Acute kidney injury

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Over 30 different definitions of AKI have been used in the literature since it was first described, which prompted the need for a uniform definition. In 2002, The Acute Dialysis Quality Initiative (ADQI) proposed the first consensus definition known as the RIFLE criteria. The acronym combines a classification of 3 levels of renal dysfunction (Risk, Injury, Failure) with 2 clinical outcomes (Loss, ESRD). This unified classification was proposed to enable a viable comparison in trials of prevention and therapy and to observe clinical outcomes of the defined stages of AKI.^[1]

RIFLE criteria for the definition of acute kidney injury (AKI)

Classification	GFR criteria	Urine output criteria
Risk	1.5x increase in SCr or GFR decrease >25%	<0.5 mL/kg/h for 6 hours
Injury	2x increase in SCr or GFR decrease >50%	<0.5 mL/kg/h for 12 hours
Failure	3x increase in SCr or GFR decrease >75%	<0.3 mL/kg/h for 24 hours or anuria for 12 hours
Loss	Complete loss of renal function >4 weeks
End-stage Renal Disease	Complete loss of renal function >3 months

In 2007, the Acute Kidney Injury Network (AKIN) proposed a modified diagnostic criteria based on the RIFLE criteria. The initiative separated the definition and staging into 2 separate entities previously combined in the RIFLE criteria. This made the definition more clinically applicable. AKI was defined as either one of the following:^[2]

An increase in serum creatinine by 0.3 mg/dL in 48 hours An increase in serum creatinine by more than 50% of baseline or 1.5 times baseline occuring in the past 7 days A decrease in urine volume <0.5 mL/kg/h for 6 hours

In March 2012, the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Acute Kidney Injury retained the AKIN definition while implementing modifications to the staging criteria of AKI. ^[3]

In 1941, Beall et al described a case of acute kidney injury during world war II. They describe a course of rapidly progressive renal insufficiency with dark urine, edema, elevated potassium levels, and disorientation. In 1946, first hemodialysis was performed by Bywaters et al to treat acute kidney injury.

Initially, the staging of AKI was a part of the proposed definition by the ADQI initiative and the RIFLE criteria. In 2007, AKIN proposed separated the 2 and created a new staging scheme modified from the RIFLE criteria. Prior to the 2012 KDIGO AKI guidelines, RIFLE and AKIN criteria were used interchangeably to stage patients with renal injury.

Acute kidney injury is defined as spontaneous deficit in kidney functions leading to urea retention and electrolyte imabalance. Etiologies of AKI can be divided based on pathophysiologic mechanisms into 3 broad categories: prerenal, intrinsic renal, and postrenal causes. Pre-renal AKI is most common and typically results from hypovolemia. Intrinsic renal is due to damage to renal parenchyma. Post-renal AKI is usually result of an obstruction, may be due to stones or strictures.

Common causes of acute kidney injury include albendazole, ciprofloxacin, foscarnet sodium, deferasirox, gadoterate and gadoxetate.

Oliguria is typically present in AKI. So, AKI should be differentiated from other causes of oliguria.

The incidence less severe AKI is approximately 200-300 per 100,000 individuals worldwide. The prevalence of acute kidney injury is approximately 400-500 per 100,000 individuals worldwide. Patients of all age groups may develop AKI. The incidence of AKI increases with age; the median age at diagnosis is 76 years. AKI affects men and women equally.

Common risk factors in the development of acute kidney injury include exposure to contrast, volume depletion, hemodynamic instability, advanced ages, hypertension and diabetes mellitus.

Several laboratory tests are useful for screening of acute kidney injury among patients with risk factors like BUN, creatinine and urine analysis.

Certain forms of AKI such as contrast induced nephropathy, usually have a shorter course with creatinine peak in 3-5 days. Common complications of acute kidney injury include anemia, metabolic acidosis, anorexia, nausea and vomiting. In general, the majority of patients that survive the initial insult recover their kidney function within 30 days.

Acute kidney injury is diagnosed and staged clinically on the basis of GFR and urinary output. In 2012, the KDIGO AKI guidelines proposed a combined staging scheme that takes into account both criteria and clinical outcome.

Symptoms of acute kidney injury include decreased urine output, dark colored urine, fatigue and malaise, nausea and vomiting.

Patients with acute kidney injury usually appear ill. Physical examination of patients with acute kidney injury is usually remarkable for hypotension, edema of the lower extremities, maculopapular rash and rales o chest ausculatation.

In prerenal azotemia, tubular function is preserved and sodium reabsorption increases with the associated renal vasoconstriction. Hence the FENa is usually <1% in prerenal azotemia. A high FENa in the context of prerenal azotemia is possible during diuretic treatment and glycosuria. FEurea is of value in states of reduced effective circulating volume, and in cases where diuretics have been administered. In these situations, a low FEurea (<35%) has a higher sensitivity and specificity than FENa in differentiating between prerenal azotemia and renal AKI.

There are usually no specific ECG findings associated with AKI. However, ECG findings may have various presentations depending on the electrolyte abnormalities presenting in ECG.

There are no x-ray specific findings associated with AKI. However, AKI may lead to fluid overload leading to pulmonary edema.

Findings on an ultrasound suggestive of acute kidney injury include obstruction, hydronephrosis, enlarged kidneys, hyperechoic kidneys and thick and echogenic cortices.

Findings on CT scan suggestive of acute kidney injury include kidney stones not detected by ultrasonography, hydronephrosis or hydroureter and renal artery stenosis.

MRI is usually not indicated in acute kidney injury.

99m Technetium (Tc) scan may be helpful in the diagnosis of acute kidney injury. 99m Technetium (Tc) scan may be hehpful in assessing renal blood flow and tubular function.

There are no other diagnostic studies associated with the acute kidney injury.

Pharmacologic medical therapies for acute kidney injury include supportive therapy, diuretics, correction of hyperglycemia.

Renal replacement is usually reserved for patients with either severe acidosis, pulmonary edema and uremic complications.

Effective measures for the primary prevention of acute kidney injury include volume expansion and/or fluid therapy, optimization of blood pressure,tight glycemic control, avoidance of drug- and nephrotoxin-induced AKI, recheck renal function 48-72 hours following the radiological contrast media, and low doses of corticosteroids in septic shock patients.

There are no established measures for the secondary prevention of acute kidney injury.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

In 1941, Beall et al described a case of acute kidney injury during world war II. They describe a course of rapidly progressive renal insufficiency with dark urine, edema, elevated potassium levels, and disorientation. In 1946, first hemodialysis was performed by Bywaters et al to treat acute kidney injury.

• In 1941, Beall et al described a case of acute kidney injury during world war II. They describe a course of rapidly progressive renal insufficiency with dark urine, edema, elevated potassium levels, and disorientation.^[1]
• The earliest definition came from Lucké in 1946 who described the histologic pathology we now know as acute tubular necrosis. The term lower nephron nephrosis was introduced and was later used to refer to abrupt renal failure secondary to excessive vomiting, thermal burns, crush injuries, hemolysis, and obstructive prostate disease.^[2][3]
• The term slowly drifted to become acute renal failure to depict a clinical syndrome rather than a pathologic finding.
• Acute renal failure was then replaced by acute kidney injury in 2006 following a consensus that even minor changes in serum creatinine not necessarily overt failure can lead to significant changes in outcome.

• In 1946, first hemodialysis was performed by Bywaters et al to treat acute kidney injury.^[4]
• Ultrafiltration technique was developed by Silverstein et al in 1967.^[5]
• Continuous arteriovenous hemofiltration technique was introduced by Kramer et al in 1980. ^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

KDIGO guidelines are used for staging acute kidney injury (AKI). Prior to the 2012 KDIGO AKI guidelines, RIFLE and AKIN criteria were used interchangeably to stage patients with renal injury. Initially, the staging of AKI was a part of the proposed definition by the ADQI initiative and the RIFLE criteria. In 2007, AKIN proposed separated the two and created a new staging scheme modified from the RIFLE criteria.

Initially, the staging of AKI was a part of the proposed definition by the ADQI initiative and the RIFLE criteria. In 2007, AKIN proposed separated the 2 and created a new staging scheme modified from the RIFLE criteria. Prior to the 2012 KDIGO AKI guidelines, RIFLE and AKIN criteria were used interchangeably to stage patients with renal injury.^[1][2] Although certain concerns about the differences between the 2 classification schemes, it was shown that the differences do not carry through to mortality and outcome measures.^[3]

Modified RIFLE staging scheme for acute kidney injury according to the Acute Kidney Injury Network (AKIN)
Classification	GFR criteria	Urine output criteria
Stage 1	Increase in SCr ≥0.3 mg/dL or 1.5x to 2x increase from baseline	<0.5 mL/kg/h for 6 hours
Stage 2	2x to 3x increase in SCr from baseline	<0.5 mL/kg/h for 12 hours
Stage 3	>3x increase in SCr or SCr≥ 4.0 mg/dL with acute increase >0.5 md/dL	<0.3 mL/kg/h for 24 hours or anuria for 12 hours

In 2012, the KDIGO AKI guidelines proposed a combined staging scheme that takes into account both criteria and clinical outcome. ^[4] The rationale behind AKI staging is the needed to determine overall outcome as higher stages of AKI carry a greater risk of all cause and cardiovascular mortality, renal replacement, as well as chronic kidney disease even after AKI resolution.^[5][6][7][8]

2012 KDIGO AKI Guidelines – Proposed staging criteria for AKI modified from AKIN
Staging	GFR criteria	Urine output criteria
Stage 1	1.5 – 1.9 times baseline or ≥ 0.3 mg/dl increase	<0.5 ml/kg/h for 6 – 12 hours
Stage 2	2.0 – 2.9 times baseline	<0.5 ml/kg/h for ≥ 12 hours
Stage 3	3.0 times baseline or increase in serum creatinine to 4.0 mg/dL or initiation of renal replacement therapy or decrease in eGFR to <35 ml/min per 1.73 m2 (in patients <18 years)	<0.3 mL/kg/h for 24 hours or anuria for 12 hours

The guidelines also advocated that in case of discordance between urine output and serum creatinine patients should be classified to the highest applicable AKI stage. Also, new emphasis on the differences seen in the pediatric population gave rise to revised definition of stage 3 AKI in patients less than 18 years of age.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Acute kidney injury is defined as spontaneous deficit in kidney functions leading to urea retention and electrolyte imbalance. Etiologies of AKI can be divided based on pathophysiologic mechanisms into 3 broad categories: prerenal, intrinsic renal, and postrenal causes. Pre-renal AKI is most common and typically results from hypovolemia. Intrinsic renal is due to damage to renal paranchyma. Post-renal AKI is usually result of an obstruction, may be due to stones or strictures.

Etiologies of AKI can be divided based on pathophysiologic mechanisms into 3 broad categories: prerenal, intrinsic renal, and postrenal causes.

• Prerenal AKI, known as prerenal azotemia, is by far the most common cause of AKI representing 30-50% of all cases.
• It is provoked by inadequate renal blood flow commonly due to decreased effective circulating blood flow.
• This causes a decrease in the intraglomerular hydrostatic pressure required to achieve proper glomerular filtration.

• Blood flow to the kidneys can vary with systemic changes; however, glomerular perfusion pressure and GFR are maintained relatively constant by the kidney itself.
• Under physiologic conditions, minor drops in blood flow to the renal circulation are counteracted by changes in the resistances across the afferent and efferent arterioles of individual glomerular capillary beds.^[1]
• The afferent arteriole vasodilates via 2 mechanisms.^[2]
  • The myogenic reflex, mediating medial smooth muscle relaxation in states of decrease perfusion pressure, vasodilates the afferent arteriole leading to increased blood flow.^[3]
  • Additionally, intrarenal synthesis of vasodilatory prostaglandins such as prostacyclin and prostaglandin E2 causes further dilation of the afferent arteriole.^[4]
  • The mechanism explains why the intake of NSAIDs leads to acute kidney injury by inhibiting this autoregulatory mechanism.^[5]

• At the level of the efferent arteriole, an increase in resistance is crucial for appropriate maintenance of glomerular hydrostatic pressure.
• This is achieved by an increase in the production of angiotensin II (via the renin-angiotensin-aldosterone system) which acts preferentially on the efferent arteriole leading to vasoconstriction.^[6]
• Important medications that target angiotensin II production and action are ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) which may be responsible for renal decompensation in patients dependent on the action of angiotensin II to maintain glomerular perfusion pressure. Such is the case in chronic kidney disease patients, whose autoregulatory mechanisms are typically operating at maximum capacity.^[7]

• As such, the pathophysiology of prerenal azotemia entails a drop in renal plasma flow beyond the capacity of autoregulation, a blunted or inadequate renal compensation for an otherwise tolerable change in perfusion, or a combination of both.
• This eventually leads to ischemic renal injury particularly to the medulla which is maintained in hypoxic conditions at baseline.
• Causes of prerenal injury are summarized in the figure below. To note, as prerenal AKI progresses with further ischemia, it transforms into acute tubular necrosis (ATN) crossing into the realm of intrinsic AKI.

Intrinsic renal AKI generally occurs due to renal parenchymal injury and may be classified according to the site of injury into: glomerular, tubular, interstitial, and vascular.

• The most common form of intrinsic renal AKI involves damage to the renal tubules.
• In this context, the most common etiologies are sepsis, nephrotoxins, and ischemia.
• Ischemic AKI is part of a disease continuum involving prerenal AKI and manifests in states of prolonged renal blood flow compromise or renal hypoperfusion with other pre-existing or concomitant renal insults.
• Although sometimes dubbed as acute tubular necrosis (ATN), ATN is non-specific to prerenal disease, and may be induced by sepsis and nephrotoxins.
• ATN is also not a very accurate pathological term, as renal biopsies have rarely shown true tubular necrosis, but rather tubular cell injury & apoptosis with secondary dysfunction are more accurate.
• These pathological manifestations are related to hypoxia and ATP depletion in areas that are physiologically hypoxic such as the renal medulla, and areas that are very metabolically active such as the proximal tubule.
• The response of the renal tubules and the microvasculature are maladaptive leading to a paradoxical increase in hypoxia and further damage and inflammation.^[8]
• Ischemia and hypoxia are known to cause increased reactivity to vasoconstrictive agents, and decreased vasodilatory responses in arterioles as compared to normal kidneys.^[9]

• AKI is seen in 20 to 25% of cases of sepsis and in 50% of cases of septic shock.
• A decrease in GFR in a septic patient is usually a marker of poor prognosis, and the combination of sepsis and AKI is associated with a mortality rate of 70%.
• Although most cases of AKI occur with severe hemodynamic compromise in septic patients, renal injury may occur without overt hypotension.
• While there is clear tubular damage in sepsis-associated AKI, interstitial inflammation and interstitial edema have also been proposed in the pathogenesis.^[10][11]
• The mechanisms of alteration of renal hemodynamics proposed in sepsis include excessive efferent arteriolar vasodilation or generalized renal vasoconstriction secondary to tumor necrosis factor induced release of endothelin.

• Another major cause of intrinsic renal AKI is nephrotoxins.
• These may be either endogenous such as myoglobin, hemoglobin, and myeloma light chains, or exogenous such as contrast agents, antibiotics, and chemotherapeutic agents.
• The kidney is a particularly susceptible organ to toxin injury mainly due to the high blood perfusion and the high concentration of substances in the kidneys destined for excretion.
• Nephrotoxic injury may be secondary to tubular, interstitial, or microvascular damage depending on the nephrotoxin itself.
• Major risk factors for nephrotoxic AKI include old age, pre-existing chronic kidney disease (CKD), and prerenal azotemia.^[12]

• Contrast induced nephropathy (CIN) recently called contrast induced AKI (CIAKI) is also major cause of intrinsic injury caused by iodinated contrast media used in cardiovascular imaging.
• This entity is virtually non-existent in healthy young individuals.
• Risk factors that increase susceptibility to CIN include advanced age, pre-existing CKD, diabetic nephropathy, severe heart failure, and concomitant exposure to other nephrotoxins.
  • The pathophysiology of CIN is not clearly understood; however, several attempts have been made to explain the underlying mechanism.
  • It is generally agreed that CIN is due to a combination of several influences brought on by contrast-media infusion rather than a single process.
  • The most important mechanism thought to be involved in CIN is a reduction in renal perfusion at the level of the microvasculature leading to tubular damage.
  • This is attributed to several alterations in the renal microenvironment including activation of the tubuloglomerular feeback, local vasoactive metabolites including adenosine, prostaglandin, NO, and endothelin as well as increased interstitial pressure.
  • Studies have also proposed injury to renal tubular cells may occur via a direct cytotoxic effect of the contrast media and via reactive oxygen species production.^[13]

• Glomerular damage causing AKI accounts for a small propotion of cases of AKI.
• Glomerulonephritis leading to AKI is usually seen in rapidly progressive glomerulonephritis (RPGN).
• Other forms of glomerulonephritis progress slowly and generally lead to chronic kidney disease.
• RPGN is characterized by a triad of hematuria, proteinuria, and hypertension progressing to a decrease in GFR and urine output.^[14]
• RPGN can be idiopathic or secondary to SLE, Henoch-Schonlein purpura, Wegener’s granulomatosis, and Goodpasture’s syndrome.
• The pathophysiology is almost always related to an autoimmune insult, but specific characteristics depend on the underlying etiologies.^[15]

• Other causes of AKI of vascular origin include diseases affecting the macro and microvasculature not only confined to the glomerular capillaries.
• Examples include TTP/HUS and DIC associated with microangiopathic hemolytic anemia (MAHA) typically arising from an endothelial cell injury with subsequent leukocyte adhesion, complement consumption, platelet aggregation and eventual ischemic damage.
• Other causes include atheroemboli, calcineurin inhibitors in renal transplant patients via vasoconstriction of the afferent arterioles (although a tubulointerstitial pattern is also seen), and vasculitides.^[16][17]

• AKI may be secondary to acute interstitial nephritis caused by an idiosyncratic immune-mediated mechanism.
• Classically, it is associated with a number of medications including penicillins (classically methicillin), cephalosporins, fluoroquinolones, NSAIDs, thiazide and loop diuretics, and allopurinol.^[18]
• AIN can also be secondary to an infectious process, or systemic syndromes such as cryoglobulinemia, Sjogren syndrome, sarcoidosis, and primary biliary cirrhosis.
• Clinically, it may be associated with fever, and urinary eosinophilia although it may often be asymptomatic.
• Pathophysiology involves a cell-mediated immune reaction with interstitial infiltrates mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, with subsequent transformation into areas of interstitial fibrosis.^[17]

• Postrenal AKI occurs due to an obstruction in the urinary flow leading to an increase in the intratubular hydrostatic pressure which interferes with proper glomerular filtration.^[19]
• Obstructions occurring at the level of the renal pelvis and the ureters must affect both kidneys simultaneously to cause AKI in healthy adults unless only one kidney is functional.
• Causes of upper tract obstructions may be intraluminal such as calculi or blood clots, transmural secondary to neoplastic invasion, or extrinsic compression by retroperitoneal fibrosis, neoplasia, or an abscess.
• The most common cause of postrenal AKI is bladder neck obstruction secondary to benign prostatic hypertrophy and prostate cancer.
• Other etiologies of lower urinary tract obstruction are calculi, and strictures. Patients usually have evident hydronephrosis unless early in the course of obstruction.

There is no genetics associated with AKI.

• On gross pathology, characteristic findings for AKI are not present.

• On microscopic histopathological analysis, characteristic findings of AKI depends on the etiology of disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Common causes of acute kidney injury include albendazole, ciprofloxacin, foscarnet sodium, deferasirox, gadoterate and gadoxetate.

Common causes of acute kidney injury may include:

• Albendazole
• Ciprofloxacin
• Cobicistat
• Deferasirox
• gadoterate
• gadoxetate
• Iodixanol
• Iopromide
• Ioxilan,
• Felbamate
• Foscarnet sodium
• Gadodiamide
• Gadobutrol
• Gadofosveset
• Gallium nitrate
• Telavancin hydrochloride
• Valganciclovir hydrochloride

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Albendazole, Ciprofloxacin, Cobicistat, Deferasirox, Gadoterate, GadoxetateIodixanol, Iopromide, Ioxilan, Felbamate, Foscarnet sodium, Gadodiamide, Gadobutrol, Gadofosveset, Gallium nitrate, Telavancin hydrochloride, Valganciclovir hydrochloride
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

List the causes of the disease in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2], Eiman Ghaffarpasand, M.D. [3], Anmol Pitliya, M.B.B.S. M.D.[4]

AKI typically results in oliguria. AKI should be differentiated on the basis of underlying etiology.

AKI typically results in oliguria. AKI should be differentiated on the basis of underlying etiology.

Abbreviations: ABG = Arterial blood gases, BUN = Blood urea nitrogen, CBC = Complete blood count, CT = Computed tomography, CRP = C – reactive protein, ECG = Electrocardiogram, ESR = Erythrocyte sedimentation rate, IVP = Intravenous pyelography, KFT = Kidney function test, GI = Gastrointestinal, GFR = Glomerular filtration rate, MRI = Magnetic resonance imaging, PT = Prothrombin time

Etiology		Clinical manifestations									Paraclinical findings											Comments
		Symptoms and signs									Lab findings						Imaging
		Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other
Prerenal causes	Alcohol poisoning[1][2]	+	–	+/-	–	+/-	+	+/-	–	–	↑PT	↑BUN, ↑Cr (isopropyl alcohol)	↓Na	NA	↓HCO3	LFT	NA	NA	NA	NA	–	Administer thiamine to prevent Wernicke’s encephalopathy
	Aspergillosis[3][4]	+/-	–	–	–	–	–	–	+/-	–	NA	NA	NA	NA	NA	Allergy test, ↑IgE (>1000 IU/dl), direct visualization of fungal hyphae	NA	Pulmonary infiltrates, mucus plug, mass in the upper lobe surrounded by a crescent of air, solitary or multiple cavities	Halo sign, wedge-shaped pulmonary infarction, granuloma	NA	–	Polymerase chain reaction (PCR) confirms the diagnosis
	Cholera[5][6][6][7]	+/-	+	+/- Depends on severity	–	–	+/-	+	–	–	Leukocytosis, ↑HCT	↑BUN, ↑Cr	↓Na, ↑Ca, ↑Mg	NA	↑Lactate, ↓HCO3	Stool PCR, stool culture, serotyping	NA	NA	NA	NA	–	–
	Congestive heart failure (CHF)[8][9]	+	–	–	–	–	–	+	–	+	Anemia, leukocytosis	↑BUN, ↑Cr	↓Na, ↑K	NA	↑Lactate, ↓HCO3,	↑BNP, ↑troponin	Cardiomegaly, pulmonary hypertension, pleural effusion	Pulmonary edema	NA	Valvular heart disease	Decreased ejection fraction in echocardiography, decreased heart function and damage in nuclear imaging	–
	Dehydration[10][11]	+	+	+/- Depends on the severity	+/-	–	+/-	+/-	–	–	NA	↑BUN, ↑Cr	↓Na, ↑K, ↓Cl	↑ Urine ketones and glucose, ↑urine specific gravity	↑Lactate, ↓HCO3	Hypoglycemia	NA	NA	NA	NA	–	–
	Diarrhea and/or vomiting[12][13]	+/-	+/-	–	–	–	+	+	–	–	Leukocytosis with predominant neutrophilia, ↑ESR	NA	NA	↑ Urine ketones, organic acids, porphobilinogen, aminolevulinic acid	NA	Stool anion gap, stool pH < 5.5, stool culture, serotyping, enzyme immunoassay (rotavirus or adenovirus), abnormal LFT, amylase, lipase	Normal	NA	NA	NA	–	–
	Etiology	Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other	Comments
	Drugs/toxins[14][15]	+/-	+/-	+/-	+/-	+/-	+/-	+/-	+/-	+/-	NA	↑BUN, ↑Cr, ↑CK	↑K, ↓Mg, ↓Ca, ↓P	Ingested drug, glucose, aminoacid, phosphate, ketone, hyaline cast, and RBC	↑Lactate, metabolic acidosis	Toxicology, rapid immunoassay	Nephropathy	Radioopaque substances, ingested drug packets	NA	NA	–	–
	Esophageal varices bleeding[16][17]	+/-	–	–	–	+/-	–	–	–	–	Normocytic normochromic anemia	↑BUN, ↑Cr	NA	NA	NA	NA	Velocity and direction of portal flow	Abnormal opacities outside ofesophageal wall, posterior mediastinal or intraparenchymal mass, dilated azygous vein	Entire portal venous system	Portrays esophageal varices as flow voids	Portal hypertension and esophageal varices in positron emission tomography, flexible endoscope, barium swallow of snake-like filling defects	–
	Congenital heart disease[18][19]	+/-	–	–	–	–	–	–	+/-	+/-	↑ESR and CRP	↑BUN, ↑Cr	NA	NA	NA	Throat culture, rapid streptococcal antigen test, hyperoxia test, pulse oximetry	NA	Cardiomegaly, dextrocardia	NA	NA	Ventricular dysfunction, left and right ventricular hypertrophy, valvular disease in echocardiography	–
	Hemorrhage[20][21]	–	+	+/- Depends on the severity	–	–	–	–	+/-	–	Normocytic normochromic anemia, ↑PT, ↑PTT	↑BUN, ↑Cr	↑Na, ↑Cl, ↓Ca	NA	Metabolic acidosis	NA	Peritoneal cavity fluid in FAST	Bilateral opacities in the lung field, hemothorax, hemoperitoneum, ruptured abdominal aortic aneurysm	Intrathoracic, intra-abdominal, and retroperitoneal bleeding	NA	Source of bleeding in the upper GI in EGD, angiography	–
	Hemolysis[22][23]	+/-	–	–	–	–	–	–	+/-	–	Thrombocytopenia, microcytic hypochromic anemia, ↑RDW, ↑retic count	NA	NA	NA	NA	↑LDH, ↓haptoglobin, ↑unconjugated bilirubin	Hepatomegaly, splenomegaly	NA	NA	NA	–	–
	Etiology	Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other	Comments
	Hepatorenal syndrome[24][25]	+/-	–	–	–	+/-	+/-	–	–	+/-	Leukocytosis, ↑PT	↓GFR, ↑BUN, ↑Cr	↓Na	Proteinuria, Na <10mEq/L, urine osmolality > plasma osmolality	NA	Alpha feto-protein, cryoglobulinemia	Exclude hydronephrosis and intrinsic renal disease	NA	NA	NA	Right ventricular preload, ventricular filling pressures, and cardiac function in echocardiography	–
	Ischemic cardiomyopathy[26][27]	+/-	–	–	–	–	–	–	+/-	+/-	Anemia	↑Cr	↓Na, ↓K, ↓Mg	NA	NA	Troponin, creatine kinase, Creatine kinase-MB, BNP	NA	Abnormal cardiac silhouette	Biventricular volume, wall motion abnormality, myocardial perfusion, hypertrophic cardiomyopathy	Mid-wall fibrosis in MRI	Ejection fraction ≤35%, pulmonary embolism, right ventricular dilation or pericardial effusion with tamponade in echocardiography	–
	Liver cirrhosis[28][29]	+/-	–	+/-	+/-	+/-	–	–	–	+/-	NA	NA	NA	NA	NA	Abnormal LFT, aspartate aminotransferase to platelet ratio, FibroTest/FibroSure, Hepascore	Portal blood flow velocity, hepatic artery enlargement, multifocal lesions or masses, hepatic contour, ascites, splenomegaly	Bowel perforation, gynecomastia, azygos vein enlargement, pleural effusion	Morphologic changes in the liver, collaterals and shunts, hyperattenuating nodule of hepatocellular carcinoma, portal vein thrombosis	Vacular patency, tumor invasion, portal vein thrombosis, steatosis	Hepatic function and portal hypertension in nuclear imaging, hepatic perfusion and the development of shunts and tumors in angiography	Irreversible and a transplant is usually needed
	Malignant hypertension[30][31]	+/-	–	+	–	–	+/-	–	+/-	+/-	Microangiopathic hemolytic anemia	↑BUN, ↑Cr	↑Na, ↑K, ↑P	Proteinuria, microscopic hematuria	Acidosis	Cardiac enzymes, urinary catecholamines, TSH, ↑Renin	NA	Cardiomegaly, pulmonary edema, rib notching, aortic coarctation, mediastinal widening, aortic dissection	NA	NA	Left atrial enlargement and left ventricular hypertrophy in echocardiography	–
	Etiology	Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other	Comments
	Myocarditis[32]	+/-	–	–	–	+/-	–	–	+/-	–	Leukocytosis (eosinophilia),↑ESR and ↑CRP	NA	NA	NA	NA	Cardiac enzymes, viral antibodies	NA	NA	NA	Inflammatory edema, degree of scarring	Endomyocardial biopsy, echocardiography, scintigraphy	NA
	Peritonitis[33][34]	+/-	–	+/-	–	+/-	+/-	+/-	–	–	Leukocytosis	NA	NA	NA	NA	Ascitic fluid neutrophil count > 500 cells/µL	NA	NA	NA	NA	–	–
	Polycythemia[35][36]	+/-	–	–	–	–	–	–	+/-	–	↑RBC, ↑HCT, ↑HGB, thrombocytosis, leukocytosis, ↑PT, and ↑aPTT	↓Erythropoietin	NA	NA	NA	Hyperuricemia	Splenomegaly	NA	NA	NA	–	Phlebotomy is the usual treatment
	Respiratory distress syndrome[37]	+	–	+/-	–	–	–	–	+	–	NA	NA	NA	NA	Metabolic and respiratory acidosis	Pulse oximetry	NA	Bilateral, diffuse, reticular granular or ground-glass appearance +/- cardiomegaly	NA	NA	Patent ductus arteriosus in echocardiography	–
	Shock[38]	+/-	+/-	+/-	+/-	+/-	+/-	–	+/-	–	↑HCT, ↑PT and aPTT, Eosinophilia, Leukocytosis	↓GFR, ↑BUN, ↑Cr	NA	NA	↑Lactate	LFT, ↑BNP, ↑troponin, D-dimer, fibrinogen	Pulmonary embolism, pericardial effusion, cardiac tamponade, pneumothorax, thoracic or abdominal aortic aneurysm in RUSH (Rapid Ultrasound for Shock and Hypotension)	Pneumonia, pneumothorax, pulmonary edema, widened mediastinum, free air under the diaphragm	Traumatic brain injury, stroke, spinal injury, pneumonia, pPneumothorax, ruptured aneurysm, aortic dissection, pulmonary embolism	NA	–	–
	Toxic megacolon[39]	+/-	+/-	+/-	–	+	+	+/-	–	–	Leukocytosis, anemia, ↑ESR and ↑CRP	↑BUN, ↑Cr	↓Na	NA	NA	Loss of haustra, hypoechoic and thick bowel walls, dilated colon > 6cm, dilatation of ileal loops	Dilated colon, free intraperitoneal air	Bowel perforation, abscess	NA	NA	Endoscopy and colonoscopy	–
Etiology		Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other	Comments
Renal causes	Acute interstitial nephritis[40][41]	+/-	–	+/-	–	+/-	+/-	+/-	+/-	+/-	Eosinophilia	↑BUN, ↑Cr, ↑FENa	NA	Eosinophiluria, sterile pyuria, mMicroscopic hematuria, proteinuria	NA	↑Total IgG, ↑IgG4	Normal-sized kidneys	NA	NA	NA	–	History of long term analgesic use
	Acute tubular necrosis[42][43]	+/-	–	–	–	–	+/-	–	–	+/-	Anemia	↑BUN, ↑Cr, ↑FENa	↓Na, ↑K, ↑Mg, ↑P, ↓Ca	Pigmented, muddy brown, granular casts	NA	NA	Obstructive uropathy, cortical thickness, hydronephrosis	Nephrolithiasis	Nephrolithiasis, area of obstruction	Nephrolithiasis, area of obstruction	Loss of tubular cells or the denuded tubules, swollen tubular cells, lLoss of the cell brush border in renal biopsy	Furosemide stress testing for staging
	Cancer[44][45]	+	–	–	–	+/-	+/-	–	–	+/-	Normocytic or microcytic anemia, leukocytosis or lymphocytosis, ↑reticulocytes, thrombocytopenia	↓GFR, ↑BUN, ↑Cr, ↓Erythropoietin	↓Na, ↑K, ↓Mg, ↑P, ↓Ca	Gross hematuria	NA	LFT	Fluid collection and morphological change, flank mass	Calcification and widened mediastinum, filling defects in barium contrast	Metastasis and staging, cystic and solid masses, lymph node, renal vein, and inferior vena cava involvement	Soft tissue invasion and staging	Malignant cystic lesions percutaneous cyst puncture	Renal cell carcinoma types: Clear cell (75%), chromophilic (15%), chromophobic (5%), oncocytoma (3%), collecting duct (2%)
	Congenital kidney disease[46][47][48] – Agenesis – Dysplasia – Hypoplasia – Polycystic	+/-	–	–	–	+/-	+/-	–	–	+/-	↑HCT	↓GFR	↓P, ↓Ca	Microalbuminuria, uricosuria	NA	Genetic testing forADPKD2	Visualization of kidney cysts	Small kidney cysts (0.5 cm)	Kidney size, intracranial aneurysms	NA	–	–
	End stage renal disease[49][50]	+	–	–	–	+/-	–	–	–	+	Anemia	↓GFR, ↑BUN, ↑Cr	↑K	Hypoalbuminuria	↓HCO3	Phosphate, 25-hydroxy vitamin D, alkaline phosphatase, parathyroid hormone	Hydronephrosis, retroperitoneal fibrosis, enlarged or shrunken kidneys	Obstruction in retrograde pyelogram	Renal masses, stones, and cysts	Renal vein thrombosis, renal artery stenosis in magnetic resonance angiography	Percutaneous renal biopsy	–
	Etiology	Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other	Comments
	Endogenous toxins[51][52][53][54][55] – Hemoglobin – Myoglobin – Uric acid	+/-	–	+/-	+	–	+/-	–	–	+/-	Anemia, thrombocytopenia	↓GFR, ↑BUN, ↑Cr	↑K, ↑urate, ↓Ca	Uricosuria, hematuria, myoglobinuria, casts	NA	Creatine kinase > 1000 U/L	Malignant or cystic lesions, hydronephrosis, nephrocalcinosis, urolithiasis	NA	Urolithiasis, wilms tumor, polycystic kidney disease	NA	Ureter or bladder abnormality in voiding cystourethrography	–
	Glomerulonephritis[56][57][58]	+/-	–	–	–	–	–	–	–	+	Pleocytosis, anemia, leukocytosis, ↑ESR	↑BUN, ↑Cr	NA	Specific gravity > 1.020, proteinuria, hematuria, red blood cell casts, white blood cell casts, cellular casts, oval fat bodies	NA	NA	↑C3, ↑C4, ↑CH50, blood and tissue culture, antinuclear antibodies, cryoglobulins, hepatitis B and C serologies, antineutrophil cytoplasmic antibody (ANCA)	Kidney size, echogenicity of the renal cortex, obstruction, degree of fibrosis	Pulmonary congestion	Visceral abscesses	–	Renal biopsy, light and electron microscopy, immunofluorescence aid diagnosis
	Goodpasture syndrome[59][60][61]	+/-	–	–	–	–	–	–	+/-	+/-	Anemia, leukocytosis, ↑ESR	↑BUN, ↑Cr	NA	Low-grade proteinuria, gross or microscopic hematuria, RBC casts	NA	Anti– glomerular basement membrane antibody, antineutrophilic cytoplasmic antibody	NA	Bilateral, basal, patchy parenchymal consolidations	NA	NA	Diffuse alveolar hemorrhage in pulmonary biopsy	–
	Hemolytic uremic syndrome[62][63][64]	+/-	–	+/-	+/-	+/-	+	+	–	+/-	Severe anemia, thrombocytopenia, ↑aPTT	↑BUN, ↑Cr	NA	Mild proteinuria, Red blood cells, Red blood cell casts	NA	Schistocytes, ↑FDP and D-dimer, ↑bilirubin, ↑LDH, ↓haptoglobin, stool culture (for E coli 0157:H7 or shigella), ↓ADAMTS-13 activity	Ruling out obstruction	NA	NA	NA	Diffuse thickening of the glomerular capillary wall, swelling of endothelial cells, fibrin thrombi in renal biopsy	–
	Nephrolithiasis[65][66][67]	–	–	–	–	+/-	+/-	–	–	–	Mild leukocytosis, ↑CRP	↑BUN, ↑Cr	↑Na, ↑K, ↑P, ↑Ca, ↑urate	Gross or microscopic hematuria, Red blood cells, urinary crystals of calcium oxalate, uric acid, or cystine, hypercalciuria, urinary pH > 7 in struvite stones (Proteus, Pseudomonas, Klebsiella), urinary pH < 5 in uric acid stones	↓HCO3, renal tubular acidosis	–	All types of stones are visible, hydronephrosis, abdominal aortic aneurysm, cholelithiasis	Calcium – containing stones, uric acid or cystine stones, stone movement	Stone density, size and composition, hydronephrosis, nephromegaly, perinephric fat streaking	NA	Intravenous pyelography (IVP), renal tomography, nuclear renal scan	–
	Etiology	Fatigue/ Lethargy	Thirst	Dizziness/ Confusion	Muscle weakness/ cramp	Somatic/ visceral pain	Vomiting	Diarrhea	Tachypnea	Edema	Blood indices	Renal Funtion test	Electrolytes	Urine analysis	ABG	Other	Ultrasound	X-ray	CT	MRI	Other	Comments

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

The incidence less severe AKI is approximately 200-300 per 100,000 individuals worldwide. The prevalence of acute kidney injury is approximately 400-500 per 100,000 individuals worldwide. Patients of all age groups may develop AKI. The incidence of AKI increases with age; the median age at diagnosis is 76 years. AKI affects men and women equally.

• The incidence less severe AKI is approximately 200-300 per 100,000 individuals worldwide.^[1]
• The incidence AKI treated with renal replacement therapy is approximately 20 to 30 per 100,000 individuals worldwide.
• Ali et al reported a high incidence of 1811 cases of AKI per 1000,000 population during 2003.^[2]

• The prevalence of acute kidney injury is approximately 400-500 per 100,000 individuals worldwide.

• In 2005, the mortality among patients with severe AKI requiring renal replacement therapy was 60.3%.

• Patients of all age groups may develop AKI.
• The incidence of AKI increases with age; the median age at diagnosis is 76 years.
• Chronic renal failure is usually first diagnosed among patients with 80 years old.

• AKI usually affects individuals of the African America race. Caucasians individuals are less likely to develop AKI.^[3]

• AKI affects men and women equally.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Common risk factors in the development of acute kidney injury include exposure to contrast, volume depletion, hemodynamic instability, advanced ages, hypertension and diabetes mellitus.

Common risk factors in the development of acute kidney injury include exposure to contrast, volume depletion, hemodynamic instability, advanced ages, hypertension and diabetes mellitus.

• Common risk factors in the development of acute kidney injury include:^{[1][2][3][4][5][6]}

• In ICU patients

• Age more than 65 years
• Diabetes
• Presence of infection
• Acute circulatory or respiratory failure
• Past history of chronic heart failure (CHF)
• Pre-existing kidney disease, lymphoma or leukemia
• Use of aminoglycosides
• Cirrhosis

• In patients undergoing open heart surgery

• Advanced age
• Diabetes mellitus
• Hypertension
• Impaired left ventricular function
• Urgent operation or reoperation
• Prolonged cardiopulmonary bypass and aortic cross-clamp periods
• Hypothermia
• Re-exploration for bleeding or pericardial tamponade
• Systemic infection
• Peripheral vascular disease
• Cerebral vascular disease
• COPD

• In patients exposed to contrast media

• Pre-existing renal disease
• Diabetes
• Hypertension
• CHF
• Advanced age (especially >75)
• Volume depletion
• IABP
• Anemia
• Hemodynamic instability
• Concurrent nephrotoxic medications
• High osmolality or large volume of contrast media

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Several laboratory tests are useful for screening of acute kidney injury among patients with risk factors like BUN, creatinine and urine analysis.

Several laboratory tests are useful for screening of acute kidney injury among patients with risk factors as following:

• BUN
• Creatinine
• Urine analysis

Electronic health record-based predictive models for acute kidney injury screening among pediatric inpatients, children aged 28 days through 21 years, with sufficient serum creatinine measurements are assessed by followings:^[1][2]

• Age
• Medication exposures
• Platelet count
• Red blood cell distribution width
• Serum phosphorus
• Serum transaminases
• Hypotension (in ICU patients only)
• PH (in ICU patients only)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Certain forms of AKI such as contrast induced nephropathy, usually have a shorter course with creatinine peak in 3-5 days. Common complications of acute kidney injury include anemia, metabolic acidosis, anorexia, nausea and vomiting. In general, the majority of patients that survive the initial insult recover their kidney function within 30 days.

• Certain forms of AKI such as contrast induced nephropathy, usually have a shorter course with creatinine peak in 3-5 days.^[1]

• Common complications of acute kidney injury include:^[2][3][4][5]
  • Anemia
  • Anorexia
  • Nausea and vomiting
  • Upper gastrointestinal bleeding
  • Metabolic acidosis
  • Hyperkalemia
  • Pulmonary edema
  • Hyperphosphatemia
  • Risk of infectious disease

• Acute interstitial nephritis causing AKI can have a variable course, sometimes resolving with the withdrawal of the inciting agent and at times requiring several weeks to restore full renal function.
• Other forms related to a more severe systemic illness such as DIC, lupus, and RPGN often result in end-stage renal disease.^[6]
• In general, the majority of patients that survive the initial insult recover their kidney function within 30 days.^[6]
• Beyond two months, patients usually will not recover their full renal function but might have some improvement that allows them to be free of renal replacement therapy.^[7][8]
• Despite the natural history showing possible recovery of renal function, AKI is associated with high mortality.
• AKI is also associated with increased length of hospital stay and costs.^[1]

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