What is late stage of uremia?

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What is late stage of uremia?/Uremia is a clinical condition associated with worsening renal function. It is characterized by fluid, electrolyte, hormonal, and metabolic abnormalities. Uremia most commonly occurs in the setting of chronic and end-stage renal disease, but may also occur as a result of acute kidney injury. This activity reviews the evaluation and management of uremia and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Uremia, a clinical condition associated with worsening renal function, is characterized by fluid, electrolyte, and hormone imbalances in addition to metabolic abnormalities. The literal meaning of uremia is “urine in the blood,” and the condition develops most commonly in the setting of chronic and end-stage renal disease (ESRD), but may also occur as a result of acute kidney injury.

Putative uremic toxins include parathyroid hormone, macroglobulin, advanced glycosylation end products, and beta2 microglobulin, though no specific uremic toxin has been identified as responsible for all clinical manifestations of uremia.

Kidney disease can result from some conditions ranging from primary renal disorders, for example, IgA nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, polycystic kidney disease) to systemic disorders that can lead to renal damage. Systematic disorders can include diabetes mellitus, lupus, multiple myeloma, amyloidosis, Goodpasture disease, Thrombotic thrombocytopenic purpura, or hemolytic uremic syndrome.

The leading cause of ESRD in the United States is diabetes. Additional causes, listed in order of decreasing incidence, include hypertension, glomerulonephritis, interstitial disease, cystitis, and neoplasms.

Uremia may also result from acute kidney injury if the injury involves a sudden increase in urea or creatinine.

Causes of Uremia

When the kidneys are not functioning properly, dysfunction can occur in acid-base homeostasis, fluid and electrolyte regulation, hormone production and secretion, and waste elimination. Altogether, these abnormalities can result in metabolic disturbances and ultimately conditions such as anemia, hypothyroidism, hypertension, acidemia, hyperkalemia, and malnutrition.

Anemia associated with kidney disease is typically normocytic, normochromic, and hyperproliferative. It occurs as a result of decreased erythropoietin production by the failing kidneys. This is associated with a glomerular filtration rate (GFR) of less than 50 mL/min (unless the patient has diabetes, then they may have anemia at GFR less than 60mL/min) or when serum creatinine is greater than 2 mg/mL.

Additional factors associated with chronic kidney disease alone may additionally contribute to the development of anemia. These include iron or vitamin deficiencies, hyperparathyroidism, hypothyroidism, or a decreased lifespan of red blood cells.

The buildup of uremic toxins in the blood may additionally contribute to the development of coagulopathy as a result of reduced platelet adhesion to the vascular endothelial wall, increased platelet turnover, and a slightly reduced absolute number of platelets. A common finding in patients with ESRD is bleeding diathesis which is the increased susceptibility to bleeding and hemorrhage.

Another major metabolic complication associated with uremia and ESRD is acidosis because renal tubular cells are the primary regulators of acid-base homeostasis in the body. As kidney failure progresses, there is decreased secretion of hydrogen ions and impaired excretion of ammonium, and eventually buildup of phosphate and additional organic acids (e.g., lactic acid, sulfuric acid, hippuric acid). In turn, the resulting increased anion-gap metabolic acidosis may lead to hyperventilation, lethargy, anorexia, muscle weakness, and congestive heart failure (due to a decreased cardiac response).

Hyperkalemia may also occur in the setting of both acute or chronic renal failure. This condition becomes a medical emergency when serum potassium reaches a level greater than 6.5 mEq/L. This level may be exacerbated with excessive potassium intake or use of certain medications (e.g., potassium-sparing diuretics, angiotensin-converting enzymes (ACE) inhibitors, angiotensin-receptor blockers, beta-blockers, NSAIDs). Acidosis resulting from renal failure may additionally contribute to the development of hyperkalemia.

Hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels may additionally occur as a result of renal failure. Hypocalcemia occurs due to decreased production of active vitamin D (1,25 dihydroxy vitamin D) which is responsible for gastrointestinal (GI) absorption of calcium and phosphorus and suppression of parathyroid hormone excretion. Hyperphosphatemia occurs because of impaired phosphate excretion in the setting of renal failure. Both hypocalcemia and hyperphosphatemia stimulate hypertrophy of the parathyroid gland and resultant increased production and secretion of parathyroid hormone. Altogether, these changes in calcium metabolism can result in osteodystrophy (renal bone disease) and may lead to calcium deposition throughout the body (i.e., metastatic calcification).

Declining renal function can result in decreased insulin clearance, necessitating a decrease in dosage of antihyperglycemic medications to avoid hypoglycemia. Uremia may also lead to impotence in men or infertility (e.g., anovulation, amenorrhea) in women as a result of dysfunctional reproductive hormone regulation.

The buildup of uremic toxins may also contribute to uremic pericarditis, and pericardial effusions leading to abnormalities in cardiac function. Together with metastatic calcification as a result of declining renal function, these may contribute to worsening of underlying valvular dysfunction or suppression of myocardial contractility.

Uremia Induce Problem

Uremia can cause serious complications if it’s not treated. Your body may accumulate excess acid, or hormone and electrolyte imbalances –especially for potassium – that can affect the heart. These problems can affect your metabolism or your body’s process of converting food to energy. The buildup of toxins in your blood can also cause blood vessels to calcify (harden). Calcification leads to bone, muscle, and heart and blood vessel problems. Other complications of uremia may include:

  • Acidosis (too much acid in your blood).
  • Anemia (too few healthy red blood cells).
  • High blood pressure.
  • Hyperkalemia (too much potassium in your blood).
  • Hyperparathyroidism (too much calcium and phosphorus in your blood leading to elevated parathyroid hormone levels and bone abnormalities).
  • Hypothyroidism (underactive thyroid).
  • Infertility (inability to get pregnant).
  • Malnutrition (lack of nutrients in your body).’
  • Pulmonary edema (fluid in your lungs).
  • Defective platelet function and blood clotting leading to bleeding
  • Uremic encephalopathy (decreased brain function due to toxin buildup).
  • Angina (chest pain).
  • Atherosclerosis (hardened arteries).
  • Heart failure.
  • Heart valve disease.
  • Pericardial effusion (fluid around your heart).
  • Stroke.
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Symptoms of Uremia

Uremic syndrome may affect any part of the body and can cause:

  • Nausea, vomiting, loss of appetite, and weight loss.
  • Changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma.
  • Abnormal bleeding, such as bleeding spontaneously or profusely from a very minor injury.
  • Heart problems, such as an irregular heartbeat, inflammation in the sac that surrounds the heart (pericarditis), and increased pressure on the heart.
  • Shortness of breath from fluid buildup in the space between the lungs and the chest wall (pleural effusion).

Kidney dialysis is usually needed to relieve the symptoms of uremic syndrome until normal kidney function can be restored.

Area affectedSigns and symptoms
Central nervous systemdiurnal somnolence, night insomnia, memory and concentration disorders, asthenia, headache, confusion, fatigue, seizures, coma, encephalopathy, decreased taste and smell, hiccups, serositis
Peripheral nervous systempolyneuritis, restless legs, cramps, peripheral neuropathy, oxidative stress, reduced body temperature
Gastrointestinalanorexia, nausea, vomiting, gastroparesis, parotitis, stomatitis, superficial gastrointestinal ulcers
Hematologicanemia, hemostasis disorders, granulocytic, lymphocytic and platelet dysfunction
Cardiovascularhypertension, atherosclerosis, coronary artery disease, pericarditis, peripheral and pulmonary edema
Skinitching, skin dryness, calciphylaxis, uremic frost (excretion of urea through the skin)
Endocrinologygrowth impairment, impotence, infertility, sterility, amenorrhea
Skeletalosteomalacia, β2-microglobulin amyloidosis, bone disease (via vitamin D deficiency, secondary hyperparathyroidism, and hyperphosphatemia)
Nutritionmalnutrition, weight loss, muscular catabolism
Otheruremic fetor
immunitythe low response rate to vaccination, increased sensitivity to infectious diseases, systemic inflammation

Kidney disease is a life-threatening condition, so people who suspect they have either kidney disease or uremia should see a doctor promptly. Some symptoms to watch for include:

  • A cluster of symptoms is called uremic neuropathy or nerve damage due to kidney failure. Neuropathy can cause tingling, numbness, or electrical sensations in the body, particularly the hands and feet.
  • Weakness, exhaustion, and confusion. These symptoms tend to get worse over time and do not go away with rest or improved nutrition.
  • Nausea, vomiting, and loss of appetite. Some people may lose weight because of these problems.
  • Changes in blood tests. Often, the first sign of uremia is urea’s presence in the blood during routine blood testing.
  • People with uremia may also show signs of metabolic acidosis where the body produces too much acid.
  • High blood pressure.
  • Swelling, particularly around the feet and ankles.
  • Dry, itchy skin.
  • More frequent urination, as the kidneys work harder to get rid of waste.

Additional Symptoms and Signs of Uremia

SystemicGastrointestinalNeurologicHematologic and ImmunologicCardiovascular
Fatigue∗Decreased appetite∗Impaired cognitionAnemia∗Hypertension∗
HypothermiaNausea∗Mental fatiguePlatelet dysfunctionLeft ventricular hypertrophy
Insulin resistanceVomiting∗Peripheral neuropathy∗Impaired antibody responseAccelerated vascular disease
InflammationDiminished taste and smellPericarditis∗∗
Restless legs
Pruritus
Coma∗∗
Seizures∗∗
Improved or mitigated by current end-stage renal disease (ESRD) treatments.

Diagnosis of

History and Physical

Symptomatic uremia tends to occur once creatinine clearance decreases below 10 mL/min unless kidney failure develops acutely, in which case, some patients may become symptomatic at higher clearance rates.

Patients presenting with uremia typically complain of nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus, or changes in mental status. The clinical presentation of uremia can be explained by the metabolic disturbances associated with the condition.

Fatigue as a result of anemia is considered one of the major components of uremic syndrome.

Patients with a history of diabetes may report improved glycemic control but are at a greater risk of developing hypoglycemic episodes as kidney function worsens.

Hypertension, atherosclerosis, valvular stenosis and insufficiency, chronic heart failure, and angina may all develop as a result of a buildup of uremic toxins and metastatic calcification associated with uremia and ESRD.

Occult GI bleeding as a result of platelet abnormalities may present with nausea or vomiting. Uremic fetor, ammonia or urine-like odor of the breath, may also occur in uremic patients.

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 illnesses of calcium metabolism.

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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.[rx]

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.[rx]

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[rx]
Solute groupExampleSourceCharacteristics
Peptides and small proteinsβ2-microglobulinshed from major histocompatibility complexpoorly dialyzed because of large size
Guanidinesguanidinosuccinic acidarginineincreased production in uremia
Phenolsρ-cresyl sulfatephenylalanine, tyrosineprotein-bound, produced by gut bacteria
Indolesindicantryptophanprotein-bound, produced by gut bacteria
Aliphatic aminesdimethylaminecholinethe large volume of distribution, produced by gut bacteria
PolyolsCMPFunknowntightly protein-bound
UcleosidespseudouridinetRNAmost prominent of several altered RNA species
Dicarboxylic acidsoxalateascorbic acidformation of crystal deposits
Carbonylsglyoxalglycolytic intermediatesreaction with proteins to form advanced glycation end-products

Uremic toxins

Uremic toxins are any biologically active compounds that are retained due to kidney impairment.[rx] 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 the 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).[rx] 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.[rx] 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.[rx][rx]

Potential uremic toxins
ToxinEffectReferences
UreaAt high concentrations [>300 mg/dL(>50 mmol/L)]: headaches, vomiting, fatigue, carbamylation of proteins[rx]
CreatininePossibly affects glucose tolerance and erythrocyte survival[rx]
CyanateDrowsiness and hyperglycemia, carbamylation of proteins, and altered protein function due to being a breakdown product of urea[rx]
Polyols (e.g., myoinositol)Peripheral neuropathy[rx]
PhenolsCan be highly toxic as they are lipid-soluble and therefore can cross cell membranes easily[rx]
“Middle moleculesPeritoneal dialysis patients clear middle molecules more efficiently than hemodialysis patients. They show fewer signs of neuropathy than hemodialysis patients[rx]
β2-MicroglobulinRenal amyloid[rx]
Indoxyl sulfateInduces renal dysfunction and cardiovascular dysfunction; associated with chronic kidney disease and cardiovascular disease[rx][rx][rx]
ρ-cresyl sulfateAccumulates in and predicts chronic kidney disease[rx]

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

A diagnosis of renal failure is based on abnormalities in GFR or creatinine clearance.

It is important to determine whether a patient presenting with uremic symptoms is experiencing acute or chronic renal failure, as acute kidney injury is reversible. Laboratory studies to evaluate for abnormalities in hemoglobin, calcium, phosphate, parathyroid hormone, albumin, potassium, and bicarbonate in addition to urinalysis (with microscopic examination) will help point towards any potential abnormalities.

A 24-hour urine collection may provide insight to both GFR and creatinine clearance, though this method is both burdensome and often inaccurate. Alternatively, a nuclear medicine radioisotope (iothalamate) clearance assay may be used to measure GFR. However, this test is also time-consuming and expensive relative to the Cockcroft-Gault formula [creatinine clearance = Sex times ((140 – Age) / (serum creatinine)) times (weight / 72)] or the Modification of Diet in Renal Disease formula [(GFR (mL/min/1.73 m) = 175 x (S) times (Age) times (0.742 if female) or times (1.212 if African American)] that are often used instead.

As per the National Kidney Foundation, patients presenting with chronic kidney disease are staged based on the estimated GFR (creatinine clearance) as calculated by the Modification of Diet in Renal Disease formula.

  • Stage 1 – normal GFR (90 mL/min or greater)
  • Stage 2 – mildly reduced GFR (60 mL/min to 90 mL/min)
  • Stage 3 – moderately reduced GFR (30 mL/min to 59 mL/min)
  • Stage 4 – severely reduced GFR (15 mL/min to -29 mL/min)
  • Stage 5 – ESRD (GFR < 15 mL/min or patient is on dialysis)

A renal ultrasound may be useful to determine the size and shape of the kidneys and to evaluate for hydronephrosis or ureteral and/or bladder obstruction. This may occur as a result of kidney stones, neurologic abnormalities, trauma, pregnancy, prostate enlargement, retroperitoneal fibrosis, abdominal tumors (secondary to cervical or prostate cancers) or additional structural abnormalities. Early diabetic nephropathy, multiple myeloma, polycystic kidney diseases, and glomerulonephritis associated with human immunodeficiency virus (HIV) are all associated with enlarged kidneys on ultrasound.  Smaller kidneys are indicative of more chronic, irreversible changes as a result of long-standing kidney disease, ischemic nephropathy, or hypertensive nephrosclerosis.

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If a patient presents with significant alterations in mental status, a brain computed tomography (CT) scan may be warranted. Uremic patients with a blood urea nitrogen (BUN) level greater than 150 mg/dL to 200 mg/dL are also at an increased risk of developing spontaneous subdural hematomas. Given the increased risk of bleeding and hemorrhage in uremia (especially in the setting of a fall or trauma), a CT scan of both the brain and abdomen may additionally be considered. An abdominal CT scan might help further elucidate the underlying cause of hydronephrosis if it was found on ultrasound without any obvious etiology.

Finally, magnetic resonance imaging (MRI) may be considered to assess for renal artery stenosis or thrombosis, or aortic and renal artery dissection- all potentially reversible causes of renal failure.

A renal biopsy may be helpful in determining the reversibility or treatability of the renal injury, and may ultimately be required to make an accurate diagnosis of acute kidney injury or chronic kidney disease. However, a biopsy should not be performed in the case of small kidneys because of the associated comorbidities and increased risk of bleeding. 

Treatment of Uremia

Dialysis is indicated in a patient with symptomatic uremia (e.g., nausea, vomiting, hyperkalemia, metabolic acidosis) that is not treatable by medical means and should be initiated as soon as possible, regardless of the patient’s GFR.

Patients presenting with a uremic emergency (e.g., hyperkalemia, acidosis, symptomatic pericardial effusion, or uremic encephalopathy) require emergent dialysis which should be initiated gently to avoid dialysis disequilibrium syndrome (neurologic symptoms secondary to cerebral edema occurring during or shortly after the initiation of dialysis).

Ultimately, the best renal replacement therapy is renal transplantation, although practitioners may also consider long-term hemodialysis and peritoneal dialysis. Renal transplantation is associated with improvements in both survival and quality of life, and should be considered early (before the need for dialysis) as the waiting list for transplantation is often longer than two to three years.

Iron replacement should be initiated in patients with anemia of chronic kidney disease and underlying iron deficiency (as long as serum ferritin is greater than 100 mcg/mL). This can be done with dialysis treatments, or as oral therapy, if dialysis has not yet been initiated. Erythropoietic stimulating agents, such as erythropoietin or darbepoetin, may additionally be used in low doses (due to the increased risk of cardiovascular mortality) once hemoglobin levels reach below 10 g/dL.

Hyperparathyroidism and associated or isolated hypocalcemia and hyperphosphatemia can be treated with oral calcium carbonate or calcium acetate, oral vitamin D therapy, and oral phosphate binders (e.g., calcium carbonate, calcium acetate, sevelamer or lanthanum carbonate).

A dietitian should be consulted if dietary alterations are being considered.  Patients with chronic kidney disease should reduce potassium, phosphate, and sodium intake to 2 g to 3 g, 2 g, and 2 g per day of each, respectively. Though there is some conflicting evidence regarding protein intake in patients with kidney failure, the current low-protein diet recommendations before initiation of dialysis are 0.8 g to 1 g of protein/kg of weight per day with an added gram of protein for each gram of protein lost in the urine in patients with nephrotic syndrome.

A low-protein diet is not recommended in patients with advanced uremia or malnutrition, as this type of diet can result in worsening of malnutrition and has been associated with increased risk of mortality with the initiation of dialysis.

Patients with a creatinine clearance of less than 20 mL/min should avoid excessive potassium intake and use certain medications with caution (e.g., potassium-sparing diuretics, angiotensin-converting enzymes (ACE) inhibitors, angiotensin-receptor blockers, beta-blockers, NSAIDs).

Due to the buildup of uremic toxins and potentially increased risk of bleeding and hemorrhage, extra care needs to be taken when prescribing oral anticoagulants or antiplatelet medications to patients who have ESRD.

Finally, nephrotoxic medications (e.g., NSAIDs, aminoglycoside antibiotics) should be avoided in all patients with renal disease.  To avoid nephrotoxicity, N-acetylcysteine may be administered before administration of intravenous contrast for radiologic imaging, although alternative modes of imaging like MRI should be considered in these patients, to avoid the risk of acute kidney injury altogether.

Complications

  • Hyperpigmented skin
  • Severe itching
  • Pericarditis plus effusion
  • Pulmonary edema
  • Valvular calcification

References

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