Uremia is a clinical syndrome marked by elevated concentrations of urea in the blood and associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function.[1] The term uremia, which literally means urine in the blood, was first used by Piorry to describe the clinical condition associated with renal failure.[2, 3] (See Pathophysiology.)
Uremia more commonly develops with chronic kidney disease (CKD), especially the later stages of CKD, but it also may occur with acute kidney injury (AKI) if loss of renal function is rapid. Urea itself has both direct and indirect toxic effects on a range of tissues.[4] A number of substances with toxic effects, such as parathyroid hormone (PTH), beta2 microglobulin, polyamines, advanced glycosylation end products, and other middle molecules, are thought to contribute to the clinical syndrome.[5] (See Pathophysiology and Workup.)
In patients with uremia, the diagnosis of renal failure is based primarily on an abnormal glomerular filtration rate (GFR) or abnormal creatinine clearance. Clinically, uremia is heralded by the onset of the following signs and symptoms:
Physical findings in patients with uremia may include the following:
Complications
Severe complications of untreated uremia include seizure, coma, cardiac arrest, and death. Spontaneous bleeding can occur with severe uremia and may include gastrointestinal (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 patients with diabetes if hyperglycemic medications are not adjusted for decreased creatinine clearance in these individuals.
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.
See Pathophysiology, Prognosis, Presentation, and Workup.
The ultimate treatment for uremia is renal replacement therapy, which can be accomplished by hemodialysis, peritoneal dialysis, or kidney transplantation. Initiation of dialysis is indicated, regardless of the GFR level, when signs or symptoms of uremia are present and are not treatable by other medical means. Despite dialysis, an array of signs and symptoms that have been labeled residual syndrome may develop; this is thought to result from the accumulation of toxic solutes not removed by dialysis. Kidney transplantation is the best renal replacement therapy and results in improved survival and quality of life. See Treatment and Medication.
Patients should be seen by a nephrologist early for education regarding renal disease and renal replacement therapy options and for evaluation and diagnosis of their underlying renal disease process. (See Treatment.)
Inform patients with diabetes about potential changes in insulin or oral hypoglycemic medication needs.
Educate patients and their families about dialysis to avoid the shock of emergent dialysis and the decreased quality of life that can occur with uremia.
For patient education information, see What Are Uremia and Uremic Syndrome? and Chronic Kidney Disease.
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.[6]
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 develops acutely. The syndrome may be heralded by the clinical onset of the following symptoms:
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 level is greater than 2 mg/dL. Patients with diabetes 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.[8]
Anemia associated with chronic kidney disease is characteristically normocytic, normochromic, and hypoproliferative.
Anemia in chronic renal failure
In the setting of CKD, 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.
Studies have shown that hepcidin, an acute phase protein involved with iron metabolism, plays a key role in erythropoiesis.[9] Hepcidin, up-regulated in states of inflammation, prevents iron absorption in the small intestine, as well as iron release from macrophages.[10]
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 accomplished through treatment of renal anemia with recombinant human erythropoietin or darbepoetin alpha, adequate dialysis, desmopressin, cryoprecipitate, tranexamic acid, or conjugated estrogens.
Patients with ESRD are at significantly increased risk for bleeding if placed on oral anticoagulants or antiplatelet agents. Thus, these classes of medicines need to be prescribed with extreme caution.
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.
In patients with CKD who are not yet on dialysis, treatment of the acidosis with oral bicarbonate supplementation has been demonstrated to help slow the progression of the renal disease.
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. (Most cases of hyperkalemia are multifactorial in etiology.)
Hyperkalemia can occur in several instances, including the following:
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.
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.[11]
Treatment
The vitamin D deficiency can be treated orally or intravenously with 1,25(OH)2 vitamin D-3 (calcitriol). There are several new vitamin D analogues that have become available for use and are more specific for vitamin D receptors in the parathyroid gland. Use of one of these analogues, paricalcitol, has been found to be associated with improved survival compared with use of calcitriol.[12] In addition, these new vitamin D analogs cause less elevation in serum calcium and phosphorus levels.[13]
Cinacalcet, a new medication that stimulates the calcium sensing receptor in the parathyroid gland and causes negative feedback on PTH production and release, can also be used to treat secondary hyperparathyroidism. Several studies have shown the following benefits of cinacalcet usage: (1) greater associated likelihood of achieving an intact PTH level of less than 300 pg/mL and (2) greater likelihood of maintaining calcium and phosphorus levels within the target range.[14] Cinacalcet usage has also been shown to lower the risk of fracture and of cardiovascular hospitalization.[15] It is as yet unknown if cinacalcet improves patient mortality rates.
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 antihyperglycemic 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, including uremic pericarditis,[16] pericardial effusions, calcium and phosphate deposition–associated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CKD.[17, 18]
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.
The function of high-density lipoprotein (HDL) cholesterol is impaired in patients with uremia. This impairment, which involves increased electronegativity and compositional changes, is associated with increased risk of coronary artery disease.[19]
Renal dysfunction may contribute to associated fluid retention, which may lead to uncontrolled hypertension and congestive heart failure.
Malnutrition usually occurs as renal failure progresses; it is manifested by the following symptoms:
However, the question of whether uremia stimulates protein catabolism directly remains controversial.[20]
Comorbid diseases, such as diabetes and congestive heart failure, 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.
The etiologies of CKD range from primary renal disorders to systemic disorders causing renal injury. Primary glomerular and tubular disorders that may result in CKD include the following:
Systemic disorders associated with CKD include the following
AKI may be caused by multiple etiologies, but it 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. Other causes include the following:
Although diabetes is the primary cause of renal disease in most other countries, other glomerulonephropathies, particularly IgA nephropathy, may be the primary cause of ESRD, depending on the country.
In a whole-genome microarray case-control study of 75 patients with ESRD and 20 healthy controls, more than 9,000 genes were differentially expressed in uremic patients compared with controls (fold change: -5.3 to +6.8), and more than 65% were lower in patients with uremia. These changes appeared to be regulated through key networks involving cMYC, SP1, P53, AP1, NFkB, HNF4 alpha, HIF1A, c-Jun, STAT1, STAT3 and CREB1.
In patients with uremia, protein transport, mRNA processing and transport, chaperone functions, the unfolded protein response, and genes involved in tumor genesis were prominently lower, while neuroactive receptor interaction, insulin-like growth factor activity, the complement system, lipoprotein metabolism, and lipid transport were higher. Down-regulation of pathways involving cytoskeletal remodeling, the clathrin-coated endosomal pathway, T-cell receptor signaling, and CD28 pathways were observed, along with up-regulation of the ubiquitin pathway.[21]
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, these symptoms arise is when creatinine clearance is less than 10 mL/min; in patients with diabetes, such symptoms appear with clearance rates of less than 15 mL/min.
Data from the US End-Stage Renal Disease (USRDS) Program showed that during 2007, the incidence rate for ESRD maintained relatively stable at 354 cases per million, with a total dialysis prevalent population of greater than 368,000 (>90% on hemodialysis).
While prevalence rates continue to increase because patients with ESRD are living longer, they have fallen for most people younger than 60 years, except for younger African Americans and Native Americans with diabetic ESRD. It has been estimated that by 2020, more than 750,000 Americans will have ESRD.
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).
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%) make up the rest. However, the incidence rate of ESRD among African Americans and Native Americans is 3.7-fold and 1.8-fold higher, respectively, than it is 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, among patients with equivalent GFRs, having a certain racial or ethnic background predisposes individuals to develop symptoms of uremia more so than other patients remains unknown.
ESRD is slightly more prevalent in men than in women (male-to-female ratio, 1.2:1). However, women are 1.7-fold more likely to have delayed initiation of dialysis than are men. In addition, due to lower muscle mass and baseline serum creatinine levels, women are more likely to develop uremic symptoms at a lower creatinine level.
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 are patients who were younger than 40 years at the initiation of dialysis.
The prognosis for patients with uremia of ESRD is poor unless the uremia is treated with renal replacement therapy, such as dialysis or transplantation.
The prognosis for AKI and renal failure secondary to a reversible or treatable cause, such as rapidly progressive glomerulonephritis (eg, lupus nephritis, granulomatosis with polyangiitis, anti–glomerular basement membrane disease, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome,[22] multiple myeloma), depends on the timing of diagnosis and the rapidity of appropriate treatment (eg, steroids, chemotherapeutic agents, plasmapheresis).
CKD 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 for the general public and not much different from dialysis patients.
Although still unacceptably high, the mortality rate for ESRD patients has been improving, especially since 1999. Indeed, the 5-year survival for patients who initiated dialysis sometime between 1998 and 2002 (34%) was found to be 10% higher than for those who initiated dialysis sometime between 1993 and 1997 (31%).
The risk for developing cardiovascular disease is 5- to 10-fold higher in patients with CKD and ESRD than in age-matched controls.[23] In patients with ESRD, cardiovascular disease is the primary cause of death, followed by sepsis and cerebrovascular disease. The dialysis population in the United States has a 10- to 20-fold higher risk of death due to cardiovascular complications than does 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 a 1.8-fold higher risk of starting dialysis with a hematocrit value lower than 28% than do patients 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 are those without a delayed onset of dialysis. Thus, the timing of the initiation of dialysis remains controversial.
Uremia can occur once the creatinine clearance is below 10-20 mL/min. Clinically, it is heralded by the onset of the following signs and symptoms:
Patients may report nonspecific symptoms, which become chronic and progressive over time because of the gradual onset of the disease. Making the diagnosis of uremia may be difficult in young children because of the nonspecificity of clinical symptoms.
Metabolic abnormalities such as anemia, acidemia, and electrolyte abnormalities are prominent.
Patients with diabetes 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 results from increased insulin secretion and insulin half-life, both of which occur as renal function declines.
Cardiovascular abnormalities such as hypertension, atherosclerosis, valvular stenosis and insufficiency, chronic heart failure, and angina accelerate as renal function declines. These abnormalities may contribute to clinical manifestations of uremia if not treated appropriately.
Occult GI bleeding may occur. Nausea and vomiting are common in patients with severe uremia. Uremic fetor (ammonia or urinelike odor to the breath) also may be present.
Clinical manifestations of uremic encephalopathy 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.
Fluid retention, pruritus associated with calcium phosphate deposition, and nail atrophy are common in persons with uremia.
Typical physical findings 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.
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).
The sclera may become slightly icteric. Calcium deposition in the sclera can cause "red eye." In patients with chronic uremia, a broad range of oral lesions may be present, such as gingival hyperplasia, enamel hypoplasia, petechiae, or gingival bleeding.[24]
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.
Fluid retention may result in pulmonary edema and corresponding crackles in the lungs. Pleural rubs occur in the setting of uremic lungs.
The diagnosis of renal failure is based primarily on an abnormal glomerular filtration rate (GFR) or abnormal creatinine clearance, which is usually evident due to an elevated serum creatinine level. Although assessment of nuclear medicine radioisotope (iothalamate) clearance is the criterion standard for measuring GFR, this test is time consuming and expensive. GFR determination can be accomplished by 24-hour urine collection for creatinine clearance, but this is often cumbersome and inaccurate due to improper collection. In practice, the estimated glomerular filtration rate (eGFR) is most often used.
It is very important to determine whether the kidney failure is acute or chronic, as acute kidney injury likely is reversible if treated properly. Review of the patient's history and of previous laboratory values can be very helpful in this regard.
Other blood studies to consider for abnormalities prevalent with clinical uremia include the following:
Urinalysis with microscopic examination should be performed on all patients to evaluate for the presence of protein, cellular casts, oval fat bodies, ketones, hemoglobin, and myoglobin, and to assess pH.
In premenopausal females and prepubertal patients, begin the workup for anemia when the hemoglobin level is less than 11 g/dL or the hematocrit value is less than 33%. In men and postmenopausal women, begin the workup when the hemoglobin is less than 12 g/dL or the hematocrit is less than 37%.
All patients with an abnormal creatinine clearance should have their GFR estimated. Several eGFR formulas that employ easily obtainable values have been developed (eg, Modification of Diet in Renal Disease (MDRD) formula, Cockcroft-Gault formula). The National Kidney Foundation (NKF) recommends using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate GFR.[25]
Staging is determined by the GFR (creatinine clearance). Currently, the National Kidney Foundation no longer recognizes the terms chronic renal insufficiency (CRI) or chronic kidney disease (CKD), but rather it recognizes the 5 stages of CKD based on the estimated GFR (eGFR), as calculated by the MDRD formula. These stages are as follows:
A renal ultrasonographic study is indicated to evaluate for hydronephrosis or obstruction. Hydronephrosis can occur with ureteral or bladder obstruction, retroperitoneal fibrosis, massive abdominal tumors due to cervical or prostate cancers, or other structural abnormalities.
Renal ultrasonography is also 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, and human immunodeficiency virus (HIV)–associated glomerulonephritis. Small kidneys usually indicate chronic, irreversible damage from diseases such as hypertensive nephrosclerosis, ischemic nephropathy, or any other long-standing kidney disease.
Consider a brain computed tomography (CT) scan in the event of a significant change in the patient’s 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 blood urea nitrogen (BUN) level is greater than 150-200 mg/dL.
CT scanning of the abdomen may be indicated to rule out retroperitoneal fibrosis, pelvic masses, lymphadenopathy, or lymphoma if bilateral hydronephrosis is found on ultrasonographic images and no obvious etiology is present (eg, stone, bladder mass, ureteral mass).
Magnetic resonance imaging (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 diagnosis because it is one cause of renal failure that is potentially reversible by angioplasty or bypass surgery of the affected renal artery.
A renal biopsy is necessary to make an accurate diagnosis of acute kidney injury (AKI) or chronic kidney disease (CKD). 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 uremia, performing a renal biopsy in a patient with small kidneys may be dangerous because of comorbid disease and the increased risk of bleeding.
In the setting of rapidly progressive renal failure or AKI of unknown etiology, a renal biopsy is indicated to determine whether potentially reversible or treatable renal disorders are present.
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.
The ultimate treatment for uremia is renal replacement therapy, which can be accomplished by hemodialysis, peritoneal dialysis, or kidney transplantation. Initiation of dialysis is indicated 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 appear, regardless of the glomerular filtration rate (GFR).
Unfortunately, although dialysis effectively removes urea, it is less effective than the normal kidney at removing a number of toxic solutes, the accumulation of which is thought to lead to signs and symptoms that have been labeled residual syndrome.[26] For patients with uremic pruritus, Shirazian et al propose a multifaceted approach that includes the following[27] :
Treatment for refractory pruritus remains less clearly defined, according to these authors. Various approaches have been studied, including gabapentin and phototherapy.[28] Results with these have been mixed. Nalbuphine hydrochloride, a mu-opioid receptor antagonist and kappa-opioid receptor agonist approved as an analgesic, is used off-label for opioid-induced pruritus and may have an effect on uremic pruritus. Nalfurafine, a kappa opioid receptor agonist, has shown promising results in large, double-blind, randomized controlled clinical trials, but neither agent is currently available in the United States.[27]
Once the modality for renal replacement therapy has been determined (ie, hemodialysis, peritoneal dialysis, or kidney transplantation), referral to an appropriate surgeon (ie, vascular, general, transplant) is made.
Kidney transplantation is the best renal replacement therapy and results in improved survival and quality of life. Patients with renal failure and uremia should be considered for transplantation using a living, related donor; a living, nonrelated donor; or a cadaveric donor. Transplants from living, related donors are best. Consider transplantation prior to the need for dialysis because the waiting list for cadaver transplants often exceeds 2-3 years.
Consider any type of surgery carefully in patients with uremia because of the increased risk for uremic bleeding, cardiovascular events, acute kidney injury, respiratory depression, and decreased metabolism of certain drugs. Vasopressin may be considered if uremic bleeding is substantial.
Consider consultation with 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.
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.
Activity for patients with uremia is self-restricted based on their level of fatigue. Early treatment of anemia with iron and erythropoietin (EPO) can improve the patient’s quality of life and energy levels even before dialysis is required.
Bleeding secondary to uremia may occur Consequently, dangerous activities may need to be restricted and potential bleeding sites may need to be assessed in the event of a fall (eg, for a subdural hematoma).
Pregnant patients with uremia require specialized evaluation and treatment; in this situation, seek immediate consultation with a specialist. Pregnant women should be under the care of an obstetrician who specializes in the management of high-risk pregnancies. A nephrologist should also be consulted, to help with hypertension control and the potential need for dialysis during the pregnancy. Medications contraindicated in pregnancy, such as angiotensin-converting enzyme (ACE) inhibitors, should be immediately discontinued.
Pediatric patients also require special consideration. A pediatric nephrologist or an adult nephrologist experienced in the care of pediatric nephrology patients should be involved in the care of children with proteinuria, renal insufficiency, or uremia or of children in whom dialysis is indicated.
For asymptomatic patients, dialysis is generally initiated when the creatinine clearance rate falls to 10 mL/min (creatinine level of 8-10 mg/dL) or less or, for diabetic patients, when the rate is 15 mL/min (creatinine level of 6 mg/dL). Early referral to a nephrologist for evaluation (when the 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, depending on their preference and level of motivation. Peritoneal dialysis is preferred for patients who are highly motivated, need flexibility in their dialysis schedule, and may have underlying cardiovascular disease.[29] Hemodialysis requires a functioning arterial venous dialysis access and may be accomplished at home or in a center.[30]
Regardless of whether a patient chooses peritoneal dialysis or hemodialysis, the dialysis access must be discussed and placed early.
Newer methods of dialysis include daily hemodialysis and nocturnal hemodialysis, the advantages of which include improvements in volume control, cardiovascular disease, calcium-phosphate balance, dietary parameters, and quality of life.
Surgical referral is necessary for dialysis access placement after the decision regarding dialysis has been made. 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.
Hemodialysis access
Arteriovenous fistulas are the dialysis access of choice for hemodialysis. Avoid arteriovenous Gore-Tex grafts if at all possible because of their poor longevity. In addition, 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.
Peritoneal dialysis access
A peritoneal dialysis catheter can be used for access in chronic ambulatory or continuous cycling peritoneal dialysis.
Placement of a Tenckhoff peritoneal dialysis catheter is carried out 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 over and flexibility with their dialysis treatment regimen.
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 electrocardiographic 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 the potassium balance.
In addition, it is imperative to discontinue any medicine that might be contributing to the hyperkalemia, including the following:
In patients found to have anemia of CKD, 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.
Due to concern about the use of erythropoietic-stimulating agents (ESAs) and increased cardiovascular mortality, major changes have been made to the recommendation for their administration. One should attempt to use the lowest ESA dose possible to reduce the need for transfusion.
Although target hemoglobin levels remain under debate, it is now recommended that patients with CKD who are not on dialysis start ESA treatment only when the hemoglobin level is less than 10 g/dL and reduce the dose or stop the ESA if the hemoglobin level exceeds 10 g/dL.
For patients on dialysis, treatment with an ESA should be administered only when the hemoglobin level is less than 10g/dL, and the dose should be reduced or interrupted if the level approaches or exceeds 11 g/dL.[31]
If the anemia is not corrected, then begin treatment with either of two subcutaneous ESA agents: recombinant human EPO, or darbepoetin, a unique molecule that stimulates erythropoiesis and has a longer half-life than erythropoietin.
Initiate iron therapy concurrently with dialysis therapy. Start with one of several intravenous iron preparations, as these are 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.
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).
Early evaluation and treatment of secondary hyperparathyroidism—manifested by low calcium levels, high phosphate levels, and low levels of 1,25(OH)2 vitamin D-3—is necessary because it is one of the first manifestations of renal osteodystrophy.
There has been significant debate about goal parathyroid hormone (PTH) levels for patients with ESRD. While previous guidelines recommended a goal PTH of 150-300 pg/mL, at least one set of more recent guidelines recommends a goal PTH of 2-9 times the upper normal limit for the assay used to measure the PTH level (approximately 150-600 pg/mL).[32, 33]
Hypocalcemia can be treated with oral calcium carbonate or calcium acetate at a dose of 500 mg to 1 g orally 3 times daily, taken 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 weekly, depending on the levels of 1,25(OH)2 vitamin D-3 and PTH.
When the creatinine clearance falls below 25-30 mL/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, therapy consists of administration of oral phosphate binders given with meals. These can include calcium-based formulations, such as calcium carbonate or calcium acetate, or noncalcium-based formulations, such as sevelamer or lanthanum carbonate.
Acidemia should be treated in patients with a serum bicarbonate level that is consistently less than 20 mEq/dL. Oral bicarbonate solution or tablets can be used; 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.
Dietary changes should be made only with the help of a dietitian knowledgeable in renal dietary 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.[34] 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 Moodification of Diet in Renal Disease (MDRD) study, which analyzed 585 patients with nondiabetic chronic renal disease and a mean GFR of 39 mL/min, found that even with good compliance, there appeared to be little overall benefit from a low-protein diet. In the study, patients were randomized to protein intakes of either 1.1 g/kg/day or 0.7 g/kg/day.[35]
Another caveat is that low-protein diets can cause a patient to become malnourished; malnourishment 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 the rate of "renal death" by 32%.[34] (The authors defined renal death as kidney transplantation, the need to begin dialysis, or the death of a patient.)
Incorporating results from 2000 patients, including 1002 who had consumed a reduced-protein diet, Fouque and Laville found that 113 renal deaths had occurred in the low-protein 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.[34]
Current recommendations for a low-protein diet prior to the initiation of dialysis are 0.8-1 g 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 CKD should be on a diet low in potassium (2-3 g/day), phosphate (2 g/day), and sodium (2 g/day).
Inpatient care is required when patients have a uremic emergency, such as hyperkalemia, hypervolemia, acidosis, pericardial effusion with symptoms, or uremic encephalopathy; these patients require emergent dialysis.
Initiate dialysis gently (2-h initial session) to avoid dialysis disequilibrium syndrome, but dialysis should continue long enough to remove potassium if it 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.
Outpatient care should be administered under the direction of the consulting nephrologist. Outpatient care may include the initiation of chronic renal replacement therapy, such as peritoneal dialysis or hemodialysis.
Inpatient medications include those that are 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.
Avoid nephrotoxic medications such as NSAIDs, renal toxic aminoglycoside antibiotics, and other potential renal toxins.
N -acetyl-cysteine 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, ultrasonography, MRI) in this setting to avoid AKI, particularly in patients with diabetes.
Usually, medications employed in the management of uremia are indicated for associated metabolic and electrolyte abnormalities, such as anemia, hyperkalemia, hypocalcemia, hyperparathyroidism, and iron deficiency. Agents used include erythropoietin (EPO) for anemia, iron, phosphate binders, calcitriol for parathyroid hormone (PTH) suppression and hypocalcemia, water-soluble vitamins (eg, folate, vitamin C), and, potentially, oral bicarbonate solution or tablets for acidosis.
Medication selection and dosage depend on the patient's clinical state, which may change with the acute clinical setting.
Clinical Context: Epoetin alfa is a purified glycoprotein produced by mammalian cells that have been modified with gene coding for human EPO. The biologic activity of epoetin alfa mimics that of human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the bloodstream. This drug is indicated for the treatment of anemia associated with CKD or renal insufficiency.
Clinical Context: Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in kidney that stimulates the development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production.
Darbepoetin contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3 such chains. Darbepoetin has longer a half-life than epoetin alfa and may be administered weekly or biweekly.
These agents increase the reticulocyte count, hematocrit value, and hemoglobin levels.
Clinical Context: Calcium carbonate is indicated for the treatment of hyperphosphatemia secondary to CKD. It effectively normalizes phosphate concentrations in dialysis patients, combining with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. Calcium carbonate is marketed in a variety of dosage forms and is relatively inexpensive.
Clinical Context: Calcium acetate is indicated for the treatment of hyperphosphatemia secondary to CKD. It effectively normalizes phosphate concentrations in dialysis patients, combining with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces.
Clinical Context: Calcium gluconate is used for cardioprotection when potassium levels are greater than 6.5 mmol/L or for patients with electrocardiographic alterations. This agent moderates nerve and muscle performance and facilitates normal cardiac function.
Clinical Context: Administer IV calcium gluconate or calcium chloride to stabilize myocardial conduction in a patient with cardiac arrhythmias. Calcium also moderates nerve and muscle performance by regulating the action potential excitation threshold. IV calcium is indicated in all cases of severe hyperkalemia (ie, >6 mEq/L), especially when accompanied by electrocardiographic changes.
Calcium chloride contains about 3 times more elemental calcium than an equal volume of calcium gluconate. Therefore, when hyperkalemia is accompanied by hemodynamic compromise, calcium chloride is preferred over calcium gluconate.
Calcium supplements are used to correct hypocalcemia and improve symptoms associated with renal osteodystrophy. They also may be used to bind phosphate in patients with hyperphosphatemia.
Clinical Context: Paricalcitol is used for the treatment of secondary hyperparathyroidism in ESRD. It reduces PTH levels and stimulates calcium and phosphorous absorption, as well as bone mineralization.
Clinical Context: Two known sites of action for calcitriol are the intestine and bone. Other evidence indicates that it also acts on the kidneys and parathyroid gland.
Vitamin D-3 must be converted into calcitriol in the liver and kidneys before it is fully active on its target tissues. Some evidence suggests, however, that uremic patients have a vitamin D–resistant state, because of a failure of their kidney to metabolically activate vitamin D-3 to calcitriol; calcitriol (1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3), the hormonally active form of vitamin D, increases calcium levels by promoting the absorption of calcium in the intestines and its retention in kidneys.
Clinical Context: Doxercalciferol is a vitamin D analog (1-alpha-hydroxyergocalciferol) that does not require activation by the kidneys. It increases calcium levels by promoting the absorption of calcium in the intestines and its retention in kidneys.
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.
Clinical Context: Ferrous sulfate is a nutritionally essential, inorganic substance that is necessary for hemoglobin formation and the oxidative processes of living tissue. It effectively treats iron deficiency anemia.
Clinical Context: Iron dextran is used to treat microcytic, hypochromic anemia resulting from iron deficiency and to replenish iron stores in individuals on erythropoietin therapy, when oral administration is infeasible or ineffective. A 0.5-mL (0.25 mL in children) test dose should be administered prior to starting therapy. This agent is available as 50 mg iron/mL (as dextran).
Clinical Context: Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) in patients receiving long-term hemodialysis. Iron deficiency in these patients is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the GI tract. There is a lower incidence of anaphylaxis with iron sucrose than with other parenteral iron products.
Clinical Context: Ferric gluconate replaces the iron found in hemoglobin, myoglobin, and specific enzyme systems, allowing transportation of oxygen via hemoglobin.
Clinical Context: This agent is indicated for iron replacement in adults with chronic kidney disease who have iron deficiency anemia.
Clinical Context: This agent exchanges sodium for potassium, binds it in the gut (primarily in the large intestine), and decreases total body potassium. The oral onset of action ranges from 2-12 hours; this period is longer when the drug is taken rectally.
Clinical Context: Insulin stimulates the cellular uptake of potassium within 20-30 minutes. Administer glucose along with insulin in order to prevent hypoglycemia. Monitor blood sugar levels frequently.
Clinical Context: Sevelamer is a cationic polymer that binds intestinal phosphate, which is then excreted in the feces. Sevelamer is 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 (LDL) cholesterol levels.
Clinical Context: Lanthanum carbonate is a noncalcium, nonaluminum phosphate binder indicated for the reduction of high phosphorus levels in patients with ESRD. It directly binds dietary phosphorus in the upper GI tract, thereby inhibiting phosphorus absorption.
Phosphate binders are used to bind phosphate when, because of a high serum calcium level, calcium carbonate or acetate cannot be used.