Acute kidney injury (Acute renal failure)

Acute kidney injury (AKI) is a sudden loss of renal function with a consecutive rise in creatinine and blood urea nitrogen (BUN). It is most frequently caused by decreased renal perfusion (prerenal) but may also be due to direct damage to the kidneys (intrarenal or intrinsic) or inadequate urine drainage (postrenal). In AKI, acid-base homeostasis, as well as the fluid and electrolyte balance, is disturbed, and the excretion of substances, including drugs, within the urine is impaired. The main symptom of AKI is oliguria or anuria; in some cases, polyuria may occur as a result of disturbed tubular reabsorption. Diagnosis of AKI requires an increase in serum creatinine concentration and/or decrease in urine output. Specific investigations are guided by the suspected cause. Rapid evaluation, diagnosis, and treatment are necessary to prevent irreversible loss of renal function.

Prerenal acute kidney injury (∼ 60% of cases)

Prerenal causes include any condition leading to decreased renal perfusion.

• Hypovolemia
  • Volume depletion: e.g., hemorrhage, vomiting, diarrhea, sweating, burns, diuretics, poor oral intake, acute pancreatitis
  • Decreased circulating volume: e.g., hepatorenal syndrome, cirrhosis, liver failure; , nephrotic syndrome, congestive heart failure
• Hypotension: e.g., sepsis, dehydration, cardiogenic shock (decreased cardiac output), anaphylactic shock
• Renal artery stenosis
• Drugs affecting glomerular perfusion: e.g., cyclosporine, tacrolimus, NSAIDs , ACE inhibitors

Avoid coadministering ACE inhibitors and NSAIDs in patients with reduced renal perfusion (e.g., congestive heart failure, renal artery stenosis) because doing so can significantly decrease the glomerular filtration rate (GFR)!

Intrinsic acute kidney injury (∼ 35% of cases)

Intrinsic causes include any disease that leads to severe direct kidney damage.

• Acute tubular necrosis (causes ∼ 85% of intrinsic AKIs): most commonly caused by sepsis, infection, ischemia, and/or nephrotoxins
• Glomerulonephritis (e.g., rapidly progressive glomerulonephritis)
• Vascular
  • Hemolytic uremic syndrome (HUS)
  • Thrombotic thrombocytopenic purpura (TTP)
  • Malignant hypertension
  • Vasculitis
• Acute tubulointerstitial nephritis
  • Drug-induced
  • Infectious
  • Immunological

Prolonged prerenal failure leads to intrinsic failure because decreased renal perfusion causes tubular necrosis!

Postrenal acute kidney injury (∼ 5% of cases)

Postrenal causes include any condition that results in bilateral obstruction of urinary flow from the renal pelvis to the urethra.

• Congenital malformations (e.g. posterior urethral valves)
• Acquired obstructions
  • Benign prostatic hyperplasia (BPH)
  • Iatrogenic/catheter-associated injuries
  • Tumors
  • Stones
  • Bleeding with blood clot formation
• Neurogenic bladder (e.g., multiple sclerosis, spinal cord lesions, or peripheral neuropathy)

As long as the contralateral kidney remains intact, patients with unilateral ureteral obstruction typically maintain normal serum creatinine levels.

References:^[1][2][3]

Prerenal

• Decreased blood supply to kidneys (due to hypovolemia, hypotension, or renal vasoconstriction) ; → failure of renal vascular autoregulation to maintain renal perfusion → decreased GFR → activation of renin-angiotensin system → increased aldosterone release → increased reabsorption of Na⁺, H₂O → increased urine osmolality → secretion of antidiuretic hormone → increased reabsorption of H₂O and urea
• Creatinine; is still secreted in the proximal tubules, so the blood BUN:creatinine ratio increases.

Intrinsic

• Damage to a vascular or tubular component of the nephron → necrosis or apoptosis of tubular cells → decreased reabsorption capacity of electrolytes (e.g., Na⁺), water, and/or urea; (depending on the location of injury along the tubular system) → increased Na⁺ and H₂O in the urine → decreased urine osmolality

Postrenal

• Bilateral urinary outflow obstruction (e.g., stones, BPH, neoplasia, congenital anomalies) → increased retrograde hydrostatic pressure within renal tubules → decreased GFR and compression of the renal vasculature → acidosis, fluid overload, and increased BUN, Na⁺, and K⁺.
• A normal GFR can be maintained as long as one kidney functions normally.

Four phases of AKI (some patients may not undergo all phases)

Phase	Characteristic features	Duration
Initiating event (kidney injury)	Symptoms of the underlying illness causing AKI may be present.	Hours to days
Oliguric or anuric phase (maintenance phase)	Progressive deterioration of kidney function Reduced urine production (oliguria), < 50 ml/24 hrs = anuria Increased retention of urea and creatinine (azotemia) Complications: fluid retention (pulmonary edema), hyperkalemia, metabolic acidosis, uremia, lethargy, asterixis	1–3 weeks
Polyuric/diuretic phase	Glomerular filtration returns to normal, which increases urine production (polyuria), while tubular reabsorption remains disturbed. Complications: loss of electrolytes and water (dehydration, hyponatremia, and hypokalemia)	∼ 2 weeks
Recovery phase	Kidney function and urine production normalize.	Months to years

References:^[4][2][1]

• May be asymptomatic.
• Oliguria or anuria
• Signs of volume depletion (in prerenal AKI caused by volume loss)
  • Orthostatic or frank hypotension and tachycardia
  • Reduced skin turgor
• Signs of fluid overload (from Na⁺ and H₂O retention)
  • Peripheral and pulmonary edema
  • Hypertension
  • Heart failure
  • Shortness of breath
• Signs of uremia
  • Anorexia, nausea
  • Encephalopathy, asterixis
  • Pericarditis
  • Platelet dysfunction
• Signs of renal obstruction (in postrenal AKI)
  • Distended bladder
  • Incomplete voiding
  • Pain over the bladder or flanks
• Fatigue, confusion, and lethargy
• In severe cases: seizures or coma
• Affected individuals have a higher risk of secondary infection throughout all phases (most common reason for fatalities).

Acute tubular necrosis

• Epidemiology: causes ∼ 85% of intrinsic AKIs
• Location
  • The straight segment of the proximal tubule and the straight segment of the distal tubule (i.e., the thick ascending limb) are particularly susceptible to ischemic damage.
  • The convoluted segment of the proximal tubule is particularly susceptible to damage from toxins.
• Etiology
  • Ischemic: Injury occurs secondary to decreased renal blood flow.
    • Severe hypotension, especially in the context of shock: hypovolemic (e.g., hemorrhage, severe dehydration), septic, cardiogenic (e.g., heart failure), or neurogenic shock
    • Thromboembolism
    • Thrombotic microangiopathy
    • Cholesterol embolism (atheroemboli)
  • Toxic: Injury occurs directly due to nephrotoxic substances.
    • Contrast-induced nephropathy
    • Medication: aminoglycosides, cisplatin, amphotericin, lead, ethylene glycol
    • Pigment nephropathy
      • Myoglobinuria due to rhabdomyolysis (crush syndrome)
      • Hemoglobinuria associated with hemolysis
    • Acute uric acid nephropathy
  • Other: sepsis, infections
• Pathophysiology: necrotic proximal tubular cells fall into the tubular lumen → debris obstructs tubules → decreased GFR → sequence of pathophysiological events similar to prerenal failure (i.e., activation of RAAS; see “Pathophysiology” above)
• Clinical features: same as AKI (see “Clinical features” and four phases of AKI above)
• Diagnostics (see “Diagnostics” below)
  • Blood findings: azotemia, hyperkalemia, and metabolic acidosis
  • Urinary findings
    • ↑ Fractional excretion of sodium (FENa)
    • Myoglobinuria, hemoglobinuria
  • Urinary sediment
    • Muddy brown granular casts
    • Epithelial cell casts
    • Free renal tubular epithelial cells (due to denudation of the tubular basement membrane)
• Management: See “Treatment” below.
• Prognosis
  • After 1–3 weeks, most patients with ATN will experience tubular re-epithelialization and spontaneous full recovery is common.
  • Can be lethal; if AKI is severe and not managed adequately (e.g., dialysis may be required in oliguric patients with volume overload or severe hyperkalemia)

Renal cortical necrosis

• Definition: rare cause of AKI caused by acute generalized ischemic necrosis of the renal cortex in both kidneys
• Etiology: septic shock, disseminated intravascular coagulation (DIC); , hemolytic uremic syndrome (HUS), obstetric complications; (e.g., abruptio placentae, septic abortion, postpartum hemorrhage)
• Pathophysiology: vasospasms and microvascular injury with vascular thrombosis → prolonged severe renal ischemia → diffuse; and/or patchy destruction of the renal cortex
• Clinical features: flank pain, CVA tenderness and signs of AKI (see also “Clinical features” above and shock)
• Management: Dialysis can improve outcomes (see “Treatment” below).
• Prognosis: high mortality rates without treatment

Contrast-induced nephropathy

• Definition: AKI after IV administration of iodinated contrast medium
• Risk factors
  • Chronic kidney disease; (CKD): esp. in patients with diabetes mellitus, multiple myeloma
  • Congestive heart failure, arterial hypotension
  • Nephrotoxic drugs: esp. NSAIDs
  • Anemia
  • Dehydration
• Clinical features/diagnostics: See “Clinical features” above and “Diagnostics” below.
• Course
  • Creatinine is highest after 3–5 days after injury and usually falls back to the baseline level within 1 week.
  • The course is typically mild because end-stage renal disease usually only occurs in patients with pre-existing CKD.
• Prevention
  • Always evaluate kidney function before administering a contrast agent.
  • Use a low dose and low concentration of contrast medium.
  • The patient should discontinue nephrotoxic substances before administration.
  • Ensure hydration: isotonic NaCl before and after administration of contrast medium
  • Acetylcysteine (no clear recommendations )

References:^{[2][5][6][7][8][9][3][10]}

Approach ^[11][12]

• The diagnosis of AKI requires an acute increase in serum creatinine and/or decrease in urine output (see the criteria for different stages in the table below); therefore, renal function tests should be done in every patient with suspected AKI
• Additional laboratory investigations and imaging should be guided by the suspected cause.

Stages of AKI by Kidney Disease Improving Global Outcomes (KDIGO, 2012)
Stage	Serum creatinine	Urine output
1	Increase of 0.3 mg/dL (26.5 μmol/L) within 48 h or 1.5–1.9 times baseline within 7 days	< 0.5 mL/kg/h for 6–12 h
2	2–2.9 times baseline	< 0.5 ml/kg/h for ≥12 h
3	≥ 3 times baseline or Increase to ≥ 4 mg/dL (354 μmol/L) or Initiation of renal replacement therapy or Patients < 18 years: decrease in eGFR to < 35 mL/min/1.73 m2	< 0.3 mL/kg/h for ≥ 24 h or Anuria for ≥ 12 h

Prerenal

• Blood test findings
  • Elevated serum creatinine concentration
  • Serum BUN:creatinine ratio > 20:1
• Urine test findings
  • Normal urinalysis
  • Low urine sodium concentration (< 20 mEq/L)
  • Low fractional excretion of sodium (FeNa < 1%)
    • The fractional excretion of sodium reveals how much filtered sodium is excreted in the urine.
    • FENa = (V*UNa)/(GFR*PNa), using plasma and urine sodium concentrations (PNa and UNa), urine flow rate (V), and GFR or
    • FENa = (SCr*UNa)/(SNa*UCr), using serum sodium (SNa), urine sodium; (UNa), serum creatinine; (SCr), and urine creatinine (UCr).
  • High urine osmolality (> 500 mosm/kg) and specific gravity (> 1.010)
  • Hyaline casts due to hypovolemia resulting in concentrated urine

Intrinsic

• Blood test findings
  • Elevated serum creatinine; concentration and rapidly rising serum creatinine level
  • BUN:creatinine ratio < 15:1.
  • Markedly elevated serum CPK level (10,000–100,000) in rhabdomyolysis
  • Hyperkalemia, metabolic acidosis; , hyperphosphatemia, hypocalcemia, hyperuricemia, and/or dyslipidemia (especially hypertriglyceridemia) may be seen.
  • Low Hb (anemia) due to decreased EPO
• Urine test findings
  • Renal tubular epithelial cells or granular, muddy brown, or pigmented casts
  • Urine dipstick is positive for blood but negative for RBCs in rhabdomyolysis
• Biopsy: in suspected rapidly progressive glomerulonephritis

Postrenal

• Blood test findings
  • Elevated serum creatinine concentration in bilateral obstruction
  • BUN:creatinine ratio varies.
• Urine test findings
  • Normal urinalysis (neurogenic bladder)
  • Hematuria (stones, bladder cancer, clots)
• Imaging: high post-void residual volume and bilateral hydronephrosis on renal ultrasound or noncontrast CT scan

Comparison of diagnostic findings in different types of AKI

	Prerenal	Intrinsic	Postrenal
BUN/Cr ratio	> 20:1	< 15:1	Varies
Fractional excretion of sodium	< 1%	> 2%
Urine sodium concentration (mEq/L)	< 20	> 40
Urine osmolality (mOsm/kg)	> 500	< 350	< 350
Urine sediments	Hyaline casts	Muddy brown, epithelial, or granular casts (ATN) RBC casts (glomerulonephritis) Fatty casts (nephrotic syndrome)	Absent

Consequences of acute and chronic renal failure (MAD HUNGER): Metabolic Acidosis, Dyslipidemia, High potassium, Uremia, Na⁺/H₂O retention, Growth retardation, Erythropoietin failure (anemia), Renal osteodystrophy.

References:^[1][13]

• General measures
  • Treat the underlying cause.
  • Patient should discontinue nephrotoxic substance use.
  • Adjust dosages of medications cleared by the kidney (e.g., amiodarone, digoxin, cyclosporin, tacrolimus, antibiotics, chemotherapeutic agents).
  • Monitor and manage changes in pH, water, and electrolyte balance.
  • Assess uremic signs and symptoms (e.g., anorexia, nausea, vomiting, metallic taste, altered mental status) daily
  • Perform dialysis if necessary. (See indications for acute dialysis.)
• Prerenal
  • Replete volume; with normal saline in patients with hypovolemia
  • Administer diuretics in patients with hypervolemia who are hemodynamically stable and not anuric
• Intrinsic
  • Replete volume with normal saline in suspected ATN or contrast-induced renal dysfunction
  • Consider corticosteroid or immunosuppressive therapy in RPGN or interstitial nephritis.
  • Treat infection.
• Postrenal: Remove outflow obstructions with Foley catheter insertion, an indwelling bladder catheter, nephrostomy, or stenting.

The longer the underlying cause, the greater the chance that AKI progresses to chronic renal failure. Treat early!

References:^[12][11]