Uremia is the condition of having high levels of urea in the blood.

Urea is one of the primary

components of urine. It can be defined as an excess of amino acid and protein metabolism end
products, such as urea and creatinine, in the blood that would be normally excreted in the
urine. Uremic syndrome can be defined as the terminal clinical manifestation of kidney failure (also
called renal failure).[1] It is the signs, symptoms and results from laboratory tests which result from
inadequate excretory, regulatory and endocrine function of the kidneys.[2] Both uremia and uremic
syndrome have been used interchangeably to denote a very high plasma urea concentration that is
the result of renal failure.[1] The former denotation will be used for the rest of the article.
Azotemia is another word that refers to high levels of urea and is used primarily when the
abnormality can be measured chemically but is not yet so severe as to produce symptoms. Uremia
describes the pathological and symptomatic manifestations of severe azotemia.[1]
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) 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 have uremic symptoms.[3] The symptoms,
such as fatigue, can be very vague, making the diagnosis of impaired kidney function difficult.
Treatment is to perform dialysis or a renal transplant.[3]

Contents

 1Signs and symptoms

o 1.1Residual syndrome
 2Causes
 3Diagnosis
o 3.1Blood tests
o 3.2Urine tests
o 3.3Radioisotope tests
o 3.4Other
 4Mechanism
o 4.1Uremic toxins
o 4.2Biochemical characteristics
 5History
 6Notes
 7References
 8External links

Signs and symptoms[edit]

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.[2] 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[3][4][5]

 Area
Signs and symptoms
affected

Central diurnal somnolence, night insomnia, memory and concentration

nervous disorders, asthenia, headache, confusion, fatigue, seizures, coma, encephalopathy,
system decreased taste and smell, hiccups, serositis

Peripheral
polyneuritis, restless legs, cramps, peripheral neuropathy, oxidative stress, reduced
nervous
body temperature
system

Gastrointestin anorexia, nausea, vomiting, gastroparesis, parotitis, stomatitis,

al superficial gastrointestinal ulcers

Hematologic anemia, hemostasis disorders, granulocytic, lymphocytic and platelet dysfunction

Cardiovascul hypertension, atherosclerosis, coronary artery

ar disease, pericarditis, peripheral and pulmonary edema

Skin itching, skin dryness, calciphylaxis, uremic frost (excretion of urea through the skin)

Endocrinolog
growth impairment, impotence, infertility, sterility, amenorrhea
y

osteomalacia, β2-microglobulin amyloidosis, bone disease (via vitamin D

Skeletal
deficiency, secondary hyperparathyroidism and hyperphosphatemia)

Nutrition malnutrition, weight loss, muscular catabolism

Other uremic fetor

low response rate to vaccination, increased sensitivity to infectious diseases,

immunity
systemic inflammation
Glomerular filtration rate (GFR) measures the amount of plasma being filtered through the kidneys.
As the GFR decreases, the prognosis worsens. Some of the effects can be reversed with dialysis.

GFR and their effects[3]

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 Possibly lead to coma

≤15 Kidney failure

Residual syndrome[edit]
People on dialysis acquire what is known as "residual syndrome".[5] 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-cresyl 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).[5][6] Dialysis increases life span but
patients may have more limited function. They gain physical limitations which include impairment of
balance, walking speed and sensory functions. They also retain cognitive impairments such as
impairment in attention, memory and performance of higher-order tasks.[3] 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.[3][5]

Causes[edit]
Urea
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).[1]
Renal causes can be attributed to decreased kidney function. These include acute and chronic
kidney failure, acute and chronic glomerular nephritis, tubular necrosis and other kidney diseases.[1]
Post renal 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.[1]

Diagnosis[edit]
A detailed and accurate history and physical 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.[7]

Blood tests[edit]
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. Principal abnormality is very low (<30)
GFR. 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 vs longstanding or unrelated illness of calcium metabolism.

Urine tests[edit]
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.[7]

Radioisotope tests[edit]
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.[7]

Other[edit]
In addition, coagulation studies may indicate prolonged bleeding time with otherwise normal values.

Mechanism[edit]
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[3]

Solute group Example Source[note 1] Characteristics

Peptides and shed from major poorly dialyzed because of

β2-microglobulin
small proteins histocompatibility complex large size

guanidinosuccinic increased production in

Guanidines arginine
acid uremia

protein bound, produced by

Phenols ρ-cresyl sulfate phenylalanine, tyrosine
gut bacteria

protein bound, produced by

Indoles indican tryptophan
gut bacteria

large volume of distribution,

Aliphatic amines dimethylamine choline
produced by gut bacteria

Polyols CMPF unknown tightly protein bound

most prominent of several

Ucleosides pseudouridine tRNA
altered RNA species

Dicarboxylic
oxalate ascorbic acid formation of crystal deposits
acids

Carbonyls glyoxal glycolytic intermediates reaction with proteins to form

advanced glycation end-
 products

Uremic toxins[edit]
Uremic toxins are any biologically active compounds that are retained due to kidney
impairment.[4] 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).[3] 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.[2]

Potential uremic toxins

Toxin Effect References

At high concentrations [>300 mg/dL(>50 mmol/L)]:

Urea [2]
headaches, vomiting, fatigue, carbamylation of proteins

Creatinine Possibly affects glucose tolerance and erythrocyte survival [2]

Drowsiness and hyperglycemia, carbamylation of proteins

Cyanate and altered protein function due to being a breakdown [2]

product of urea

Polyols (e.g., myoinositol) Peripheral neuropathy [2]

Can be highly toxic as they are lipid-soluble and therefore [2]

Phenols
can cross cell membranes easily

Peritoneal dialysis patients clear middle molecules more

"Middle molecules"[note 2] efficiently than hemodialysis patients. They show fewer [2]

signs of neuropathy than hemodialysis patients

β2-Microglobulin Renal amyloid [2]

 Induces renal dysfunction and cardiovascular dysfunction;
[8]
Indoxyl sulfate associated with chronic kidney disease and cardiovascular
disease

ρ-cresyl sulfate Accumulates in and predicts chronic kidney disease [8]

Biochemical characteristics[edit]
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.[2]

Biochemistry[2][3][5]

Retaine
d
Anormal
nitroge Fluid, acid-base, and Carbohydrate Altered endocrine
lipid
nous electrolyte disturbances intolerance function
metabolism
metabo
lites

Insulin
resistance (hyp Hypertriglyc Secondary
Urea Fixed urine osmolality
oglycemia may eridemia hyperparathyroidism
also occur)

Decreased
Plasma insulin
Cyanat high-density Altered thyroxine
Metabolic acidosis normal or
e lipoprotein metabolism
increased
cholesterol

Delayed
Creatini Hyponatremia or hypernatrem response to Hyperlipopro Hyperreninemia and hyp
ne ia or hypercalcemia carbohydrate teinemia eraldosteronism
loading

Guanidi Hyperglucagon
Hyperchloremia Hyporeninemia
ne emia
compou
nds

"Middle
molecul Hypocalcemia Hypoaldosteronism
es"[note 2]

Uric Decreased
Hyperphosphatemia
acid erythropoietin production

Gonadal dysfunction
(increased prolactin and
Hypermagnesemia
luteinizing hormone,
decreased testosterone)

Increased
Decreased sodium-potassium serum gastrin and melan
ATPase activity ocyte-stimulating
hormone

History[edit]
Urea was crystallized and identified between 1797 and 1808.[9] Urea was hypothesized to be the
source of urinary ammonia during this time and was confirmed in 1817. It was hypothesized that
excess urea may lead to specific disorders. Later in 1821, it was confirmed that the body did
produce urea and that it was excreted by the kidneys.[9] In 1827, urea was first synthesized in the lab,
confirming the composition of urea and making it the first biological substance synthesized. In 1856,
urea was produced in vitro via oxidation of proteins. It was in 1850 that Thomas Dutrochet seeded
the idea of dialysis with the discovery of separating smaller molecules from larger molecules through
a semipermeable membrane.[9] It was in 1829 and 1831 when convincing proof was obtained that in
certain patients, blood urea was elevated. They also suggested that harm may be caused by this.
Later research suggested that major neurological disorders like coma and convulsions did not
correlate with physical findings which included generalized edema of the brain. This suggested that
uremia was a form of blood poisoning.[9] In 1851, E.T. Frerich described clinical uremic syndrome
and suggested that a toxicity was the mechanism of its cause. It was in 1856 that J. Picard
developed a sensitive method to reproducibly measure blood urea. He was able to detect a 40%
decrease of urea concentration between the renal artery and the renal vein. This work solidified the
fact that renal failure coincided with an increase in blood urea. It was J. Picard with E.T. Frerich's
work that made the term uremia popular.[9]