40 Cardiovascular Complicationsin Patients With Renal Disease

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From: Essential Cardiology: Principles and Practice, 2nd Ed.

Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ

40 Cardiovascular Complications in Patients With Renal Disease

Richard A. Preston, ^{MD, MBA} ,

Simon Chakko, ^MD , and Murray Epstein, ^MD

INTRODUCTION

The heart and kidney are invariably intertwined. Heart failure is associated with the important alterations in renal hemodynamics and function that constitute a major problem of clinical man- agement. Conversely, in chronic renal disease, rarely does the heart escape consequences. Cardio- vascular complications comprise the major cause of death in the end-stage renal disease (ESRD) population. The effects of chronic renal failure on the heart are diverse and involve numerous ana- tomical and functional aspects of the cardiovascular system.

Given the broad scope of this subject, we have elected to focus our review primarily on the more common cardiovascular alterations that complicate the course of progressive renal disease: peri- carditis, renal parenchymal hypertension, coronary arteriosclerosis, and left ventricular dysfunc- tion. Finally, we have included a discussion of ischemic renal disease, a common but underdiagnosed disorder that is an important complication of systemic arteriosclerosis.

PERICARDITIS

Pericarditis (1–11) is a common and often severe complication of advanced chronic renal failure.

Before emergency dialysis was available the appearance of a pericardial friction rub in a patient with ESRD was a harbinger of death within the ensuing 2 wk. Many authorities group pericarditis associated with ESRD into two main categories (1–3). Early or uremic pericarditis occurs in the ESRD patient prior to the initiation of chronic dialysis therapy and is probably secondary to the bio- chemical perturbations of uremia per se. Early or uremic pericarditis generally responds rapidly to renal replacement therapy in the majority of patients. Late or dialysis-associated pericarditis occurs in patients who are already receiving renal replacement therapy. In general, dialysis-asso- ciated pericarditis tends to be more severe, has a higher rate of complications, responds less readily to dialysis, and is more likely to result in pericardial tamponade (1–4).

Incidence

In 1968, a 41% incidence of uremic pericarditis was reported in patients beginning dialysis (5).

The incidence of uremic pericarditis has fallen in recent years, probably because of the greater avail-

ability and earlier initiation of renal replacement therapy. More recent reports indicate a much

lower incidence, less than 10% (6). Pericarditis has been found to occur in approx 10 to 20% of

patients receiving regular dialysis therapy. The 10 to 20% incidence of dialysis-associated peri-

carditis has not changed appreciably over the past decade.

Pathology

The basic pathologic process of pericarditis associated with ESRD is an aseptic inflammatory reaction with fibrin formation. The process is similar in both uremic pericarditis and dialysis- associated pericarditis. Both parietal and visceral pericardia are covered with a fibrinous exudate.

Fibrinous bands are usually present and form adhesions and areas of loculation between the two layers. The effusion is usually serosanguinous, but is uniformly hemorrhagic in cases of tamponade.

The white blood cell count in the effusion is variable but usually in the 500–700/mm

range with a variable proportion of polymorphonuclear and mononuclear leukocytes. Cultures are routinely negative.

Pathogenesis

Pericarditis in ESRD patients who have not yet begun dialysis is most likely related to the bio- chemical milieu of untreated uremia, as evidenced by the rapid response to the initiation of dialysis and the clinical correlation with biochemical control of uremia in the majority of patients (1–4, 6,8). Dialysis-associated pericarditis, on the other hand, is less well understood. It is not clear why a substantial percentage of patients receiving regular renal replacement should develop pericardi- tis. Dialysis-associated pericarditis may be related to underdialysis in some patients, but this is not always the case. The etiology of dialysis-associated pericarditis is probably multifactorial, and is not well understood (1–4,6).

A number of potential pathogenic factors have been proposed to explain dialysis-associate peri- carditis, including inadequate dialysis therapy, hypercatabolic states, poorly controlled hyperpara- thyroidism, heparin received during dialysis, and an abnormal immunologic response. Underdial- ysis has been noted in a significant percent of patients developing dialysis-associated pericarditis, often as a result of vascular access failure or missing dialysis. In addition, pericarditis has been observed to occur during periods of hypercatabolism such as following major surgery or during sepsis (1–4).

Clinical Features

The presentation of pericarditis in a patient with ESRD (1–11) may be dramatic, marked by a fulminant course resulting in acute tamponade. On the other hand, a patient may present with only vague chest pain or mild constitutional symptoms. Dialysis-associated pericarditis may occasion- ally present as recurrent hypotension during hemodialysis. Clinical and laboratory features of the pericarditis of ESRD are summarized in Table 1 (5,8–11). Pericardial friction rub and chest pain are important in the diagnosis of pericarditis but are not always present. Dialysis-associated peri- carditis is often associated with a more severe clinical illness, more systemic manifestations, a higher likelihood of tamponade, and a less favorable response to dialysis (1–4).

Chest pain occurs in the majority of patients and may be variable in character and severity. The pain may be located anywhere in the precordium and may precede the development of a friction rub.

There is often a pleuritic component to the pain, and the pain may be aggravated by lying supine and partially relieved by sitting forward. A pericardial friction rub may be detected in more than 90%

Table 1

Clinical Features of Pericarditis Associated With ESRD

Pericardial rub 95%

Chest pain 60–70%

Hypotension 13–56%

Fever 63–76%

Leukocytosis 35–71%

ECG (classical changes) 2–5%

Arrhythmias 20–28%

Pericardial effusion (echocardiogram) 89%

of patients. The rub is typically evanescent in nature and may change in quality with time. There- fore, the absence of a rub on any given physical examination does not rule out pericarditis.

Hemodynamic compromise, including hypotension during hemodialysis, may occur as a pre- senting clinical feature (1–3,7,8). Dialysis-associated pericarditis should be suspected and sought in any patient suffering from repeated episodes of hypotension during dialysis or in patients with ESRD presenting with hypotension despite signs of fluid overload.

Fever and leukocytosis may be present more commonly in dialysis-associated pericarditis, and, if severe, may predict a less favorable response to an intensification of the dialysis regimen (7).

The ECG is of very limited usefulness in the diagnosis of pericarditis in ESRD. ECG abnormalities are common but lack specificity. The classic ST segment elevations described in several types of acute pericarditis are uncommon in this form of pericarditis; the most common findings are non- specific ST and T-wave abnormalities. Atrial arrhythmias, including atrial flutter and fibrillation, have been observed in a significant number of cases.

Echocardiography is the easiest and most accurate method for diagnosing pericardial effusion, provides useful information regarding the size of a pericardial effusion, and can detect early or impending tamponade. This information concerning quantity of effusion and hemodynamic sig- nificance is important when reaching a decision regarding early management of uremic pericardi- tis. A large effusion or one that causes hemodynamic embarrassment will generally not respond to conservative management with dialysis alone, but will often require surgical drainage.

Acute cardiac tamponade is the most serious and potentially lethal complication of pericarditis associated with ESRD, and is more common in dialysis-associated pericarditis than in uremic peri- carditis. Tamponade may occur during or shortly following a dialysis session. It may be difficult to distinguish acute tamponade from hypovolemia-induced hypotension. In cases of unexplained hypotension during or shortly following dialysis, the echocardiogram may be very useful in mak- ing this important differential diagnosis. It is important to maintain a high index of suspicion for peri- carditis-related tamponade in patients with hypotension during hemodialysis because it is potentially reversible.

Management

When uremic pericarditis presents in a patient with renal disease reaching ESRD, then the initi- ation of renal replacement therapy is indicated. Cardiac tamponade is unusual in this form of pericar- ditis and most patients will respond well to dialysis therapy with resolution of the signs and symptoms of pericarditis.

Management of dialysis-associated pericarditis has been less satisfactory. The initial treatment is determined by the hemodynamic stability of the patient. In the stable patient who does not have evidence of tamponade or impending tamponade, the first line of treatment is generally intensifi- cation of dialysis therapy, monitored by repeat echocardiographic evaluation of effusion size. This approach has yielded a response rate of approx 60 to 70%. In the majority of cases, the response is seen within the first 10 to 14 d of initiating intensive dialysis therapy. If hemodynamic com- promise develops or the effusion fails to reduce in size or becomes larger over a course of 10 to 14 d, then a drainage procedure should be undertaken.

A positive effect from the use of nonsteroidal antiinflammatory agents in the treatment of peri- carditis has been difficult to prove and is associated with gastrointestinal toxicity and bleeding com- plications. Similarly, systemic corticosteroids have been reported to improve the clinical course of pericarditis but are associated with side effects and do not seem to prevent the development of constrictive pericarditis. Nonsteroidal antiinflammatory agents and steroids in pericarditis asso- ciated with ESRD are controversial.

There are several clinical features that predict the failure of intensive dialytic intervention and hence the need for early surgical drainage in the treatment of pericarditis. A report by De Pace et al.

(7) suggests that in the presence of a large pericardial effusion, temperature greater than 102°F, and

rales, peritoneal dialysis is required because the patient is too hemodynamically unstable to permit

hemodialysis. Systolic blood pressure under 100 mmHg, jugular venous distention, white blood

cell count over 15,000/mm

, and white blood cell count left shift all correlate with poor out-come of dialysis treatment alone. The simultaneous presence of several of these features describes a patient at risk of failing to respond favorably to intensive dialysis therapy. Thus, the febrile, toxic patient with a large effusion and evidence of hemodynamic compromise is at high risk of failing to respond to dialysis treatment alone, and the need for a drainage procedure should be anticipated.

Pericardiocentesis is associated with a high rate of severe complications including laceration of atrial or ventricular wall or coronary arteries. Most series report a high morbidity and mortality rate with pericardiocentesis. In addition, pericardiocentesis has a high rate of reaccumulation of peri- cardial fluid and thus does not represent a definitive procedure. Because purulent pericarditis is rare in patients with ESRD, there is little need for a diagnostic pericardiocentesis. Therefore, pericardio- centesis is generally recommended only for extreme emergency situations as a last-resort measure.

Subxiphoid pericardiotomy is considered a relatively safe and effective procedure to achieve pericardial drainage. It is generally well tolerated in the uremic patient who is ill and often with hemo- dynamic compromise in comparison with the more extensive (albeit more definitive) pericardiec- tomy. Subxiphoid pericardiotomy is associated with a 6% failure rate, but a low rate of complications.

Pericardiectomy is a definitive surgical procedure with essentially a nonexistent rate of fluid reac- cumulation and the prevention of the late complication of constrictive pericarditis. It is, however, an extensive major surgical intervention requiring general anesthesia and either a median sterno- tomy or anterior thoracotomy. Pericardiectomy remains the treatment of choice for constrictive pericarditis.

RENAL PARENCHYMAL HYPERTENSION

Any consideration of cardiovascular complications in renal disease must a priori consider the generation of renal parenchymal hypertension and its effects on cardiac structure and function.

Renal parenchymal hypertension (12–22) is hypertension that is caused by kidney disease and is the most common cause of secondary hypertension. Chronic renal disease and systemic hyperten- sion may coexist in three very different clinical settings. First, primary hypertension is an impor- tant cause of chronic renal disease. Poorly controlled, severe, sustained hypertension over an extended period results in hypertensive nephrosclerosis. In the second situation, renal parenchymal disease is a well established and important cause of secondary hypertension. Therefore, hyperten- sion is both a cause and a consequence of renal disease. Renal parenchymal hypertension is the most common secondary form of hypertension and accounts for 3.0 to 5.0% of all cases of systemic hypertension. The secondary hypertension produced by the diseased kidneys may accelerate the decline in renal function if inadequately controlled. Sometimes it may be difficult to distinguish clinically between primary hypertension causing nephrosclerosis and renal disease causing hyper- tension. The third clinical setting in which chronic renal disease and hypertension may coexist is ischemic renal disease, which will be discussed briefly later in this chapter.

Renal parenchymal hypertension may be caused by almost any disease of the renal parenchyma (Table 2). A patient who appears to have primary hypertension may have an underlying renal dis- ease causing the hypertension. The initial evaluation of all hypertensive patients should include a screen for renal disease. Determination of blood urea nitrogen and serum creatinine values, and careful urinalysis with examination of the urinary sediment, often, but not invariably, will exclude significant underlying renal disease. Urinary findings that suggest that a renal disease is causing the hypertension are cellular and granular casts, significant hematuria, pyuria, and urine protein excre- tion >150 mg/24 h.

Pathogenesis

Renal parenchymal hypertension most probably represents the combined interactions of many independent mechanisms: potential factors include sodium retention leading to volume expansion, increases in endogenous pressor activity, and decreases in endogenous vasodepressor compounds.

The precise mechanisms that lead to hypertension in chronic renal failure have not been completely

defined, but recent investigations have provided exciting new insights. The traditional focus has been on volume-mediated mechanisms, the renin-angiotensin system, and renal prostaglandins;

recently, increasing attention has been given to other pressor and vasodilator systems, including endogenous digitalis-like factor, endothelin and endothelium-derived relaxing factor, and nitric oxide (NO). The sodium intake and the volume-mediated mechanisms of renal parenchymal hyper- tension are of central importance to management and will be discussed in more detail.

Sodium Intake

Impaired renal sodium excretion leads to positive sodium balance and contributes to the devel- opment of renal parenchymal hypertension. Abnormal renal sodium excretion is the most important mechanism of renal parenchymal hypertension from a clinical standpoint. Patients with renal failure have increased total extracellular fluid volume (ECFV) sodium compared with normal controls or patients with primary hypertension. This increase in ECFV sodium correlates directly with an increased ECFV and with hypertension. Changes in sodium intake directly influence blood pressure in patients with chronic renal failure, and this relationship seems stronger at lower levels of renal function. Increasing sodium intake in patients with chronic renal failure increases ECFV and blood pressure. The increment in blood pressure for a given increase in ECFV tends to be greater in the patients with further advanced renal failure. Reduction of dietary sodium will lower ECFV and blood pressure in many patients with chronic renal insufficiency. This sodium sensitivity of the hypertension caused by renal disease is key to appropriate antihypertensive therapy.

Despite the importance of impaired sodium excretion and ECFV expansion in the genesis of renal parenchymal hypertension, the most consistently observed hemodynamic alteration in estab- lished cases is an elevation of peripheral vascular resistance rather than an increase in cardiac output.

The mechanism(s) for this elevation in peripheral vascular resistance is not known exactly: The relationship of ECFV expansion to pressure elevation appears to be complex and may involve alter- ations in autonomic function, in neurohumoral control of blood pressure, and possibly in local vas- cular factors such as increased cytosolic calcium concentration in vascular smooth muscle. There is a complex connection between volume expansion and peripheral vascular resistance in patients with the sodium-sensitive hypertension of chronic renal disease.

Treatment of Renal Parenchymal Hypertension: Focus on Sodium Balance Regardless of the mechanisms leading from ECFV expansion to hypertension, sodium reten- tion with associated ECFV expansion plays a central role in the pathogenesis of renal parenchymal hypertension. Consequently, therapeutic modalities that reduce total body sodium are frequently very effective in lowering blood pressure in patients with renal parenchymal hypertension. Even small net gains in total body sodium can produce significant increases in blood pressure. The first step in managing renal parenchymal hypertension is reduction of ECFV sodium.

Table 2

Common Etiologies of Renal Parenchymal Hypertension Glomerular diseases

Postinfectious glomerulonephritis Focal segmental sclerosis Membranous glomerulonephritis Renal vasculitis

Diabetic nephropathy Crescentic glomerulonephritis Systemic lupus erythematosis nephritis Interstitial diseases

Polycystic kidney disease

Chronic interstitial nephritis

The management of patients with hypertension secondary to chronic renal insufficiency is a common and often perplexing problem confronting the general internist. Elevated systemic arterial blood pressure indicates a poor prognosis in a number of renal disorders, and there is extensive evidence that hypertension of any cause accelerates the deterioration of renal function. Therefore, preservation of renal function is a compelling reason for early identification and vigorous treat- ment of hypertension: Regardless of the mechanism(s) involved, treatment of hypertension has been shown to retard the rate of progression of renal impairment in several disease states. Because both the prevalence and the severity of hypertension increase as the glomerular filtration rate (GFR) declines, it is important to continue close follow-up and frequent reassessment of therapy.

Sodium Restriction

As discussed, renal sodium retention with associated ECFV expansion plays a central role in the genesis of renal parenchymal hypertension and therapeutic measures that will reduce extra- cellular fluid sodium are frequently very effective in lowering blood pressure. Sodium restriction and diuretics constitute critical components of effective antihypertensive therapy in patients with renal disease. Control of blood pressure in patients with chronic renal disease is difficult, if not impossible, without dietary sodium restriction.

Reasonable guidelines for dietary sodium restriction are summarized in Table 3. Realistically, 2 g sodium/d (i.e., 88 mEq sodium) is the minimum sodium intake attainable on an outpatient basis. To maintain this modestly low level of sodium intake requires intensive dietary education and patient cooperation. For example, processed foods, such as canned vegetables and soups, pre- pared meat products, and most so-called “fast foods,” are extremely high in sodium content, as are most seasonings. The preparation of many processed foods adds a great deal of sodium. A variety of educational material listing the sodium contents of different foods for sodium-restricted diets is readily available, and we find repeated counseling and education by clinical dietitians along with diligent follow up to be quite useful. Patients should be cautioned about the use of salt sub- stitutes: Many contain potassium and should be avoided altogether in patients with renal impair- ment and diminished potassium excretory capacity.

Because the chronically diseased kidney may adapt poorly to rapid changes in sodium intake, sodium restriction should be initiated under close observation. When confronted with an abrupt decrease of dietary sodium, some patients may not be able to reduce urinary sodium excretion quickly and a period of negative sodium balance may ensue. This sodium-wasting tendency is generally reversible after several weeks but early negative sodium balance may decrease ECFV and lead to prerenal azotemia.

Sodium intake must be individualized and carefully monitored. Every renal patient should be fol- lowed carefully for signs of ECFV depletion (orthostatic blood pressure change or rapid decline in body weight) or worsening azotemia. Serial measurements of body weight and blood chemis- tries are often useful to identify an “ideal” weight (ECFV) for optimal blood pressure control.

Diuretic Therapy

Because attempts to lower blood pressure by rigid dietary salt restriction are often not tolerated by patients, particularly in view of the concomitant dietary restrictions often needed to manage

Table 3

Dietary Sodium Restriction in Chronic Renal Failure

1. Initiate Na restriction with 2 g/d (88 mEq/d)

2. Serial measurements of weight and blood pressure

3. Serial measurements of blood urea nitrogen and creatinine

4. If NaHCO

replacement is required, monitor Na intake

5. Avoid potassium-containing salt substitutes

renal failure (i.e., protein restriction), in most cases the next step to control sodium balance is a trial of diuretic therapy. If a trial of sodium restriction is not tolerated or does not produce an adequate reduction of total body sodium, then a diuretic should be added to the antihypertensive regimen.

T

D

Thiazides alone are not usually effective natriuretics in a patient with a serum creatinine above 2.0 mg/dL or a creatinine clearance below 30 mL/min, probably due to diminished delivery of the sodium load to the distal nephron and of the drug to its site of action. Therefore, the use of thiazide diuretics alone is not recommended at low levels of renal function.

L

D

The loop-acting diuretics (furosemide, ethacrynic acid, bumetanide, torasemide) are the agents of choice for the management of extracellular fluid volume and hypertension when the GFR falls below 30 mL/min. Unlike the thiazides, the loop agents are effective natriuretics at GFRs well below 30 mL/min, even when used alone, although very high doses may be required as renal failure progresses. The loop diuretics act by inhibiting chloride (and sodium) reabsorption at the medul- lary thick ascending limb of the loop of Henle, which reabsorbs approx 25 to 30% of the filtered sodium load. Because so much filtered sodium is reabsorbed in this nephron segment, it is under- standable why these agents are such potent natriuretics.

Because these agents act from the luminal side, they must enter the tubular lumen, both by glom- erular filtration and by tubular secretion, before they can act. The dose-response curve of the loop diuretics is sigmoidal, because the natriuretic response depends on a threshold concentration of drug being delivered to its site of action. One approach to obtaining the optimal diuretic dose is to increase the dosage of diuretic carefully until the desired natriuresis occurs. This dosage would correspond to some point on the “steep” part of the curve, where a small increase in diuretic delivery results in a large increase in natriuresis.

A common pitfall in the practical use of loop diuretics is increasing dose frequency rather than dose size: A dosage is tried that produces an insufficient natriuresis, but rather than increasing the dose, the clinician repeatedly administers the same dose, mistakenly expecting an additive response.

The single dose should be increased until a satisfactory natriuresis is achieved. If still more natri- uresis is desired, either the dose size or the dose frequency can be increased. Note that the dose- response curve flattens above a certain dose. Beyond this point there is no advantage to increasing the single dose. If further sodium excretion is required than is produced with the maximum single effective dose, then additional effective doses of the diuretic may be prescribed. In general, furose- mide requires twice daily dosing whereas bumetanide is usually given once daily. If the response is insufficient, single doses can be increased to a maximum of about 480 mg. Larger single doses are unlikely to be more effective, and increase the risk of ototoxicity.

Continued dietary sodium restriction is important during diuretic therapy because sodium reten- tion may occur between doses of diuretic. This sodium retention may be sufficient to completely neutralize the natriuretic effects of the loop diuretics if sodium restriction is not imposed.

In our clinical practice, we have found daily weight to be the most useful indicator of changes in extracellular sodium. When done at the same time of day and on the same scale, daily weight is quite helpful in determining net changes in sodium balance. An “ideal” weight can often be estab- lished, at which the blood pressure becomes easier to manage. Measurements of 24-h urinary excre- tion of sodium are somewhat time-consuming and cumbersome, but may be useful for the evaluation of patient compliance with sodium restriction or suspected sodium wasting.

Patients with nephrotic syndrome may demonstrate diuretic resistance even with a preserved GFR, possibly due to intraluminal binding of the diuretic by albumin, which inactivates the diure- tic before it reaches its site of action at the loop of Henle. Conclusive human data have been diffi- cult to obtain, but diuretic resistance in nephrotic patients is a serious clinical problem.

The initial dose of furosemide in patients with a 50% or greater reduction in GFR is about 40

mg iv or 80 mg po. The corresponding dosage of bumetanide is about 1 mg iv or po. Furosemide

may be titrated as high as 120 to 160 mg iv or 240 to 320 mg po and bumetanide may be titrated as high as 4 to 6 mg iv or po.

Hypokalemia and glucose intolerance may complicate therapy with the loop diuretics. The risk of their ototoxicity is increased by renal insufficiency and by concomitant administration of amino- glycosides. In addition, care must be exercised to avoid overdiuresis, with consequent intravascu- lar volume depletion and prerenal azotemia.

Blockade of Renin-Angiotensin System

There is a body of evidence suggesting that blockade of the renin-angiotensin system affords renal protection in the patient with hypertension and renal parenchymal disease beyond its effects on blood pressure (16–22). There have been several clinical trials demonstrating the benefit of ACE inhibitors in type I diabetic nephropathy, nondiabetic renal disease, and hypertensive neph- rosclerosis (17–19). More recently several trials have emerged that suggest a preferential benefit of angiotensin AT1 receptor blockers in type 2 diabetes mellitus with nephropathy (20–22). In the IDNT trial (21), a total of 1715 hypertensive patients with type 2 diabetes and nephropathy were allocated to treatment with 300 mg irbesartan daily, 10 mg amlodipine daily, or placebo. The mean duration of follow-up was 2.6 yr, and the goal blood pressure was 135/85 mmHg. Treatment with irbesartan was associated with a risk of the primary composite endpoint of a doubling of the base- line serum creatinine concentration, the development of end-stage renal disease, or death from any cause that was 20% lower than that in the placebo group (p = 0.02) and 23% lower than that in the amlodipine group (p = 0.006). These differences were not explained by differences in the blood pres- sures that were achieved. In the IDNT trial, although irbesartan had more favorable effects on ESRD than did amlodipine, there were no significant differences between the two treatment groups in the rates of death from any cause, or in the cardiovascular composite endpoint.

The RENAAL study (20) compared 50 to 100 mg losartan once daily with placebo in patients with type 2 diabetes with nephropathy for a mean of 3.4 yr. The primary outcome was the compos- ite of a doubling of the baseline serum creatinine concentration, end-stage renal disease, or death.

A total of 327 patients in the losartan group reached the primary endpoint, as compared with 359 in the placebo group (risk reduction, 16%; p = 0.02). The benefit exceeded that attributable to changes in blood pressure. The level of proteinuria declined by 35% with losartan (p < 0.001 for the com- parison with placebo).

These studies suggest that blockade of the renin-angiotensin system is perhaps a logical initial choice of antihypertensive agent along with control of the extracellular fluid volume.

Calcium-Channel Antagonists and Renal Parenchymal Hypertension Two randomized trials in patients with chronic kidney disease have delineated the role of calcium- channel antagonists in the antihypertensive armamentarium to retard the progression of renal dis- ease. In the IDNT trial patients treated with amlodipine or with placebo had greater probability of progression of renal disease than patients treated with irbesartan (21). The AASK trial was designed to compare the effects of three different treatments on progression of renal disease in African-Ameri- cans with a clinical diagnosis of hypertensive nephrosclerosis (17). One group received amlodipine, one received an ACE inhibitor and one a -blocker as initial therapy. Additional drugs were used to achieve two levels of mean arterial pressure, 92 or 107 mmHg. The amlodipine arm was stopped prematurely because of a more rapid decline in GFR in patients treated with amlodipine than in those treated with the ACE inhibitor. The difference, however, was significant only in patients with proteinuria greater than 220 mg/g creatinine, whereas no difference was apparent in the majority of patients with less proteinuria.

Whereas a body of evidence indicates that CCBs, when used as first-line therapy, may be less

protective against progression of kidney diseases than ACE inhibitors or angiotensin AT1 recep-

tor blockers even when similar blood pressure control is achieved, in clinical practice it is unlikely

that monotherapy with an ACE inhibitor or angiotensin AT1 receptor blocker alone will suffice

(17,20,21). On average, patients with significant renal parenchymal disease and renal functional impairment will require at least three to four antihypertensives to reach goal BP (20,21). Indeed, an efficacious antihypertensive regimen includes multiple agents, in which diuretics and calcium antagonists constitute integral parts. For example, in a given patient with renal parenchymal hyper- tension, one might begin with a diuretic combined with an ACE inhibitor or angiotensin AT1 recep- tor blocker with a CCB added to reach the recommended goal blood pressure of 130/80.

In conclusion, the body of evidence seems to indicate that, when used as first-line therapy, ACE- inhibitors and AT1 antagonists appear to provide greater renal protection in patients with nephrop- athy and significant proteinuria than other classes of antihypertensive drugs, including CCBs. In contrast, in patients without significant proteinuria, there is no conclusive evidence that one class of drugs offers benefits over the other. Because the majority of hypertensive patients with renal dis- ease require multiple antihypertensive agents to achieve adequate control, it appears that adminis- tration of CCBs in addition to ACE inhibitors or ARBs is effective and safe. Further, there is no sub- stantial clinical evidence to suggest that dihydropyridine CCBs are inferior to non-dihydropyridine in the management of hypertension in patients with chronic kidney disease with or without dia- betes mellitus, particularly when these agents are used in combination with ACE inhibitors or ARBs.

Importance of End-Stage Renal Disease to the Cardiologist

Because many patients with cardiovascular disease also have concomitant renal disease, and because this often progresses to end-stage renal disease, it is extremely important for the cardiolog- ist to consider the importance of treating to an appropriate goal pressure in this population (23–25).

Among patients with end-stage renal disease, the annual mortality rate is nearly 25%. Cardiovascu- lar diseases are the leading cause of death in patients receiving maintenance hemodialysis, espe- cially in the first year of treatment. A history of long-lasting arterial hypertension is associated with an increase in cardiovascular deaths in these patients. Controlled studies are not available on the beneficial effect of antihypertensive therapy on patients in hemodialysis. However, there is unanim- ity that maintaining a controlled blood pressure is of great importance for long-term survival. Hyper- tension is the single most important predictor of coronary artery disease in uremic patients, even more so than cigarette smoking and hypertriglyceridemia. There is a paucity of studies comparing different antihypertensive regimens in this patient population and in clinical practice most nephro- logists need to extrapolate results obtained from patients with relatively normal kidney function to patients with advanced kidney disease.

A recent study supports the safety of calcium antagonists in hemodialysis patients. Tepel et al.

(25) have retrospectively studied the association of calcium-channel blockers and mortality in 188 hemodialysis patients. After a follow up of 30 mo, 51 patients (27%) had died, and 72% of those died of cardiovascular causes. In the deceased group, age was significantly higher, smoking was more frequent, and body mass index was lower compared with the group that survived. The percent- age of patients taking CCBs was significantly higher in the survival group than in the group of patients that died. Among patients assigned to CCB therapy, there was a significant reduction in mortality of 67% (p < 0.001). Because of the retrospective nature of this study, a cause-effect rela- tionship between CCB use and mortality cannot be established with certainty; however, at the very least, the study suggests that use of CCBs in hemodialysis patients may be considered safe.

CORONARY ATHEROSCLEROSIS

Ischemic heart disease is common in patients with ESRD. In the United States Renal Data System,

ischemic heart disease was already present in 40.8% of 3399 patients starting chronic hemodialy-

sis (26). The incidence of ischemic heart disease is even higher among patients receiving dialysis

therapy. In the Canadian Hemodialysis Morbidity Study, the annual incidence of myocardial infarc-

tion or angina requiring hospitalization was 10% per year (24). Patients with chronic pyelonephritis

or interstitial renal disease develop coronary artery disease more frequently than those with other

forms of renal failure (27).

The development and progression of coronary atherosclerosis is accelerated in the presence of renal failure. In general, risk factors for coronary artery disease in the general population applies to patients with ESRD. Advancing age is associated with increased risk for arteriographic coronary dis- ease inpatients with ESRD. Hypertension and diabetes mellitus are common among these patients.

Glucose intolerance and insulin resistance have been demonstrated in the absence of overt diabe- tes. Decreased fibrinolytic activity, platelet dysfunction, and vascular calcification may increase the risk for cardiac events. Lipid abnormalities have been reported in ESRD. Total cholesterol level may be normal. Elevated triglyceride levels and decreased HDL levels are seen in hemodialysis patients and also in peritoneal dialysis patients who may also have high LDL levels (28). Hypertri- glyceridemia is caused by impaired degradation of very low-density lipoprotein. Lp(a) levels are increased in hemodialysis patients; in these patients, Lp(a) is an independent risk factor for cardio- vascular disease. Caucasian men with ESRD have lower levels of HDL when compared to African- Americans (27). In nephrotic syndrome, elevated total cholesterol and LDL and low HDL are pres- ent. Elevated homocysteine, a risk factor for atherosclerosis, is also common in ESRD patients.

Clinical presentation of ischemic heart disease in patients with ESRD may be atypical. Myo- cardial ischemia may be silent due to autonomic neuropathy induced by diabetes mellitus or other diseases. Symptomatic myocardial ischemia may occur in the absence of significant obstructive disease of epicardial coronary arteries. Small-vessel coronary disease has been reported in hyper- tension, left ventricular hypertrophy, and diabetes, which are common among patients with ESRD.

Increase in myocardial oxygen demand may result from left ventricular hypertrophy, volume and pressure overload, and high output state from anemia and AV fistula. Anemia worsens myocardial oxygen delivery. Electrocardiographic findings such as ST segment and T-wave abnormalities, which suggest ischemia, are common in many ESRD patients without coronary disease. The speci- ficity of stress test with thallium imaging to diagnose coronary disease is poor in these patients (29).

Dobutamine stress echocardiography may be a better diagnostic test (30). Coronary angiography may be necessary for definitive diagnosis.

Management of ischemic heart disease is similar to that used in patients without kidney disease.

Dosages of drugs that are excreted by the kidney need to be lowered. Maintaining the hematocrit above 30 using erythropoietin improves exercise capacity (31,32). Patients on long-term dialysis have a poor prognosis following acute myocardial infarction. Mortality from cardiac causes was 41% at 1 yr, 52% at 2 yr and 70% at 5 yr following acute myocardial infarction (33). Thus an aggres- sive approach toward the prevention and treatment of acute myocardial infarction is justified. If coronary angiography is performed nonionic contrast media is preferred. Pre- and postprocedural hydration, and ultrafiltration, and possibly N-acetyl cysteine, may reduce the risk (34). Coronary angioplasty provides good results initially but restenosis rate is high. Coronary bypass surgery is a good option for selected patients but the mortality rate is increased to about 10% and the peri- operative morbidity rate is also higher (35).

LEFT VENTRICULAR FUNCTION

Among chronic renal failure patients, alterations in cardiac structure and function have been dem- onstrated using hemodynamic and echocardiographic studies (37). The etiology of these altera- tions is multifactorial (Table 4). They can be divided into four major categories: (1) loading conditions that affect the myocardial function; (2) conditions that impair systolic function directly by their negative inotropic effect or indirectly by causing myocardial damage; (3) impaired diastolic filling of the heart; and (4) alterations in neural control of circulation.

Loading Conditions

Low cardiac output stimulates the sympathetic nervous system, renin-angiotensin-aldosterone

axis, and arginine-vasopressin, which results in salt and water retention. In accordance with the

Frank-Starling mechanism, the increase in preload (left ventricular end-diastolic volume or pres-

sure) leads to an increase in stroke volume. However, an increase in preload beyond an optimal

level causes pulmonary venous congestion. Usually pulmonary capillary wedge pressure >20 mmHg leads to pulmonary congestion and >30 mmHg leads to pulmonary edema. However, if the pulmo- nary capillary permeability is increased or plasma oncotic pressure is low, pulmonary congestion and edema may result at lower pressures. Retention of water and sodium may cause pulmonary edema in patients with acute renal failure or in chronic renal failure when fluid intake is excessive.

In addition, an increase in pulmonary capillary permeability leading to pulmonary edema, even in the absence of elevated pulmonary capillary wedge pressure, has been reported in end-stage renal failure (36). The ease with which these patients develop pleural and pericardial effusions supports this possible mechanism. Diluting effect of volume overload on plasma protein concen- tration, which may already be reduced if significant proteinuria is a feature of the underlying nephro- pathy, accentuates the tendency for fluid transudation and edema formation.

While increases in afterload have little effect on the stroke volume of the normal ventricle, it can lead to a marked decrease in stroke volume when myocardial dysfunction is present. Most patients with chronic renal failure are hypertensive. In end-stage renal failure and in the dialysis population, severe hypertension is usually secondary to sodium and water retention. Such hyper- tension is usually present even in anephric patients and is exquisitely dependent on blood volume.

In some patients, the hypertension is secondary to elevation of peripheral resistance due to increased plasma renin activity; it is not controlled by lowering the blood volume but responds to bilateral nephrectomy. Thus retention of water and sodium leads to increases in both preload and afterload in chronic renal failure and may precipitate congestive heart failure. Chronic renal failure causes reduced compliance of the aorta and large arteries, thus increasing the afterload. Pressure and vol- ume overload leads to concentric and eccentric left ventricular hypertrophy, respectively. Regres- sion of left ventricular hypertrophy may follow renal transplantation.

Heart failure exists when the cardiac output is insufficient to meet the demands of the metaboliz- ing tissue. In anemia and arteriovenous fistula, a high cardiac output state is present; cardiac out- put and mean arterial pressure are elevated but the systemic vascular resistance is normal. Using hypertrophy and dilation as compensatory mechanisms, the normal heart can maintain tissue oxy- genation for prolonged periods. But when myocardial function is impaired, these compensatory mechanisms are insufficient and the high cardiac output state will lead to clinical manifestations

Table 4

Factors Affecting Myocardial Function in Chronic Renal Failure Loading conditions

Anemia Hypertension Fluid retention A-V fistula

Thiamine deficiency Systolic dysfunction

Myocardial ischemia, infarction Hyperkalemia

Hypocalcemia Metabolic acidosis Uremic toxins (?) Myocardial fibrosis Valvular disease Diastolic filling

Pericardial disease

Left ventricular hypertrophy Myocardial fibrosis Neural control

Autonomic neuropathy

of heart failure. An increase in cardiac output occurs when the hematocrit falls below 25%; lowered blood viscosity is the major cause of increased cardiac output. In patients with congestive heart failure who are receiving hemodialysis, use of erythropoietin raised the hematocrit and provided symptom relief but did not improve survival (31,32). Many end-stage renal failure patients treated with erythropoietin experience an increase in arterial pressure due to an increase in peripheral vas- cular resistance. Tissue hypoxia resulting from anemia can lead to an autonomic reflex response resulting in reduced arteriolar resistance.

High-output heart failure resulting from the arteriovenous shunts, surgically constructed for vascular access for hemodialysis, is not uncommon (38). Mean flow rate through these shunts is 1.5 L/min. However, cardiac outputs as high as 11 L/min/m

, which decrease substantially during the occlusion of the shunt, have been reported. Although anemia may play role in such high car- diac output states, the added hemodynamic burden of the shunt may explain heart failure. Banding or revising the fistula to an appropriate size may relieve heart failure symptoms. Water soluble vita- mins are dialyzable, and it has been suggested that loss of thiamine may rarely lead to high-output heart failure due to beriberi.

Systolic Dysfunction

Although the presence of a cardiomyopathy caused by “uremic toxins” has been suspected for five decades, its existence as a separate entity has not been clearly demonstrated. Since uremic patients often have other conditions that may alter myocardial function—e.g., anemia, arterio- venous fistula, hypertension, and coronary artery disease—it is difficult to establish the indepen- dent contribution of uremia per se to ventricular dysfunction. In an echocardiographic study, uremic patients had left ventricular dilation, hypertrophy, and a higher ratio of left ventricular radius to wall thickness, indicating inadequate hypertrophy. Myocardial dysfunction associated with ure- mia is often multifactorial, but is reversible. Left ventricular systolic function may improve after peritoneal and hemodialysis. However, such improvement may be secondary to reductions in pre- load and afterload. Following renal transplantation, four patients with dilated cardiomyopathy, normal coronary angiograms, and severe left ventricular dysfunction were reported to have resolu- tion of heart failure symptoms and return of left ventricular ejection fraction to normal (39). Thus, although the existence of uremic cardiomyopathy is controversial, it is important to remember that the idiopathic cardiomyopathy seen in uremia may be reversible.

Calcium is fundamental to the process of myocardial contraction since its influx through sarco- lemmal channels regulates the force of contraction. However, chronic hypocalcemia usually does not cause heart failure. Severe hypocalcemia (<6 mg/dL) in association with congestive heart failure has been described in dialysis patients after parathyroidectomy, with prompt improvement in car- diac function and resolution of heart failure following intravenous calcium replacement. Parathy- roid hormone may be a myocardial depressant since cardiac function reportedly improves after parathyroidectomy but the negative inotropic effect of parathyroid hormone has not been estab- lished. Hyperkalemia has a negative inotropic effect but the principal detrimental effect is in its electrical effect on the heart. Severe metabolic acidosis impairs calcium release from the sarcoplas- mic reticulum and myocardial contractility is impaired at a systemic pH below 7.2. Dystrophic cal- cification of the myocardial fibers occurs in secondary hyperparathyroidism of chronic renal failure.

An increased incidence of calcific aortic stenosis and mitral annular calcification is noted in chronic renal failure. When valvular lesions are severe, myocardial dysfunction may result.

Diastolic Filling

Recently it has become apparent that diastolic dysfunction may lead to heart failure even in the

presence of normal systolic function, especially in patients with left ventricular hypertrophy and

in the older population. Doppler echocardiography is now used to evaluate the diastolic function

of the ventricles; numerous studies have shown that diastolic filling is abnormal in the majority

of patients with ventricular hypertrophy. Echocardiographic left ventricular hypertrophy is com-

mon among patients with chronic renal failure. Left ventricular hypertrophy often develops and

progresses with time on dialysis. Asymmetric septal hypertrophy has also been reported, but this is an unusual manifestation of the hypertrophy resulting from hemodynamic stress and is not asso- ciated with left ventricular outflow obstruction.

Development of hypotension during dialysis that cannot be explained by changes in intravas- cular volume is a clue to impaired diastolic filling. Effect of hemodialysis on diastolic filling has been evaluated using Doppler echocardiography. Fluid removal during hemodialysis reduces the left ventricular preload to the extent that early diastolic filling becomes impaired without a com- pensatory increase in the atrial phase of filling. Hemodialysis without fluid removal does not alter the left ventricular diastolic filling pattern (40).

Management of heart failure in ESRD patients includes correction of reversible conditions (e.g., coronary revascularization), improving exacerbating conditions (e.g., correction of severe ane- mia, hypocalcemia) and optimizing the volume status and blood pressure. Angiotensin-converting enzyme inhibitors, vasodilators, -adrenergic blockers, and low dose digoxin therapy are all useful.

ISCHEMIC RENAL DISEASE

To this point, our review has been confined to a discussion of cardiac problems that arise in patients with renal disease. Ischemic renal disease (IRD), however, is a renal disease that occurs in cardiac patients. We include a discussion of this entity because IRD is very common in patients with arteriosclerotic cardiovascular disease, and consequently, the cardiologist may encounter the patient with IRD well in advance of the nephrologist. IRD is now recognized as an important and potentially reversible cause of end-stage renal disease that is often unrecognized by physicians caring for patients with arteriosclerotic complications. In addition, the prevalence of IRD is increas- ing. For these reasons, we feel that a working knowledge of when to suspect IRD, how to recognize its chief clinical manifestations, and an understanding of the potential benefits of intervention before ESRD supervenes can be of great utility to the practicing cardiologist.

Ischemic renal disease is defined as a clinically significant reduction in glomerular filtration rate and/or loss of renal parenchyma caused by hemodynamically significant arteriosclerotic renal artery stenosis (41–54). IRD is an important cause of progressive renal disease, and the prevalence of IRD is increasing, especially in older patients (41–54). Ischemic renal disease is an important and common consequence of arteriosclerotic renal artery stenosis that is separate and distinct from the problem of renovascular hypertension. In the past, the focus of treatment of patients with renal artery stenosis has primarily been on the goal of lowering blood pressure, but it has been recognized that renal artery stenosis secondary to atherosclerosis may produce progressive loss of renal func- tion due to renal ischemia. Renal ischemia is now understood to be an important and potentially reversible cause of end-stage renal disease (ESRD). With increasing awareness of ischemic nephr- opathy as a common and important clinical entity there is greater potential for favorably impacting the course of this disease. Consequently, recent interest in renovascular disease has been directed at preservation of renal function in addition to correction of hypertension.

Prevalence of IRD

Unsuspected renal artery stenosis is commonly found in patients with coronary artery disease.

Patients screened for renal artery disease with abdominal aortography while undergoing elective cardiac catheterization have been found to have a high prevalence of renal artery disease. A study of 1302 of 1651 consecutive cardiac catheterizations revealed significant unilateral renal artery ste- nosis in 11% of the patients and bilateral renal artery stenosis in 4% (47). Other large studies estimate that 18 to 30% of patients undergoing cardiac catheterization had significant renal artery stenosis.

Natural History of IRD

Stenosis of the renal arteries, when high-grade, has a high likelihood of progressing over a 2-

yr period, and progression is associated with loss of renal mass and function. Progressive arterial

obstruction occurs in 42 to 53% of patients with renal artery stenosis, with progression to complete

renal artery occlusion ranging from 9 to 16%. Complete occlusion is more likely to occur in patients with high-grade stenosis on initial examination (41–46).

The prevalence of IRD as the etiology of ESRD may be between 11 and 14% (65–70,73). More- over, patients with IRD as the cause of their ESRD have a high mortality rate following the initia- tion of renal replacement therapy, possibly because of the severity of the underlying atherosclerotic disease (50). IRD patients have a median survival of 27 mo and 5- and 10-yr survival rates of 18%

and 5%, respectively. Patients with renal insufficiency secondary to IRD are often considered to be poor candidates for intervention, but the poor survival of these patients once they reach ESRD makes intervention with PTRA or surgical revascularization a reasonable alternative to “conservative”

medical therapy.

Pathophysiology of IRD

Reduction in glomerular filtration rate sufficient to cause an elevation of the serum creatinine concentration requires injury to both kidneys. Therefore, IRD may arise from one of two principal clinical situations. The first situation is bilateral hemodynamically significant renal artery stenosis leading to bilateral renal ischemia. The second situation is hemodynamically significant renal artery stenosis in a solitary functioning kidney, or in a kidney that is providing the majority of a patient’s glomerular filtration. In the second situation, the stenotic kidney suffers from chronic ischemia, while the contralateral kidney has been damaged from other causes. Possible causes of impaired function of the contralateral kidney are damage from severe renovascular hypertension induced by the stenotic kidney and from renal diseases that are typically unilateral, such as pyelonephritis and trauma.

Chronic reduction of blood low to the kidney results in decreased renal size: the well-known clin- ical hallmark of chronic renal ischemia from atherosclerotic renovascular disease is a unilateral small kidney.

Diagnosis of IRD

Clinical features that suggest renovascular hypertension point to IRD as the cause of renal insuf- ficiency in a patient with coexisting renal failure and hypertension. The lengths of the two kidneys normally differ by less than 1 to 1.5 cm. Asymmetry of renal size in a hypertensive patient strongly suggests IRD. Hypertension is often abrupt in onset, severe, drug-resistant, and may present first after age 50. An abdominal bruit that is localized over the kidneys, prolonged into diastole, or heard in the flank suggests renovascular disease. In addition, there are six major clinical settings in which the clinician could suspect IRD (51,52) (Table 5).

A typical clinical presentation of a patient likely to have IRD is that of an older (>50 yr) patient with generalized atherosclerosis and refractory hypertension demonstrating progressive azotemia in conjunction with antihypertensive drug therapy (41–45). Patients with unsuspected arterioscle- rotic IRD may present with acute renal failure caused by treatment of hypertension, particularly with angiotensin-converting enzyme (ACE) inhibitors. A reversible worsening of azotemia during ACE inhibitor therapy should raise the suspicion of IRD. ACE inhibitors may acutely alter intra- renal hemodynamics. The stenotic kidney depends on angiotensin II to maintain GFR. All causes

Table 5

Clinical Presentations Suggesting Ischemic Renal Disease

1. Acute renal failure (ARF) caused by the treatment of hypertension, especially with angiotensin-converting enzyme (ACE) inhibitors

2. Progressive azotemia in a patient with known renovascular hypertension

3. Acute pulmonary edema superimposed on poorly controlled hypertension and renal failure 4. Progressive azotemia in an elderly patient with refractory or severe hypertension

5. Progressive azotemia in an elderly patient with evidence of atherosclerotic disease

6. Unexplained progressive azotemia in an elderly patient

vasoconstriction of both afferent and efferent arterioles, but with preferential effects on the efferent arterioles. This differential vasoconstriction increases the glomerular capillary pressure and there- fore maintains or increases the single-nephron glomerular filtration rate (SNGFR). When the vaso- constrictor effect of angiotensin II on the efferent arteriole is blocked by an ACE inhibitor, efferent arteriolar constriction relaxes and glomerular capillary filtration pressures and glomerular filtra- tion rate decrease. Although ACE inhibitor-induced acute renal failure (ARF) is an important clin- ical marker for IRD, the absence of ARF does not rule out the possibility of significant IRD because only 6–38% of patients with significant renal vascular disease will develop ARF when treated with these agents (53). The ARF associated with the use of antihypertensive agents in patients with IRD is generally reversible and indicates further clinical evaluation.

Recurrent acute pulmonary edema in patients with poorly controlled hypertension and renal insufficiency has also been reported to be a marker of severe bilateral atherosclerotic renal artery disease (51,52). Volume-dependent renovascular hypertension caused by bilateral renal artery ste- noses appears to be the dominant factor in producing the pulmonary edema. Patients with pulmo- nary edema, uncontrolled hypertension, and azotemia have not been prospectively evaluated to establish what percent of patients with this scenario have IRD, but this clinical picture should alert the clinician to the possibility of IRD. The episodes of pulmonary edema may cease following renal revascularization.

A common presentation of IRD is unexplained progressive azotemia in an elderly patient with evidence of atherosclerotic disease. As discussed previously, angiographic studies have indicated a high prevalence of renal artery stenosis among patients with atherosclerotic disease in other ves- sels. Therefore, a history or physical findings of generalized are strongly suggestive of ischemic nephropathy.

P

-ACE I

R

ACE inhibitor renography is the most accurate noninvasive functional test for diagnosing reno- vascular hypertension, but its accuracy is diminished in the setting of renal failure. ACE inhibitor renography generally has difficulty differentiating ischemic renal disease from intrinsic renal disease.

D

D

S

Duplex Doppler sonography (DDS) is useful for diagnosing IRD. DDS combines ultrasound and Doppler techniques to locate the renal artery and assess renal artery blood flow velocity. DDS has several major advantages: it is useful in the presence of azotemia; it is not necessary to discon- tinue antihypertensive agents as in ACE inhibitor renography; there is no risk of contrast nephrop- athy or cholesterol embolization; and bilateral renal artery stenosis can be assessed. Even total obstruction of a renal artery can be diagnosed by scanning over the kidney. The main limitation of DDS is inadequate studies because of patient obesity, the presence of bowel gas, and previous abdominal surgery.

Magnetic resonance angiography and spiral computed tomography (spiral CT) angiography are recently developed techniques that have been used to detect renal vascular disease with a high sen- sitivity and specificity, but 100 to 150 mL of contrast medium must be given in the latter procedure.

Treatment of IRD S

P

I

The prognosis of medically treated IRD is poor, with many patients showing a deterioration

of renal function during follow-up. Patients with high-grade (>75%) arterial stenosis bilaterally

or involving a solitary functioning kidney are at risk of complete renal arterial occlusion. Interven-

tion is indicated to restore renal arterial blood flow to preserve renal function. Total occlusion of

the renal artery does not always indicate irreversible ischemic parenchymal damage because the via-

bility of the kidney can be maintained through development of collateral arterial supply. This situa-

tion occurs when the arterial occlusion is gradual. Several clinical clues suggest that reestablishment

of renal arterial flow can lead to recovery of renal function: (1) kidney size more than 9 cm; (2) evidence of acceptable function of the involved kidney on isotope renography; (3) angiographic filling of the distal renal arterial tree by collateral circulation in patients with total renal arterial occlusion proximally; (4) renal biopsy demonstrating well-preserved glomeruli with minimal arteriolar sclerosis; (5) preoperative serum creatinine levels of less than 3.0 mg/dL; and (6) presen- tation with acute deterioration of renal function after initiation of medical antihypertensive therapy, especially with an ACE inhibitor (41–45).

The rate of decline in renal function is also an important determinant of the outcome after inter- vention in atherosclerotic ischemic renal disease. Rapid deterioration of renal function in a patient with renal artery stenosis (especially in association with ACE inhibitor therapy), suggests a strong possibility of retrieval of function by intervention to restore renal arterial flow. Patients with chronic severe azotemia (serum creatinine >4 mg/dL) are likely to have severe renal parenchymal disease, and improvement in renal function following revascularization or angioplasty is less likely. Excep- tions to this observation are cases of total main renal artery occlusion, wherein kidney viability is maintained via collateral circulation.

P

T

R

A

Percutaneous transluminal renal angioplasty (PTRA) does not require general anesthesia and can be repeated if needed. In patients with nonostial renal artery disease, the success rate of PTRA has been excellent. PTRA is less effective treatment for ostial lesions. Restenosis is the predomi- nant cause of failure in patients with ostial lesions, due either to elastic recoil of the dilated artery, neointimal hyperplasia, or recurrent atheromatous disease. Technical difficulties and complica- tions of angiographic investigation and PTRA in these patients include contrast media-induced acute renal failure and atheroembolic renal disease.

Endovascular stents are a newer treatment option for patients with ostial lesions or who are con- sidered poor risks for surgical revascularization (53). Early recurrent arterial stenosis is a problem.

This technique requires further experience and evaluation, but offers promise to patients with ostial lesions who are not candidates for surgery.

S

R

The surgical treatment of renovascular disease has been recently reviewed by Novick (78). Sur- gical revascularization to preserve renal function in patients with high-grade atherosclerotic arterial occlusive disease affecting both kidneys or a solitary kidney may result in improvement or stabil- ization of renal function postoperatively in 75–89% of patients. For example, the Cleveland Clinic performed surgical revascularization for preservation of renal function in 161 patients with criti- cal stenosis bilaterally or in a solitary kidney and achieved postoperative improvement in renal function in 93 patients (58%), stabilization in 50 patients (31%), and deterioration in only 18 patients (11%).

Surgical renal vascular reconstruction can be performed with operative mortality rates in the range of 2.1–6.1% and a high technical success rate. An increased risk of operative mortality has been observed with bilateral simultaneous renal revascularization, or when renal revascularization is performed in conjunction with another major vascular operation such as aortic replacement.

Most studies have indicated a high technical success rate for surgical vascular reconstruction with postoperative thrombosis or stenosis rates of less than 10%.

SUMMARY

It is readily apparent that progressive renal disease is complicated by several common cardio-

vascular alterations including pericarditis, renal parenchymal hypertension, primary arterioscle-

rosis, and left ventricular dysfunction. We have reviewed the pathogenesis, clinical features, and

management of the cardiovascular disorders. In addition, we have included a reviewed of ischemic

renal disease (IRD), a common, albeit underdiagnosed, disorder that cardiologists may frequently

encounter well in advance of the nephrologist. Increasing recognition that IRD is a potentially rever- sible cause of end-stage renal disease underscores the importance of its inclusion in our review. We are hopeful that the management approaches proposed in this chapter will facilitate the optimal care of these difficult patients.

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