In medicine, uremia is the presence in the blood of high levels of urea (one of the primary components of urine). It can be defined as an excess in the blood of such end products of amino acid and protein metabolism as urea and creatinine, which would normally be excreted in the urine. By comparison, uremic syndrome can be defined as the terminal clinical manifestation of kidney failure (also called renal failure). It is the signs, symptoms and results from laboratory tests which result from inadequate excretory, regulatory, and endocrine function of the kidneys. The terms uremia and uremic syndrome have been used interchangeably to denote a very high plasma urea concentration that is the result of renal failure. The former denotation will be used for the rest of the article.
A similar, less severe condition involving high levels of urea is azotemia, in which the abnormality can be measured chemically but is not yet so severe as to produce symptoms. Uremia is thus the collection of the pathological and symptomatic manifestations of severe azotemia.
There is no specific time for the onset of uremia for people with progressive loss of kidney function. People with kidney function below 50% (i.e. a glomerular filtration rate [GFR] between 50 and 60 mL/min) and over 30 years of age may have uremia to a degree. This means an estimated 8 million people in the United States with a GFR of less than 60 mL/min have uremic symptoms. The symptoms, such as fatigue, can be very vague, making the diagnosis of impaired kidney function difficult. Treatment can be by dialysis or a kidney transplant, though some patients choose to pursue symptom control and conservative care instead.
Signs and symptoms Classical signs of uremia are: progressive weakness and easy fatigue, loss of appetite due to nausea and vomiting, muscle atrophy, tremors, abnormal mental function, frequent shallow respiration, and metabolic acidosis. Without intervention via dialysis or kidney transplant, uremia due to renal failure will progress and cause stupor, coma, and death. Because uremia is mostly a consequence of kidney failure, its signs and symptoms often occur concomitantly with other signs and symptoms of kidney failure.
+ Clinical features of uremia Area affected Signs and symptoms Central nervous system diurnal somnolence, night insomnia, memory and concentration disorders, asthenia, headache, confusion, fatigue, seizures, coma, encephalopathy, decreased taste and smell, hiccups, serositis Peripheral nervous system polyneuritis, restless legs, cramps, peripheral neuropathy, oxidative stress, reduced body temperature Gastrointestinal anorexia, nausea, vomiting, gastroparesis, parotitis, stomatitis, superficial gastrointestinal ulcers Hematologic anemia, hemostasis disorders, granulocytic, lymphocytic and thrombocytic dysfunction Cardiovascular hypertension, atherosclerosis, coronary artery disease, pericarditis, peripheral and pulmonary edema Skin itching, skin dryness, calciphylaxis, uremic frost (excretion of urea through the skin) Endocrinology growth impairment, impotence, infertility, sterility, amenorrhea Skeletal osteomalacia, β2-microglobulin amyloidosis, bone disease (via vitamin D deficiency, secondary hyperparathyroidism and hyperphosphatemia) Nutrition malnutrition, weight loss, muscular catabolism Other uremic fetor Immunity low response rate to vaccination, increased sensitivity to infectious diseases, systemic inflammation
Glomerular filtration rate (GFR) measures the amount of plasma in millilitres being filtered through the kidneys each minute. As the GFR decreases, the prognosis worsens. Some of the effects can be reversed, albeit temporarily, with dialysis. + GFR and their effects GFR (mL/min) Effects 100–120 Normal GFR <60 Uremic symptoms may be present, reduced well-being 30–60 Cognitive impairment 55 Fatigue and reduced stamina <50 Insulin resistance <30 Increasing likelihood of symptoms ≤15 Kidney failure
Residual syndrome People on dialysis acquire what is known as "residual syndrome". Residual syndrome is a non-life-threatening disease which is displayed as toxic effects causing many of the same signs and symptoms that uremia displays. There are several hypotheses why residual syndrome is present. They are: the accumulation of large molecular weight solutes that are poorly dialyzed (e.g. β2-microglobulin); the accumulation of protein-bound small molecular weight solutes that are poorly dialyzed (e.g., p-cresol sulfate and indoxyl sulfate); the accumulation of dialyzable solutes that are incompletely removed (e.g., sequestered solutes like phosphate in cells, or insufficient elimination of other more toxic solutes); indirect phenomena such as carbamylation of proteins, tissue calcification, or a toxic effect of hormone imbalance (e.g., parathyroid hormone); and the toxic effects of dialysis itself (e.g., removal of unknown important vitamins or minerals). Dialysis increases life span, but patients may have more limited function. They have physical limitations which include impairment of balance, walking speed, and sensory functions. They also have cognitive impairments such as impairment in attention, memory, and performance of higher-order tasks. Patients have been maintained longer than three decades on dialysis, but average mortality rates and hospitalizations are high. Also, patient rehabilitation and quality of life is poor.
Causes
Conditions causing increased blood urea fall into three different categories: prerenal, renal, and postrenal.
Prerenal azotemia can be caused by decreased blood flow through the kidneys (e.g. low blood pressure, congestive heart failure, shock, bleeding, dehydration) or by increased production of urea in the liver via a high protein diet or increased protein catabolism (e.g. stress, fever, major illness, corticosteroid therapy, or gastrointestinal bleeding).
Renal causes can be attributed to decreased kidney function. These include acute and chronic kidney failure, acute and chronic glomerulonephritis, tubular necrosis, and other kidney diseases.
Postrenal causes can be due to decreased elimination of urea. These could be due to urinary outflow obstruction such as by calculi, tumours of the bladder or prostate, or a severe infection.
Diagnosis A detailed and accurate history and physical examination will help determine if uremia is acute or chronic. In the cases of acute uremia, causes may be identified and eliminated, leading to a higher chance for recovery of normal kidney function, if treated correctly."Uremia Workup". A Brent Alper Jr. Medscape
Blood tests Primary tests performed for the diagnosis of uremia are basic metabolic panel with serum calcium and phosphorus to evaluate the GFR, blood urea nitrogen and creatinine as well as serum potassium, phosphate, calcium and sodium levels. The principal abnormality is very low GFR (<30 mL/min). Uremia will demonstrate elevation of both urea and creatinine, likely elevated potassium, high phosphate and normal or slightly high sodium, as well as likely depressed calcium levels. As a basic work up a physician will also evaluate for anemia, and thyroid and parathyroid functions. Chronic anemia may be an ominous sign of established renal failure. The thyroid and parathyroid panels will help work up any symptoms of fatigue, as well as determine calcium abnormalities as they relate to uremia versus longstanding or unrelated illness of calcium metabolism.
Urine tests A 24-hour urine collection for determination of creatinine clearance may be an alternative, although not a very accurate test due to the collection procedure. Another laboratory test that should be considered is urinalysis with microscopic examination for the presence of protein, casts, blood and pH.
Radioisotope tests The most trusted test for determining GFR is iothalamate clearance. However, it may be cost-prohibitive and time-consuming. Clinical laboratories generally calculate the GFR with the modification of diet in renal disease (MDRD) formula or the Cockcroft-Gault formula.
Other In addition, coagulation studies may indicate prolonged bleeding time with otherwise normal values.
Mechanism Uremia results in many different compounds being retained by the body. With the failure of the kidneys, these compounds can build up to dangerous levels. There are more than 90 different compounds that have been identified. Some of these compounds can be toxic to the body. + Uremic solutes Solute group Example Source Characteristics Peptides and small proteins β2-microglobulin shed from major histocompatibility complex poorly dialyzed because of large size Guanidines guanidinosuccinic acid arginine increased production in uremia Phenols ρ-cresyl sulfate phenylalanine, tyrosine protein bound, produced by gut bacteria Indoles indican tryptophan protein bound, produced by gut bacteria Aliphatic amines dimethylamine choline large volume of distribution, produced by gut bacteria Polyols unknown tightly protein bound Ucleosides pseudouridine tRNA most prominent of several altered RNA species Dicarboxylic acids oxalate ascorbic acid formation of crystal deposits Carbonyls glyoxal glycolytic intermediates reaction with proteins to form advanced glycation end-products
Uremic toxins
Uremic toxins are any biologically active compounds that are retained due to kidney impairment. Many uremic salts can also be uremic toxins.
Urea was one of the first metabolites identified. Its removal is directly related to patient survival but its effect on the body is not yet clear. Still, it is not certain that the symptoms currently associated with uremia are actually caused by excess urea, as one study showed that uremic symptoms were relieved by initiation of dialysis, even when urea was added to the dialysate to maintain the blood urea nitrogen level at approximately 90 mg per deciliter (that is, approximately 32 mmol per liter). Urea could be the precursor of more toxic molecules, but it is more likely that damage done to the body is from a combination of different compounds which may act as enzyme inhibitors or derange membrane transport. Indoxyl sulfate is one of the better characterized uremic toxins. Indoxyl sulfate has been shown to aggravate vascular inflammation in atherosclerosis by modulating macrophage behavior.
+ Potential uremic toxins Toxin Effect References Urea At high concentrations [>300 mg/dL(>50 mmol/L)]: headaches, vomiting, fatigue, carbamylation of proteins Creatinine Possibly affects glucose tolerance and erythrocyte survival Cyanate Drowsiness and hyperglycemia, carbamylation of proteins and altered protein function due to being a breakdown product of urea Polyols (e.g., myoinositol) Peripheral neuropathy Phenols Can be highly toxic as they are lipid-soluble and therefore can cross cell membranes easily "Middle molecules" Peritoneal dialysis patients clear middle molecules more efficiently than hemodialysis patients. They show fewer signs of neuropathy than hemodialysis patients β2-Microglobulin Renal amyloid Indoxyl sulfate Induces renal dysfunction and cardiovascular dysfunction; associated with chronic kidney disease and cardiovascular disease Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and diseaseFigure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease ρ-cresyl sulfate Accumulates in and predicts chronic kidney disease
Biochemical characteristics Many regulatory functions of the body are affected. Regulation of body fluids, salt retention, acid and nitrogenous metabolite excretion are all impaired and can fluctuate widely. Body fluid regulation is impaired due to a failure to excrete fluids, or due to fluid loss from vomiting or diarrhea. Regulation of salt is impaired when salt intake is low or the vascular volume is inadequate. Acid excretion and nitrogenous metabolite excretion are impaired with the loss of kidney function.