Acute Kidney Injury

Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Uremia refers specifically to the constellation of symptoms that occur with severe renal dysfunction. The etiologies of AKI are classified as prerenal, intrinsic renal, or post-renal, and there is a varied clinical presentation depending on the severity of kidney dysfunction. Acute kidney injury is diagnosed initially by a change in serum creatinine levels, and then the etiology is determined by clinical history, lab testing, imaging, and possibly kidney biopsy. The management of AKI depends on the etiology; however, attention to the individual’s volume status and serum electrolytes is always important. If management is unsuccessful and AKI progresses to CKD, then renal replacement therapy with dialysis or kidney transplantation is necessary.

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Acute kidney injury refers to an abrupt decrease in kidney function, manifested by an increase in serum creatinine level, with or without reduced urine output.


Previously there had been more than 30 definitions of “acute renal failure” in the literature, and these have been updated to the term AKI.

  • The RIFLE criteria:
    • Risk
    • Injury
    • Failure
    • Loss of kidney function
    • End-stage kidney disease
  • The Acute Kidney Injury Network (AKIN) criteria
  • Kidney Disease: Improving Global Outcomes (KDIGO) staging of AKI:
    • Supersedes the other staging systems; currently preferred
    • Classifies individuals according to criteria that result in the highest degree of injury, as do the other systems
    • Stage 1:
      • ≥ 0.3 mg/dL increase in serum creatinine within 48 hours, or
      • Increase in serum creatinine > 1.5–1.9 times baseline in the past 7 days, or
      • Urine volume/urine output < 0.5 mL/kg/hr for 6–12 hours
    • Stage 2:
      • Serum creatinine 2.0‒2.9 times baseline, or
      • Urine volume/urine output < 0.5 mL/kg/hr for ≥ 12 hours
    • Stage 3:
      • Serum creatinine 3 times baseline, or
      • Serum creatinine ≥ 4 mg/dL, or
      • Initiation of renal replacement therapy, or
      • Decrease in estimated GFR < 35 mL/min/1.73 m2 in individuals < 18 years of age, or
      • Urine volume/urine output < 0.3 mL/kg/hr for ≥ 24 hours, or
      • Anuria for ≥ 12 hours


  • 7% of individuals who are hospitalized develop AKI.
  • 20% of acutely ill individuals develop AKI.
  • Mortality is low in uncomplicated AKI.
  • Mortality is 50%‒70% in AKI associated with sepsis and multiple organ failure.
  • No gender predilection
  • More common in extremes of age

Etiology and Pathogenesis

The causes of AKI are commonly organized into prerenal, intrinsic renal, or postrenal etiologies. With prerenal and postrenal causes, the kidneys have normal anatomy and the injury is due to the effects of the inciting factor.

Normal physiology

  • Normally, GFR is maintained by compensatory mechanisms:
    • At the afferent arteriole: prostaglandins → vasodilation → increase in glomerular hydrostatic pressure
    • At the efferent arteriole: angiotensin II → vasoconstriction → maintains or increases pressure in the glomerulus
  • With decreased renal perfusion, compensatory mechanisms will:
    • Activate antidiuretic hormone (ADH) → increased sodium and water absorption in the proximal tubule → concentrated urine
    • Increase filtration fraction → increased oncotic pressure in the glomerulus

Etiology and pathophysiology

  • Prerenal causes of AKI result in renal hypoperfusion due to:
    • True volume depletion: loss of sodium from the extracellular fluid (ECF) due to:
      • Acute blood loss/hemorrhage
      • GI losses with vomiting or diarrhea
      • Diuretics
    • Perceived decreased blood volume by the kidney/glomerular afferent arterioles (although total ECF may be increased) due to:
      • Hypotension
      • Sepsis
      • Congestive heart failure
      • Cirrhosis
      • Severe burns/3rd spacing of fluids
    • Effects of medications:
      • NSAIDs block vasodilation of the afferent arteriole → decreased GFR
      • ACE inhibitors block constriction of the efferent arteriole → decreased GFR
    • Often rapidly reversible
  • Intrarenal causes of AKI: direct damage to the glomeruli and/or tubulointerstitial structures
    • Acute tubular necrosis (ATN): most common cause of intrarenal AKI:
      • Decreased renal perfusion due to patch necrosis of the proximal tubule and thick ascending limb of the loop of Henle
      • Endothelial AND epithelial cell injury
      • Tubular obstruction due to casts
      • Microvascular ischemic changes in blood flow and reperfusion injuries
      • Immunological factors
      • Risk factors include volume depletion, underlying kidney disease, NSAIDs, and diabetes mellitus.
    • Acute interstitial nephritis:
      • Inflammatory cell infiltration into the kidney interstitium
      • Caused by medications, infections, or autoimmune diseases
    • Acute tubular obstruction:
      • Multiple myeloma
      • Tumor lysis syndrome
    • Vascular disease:
      • Atherosclerosis
      • Vasculitis
    • Glomerular disease:
      • Glomerulonephritis (presents with hematuria)
      • Nephrotic syndrome (presents with proteinuria)
  • Postrenal causes of AKI: obstruction
    • May occur at any point in its course from the renal pelvis to the urethra
    • Requires bilateral obstruction of the urinary tract if the individual has 2 functioning kidneys
    • If only 1 functioning kidney, obstruction will cause an increase in serum creatinine
    • Mechanism:
      • Obstruction induces apoptosis of the renal tubular cells.
      • Apoptosis is mediated by caspases (a family of protease enzymes that play essential roles in programmed cell death), which are generated from cytokine release and inflammatory responses.
      • Prolonged obstructive processes induce tubulointerstitial fibrosis and inflammation.
    • Causes of obstruction:
      • Bladder outlet obstruction
      • Benign prostatic hyperplasia (BPH)
      • Neurogenic bladder
      • Gynecologic tumors (ovarian cancer, uterine fibroids, cervical cancer)
      • Retroperitoneal fibrosis (rare)
    • Often rapidly reversible
  • Pathophysiologic effects of AKI on electrolytes and acid-base balance:
    • Hyperkalemia:
      • Due to decreased renal excretion of potassium
      • Increases the probability of cardiac arrhythmias
    • Hyperphosphatemia: due to decreased renal excretion of phosphate
    • Metabolic acidosis:
      • Inability of the kidneys to excrete acids
      • Exacerbates hyperkalemia
      • Increases the probability of cardiac arrhythmias

Clinical Presentation

Acute kidney injury can present with a wide range of symptoms, from being asymptomatic with only laboratory abnormalities to being comatose due to severe uremia.

Clinical presentation with hypovolemia

  • Symptoms:
    • Dizziness
    • Fatigue
    • Confusion
    • Decreased urine output (oliguria)
  • Physical exam findings:
    • Hypotension
    • Tachycardia
    • Poor skin turgor
    • Dry mucous membranes

Clinical presentation with hypervolemia/fluid overload

  • Symptoms:
    • Dyspnea
    • Abdominal distension
    • Swelling in the extremities
  • Physical exam findings:
    • Edema
    • Crackles
    • Ascites
    • Pleural effusion
    • Elevated jugular venous pressure (JVP)
    • S3 heart sound

Clinical presentation with hyperkalemia

  • Symptoms:
    • Severe muscle weakness
    • Paralysis
  • Cardiac conduction abnormalities:
    • Right bundle branch block (RBBB)
    • Left bundle branch block (LBBB)
    • Advanced atrioventricular block
  • Arrhythmias:
    • Sinus bradycardia
    • Sinus arrest
    • Ventricular tachycardia
    • Ventricular fibrillation
    • Asystole

Clinical presentation with hypokalemia

  • Usually found in the same instances as hypovolemia
  • Symptoms:
    • Muscle cramps
    • Ileus
  • Physical exam findings:
    • Usually normal
    • May have muscle weakness and rhabdomyolysis, if severe
  • ECG changes:
    • ST depression
    • T wave flattening
    • U waves
    • QT interval prolongation
    • May not show any overt ECG manifestations

Clinical presentation with uremia

  • Symptoms:
    • GI:
      • Anorexia
      • Nausea/vomiting
    • Dysgeusia (abnormal taste)
    • Neurologic:
      • Confusion
      • Drowsiness
      • Encephalopathy
      • Seizure
      • Coma
    • Bleeding due to qualitative platelet dysfunction from uremic toxins
  • Physical exam findings:
    • Asterixis: tremor of the hand when the wrist is extended
    • Myoclonus: quick involuntary muscle jerks
    • Pericarditis/pericardial rub: audible grating sound best heard between the apex and sternum
    • Pericardial effusion

Clinical presentations with specific etiologies of AKI

  • Classic triad of acute interstitial nephritis (all 3 are only seen in 10% of affected individuals):
    • Rash
    • Fever
    • Eosinophilia
  • Other causes of AKI presenting with a rash:
    • Petechial rash, palpable purpura‒glomerulonephritis/vasculitis
    • Livedo reticularis‒cholesterol emboli
  • Anuria: < 50‒100 mL urine volume/urine output per day:
    • Shock
    • Bilateral urinary tract obstruction
    • Rapidly progressive glomerulonephritis
    • Hemolytic uremic syndrome
    • Bilateral renal artery occlusion
  • Hematuria:
    • Microscopic: seen with glomerulonephritis
    • Gross: seen with IgA nephropathy
  • Foamy urine: very high levels of proteinuria → nephrotic syndrome
  • Urinary frequency/hesitancy → urinary tract obstruction with BPH

Acute tubular necrosis phases

Acute tubular necrosis follows a characteristic clinical course involving 3 phases.

Clinical course of atn

Clinical course of acute tubular necrosis (ATN)

Image by Lecturio. License CC BY-NC-SA 4.0


The diagnosis of AKI includes identifying inciting factors and determining if the etiology is prerenal, intrarenal, or postrenal, in order to plan appropriate treatment.

History and physical examination

  • Volume depletion/dehydration:
    • Diarrhea
    • Vomiting
    • Excessive sweating
  • Common medications associated with AKI:
    • Diuretics
    • ACE inhibitors
    • Angiotensin receptor blockers
    • NSAIDs
    • Calcineurin inhibitors: Cyclosporin, tacrolimus
  • Look for common IV nephrotoxic drugs used in the hospital as a cause of AKI:
    • Aminoglycosides
    • Amphotericin B
    • Platinum-based chemotherapies
    • Vancomycin
  • Common comorbidities:
    • Sepsis
    • Congestive heart failure (CHF)
    • Cirrhosis

Regular laboratory testing

  • Serum BUN and creatinine
  • BUN/creatinine ratio:
    • Normal ratio is approximately 15.
    • Prerenal > 20
    • Intrinsic renal < 15
  • Electrolyte abnormalities/hyperkalemia
  • CMP/bicarbonate for metabolic acidosis
  • BNP for heart failure/volume overload
  • Urinalysis: 
    • Proteinuria: seen with nephrotic syndrome
    • Hematuria: seen with nephritic syndromes
    • RBC casts are a finding of glomerulonephritis.
    • WBC casts are a finding of acute interstitial nephritis.
    • Renal tubular cell casts and muddy brown casts are findings of ATN.
  • Urine sodium (UNa+):
    • UNa+ < 10 suggests a prerenal cause.
    • UNa+ > 20 suggests an intrinsic renal cause.
  • Fractional excretion of sodium (FENa) is calculated by simultaneously obtaining urine and plasma specimens of Na+ and creatinine:
    • FENa < 1% suggests a prerenal cause of AKI.
    • FENa > 1% suggests an intrinsic renal cause.
$$FENa \%=\frac{Urine\ Na\times serum\ creatinine}{Serum\ Na \times urine\ creatinine}\times 100$$

Other specific testing

Consider other specific testing for less common etiologies:

  • Serum CK for rhabdomyolysis
  • Serum free light chains, serum/urine protein electrophoresis for multiple myeloma
  • Serologies for glomerulonephritis:
    • HIV, hepatitis B, and hepatitis C serologies
    • Serum complement (C3, C4) levels
    • PLA2R antibody for membranous nephropathy
    • Anticytoplasmic neutrophil antibodies (ANCA) for vasculitis
    • Antiglomerular basement membrane for Goodpasture disease
    • ANA and anti-dsDNA for lupus


  • Consider renal artery Doppler ultrasound if high suspicion for renal artery stenosis
  • Ultrasound for kidney stones or obstruction:
    • BPH in men
    • Gynecologic tumors in women

Parameters to differentiate prerenal from renal AKI

Table: Parameters to differentiate prerenal from renal AKI
Prerenal Renal (ATN)
Specific gravity ≥ 1.020 ≤ 1.010
Urine osmolality (mOsm/kg) > 500 < 350
Urine sodium (mEq/L) < 20 > 20
FENa < 1% > 1%
Urine protein Minimal Minimal to severe, depending on etiology
ATN: acute tubular necrosis
FENa: fractional excretion of sodium

Urine microscopy findings

Table: Urine microscopy findings
Finding Significance
Renal tubular cells Acute tubular injury
RBCs Nonglomerular bleeding/anywhere in the urinary tract
Dysmorphic red cells Glomerular disease
Red cell casts Diagnostic of glomerular disease
Leukocytes/WBCs Urinary tract infection
White cell casts Renal infection
Hyaline casts Any type of renal disease
Granular casts More significant renal disease
“Muddy brown cast” Necrotic tubular cells/acute tubular injury


The etiology of AKI dictates the treatment; further testing with biopsy may be indicated after appropriate workup and treatment for hypovolemia or fluid overload are completed.


  • Based on the etiology of AKI, may not be immediately apparent on initial investigation:
    • If prerenal with hypovolemia → treat with IV fluids
    • If hypervolemia/fluid overload → treat with diuretics
    • If postrenal with obstruction → Foley catheter to relieve urinary retention: 
      • Percutaneous nephrostomy tubes may be necessary.
      • Specialist consultation to treat underlying conditions (urology or gynecology)
    • Stop any offending agents (medications) if identified as the cause of AKI.
  • Treat electrolyte and acid-base imbalances urgently:
    • Metabolic acidosis → treat with oral or IV sodium bicarbonate
    • Hyperkalemia:
      • IV calcium to stabilize cardiac membranes (temporary effect)
      • IV insulin and IV dextrose to shift potassium intracellularly (temporary effect)
      • Oral cation exchange resins that cause GI loss of potassium (lasting effect)
      • Loop diuretics cause renal loss of potassium (lasting effect).
      • Dialysis directly removes potassium from the blood (lasting effect).
    • Hyperphosphatemia:
      • Usually asymptomatic and does not require treatment during AKI.
      • Causes important complications if CKD
  • For all cases of AKI:
    • Avoid nephrotoxins, including IV iodinated contrast for CT scans.
    • Avoid gadolinium-based contrast for MRI studies.
    • Restrict sodium, potassium, and phosphate in the diet.
    • Repeat serum creatinine and potassium levels.
  • Indications for kidney biopsy:
    • Worsening serum creatinine with no clear diagnosis
    • Suspicion for glomerulonephritis or vasculitis: may require aggressive specific treatments such as high-dose corticosteroids
      • Rapidly progressive glomerulonephritis (RPGN)
      • IgA nephropathy
      • Goodpasture’s disease (antiglomerular basement membrane disease)
      • ANCA-positive vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis)
      • Pauci-immune glomerulonephritis
  • Indications for acute dialysis:
    • Uncontrolled hyperkalemia
    • Fluid overload causing respiratory compromise
    • Uremia:
      • With pericardial effusion
      • With encephalopathy
    • Severe metabolic acidosis
  • Prognosis is variable, depending on severity and etiology.
  • Long-term follow up with a nephrologist if less than full recovery


  • In the recovery phase, serum creatinine should decrease back to baseline or to a new steady state if permanent damage has been incurred.
  • Monitor the degree of renal recovery:
    • Determine if the individual had previous CKD:
      • Previously elevated creatinine
      • Small kidneys on renal ultrasound
      • Proteinuria
    • An individual’s baseline serum creatinine will worsen at least slightly with each successive episode of AKI, reflecting long-term damage from acute events.
  • It is important for individuals with CKD to follow up closely with a nephrologist.
  • Complications: possible development of CKD

Differential Diagnosis

  • Renal calculi: hard deposits made of minerals and salts that form inside the kidneys. Individuals are often asymptomatic until the renal calculi migrate to the ureter, when they present with severe sharp flank pain, hematuria, and/or urinary tract infection. Diagnosis is by clinical presentation, urinalysis, and imaging. Management may be self-limiting by passing the stone or may require intervention with lithotripsy or surgery.
  • CKD: kidney damage or an estimated GFR (eGFR) < 60 mL/min/1.73 m2 for ≥ 3 months. Symptoms depend on the cause; prerenal, renal, or postrenal. Diagnosis includes detailed blood and urine workup with additional screening tests. Management includes adjusting drug doses for the level of eGFR and preparation for renal replacement therapy.
  • Urinary tract infection: infection of any part of the urinary system, more commonly observed in women. Individuals present with frequent and painful urination, fever, chills, hematuria, and/or abdominal and back pain. Diagnosis is made clinically and by urinalysis with a urine culture. Management is with fluids and antibiotics.


  1. Ralston, S.H., et al. (Eds.). (2018). Davidson’s Principles and Practice of Medicine. pp. 411–414.
  2. Goyal, A., et al. (2020). Acute kidney injury. StatPearls. Retrieved July 24, 2021, from
  3. Ostermann, M., Joannidis, M. (2016). Acute kidney injury: Diagnosis and diagnostic workup. Critical Care. 20, 299.
  4. Khwaja, A. (2012). KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical Practice. 120(4), c179–84.
  5. Chawla, L.S., et al. (2017). Acute kidney disease and renal recovery: Consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nature Reviews. Nephrology. 13(4), 241–57. 
  6. Palevsky, P. (2021). Definition and staging criteria of acute kidney injury in adults. UpToDate. Retrieved February 23, 2021, from
  7. Mount, D.B. (2020). Clinical manifestations of hyperkalemia in adults. UpToDate. Retrieved July 27, 2021, from

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