End-stage renal disease (ESRD) is the irreversible loss of renal function, resulting in the accumulation of toxins and the loss of internal homeostasis. Uremia, the clinical syndrome resulting from ESRD, is universally fatal without some form of renal replacement therapy. At present, renal replacement therapy consists of two basic modalities: renal transplant and dialytic therapy, either hemodialysis or peritoneal dialysis (PD).

Hemodialysis is the initial therapy in the vast majority of new cases of adult ESRD, with a few starting PD and an even smaller number receiving predialytic renal transplants. The proportions are reversed in children, with most children receiving transplants. More than 90,000 Americans await a renal transplant, with a median time of 2.6 years on a transplant wait list.

Approximately half of hemodialysis and PD patients will be alive 3 years after starting therapy, with cardiac causes accounting for about half of all deaths. Infections trigger death in up to a quarter of patients, with cerebrovascular events and malignancy being other causes.

Uremia, contamination of the blood with urine, differs from azotemia, the buildup of nitrogen in the blood. Renal failure assumes many forms, often co-existing.

Excretory failure leads to elevated levels of >70 chemicals in uremic plasma, which gives rise to the hypothesis that these toxins, individually or in combination, cause uremic organ dysfunction and produce the symptoms of uremia. Urea is not the major toxin, and potential uremic toxins include cyanate, guanidine, polyamines, and β2-microglobulin.¹ If uremia were simply a toxidrome, then dialysis would reverse all its untoward effects; however, it does not, in part because many toxins are highly protein bound and nondialyzable.² Because many uremia-related organ dysfunctions persist after dialysis, other processes are clearly important.

Biosynthetic failure refers to the aspects of uremia caused by loss of the renal hormones 1,25(OH)₂-vitamin D₃ and erythropoietin. The kidneys are primarily responsible for the secretion of erythropoietin and 1α-hydroxylase, which is necessary to produce the active form of vitamin D₃. Because 85% of erythropoietin is produced in the kidneys, ESRD patients have depressed levels of erythropoietin, which contributes to anemia. Vitamin D₃ deficiency results in decreased GI calcium absorption, inducing secondary hyperparathyroidism, leading to renal bone disease.

Regulatory failure results in an oversecretion of hormones, leading to uremia by disruption of normal feedback mechanisms. The uremic state produces excess free oxygen radicals, which react with carbohydrates, lipids, and amino acids to create advanced glycation end products, linked to atherosclerosis and amyloidosis in ESRD patients.³ This may explain the progressive nature of the atherosclerosis and amyloidosis seen in ESRD patients.⁴

Uremia is a clinical syndrome, and no single symptom, sign, or laboratory test result reflects all aspects of uremia. Although a correlation exists between the symptoms of uremia and low glomerular filtration rate (8 to 10 mL/min/1.73 m²), BUN and serum creatinine levels are inaccurate markers of the clinical syndrome of uremia. The decision to start long-term dialysis is based on the severity of the patient’s symptoms related to uremia (Table 90-1). The most common reasons for emergency dialysis are hyperkalemia, severe acid-base disturbances, and pulmonary edema resistant to usual therapy.

NEUROLOGIC COMPLICATIONS

Stroke occurs in approximately 6% of hemodialysis patients, with about half being hemorrhagic and half ischemic. Subdural hematomas occur 10 times more frequently in dialysis patients than in the general population.

Uremic encephalopathy is a constellation of nonspecific central neurologic symptoms associated with renal failure. Uremic encephalopathy is best diagnosed after eliminating structural, vascular, infectious, toxic, and metabolic causes of neurologic dysfunction. Neurologic findings of uremic encephalopathy improve with dialysis.

Dialysis dementia is nonspecific in presentation from other encephalopathies. This manifestation of ESRD and treatment is progressive, with the 2- to 4-year survival for these patients being 24%. This disorder usually becomes evident after at least 2 years of dialysis therapy and fails to respond to increases in dialysis frequency or renal transplantation.

Peripheral neuropathy is one of the most frequent neurologic manifestations of ESRD, with greater lower than upper limb involvement. The most frequent clinical features reflect large-fiber involvement, with paresthesias, reduction in deep tendon reflexes, impaired vibration sense, muscle wasting, and weakness. Autonomic dysfunction results in impotence, postural dizziness, gastric fullness, bowel dysfunction, and reduced sweating. Reduced heart rate variability and baroreceptor control impairment occur.

Nerve conduction studies demonstrate findings consistent with a generalized neuropathy of the axonal type. No single pathologic correlate has been identified for peripheral uremic neuropathy. Conventional hemodialysis does not seem to improve autonomic dysfunction; however, daily short hemodialysis and long nocturnal hemodialysis may reduce the elevated sympathetic activity.

CARDIOVASCULAR COMPLICATIONS

The mortality from cardiovascular disease is 10 to 30 times higher in dialysis patients than in the general population. Coronary artery disease, left ventricular hypertrophy, and congestive heart failure are common. The etiology of cardiovascular disease in ESRD patients is multifactorial, related to preexisting conditions (e.g., hypertension, diabetes), uremia (e.g., uremic toxins, hyperlipidemias, homocysteine level, hyperparathyroidism), and dialysis-related conditions (e.g., hypotension, dialysis membrane reactions, hypoalbuminemia).⁵

The diagnosis of ischemic cardiovascular disease in ESRD patients often has been clouded by the misconception that the traditional serum protein markers of myocardial damage (troponins I and T) are unreliable in dialysis patients. Elevated levels of troponin I and T are common even in asymptomatic hemodialysis patients and probably reflect left ventricular hypertrophy and microvascular disease. Asymptomatic elevations of cardiac biomarkers are, however, associated with long-term risks of coronary artery disease.⁶ To account for higher baseline levels of troponin T and I, many define myocardial infarction only by a 20% or more dynamic rise and with at least one value above the 99th percentile (see chapter 48, “Chest Pain”).

Hypertension is present in most patients starting dialysis. Maintenance of hypertension depends mostly on increased total peripheral resistance. Increases in blood volume, decreased vascular compliance, the vasopressor effects of native kidneys, the renin-angiotensin system, and the sympathetic nervous system also play roles in ESRD hypertension.⁷

Management of hypertension in ESRD patients begins with control of blood volume. If that is unsuccessful, most cases can be controlled with adrenergic blocking agents, angiotensin-converting enzyme inhibitors, or vasodilating agents, such as hydralazine or minoxidil. Bilateral nephrectomy is rarely necessary for blood pressure control.

Heart failure most commonly results from hypertension, followed by coronary artery disease and valvular defects. Causes unique to ESRD include uremic cardiomyopathy, fluid overload, and arteriovenous fistula–related high-output failure (see section “Complications of Vascular Access” later in the chapter). Natriuretic peptide levels are elevated in hemodialysis patients, often from concomitant left ventricular hypertrophy and systolic dysfunction. Elevation of natriuretic peptides in hemodialysis patients correlates with higher short-term mortality rates, but there are no reliable thresholds to identify fluid overload.

Uremic cardiomyopathy is a diagnosis of exclusion when all other causes of congestive heart failure have been excluded. In most uremic patients, left ventricular dysfunction is related to ischemic heart disease, hypertension, and hypoalbuminemia. Dialysis rarely improves left ventricular function in uremic patients with congestive heart failure.

Pulmonary edema in ESRD patients is commonly ascribed to fluid overload, but acute myocardial ischemia can also trigger depressed left ventricular function. Cornerstones of therapy are supplemental oxygen if needed, bilevel positive airway pressure, nitrates, and angiotensin-converting enzyme inhibitors. Loop diuretics, such as furosemide (60 to 100 milligrams IV), may aid even in those with minimal urine output from their short-lived vasodilatory actions. Hemodialysis is the ultimate treatment for fluid overload in ESRD patients. Preload reduction by inducing diarrhea with sorbitol or by phlebotomy may help in low-resource situations. Removing as little as 150 mL of blood is safe and effective in some with pulmonary edema. Improved oxygenation produced by phlebotomy offsets the decrease in oxygen-carrying capacity due to the decrease in hemoglobin. Blood withdrawn during phlebotomy should be collected in transfusion bags, so plasma can be extracted by the blood bank and the red blood cells transfused back to the patient later during dialysis. PD does not remove volume fast enough to have a significant impact on pulmonary edema.

Cardiac tamponade is a concern in any critically ill ESRD patient, often presenting without classic findings. Instead, signs of cardiac tamponade in these patients include changes in mental status, hypotension, or shortness of breath. Increased interdialytic weight gain, increased edema, and intradialytic hypotension are other warning signs suggesting the diagnosis of tamponade. In addition to hypotension, an increased heart size on chest radiograph suggest effusion and potential tamponade. Bedside US is the best method to detect pericardial effusion and tamponade. Hemodynamically significant pericardial effusions require pericardiocentesis under fluoroscopic or US guidance. Bedside pericardiocentesis (see chapter 34, “Pericardiocentesis”) is used only in hemodynamically unsTable patients because of its high complication rate.

Pericarditis is usually due to uremia. Uremic pericarditis is linked to fluid overload, abnormal platelet function, and increased fibrinolysis and inflammation. Pericardial contents are sterile unless infected and are abundant with fibrin and inflammatory cells.

Uremic pericarditis causes pericardial friction rubs, which are louder than in most other forms of pericarditis, often palpable, and frequently persist for some time after metabolic abnormalities have been corrected. BUN level is nearly always >60 milligrams/dL. One of the unique features of uninfected uremic pericarditis is that the inflammatory cells do not penetrate into the myocardium, so typical ECG changes of acute pericarditis are absent. Most often, the ECG demonstrates associated abnormalities, such as left ventricular hypertrophy, ischemia, and metabolic abnormalities (e.g., hyperkalemia and hypocalcemia). When the ECG has features typical of acute pericarditis, infection should be suspected.

Dialysis-related pericarditis is most common during periods of increased catabolism (trauma and sepsis) or inadequate dialysis due to missed sessions or vascular access problems. The pathophysiology of dialysis-related pericarditis is the buildup of middle molecules and hyperparathyroidism. Dialysis-related pericarditis is more common during hemodialysis than during PD, although now somewhat less frequent because of improved dialysis techniques. Fever and malaise are more common and severe than in uremic pericarditis. Pericardial effusion is the most important complication and tends to be recurrent. Due to the recurrent nature of dialysis pericarditis, adhesions and fluid loculations are common, which complicates the interpretation of echocardiographic scans and images obtained using other modalities.

Management of uremic and dialysis-related pericarditis in patients in hemodynamically sTable condition is intensive dialysis. Hemodialysis is preferred over PD because of the higher clearance rates of the former, recognizing the risks of tamponade from heparin and rapid fluid shifts. Hemodialysis is effective in the majority of cases of dialysis-related pericarditis, usually after 10 to 14 days. Indomethacin, colchicine, and steroids are not useful for ESRD pericarditis. If pericardial effusion persists for longer than 10 to 14 days with intensive dialysis, anterior pericardiectomy is often used, with total pericardiectomy reserved for constrictive pericarditis.

HEMATOLOGIC COMPLICATIONS

Anemia

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