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,[2] 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. In a study of 832 hospitalized patients with diabetes, Almoznino-Sarafian et al determined that 334 of the patients had anemia, a rate (40%) higher than that reported in ambulatory patient populations. The investigators found that the anemic patients tended to be older (mean age 71.4 years) than were the nonanemic patients with diabetes (mean age 64.4 years) and that a greater percentage were female (52.4% vs 44.4% of the nonanemic patients). In addition, 39% of the anemic patients had renal dysfunction.[3] 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.

Coagulopathy
Bleeding diatheses are characteristic findings in patients with end-stage renal disease (ESRD). The pathogenesis of uremic bleeding tendency is related to multiple dysfunctions of the platelets. The platelet numbers may be reduced slightly, while platelet turnover is increased. The reduced adhesion of platelets to the vascular subendothelial wall is due to reduction of GPIb and altered conformational changes of GPIIb/IIIa receptors. Alterations of platelet adhesion and aggregation are caused by uremic toxins, increased platelet production of NO, PGI(2), calcium and cAMP as well as renal anemia. Correction of uremic bleeding is caused by treatment of renal anemia with recombinant human erythropoietin or darbepoetin alpha, adequate dialysis, desmopressin, cryoprecipitate, tranexamic acid, or conjugated estrogens.

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.[4] In addition, these new vitamin D analogs cause less elevation in serum calcium and phosphorus levels.[5] 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.[6]

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 depositionassociated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CRF.[7] 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.[8] 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.

Epidemiology
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 years 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.

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[9] ).

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.

Laboratory Studies

The diagnosis of renal failure is primarily based on an abnormal GFR or creatinine clearance, usually evident due to an elevated serum creatinine level. GFR determination can be accomplished by 24-hour urine collection for creatinine clearance, although this is often cumbersome and inaccurate due to improper collection. All patients with an abnormal creatinine clearance should have their GFR estimated using one of several formulas that use easily obtained values. These include the Modification of Diet in Renal Disease (MDRD) formula or the Cockcroft-Gault formula. Both formulas have been shown to provide similar values within a wide range of patient ages and to be accurate in those with renal insufficiency, regardless of race or sex. It is very important to determine if the renal failure is acute or chronic, as acute renal failure will likely be reversible if treated properly. Review of the patient's history as well as previous laboratory values can be very helpful in this regard. Other laboratory tests to consider for abnormalities prevalent with clinical uremia include hemoglobin, calcium, phosphate, PTH, albumin, potassium, and serum bicarbonate values. Urinalysis with microscopic examination should be performed on all patients to evaluate for the presence of protein, cellular casts, oval fat bodies, ketones, hemoglobin, myoglobin, and pH.

Imaging Studies

A renal ultrasound study is indicated to estimate the size of the kidneys and to evaluate for hydronephrosis or obstruction. o Hydronephrosis can occur with ureteral or bladder obstruction, retroperitoneal fibrosis, massive abdominal tumors due to cervical or prostate cancers, and other structural abnormalities. o Renal ultrasound is performed to determine the size and shape of the kidneys; large kidneys are associated with diseases, such as early diabetic nephropathy, multiple myeloma, polycystic kidney disease, or HIV associated glomerulonephritis, while small kidneys usually indicate chronic, irreversible damage from diseases, such as hypertensive nephrosclerosis, ischemic nephropathy, or any other long-standing kidney disease. o CT scan of the abdomen may be indicated to rule out retroperitoneal fibrosis, pelvic masses, lymphadenopathy, or lymphoma if bilateral hydronephrosis is found on ultrasound images and no obvious etiology is present (eg, stone, bladder mass, ureteral mass). MRI arteriograms can be used to assess the kidneys for renal artery stenosis, acute arterial thrombosis, or aortic dissection involving the aorta and renal arteries. It is important to consider renal artery stenosis in the differential because it is one cause of

renal failure that is potentially reversible by angioplasty or bypass surgery of the affected renal artery. Consider a brain CT scan in the event of a significant change in mental status, especially if the change occurs after a fall or in association with mild trauma. Spontaneous subdural hematomas occur in patients with uremia, particularly if the BUN level is greater than 150-200 mg/dL.

Other Tests

Nuclear medicine radioisotope (iothalamate) clearances can also be obtained and are the criterion standard for measuring GFR. However, this test is time-consuming and more expensive than estimating GFR using either the MDRD formula or the Cockcroft-Gault formula.

Procedures

To make an accurate diagnosis of ARF or CRF, a renal biopsy is necessary. However, if the renal failure has been slowly progressive and the kidneys are small, renal biopsy results are of little benefit. In the setting of rapidly progressive renal failure or ARF for which the etiology is not known, a renal biopsy is indicated to determine if potentially reversible or treatable renal disorders are present.

Histologic Findings
Histologic findings vary depending on the underlying etiology. However, in the setting of late stage CKD and uremia in which renal function has deteriorated over a prolonged period and the kidneys are relatively small, renal biopsy results may show significant glomerulosclerosis and obsolescent glomeruli (completely scarred and sclerosed) with significant interstitial fibrosis. These findings are nonspecific and do not aid in determining the underlying cause of renal failure. In the setting of uremia, performing a renal biopsy in a patient with small kidneys may be dangerous because of comorbid disease and the increased risk of bleeding. Consider this procedure if a reversible cause of renal function is in the differential.

Staging
Staging is determined by the GFR (creatinine clearance). Currently, the National Kidney Foundation no longer recognizes the terms chronic renal insufficiency (CRI) or CRF, but rather it recognizes the 5 stages of CKD based on the estimated GFR (eGFR), as calculated by the MDRD formula.

Stage 1 - Kidney damage with normal GFR, 90 mL/min or greater Stage 2 - Kidney damage with a mild decrease in GFR, 60-89 mL/min Stage 3 - Kidney damage with a moderate decrease in GFR, 30-59 mL/min Stage 4 - Kidney damage with a severe decrease in GFR, 15-29 mL/min

Stage 5 - End-stage renal disease, less than 15 mL/min or on dialysis

Medical Care
The ultimate treatment for uremia is dialysis. Initiate dialysis when signs or symptoms of uremia (eg, nausea, vomiting, volume overload, hyperkalemia, severe acidosis) are present and are not treatable by other medical means. Patients with uremia must have dialysis initiated as soon as symptoms are present, regardless of GFR. For asymptomatic patients, dialysis is generally initiated when their creatinine clearance is 10 mL/min (creatinine level of 8-10 mg/dL) or less or, for diabetic patients, when their creatinine clearance is 15 mL/min (creatinine level of 6 mg/dL). Early referral to a nephrologist for evaluation (when creatinine level is > 3 mg/dL) is essential for patient education and preparation for dialysis or transplantation. Patients may decide on peritoneal dialysis or hemodialysis, a decision dependent on their preference and level of motivation. Peritoneal dialysis is preferred for patients who are highly motivated, need flexibility in their dialysis schedule, and who may have underlying cardiovascular disease.[10] Hemodialysis requires a functioning arterial venous dialysis access and may be accomplished at home or in a center.[11] Regardless of whether a patient chooses peritoneal dialysis or hemodialysis, dialysis access must be discussed and placed early. Newer methods of dialysis include daily hemodialysis and nocturnal hemodialysis, the advantages of which include improved volume control, improved cardiovascular disease, improved calciumphosphate balance, improved dietary parameters, and improved quality of life. Renal transplantation is the best renal replacement therapy and results in improved survival and quality of life. Transplants from living, related donors are best, but transplants from living, unrelated donors should also be considered. Consider transplantation prior to the need for dialysis because the waiting list for cadaver transplants often exceeds 2-3 years.

Hyperkalemia: Patients with renal failure associated hyperkalemia of 6.5 mEq/L or greater are candidates for emergent dialysis therapy, particularly if the hyperkalemia is associated with ECG changes (eg, peaked T waves, atrioventricular block, bradycardia). Short-term temporizing measures include intravenous infusion of calcium gluconate to stabilize cardiac membranes, bicarbonate, insulin and glucose administration, or inhaled or intravenous beta-agonists. Nonemergent hyperkalemia can be treated with oral potassium binders (eg, sodium polystyrene sulfonate [Kayexalate]). Correction of acidemia may improve potassium balance. Also, it is imperative to discontinue any medicine that might be contributing to the hyperkalemia, including ACE inhibitors, angiotensin-receptor blockers, beta-blockers, potassium-sparing diuretics, and nonsteroidal anti-inflammatory drugs. Anemia: Begin the workup for anemia when the hemoglobin level is less than 11 g/dL or the hematocrit value is less than 33% in premenopausal females and prepubertal patients or when the hemoglobin level is less than 12 g/dL or the hematocrit value is less than 37% in men and postmenopausal women. In patients found to have anemia of chronic kidney disease, it is important to check iron studies and to begin the initial treatment with iron replacement if there is evidence of iron deficiency. The serum ferritin level should be greater than 100 mcg/mL.

For patients with ESRD and CKD, the goal hemoglobin level should be 11-13 g/dL. There is insufficient evidence to recommend routinely maintaining hemoglobin levels at 13 g/dL or greater in ESA-treated patients, especially because several trials have demonstrated a potential for increased cardiac events in subjects treated to higher hemoglobin levels.[12, 13] o If the anemia is not corrected, then begin treatment with 1 of 2 subcutaneous erythropoiesis stimulating agents, recombinant human erythropoietin (Epo) or darbepoetin, a unique molecule that stimulates erythropoiesis and has a longer half-life than erythropoietin. o Initiate iron therapy concurrently with dialysis therapy. Start with one of several intravenous iron preparations as these better absorbed than oral formulations. These can be administered with each dialysis treatment to load the patient with iron or once weekly to maintain iron stores. o For patients not yet on dialysis, oral iron preparations are used initially. For significant iron deficiency, intravenous iron (InFeD Injection) may be administered slowly (500 mg over 4-6 h) after the administration of a test dose (25 mg). Hyperparathyroidism, hypocalcemia, hyperphosphatemia, and renal osteodystrophy: Evaluate and treat secondary hyperparathyroidism, manifested by low calcium levels, high phosphate levels, and low levels of 1,25(OH)2 vitamin D-3, early because it is one of the first manifestations of renal osteodystrophy. Hypocalcemia can be treated with oral calcium carbonate or calcium acetate at a dose of 500 mg to 1 gram orally 3 times a day taken in between meals. If 1,25(OH)2 vitamin D-3 levels are depressed, calcium levels are decreased, and parathyroid levels are elevated (>300), consider initiating oral vitamin D therapy. The dosage of calcitriol is 0.25 mcg orally once daily or 3 times a week, depending on the levels of 1,25(OH)2 vitamin D-3 and PTH. When the creatinine clearance falls below 25-30 cc/min, the kidney begins to lose the ability to completely excrete excess amounts of phosphorus. Thus, it is not uncommon for many patients with CKD and ESRD to become hyperphosphatemic. Initial treatment is dietary counseling and modification. If this fails, treatment then consists of administration of oral phosphate binders given with meals. These can include calciumbased formulations, such as calcium carbonate or calcium acetate, or noncalcium-based formulations, such as sevelamer or lanthanum carbonate. Acidemia: Acidemia should be treated in patients with a serum bicarbonate level consistently less than 20 mEq/dL. Oral bicarbonate solution or tablets can be used, and most patients will require 0.5-1 mEq/kg of body weight of bicarbonate. Use this therapy cautiously in persons with significant fluid retention and hypertension because of the risk of worsening the fluid retention.

Surgical Care
Surgical referral is necessary for dialysis access placement after the decision regarding dialysis has been made. Renal replacement therapy can be accomplished by hemodialysis, peritoneal dialysis, or transplantation. Referral to an appropriate surgeon (ie, vascular, general, transplant) is made after the modality for renal replacement therapy has been determined.

In general, referral to a vascular surgeon for consideration of dialysis access is initiated by the nephrologist early in the patient's course of renal failure to avoid emergent dialysis access placement. Dialysis access can be conducted through either an arteriovenous fistula for hemodialysis or a peritoneal dialysis catheter for chronic ambulatory peritoneal dialysis or continuous cycling peritoneal dialysis.

Arteriovenous fistulas are the dialysis access of choice for hemodialysis. o Avoid arteriovenous Gore-Tex grafts if at all possible because of their poor longevity. Avoid long-term use of tunneled catheters because of the increased risk of infection and poor dialysis adequacy. Avoid subclavian catheters because of their association with increased venous stenosis, thrombosis, or both. o Peritoneal dialysis access can be accomplished by the placement of a Tenckhoff peritoneal dialysis catheter by either an experienced nephrologist or a surgeon. Direct visualization of the peritoneum is associated with fewer complications and better function of the catheter. Peritoneal dialysis allows patients more control and flexibility with their dialysis treatment regimen. Consider any surgery carefully in patients with uremia because of the increased risk for uremic bleeding, cardiovascular events, ARF, respiratory depression, and decreased metabolism of certain drugs. Vasopressin may be considered if uremic bleeding is substantial.

Consultations
Consider consulting a nephrologist as soon as possible in the course of the patient's disease, particularly when renal function test results are only mildly abnormal. Acute hyperkalemia, volume overload, severe acidemia, or a change in mental status, which can progress to stupor or coma, requires emergent consultation with a nephrologist and, possibly, the initiation of dialysis.

Diet
Dietary changes should be made only with the help of a dietitian knowledgeable in renal diet treatment, particularly in patients who have not yet started dialysis therapy.

A low-protein diet has been advocated for persons with mild-to-moderate renal failure, although this matter remains controversial. Low-protein diets may alleviate some of the symptoms of uremia, such as nausea; however, data regarding the renoprotective effect of low-protein diets are conflicting. The MDRD study analyzed 585 patients with nondiabetic chronic renal disease and a mean GFR of 39 mL/min. Patients were randomized to protein intakes of either 1.1 g/kg/d or 0.7 g/kg/d. Despite good compliance, there appeared to be little overall benefit with the low-protein diet. Also, low-protein diets can cause the patient to become malnourished, which has been associated with higher mortality upon the initiation of dialysis. On the other hand, in an analysis of studies comparing the consumption of different protein levels by nondiabetic adults with moderate to severe kidney failure, Fouque and Laville concluded that a low-protein diet can lower rate of "renal death" (which they

defined as kidney transplantation, the need to begin dialysis, or the death of a patient) by 32%.[14] Incorporating results from 2000 patients, including 1002 who had consumed a reduced-protein diet, the authors found that 113 renal deaths had occurred in the lowprotein group and 168 in the higher-protein group. However, the authors stated that they were unable to confirm through their analysis an optimal protein intake level for persons with renal failure. Current recommendations for a low-protein diet prior to the initiation of dialysis are 0.8-1 gram of protein/kg of weight, with an additional gram of protein added for each gram of protein lost in the urine (for patients with nephrotic syndrome). Patients with advanced uremia or malnutrition are not candidates for a low-protein diet. Patients with CRF should be on a low-potassium (2-3 g/d), low-phosphate (2 g/d), and low-sodium (2 g/d) diet.

Activity
Activity for patients with uremia is self-restricted based on their level of fatigue.

Early treatment of anemia with iron and EPO improves the quality of life and energy levels even before the patient needs dialysis. Bleeding secondary to uremia may occur; dangerous activities may need to be restricted and potential bleeding sites assessed in the event of a fall (eg, for a subdural hematoma).

Medication Summary
Usually, medications used for uremia are indicated to treat associated metabolic and electrolyte abnormalities, such as anemia, hyperkalemia, hypocalcemia, hyperparathyroidism, and iron deficiency. Medication selection and dosage depend on the patient's clinical state, which may change with the acute clinical setting. Dialysis is the primary treatment for uremia, but medications can effectively treat some of the associated symptoms and clinical abnormalities (eg, anemia, hypocalcemia).

Colony-stimulating factors
Class Summary
Increase reticulocyte count, hematocrit value, and hemoglobin levels. View full drug information

Epoetin alfa (Epogen, Procrit)

Purified glycoprotein produced from mammalian cells modified with gene coding for human EPO. Biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces release of reticulocytes from bone marrow into the blood stream. Indicated for treatment of anemia associated with CRF or renal insufficiency.

Calcium supplements
Class Summary
Used to correct hypocalcemia and improve symptoms associated with renal osteodystrophy. Also may be used to bind phosphate in patients with hyperphosphatemia. View full drug information

Calcium carbonate (Caltrate, Os-Cal 500, Alka-Mints, Tums)

Indicated for treatment of hyperphosphatemia secondary to CRF. Effectively normalizes phosphate concentrations in dialysis patients. Combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. Marketed in a variety of dosage forms and is relatively inexpensive. View full drug information

Calcium acetate (PhosLo, Calphron)

Indicated for treatment of hyperphosphatemia secondary to CRF. Effectively normalizes phosphate concentrations in dialysis patients. Combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces.

Vitamins
Class Summary
Essential for normal metabolism of proteins, carbohydrates, and fats and normal DNA synthesis. Used in the treatment of hyperparathyroidism, vitamin D deficiency, and renal osteodystrophy. View full drug information

Paricalcitol (Zemplar)
For treatment of secondary hyperparathyroidism in ESRD. Reduces PTH levels, stimulates calcium and phosphorous absorption, and stimulates bone mineralization. View full drug information

Calcitriol (Rocaltrol)
Two known sites of action are intestine and bone. Other evidence indicates that it also acts on kidneys and parathyroid gland. Vitamin D-3 must be converted to calcitriol in liver and kidneys before it is fully active on its target tissues. Some evidence suggests that uremic patients have vitamin Dresistant state because of a failure of their kidney to metabolically activate vitamin D-3 to calcitriol, which increases calcium levels by promoting absorption of calcium in intestines and retention in kidneys.

Iron salts
Class Summary
Used to correct iron deficiency symptoms. View full drug information

Ferrous sulfate (Feosol)

A nutritionally essential inorganic substance necessary for hemoglobin formation and oxidative processes of living tissue. Effectively treats iron deficiency anemia.

Antidotes
Class Summary
Used to reduce serum potassium levels. View full drug information

Sodium polystyrene sulfonate (Kayexalate)

Exchanges sodium for potassium, binds it in the gut (primarily in the large intestine), and decreases total body potassium. PO onset of action ranges from 2-12 h and is longer when PR.

Antidiabetic agents
Class Summary
Stimulate cellular uptake of potassium. View full drug information

Insulin (Humulin R, Novolin R)

Stimulates cellular uptake of potassium within 20-30 min. Administer glucose along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.

Phosphate binders
Class Summary
Used to bind phosphate when calcium carbonate or acetate cannot be used because of a high serum calcium level. View full drug information

Sevelamer (Renagel)
Cationic polymer that binds intestinal phosphate, which is excreted in the feces. Not absorbed and does not contain calcium or aluminum ions. Binding of bile salts may also occur, which may result in lowered low-density lipoprotein cholesterol levels. View full drug information

Lanthanum carbonate (Fosrenol)

Noncalcium, nonaluminum phosphate binder indicated for reduction of high phosphorus levels in patients with end-stage renal disease. Directly binds dietary phosphorus in upper GI tract, thereby inhibiting phosphorus absorption.

Further Inpatient Care

Inpatient care is required when patients have a uremic emergency, such as hyperkalemia, hypervolemia, acidosis, pericardial effusion with symptoms, and uremic encephalopathy; these patients require emergent dialysis. Initiate dialysis gently (2-h initial session) to avoid dialysis disequilibrium syndrome, but dialysis should be long enough to remove potassium if dialysis is being initiated for this reason. Therapy should be initiated with the care and oversight of a nephrologist and may need to occur in the intensive care unit if the patient is unstable or has cardiac abnormalities secondary to acidemia or hyperkalemia.

Further Outpatient Care

Continue outpatient care under the direction of the consulting nephrologist. Outpatient care may include initiation of chronic renal replacement therapy such as peritoneal dialysis or hemodialysis. Patients with renal failure and uremia should also be considered for transplantation using a living, related donor; a living, nonrelated donor; or a cadaveric donor.

Inpatient & Outpatient Medications

Inpatient medications include medications necessary for emergent treatment of underlying disorders associated with uremia (emergent treatment of hyperkalemia, acidosis, and hypocalcemia). Outpatient medications include EPO for anemia, iron, phosphate binders, calcitriol for PTH suppression and hypocalcemia, water-soluble vitamins (eg, folate, vitamin C), and, potentially, oral bicarbonate solution or tablets for acidosis.

Transfer

Consider transferring patients to centers with dialysis capabilities if a nephrologist and/or dialysis facilities are not available to assist with management and potential interventions if necessary.

Deterrence/Prevention

Avoid nephrotoxic medications such as nonsteroidal anti-inflammatory drugs, renal toxic aminoglycoside antibiotics, and other potential renal toxins. N -acetyl-cystine can be administered before and after radiologic imaging that requires intravenous contrast (eg, CT scan, renal angiogram, intravenous pyelogram) to avoid nephrotoxicity. However, consider an alternative method of imaging (eg, ultrasound, MRI) in this setting to avoid ARF, particularly in patients with diabetes.

Complications

Severe complications of untreated uremia include seizure, coma, cardiac arrest, and death. Spontaneous bleeding can occur with severe uremia and may include GI bleeding, spontaneous subdural hematomas, increased bleeding from any underlying disorder, or bleeding associated with trauma. Cardiac arrest may occur from severe underlying electrolyte abnormalities such as hyperkalemia, metabolic acidosis, or hypocalcemia. Severe hypoglycemic reactions may occur in diabetic patients if hyperglycemic medications are not adjusted for their decreased creatinine clearance. Renal failure associated bone disease (renal osteodystrophy) may lead to an increased risk of osteoporosis or bone fracture with trauma.

Medication clearance is decreased in persons with renal failure and may lead to untoward adverse effects, such as a digoxin overdose, an increased sensitivity to narcotics, and a decreased excretion of normal medications.

Prognosis

The prognosis for patients with uremia of CRF is poor unless the uremia is treated with renal replacement therapy such as dialysis or transplantation. The prognosis for ARF and renal failure secondary to a reversible or treatable cause, such as rapidly progressive glomerulonephritis (eg, lupus nephritis, Wegener disease, Goodpasture disease, thrombotic thrombocytopenic purpura, hemolytic uremia syndrome, multiple myeloma), depends on the timing of diagnosis and the rapidity of appropriate treatment (eg, steroids, chemotherapeutic agents, plasmapheresis).

Patient Education

Patients should be sent to the nephrologist early for education regarding renal disease and renal replacement therapy options and for evaluation and diagnosis of their underlying renal disease process. Inform diabetic patients about potential changes in insulin or oral hypoglycemic medication needs. Inform patients and their families regarding dialysis to avoid the shock of emergent dialysis and the decreased quality of life that occurs with this disease.