 ±10 mm Hg in patients with uncontrolled hypertension, 53 ±18 mm Hg in persons with treated hypertension, and 43 ±8 mm Hg in normotensive persons. The numbers on the bars illustrate that these MAP values were approximately 45% of the baseline blood pressure level in each group. Thus, symptoms of cerebral hypoperfusion did not occur until the MAP was reduced by an average of 55% from the presenting level. In the reported cases of neurologic sequelae sustained during rapid reduction of blood pressure in patients with hypertensive crises, the MAP was reduced by more than 55% of the presenting blood pressure. This frank hypotension was sustained for a period of hours to days, mostly as a result of treatment with bolus diazoxide, which has long duration of action [54]. The general guideline for acute blood pressure reduction in the treatment of hypertensive crises is reduction of systolic blood pressure to 160 to 170 mm Hg and diastolic pressure to 100 to 110 mm Hg, which equates to MAPs of 120 to 130 mm Hg. Alternatively, the initial goal of antihypertensive therapy can be a 20% reduction of the MAP from the patient’s initial level at presentation. This level should be above the predicted autoregulatory threshold. Once this goal is obtained the patient should be evaluated carefully for evidence of cerebral hypoperfusion. Further reduction of blood pressure can then be undertaken in a controlled fashion based on the overall clinical status of the patient. Of course, in previously normotensive persons in whom hypertensive crises develop, such as patients with acute glomerulonephritis complicated by hypertensive encephalopathy, the autoregulatory curve should not yet be shifted. Therefore, the initial goal of therapy should be normalization of blood pressure. In terms of avoiding sustained overshoot hypotension in the treatment of hypertensive crises, the use of potent parenteral agents with short duration of action, such as sodium nitroprusside or intravenous nitroglycerin, has obvious advantages. If neurologic sequelae develop during blood pressure reduction with these agents, these sequelae can be reversed quickly by tapering the infusion and allowing the blood pressure to stabilize at a higher level. Agents with a long duration of action have an inherent disadvantage in that excessive reduction of blood pressure cannot be reversed easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine, converting enzyme inhibitors, calcium channel blockers, and central 2-agonists should be used with extreme caution in patients requiring rapid but controlled blood pressure reduction in the setting of hypertensive crises. (Adapted from Strandgaard [53]; with permission.)

Hypertensive Crises

Severe uncomplicated hypertension Severe hypertension (diastolic blood pressure > 115 mm Hg)

Hypertensive neuroretinopathy present (striate hemorrhages, cotton-wool spots with or without papilledema) Treat malignant hypertension (Fig. 8-20)

Hypertensive neuroretinopathy absent

No acute end-organ dysfunction

Acute end-organ dysfunction Treat as hypertensive crisis (see preceding figures)

Severe uncomplicated hypertension Step 1 Patient education regarding the chronic nature of hypertension and importance of long-term compliance and blood pressure control to prevent complications

Step 2

Step 3

Evaluate reason for inadequate blood pressure control and adjust maintenance antihypertensive drug regimen

Noncompliant

Arrange outpatient follow-up to document adequate blood pressure control over the ensuing days to weeks and change drug treatment regimen as required

Compliant with current blood pressure regimen

"Ran out" of medications

Drug side effects

Cannot afford drugs

Restart

Switch to drug of another class

Switch to generic thiazide diuretic

Add low-dose thiazide diuretic to existing monotherapy with CCB, CEI, β-blocker, α2-agonist

FIGURE 8-36 Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relatively rare events that almost never affect hypertensive patients. Another type of presentation that is much more common than are true hypertensive crises is that of the patient who initially exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hypertensive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity, known as severe uncomplicated hypertension, is very commonly seen in the emergency department or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are entirely asymptomatic and present for prescription refills or routine blood pressure checks, or are found to have elevated pressure during routine physical examinations. The other 40% of patients initially exhibit nonspecific findings such as headache, dizziness, or weakness in the absence of evidence of acute end-organ dysfunction. In the past, this entity was referred to as urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure, over a few hours before discharge from the acute-care facility, was essential to minimize the risk of short-term complications from severe hypertension. Commonly employed treatment regimens included oral clonidine loading or sublingual nifedipine. However, in recent years the practice of acute blood pressure reduction in severe uncomplicated hypertension has been questioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hypertension, there were 70 placebo-treated patients who had an average diastolic blood pressure of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at a mean of 11 ± 8 months of follow-up. However, the earliest morbid event occurred only after 2 months [57]. These data suggest that in patients with severe uncomplicated hypertension in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive

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heart failure tend to occur over months to years, rather than hours to days. Although long-term control of blood pressure clearly can prevent these eventual complications, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in an improvement in short- or long-term prognosis. Acute reduction of blood pressure in patients with severe uncomplicated hypertension with sublingual nifedipine or oral clonidine loading was once the de facto standard of care. This practice, however, often was an emotional response on the part of the treating physician to the dramatic elevation of blood pressure or motivated by the fear of medico-legal repercussions in the unlikely event of a hypertensive complication occurring within hours to days [55]. Although observing and documenting the dramatic decrease in blood pressure is a satisfying therapeutic maneuver, there is no scientific basis for this approach. At present, no literature exists to support the notion that some goal level of blood pressure reduction must be achieved before the patient with severe uncomplicated hypertension leaves the acute-care setting [58]. In fact, acute reduction of blood pressure often is counterproductive because it can produce untoward side effects that render the patient less likely to comply with long-term drug therapy. Instead, the therapeutic intervention should focus on tailoring an effective welltolerated maintenance antihypertensive regimen with patient education regarding the chronic nature of the disease process and the importance of long-term compliance and medical follow-up. If the patient has simply run out of medicines, reinstitution of the previously effective drug regimen should suffice. If the patient is thought to be compliant with an existing drug regimen, a sensible change in the regimen is appropriate, such as an increase in a suboptimal dosage of an existing drug or the addition of a drug of another class. In this regard, addition of a low dose of a thiazide diuretic as a second-step agent to existing monotherapy with converting enzyme inhibitor (CEI), angiotensin II receptor blocker, calcium channel blocker (CCB), -blocker, or central 2-agonist often is remarkably effective. Another essential goal of the acute intervention should be to arrange suitable outpatient follow-up within a few days. Gradual reduction of blood pressure to normotensive levels over the next few days to a week should be accomplished in conjunction with frequent outpatient visits to modify the drug regimen and reinforce the importance of lifelong compliance with therapy. Although less dramatic than acute reduction of blood pressure in the acute-care setting, this type of approach to the treatment of chronic hypertension is more likely to prevent long-term hypertensive complications and recurrent episodes of severe uncomplicated hypertension.

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Hypertension and the Kidney

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