Category Archive Urology

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.[rx][rx][rx]

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.[rx][rx][rx]

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.[rx][rx]

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.

Symptoms of Uremia

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

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.

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 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]

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.[rx]

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.

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.[rx][rx][rx]

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.[rx]

Complications

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

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine
• https://www.nuh.nhs.uk/creatinine-clearance-calculator
• https://www.sciencedirect.com/topics/medicine-and-dentistry/uremia
• https://en.wikipedia.org/wiki/Uremia

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.[rx][rx][rx]

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.[rx][rx][rx]

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.[rx][rx]

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.

Symptoms of Uremia

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

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.

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 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]

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.[rx]

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.

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.[rx][rx][rx]

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.[rx]

Complications

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

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine
• https://www.nuh.nhs.uk/creatinine-clearance-calculator
• https://www.sciencedirect.com/topics/medicine-and-dentistry/uremia
• https://en.wikipedia.org/wiki/Uremia

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.[rx][rx][rx]

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.[rx][rx][rx]

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.[rx][rx]

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.

Symptoms of Uremia

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

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.

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 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]

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.[rx]

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.

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.[rx][rx][rx]

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.[rx]

Complications

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

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine
• https://www.nuh.nhs.uk/creatinine-clearance-calculator
• https://www.sciencedirect.com/topics/medicine-and-dentistry/uremia
• https://en.wikipedia.org/wiki/Uremia

What is normal creatinine clearance in elderly?/Creatinine clearance (CrCl) is the volume of blood plasma cleared of creatinine per unit time. It is a rapid and cost-effective method for the measurement of renal function. Both CrCl and GFR can be measured using the comparative values of creatinine in blood and urine.

The measurement of accurate renal function is vital for the routine care of patients. Determining the renal function status can predict kidney disease progression and prevent toxic drug levels in the body.[rx] The glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidneys. The gold standard measurement of GFR involves the injection of inulin and its clearance by the kidneys.[rx] However, the use of inulin is invasive, time-consuming, and an expensive procedure. Alternatively, the biochemical marker creatinine found in serum and urine is commonly used in the estimation of GFR.[rx]

Glomerular Filtration Rate

The GFR in the measurement of volume filtered through the glomerular capillaries and into the Bowman’s capsule per unit of time.[rx] The filtration in the kidney is dependent on the difference in high and low blood pressure created by the afferent (input) and efferent (output) arterioles, respectively.[rx] The clearance rate for a given substance equals the GFR when it is neither secreted nor reabsorbed by the kidneys.[rx] For such given substance, the urine concentration multiplied by the urine flow equals the mass of substance excreted during the time of urine collection. This mass divided by the plasma concentration is equivalent to the volume of plasma from which the mass was originally filtered. Below is the equation used to determine GFR, typically recorded in volume per time (e.g., mL/min):

GFR = [UrineX (mL/mg)] * urine flow (mL/min)/ [PlasmaX (mL/mg)], where X is a substance that is completely excreted.

GFR approximation using Creatinine Clearance

Creatinine is a breakdown product of dietary meat and creatine phosphate found in skeletal muscle. Its production in the body is dependent on muscle mass.[rx] The CrCl rate approximates the calculation of GFR since the glomerulus freely filters creatinine. However, it is also secreted by the peritubular capillaries, causing CrCl to overestimate the GFR by approximately 10% to 20%.[rx] Despite the marginal error, it is an accepted method for measuring GFR due to the ease of measurement of CrCl.

Cockcroft-Gault formula: Estimated creatinine clearance rate (eCCR)

Creatinine clearance can be estimated using serum creatinine levels. The Cockcroft-Gault (C-G) formula uses a patient’s weight (kg) and gender to predict CrCl (mg/dL).[rx] The resulting CrCl is multiplied by 0.85 if the patient is female to correct for the lower CrCl in females.[rx] The C-G formula is dependent on age as its main predictor for CrCl. Below is the formula:

eCCr = (140 – Age) x Mass (kg) x [0.85 if female] / 72 x [Serum Creatinine (mg/dL)]

Formulas used in the prediction of GFR

Formulas derived using variables that influence GFR can provide varying degrees of accuracy in estimating GFR. The widely used Modification of Diet in Renal Disease Study Group (MDRD) employs four variables, including serum creatinine, age, ethnicity, and albumin levels.[rx] A further complex version of MDRD includes blood urea nitrogen and serum albumin in its formula. However, since the MDRD formula does not adjust for body size, results of eGFR are given in units of ml^-1 min^-1 1.73m^-2, 1.73m^2 due to body surface area in an adult with a mass of 63kg and height of 1.7m.[rx]

Other formulas used for GFR calculations and their employed variables to estimate GFR include Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas.[rx] The CKD-EPI formulas are in categories based on patients that are a black female, black male, non-black female, and non-black male. The Mayo Quadratic formula was developed to better estimate GFR in patients that have preserved renal function.[rx] Estimation of GFR in children uses the Schwartz formula, which employs serum creatinine (mg/dL) and child’s height (cm).[rx]

In current clinical practice, the use of creatinine derived the KDIGO clinical practice guidelines recommend the CKD-EPI formula for the estimation of GFR.[rx]

Why Creatinine Tests Are Done

Doctors use creatinine and creatinine clearance tests to check how well your kidneys work. This is called renal function. Testing the rate of creatinine clearance shows the kidneys’ ability to filter the blood. As renal function gets worse, creatinine clearance also goes down. Your doctor may also order a creatinine test if you have symptoms of kidney disease, including:

• Nausea
• Throwing up
• A loss of appetite
• Tiredness and weakness
• Trouble sleeping
• Changes in how much you pee
• Swollen feet and ankles

Preparing for a Creatinine Test

Before you take a creatinine test, your doctor may tell you not to eat cooked meat for 24 hours. Studies show that it can raise your creatinine levels for a short time.

How Is a Creatinine Test Done?

There are two main ways doctors use creatinine tests to measure kidney function:

• Urine tests – Creatinine clearance can be pinpointed by measuring the amount of creatinine in a sample of pee collected over 24 hours. For this method, you store all your urine in a plastic jug for one day and then bring it in for testing. This method is inconvenient, but it may be necessary to diagnose some kidney conditions.
• Blood tests – Doctors can estimate GFR using a single blood level of creatinine, which they enter into a formula. Different formulas take into account your age, sex, and sometimes weight and ethnicity. The higher the blood creatinine level, the lower the estimated GFR and creatinine clearance.

For practical reasons, the blood test method for GFR is used far more often than the 24-hour urine collection test for creatinine clearance. But urine collections may still be useful in people who have large muscle mass or a marked decrease in muscle mass. Serum and urine samples are required. The serum collection must be within 24 hours of urine collection.

Blood specimen

A blood sample of 1 mL (minimum 0.5 mL) in a labeled tube, preferably stored in refrigerated or frozen temperature.

Urine specimen

A 24-hour urine sample is collected from the patient to measure creatinine clearance.  A plastic collection container is used to collect urine. The collection starts with an empty bladder. At the start, the patient urinates into the toilet and flushes. The date and time get recorded at the start of the collection. For the next 24 hours, the patient will collect urine and store in a container at room temperature. Total urine collected for 24 hours gets sent to the laboratory for analysis. The patient is required to drink at least 8 cups of liquid on the day of urine collection.

Specimen Requirements and Procedure

A physician may require a creatinine clearance test from patients when routine blood creatinine levels or the estimated GFR are not within normal ranges. Patients with signs and symptoms of deteriorating kidney function are candidates for the CrCl test.[rx] Patients presenting with an obstruction within the kidney or dysfunction from another disease such as congestive heart failure may be required to perform a CrCl test.

Diagnostic Tests

Elevated serum creatinine levels and a decreased CrCl rate are usually indications of abnormal renal function. For these patients, it is recommended to perform a thorough history, physical exam, renal ultrasound, and urinalysis.[rx] Relevant patient history includes medications, history of edema, gross hematuria, diabetes, and polyuria.[rx] Physical examination for signs of vasculitis, lupus erythematosus, endocarditis, and hypertension can help narrow the diagnosis — renal ultrasound assesses the kidney size, echogenicity, and possible hydronephrosis. Enlarged kidneys usually indicate diabetic nephropathy, focal segmental glomerulosclerosis, or multiple myeloma. A urinalysis positive for proteinuria or urinary sediment indicates the presence of glomerular disease.[rx]

Testing Procedures

The normal range of CrCl is 110 to 150mL/min in males and 100 to 130mL/min in females.[rx] Serum creatinine level for men with normal kidney function is approximately 0.6 to 1.2mg/dL and between 0.5 to 1.1 mg/dL for women.[rx] Creatine levels above the normal range correlate with a reduction of GFR and indicate renal dysfunction.

• Creatinine 1 mg/dL is the baseline for a given patient with normal GFR
• Creatinine 2 mg/dL is 50% reduction in GFR
• Creatinine 4 mg/dL is 70 to 85% reduction in GFR
• Creatine 8 mg/dL is 90 to 95% reduction in GFR

Alteration of serum creatinine values can occur as its generation is subject to influence by muscle function, activity, diet, and health status of the patient.[rx] Increased tubular secretion of creatinine in certain patients with dysfunctional kidneys could provide a false negative value.[rx] Elevated serum creatinine levels also present in patients with muscular dystrophy paralysis, anemia, leukemia, and hyperthyroidism. Meanwhile, decreased values present in patients with glomerulonephritis, shock, congestive heart failure, polycystic kidney disease, acute tubular necrosis, and dehydration.[rx]

Interfering Factors

Results obtained from a 24-hour urine collection depend on accurate timing and completion. Improper urine sample collection leads to an underestimation of creatinine excretion; therefore, incorrect GFR. A significant limitation of CrCl measurement is an age-related increase in the tubular secretion of creatinine that results in an overestimation of GFR[rx]

Creatinine clearance is affected by sex and race. Women have less muscle mass and a lower rate of creatinine production in comparison to men. Latinos produce lower clearance values while blacks produce higher values, indicating greater muscle mass in blacks.[rx] Patients with a unique dietary intake (e.g., vegetarian, creatine supplements) or have muscle wasting (e.g., malnutrition, amputation) can produce levels of creatinine that deviate from the general population. Drugs such as trimethoprim-sulfamethoxazole can increase serum creatinine level by approximately 0.4 to 0.5 mg/dL[rx]

Results, Reporting, Critical Findings

It is essential to determine CrCl and serum creatine levels when there is suspicion of renal dysfunction. A common complication that results in increased serum creatine levels is acute kidney injury (AKI)[rx] A sudden decrease in GFR and oliguria are signs of AKI. This type of injury is common in 20% of hospitalized patients and leads to volume overload, electrolyte imbalances and drug toxicity[rx] Management for patients with AKI is to perverse kidney function and prevent further complications.

Persistently elevated levels of serum creatinine and severely reduced GFR are indicative of chronic kidney disease. CKD occurs through multiple pathologic mechanisms of injury and affects several compartments of the kidney.[rx] The loss of microvasculature and increased fibrosis leads to hypoxia within the kidney, making patients more substile to acute kidney injuries with poor healing.  The continued loss of tubular cells becomes replaced with collagen scars and macrophage infiltration.[rx] These chronic changes are associated with further loss of renal function and progression towards end-stage renal failure[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine
• https://www.nuh.nhs.uk/creatinine-clearance-calculator

What level of creatinine indicates kidney failure?/Creatinine clearance (CrCl) is the volume of blood plasma cleared of creatinine per unit time. It is a rapid and cost-effective method for the measurement of renal function. Both CrCl and GFR can be measured using the comparative values of creatinine in blood and urine.

The measurement of accurate renal function is vital for the routine care of patients. Determining the renal function status can predict kidney disease progression and prevent toxic drug levels in the body.[rx] The glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidneys. The gold standard measurement of GFR involves the injection of inulin and its clearance by the kidneys.[rx] However, the use of inulin is invasive, time-consuming, and an expensive procedure. Alternatively, the biochemical marker creatinine found in serum and urine is commonly used in the estimation of GFR.[rx]

Glomerular Filtration Rate

The GFR in the measurement of volume filtered through the glomerular capillaries and into the Bowman’s capsule per unit of time.[rx] The filtration in the kidney is dependent on the difference in high and low blood pressure created by the afferent (input) and efferent (output) arterioles, respectively.[rx] The clearance rate for a given substance equals the GFR when it is neither secreted nor reabsorbed by the kidneys.[rx] For such given substance, the urine concentration multiplied by the urine flow equals the mass of substance excreted during the time of urine collection. This mass divided by the plasma concentration is equivalent to the volume of plasma from which the mass was originally filtered. Below is the equation used to determine GFR, typically recorded in volume per time (e.g., mL/min):

GFR = [UrineX (mL/mg)] * urine flow (mL/min)/ [PlasmaX (mL/mg)], where X is a substance that is completely excreted.

GFR approximation using Creatinine Clearance

Creatinine is a breakdown product of dietary meat and creatine phosphate found in skeletal muscle. Its production in the body is dependent on muscle mass.[rx] The CrCl rate approximates the calculation of GFR since the glomerulus freely filters creatinine. However, it is also secreted by the peritubular capillaries, causing CrCl to overestimate the GFR by approximately 10% to 20%.[rx] Despite the marginal error, it is an accepted method for measuring GFR due to the ease of measurement of CrCl.

Cockcroft-Gault formula: Estimated creatinine clearance rate (eCCR)

Creatinine clearance can be estimated using serum creatinine levels. The Cockcroft-Gault (C-G) formula uses a patient’s weight (kg) and gender to predict CrCl (mg/dL).[rx] The resulting CrCl is multiplied by 0.85 if the patient is female to correct for the lower CrCl in females.[rx] The C-G formula is dependent on age as its main predictor for CrCl. Below is the formula:

eCCr = (140 – Age) x Mass (kg) x [0.85 if female] / 72 x [Serum Creatinine (mg/dL)]

Formulas used in the prediction of GFR

Formulas derived using variables that influence GFR can provide varying degrees of accuracy in estimating GFR. The widely used Modification of Diet in Renal Disease Study Group (MDRD) employs four variables, including serum creatinine, age, ethnicity, and albumin levels.[rx] A further complex version of MDRD includes blood urea nitrogen and serum albumin in its formula. However, since the MDRD formula does not adjust for body size, results of eGFR are given in units of ml^-1 min^-1 1.73m^-2, 1.73m^2 due to body surface area in an adult with a mass of 63kg and height of 1.7m.[rx]

Other formulas used for GFR calculations and their employed variables to estimate GFR include Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas.[rx] The CKD-EPI formulas are in categories based on patients that are a black female, black male, non-black female, and non-black male. The Mayo Quadratic formula was developed to better estimate GFR in patients that have preserved renal function.[rx] Estimation of GFR in children uses the Schwartz formula, which employs serum creatinine (mg/dL) and child’s height (cm).[rx]

In current clinical practice, the use of creatinine derived the KDIGO clinical practice guidelines recommend the CKD-EPI formula for the estimation of GFR.[rx]

Why Creatinine Tests Are Done

Doctors use creatinine and creatinine clearance tests to check how well your kidneys work. This is called renal function. Testing the rate of creatinine clearance shows the kidneys’ ability to filter the blood. As renal function gets worse, creatinine clearance also goes down. Your doctor may also order a creatinine test if you have symptoms of kidney disease, including:

• Nausea
• Throwing up
• A loss of appetite
• Tiredness and weakness
• Trouble sleeping
• Changes in how much you pee
• Swollen feet and ankles

Preparing for a Creatinine Test

Before you take a creatinine test, your doctor may tell you not to eat cooked meat for 24 hours. Studies show that it can raise your creatinine levels for a short time.

How Is a Creatinine Test Done?

There are two main ways doctors use creatinine tests to measure kidney function:

• Urine tests – Creatinine clearance can be pinpointed by measuring the amount of creatinine in a sample of pee collected over 24 hours. For this method, you store all your urine in a plastic jug for one day and then bring it in for testing. This method is inconvenient, but it may be necessary to diagnose some kidney conditions.
• Blood tests – Doctors can estimate GFR using a single blood level of creatinine, which they enter into a formula. Different formulas take into account your age, sex, and sometimes weight and ethnicity. The higher the blood creatinine level, the lower the estimated GFR and creatinine clearance.

For practical reasons, the blood test method for GFR is used far more often than the 24-hour urine collection test for creatinine clearance. But urine collections may still be useful in people who have large muscle mass or a marked decrease in muscle mass. Serum and urine samples are required. The serum collection must be within 24 hours of urine collection.

Blood specimen

A blood sample of 1 mL (minimum 0.5 mL) in a labeled tube, preferably stored in refrigerated or frozen temperature.

Urine specimen

A 24-hour urine sample is collected from the patient to measure creatinine clearance.  A plastic collection container is used to collect urine. The collection starts with an empty bladder. At the start, the patient urinates into the toilet and flushes. The date and time get recorded at the start of the collection. For the next 24 hours, the patient will collect urine and store in a container at room temperature. Total urine collected for 24 hours gets sent to the laboratory for analysis. The patient is required to drink at least 8 cups of liquid on the day of urine collection.

Specimen Requirements and Procedure

A physician may require a creatinine clearance test from patients when routine blood creatinine levels or the estimated GFR are not within normal ranges. Patients with signs and symptoms of deteriorating kidney function are candidates for the CrCl test.[rx] Patients presenting with an obstruction within the kidney or dysfunction from another disease such as congestive heart failure may be required to perform a CrCl test.

Diagnostic Tests

Elevated serum creatinine levels and a decreased CrCl rate are usually indications of abnormal renal function. For these patients, it is recommended to perform a thorough history, physical exam, renal ultrasound, and urinalysis.[rx] Relevant patient history includes medications, history of edema, gross hematuria, diabetes, and polyuria.[rx] Physical examination for signs of vasculitis, lupus erythematosus, endocarditis, and hypertension can help narrow the diagnosis — renal ultrasound assesses the kidney size, echogenicity, and possible hydronephrosis. Enlarged kidneys usually indicate diabetic nephropathy, focal segmental glomerulosclerosis, or multiple myeloma. A urinalysis positive for proteinuria or urinary sediment indicates the presence of glomerular disease.[rx]

Testing Procedures

The normal range of CrCl is 110 to 150mL/min in males and 100 to 130mL/min in females.[rx] Serum creatinine level for men with normal kidney function is approximately 0.6 to 1.2mg/dL and between 0.5 to 1.1 mg/dL for women.[rx] Creatine levels above the normal range correlate with a reduction of GFR and indicate renal dysfunction.

• Creatinine 1 mg/dL is the baseline for a given patient with normal GFR
• Creatinine 2 mg/dL is 50% reduction in GFR
• Creatinine 4 mg/dL is 70 to 85% reduction in GFR
• Creatine 8 mg/dL is 90 to 95% reduction in GFR

Alteration of serum creatinine values can occur as its generation is subject to influence by muscle function, activity, diet, and health status of the patient.[rx] Increased tubular secretion of creatinine in certain patients with dysfunctional kidneys could provide a false negative value.[rx] Elevated serum creatinine levels also present in patients with muscular dystrophy paralysis, anemia, leukemia, and hyperthyroidism. Meanwhile, decreased values present in patients with glomerulonephritis, shock, congestive heart failure, polycystic kidney disease, acute tubular necrosis, and dehydration.[rx]

Interfering Factors

Results obtained from a 24-hour urine collection depend on accurate timing and completion. Improper urine sample collection leads to an underestimation of creatinine excretion; therefore, incorrect GFR. A significant limitation of CrCl measurement is an age-related increase in the tubular secretion of creatinine that results in an overestimation of GFR[rx]

Creatinine clearance is affected by sex and race. Women have less muscle mass and a lower rate of creatinine production in comparison to men. Latinos produce lower clearance values while blacks produce higher values, indicating greater muscle mass in blacks.[rx] Patients with a unique dietary intake (e.g., vegetarian, creatine supplements) or have muscle wasting (e.g., malnutrition, amputation) can produce levels of creatinine that deviate from the general population. Drugs such as trimethoprim-sulfamethoxazole can increase serum creatinine level by approximately 0.4 to 0.5 mg/dL[rx]

Results, Reporting, Critical Findings

It is essential to determine CrCl and serum creatine levels when there is suspicion of renal dysfunction. A common complication that results in increased serum creatine levels is acute kidney injury (AKI)[rx] A sudden decrease in GFR and oliguria are signs of AKI. This type of injury is common in 20% of hospitalized patients and leads to volume overload, electrolyte imbalances and drug toxicity[rx] Management for patients with AKI is to perverse kidney function and prevent further complications.

Persistently elevated levels of serum creatinine and severely reduced GFR are indicative of chronic kidney disease. CKD occurs through multiple pathologic mechanisms of injury and affects several compartments of the kidney.[rx] The loss of microvasculature and increased fibrosis leads to hypoxia within the kidney, making patients more substile to acute kidney injuries with poor healing.  The continued loss of tubular cells becomes replaced with collagen scars and macrophage infiltration.[rx] These chronic changes are associated with further loss of renal function and progression towards end-stage renal failure[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine

Creatinine clearance (CrCl) is the volume of blood plasma cleared of creatinine per unit time. It is a rapid and cost-effective method for the measurement of renal function. Both CrCl and GFR can be measured using the comparative values of creatinine in blood and urine.

The measurement of accurate renal function is vital for the routine care of patients. Determining the renal function status can predict kidney disease progression and prevent toxic drug levels in the body.[rx] The glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidneys. The gold standard measurement of GFR involves the injection of inulin and its clearance by the kidneys.[rx] However, the use of inulin is invasive, time-consuming, and an expensive procedure. Alternatively, the biochemical marker creatinine found in serum and urine is commonly used in the estimation of GFR.[rx]

Glomerular Filtration Rate

The GFR in the measurement of volume filtered through the glomerular capillaries and into the Bowman’s capsule per unit of time.[rx] The filtration in the kidney is dependent on the difference in high and low blood pressure created by the afferent (input) and efferent (output) arterioles, respectively.[rx] The clearance rate for a given substance equals the GFR when it is neither secreted nor reabsorbed by the kidneys.[rx] For such given substance, the urine concentration multiplied by the urine flow equals the mass of substance excreted during the time of urine collection. This mass divided by the plasma concentration is equivalent to the volume of plasma from which the mass was originally filtered. Below is the equation used to determine GFR, typically recorded in volume per time (e.g., mL/min):

GFR = [UrineX (mL/mg)] * urine flow (mL/min)/ [PlasmaX (mL/mg)], where X is a substance that is completely excreted.

GFR approximation using Creatinine Clearance

Creatinine is a breakdown product of dietary meat and creatine phosphate found in skeletal muscle. Its production in the body is dependent on muscle mass.[rx] The CrCl rate approximates the calculation of GFR since the glomerulus freely filters creatinine. However, it is also secreted by the peritubular capillaries, causing CrCl to overestimate the GFR by approximately 10% to 20%.[rx] Despite the marginal error, it is an accepted method for measuring GFR due to the ease of measurement of CrCl.

Cockcroft-Gault formula: Estimated creatinine clearance rate (eCCR)

Creatinine clearance can be estimated using serum creatinine levels. The Cockcroft-Gault (C-G) formula uses a patient’s weight (kg) and gender to predict CrCl (mg/dL).[rx] The resulting CrCl is multiplied by 0.85 if the patient is female to correct for the lower CrCl in females.[rx] The C-G formula is dependent on age as its main predictor for CrCl. Below is the formula:

eCCr = (140 – Age) x Mass (kg) x [0.85 if female] / 72 x [Serum Creatinine (mg/dL)]

Formulas used in the prediction of GFR

Formulas derived using variables that influence GFR can provide varying degrees of accuracy in estimating GFR. The widely used Modification of Diet in Renal Disease Study Group (MDRD) employs four variables, including serum creatinine, age, ethnicity, and albumin levels.[rx] A further complex version of MDRD includes blood urea nitrogen and serum albumin in its formula. However, since the MDRD formula does not adjust for body size, results of eGFR are given in units of ml^-1 min^-1 1.73m^-2, 1.73m^2 due to body surface area in an adult with a mass of 63kg and height of 1.7m.[rx]

Other formulas used for GFR calculations and their employed variables to estimate GFR include Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas.[rx] The CKD-EPI formulas are in categories based on patients that are a black female, black male, non-black female, and non-black male. The Mayo Quadratic formula was developed to better estimate GFR in patients that have preserved renal function.[rx] Estimation of GFR in children uses the Schwartz formula, which employs serum creatinine (mg/dL) and child’s height (cm).[rx]

In current clinical practice, the use of creatinine derived the KDIGO clinical practice guidelines recommend the CKD-EPI formula for the estimation of GFR.[rx]

Why Creatinine Tests Are Done

Doctors use creatinine and creatinine clearance tests to check how well your kidneys work. This is called renal function. Testing the rate of creatinine clearance shows the kidneys’ ability to filter the blood. As renal function gets worse, creatinine clearance also goes down. Your doctor may also order a creatinine test if you have symptoms of kidney disease, including:

• Nausea
• Throwing up
• A loss of appetite
• Tiredness and weakness
• Trouble sleeping
• Changes in how much you pee
• Swollen feet and ankles

Preparing for a Creatinine Test

Before you take a creatinine test, your doctor may tell you not to eat cooked meat for 24 hours. Studies show that it can raise your creatinine levels for a short time.

How Is a Creatinine Test Done?

There are two main ways doctors use creatinine tests to measure kidney function:

• Urine tests – Creatinine clearance can be pinpointed by measuring the amount of creatinine in a sample of pee collected over 24 hours. For this method, you store all your urine in a plastic jug for one day and then bring it in for testing. This method is inconvenient, but it may be necessary to diagnose some kidney conditions.
• Blood tests – Doctors can estimate GFR using a single blood level of creatinine, which they enter into a formula. Different formulas take into account your age, sex, and sometimes weight and ethnicity. The higher the blood creatinine level, the lower the estimated GFR and creatinine clearance.

For practical reasons, the blood test method for GFR is used far more often than the 24-hour urine collection test for creatinine clearance. But urine collections may still be useful in people who have large muscle mass or a marked decrease in muscle mass. Serum and urine samples are required. The serum collection must be within 24 hours of urine collection.

Blood specimen

A blood sample of 1 mL (minimum 0.5 mL) in a labeled tube, preferably stored in refrigerated or frozen temperature.

Urine specimen

A 24-hour urine sample is collected from the patient to measure creatinine clearance.  A plastic collection container is used to collect urine. The collection starts with an empty bladder. At the start, the patient urinates into the toilet and flushes. The date and time get recorded at the start of the collection. For the next 24 hours, the patient will collect urine and store in a container at room temperature. Total urine collected for 24 hours gets sent to the laboratory for analysis. The patient is required to drink at least 8 cups of liquid on the day of urine collection.

Specimen Requirements and Procedure

A physician may require a creatinine clearance test from patients when routine blood creatinine levels or the estimated GFR are not within normal ranges. Patients with signs and symptoms of deteriorating kidney function are candidates for the CrCl test.[rx] Patients presenting with an obstruction within the kidney or dysfunction from another disease such as congestive heart failure may be required to perform a CrCl test.

Diagnostic Tests

Elevated serum creatinine levels and a decreased CrCl rate are usually indications of abnormal renal function. For these patients, it is recommended to perform a thorough history, physical exam, renal ultrasound, and urinalysis.[rx] Relevant patient history includes medications, history of edema, gross hematuria, diabetes, and polyuria.[rx] Physical examination for signs of vasculitis, lupus erythematosus, endocarditis, and hypertension can help narrow the diagnosis — renal ultrasound assesses the kidney size, echogenicity, and possible hydronephrosis. Enlarged kidneys usually indicate diabetic nephropathy, focal segmental glomerulosclerosis, or multiple myeloma. A urinalysis positive for proteinuria or urinary sediment indicates the presence of glomerular disease.[rx]

Testing Procedures

The normal range of CrCl is 110 to 150mL/min in males and 100 to 130mL/min in females.[rx] Serum creatinine level for men with normal kidney function is approximately 0.6 to 1.2mg/dL and between 0.5 to 1.1 mg/dL for women.[rx] Creatine levels above the normal range correlate with a reduction of GFR and indicate renal dysfunction.

• Creatinine 1 mg/dL is the baseline for a given patient with normal GFR
• Creatinine 2 mg/dL is 50% reduction in GFR
• Creatinine 4 mg/dL is 70 to 85% reduction in GFR
• Creatine 8 mg/dL is 90 to 95% reduction in GFR

Alteration of serum creatinine values can occur as its generation is subject to influence by muscle function, activity, diet, and health status of the patient.[rx] Increased tubular secretion of creatinine in certain patients with dysfunctional kidneys could provide a false negative value.[rx] Elevated serum creatinine levels also present in patients with muscular dystrophy paralysis, anemia, leukemia, and hyperthyroidism. Meanwhile, decreased values present in patients with glomerulonephritis, shock, congestive heart failure, polycystic kidney disease, acute tubular necrosis, and dehydration.[rx]

Interfering Factors

Results obtained from a 24-hour urine collection depend on accurate timing and completion. Improper urine sample collection leads to an underestimation of creatinine excretion; therefore, incorrect GFR. A significant limitation of CrCl measurement is an age-related increase in the tubular secretion of creatinine that results in an overestimation of GFR[rx]

Creatinine clearance is affected by sex and race. Women have less muscle mass and a lower rate of creatinine production in comparison to men. Latinos produce lower clearance values while blacks produce higher values, indicating greater muscle mass in blacks.[rx] Patients with a unique dietary intake (e.g., vegetarian, creatine supplements) or have muscle wasting (e.g., malnutrition, amputation) can produce levels of creatinine that deviate from the general population. Drugs such as trimethoprim-sulfamethoxazole can increase serum creatinine level by approximately 0.4 to 0.5 mg/dL[rx]

Results, Reporting, Critical Findings

It is essential to determine CrCl and serum creatine levels when there is suspicion of renal dysfunction. A common complication that results in increased serum creatine levels is acute kidney injury (AKI)[rx] A sudden decrease in GFR and oliguria are signs of AKI. This type of injury is common in 20% of hospitalized patients and leads to volume overload, electrolyte imbalances and drug toxicity[rx] Management for patients with AKI is to perverse kidney function and prevent further complications.

Persistently elevated levels of serum creatinine and severely reduced GFR are indicative of chronic kidney disease. CKD occurs through multiple pathologic mechanisms of injury and affects several compartments of the kidney.[rx] The loss of microvasculature and increased fibrosis leads to hypoxia within the kidney, making patients more substile to acute kidney injuries with poor healing.  The continued loss of tubular cells becomes replaced with collagen scars and macrophage infiltration.[rx] These chronic changes are associated with further loss of renal function and progression towards end-stage renal failure[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine

How long does it take to recover from acute kidney injury?/Acute kidney injury (AKI) is where your kidneys suddenly stop working properly. It can range from minor loss of kidney function to complete kidney failure. AKI normally happens as a complication of another serious illness.

Acute kidney injury, previously known as acute renal failure, denotes a sudden and often reversible reduction in kidney function, as measured by increased creatinine or decreased urine volume. This activity reviews the evaluation and management of acute kidney injury and highlights the role of the interprofessional team in managing patients affected by this condition.

Acute kidney injury (AKI), previously called acute renal failure (ARF), denotes a sudden and often reversible reduction in kidney function, as measured by glomerular filtration rate (GFR).[rx][rx][rx] Although, immediately after a renal insult, blood urea nitrogen (BUN) or creatinine levels may be within the normal range. The only sign of acute kidney injury may be a decline in urine output. AKI can lead to the accumulation of water, sodium, and other metabolic products. It can also result in several electrolyte disturbances. It is a very common condition, especially among hospitalized patients. It can be seen in up to 7% of hospital admissions and 30% of ICU admissions. There is no clear definition of AKI; however, several different criteria have been used in research studies such as RIFLE, AKIN (Acute Kidney Injury Network), and KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Among these, KDIGO is the most recent and most commonly used tool. According to KDIGO, AKI is the presence of any of the following:

• Increase in serum creatinine by 0.3 mg/dL or more (26.5 micromoles/L or more) within 48 hours
• Increase in serum creatinine to 1.5 times or more baseline within the prior seven days
• Urine volume less than 0.5 mL/kg/h for at least 6 hours

Causes of Acute Kidney Injury

The impetus for glomerular filtration is the difference in the pressures between the glomerulus and the Bowman space. This pressure gradient is affected by the renal blood flow and is under the direct control of the combined resistances of afferent and efferent vascular pathways. Nevertheless, whatever the cause of AKI, renal blood flow reduction is a common pathologic pathway for declining glomerular filtration rate. Pathophysiology of AKI has always been traditionally divided into three categories: prerenal, renal, and post-renal. Each of these categories has several different causes associated with it.[rx][rx]

The prerenal form of AKI is because of any cause of reduced blood flow to the kidney. This may be part of systemic hypoperfusion resulting from hypovolemia or hypotension, or maybe due to selective hypoperfusion to the kidneys, such as those resulting from renal artery stenosis and aortic dissection. However, tubular and glomerular function tends to stay normal. Few examples with the mechanism of prerenal AKI are listed below:

• Hypovolemia: hemorrhage, severe burns, and gastrointestinal fluid losses such as diarrhea, vomiting, high ostomy output.
• Hypotension from the decreased cardiac output: cardiogenic shock, massive pulmonary embolism, acute coronary syndrome
• Hypotension from systemic vasodilation: septic shock, anaphylaxis, anesthesia administration, hepatorenal syndrome
• Renal vasoconstriction: NSAIDs, iodinated contrast, amphotericin B, calcineurin inhibitors, hepatorenal syndrome
• Glomerular efferent arteriolar vasodilation: ACE inhibitors, angiotensin receptor blockers
• Renal calculi
• Sickle cell anemia
• Chronic renal failure
• Dehydration
• Gastrointestinal bleeding
• Heart failure
• Urinary tract infection
• Protein overloading
• Diabetic ketoacidosis
• Urinary obstruction

Intrinsic renal causes include conditions that affect the glomerulus or tubule, such as acute tubular necrosis and acute interstitial nephritis. This underlying glomerular or tubular injury is associated with the release of vasoconstrictors from the renal afferent pathways. Prolonged renal ischemia, sepsis, and nephrotoxins being the most common ones. It is worth mentioning that prerenal injury can convert into a renal injury if the offending factor’s exposure is prolonged enough to cause cellular damage. Few examples of this mechanism are listed below:

• Acute tubular necrosis: ischemia from prolonged prerenal injury, drugs such as aminoglycosides, vancomycin, amphotericin B, pentamidine; rhabdomyolysis, intravascular hemolysis
• Acute interstitial nephritis: Drugs such as beta-lactam antibiotics, penicillins, NSAIDs, proton pump inhibitors (PPIs), 5-ASA; infections, autoimmune conditions (SLE, IgG related disease)
• Glomerulonephritis: anti-glomerular basement membrane disease, immune complex-mediated diseases such as SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy, Henoch-Schonlein purpura.
• Intratubular obstruction: monoclonal gammopathy seen in multiple myeloma, tumor lysis syndrome, toxins such as ethylene glycol.

Post-renal causes mainly include obstructive causes, which lead to congestion of the filtration system leading to a shift in the filtration driving forces. The most common ones being renal/ureteral calculi, tumors, blood clots, or any urethral obstruction. Another noteworthy fact is that a unilateral obstruction may not always present as AKI, especially if the obstruction is gradual such as a tumor, because a normal working contralateral kidney may compensate for the function of the affected kidney. Therefore, the most common etiology of post-renal AKI is bladder outlet obstruction.

Decreased blood flow

Some diseases and conditions can slow blood flow to your kidneys and cause AKI.

These diseases and conditions include:

• Low blood pressure (called “hypotension”) or shock
• Blood or fluid loss (such as bleeding, severe diarrhea)
• Heart attack, heart failure, and other conditions leading to decreased heart function
• Organ failure (e.g., heart, liver)
• Overuse of pain medicines called “NSAIDs”, which are used to reduce swelling or relieve pain from headaches, colds, flu, and other ailments.  Examples include ibuprofen, ketoprofen, and naproxen.
• Severe allergic reactions
• Burns
• Injury
• Major surgery

Direct Damage to the Kidneys

Some diseases and conditions can damage your kidneys and lead to AKI. Some examples include:

• A type of severe, life-threatening infection called “sepsis”
• A type of cancer called “multiple myeloma”
• A rare condition that causes inflammation and scarring to your blood vessels, making them stiff, weak, and narrow (called “vasculitis”)
• An allergic reaction to certain types of drugs (called “interstitial nephritis”)
• A group of diseases (called “scleroderma”) that affect the connective tissue that supports your internal organs
• Conditions that cause inflammation or damage to the kidney tubules, to the small blood vessels in the kidneys, or to the filtering units in the kidneys (such as “tubular necrosis,” “glomerulonephritis, “vasculitis” or “thrombotic microangiopathy”).
• Blood clots in or around the kidneys
• Diseases that affect the kidneys, such as glomerulonephritis and lupus
• Infection
• Certain medicines, such as some chemotherapy drugs, some antibiotics, and contrast dyes used during CT scans, MRI scans, and other imaging tests
• Alcohol or drug abuse
• Some blood or blood vessel disorders

Blockage of the urinary tract

In some people, conditions or diseases can block the passage of urine out of the body and can lead to AKI.

Blockage can be caused by:

• Bladder, prostate, or cervical cancer
• Enlarged prostate
• Problems with the nervous system that affect the bladder and urination
• Kidney stones
• Blood clots in the urinary tract
• Some cancers
• Blood clots in or around the kidneys
• Bladder problems
• Enlarged prostate (in men)

Some examples of problems that can cause you to have too little blood flowing through your kidneys are:

• Low blood pressure
• Bleeding too much
• Having severe diarrhea
• Heart disease or heart attack
• Infection
• Liver failure
• Using NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, ibuprofen and naproxen
• Serious burns
• Being very dehydrated (not having enough fluid in your body)
• Severe allergic reaction

Symptoms of Acute Kidney Injury

• Too little urine leaving the body
• Swelling in legs, ankles, and around the eyes
• Fatigue or tiredness
• Shortness of breath
• Confusion
• Nausea
• Seizures or coma in severe cases
• Chest pain or pressure

In some cases, AKI causes no symptoms and is only found through other tests done by your healthcare provider.

• Loss of appetite
• Fatigue and weakness
• Sleep problems
• Changes in how much you urinate
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that’s difficult to control

Diagnosis of Acute Kidney Injury

Histopathology can reliably differentiate the intrinsic renal pattern of AKI from others; however, histopathology may not be reliable at narrowing down a specific cause in every situation. Renal biopsy is an invasive procedure and is usually only pursued in cases where a significant impact on management is expected, such as suspected glomerulonephritis. In those cases, immunofluorescence patterns and electron microscopy can help differentiate between various causes.

History and Physical

The history and physical exam should focus on determining the etiology of AKI and the timeline of progression. If the history points towards hypovolemia or hypotension, then the treatment is guided towards volume repletion. The providers need to look for inciting events such as diarrhea, nausea, vomiting, which may have caused volume loss, or any over-the-counter drugs such as NSAIDs or other nephrotoxins. Differentiating between AKI and chronic kidney disease (CKD) is essential as CKD itself is not an uncommon risk factor for AKI. This can be achieved with the help of history in which one may find features suggestive of CKD such as chronic fatigue, anorexia, nocturia, disturbed sleep-wake cycle, polyuria, and pruritis. Moreover, a careful review of past medical history to reveal any co-morbid conditions can also help narrow down the etiology of AKI, for instance, cirrhosis and history of blood clots requiring anticoagulation. History and physical examination are very important in AKI because, more often than not, labs are unable to provide a clear answer as to the etiology of AKI.

The most common causes of AKI in hospitalized patients are in this order:

• ATN – 45%
• Prerenal disease – 21%
• Acute superimposed on CKD – 13%
• Urinary tract obstruction – 10% (most often due to Benign prostatic hypertrophy in older men)
• Glomerulonephritis or vasculitis – 4%
• AIN – 2%
• Atheroemboli – 1%

A history of urine output is important, which may give clues to the cause of AKI. Following are some associations:

• Oliguria – favors AKI
• Sudden anuria – suggests acute urinary tract obstruction, acute glomerulonephritis, or vascular catastrophe
• Gradually diminishing urine output – may be secondary to urethral stricture or bladder outlet obstruction due to causes such as prostate enlargement.

Performing a detailed examination is imperative as it provides extremely valuable information in establishing the etiology of AKI. A crucial part of the physical exam should be orthostatic vital signs since they are an important clue for hypovolemia and, in an appropriate clinical context, would guide treatment. Several organ systems need to be examined to find clues regarding the cause of AKI.

Lab Test and Imaging

• Skin – livedo reticularis, digital ischemia, butterfly rash, and purpuras to suggest vasculitis. Track marks to suggest endocarditis in an IV drug abuser.
• Eyes and ears – jaundice in liver disease, band keratopathy in multiple myeloma, signs of diabetes mellitus, atheroemboli in retinopathy, and signs of hypertension. Keratitis, iritis, and uveitis in autoimmune vasculitis. Hearing loss in Alport disease.
• Cardiovascular system – pulse rate, blood pressure, and jugulovenous pulse in establishing volume status. Irregular rhythm may indicate electrolyte imbalance-related arrhythmias. Pericardial friction rub in uremic pericarditis.
• Measuring urine output – Your healthcare provider will track how much urine you pass each day to help find the cause of your AKI.
• Urine tests – Your healthcare provider will look at your urine (urinalysis) to find signs of kidney failure
• Blood tests – Blood tests will help find levels of creatinine, urea nitrogen phosphorus and potassium should be done in addition to blood tests for protein in order to look at kidney function.
• Serum creatinine test – This test helps your doctor check whether creatinine is building up in your blood. Creatinine is a waste product that your kidneys should filter out of your body.
• Blood urea nitrogen test – This test helps your doctor check how much nitrogen is in your blood.
• Estimated glomerular filtration rate – This test allows your doctor to estimate how well your kidneys filter waste.
• Imaging tests – such as ultrasound, magnetic resonance imaging or computed tomography (CT) scan, to assess your kidneys’ structure and size and look for abnormalities.
• Removing a sample of kidney tissue (biopsy) – to examine under a microscope to learn what type of kidney disease you have and how much damage there is.
• GFR – Your blood test will also help find your GFR (glomerular filtration rate) to estimate the decrease in kidney function
• Kidney biopsy –  In some situations, your healthcare provider will do a procedure where a tiny piece of your kidney is removed with a special needle, and looked at under a microscope.
• Removing a sample of kidney tissue for testing. In some situations, your doctor may recommend a kidney biopsy to remove a small sample of kidney tissue for lab testing. Your doctor inserts a needle through your skin and into your kidney to remove the sample.

Evaluation of AKI should include a thorough search for all possible etiologies of AKI, including prerenal, renal, and post renal disease. The timing of the onset of AKI can be especially helpful when dealing with hospitalized patients. For example, if a patient’s labs are being checked every day and creatinine suddenly starts to rise on the fourth day of admission then an inciting factor can usually be found in 24-48 hours preceding the onset. It is especially important to look for any radiologic studies that might have been done involving the use of iodinated contrast agents which are not an uncommon cause of AKI. It is also imperative to review the list of medications that the patient is receiving as they may be contributing to renal failure, therefore in view of decreased renal function, the doses of such drugs need to be modified. ACE inhibitors and ARBs are often the co-contributors to AKI. A good physical exam can also be helpful sometimes e.g. the presence of a drug rash may point to acute interstitial nephritis being the etiology, cyanotic toes could suggest cholesterol emboli in a patient post cardiac catheterization.

All patients presenting with AKI warrant a basic lab panel including a basic metabolic panel. Sometimes, urine electrolytes can be helpful in suggesting an etiology of the AKI. Urine protein, urine osmolality, and urine albumin to creatinine ratios can also be helpful clues in determining the etiology of AKI. Older patients without any obvious etiology should also be subjected to serum and urine protein electrophoresis (SPEP and UPEP) to rule out monoclonal gammopathy and multiple myeloma. Renal ultrasound can be helpful if obstructive causes are suspected. However, routine renal ultrasound for every patient with AKI is not warranted. CT non-contrast is another important radiographic modality and can be used to look for nephrolithiasis or urolithiasis. Urine sediment examination can also provide important clues as to the etiology such as muddy brown casts seen in acute tubular necrosis. Sterile pyuria is the most sensitive sign of acute interstitial nephritis.[rx][rx]

A kidney biopsy is an excellent but infrequently utilized tool. It is usually indicated in patients with rapidly declining renal function without apparent cause or to find out the exact etiology of AKI in a setting where multiple etiologies could be responsible. It is a test with a number of risks such as bleeding particularly in patients with platelet dysfunction from uremia.

There are markers of tubular function that can be calculated to help distinguish prerenal causes from renal/postrenal, like the fractional excretion of sodium and urea, and urine osmolality; however, the sensitivity of all these markers is very poor, and they are affected by many drugs very commonly used in clinical practice such as diuretics. Therefore, no single marker can be reliably used in isolation to distinguish prerenal from renal causes of AKI, which is a common misconception in clinical practice.

Lastly, attention also needs to be paid to the overall clinical picture. It is important to assess the volume status of the patient to exclude possible cardiorenal or hepatorenal syndrome. The cardiorenal syndrome is usually due to poor glomerular filtration due to venous congestion along with a lack of forwarding flow in some cases due to poor cardiac output. Hepatorenal syndrome is due to the differential distribution of circulation volume with systemic vasodilation and splanchnic vasoconstriction leading to the diversion of blood into the periphery and paucity of blood supply to the kidneys.

Treatment of Acute Kidney Injury

With the exception of post-renal AKI, most cases are an overlap between pre-renal and acute tubular necrosis type of AKI. [rx][rx] The best way to determine if the AKI is pre-renal or not is a fluid challenge. If the clinical scenario doesn’t contradict it, all patients with acute renal dysfunction should receive a fluid challenge. They require close monitoring of urine output and renal function. If the renal function improves with fluid, that is the best indicator of a pre-Renal AKI. Acute tubular necrosis is very slow to recover and can take weeks to months for complete recovery of renal function. It may not normalize at all sometimes. Diuretics may be required during the oliguric phase of ATN if significant volume overload develops. Another important thing to consider for these patients is to avoid any further insult to the kidneys, such as nephrotoxic drugs. Any and the doses of all medications need to be really adjusted once a patient develops AKI. Another vital step is to limit the dietary ingestion of potassium and phosphorus.

If hyperkalemia develops, it needs to be managed in a robust manner because, in AKI patients, it can be catastrophic. Approaches to lower potassium in the body include:

• Dietary restriction
• Insulin, IV dextrose and beta-agonists
• potassium-binding resins
• Calcium gluconate to stabilize cardiac membrane
• Dialysis for nonresponsive hyperkalemia

Some AKI patients would tend to develop volume overload, which should be corrected as early as possible to avoid pulmonary and cardiac complications. Euvolemic state can be achieved with the help of furosemide, which is a cornerstone in the management of such patients. Usually, high doses of IV furosemide are needed to correct volume overload in AKI patients; however, it plays no role in the conversion of oliguric AKI to non-oliguric AKI.

Sometimes, AKI may need short-term renal replacement therapy until the kidney function recovers. Dialysis is usually required to manage the complications of AKI, such as severe and nonresponsive hyperkalemia, uremic pericarditis, and pulmonary edema. This is seen especially in the oliguric phase of acute tubular necrosis, where the patient is prone to develop multiple electrolyte and acid-base abnormalities as well as fluid overload.[rx] When required, dialysis in this setting is usually performed through a double-lumen central venous catheter. Continuous renal replacement therapy can also be utilized in patients who cannot tolerate hemodialysis due to hypotension. It is a much slower, continuous type of dialysis. Correction of some of the metabolic abnormalities, along with dialysis, may be required. Metabolic acidosis is one such instance where systemic administration of citrate or bicarbonate is often required to maintain a suitable blood pH. The requirement for renal replacement therapy should be reevaluated in these patients daily while they are hospitalized and at least weekly thereafter until the kidney function is stable. Renal replacement therapy is usually required for the short term ranging from a few days to a few weeks in most cases; however, acute tubular necrosis can take up to months to recover and may, therefore, require intermittent hemodialysis support during that time.

There are certain specific treatments that are required for acute kidney injury in specific circumstances, such as administration of vasoactive medications and colloids for treatment of hepatorenal syndrome and cautious diuresis in cardiorenal syndrome. Acute kidney injury from various glomerulonephritides may require immunosuppressive medications for treatment. Acute interstitial nephritis, which does not recover with supportive care, may benefit from a trial of steroids. Post renal obstruction may need to be relieved operatively in certain situations. For example, benign prostatic hypertrophy may require surgical relief of bladder outlet obstruction. Urethral calculi may require stenting and lithotripsy.

It is also important to note that in a certain situation, the risk of acute kidney injury may be decreased by taking some measures. For example, in high-risk patients such as those with compromised renal function at baseline, it may be beneficial to administer peri-procedure intravenous fluids to prevent contrast-induced nephropathy when performing cardiac catheterization.

Treating complications until your kidneys recover

Your doctor will also work to prevent complications and allow your kidneys time to heal. Treatments that help prevent complications include:

• Treatments to balance the number of fluids in your blood – If your acute kidney failure is caused by a lack of fluids in your blood, your doctor may recommend intravenous (IV) fluids. In other cases, acute kidney failure may cause you to have too much fluid, leading to swelling in your arms and legs. In these cases, your doctor may recommend medications (diuretics) to cause your body to expel extra fluids.
• Medications to control blood potassium – If your kidneys aren’t properly filtering potassium from your blood, your doctor may prescribe calcium, glucose or sodium polystyrene sulfonate (Kionex) to prevent the accumulation of high levels of potassium in your blood. Too much potassium in the blood can cause dangerous irregular heartbeats (arrhythmias) and muscle weakness.
• Medications to restore blood calcium levels – If the levels of calcium in your blood drop too low, your doctor may recommend an infusion of calcium.
• Dialysis to remove toxins from your blood – If toxins build up in your blood, you may need temporary hemodialysis — often referred to simply as dialysis — to help remove toxins and excess fluids from your body while your kidneys heal. Dialysis may also help remove excess potassium from your body. During dialysis, a machine pumps blood out of your body through an artificial kidney (dialyzer) that filters out waste. The blood is then returned to your body.

Prerenal

• In prerenal AKI without fluid overload, administration of intravenous fluids is typically the first step to improving kidney function. Volume status may be monitored with the use of a central venous catheter to avoid over-or under-replacement of fluid.
• If low blood pressure persists despite providing a person with adequate amounts of intravenous fluid, medications that increase blood pressure (vasopressors) such as norepinephrine, and in certain circumstances medications that improve the heart’s ability to pump (known as inotropes) such as dobutamine may be given to improve blood flow to the kidney. While a useful vasopressor, there is no evidence to suggest that dopamine is of any specific benefit and may in fact be harmful.^[rx]

Intrinsic

• The myriad causes of intrinsic AKI require specific therapies. For example, intrinsic AKI due to vasculitis or glomerulonephritis may respond to steroid medication, cyclophosphamide, and (in some cases) plasma exchange. Toxin-induced prerenal AKI often responds to discontinuation of the offending agent, such as ACE inhibitors, ARB antagonists, aminoglycosides, penicillins, NSAIDs, or paracetamol.^[rx]
• The use of diuretics such as furosemide is widespread and sometimes convenient in improving fluid overload. It is not associated with higher mortality (risk of death),^[rx] nor with any reduced mortality or length of intensive care unit or hospital stay.^[rx]

Postrenal

• If the cause is obstruction of the urinary tract, relief of the obstruction (with a nephrostomy or urinary catheter) may be necessary.

Renal replacement therapy

• Renal replacement therapy, such as with hemodialysis, may be instituted in some cases of AKI. Renal replacement therapy can be applied intermittently (IRRT) and continuously (CRRT). Study results regarding differences in outcomes between IRRT and CRRT are inconsistent.
• A systematic review of the literature in 2008 demonstrated no difference in outcomes between the use of intermittent hemodialysis and continuous venovenous hemofiltration (CVVH) (a type of continuous hemodialysis).^[rx] Among critically ill patients, intensive renal replacement therapy with CVVH does not appear to improve outcomes compared to less intensive intermittent hemodialysis.^[rx][rx]
• However, other clinical and health economic studies demonstrated that, initiation of CRRT is associated with a lower likelihood of chronic dialysis and was cost-effective compared with IRRT in patients with acute kidney injury.^[rx][rx][rx]

Complications

Several complications may associate AKI with mortality. Some of these complications are directly associated with AKI and can easily be gauged (hyperkalemia, volume overload, metabolic acidosis, hyponatremia); however, the effect of other complications on AKI-related mortality, such as inflammation and infection, is difficult to assess. Most common complications include metabolic derangements such as:

• Hyperkalemia –  If severe, it can lead to arrhythmias because of which renal replacement therapy is required in cases of severe hyperkalemia.
• Metabolic acidosis – The kidney’s inability to excrete acids leads to metabolic acidosis and may necessitate systemic administration of bicarbonate or citrate buffers.
• Hyperphosphatemia – can usually be prevented by decreasing dietary ingestion or using phosphate binders. Other effects include pulmonary edema from volume overload, peripheral edema from an inability to excrete body water. This is especially common in the oliguric phase of acute tubular necrosis. It may necessitate the use of diuretics or renal replacement therapy.
• Cardiovascular – Heart failure secondary to fluid overload is attributable to oliguric AKI, arrhythmias secondary to acidotic state and electrolyte abnormalities, cardiac arrest due to metabolic derangements, and myocardial infarction, and rarely pericarditis.
• Gastrointestinal (GI) – Nausea, vomiting, GI bleeding, and anorexia. A mildly raised level of amylase is commonly found in patients suffering from AKI. Elevation of amylase concentration can make the diagnosis of pancreatitis difficult, therefore measuring lipase, which is not raised in AKI, is necessary to establish AKI diagnosis.
• Neurologic – CNS-related signs of uremic burden are common in AKI, and they include lethargy, somnolence, disturbed sleep-wake cycle, and cognitive impairment.
• Fluid buildup – Acute kidney failure may lead to a buildup of fluid in your lungs, which can cause shortness of breath.
• Chest pain – If the lining that covers your heart (pericardium) becomes inflamed, you may experience chest pain.
• Muscle weakness – When your body’s fluids and electrolytes — your body’s blood chemistry — are out of balance, muscle weakness can result.
• Permanent kidney damage – Occasionally, acute kidney failure causes permanent loss of kidney function or end-stage renal disease. People with the end-stage renal disease require either permanent dialysis — a mechanical filtration process used to remove toxins and wastes from the body — or a kidney transplant to survive.
• Death – Acute kidney failure can lead to loss of kidney function and, ultimately, death.

Prevention

Acute kidney failure is often difficult to predict or prevent. But you may reduce your risk by taking care of your kidneys. Try to:

• Pay attention to labels when taking over-the-counter (OTC) pain medications. Follow the instructions for OTC pain medications, such as aspirin, acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve, others). Taking too much of these medications may increase your risk of kidney injury. This is especially true if you have pre-existing kidney disease, diabetes, or high blood pressure.
• Work with your doctor to manage kidney and other chronic conditions. If you have kidney disease or another condition that increases your risk of acute kidney failures, such as diabetes or high blood pressure, stay on track with treatment goals and follow your doctor’s recommendations to manage your condition.
• Make a healthy lifestyle a priority. Be active; eat a sensible, balanced diet; and drink alcohol only in moderation — if at all.

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What are the stages of acute kidney injury?/Acute kidney injury (AKI) is where your kidneys suddenly stop working properly. It can range from minor loss of kidney function to complete kidney failure. AKI normally happens as a complication of another serious illness.

Acute kidney injury, previously known as acute renal failure, denotes a sudden and often reversible reduction in kidney function, as measured by increased creatinine or decreased urine volume. This activity reviews the evaluation and management of acute kidney injury and highlights the role of the interprofessional team in managing patients affected by this condition.

Acute kidney injury (AKI), previously called acute renal failure (ARF), denotes a sudden and often reversible reduction in kidney function, as measured by glomerular filtration rate (GFR).[rx][rx][rx] Although, immediately after a renal insult, blood urea nitrogen (BUN) or creatinine levels may be within the normal range. The only sign of acute kidney injury may be a decline in urine output. AKI can lead to the accumulation of water, sodium, and other metabolic products. It can also result in several electrolyte disturbances. It is a very common condition, especially among hospitalized patients. It can be seen in up to 7% of hospital admissions and 30% of ICU admissions. There is no clear definition of AKI; however, several different criteria have been used in research studies such as RIFLE, AKIN (Acute Kidney Injury Network), and KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Among these, KDIGO is the most recent and most commonly used tool. According to KDIGO, AKI is the presence of any of the following:

• Increase in serum creatinine by 0.3 mg/dL or more (26.5 micromoles/L or more) within 48 hours
• Increase in serum creatinine to 1.5 times or more baseline within the prior seven days
• Urine volume less than 0.5 mL/kg/h for at least 6 hours

Causes of Acute Kidney Injury

The impetus for glomerular filtration is the difference in the pressures between the glomerulus and the Bowman space. This pressure gradient is affected by the renal blood flow and is under the direct control of the combined resistances of afferent and efferent vascular pathways. Nevertheless, whatever the cause of AKI, renal blood flow reduction is a common pathologic pathway for declining glomerular filtration rate. Pathophysiology of AKI has always been traditionally divided into three categories: prerenal, renal, and post-renal. Each of these categories has several different causes associated with it.[rx][rx]

The prerenal form of AKI is because of any cause of reduced blood flow to the kidney. This may be part of systemic hypoperfusion resulting from hypovolemia or hypotension, or maybe due to selective hypoperfusion to the kidneys, such as those resulting from renal artery stenosis and aortic dissection. However, tubular and glomerular function tends to stay normal. Few examples with the mechanism of prerenal AKI are listed below:

• Hypovolemia: hemorrhage, severe burns, and gastrointestinal fluid losses such as diarrhea, vomiting, high ostomy output.
• Hypotension from the decreased cardiac output: cardiogenic shock, massive pulmonary embolism, acute coronary syndrome
• Hypotension from systemic vasodilation: septic shock, anaphylaxis, anesthesia administration, hepatorenal syndrome
• Renal vasoconstriction: NSAIDs, iodinated contrast, amphotericin B, calcineurin inhibitors, hepatorenal syndrome
• Glomerular efferent arteriolar vasodilation: ACE inhibitors, angiotensin receptor blockers
• Renal calculi
• Sickle cell anemia
• Chronic renal failure
• Dehydration
• Gastrointestinal bleeding
• Heart failure
• Urinary tract infection
• Protein overloading
• Diabetic ketoacidosis
• Urinary obstruction

Intrinsic renal causes include conditions that affect the glomerulus or tubule, such as acute tubular necrosis and acute interstitial nephritis. This underlying glomerular or tubular injury is associated with the release of vasoconstrictors from the renal afferent pathways. Prolonged renal ischemia, sepsis, and nephrotoxins being the most common ones. It is worth mentioning that prerenal injury can convert into a renal injury if the offending factor’s exposure is prolonged enough to cause cellular damage. Few examples of this mechanism are listed below:

• Acute tubular necrosis: ischemia from prolonged prerenal injury, drugs such as aminoglycosides, vancomycin, amphotericin B, pentamidine; rhabdomyolysis, intravascular hemolysis
• Acute interstitial nephritis: Drugs such as beta-lactam antibiotics, penicillins, NSAIDs, proton pump inhibitors (PPIs), 5-ASA; infections, autoimmune conditions (SLE, IgG related disease)
• Glomerulonephritis: anti-glomerular basement membrane disease, immune complex-mediated diseases such as SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy, Henoch-Schonlein purpura.
• Intratubular obstruction: monoclonal gammopathy seen in multiple myeloma, tumor lysis syndrome, toxins such as ethylene glycol.

Post-renal causes mainly include obstructive causes, which lead to congestion of the filtration system leading to a shift in the filtration driving forces. The most common ones being renal/ureteral calculi, tumors, blood clots, or any urethral obstruction. Another noteworthy fact is that a unilateral obstruction may not always present as AKI, especially if the obstruction is gradual such as a tumor, because a normal working contralateral kidney may compensate for the function of the affected kidney. Therefore, the most common etiology of post-renal AKI is bladder outlet obstruction.

Decreased blood flow

Some diseases and conditions can slow blood flow to your kidneys and cause AKI.

These diseases and conditions include:

• Low blood pressure (called “hypotension”) or shock
• Blood or fluid loss (such as bleeding, severe diarrhea)
• Heart attack, heart failure, and other conditions leading to decreased heart function
• Organ failure (e.g., heart, liver)
• Overuse of pain medicines called “NSAIDs”, which are used to reduce swelling or relieve pain from headaches, colds, flu, and other ailments.  Examples include ibuprofen, ketoprofen, and naproxen.
• Severe allergic reactions
• Burns
• Injury
• Major surgery

Direct Damage to the Kidneys

Some diseases and conditions can damage your kidneys and lead to AKI. Some examples include:

• A type of severe, life-threatening infection called “sepsis”
• A type of cancer called “multiple myeloma”
• A rare condition that causes inflammation and scarring to your blood vessels, making them stiff, weak, and narrow (called “vasculitis”)
• An allergic reaction to certain types of drugs (called “interstitial nephritis”)
• A group of diseases (called “scleroderma”) that affect the connective tissue that supports your internal organs
• Conditions that cause inflammation or damage to the kidney tubules, to the small blood vessels in the kidneys, or to the filtering units in the kidneys (such as “tubular necrosis,” “glomerulonephritis, “vasculitis” or “thrombotic microangiopathy”).
• Blood clots in or around the kidneys
• Diseases that affect the kidneys, such as glomerulonephritis and lupus
• Infection
• Certain medicines, such as some chemotherapy drugs, some antibiotics, and contrast dyes used during CT scans, MRI scans, and other imaging tests
• Alcohol or drug abuse
• Some blood or blood vessel disorders

Blockage of the urinary tract

In some people, conditions or diseases can block the passage of urine out of the body and can lead to AKI.

Blockage can be caused by:

• Bladder, prostate, or cervical cancer
• Enlarged prostate
• Problems with the nervous system that affect the bladder and urination
• Kidney stones
• Blood clots in the urinary tract
• Some cancers
• Blood clots in or around the kidneys
• Bladder problems
• Enlarged prostate (in men)

Some examples of problems that can cause you to have too little blood flowing through your kidneys are:

• Low blood pressure
• Bleeding too much
• Having severe diarrhea
• Heart disease or heart attack
• Infection
• Liver failure
• Using NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, ibuprofen and naproxen
• Serious burns
• Being very dehydrated (not having enough fluid in your body)
• Severe allergic reaction

Symptoms of Acute Kidney Injury

• Too little urine leaving the body
• Swelling in legs, ankles, and around the eyes
• Fatigue or tiredness
• Shortness of breath
• Confusion
• Nausea
• Seizures or coma in severe cases
• Chest pain or pressure

In some cases, AKI causes no symptoms and is only found through other tests done by your healthcare provider.

• Loss of appetite
• Fatigue and weakness
• Sleep problems
• Changes in how much you urinate
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that’s difficult to control

Diagnosis of Acute Kidney Injury

Histopathology can reliably differentiate the intrinsic renal pattern of AKI from others; however, histopathology may not be reliable at narrowing down a specific cause in every situation. Renal biopsy is an invasive procedure and is usually only pursued in cases where a significant impact on management is expected, such as suspected glomerulonephritis. In those cases, immunofluorescence patterns and electron microscopy can help differentiate between various causes.

History and Physical

The history and physical exam should focus on determining the etiology of AKI and the timeline of progression. If the history points towards hypovolemia or hypotension, then the treatment is guided towards volume repletion. The providers need to look for inciting events such as diarrhea, nausea, vomiting, which may have caused volume loss, or any over-the-counter drugs such as NSAIDs or other nephrotoxins. Differentiating between AKI and chronic kidney disease (CKD) is essential as CKD itself is not an uncommon risk factor for AKI. This can be achieved with the help of history in which one may find features suggestive of CKD such as chronic fatigue, anorexia, nocturia, disturbed sleep-wake cycle, polyuria, and pruritis. Moreover, a careful review of past medical history to reveal any co-morbid conditions can also help narrow down the etiology of AKI, for instance, cirrhosis and history of blood clots requiring anticoagulation. History and physical examination are very important in AKI because, more often than not, labs are unable to provide a clear answer as to the etiology of AKI.

The most common causes of AKI in hospitalized patients are in this order:

• ATN – 45%
• Prerenal disease – 21%
• Acute superimposed on CKD – 13%
• Urinary tract obstruction – 10% (most often due to Benign prostatic hypertrophy in older men)
• Glomerulonephritis or vasculitis – 4%
• AIN – 2%
• Atheroemboli – 1%

A history of urine output is important, which may give clues to the cause of AKI. Following are some associations:

• Oliguria – favors AKI
• Sudden anuria – suggests acute urinary tract obstruction, acute glomerulonephritis, or vascular catastrophe
• Gradually diminishing urine output – may be secondary to urethral stricture or bladder outlet obstruction due to causes such as prostate enlargement.

Performing a detailed examination is imperative as it provides extremely valuable information in establishing the etiology of AKI. A crucial part of the physical exam should be orthostatic vital signs since they are an important clue for hypovolemia and, in an appropriate clinical context, would guide treatment. Several organ systems need to be examined to find clues regarding the cause of AKI.

Lab Test and Imaging

• Skin – livedo reticularis, digital ischemia, butterfly rash, and purpuras to suggest vasculitis. Track marks to suggest endocarditis in an IV drug abuser.
• Eyes and ears – jaundice in liver disease, band keratopathy in multiple myeloma, signs of diabetes mellitus, atheroemboli in retinopathy, and signs of hypertension. Keratitis, iritis, and uveitis in autoimmune vasculitis. Hearing loss in Alport disease.
• Cardiovascular system – pulse rate, blood pressure, and jugulovenous pulse in establishing volume status. Irregular rhythm may indicate electrolyte imbalance-related arrhythmias. Pericardial friction rub in uremic pericarditis.
• Measuring urine output – Your healthcare provider will track how much urine you pass each day to help find the cause of your AKI.
• Urine tests – Your healthcare provider will look at your urine (urinalysis) to find signs of kidney failure
• Blood tests – Blood tests will help find levels of creatinine, urea nitrogen phosphorus and potassium should be done in addition to blood tests for protein in order to look at kidney function.
• Serum creatinine test – This test helps your doctor check whether creatinine is building up in your blood. Creatinine is a waste product that your kidneys should filter out of your body.
• Blood urea nitrogen test – This test helps your doctor check how much nitrogen is in your blood.
• Estimated glomerular filtration rate – This test allows your doctor to estimate how well your kidneys filter waste.
• Imaging tests – such as ultrasound, magnetic resonance imaging or computed tomography (CT) scan, to assess your kidneys’ structure and size and look for abnormalities.
• Removing a sample of kidney tissue (biopsy) – to examine under a microscope to learn what type of kidney disease you have and how much damage there is.
• GFR – Your blood test will also help find your GFR (glomerular filtration rate) to estimate the decrease in kidney function
• Kidney biopsy –  In some situations, your healthcare provider will do a procedure where a tiny piece of your kidney is removed with a special needle, and looked at under a microscope.
• Removing a sample of kidney tissue for testing. In some situations, your doctor may recommend a kidney biopsy to remove a small sample of kidney tissue for lab testing. Your doctor inserts a needle through your skin and into your kidney to remove the sample.

Evaluation of AKI should include a thorough search for all possible etiologies of AKI, including prerenal, renal, and post renal disease. The timing of the onset of AKI can be especially helpful when dealing with hospitalized patients. For example, if a patient’s labs are being checked every day and creatinine suddenly starts to rise on the fourth day of admission then an inciting factor can usually be found in 24-48 hours preceding the onset. It is especially important to look for any radiologic studies that might have been done involving the use of iodinated contrast agents which are not an uncommon cause of AKI. It is also imperative to review the list of medications that the patient is receiving as they may be contributing to renal failure, therefore in view of decreased renal function, the doses of such drugs need to be modified. ACE inhibitors and ARBs are often the co-contributors to AKI. A good physical exam can also be helpful sometimes e.g. the presence of a drug rash may point to acute interstitial nephritis being the etiology, cyanotic toes could suggest cholesterol emboli in a patient post cardiac catheterization.

All patients presenting with AKI warrant a basic lab panel including a basic metabolic panel. Sometimes, urine electrolytes can be helpful in suggesting an etiology of the AKI. Urine protein, urine osmolality, and urine albumin to creatinine ratios can also be helpful clues in determining the etiology of AKI. Older patients without any obvious etiology should also be subjected to serum and urine protein electrophoresis (SPEP and UPEP) to rule out monoclonal gammopathy and multiple myeloma. Renal ultrasound can be helpful if obstructive causes are suspected. However, routine renal ultrasound for every patient with AKI is not warranted. CT non-contrast is another important radiographic modality and can be used to look for nephrolithiasis or urolithiasis. Urine sediment examination can also provide important clues as to the etiology such as muddy brown casts seen in acute tubular necrosis. Sterile pyuria is the most sensitive sign of acute interstitial nephritis.[rx][rx]

A kidney biopsy is an excellent but infrequently utilized tool. It is usually indicated in patients with rapidly declining renal function without apparent cause or to find out the exact etiology of AKI in a setting where multiple etiologies could be responsible. It is a test with a number of risks such as bleeding particularly in patients with platelet dysfunction from uremia.

There are markers of tubular function that can be calculated to help distinguish prerenal causes from renal/postrenal, like the fractional excretion of sodium and urea, and urine osmolality; however, the sensitivity of all these markers is very poor, and they are affected by many drugs very commonly used in clinical practice such as diuretics. Therefore, no single marker can be reliably used in isolation to distinguish prerenal from renal causes of AKI, which is a common misconception in clinical practice.

Lastly, attention also needs to be paid to the overall clinical picture. It is important to assess the volume status of the patient to exclude possible cardiorenal or hepatorenal syndrome. The cardiorenal syndrome is usually due to poor glomerular filtration due to venous congestion along with a lack of forwarding flow in some cases due to poor cardiac output. Hepatorenal syndrome is due to the differential distribution of circulation volume with systemic vasodilation and splanchnic vasoconstriction leading to the diversion of blood into the periphery and paucity of blood supply to the kidneys.

Treatment of Acute Kidney Injury

With the exception of post-renal AKI, most cases are an overlap between pre-renal and acute tubular necrosis type of AKI. [rx][rx] The best way to determine if the AKI is pre-renal or not is a fluid challenge. If the clinical scenario doesn’t contradict it, all patients with acute renal dysfunction should receive a fluid challenge. They require close monitoring of urine output and renal function. If the renal function improves with fluid, that is the best indicator of a pre-Renal AKI. Acute tubular necrosis is very slow to recover and can take weeks to months for complete recovery of renal function. It may not normalize at all sometimes. Diuretics may be required during the oliguric phase of ATN if significant volume overload develops. Another important thing to consider for these patients is to avoid any further insult to the kidneys, such as nephrotoxic drugs. Any and the doses of all medications need to be really adjusted once a patient develops AKI. Another vital step is to limit the dietary ingestion of potassium and phosphorus.

If hyperkalemia develops, it needs to be managed in a robust manner because, in AKI patients, it can be catastrophic. Approaches to lower potassium in the body include:

• Dietary restriction
• Insulin, IV dextrose and beta-agonists
• potassium-binding resins
• Calcium gluconate to stabilize cardiac membrane
• Dialysis for nonresponsive hyperkalemia

Some AKI patients would tend to develop volume overload, which should be corrected as early as possible to avoid pulmonary and cardiac complications. Euvolemic state can be achieved with the help of furosemide, which is a cornerstone in the management of such patients. Usually, high doses of IV furosemide are needed to correct volume overload in AKI patients; however, it plays no role in the conversion of oliguric AKI to non-oliguric AKI.

Sometimes, AKI may need short-term renal replacement therapy until the kidney function recovers. Dialysis is usually required to manage the complications of AKI, such as severe and nonresponsive hyperkalemia, uremic pericarditis, and pulmonary edema. This is seen especially in the oliguric phase of acute tubular necrosis, where the patient is prone to develop multiple electrolyte and acid-base abnormalities as well as fluid overload.[rx] When required, dialysis in this setting is usually performed through a double-lumen central venous catheter. Continuous renal replacement therapy can also be utilized in patients who cannot tolerate hemodialysis due to hypotension. It is a much slower, continuous type of dialysis. Correction of some of the metabolic abnormalities, along with dialysis, may be required. Metabolic acidosis is one such instance where systemic administration of citrate or bicarbonate is often required to maintain a suitable blood pH. The requirement for renal replacement therapy should be reevaluated in these patients daily while they are hospitalized and at least weekly thereafter until the kidney function is stable. Renal replacement therapy is usually required for the short term ranging from a few days to a few weeks in most cases; however, acute tubular necrosis can take up to months to recover and may, therefore, require intermittent hemodialysis support during that time.

There are certain specific treatments that are required for acute kidney injury in specific circumstances, such as administration of vasoactive medications and colloids for treatment of hepatorenal syndrome and cautious diuresis in cardiorenal syndrome. Acute kidney injury from various glomerulonephritides may require immunosuppressive medications for treatment. Acute interstitial nephritis, which does not recover with supportive care, may benefit from a trial of steroids. Post renal obstruction may need to be relieved operatively in certain situations. For example, benign prostatic hypertrophy may require surgical relief of bladder outlet obstruction. Urethral calculi may require stenting and lithotripsy.

It is also important to note that in a certain situation, the risk of acute kidney injury may be decreased by taking some measures. For example, in high-risk patients such as those with compromised renal function at baseline, it may be beneficial to administer peri-procedure intravenous fluids to prevent contrast-induced nephropathy when performing cardiac catheterization.

Treating complications until your kidneys recover

Your doctor will also work to prevent complications and allow your kidneys time to heal. Treatments that help prevent complications include:

• Treatments to balance the number of fluids in your blood – If your acute kidney failure is caused by a lack of fluids in your blood, your doctor may recommend intravenous (IV) fluids. In other cases, acute kidney failure may cause you to have too much fluid, leading to swelling in your arms and legs. In these cases, your doctor may recommend medications (diuretics) to cause your body to expel extra fluids.
• Medications to control blood potassium – If your kidneys aren’t properly filtering potassium from your blood, your doctor may prescribe calcium, glucose or sodium polystyrene sulfonate (Kionex) to prevent the accumulation of high levels of potassium in your blood. Too much potassium in the blood can cause dangerous irregular heartbeats (arrhythmias) and muscle weakness.
• Medications to restore blood calcium levels – If the levels of calcium in your blood drop too low, your doctor may recommend an infusion of calcium.
• Dialysis to remove toxins from your blood – If toxins build up in your blood, you may need temporary hemodialysis — often referred to simply as dialysis — to help remove toxins and excess fluids from your body while your kidneys heal. Dialysis may also help remove excess potassium from your body. During dialysis, a machine pumps blood out of your body through an artificial kidney (dialyzer) that filters out waste. The blood is then returned to your body.

Prerenal

• In prerenal AKI without fluid overload, administration of intravenous fluids is typically the first step to improving kidney function. Volume status may be monitored with the use of a central venous catheter to avoid over-or under-replacement of fluid.
• If low blood pressure persists despite providing a person with adequate amounts of intravenous fluid, medications that increase blood pressure (vasopressors) such as norepinephrine, and in certain circumstances medications that improve the heart’s ability to pump (known as inotropes) such as dobutamine may be given to improve blood flow to the kidney. While a useful vasopressor, there is no evidence to suggest that dopamine is of any specific benefit and may in fact be harmful.^[rx]

Intrinsic

• The myriad causes of intrinsic AKI require specific therapies. For example, intrinsic AKI due to vasculitis or glomerulonephritis may respond to steroid medication, cyclophosphamide, and (in some cases) plasma exchange. Toxin-induced prerenal AKI often responds to discontinuation of the offending agent, such as ACE inhibitors, ARB antagonists, aminoglycosides, penicillins, NSAIDs, or paracetamol.^[rx]
• The use of diuretics such as furosemide is widespread and sometimes convenient in improving fluid overload. It is not associated with higher mortality (risk of death),^[rx] nor with any reduced mortality or length of intensive care unit or hospital stay.^[rx]

Postrenal

• If the cause is obstruction of the urinary tract, relief of the obstruction (with a nephrostomy or urinary catheter) may be necessary.

Renal replacement therapy

• Renal replacement therapy, such as with hemodialysis, may be instituted in some cases of AKI. Renal replacement therapy can be applied intermittently (IRRT) and continuously (CRRT). Study results regarding differences in outcomes between IRRT and CRRT are inconsistent.
• A systematic review of the literature in 2008 demonstrated no difference in outcomes between the use of intermittent hemodialysis and continuous venovenous hemofiltration (CVVH) (a type of continuous hemodialysis).^[rx] Among critically ill patients, intensive renal replacement therapy with CVVH does not appear to improve outcomes compared to less intensive intermittent hemodialysis.^[rx][rx]
• However, other clinical and health economic studies demonstrated that, initiation of CRRT is associated with a lower likelihood of chronic dialysis and was cost-effective compared with IRRT in patients with acute kidney injury.^[rx][rx][rx]

Complications

Several complications may associate AKI with mortality. Some of these complications are directly associated with AKI and can easily be gauged (hyperkalemia, volume overload, metabolic acidosis, hyponatremia); however, the effect of other complications on AKI-related mortality, such as inflammation and infection, is difficult to assess. Most common complications include metabolic derangements such as:

• Hyperkalemia –  If severe, it can lead to arrhythmias because of which renal replacement therapy is required in cases of severe hyperkalemia.
• Metabolic acidosis – The kidney’s inability to excrete acids leads to metabolic acidosis and may necessitate systemic administration of bicarbonate or citrate buffers.
• Hyperphosphatemia – can usually be prevented by decreasing dietary ingestion or using phosphate binders. Other effects include pulmonary edema from volume overload, peripheral edema from an inability to excrete body water. This is especially common in the oliguric phase of acute tubular necrosis. It may necessitate the use of diuretics or renal replacement therapy.
• Cardiovascular – Heart failure secondary to fluid overload is attributable to oliguric AKI, arrhythmias secondary to acidotic state and electrolyte abnormalities, cardiac arrest due to metabolic derangements, and myocardial infarction, and rarely pericarditis.
• Gastrointestinal (GI) – Nausea, vomiting, GI bleeding, and anorexia. A mildly raised level of amylase is commonly found in patients suffering from AKI. Elevation of amylase concentration can make the diagnosis of pancreatitis difficult, therefore measuring lipase, which is not raised in AKI, is necessary to establish AKI diagnosis.
• Neurologic – CNS-related signs of uremic burden are common in AKI, and they include lethargy, somnolence, disturbed sleep-wake cycle, and cognitive impairment.
• Fluid buildup – Acute kidney failure may lead to a buildup of fluid in your lungs, which can cause shortness of breath.
• Chest pain – If the lining that covers your heart (pericardium) becomes inflamed, you may experience chest pain.
• Muscle weakness – When your body’s fluids and electrolytes — your body’s blood chemistry — are out of balance, muscle weakness can result.
• Permanent kidney damage – Occasionally, acute kidney failure causes permanent loss of kidney function or end-stage renal disease. People with the end-stage renal disease require either permanent dialysis — a mechanical filtration process used to remove toxins and wastes from the body — or a kidney transplant to survive.
• Death – Acute kidney failure can lead to loss of kidney function and, ultimately, death.

Prevention

Acute kidney failure is often difficult to predict or prevent. But you may reduce your risk by taking care of your kidneys. Try to:

• Pay attention to labels when taking over-the-counter (OTC) pain medications. Follow the instructions for OTC pain medications, such as aspirin, acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve, others). Taking too much of these medications may increase your risk of kidney injury. This is especially true if you have pre-existing kidney disease, diabetes, or high blood pressure.
• Work with your doctor to manage kidney and other chronic conditions. If you have kidney disease or another condition that increases your risk of acute kidney failures, such as diabetes or high blood pressure, stay on track with treatment goals and follow your doctor’s recommendations to manage your condition.
• Make a healthy lifestyle a priority. Be active; eat a sensible, balanced diet; and drink alcohol only in moderation — if at all.

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What is the most common cause of acute kidney injury?/Acute kidney injury (AKI) is where your kidneys suddenly stop working properly. It can range from minor loss of kidney function to complete kidney failure. AKI normally happens as a complication of another serious illness.

Acute kidney injury, previously known as acute renal failure, denotes a sudden and often reversible reduction in kidney function, as measured by increased creatinine or decreased urine volume. This activity reviews the evaluation and management of acute kidney injury and highlights the role of the interprofessional team in managing patients affected by this condition.

Acute kidney injury (AKI), previously called acute renal failure (ARF), denotes a sudden and often reversible reduction in kidney function, as measured by glomerular filtration rate (GFR).[rx][rx][rx] Although, immediately after a renal insult, blood urea nitrogen (BUN) or creatinine levels may be within the normal range. The only sign of acute kidney injury may be a decline in urine output. AKI can lead to the accumulation of water, sodium, and other metabolic products. It can also result in several electrolyte disturbances. It is a very common condition, especially among hospitalized patients. It can be seen in up to 7% of hospital admissions and 30% of ICU admissions. There is no clear definition of AKI; however, several different criteria have been used in research studies such as RIFLE, AKIN (Acute Kidney Injury Network), and KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Among these, KDIGO is the most recent and most commonly used tool. According to KDIGO, AKI is the presence of any of the following:

• Increase in serum creatinine by 0.3 mg/dL or more (26.5 micromoles/L or more) within 48 hours
• Increase in serum creatinine to 1.5 times or more baseline within the prior seven days
• Urine volume less than 0.5 mL/kg/h for at least 6 hours

Causes of Acute Kidney Injury

The impetus for glomerular filtration is the difference in the pressures between the glomerulus and the Bowman space. This pressure gradient is affected by the renal blood flow and is under the direct control of the combined resistances of afferent and efferent vascular pathways. Nevertheless, whatever the cause of AKI, renal blood flow reduction is a common pathologic pathway for declining glomerular filtration rate. Pathophysiology of AKI has always been traditionally divided into three categories: prerenal, renal, and post-renal. Each of these categories has several different causes associated with it.[rx][rx]

The prerenal form of AKI is because of any cause of reduced blood flow to the kidney. This may be part of systemic hypoperfusion resulting from hypovolemia or hypotension, or maybe due to selective hypoperfusion to the kidneys, such as those resulting from renal artery stenosis and aortic dissection. However, tubular and glomerular function tends to stay normal. Few examples with the mechanism of prerenal AKI are listed below:

• Hypovolemia: hemorrhage, severe burns, and gastrointestinal fluid losses such as diarrhea, vomiting, high ostomy output.
• Hypotension from the decreased cardiac output: cardiogenic shock, massive pulmonary embolism, acute coronary syndrome
• Hypotension from systemic vasodilation: septic shock, anaphylaxis, anesthesia administration, hepatorenal syndrome
• Renal vasoconstriction: NSAIDs, iodinated contrast, amphotericin B, calcineurin inhibitors, hepatorenal syndrome
• Glomerular efferent arteriolar vasodilation: ACE inhibitors, angiotensin receptor blockers
• Renal calculi
• Sickle cell anemia
• Chronic renal failure
• Dehydration
• Gastrointestinal bleeding
• Heart failure
• Urinary tract infection
• Protein overloading
• Diabetic ketoacidosis
• Urinary obstruction

Intrinsic renal causes include conditions that affect the glomerulus or tubule, such as acute tubular necrosis and acute interstitial nephritis. This underlying glomerular or tubular injury is associated with the release of vasoconstrictors from the renal afferent pathways. Prolonged renal ischemia, sepsis, and nephrotoxins being the most common ones. It is worth mentioning that prerenal injury can convert into a renal injury if the offending factor’s exposure is prolonged enough to cause cellular damage. Few examples of this mechanism are listed below:

• Acute tubular necrosis: ischemia from prolonged prerenal injury, drugs such as aminoglycosides, vancomycin, amphotericin B, pentamidine; rhabdomyolysis, intravascular hemolysis
• Acute interstitial nephritis: Drugs such as beta-lactam antibiotics, penicillins, NSAIDs, proton pump inhibitors (PPIs), 5-ASA; infections, autoimmune conditions (SLE, IgG related disease)
• Glomerulonephritis: anti-glomerular basement membrane disease, immune complex-mediated diseases such as SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy, Henoch-Schonlein purpura.
• Intratubular obstruction: monoclonal gammopathy seen in multiple myeloma, tumor lysis syndrome, toxins such as ethylene glycol.

Post-renal causes mainly include obstructive causes, which lead to congestion of the filtration system leading to a shift in the filtration driving forces. The most common ones being renal/ureteral calculi, tumors, blood clots, or any urethral obstruction. Another noteworthy fact is that a unilateral obstruction may not always present as AKI, especially if the obstruction is gradual such as a tumor, because a normal working contralateral kidney may compensate for the function of the affected kidney. Therefore, the most common etiology of post-renal AKI is bladder outlet obstruction.

Decreased blood flow

Some diseases and conditions can slow blood flow to your kidneys and cause AKI.

These diseases and conditions include:

• Low blood pressure (called “hypotension”) or shock
• Blood or fluid loss (such as bleeding, severe diarrhea)
• Heart attack, heart failure, and other conditions leading to decreased heart function
• Organ failure (e.g., heart, liver)
• Overuse of pain medicines called “NSAIDs”, which are used to reduce swelling or relieve pain from headaches, colds, flu, and other ailments.  Examples include ibuprofen, ketoprofen, and naproxen.
• Severe allergic reactions
• Burns
• Injury
• Major surgery

Direct Damage to the Kidneys

Some diseases and conditions can damage your kidneys and lead to AKI. Some examples include:

• A type of severe, life-threatening infection called “sepsis”
• A type of cancer called “multiple myeloma”
• A rare condition that causes inflammation and scarring to your blood vessels, making them stiff, weak, and narrow (called “vasculitis”)
• An allergic reaction to certain types of drugs (called “interstitial nephritis”)
• A group of diseases (called “scleroderma”) that affect the connective tissue that supports your internal organs
• Conditions that cause inflammation or damage to the kidney tubules, to the small blood vessels in the kidneys, or to the filtering units in the kidneys (such as “tubular necrosis,” “glomerulonephritis, “vasculitis” or “thrombotic microangiopathy”).
• Blood clots in or around the kidneys
• Diseases that affect the kidneys, such as glomerulonephritis and lupus
• Infection
• Certain medicines, such as some chemotherapy drugs, some antibiotics, and contrast dyes used during CT scans, MRI scans, and other imaging tests
• Alcohol or drug abuse
• Some blood or blood vessel disorders

Blockage of the urinary tract

In some people, conditions or diseases can block the passage of urine out of the body and can lead to AKI.

Blockage can be caused by:

• Bladder, prostate, or cervical cancer
• Enlarged prostate
• Problems with the nervous system that affect the bladder and urination
• Kidney stones
• Blood clots in the urinary tract
• Some cancers
• Blood clots in or around the kidneys
• Bladder problems
• Enlarged prostate (in men)

Some examples of problems that can cause you to have too little blood flowing through your kidneys are:

• Low blood pressure
• Bleeding too much
• Having severe diarrhea
• Heart disease or heart attack
• Infection
• Liver failure
• Using NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, ibuprofen and naproxen
• Serious burns
• Being very dehydrated (not having enough fluid in your body)
• Severe allergic reaction

Symptoms of Acute Kidney Injury

• Too little urine leaving the body
• Swelling in legs, ankles, and around the eyes
• Fatigue or tiredness
• Shortness of breath
• Confusion
• Nausea
• Seizures or coma in severe cases
• Chest pain or pressure

In some cases, AKI causes no symptoms and is only found through other tests done by your healthcare provider.

• Loss of appetite
• Fatigue and weakness
• Sleep problems
• Changes in how much you urinate
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that’s difficult to control

Diagnosis of Acute Kidney Injury

Histopathology can reliably differentiate the intrinsic renal pattern of AKI from others; however, histopathology may not be reliable at narrowing down a specific cause in every situation. Renal biopsy is an invasive procedure and is usually only pursued in cases where a significant impact on management is expected, such as suspected glomerulonephritis. In those cases, immunofluorescence patterns and electron microscopy can help differentiate between various causes.

History and Physical

The history and physical exam should focus on determining the etiology of AKI and the timeline of progression. If the history points towards hypovolemia or hypotension, then the treatment is guided towards volume repletion. The providers need to look for inciting events such as diarrhea, nausea, vomiting, which may have caused volume loss, or any over-the-counter drugs such as NSAIDs or other nephrotoxins. Differentiating between AKI and chronic kidney disease (CKD) is essential as CKD itself is not an uncommon risk factor for AKI. This can be achieved with the help of history in which one may find features suggestive of CKD such as chronic fatigue, anorexia, nocturia, disturbed sleep-wake cycle, polyuria, and pruritis. Moreover, a careful review of past medical history to reveal any co-morbid conditions can also help narrow down the etiology of AKI, for instance, cirrhosis and history of blood clots requiring anticoagulation. History and physical examination are very important in AKI because, more often than not, labs are unable to provide a clear answer as to the etiology of AKI.

The most common causes of AKI in hospitalized patients are in this order:

• ATN – 45%
• Prerenal disease – 21%
• Acute superimposed on CKD – 13%
• Urinary tract obstruction – 10% (most often due to Benign prostatic hypertrophy in older men)
• Glomerulonephritis or vasculitis – 4%
• AIN – 2%
• Atheroemboli – 1%

A history of urine output is important, which may give clues to the cause of AKI. Following are some associations:

• Oliguria – favors AKI
• Sudden anuria – suggests acute urinary tract obstruction, acute glomerulonephritis, or vascular catastrophe
• Gradually diminishing urine output – may be secondary to urethral stricture or bladder outlet obstruction due to causes such as prostate enlargement.

Performing a detailed examination is imperative as it provides extremely valuable information in establishing the etiology of AKI. A crucial part of the physical exam should be orthostatic vital signs since they are an important clue for hypovolemia and, in an appropriate clinical context, would guide treatment. Several organ systems need to be examined to find clues regarding the cause of AKI.

Lab Test and Imaging

• Skin – livedo reticularis, digital ischemia, butterfly rash, and purpuras to suggest vasculitis. Track marks to suggest endocarditis in an IV drug abuser.
• Eyes and ears – jaundice in liver disease, band keratopathy in multiple myeloma, signs of diabetes mellitus, atheroemboli in retinopathy, and signs of hypertension. Keratitis, iritis, and uveitis in autoimmune vasculitis. Hearing loss in Alport disease.
• Cardiovascular system – pulse rate, blood pressure, and jugulovenous pulse in establishing volume status. Irregular rhythm may indicate electrolyte imbalance-related arrhythmias. Pericardial friction rub in uremic pericarditis.
• Measuring urine output – Your healthcare provider will track how much urine you pass each day to help find the cause of your AKI.
• Urine tests – Your healthcare provider will look at your urine (urinalysis) to find signs of kidney failure
• Blood tests – Blood tests will help find levels of creatinine, urea nitrogen phosphorus and potassium should be done in addition to blood tests for protein in order to look at kidney function.
• Serum creatinine test – This test helps your doctor check whether creatinine is building up in your blood. Creatinine is a waste product that your kidneys should filter out of your body.
• Blood urea nitrogen test – This test helps your doctor check how much nitrogen is in your blood.
• Estimated glomerular filtration rate – This test allows your doctor to estimate how well your kidneys filter waste.
• Imaging tests – such as ultrasound, magnetic resonance imaging or computed tomography (CT) scan, to assess your kidneys’ structure and size and look for abnormalities.
• Removing a sample of kidney tissue (biopsy) – to examine under a microscope to learn what type of kidney disease you have and how much damage there is.
• GFR – Your blood test will also help find your GFR (glomerular filtration rate) to estimate the decrease in kidney function
• Kidney biopsy –  In some situations, your healthcare provider will do a procedure where a tiny piece of your kidney is removed with a special needle, and looked at under a microscope.
• Removing a sample of kidney tissue for testing. In some situations, your doctor may recommend a kidney biopsy to remove a small sample of kidney tissue for lab testing. Your doctor inserts a needle through your skin and into your kidney to remove the sample.

Evaluation of AKI should include a thorough search for all possible etiologies of AKI, including prerenal, renal, and post renal disease. The timing of the onset of AKI can be especially helpful when dealing with hospitalized patients. For example, if a patient’s labs are being checked every day and creatinine suddenly starts to rise on the fourth day of admission then an inciting factor can usually be found in 24-48 hours preceding the onset. It is especially important to look for any radiologic studies that might have been done involving the use of iodinated contrast agents which are not an uncommon cause of AKI. It is also imperative to review the list of medications that the patient is receiving as they may be contributing to renal failure, therefore in view of decreased renal function, the doses of such drugs need to be modified. ACE inhibitors and ARBs are often the co-contributors to AKI. A good physical exam can also be helpful sometimes e.g. the presence of a drug rash may point to acute interstitial nephritis being the etiology, cyanotic toes could suggest cholesterol emboli in a patient post cardiac catheterization.

All patients presenting with AKI warrant a basic lab panel including a basic metabolic panel. Sometimes, urine electrolytes can be helpful in suggesting an etiology of the AKI. Urine protein, urine osmolality, and urine albumin to creatinine ratios can also be helpful clues in determining the etiology of AKI. Older patients without any obvious etiology should also be subjected to serum and urine protein electrophoresis (SPEP and UPEP) to rule out monoclonal gammopathy and multiple myeloma. Renal ultrasound can be helpful if obstructive causes are suspected. However, routine renal ultrasound for every patient with AKI is not warranted. CT non-contrast is another important radiographic modality and can be used to look for nephrolithiasis or urolithiasis. Urine sediment examination can also provide important clues as to the etiology such as muddy brown casts seen in acute tubular necrosis. Sterile pyuria is the most sensitive sign of acute interstitial nephritis.[rx][rx]

A kidney biopsy is an excellent but infrequently utilized tool. It is usually indicated in patients with rapidly declining renal function without apparent cause or to find out the exact etiology of AKI in a setting where multiple etiologies could be responsible. It is a test with a number of risks such as bleeding particularly in patients with platelet dysfunction from uremia.

There are markers of tubular function that can be calculated to help distinguish prerenal causes from renal/postrenal, like the fractional excretion of sodium and urea, and urine osmolality; however, the sensitivity of all these markers is very poor, and they are affected by many drugs very commonly used in clinical practice such as diuretics. Therefore, no single marker can be reliably used in isolation to distinguish prerenal from renal causes of AKI, which is a common misconception in clinical practice.

Lastly, attention also needs to be paid to the overall clinical picture. It is important to assess the volume status of the patient to exclude possible cardiorenal or hepatorenal syndrome. The cardiorenal syndrome is usually due to poor glomerular filtration due to venous congestion along with a lack of forwarding flow in some cases due to poor cardiac output. Hepatorenal syndrome is due to the differential distribution of circulation volume with systemic vasodilation and splanchnic vasoconstriction leading to the diversion of blood into the periphery and paucity of blood supply to the kidneys.

Treatment of Acute Kidney Injury

With the exception of post-renal AKI, most cases are an overlap between pre-renal and acute tubular necrosis type of AKI. [rx][rx] The best way to determine if the AKI is pre-renal or not is a fluid challenge. If the clinical scenario doesn’t contradict it, all patients with acute renal dysfunction should receive a fluid challenge. They require close monitoring of urine output and renal function. If the renal function improves with fluid, that is the best indicator of a pre-Renal AKI. Acute tubular necrosis is very slow to recover and can take weeks to months for complete recovery of renal function. It may not normalize at all sometimes. Diuretics may be required during the oliguric phase of ATN if significant volume overload develops. Another important thing to consider for these patients is to avoid any further insult to the kidneys, such as nephrotoxic drugs. Any and the doses of all medications need to be really adjusted once a patient develops AKI. Another vital step is to limit the dietary ingestion of potassium and phosphorus.

If hyperkalemia develops, it needs to be managed in a robust manner because, in AKI patients, it can be catastrophic. Approaches to lower potassium in the body include:

• Dietary restriction
• Insulin, IV dextrose and beta-agonists
• potassium-binding resins
• Calcium gluconate to stabilize cardiac membrane
• Dialysis for nonresponsive hyperkalemia

Some AKI patients would tend to develop volume overload, which should be corrected as early as possible to avoid pulmonary and cardiac complications. Euvolemic state can be achieved with the help of furosemide, which is a cornerstone in the management of such patients. Usually, high doses of IV furosemide are needed to correct volume overload in AKI patients; however, it plays no role in the conversion of oliguric AKI to non-oliguric AKI.

Sometimes, AKI may need short-term renal replacement therapy until the kidney function recovers. Dialysis is usually required to manage the complications of AKI, such as severe and nonresponsive hyperkalemia, uremic pericarditis, and pulmonary edema. This is seen especially in the oliguric phase of acute tubular necrosis, where the patient is prone to develop multiple electrolyte and acid-base abnormalities as well as fluid overload.[rx] When required, dialysis in this setting is usually performed through a double-lumen central venous catheter. Continuous renal replacement therapy can also be utilized in patients who cannot tolerate hemodialysis due to hypotension. It is a much slower, continuous type of dialysis. Correction of some of the metabolic abnormalities, along with dialysis, may be required. Metabolic acidosis is one such instance where systemic administration of citrate or bicarbonate is often required to maintain a suitable blood pH. The requirement for renal replacement therapy should be reevaluated in these patients daily while they are hospitalized and at least weekly thereafter until the kidney function is stable. Renal replacement therapy is usually required for the short term ranging from a few days to a few weeks in most cases; however, acute tubular necrosis can take up to months to recover and may, therefore, require intermittent hemodialysis support during that time.

There are certain specific treatments that are required for acute kidney injury in specific circumstances, such as administration of vasoactive medications and colloids for treatment of hepatorenal syndrome and cautious diuresis in cardiorenal syndrome. Acute kidney injury from various glomerulonephritides may require immunosuppressive medications for treatment. Acute interstitial nephritis, which does not recover with supportive care, may benefit from a trial of steroids. Post renal obstruction may need to be relieved operatively in certain situations. For example, benign prostatic hypertrophy may require surgical relief of bladder outlet obstruction. Urethral calculi may require stenting and lithotripsy.

It is also important to note that in a certain situation, the risk of acute kidney injury may be decreased by taking some measures. For example, in high-risk patients such as those with compromised renal function at baseline, it may be beneficial to administer peri-procedure intravenous fluids to prevent contrast-induced nephropathy when performing cardiac catheterization.

Treating complications until your kidneys recover

Your doctor will also work to prevent complications and allow your kidneys time to heal. Treatments that help prevent complications include:

• Treatments to balance the number of fluids in your blood – If your acute kidney failure is caused by a lack of fluids in your blood, your doctor may recommend intravenous (IV) fluids. In other cases, acute kidney failure may cause you to have too much fluid, leading to swelling in your arms and legs. In these cases, your doctor may recommend medications (diuretics) to cause your body to expel extra fluids.
• Medications to control blood potassium – If your kidneys aren’t properly filtering potassium from your blood, your doctor may prescribe calcium, glucose or sodium polystyrene sulfonate (Kionex) to prevent the accumulation of high levels of potassium in your blood. Too much potassium in the blood can cause dangerous irregular heartbeats (arrhythmias) and muscle weakness.
• Medications to restore blood calcium levels – If the levels of calcium in your blood drop too low, your doctor may recommend an infusion of calcium.
• Dialysis to remove toxins from your blood – If toxins build up in your blood, you may need temporary hemodialysis — often referred to simply as dialysis — to help remove toxins and excess fluids from your body while your kidneys heal. Dialysis may also help remove excess potassium from your body. During dialysis, a machine pumps blood out of your body through an artificial kidney (dialyzer) that filters out waste. The blood is then returned to your body.

Prerenal

• In prerenal AKI without fluid overload, administration of intravenous fluids is typically the first step to improving kidney function. Volume status may be monitored with the use of a central venous catheter to avoid over-or under-replacement of fluid.
• If low blood pressure persists despite providing a person with adequate amounts of intravenous fluid, medications that increase blood pressure (vasopressors) such as norepinephrine, and in certain circumstances medications that improve the heart’s ability to pump (known as inotropes) such as dobutamine may be given to improve blood flow to the kidney. While a useful vasopressor, there is no evidence to suggest that dopamine is of any specific benefit and may in fact be harmful.^[rx]

Intrinsic

• The myriad causes of intrinsic AKI require specific therapies. For example, intrinsic AKI due to vasculitis or glomerulonephritis may respond to steroid medication, cyclophosphamide, and (in some cases) plasma exchange. Toxin-induced prerenal AKI often responds to discontinuation of the offending agent, such as ACE inhibitors, ARB antagonists, aminoglycosides, penicillins, NSAIDs, or paracetamol.^[rx]
• The use of diuretics such as furosemide is widespread and sometimes convenient in improving fluid overload. It is not associated with higher mortality (risk of death),^[rx] nor with any reduced mortality or length of intensive care unit or hospital stay.^[rx]

Postrenal

• If the cause is obstruction of the urinary tract, relief of the obstruction (with a nephrostomy or urinary catheter) may be necessary.

Renal replacement therapy

• Renal replacement therapy, such as with hemodialysis, may be instituted in some cases of AKI. Renal replacement therapy can be applied intermittently (IRRT) and continuously (CRRT). Study results regarding differences in outcomes between IRRT and CRRT are inconsistent.
• A systematic review of the literature in 2008 demonstrated no difference in outcomes between the use of intermittent hemodialysis and continuous venovenous hemofiltration (CVVH) (a type of continuous hemodialysis).^[rx] Among critically ill patients, intensive renal replacement therapy with CVVH does not appear to improve outcomes compared to less intensive intermittent hemodialysis.^[rx][rx]
• However, other clinical and health economic studies demonstrated that, initiation of CRRT is associated with a lower likelihood of chronic dialysis and was cost-effective compared with IRRT in patients with acute kidney injury.^[rx][rx][rx]

Complications

Several complications may associate AKI with mortality. Some of these complications are directly associated with AKI and can easily be gauged (hyperkalemia, volume overload, metabolic acidosis, hyponatremia); however, the effect of other complications on AKI-related mortality, such as inflammation and infection, is difficult to assess. Most common complications include metabolic derangements such as:

• Hyperkalemia –  If severe, it can lead to arrhythmias because of which renal replacement therapy is required in cases of severe hyperkalemia.
• Metabolic acidosis – The kidney’s inability to excrete acids leads to metabolic acidosis and may necessitate systemic administration of bicarbonate or citrate buffers.
• Hyperphosphatemia – can usually be prevented by decreasing dietary ingestion or using phosphate binders. Other effects include pulmonary edema from volume overload, peripheral edema from an inability to excrete body water. This is especially common in the oliguric phase of acute tubular necrosis. It may necessitate the use of diuretics or renal replacement therapy.
• Cardiovascular – Heart failure secondary to fluid overload is attributable to oliguric AKI, arrhythmias secondary to acidotic state and electrolyte abnormalities, cardiac arrest due to metabolic derangements, and myocardial infarction, and rarely pericarditis.
• Gastrointestinal (GI) – Nausea, vomiting, GI bleeding, and anorexia. A mildly raised level of amylase is commonly found in patients suffering from AKI. Elevation of amylase concentration can make the diagnosis of pancreatitis difficult, therefore measuring lipase, which is not raised in AKI, is necessary to establish AKI diagnosis.
• Neurologic – CNS-related signs of uremic burden are common in AKI, and they include lethargy, somnolence, disturbed sleep-wake cycle, and cognitive impairment.
• Fluid buildup – Acute kidney failure may lead to a buildup of fluid in your lungs, which can cause shortness of breath.
• Chest pain – If the lining that covers your heart (pericardium) becomes inflamed, you may experience chest pain.
• Muscle weakness – When your body’s fluids and electrolytes — your body’s blood chemistry — are out of balance, muscle weakness can result.
• Permanent kidney damage – Occasionally, acute kidney failure causes permanent loss of kidney function or end-stage renal disease. People with the end-stage renal disease require either permanent dialysis — a mechanical filtration process used to remove toxins and wastes from the body — or a kidney transplant to survive.
• Death – Acute kidney failure can lead to loss of kidney function and, ultimately, death.

Prevention

Acute kidney failure is often difficult to predict or prevent. But you may reduce your risk by taking care of your kidneys. Try to:

• Pay attention to labels when taking over-the-counter (OTC) pain medications. Follow the instructions for OTC pain medications, such as aspirin, acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve, others). Taking too much of these medications may increase your risk of kidney injury. This is especially true if you have pre-existing kidney disease, diabetes, or high blood pressure.
• Work with your doctor to manage kidney and other chronic conditions. If you have kidney disease or another condition that increases your risk of acute kidney failures, such as diabetes or high blood pressure, stay on track with treatment goals and follow your doctor’s recommendations to manage your condition.
• Make a healthy lifestyle a priority. Be active; eat a sensible, balanced diet; and drink alcohol only in moderation — if at all.

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Acute kidney injury (AKI) is where your kidneys suddenly stop working properly. It can range from minor loss of kidney function to complete kidney failure. AKI normally happens as a complication of another serious illness.

Acute kidney injury, previously known as acute renal failure, denotes a sudden and often reversible reduction in kidney function, as measured by increased creatinine or decreased urine volume. This activity reviews the evaluation and management of acute kidney injury and highlights the role of the interprofessional team in managing patients affected by this condition.

Acute kidney injury (AKI), previously called acute renal failure (ARF), denotes a sudden and often reversible reduction in kidney function, as measured by glomerular filtration rate (GFR).[rx][rx][rx] Although, immediately after a renal insult, blood urea nitrogen (BUN) or creatinine levels may be within the normal range. The only sign of acute kidney injury may be a decline in urine output. AKI can lead to the accumulation of water, sodium, and other metabolic products. It can also result in several electrolyte disturbances. It is a very common condition, especially among hospitalized patients. It can be seen in up to 7% of hospital admissions and 30% of ICU admissions. There is no clear definition of AKI; however, several different criteria have been used in research studies such as RIFLE, AKIN (Acute Kidney Injury Network), and KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Among these, KDIGO is the most recent and most commonly used tool. According to KDIGO, AKI is the presence of any of the following:

• Increase in serum creatinine by 0.3 mg/dL or more (26.5 micromoles/L or more) within 48 hours
• Increase in serum creatinine to 1.5 times or more baseline within the prior seven days
• Urine volume less than 0.5 mL/kg/h for at least 6 hours

Causes of Acute Kidney Injury

The impetus for glomerular filtration is the difference in the pressures between the glomerulus and the Bowman space. This pressure gradient is affected by the renal blood flow and is under the direct control of the combined resistances of afferent and efferent vascular pathways. Nevertheless, whatever the cause of AKI, renal blood flow reduction is a common pathologic pathway for declining glomerular filtration rate. Pathophysiology of AKI has always been traditionally divided into three categories: prerenal, renal, and post-renal. Each of these categories has several different causes associated with it.[rx][rx]

The prerenal form of AKI is because of any cause of reduced blood flow to the kidney. This may be part of systemic hypoperfusion resulting from hypovolemia or hypotension, or maybe due to selective hypoperfusion to the kidneys, such as those resulting from renal artery stenosis and aortic dissection. However, tubular and glomerular function tends to stay normal. Few examples with the mechanism of prerenal AKI are listed below:

• Hypovolemia: hemorrhage, severe burns, and gastrointestinal fluid losses such as diarrhea, vomiting, high ostomy output.
• Hypotension from the decreased cardiac output: cardiogenic shock, massive pulmonary embolism, acute coronary syndrome
• Hypotension from systemic vasodilation: septic shock, anaphylaxis, anesthesia administration, hepatorenal syndrome
• Renal vasoconstriction: NSAIDs, iodinated contrast, amphotericin B, calcineurin inhibitors, hepatorenal syndrome
• Glomerular efferent arteriolar vasodilation: ACE inhibitors, angiotensin receptor blockers
• Renal calculi
• Sickle cell anemia
• Chronic renal failure
• Dehydration
• Gastrointestinal bleeding
• Heart failure
• Urinary tract infection
• Protein overloading
• Diabetic ketoacidosis
• Urinary obstruction

Intrinsic renal causes include conditions that affect the glomerulus or tubule, such as acute tubular necrosis and acute interstitial nephritis. This underlying glomerular or tubular injury is associated with the release of vasoconstrictors from the renal afferent pathways. Prolonged renal ischemia, sepsis, and nephrotoxins being the most common ones. It is worth mentioning that prerenal injury can convert into a renal injury if the offending factor’s exposure is prolonged enough to cause cellular damage. Few examples of this mechanism are listed below:

• Acute tubular necrosis: ischemia from prolonged prerenal injury, drugs such as aminoglycosides, vancomycin, amphotericin B, pentamidine; rhabdomyolysis, intravascular hemolysis
• Acute interstitial nephritis: Drugs such as beta-lactam antibiotics, penicillins, NSAIDs, proton pump inhibitors (PPIs), 5-ASA; infections, autoimmune conditions (SLE, IgG related disease)
• Glomerulonephritis: anti-glomerular basement membrane disease, immune complex-mediated diseases such as SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy, Henoch-Schonlein purpura.
• Intratubular obstruction: monoclonal gammopathy seen in multiple myeloma, tumor lysis syndrome, toxins such as ethylene glycol.

Post-renal causes mainly include obstructive causes, which lead to congestion of the filtration system leading to a shift in the filtration driving forces. The most common ones being renal/ureteral calculi, tumors, blood clots, or any urethral obstruction. Another noteworthy fact is that a unilateral obstruction may not always present as AKI, especially if the obstruction is gradual such as a tumor, because a normal working contralateral kidney may compensate for the function of the affected kidney. Therefore, the most common etiology of post-renal AKI is bladder outlet obstruction.

Decreased blood flow

Some diseases and conditions can slow blood flow to your kidneys and cause AKI.

These diseases and conditions include:

• Low blood pressure (called “hypotension”) or shock
• Blood or fluid loss (such as bleeding, severe diarrhea)
• Heart attack, heart failure, and other conditions leading to decreased heart function
• Organ failure (e.g., heart, liver)
• Overuse of pain medicines called “NSAIDs”, which are used to reduce swelling or relieve pain from headaches, colds, flu, and other ailments.  Examples include ibuprofen, ketoprofen, and naproxen.
• Severe allergic reactions
• Burns
• Injury
• Major surgery

Direct Damage to the Kidneys

Some diseases and conditions can damage your kidneys and lead to AKI. Some examples include:

• A type of severe, life-threatening infection called “sepsis”
• A type of cancer called “multiple myeloma”
• A rare condition that causes inflammation and scarring to your blood vessels, making them stiff, weak, and narrow (called “vasculitis”)
• An allergic reaction to certain types of drugs (called “interstitial nephritis”)
• A group of diseases (called “scleroderma”) that affect the connective tissue that supports your internal organs
• Conditions that cause inflammation or damage to the kidney tubules, to the small blood vessels in the kidneys, or to the filtering units in the kidneys (such as “tubular necrosis,” “glomerulonephritis, “vasculitis” or “thrombotic microangiopathy”).
• Blood clots in or around the kidneys
• Diseases that affect the kidneys, such as glomerulonephritis and lupus
• Infection
• Certain medicines, such as some chemotherapy drugs, some antibiotics, and contrast dyes used during CT scans, MRI scans, and other imaging tests
• Alcohol or drug abuse
• Some blood or blood vessel disorders

Blockage of the urinary tract

In some people, conditions or diseases can block the passage of urine out of the body and can lead to AKI.

Blockage can be caused by:

• Bladder, prostate, or cervical cancer
• Enlarged prostate
• Problems with the nervous system that affect the bladder and urination
• Kidney stones
• Blood clots in the urinary tract
• Some cancers
• Blood clots in or around the kidneys
• Bladder problems
• Enlarged prostate (in men)

Some examples of problems that can cause you to have too little blood flowing through your kidneys are:

• Low blood pressure
• Bleeding too much
• Having severe diarrhea
• Heart disease or heart attack
• Infection
• Liver failure
• Using NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, ibuprofen and naproxen
• Serious burns
• Being very dehydrated (not having enough fluid in your body)
• Severe allergic reaction

Symptoms of Acute Kidney Injury

• Too little urine leaving the body
• Swelling in legs, ankles, and around the eyes
• Fatigue or tiredness
• Shortness of breath
• Confusion
• Nausea
• Seizures or coma in severe cases
• Chest pain or pressure

In some cases, AKI causes no symptoms and is only found through other tests done by your healthcare provider.

• Loss of appetite
• Fatigue and weakness
• Sleep problems
• Changes in how much you urinate
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that’s difficult to control

Diagnosis of Acute Kidney Injury

Histopathology can reliably differentiate the intrinsic renal pattern of AKI from others; however, histopathology may not be reliable at narrowing down a specific cause in every situation. Renal biopsy is an invasive procedure and is usually only pursued in cases where a significant impact on management is expected, such as suspected glomerulonephritis. In those cases, immunofluorescence patterns and electron microscopy can help differentiate between various causes.

History and Physical

The history and physical exam should focus on determining the etiology of AKI and the timeline of progression. If the history points towards hypovolemia or hypotension, then the treatment is guided towards volume repletion. The providers need to look for inciting events such as diarrhea, nausea, vomiting, which may have caused volume loss, or any over-the-counter drugs such as NSAIDs or other nephrotoxins. Differentiating between AKI and chronic kidney disease (CKD) is essential as CKD itself is not an uncommon risk factor for AKI. This can be achieved with the help of history in which one may find features suggestive of CKD such as chronic fatigue, anorexia, nocturia, disturbed sleep-wake cycle, polyuria, and pruritis. Moreover, a careful review of past medical history to reveal any co-morbid conditions can also help narrow down the etiology of AKI, for instance, cirrhosis and history of blood clots requiring anticoagulation. History and physical examination are very important in AKI because, more often than not, labs are unable to provide a clear answer as to the etiology of AKI.

The most common causes of AKI in hospitalized patients are in this order:

• ATN – 45%
• Prerenal disease – 21%
• Acute superimposed on CKD – 13%
• Urinary tract obstruction – 10% (most often due to Benign prostatic hypertrophy in older men)
• Glomerulonephritis or vasculitis – 4%
• AIN – 2%
• Atheroemboli – 1%

A history of urine output is important, which may give clues to the cause of AKI. Following are some associations:

• Oliguria – favors AKI
• Sudden anuria – suggests acute urinary tract obstruction, acute glomerulonephritis, or vascular catastrophe
• Gradually diminishing urine output – may be secondary to urethral stricture or bladder outlet obstruction due to causes such as prostate enlargement.

Performing a detailed examination is imperative as it provides extremely valuable information in establishing the etiology of AKI. A crucial part of the physical exam should be orthostatic vital signs since they are an important clue for hypovolemia and, in an appropriate clinical context, would guide treatment. Several organ systems need to be examined to find clues regarding the cause of AKI.

Lab Test and Imaging

• Skin – livedo reticularis, digital ischemia, butterfly rash, and purpuras to suggest vasculitis. Track marks to suggest endocarditis in an IV drug abuser.
• Eyes and ears – jaundice in liver disease, band keratopathy in multiple myeloma, signs of diabetes mellitus, atheroemboli in retinopathy, and signs of hypertension. Keratitis, iritis, and uveitis in autoimmune vasculitis. Hearing loss in Alport disease.
• Cardiovascular system – pulse rate, blood pressure, and jugulovenous pulse in establishing volume status. Irregular rhythm may indicate electrolyte imbalance-related arrhythmias. Pericardial friction rub in uremic pericarditis.
• Measuring urine output – Your healthcare provider will track how much urine you pass each day to help find the cause of your AKI.
• Urine tests – Your healthcare provider will look at your urine (urinalysis) to find signs of kidney failure
• Blood tests – Blood tests will help find levels of creatinine, urea nitrogen phosphorus and potassium should be done in addition to blood tests for protein in order to look at kidney function.
• Serum creatinine test – This test helps your doctor check whether creatinine is building up in your blood. Creatinine is a waste product that your kidneys should filter out of your body.
• Blood urea nitrogen test – This test helps your doctor check how much nitrogen is in your blood.
• Estimated glomerular filtration rate – This test allows your doctor to estimate how well your kidneys filter waste.
• Imaging tests – such as ultrasound, magnetic resonance imaging or computed tomography (CT) scan, to assess your kidneys’ structure and size and look for abnormalities.
• Removing a sample of kidney tissue (biopsy) – to examine under a microscope to learn what type of kidney disease you have and how much damage there is.
• GFR – Your blood test will also help find your GFR (glomerular filtration rate) to estimate the decrease in kidney function
• Kidney biopsy –  In some situations, your healthcare provider will do a procedure where a tiny piece of your kidney is removed with a special needle, and looked at under a microscope.
• Removing a sample of kidney tissue for testing. In some situations, your doctor may recommend a kidney biopsy to remove a small sample of kidney tissue for lab testing. Your doctor inserts a needle through your skin and into your kidney to remove the sample.

Evaluation of AKI should include a thorough search for all possible etiologies of AKI, including prerenal, renal, and post renal disease. The timing of the onset of AKI can be especially helpful when dealing with hospitalized patients. For example, if a patient’s labs are being checked every day and creatinine suddenly starts to rise on the fourth day of admission then an inciting factor can usually be found in 24-48 hours preceding the onset. It is especially important to look for any radiologic studies that might have been done involving the use of iodinated contrast agents which are not an uncommon cause of AKI. It is also imperative to review the list of medications that the patient is receiving as they may be contributing to renal failure, therefore in view of decreased renal function, the doses of such drugs need to be modified. ACE inhibitors and ARBs are often the co-contributors to AKI. A good physical exam can also be helpful sometimes e.g. the presence of a drug rash may point to acute interstitial nephritis being the etiology, cyanotic toes could suggest cholesterol emboli in a patient post cardiac catheterization.

All patients presenting with AKI warrant a basic lab panel including a basic metabolic panel. Sometimes, urine electrolytes can be helpful in suggesting an etiology of the AKI. Urine protein, urine osmolality, and urine albumin to creatinine ratios can also be helpful clues in determining the etiology of AKI. Older patients without any obvious etiology should also be subjected to serum and urine protein electrophoresis (SPEP and UPEP) to rule out monoclonal gammopathy and multiple myeloma. Renal ultrasound can be helpful if obstructive causes are suspected. However, routine renal ultrasound for every patient with AKI is not warranted. CT non-contrast is another important radiographic modality and can be used to look for nephrolithiasis or urolithiasis. Urine sediment examination can also provide important clues as to the etiology such as muddy brown casts seen in acute tubular necrosis. Sterile pyuria is the most sensitive sign of acute interstitial nephritis.[rx][rx]

A kidney biopsy is an excellent but infrequently utilized tool. It is usually indicated in patients with rapidly declining renal function without apparent cause or to find out the exact etiology of AKI in a setting where multiple etiologies could be responsible. It is a test with a number of risks such as bleeding particularly in patients with platelet dysfunction from uremia.

There are markers of tubular function that can be calculated to help distinguish prerenal causes from renal/postrenal, like the fractional excretion of sodium and urea, and urine osmolality; however, the sensitivity of all these markers is very poor, and they are affected by many drugs very commonly used in clinical practice such as diuretics. Therefore, no single marker can be reliably used in isolation to distinguish prerenal from renal causes of AKI, which is a common misconception in clinical practice.

Lastly, attention also needs to be paid to the overall clinical picture. It is important to assess the volume status of the patient to exclude possible cardiorenal or hepatorenal syndrome. The cardiorenal syndrome is usually due to poor glomerular filtration due to venous congestion along with a lack of forwarding flow in some cases due to poor cardiac output. Hepatorenal syndrome is due to the differential distribution of circulation volume with systemic vasodilation and splanchnic vasoconstriction leading to the diversion of blood into the periphery and paucity of blood supply to the kidneys.

Treatment of Acute Kidney Injury

With the exception of post-renal AKI, most cases are an overlap between pre-renal and acute tubular necrosis type of AKI. [rx][rx] The best way to determine if the AKI is pre-renal or not is a fluid challenge. If the clinical scenario doesn’t contradict it, all patients with acute renal dysfunction should receive a fluid challenge. They require close monitoring of urine output and renal function. If the renal function improves with fluid, that is the best indicator of a pre-Renal AKI. Acute tubular necrosis is very slow to recover and can take weeks to months for complete recovery of renal function. It may not normalize at all sometimes. Diuretics may be required during the oliguric phase of ATN if significant volume overload develops. Another important thing to consider for these patients is to avoid any further insult to the kidneys, such as nephrotoxic drugs. Any and the doses of all medications need to be really adjusted once a patient develops AKI. Another vital step is to limit the dietary ingestion of potassium and phosphorus.

If hyperkalemia develops, it needs to be managed in a robust manner because, in AKI patients, it can be catastrophic. Approaches to lower potassium in the body include:

• Dietary restriction
• Insulin, IV dextrose and beta-agonists
• potassium-binding resins
• Calcium gluconate to stabilize cardiac membrane
• Dialysis for nonresponsive hyperkalemia

Some AKI patients would tend to develop volume overload, which should be corrected as early as possible to avoid pulmonary and cardiac complications. Euvolemic state can be achieved with the help of furosemide, which is a cornerstone in the management of such patients. Usually, high doses of IV furosemide are needed to correct volume overload in AKI patients; however, it plays no role in the conversion of oliguric AKI to non-oliguric AKI.

Sometimes, AKI may need short-term renal replacement therapy until the kidney function recovers. Dialysis is usually required to manage the complications of AKI, such as severe and nonresponsive hyperkalemia, uremic pericarditis, and pulmonary edema. This is seen especially in the oliguric phase of acute tubular necrosis, where the patient is prone to develop multiple electrolyte and acid-base abnormalities as well as fluid overload.[rx] When required, dialysis in this setting is usually performed through a double-lumen central venous catheter. Continuous renal replacement therapy can also be utilized in patients who cannot tolerate hemodialysis due to hypotension. It is a much slower, continuous type of dialysis. Correction of some of the metabolic abnormalities, along with dialysis, may be required. Metabolic acidosis is one such instance where systemic administration of citrate or bicarbonate is often required to maintain a suitable blood pH. The requirement for renal replacement therapy should be reevaluated in these patients daily while they are hospitalized and at least weekly thereafter until the kidney function is stable. Renal replacement therapy is usually required for the short term ranging from a few days to a few weeks in most cases; however, acute tubular necrosis can take up to months to recover and may, therefore, require intermittent hemodialysis support during that time.

There are certain specific treatments that are required for acute kidney injury in specific circumstances, such as administration of vasoactive medications and colloids for treatment of hepatorenal syndrome and cautious diuresis in cardiorenal syndrome. Acute kidney injury from various glomerulonephritides may require immunosuppressive medications for treatment. Acute interstitial nephritis, which does not recover with supportive care, may benefit from a trial of steroids. Post renal obstruction may need to be relieved operatively in certain situations. For example, benign prostatic hypertrophy may require surgical relief of bladder outlet obstruction. Urethral calculi may require stenting and lithotripsy.

It is also important to note that in a certain situation, the risk of acute kidney injury may be decreased by taking some measures. For example, in high-risk patients such as those with compromised renal function at baseline, it may be beneficial to administer peri-procedure intravenous fluids to prevent contrast-induced nephropathy when performing cardiac catheterization.

Treating complications until your kidneys recover

Your doctor will also work to prevent complications and allow your kidneys time to heal. Treatments that help prevent complications include:

• Treatments to balance the number of fluids in your blood – If your acute kidney failure is caused by a lack of fluids in your blood, your doctor may recommend intravenous (IV) fluids. In other cases, acute kidney failure may cause you to have too much fluid, leading to swelling in your arms and legs. In these cases, your doctor may recommend medications (diuretics) to cause your body to expel extra fluids.
• Medications to control blood potassium – If your kidneys aren’t properly filtering potassium from your blood, your doctor may prescribe calcium, glucose or sodium polystyrene sulfonate (Kionex) to prevent the accumulation of high levels of potassium in your blood. Too much potassium in the blood can cause dangerous irregular heartbeats (arrhythmias) and muscle weakness.
• Medications to restore blood calcium levels – If the levels of calcium in your blood drop too low, your doctor may recommend an infusion of calcium.
• Dialysis to remove toxins from your blood – If toxins build up in your blood, you may need temporary hemodialysis — often referred to simply as dialysis — to help remove toxins and excess fluids from your body while your kidneys heal. Dialysis may also help remove excess potassium from your body. During dialysis, a machine pumps blood out of your body through an artificial kidney (dialyzer) that filters out waste. The blood is then returned to your body.

Prerenal

• In prerenal AKI without fluid overload, administration of intravenous fluids is typically the first step to improving kidney function. Volume status may be monitored with the use of a central venous catheter to avoid over-or under-replacement of fluid.
• If low blood pressure persists despite providing a person with adequate amounts of intravenous fluid, medications that increase blood pressure (vasopressors) such as norepinephrine, and in certain circumstances medications that improve the heart’s ability to pump (known as inotropes) such as dobutamine may be given to improve blood flow to the kidney. While a useful vasopressor, there is no evidence to suggest that dopamine is of any specific benefit and may in fact be harmful.^[rx]

Intrinsic

• The myriad causes of intrinsic AKI require specific therapies. For example, intrinsic AKI due to vasculitis or glomerulonephritis may respond to steroid medication, cyclophosphamide, and (in some cases) plasma exchange. Toxin-induced prerenal AKI often responds to discontinuation of the offending agent, such as ACE inhibitors, ARB antagonists, aminoglycosides, penicillins, NSAIDs, or paracetamol.^[rx]
• The use of diuretics such as furosemide is widespread and sometimes convenient in improving fluid overload. It is not associated with higher mortality (risk of death),^[rx] nor with any reduced mortality or length of intensive care unit or hospital stay.^[rx]

Postrenal

• If the cause is obstruction of the urinary tract, relief of the obstruction (with a nephrostomy or urinary catheter) may be necessary.

Renal replacement therapy

• Renal replacement therapy, such as with hemodialysis, may be instituted in some cases of AKI. Renal replacement therapy can be applied intermittently (IRRT) and continuously (CRRT). Study results regarding differences in outcomes between IRRT and CRRT are inconsistent.
• A systematic review of the literature in 2008 demonstrated no difference in outcomes between the use of intermittent hemodialysis and continuous venovenous hemofiltration (CVVH) (a type of continuous hemodialysis).^[rx] Among critically ill patients, intensive renal replacement therapy with CVVH does not appear to improve outcomes compared to less intensive intermittent hemodialysis.^[rx][rx]
• However, other clinical and health economic studies demonstrated that, initiation of CRRT is associated with a lower likelihood of chronic dialysis and was cost-effective compared with IRRT in patients with acute kidney injury.^[rx][rx][rx]

Complications

Several complications may associate AKI with mortality. Some of these complications are directly associated with AKI and can easily be gauged (hyperkalemia, volume overload, metabolic acidosis, hyponatremia); however, the effect of other complications on AKI-related mortality, such as inflammation and infection, is difficult to assess. Most common complications include metabolic derangements such as:

• Hyperkalemia –  If severe, it can lead to arrhythmias because of which renal replacement therapy is required in cases of severe hyperkalemia.
• Metabolic acidosis – The kidney’s inability to excrete acids leads to metabolic acidosis and may necessitate systemic administration of bicarbonate or citrate buffers.
• Hyperphosphatemia – can usually be prevented by decreasing dietary ingestion or using phosphate binders. Other effects include pulmonary edema from volume overload, peripheral edema from an inability to excrete body water. This is especially common in the oliguric phase of acute tubular necrosis. It may necessitate the use of diuretics or renal replacement therapy.
• Cardiovascular – Heart failure secondary to fluid overload is attributable to oliguric AKI, arrhythmias secondary to acidotic state and electrolyte abnormalities, cardiac arrest due to metabolic derangements, and myocardial infarction, and rarely pericarditis.
• Gastrointestinal (GI) – Nausea, vomiting, GI bleeding, and anorexia. A mildly raised level of amylase is commonly found in patients suffering from AKI. Elevation of amylase concentration can make the diagnosis of pancreatitis difficult, therefore measuring lipase, which is not raised in AKI, is necessary to establish AKI diagnosis.
• Neurologic – CNS-related signs of uremic burden are common in AKI, and they include lethargy, somnolence, disturbed sleep-wake cycle, and cognitive impairment.
• Fluid buildup – Acute kidney failure may lead to a buildup of fluid in your lungs, which can cause shortness of breath.
• Chest pain – If the lining that covers your heart (pericardium) becomes inflamed, you may experience chest pain.
• Muscle weakness – When your body’s fluids and electrolytes — your body’s blood chemistry — are out of balance, muscle weakness can result.
• Permanent kidney damage – Occasionally, acute kidney failure causes permanent loss of kidney function or end-stage renal disease. People with the end-stage renal disease require either permanent dialysis — a mechanical filtration process used to remove toxins and wastes from the body — or a kidney transplant to survive.
• Death – Acute kidney failure can lead to loss of kidney function and, ultimately, death.

Prevention

Acute kidney failure is often difficult to predict or prevent. But you may reduce your risk by taking care of your kidneys. Try to:

• Pay attention to labels when taking over-the-counter (OTC) pain medications. Follow the instructions for OTC pain medications, such as aspirin, acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve, others). Taking too much of these medications may increase your risk of kidney injury. This is especially true if you have pre-existing kidney disease, diabetes, or high blood pressure.
• Work with your doctor to manage kidney and other chronic conditions. If you have kidney disease or another condition that increases your risk of acute kidney failures, such as diabetes or high blood pressure, stay on track with treatment goals and follow your doctor’s recommendations to manage your condition.
• Make a healthy lifestyle a priority. Be active; eat a sensible, balanced diet; and drink alcohol only in moderation — if at all.

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053

Causes of Stage 3 Kidney Disease

Many chronic diseases can cause end-stage renal disease. In the United States, diabetes mellitus is the leading cause. Other causes include hypertension, glomerulonephritis, polycystic kidney disease, prolonged obstruction of the urinary tract, vesicoureteral reflux, recurrent pyelonephritis, and certain medications, including non-steroidal anti-inflammatory drugs (NSAIDs), calcineurin inhibitors, and antiretrovirals.[rx][rx]

The decline of kidney function is gradual and initially may present asymptomatically. The natural history of renal failure depends on the etiology of the disease but ultimately involves early homeostatic mechanisms involving hyperfiltration of the nephrons. As nephrons become damaged, the kidney increases the rate of filtration in the residual normal ones. As a result, the patient with mild renal impairment can show normal creatinine values, and the disease can go undetected for some time.[rx] This adaptive mechanism will run its course and eventually cause damage to the glomeruli of the remaining nephrons. At this point, antihypertensives such as ACEs or ARBs may be beneficial in slowing the progress of the disease and preserving renal function.

Factors that may worsen renal injury include:

• Glomerulonephritis (gloe-mer-u-low-nuh-FRY-tis), an inflammation of the kidney’s filtering units (glomeruli)
• Interstitial nephritis (in-tur-STISH-ul nuh-FRY-tis), an inflammation of the kidney’s tubules and surrounding structures
• Polycystic kidney disease
• Prolonged obstruction of the urinary tract, from conditions such as enlarged prostate, kidney stones and some cancers
• Vesicoureteral (ves-ih-koe-yoo-REE-tur-ul) reflux, a condition that causes urine to back up into your kidneys
• Recurrent kidney infection also called pyelonephritis (pie-uh-low-nuh-FRY-tis)
• Nephrotoxins (NSAIDs)
• Systemic hypertension
• Proteinuria
• Dehydration
• Smoking
• Hyperlipidemia
• Uncontrolled diabetes
• Hyperphosphatemia
• Chronic glomerulonephritis
• Chronic pyelonephritis
• Rapidly progressive glomerulonephritis
• Nephropathy of pregnancy/pregnancy toxemia
• Unclassifiable nephritis
• Polycystic kidney disease
• Nephrosclerosis
• Malignant hypertension
• Diabetic nephropathy
• Systemic lupus erythematosus nephritis
• Amyloidal kidney
• Gouty kidney
• Renal failure due to a congenital abnormality of metabolism
• Renal/urinary tract tuberculosis
• Renal/urinary tract calculus
• Renal/urinary tract tumor
• Obstructive urinary tract disease
• Myeloma
• Renal hypoplasia

Symptoms of Stage 3 Kidney Disease

Early in chronic kidney disease, you may have no signs or symptoms. As chronic kidney disease progresses to end-stage renal disease, signs and symptoms might include:

• Nausea
• Vomiting
• Loss of appetite
• Fatigue and weakness
• Sleep problems
• Changes in how much you urinate
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that’s difficult to control

Signs and symptoms of kidney disease are often nonspecific, meaning they can also be caused by other illnesses. Because your kidneys are highly adaptable and able to compensate for lost function, signs and symptoms may not appear until irreversible damage has occurred.

You may experience a wide range of symptoms, including

• a decrease in how much you urinate
• inability to urinate
• fatigue
• malaise, or a general ill feeling
• headaches
• unexplained weight loss
• loss of appetite
• nausea and vomiting
• dry skin and itching
• changes in skin color
• bone pain
• confusion and difficulty concentrating
• bruising easily
• frequent nosebleeds
• numbness in your hands and feet
• bad breath
• excessive thirst
• frequent hiccups
• the absence of menstrual cycles
• sleeping problems, such as obstructive sleep apnea and restless leg syndrome (RLS)
• low libido or impotence
• edema, or swelling, especially in your legs and hands

See your doctor right away if any of these symptoms interfere with your life, especially if you can’t urinate or sleep, are vomiting frequently, or feel weak and unable to do daily tasks.

Diagnosis of Stage 3 Kidney Disease

History and Physical

End-stage renal disease can present with a constellation of signs and symptoms. Some include volume overload refractory to diuretics, hypertension poorly responsive to medication, anemia, mineral and bone disorders, and metabolic derangements including hyperkalemia, hyponatremia, metabolic acidosis, hypo/hypercalcemia, and hyperphosphatemia. Uremic toxicity can present as anorexia, nausea, vomiting, bleeding diatheses, pericarditis, uremic neuropathy or encephalopathy, seizure, coma, and death. Uremic toxicity is an indication for urgent dialysis.[rx]

In general, ESRD symptoms appear in stages 4 and 5 when the GFR is less than 30 ml/min. Some patients with nephrotic syndrome and cystic renal disease may present earlier.

Depression is ubiquitous in patients with ESRD and should be screened for on presentation.[rx]

Lab Test and Imaging

ESRD changes the results of many tests. People receiving dialysis will need these and other tests done often:

• Potassium
• Sodium
• Albumin
• Phosphorous
• Calcium
• Cholesterol
• Magnesium
• Electrolytes
• A physical exam – during which your doctor measures your height, weight, and blood pressure and also looks for signs of problems with your heart or blood vessels and conducts a neurological exam.
• Blood tests – Complete blood count (CBC) and measure the number of waste products, such as creatinine and urea, in your blood.
• Urine tests – to check the level of the protein albumin in your urine — a high albumin level may indicate kidney disease.
• Urinalysis – This test helps your doctor check for protein and blood in your urine. These substances indicate that your kidneys aren’t processing waste properly.
• Serum creatinine test – This test helps your doctor check whether creatinine is building up in your blood. Creatinine is a waste product that your kidneys should filter out of your body.
• Blood urea nitrogen test – This test helps your doctor check how much nitrogen is in your blood.
• Estimated glomerular filtration rate (GFR) – This test allows your doctor to estimate how well your kidneys filter waste.
• Imaging tests – such as ultrasound, magnetic resonance imaging or computed tomography (CT) scan, to assess your kidneys’ structure and size and look for abnormalities.
• Removing a sample of kidney tissue (biopsy) – to examine under a microscope to learn what type of kidney disease you have and how much damage there is.

Chronic kidney disease is diagnosed when there is evidence of kidney damage for at least three months or in any patient with a GFR of less than 60 mL/min for that same amount of time.[rx][rx]

To calculate GFR, three equations are commonly used (the MDRD [Modification of Diet in Renal Disease Study], CKD-EPI, and Cockcroft-Gault formula). However, the best estimate of GFR is the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, which adjusts for age, race, and gender. However, it is important to note that the formula tends to underestimate the actual GFR at a GFR greater than 60 mL/min.[rx]

To quantitate albuminuria, a spot urine protein/creatinine ratio can be done. A value higher than 30 mg of albumin per gram of creatinine is considered abnormal, while values greater than 300mg/g are considered severely impaired renal function. Additionally, a 24-hour urine protein can also be performed. A value greater than 3.5 g is concerning for nephrotic range proteinuria.

Further evaluation of kidney disease can include a renal ultrasound, complete blood count (CBC), basic metabolic panel (BMP), urinalysis, and/or kidney biopsy. An ultrasound can provide data estimating size, obstructions, stones, cystic renal disease, mass lesions, echogenicity, and cortical thinning. Blood work will determine if there is secondary anemia and will detect evidence of electrolyte derangement. In cases of severe anemia secondary to CKD, erythropoiesis-stimulating agents should be started at a hemoglobin level below 10 g/dL. Finally, a renal biopsy may be necessary if the etiology remains unclear.[rx]

Treatment of Stage 3 Kidney Disease

Treatment of end-stage renal disease involves correcting parameters at the level of the patient’s presentation.[rx] Interventions aimed at slowing the rate of kidney disease should be initiated and can include:

• Treating the underlying cause and managing blood pressure and proteinuria. Blood pressure should be targeted to a systolic blood pressure less than 130 mmHg and diastolic blood pressure less than 80 mmHg in adults with or without diabetes mellitus whose urine albumin excretion exceeds 30 mg for 24 hours. For diabetic patients with proteinuria, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) should be started in cases where urine albumin values range between 30 and 300 mg in 24 hours and greater than 300 mg in 24 hours. These drugs slow the disease progression, particularly when initiated before the GFR decreases to less than 60 mL/min or before plasma creatinine concentration exceeds 1.2 and 1.5 in women and men, respectively.[rx]
• Other targets in preventive care and monitoring should include tight glycemic control, cardiovascular risk reduction, and general lifestyle recommendations such as smoking cessation and dietary restriction. Glycemic control is critical. A hemoglobin A1C of less than 7% is generally recommended to prevent or delay microvascular complications in this population. Management with sodium-glucose transporter 2 (SGLT-2) inhibitors may reduce the disease burden in those with type II diabetes mellitus.[rx]
• Treatment of chronic metabolic acidosis with supplemental renal bicarbonate also may slow the progression of end-stage renal disease.[rx]
• Patients with CKD tend to have dyslipidemia, particularly hypertriglyceridemia. Monitoring fasting lipid panels and initiation of cholesterol-lowering agents such as HMG-CoA reductase inhibitors should be done early in the course of the disease.[rx]
• Lifestyle modification and dietary restrictions are routinely recommended. Adhering to a low salt diet (less than 2 g/day), a renal diet (avoiding foods that are high in phosphorus), and restricting daily protein to 0.8 g per kg body weight per day is essential to managing disease burden.
• Hypocalcemia should also be monitored. A 25-OH vitamin D level less than 10 ng/mL warrants initiation of ergocalciferol 50,000 IU weekly for 6 to 8 weeks before switching to cholecalciferol 800 to 1000 IU daily.[rx]

Kidney transplant

A kidney transplant is a surgical procedure to place a healthy kidney from a live or deceased donor into a person whose kidneys no longer function properly. A kidney transplant is often the treatment of choice for end-stage renal disease, compared with a lifetime on dialysis.

The kidney transplant process takes time. It involves finding a donor, living or deceased, whose kidney best matches your own. You then undergo a surgical procedure to place the new kidney in your lower abdomen and attach the blood vessels and ureter — the tube that links the kidney to the bladder — that will allow the new kidney to function.

You’ll spend several days to a week in the hospital. After leaving the hospital, you’ll have frequent checkups as your recovery continues. You’ll take a number of medications to help keep your immune system from rejecting your new kidney and to reduce the risk of post-surgery complications, such as infection.

After a successful kidney transplant, your new kidney filters your blood, and you no longer need dialysis.

Dialysis

Dialysis does some of the work of your kidneys when your kidneys can’t do it themselves. This includes removing extra fluids and waste products from your blood, restoring electrolyte levels, and helping control your blood pressure.

Dialysis options include peritoneal dialysis and hemodialysis.

• Peritoneal dialysis – During peritoneal dialysis, blood vessels in your abdominal lining (peritoneum) fill in for your kidneys with the help of a fluid that washes in and out of the peritoneal space. Peritoneal dialysis is done in your home.
• Hemodialysis – During hemodialysis, a machine does some of the work of the kidneys by filtering harmful wastes, salts, and fluid from your blood. Hemodialysis may be done at a center or in your home.[rx]

For dialysis to be successful, you may need to make lifestyle changes, such as following certain dietary recommendations.

Supportive care

With supportive care, your symptoms are managed so that you feel better. You may choose supportive care alone or combine it with other treatment options.

Without either dialysis or a transplant, kidney failure progresses, eventually leading to death. In some people, the disease progresses slowly over months and years, while in others the disease progresses quickly.

Potential future treatments

Regenerative medicine holds the potential to fully heal damaged tissues and organs, offering solutions and hope for people who have conditions that today are beyond repair.

Regenerative medicine approaches include:

• Boosting the body’s natural ability to heal itself
• Using healthy cells, tissues, or organs from a living or deceased donor to replace damaged ones
• Delivering specific types of cells or cell products to diseased tissues or organs to restore tissue and organ function

For people with kidney disease, regenerative medicine approaches may be developed in the future to help slow the progression of the disease.

Complications

Kidney damage, once it occurs, can’t be reversed. Potential complications can affect almost any part of your body and can include:

• Fluid retention, which could lead to swelling in your arms and legs, high blood pressure, or fluid in your lungs (pulmonary edema)
• A sudden rise in potassium levels in your blood (hyperkalemia), which could impair your heart’s ability to function and may be life-threatening
• Heart and blood vessel (cardiovascular) disease
• Weak bones and an increased risk of bone fractures
• Anemia
• Decreased sex drive, erectile dysfunction or reduced fertility
• Damage to your central nervous system, which can cause difficulty concentrating, personality changes or seizures
• Decreased immune response, which makes you more vulnerable to infection
• Pericarditis, an inflammation of the saclike membrane that envelops your heart (pericardium)
• Pregnancy complications that carry risks for the mother and the developing fetus
• Irreversible damage to your kidneys (end-stage kidney disease), eventually requiring either dialysis or a kidney transplant for survival

Prevention

If you have kidney disease, you may be able to slow its progress by making healthy lifestyle choices:

• Lose weight if you need to
• Be active most days
• Eat a balanced diet of nutritious, low-sodium foods
• Control your blood pressure
• Take your medications as prescribed
• Have your cholesterol levels checked every year
• Control your blood sugar level
• Don’t smoke or use tobacco products
• Get regular checkups

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm

Causes of Stage Stage 4 Kidney Disease

Many chronic diseases can cause end-stage renal disease. In the United States, diabetes mellitus is the leading cause. Other causes include hypertension, glomerulonephritis, polycystic kidney disease, prolonged obstruction of the urinary tract, vesicoureteral reflux, recurrent pyelonephritis, and certain medications, including non-steroidal anti-inflammatory drugs (NSAIDs), calcineurin inhibitors, and antiretrovirals.[rx][rx]

The decline of kidney function is gradual and initially may present asymptomatically. The natural history of renal failure depends on the etiology of the disease but ultimately involves early homeostatic mechanisms involving hyperfiltration of the nephrons. As nephrons become damaged, the kidney increases the rate of filtration in the residual normal ones. As a result, the patient with mild renal impairment can show normal creatinine values, and the disease can go undetected for some time.[rx] This adaptive mechanism will run its course and eventually cause damage to the glomeruli of the remaining nephrons. At this point, antihypertensives such as ACEs or ARBs may be beneficial in slowing the progress of the disease and preserving renal function.

Factors that may worsen renal injury include:

• Glomerulonephritis (gloe-mer-u-low-nuh-FRY-tis), an inflammation of the kidney’s filtering units (glomeruli)
• Interstitial nephritis (in-tur-STISH-ul nuh-FRY-tis), an inflammation of the kidney’s tubules and surrounding structures
• Polycystic kidney disease
• Prolonged obstruction of the urinary tract, from conditions such as enlarged prostate, kidney stones and some cancers
• Vesicoureteral (ves-ih-koe-yoo-REE-tur-ul) reflux, a condition that causes urine to back up into your kidneys
• Recurrent kidney infection also called pyelonephritis (pie-uh-low-nuh-FRY-tis)
• Nephrotoxins (NSAIDs)
• Systemic hypertension
• Proteinuria
• Dehydration
• Smoking
• Hyperlipidemia
• Uncontrolled diabetes
• Hyperphosphatemia
• Chronic glomerulonephritis
• Chronic pyelonephritis
• Rapidly progressive glomerulonephritis
• Nephropathy of pregnancy/pregnancy toxemia
• Unclassifiable nephritis
• Polycystic kidney disease
• Nephrosclerosis
• Malignant hypertension
• Diabetic nephropathy
• Systemic lupus erythematosus nephritis
• Amyloidal kidney
• Gouty kidney
• Renal failure due to a congenital abnormality of metabolism
• Renal/urinary tract tuberculosis
• Renal/urinary tract calculus
• Renal/urinary tract tumor
• Obstructive urinary tract disease
• Myeloma
• Renal hypoplasia

Symptoms of Stage 4 Kidney Disease

Early in chronic kidney disease, you may have no signs or symptoms. As chronic kidney disease progresses to end-stage renal disease, signs and symptoms might include:

• Nausea
• Vomiting
• Loss of appetite
• Fatigue and weakness
• Sleep problems
• Changes in how much you urinate
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that’s difficult to control

Signs and symptoms of kidney disease are often nonspecific, meaning they can also be caused by other illnesses. Because your kidneys are highly adaptable and able to compensate for lost function, signs and symptoms may not appear until irreversible damage has occurred.

You may experience a wide range of symptoms, including

• a decrease in how much you urinate
• inability to urinate
• fatigue
• malaise, or a general ill feeling
• headaches
• unexplained weight loss
• loss of appetite
• nausea and vomiting
• dry skin and itching
• changes in skin color
• bone pain
• confusion and difficulty concentrating
• bruising easily
• frequent nosebleeds
• numbness in your hands and feet
• bad breath
• excessive thirst
• frequent hiccups
• the absence of menstrual cycles
• sleeping problems, such as obstructive sleep apnea and restless leg syndrome (RLS)
• low libido or impotence
• edema, or swelling, especially in your legs and hands

See your doctor right away if any of these symptoms interfere with your life, especially if you can’t urinate or sleep, are vomiting frequently, or feel weak and unable to do daily tasks.

Diagnosis of Stage 4 Kidney Disease

History and Physical

End-stage renal disease can present with a constellation of signs and symptoms. Some include volume overload refractory to diuretics, hypertension poorly responsive to medication, anemia, mineral and bone disorders, and metabolic derangements including hyperkalemia, hyponatremia, metabolic acidosis, hypo/hypercalcemia, and hyperphosphatemia. Uremic toxicity can present as anorexia, nausea, vomiting, bleeding diatheses, pericarditis, uremic neuropathy or encephalopathy, seizure, coma, and death. Uremic toxicity is an indication for urgent dialysis.[rx]

In general, ESRD symptoms appear in stages 4 and 5 when the GFR is less than 30 ml/min. Some patients with nephrotic syndrome and cystic renal disease may present earlier.

Depression is ubiquitous in patients with ESRD and should be screened for on presentation.[rx]

Lab Test and Imaging

ESRD changes the results of many tests. People receiving dialysis will need these and other tests done often:

• Potassium
• Sodium
• Albumin
• Phosphorous
• Calcium
• Cholesterol
• Magnesium
• Electrolytes
• A physical exam – during which your doctor measures your height, weight, and blood pressure and also looks for signs of problems with your heart or blood vessels and conducts a neurological exam.
• Blood tests – Complete blood count (CBC) and measure the number of waste products, such as creatinine and urea, in your blood.
• Urine tests – to check the level of the protein albumin in your urine — a high albumin level may indicate kidney disease.
• Urinalysis – This test helps your doctor check for protein and blood in your urine. These substances indicate that your kidneys aren’t processing waste properly.
• Serum creatinine test – This test helps your doctor check whether creatinine is building up in your blood. Creatinine is a waste product that your kidneys should filter out of your body.
• Blood urea nitrogen test – This test helps your doctor check how much nitrogen is in your blood.
• Estimated glomerular filtration rate (GFR) – This test allows your doctor to estimate how well your kidneys filter waste.
• Imaging tests – such as ultrasound, magnetic resonance imaging or computed tomography (CT) scan, to assess your kidneys’ structure and size and look for abnormalities.
• Removing a sample of kidney tissue (biopsy) – to examine under a microscope to learn what type of kidney disease you have and how much damage there is.

Chronic kidney disease is diagnosed when there is evidence of kidney damage for at least three months or in any patient with a GFR of less than 60 mL/min for that same amount of time.[rx][rx]

To calculate GFR, three equations are commonly used (the MDRD [Modification of Diet in Renal Disease Study], CKD-EPI, and Cockcroft-Gault formula). However, the best estimate of GFR is the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, which adjusts for age, race, and gender. However, it is important to note that the formula tends to underestimate the actual GFR at a GFR greater than 60 mL/min.[rx]

To quantitate albuminuria, a spot urine protein/creatinine ratio can be done. A value higher than 30 mg of albumin per gram of creatinine is considered abnormal, while values greater than 300mg/g are considered severely impaired renal function. Additionally, a 24-hour urine protein can also be performed. A value greater than 3.5 g is concerning for nephrotic range proteinuria.

Further evaluation of kidney disease can include a renal ultrasound, complete blood count (CBC), basic metabolic panel (BMP), urinalysis, and/or kidney biopsy. An ultrasound can provide data estimating size, obstructions, stones, cystic renal disease, mass lesions, echogenicity, and cortical thinning. Blood work will determine if there is secondary anemia and will detect evidence of electrolyte derangement. In cases of severe anemia secondary to CKD, erythropoiesis-stimulating agents should be started at a hemoglobin level below 10 g/dL. Finally, a renal biopsy may be necessary if the etiology remains unclear.[rx]

Treatment of Stage 4 Kidney Disease

Treatment of end-stage renal disease involves correcting parameters at the level of the patient’s presentation.[rx] Interventions aimed at slowing the rate of kidney disease should be initiated and can include:

• Treating the underlying cause and managing blood pressure and proteinuria. Blood pressure should be targeted to a systolic blood pressure less than 130 mmHg and diastolic blood pressure less than 80 mmHg in adults with or without diabetes mellitus whose urine albumin excretion exceeds 30 mg for 24 hours. For diabetic patients with proteinuria, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) should be started in cases where urine albumin values range between 30 and 300 mg in 24 hours and greater than 300 mg in 24 hours. These drugs slow the disease progression, particularly when initiated before the GFR decreases to less than 60 mL/min or before plasma creatinine concentration exceeds 1.2 and 1.5 in women and men, respectively.[rx]
• Other targets in preventive care and monitoring should include tight glycemic control, cardiovascular risk reduction, and general lifestyle recommendations such as smoking cessation and dietary restriction. Glycemic control is critical. A hemoglobin A1C of less than 7% is generally recommended to prevent or delay microvascular complications in this population. Management with sodium-glucose transporter 2 (SGLT-2) inhibitors may reduce the disease burden in those with type II diabetes mellitus.[rx]
• Treatment of chronic metabolic acidosis with supplemental renal bicarbonate also may slow the progression of end-stage renal disease.[rx]
• Patients with CKD tend to have dyslipidemia, particularly hypertriglyceridemia. Monitoring fasting lipid panels and initiation of cholesterol-lowering agents such as HMG-CoA reductase inhibitors should be done early in the course of the disease.[rx]
• Lifestyle modification and dietary restrictions are routinely recommended. Adhering to a low salt diet (less than 2 g/day), a renal diet (avoiding foods that are high in phosphorus), and restricting daily protein to 0.8 g per kg body weight per day is essential to managing disease burden.
• Hypocalcemia should also be monitored. A 25-OH vitamin D level less than 10 ng/mL warrants initiation of ergocalciferol 50,000 IU weekly for 6 to 8 weeks before switching to cholecalciferol 800 to 1000 IU daily.[rx]

Kidney transplant

A kidney transplant is a surgical procedure to place a healthy kidney from a live or deceased donor into a person whose kidneys no longer function properly. A kidney transplant is often the treatment of choice for end-stage renal disease, compared with a lifetime on dialysis.

The kidney transplant process takes time. It involves finding a donor, living or deceased, whose kidney best matches your own. You then undergo a surgical procedure to place the new kidney in your lower abdomen and attach the blood vessels and ureter — the tube that links the kidney to the bladder — that will allow the new kidney to function.

You’ll spend several days to a week in the hospital. After leaving the hospital, you’ll have frequent checkups as your recovery continues. You’ll take a number of medications to help keep your immune system from rejecting your new kidney and to reduce the risk of post-surgery complications, such as infection.

After a successful kidney transplant, your new kidney filters your blood, and you no longer need dialysis.

Dialysis

Dialysis does some of the work of your kidneys when your kidneys can’t do it themselves. This includes removing extra fluids and waste products from your blood, restoring electrolyte levels, and helping control your blood pressure.

Dialysis options include peritoneal dialysis and hemodialysis.

• Peritoneal dialysis – During peritoneal dialysis, blood vessels in your abdominal lining (peritoneum) fill in for your kidneys with the help of a fluid that washes in and out of the peritoneal space. Peritoneal dialysis is done in your home.
• Hemodialysis – During hemodialysis, a machine does some of the work of the kidneys by filtering harmful wastes, salts, and fluid from your blood. Hemodialysis may be done at a center or in your home.[rx]

For dialysis to be successful, you may need to make lifestyle changes, such as following certain dietary recommendations.

Supportive care

With supportive care, your symptoms are managed so that you feel better. You may choose supportive care alone or combine it with other treatment options.

Without either dialysis or a transplant, kidney failure progresses, eventually leading to death. In some people, the disease progresses slowly over months and years, while in others the disease progresses quickly.

Potential future treatments

Regenerative medicine holds the potential to fully heal damaged tissues and organs, offering solutions and hope for people who have conditions that today are beyond repair.

Regenerative medicine approaches include:

• Boosting the body’s natural ability to heal itself
• Using healthy cells, tissues, or organs from a living or deceased donor to replace damaged ones
• Delivering specific types of cells or cell products to diseased tissues or organs to restore tissue and organ function

For people with kidney disease, regenerative medicine approaches may be developed in the future to help slow the progression of the disease.

Complications

Kidney damage, once it occurs, can’t be reversed. Potential complications can affect almost any part of your body and can include:

• Fluid retention, which could lead to swelling in your arms and legs, high blood pressure, or fluid in your lungs (pulmonary edema)
• A sudden rise in potassium levels in your blood (hyperkalemia), which could impair your heart’s ability to function and may be life-threatening
• Heart and blood vessel (cardiovascular) disease
• Weak bones and an increased risk of bone fractures
• Anemia
• Decreased sex drive, erectile dysfunction or reduced fertility
• Damage to your central nervous system, which can cause difficulty concentrating, personality changes or seizures
• Decreased immune response, which makes you more vulnerable to infection
• Pericarditis, an inflammation of the saclike membrane that envelops your heart (pericardium)
• Pregnancy complications that carry risks for the mother and the developing fetus
• Irreversible damage to your kidneys (end-stage kidney disease), eventually requiring either dialysis or a kidney transplant for survival

Prevention

If you have kidney disease, you may be able to slow its progress by making healthy lifestyle choices:

• Lose weight if you need to
• Be active most days
• Eat a balanced diet of nutritious, low-sodium foods
• Control your blood pressure
• Take your medications as prescribed
• Have your cholesterol levels checked every year
• Control your blood sugar level
• Don’t smoke or use tobacco products
• Get regular checkups

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