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.
TABLE 90-1Clinical Features of Uremia and Dialysis ||Download (.pdf) TABLE 90-1 Clinical Features of Uremia and Dialysis
Uremic encephalopathy: cognitive defects, memory loss, decreased attentiveness, slurred speech, reversal of sleep-wake cycle, asterixis, seizure, coma, symptomatic improvement with dialysis
Dialysis dementia: progressive neurologic decline, failure to improve with dialysis, fatal
Subdural hematoma: headache, focal neurologic deficits, seizure, coma
Peripheral neuropathy: singultus (hiccups), restless leg syndrome, sensorimotor neuropathy, autonomic neuropathy
Coronary artery disease
Hypertension: essential hypertension, glomerulonephritis, renal artery stenosis, fluid overload
Heart failure: fluid overload, uremic cardiomyopathy, high-output arteriovenous fistula
Pericarditis: uremic, dialysis related, pericardial tamponade
Anemia, decreased red blood cell survival, decreased erythropoietin levels
Immunodeficiency (humoral and cellular)
Anorexia, metallic taste, nausea, vomiting
Renal bone disease
Metastatic calcification (calciphylaxis)
Hyperparathyroidism (osteitis fibrosa cystica)
Vitamin D3 deficiency and aluminum intoxication (osteomalacia)
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.
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.
Anemia is multifactorial, caused by decreased erythropoietin, blood loss from dialysis, frequent phlebotomy, and decreased red blood cell survival times. In addition, the wide fluctuations in plasma blood volume seen in dialysis patients often cause factitious anemia. Without treatment, the hematocrit should stabilize at 15% to 20%, with normocytic and normochromic red blood cells. Bone marrow shows erythroid hypoplasia, with little effect on leukopoiesis or megakaryocytopoiesis. Anemia is treated with regular infusions of human recombinant erythropoietin. Erythropoietin replacement therapy improves the quality of life for ESRD patients by increasing exercise capacity and tolerance.
The bleeding diathesis of ESRD patients increases the risks of GI tract bleeding, subdural hematomas, subcapsular liver hematomas, and intraocular bleeding. Several mechanisms, including decreased platelet function, abnormal platelet-vessel wall interactions, altered von Willebrand factor, anemia, and abnormal guanidinosuccinic acid–dependent production of nitric oxide, create uremic bleeding. The skin bleeding test is the best predictor of clinically important defects in hemostasis. Patients receiving aspirin or warfarin are at greater risk of major bleeding. Improvement in bleeding times with infusions of desmopressin (benefit in 1 h), cryoprecipitate (benefit in 4 h), or conjugated estrogens (benefit in 6 h) is an option (see chapter 233, "Acquired Bleeding Disorders" for further discussion).
Immunologic deficiency in ESRD patients results in high morbidity and mortality from infectious diseases. Depressed leukocyte chemotaxis and phagocytosis from many causes is the key feature, along with abnormal T-cell activation. Dialysis does not improve the immune function and may exacerbate immunodeficiency by complement activation after exposure to the hemodialysis filter membrane.
Anorexia, nausea, and vomiting are common symptoms of uremia and used to initiate and monitor dialysis adequacy. There is an increased incidence of gastritis and upper GI bleeding in ESRD patients, but the incidence of gastric and duodenal ulcers is similar in ESRD patients and the general population.
Chronic constipation is common secondary to decreased fluid intake and the use of phosphate-bonding gels. ESRD patients have an increased incidence of diverticular disease and colonic perforation, especially patients with polycystic kidney disease.
Dialysis-related ascites is secondary to fluid overload, portal hypertension from polycystic liver disease, and osmotic disequilibrium. Treatment of refractory ascites is possible with peritoneovenous shunts.
As the glomerular filtration rate falls, phosphate excretion decreases, which results in increased serum phosphate levels. When the calcium-phosphate product [Ca2+ (milligrams/dL) × PO4 (milligrams/dL)] is higher than 70 to 80, metastatic calcification can ensue. Joint pain from pseudogout develops from calcification of synovial membrane–lined joints. Metastatic calcification in small vessels results in skin and finger necrosis, and life-threatening calcifications can occur in the cardiac and pulmonary systems. Short-term mortality rate is higher in ESRD patients with a calcium-phosphate product of >72. Treatment consists of the use of low-calcium dialysate and phosphate-binding gels.
As ESRD progresses, the combination of calciphylaxis and vitamin D3 deficiency results in depressed ionized calcium levels and stimulation of the parathyroid gland, causing hyperparathyroidism. The increased production of parathyroid hormone results in high bone turnover and weakened bones susceptible to fracture. Bone pain and muscle weakness are other symptoms. High alkaline phosphatase and parathyroid hormone levels make the diagnosis. Treatment consists of control of serum phosphate levels with binding gels, vitamin D3 replacement, and, if necessary, subtotal parathyroidectomy.
A subset of ESRD patients develops osteomalacia, a defect in bone calcification. The signs and symptoms are weakened bones, bone pain, and muscle weakness, similar to those of hyperparathyroidism. Osteomalacia is characterized by low to normal alkaline phosphatase levels and low parathyroid hormone levels. Elevated serum aluminum and bone aluminum levels are useful for confirming the diagnosis. Treatment with desferrioxamine helps aluminum bone disease.
Dialysis-related amyloidosis (β2-microglobulin amyloidosis) can occur in dialysis patients >50 years of age and on dialysis for >10 years. Advanced glycation end products appear central to the chronic inflammatory condition, leading to amyloidosis. Amyloid deposits are found in the GI tract, bones, and joints. Complications include GI perforation, bone cysts with pathologic fractures, and arthropathies, including carpal tunnel syndrome and rotator cuff tears. Patients with amyloidosis have higher mortality rates than do those without this disorder.