eMedicine Specialties > Nephrology > Chronic Kidney Disease

Uremia

Author: A Brent Alper Jr, MD, MPH, Associate Professor of Medicine, Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine
Coauthor(s): Rajesh G Shenava, MD, Fellow, Department of Nephrology, Tulane University Medical Center; Bessie A Young, MD, MPH, Associate Professor, Division of Nephrology, Department of Medicine, University of Washington; Director of Home Hemodialysis, Northwest Kidney Center, Seattle
Contributor Information and Disclosures

Updated: Oct 2, 2009

Introduction

Background

Uremia is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function. The term uremia, which literally means urine in the blood, was first used by Piorry to describe the clinical condition associated with renal failure.¹ Uremia more commonly develops with chronic renal failure (CRF) or the later stages of chronic kidney disease (CKD), but it also may occur with acute renal failure (ARF) if loss of renal function is rapid. As yet, no single uremic toxin has been identified that accounts for all of the clinical manifestations of uremia. Toxins, such as parathyroid hormone (PTH), beta2-microglobulin, polyamines, advanced glycosylation end products, and other middle molecules, are thought to contribute to the clinical syndrome.

Pathophysiology

Normally, the kidney is the site of hormone production and secretion, acid-base homeostasis, fluid and electrolyte regulation, and waste-product elimination. In the presence of renal failure, these functions are not performed adequately and metabolic abnormalities, such as anemia, acidemia, hyperkalemia, hyperparathyroidism, malnutrition, and hypertension, can occur. Uremia usually develops only after the creatinine clearance falls to less than 10 mL/min, although some patients may be symptomatic at higher clearance levels, especially if renal failure acutely develops. The syndrome may be heralded by the clinical onset of nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus, and change in mental status.

Anemia

Anemia-induced fatigue is thought to be one of the major contributors to the uremic syndrome. Erythropoietin (EPO), a hormone necessary for red blood cell production in bone marrow, is produced by peritubular cells in the kidney in response to hypoxia. Anemia associated with renal failure can be observed when the glomerular filtration rate (GFR) is less than 50 mL/min or when the serum creatinine is greater than 2 mg/dL. Diabetic patients may experience anemia with a GFR of less than 60 mL/min. Anemia associated with chronic kidney disease is characteristically normocytic, normochromic, and hypoproliferative.

In the setting of CRF, anemia may be due to other clinical factors or diseases, such as iron deficiency, vitamin deficiencies (eg, folate, vitamin B-12), hyperparathyroidism, hypothyroidism, and decreased red blood cell survival. Iron deficiency, which may occur as a result of occult GI bleeding or frequent blood draws, should be excluded in all patients. Elevated PTH levels are thought to be associated with marrow calcification, which may suppress red blood cell production and lead to a hypoproliferative anemia. Parathyroid-induced marrow calcification tends to regress after parathyroidectomy.

Acidosis

Acidosis is another major metabolic abnormality associated with uremia. Metabolic acid-base regulation is controlled primarily by tubular cells located in the kidney, while respiratory compensation is accomplished in the lungs. Failure to secrete hydrogen ions and impaired excretion of ammonium may initially contribute to metabolic acidosis. As kidney disease continues to progress, accumulation of phosphate and other organic acids, such as sulfuric acid, hippuric acid, and lactic acid, creates an increased anion-gap metabolic acidosis. In uremia, metabolic acidemia may contribute to other clinical abnormalities, such as hyperventilation, anorexia, stupor, decreased cardiac response (congestive heart failure), and muscle weakness.

Hyperkalemia

Hyperkalemia (potassium, >6.5 mEq/L) may be an acute or chronic manifestation of renal failure, but regardless of the etiology, a potassium level of greater than 6.5 mEq/L is a clinical emergency. As renal function declines, the nephron is unable to excrete a normal potassium load, which can lead to hyperkalemia if dietary intake remains constant. In addition, other metabolic abnormalities, such as acidemia or type IV renal tubular acidosis, may contribute to decreased potassium excretion and lead to hyperkalemia. However, remember that most cases of hyperkalemia are multifactorial in etiology.

Hyperkalemia can occur in several instances, which include (1) excessive potassium intake in patients with a creatinine clearance of less than 20 mL/min, (2) hyporeninemic hypoaldosteronism or type IV renal tubular acidosis in patients with diabetes, urinary obstruction, or interstitial nephritis, (3) significant acidemia, or (4) with drug therapy. Hyperkalemia is common when drugs, such as potassium-sparing diuretics (eg, spironolactone, amiloride, triamterene), ACE inhibitors, angiotensin-receptor blockers, beta-blockers, or nonsteroidal anti-inflammatory drugs are used in the setting of renal insufficiency or renal failure.

Calcium, parathyroid, and vitamin D abnormalities

In the setting of renal failure, there are a number of abnormalities of the calcium-vitamin D metabolic pathway, such as hypocalcemia, hyperphosphatemia, and increased PTH levels, that ultimately lead to renal bone disease (osteodystrophy). After exposure to the sun, vitamin D-3 is produced in the skin and transported to the liver for hydroxylation (25[OH] vitamin D-3). Hydroxylated vitamin D-3 is then transported to the kidney, where a second hydroxylation occurs, and 1,25(OH)2 vitamin D-3 is formed. As the clinically active form of vitamin D, 1,25(OH)2 vitamin D-3 is responsible for GI absorption of calcium and phosphorus and suppression of PTH. During renal failure, 1,25(OH)2 vitamin D-3 levels are reduced secondary to decreased production in renal tissue as well as hyperphosphatemia, which leads to decreased calcium absorption from the GI tract and results in low serum calcium levels. Hypocalcemia stimulates the parathyroid gland to excrete PTH, a process termed secondary hyperparathyroidism.

In this setting, the vitamin deficiency can be replaced orally or intravenously with 1,25(OH)2 vitamin D-3 (calcitriol). There are several new vitamin D analogs that have become available for use and are more specific for vitamin D receptors in the parathyroid gland. Use of one of these analogs, paracalcitol, has been found to be associated with improved survival compared to use of calcitriol.² In addition, these new vitamin D analogs cause less elevation in serum calcium and phosphorus levels.³ Also, cinacalcet, a new medication that stimulates the calcium sensing receptor in the parathyroid gland and causes negative feedback on PTH production and release, can be used to treat secondary hyperparathyroidism.

In addition to the calcium abnormalities, hyperphosphatemia occurs as excretion of phosphate decreases with progressive renal failure. Hyperphosphatemia stimulates parathyroid gland hypertrophy and stimulates increased production and secretion of PTH. Elevated PTH levels have been associated with uremic neuropathy and other metabolic disturbances, which include altered pancreatic response, erythropoiesis, and cardiac and liver function abnormalities. The direct deposit of calcium and phosphate in the skin, blood vessels, and other tissue, termed metastatic calcification, can occur when the calcium-phosphate product is greater than 70.

Endocrine abnormalities

Other endocrine abnormalities that may occur in the setting of uremia include changes in carbohydrate metabolism, decreased thyroid hormone excretion, and abnormal sexual hormone regulation. Reduced insulin clearance and increased insulin secretion can lead to increased episodes of hypoglycemia and normalization of hyperglycemia in diabetic patients. Glycemic control may appear to be improved; however, this may be an ominous sign of renal function decline. Consider appropriate decreases in doses of antihyperglycemia medications (ie, insulin and oral antihyperglycemic medications) as renal function declines to avoid hypoglycemic reactions.

Levels of thyroid hormones, such as thyroxine, may become depressed, while reverse triiodothyronine levels may increase because of impaired conversion of triiodothyronine to thyroxine.

Reproductive hormone dysfunction is common and can cause impotence in men and infertility in women. Renal failure is associated with decreased spermatogenesis, reduced testosterone levels, increased estrogen levels, and elevated luteinizing hormone levels in men, all of which contribute to impotence and decreased libido. In women, uremia reduces the cyclic luteinizing hormone surge, which results in anovulation and amenorrhea. Infertility is common and pregnancy is rare in women with advanced uremia and renal failure, but this may be reversed with renal transplantation.

Cardiovascular abnormalities

Cardiovascular abnormalities, including uremic pericarditis, pericardial effusions, calcium and phosphate deposition–associated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CRF. Left ventricular hypertrophy is a common disorder found in approximately 75% of patients who have not yet undergone dialysis. Left ventricular hypertrophy is associated with increased ventricular thickness, arterial stiffening, coronary atherosclerosis, and/or coronary artery calcification. Patients are at increased risk for cardiac arrhythmias due to underlying electrolyte and acid-base abnormalities. Renal dysfunction may contribute to associated fluid retention, which may lead to uncontrolled hypertension and congestive heart failure.

Malnutrition

Malnutrition usually occurs as renal failure progresses and is manifested by anorexia, weight loss, loss of muscle mass, low cholesterol levels, low BUN levels in the setting of an elevated creatinine level, low serum transferrin levels, and hypoalbuminemia. However, whether uremia stimulates protein catabolism directly remains controversial.⁴

Comorbid diseases, such as diabetes, congestive heart failure, or other diseases, that require reduced food intake or restrictions of certain foods may contribute to anorexia.

Numerous epidemiologic studies have shown that a decreased serum albumin concentration is a very strong and independent predictor of mortality among dialysis patients. Thus, it is important that dialysis be initiated prior to the occurrence of significant malnutrition.

Frequency

United States

The prevalence of uremia has not been evaluated specifically and is very difficult to ascertain, as most patients start dialysis prior to developing any uremic symptoms. For most patients, this is when the creatinine clearance is less than 10 mL/min or less than 15 mL/min in diabetic patients.

The 19th Annual Data Report from the US End-Stage Renal Disease (USRDS) Program entered 106,912 patients during 2005 and had 485,012 prevalent patients; 17,429 transplants were performed, and 143,693 patients had functioning grafts at year’s end. While prevalence rates continue to increase as patients with ESRD are living longer, incidence rates have stabilized at 347 per million, and they have fallen for most people younger than 60 years, except for younger African Americans and Native Americans with diabetic ESRD.

International

The highest prevalence rate for treated ESRD is reported in Japan, followed by Taiwan and then the United States. Of the world's population with ESRD, 58% live in just 5 countries (ie, United States, Japan, Germany, Brazil, Italy).

Mortality/Morbidity

Chronic renal failure is associated with a very high morbidity and hospitalization rate, likely due to existing comorbid conditions, such as hypertension, coronary artery disease, and peripheral vascular disease. The rate of hospitalization and hospital days is 3 times greater than the general public and not much different from dialysis patients.

• The first-year age-adjusted mortality rate of patients on dialysis is 9.4%, the second-year mortality rate is 32.3%, and the 5-year mortality rate is 60.8%. In contrast, diabetic ESRD patients have a first-year mortality rate of 23%.
• In patients with ESRD, cardiovascular disease, which is followed by sepsis and cerebrovascular disease, is the primary cause of death. The dialysis population in the United States has a 10- to 20-fold higher risk of death due to cardiovascular complications than the general population after adjusting for age, race, and sex. The relative risk with respect to the general population is much higher in younger patients
• Patients who have delayed initiation of dialysis have a 1.5-fold higher risk of a low serum albumin level and 1.8-fold higher risk of starting dialysis with a hematocrit value lower than 28% compared with those who do not have a low creatinine clearance. However, patients with delayed onset of dialysis are not more likely to have prevalent cardiac disease, peripheral vascular disease, hypertension, or poor functional status than those without a delayed onset of dialysis. Thus the timing of the initiation of dialysis remains controversial

Race

ESRD disproportionately affects minority populations. Whites represent the majority of the ESRD population (59.8%), while African Americans (33.2%), Asians (3.6%), and Native Americans (1.6%) comprise the rest of the ESRD population. However, the incidence rate of ESRD among African Americans is 4-fold higher and Native Americans 2-fold higher than that for whites.

• Minority populations are more likely to have delayed onset of dialysis care and are more likely to start dialysis when their GFRs are significantly decreased.
• Whether a certain racial or ethnic background predisposes patients to symptoms of uremia more so than another racial or ethnic background in patients with equivalent GFRs remains unknown.

Sex

ESRD is slightly more prevalent in men than in women (male-to-female ratio, 1.2:1).

• Women are 1.7-fold more likely to have delayed initiation of dialysis than men.
• Women, due to lower muscle mass and baseline serum creatinine levels, are more likely to develop uremic symptoms at a lower level of creatinine.

Age

ESRD is much more prevalent in older adults, but the prevalence of uremia among different age groups is unknown. 

• Individuals aged 75 years and older have experienced the greatest increase in incidence (98% over the last decade), attributable in part to improved survival of individuals with cardiovascular disease and diabetes mellitus and expanded access to renal replacement therapy for older patients.
• Information from the United States Renal Data System indicates that older adults are 31% less likely to have delayed initiation of dialysis than patients who were younger than 40 years at the initiation of dialysis.
• Making the diagnosis of uremia may be difficult in young children because of the nonspecificity of clinical symptoms.

Clinical

History

• Uremia can occur once the creatinine clearance is below 10-20 mL/min, and it is heralded by the clinical onset of nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus, mental status changes, visual disturbances, and increased thirst.
• Uremic encephalopathy can progress to seizures, stupor, coma, and, eventually, death.
• Patients may report of nonspecific symptoms, which become chronic and progressive over time because of the gradual onset of the disease.
• Metabolic abnormalities such as anemia, acidemia, and electrolyte abnormalities are prominent.
• Cardiovascular abnormalities such as hypertension, atherosclerosis, valvular stenosis and insufficiency, congestive heart failure, and angina accelerate as renal function declines. These abnormalities may contribute to clinical symptoms of uremia if not treated appropriately.
• Diabetic patients may appear to be in better glycemic control but may tend to have more hypoglycemic episodes as renal function declines. This paradoxical improvement in glycemic control is a result of increased insulin secretion and insulin half-life, both of which occur as renal function declines.

Physical

Typical physical findings found in persons with uremia are those associated with fluid retention, anemia, and acidemia. Severe malnutrition can contribute to muscle wasting, while electrolyte abnormalities may cause muscle cramping, cardiac arrhythmias, and mental status changes.

• Skin: The classic skin finding in persons with uremia is uremic frost, which is a fine residue thought to consist of excreted urea left on the skin after evaporation of water. The skin may have a velvety appearance and feel, particularly in patients who are pigmented. Patients who are uremic also may have a sallow coloration of the skin due to urochrome, the pigment that gives urine its color. Patients may become hyperpigmented as uremia worsens (melanosis).
• Head, ears, eyes, nose, and throat: Sclera may become slightly icteric. The oral pharynx may be dry. Stomatitis may be present. Calcium deposition in the sclera can cause "red eye."
• Cardiovascular system: Uremic pericarditis can be associated with a pericardial rub or a pericardial effusion. Increased fluid retention may result in pulmonary edema, peripheral edema, and severe hypertension. Valvular calcification may cause aortic stenosis or accelerate underlying disease.
• Lungs: Fluid retention may result in pulmonary edema and corresponding crackles in the lungs. Pleural rubs occur in the setting of uremic lungs.
• Gastrointestinal system: Occult GI bleeding may occur. Nausea and vomiting are common in those with severe uremia. Uremic fetor (ammonia or urinelike odor to the breath) also may be present.
• Extremities: Fluid retention, pruritus associated with calcium phosphate deposition, and nail atrophy are common in persons with uremia.
• Neurologic system: Uremic encephalopathy symptoms include fatigue, muscle weakness, malaise, headache, restless legs, asterixis, polyneuritis, mental status changes, muscle cramps, seizures, stupor, and coma. Amyloid deposits may result in medial nerve neuropathy, carpal tunnel syndrome, or other nerve entrapment syndromes.

Causes

The etiologies of CKD range from primary glomerular and tubular disorders (eg, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, polycystic kidney disease) to systemic disorders causing renal injury (eg, diabetes, lupus, amyloidosis, Goodpasture disease, multiple myeloma, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome).

• ARF may be caused by multiple etiologies but is associated with uremia when a rapid rise in urea or creatinine occurs.
• Diabetes is the primary cause of ESRD in the United States and accounts for 40% of new dialysis patients, followed by hypertension (25.2%), glomerulonephritis (11.3%), interstitial disease (3.8%), cystitis (2.8%), and neoplasms (1.7%).
• Diabetes is the primary cause of renal disease in most other countries; however, other glomerulonephropathies, particularly IgA nephropathy, may be the primary cause of ESRD, depending upon the country.

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