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Acute Kidney Injury¶

Chapter 321 | Part 9: Disorders of the Kidney and Urinary Tract · Part 9 – Renal & Urinary Tract Disorders · Chapter 321

Key Clinical Points¶

AKI is a clinical diagnosis based on functional impairment (KDIGO criteria), not necessarily structural damage.
Prerenal azotemia is the most common form, caused by inadequate renal perfusion.
Intrinsic AKI includes sepsis-associated, ischemia-associated, and nephrotoxin-induced injury.
Postrenal AKI results from physical obstruction of urinary flow.
The renal medulla is a highly hypoxic region and particularly vulnerable to ischemic damage.
SGLT-2 inhibitors do not appear to increase AKI risk and may have a protective effect.
Hepatorenal syndrome is a diagnosis of exclusion with poor prognosis in type 1.
Acute tubular necrosis (ATN) is a common clinical term, but biopsy confirmation is often lacking in sepsis/ischemia.
Urinary sediment analysis is critical for differentiating prerenal, intrinsic, and postrenal etiologies.
Management focuses on hemodynamic optimization, removal of nephrotoxins, and treatment of metabolic complications.

DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): Acute kidney injury (AKI) is defined by the impairment of kidney filtration and excretory function over days to weeks (generally known or expected to have occurred within 7 days), resulting in the retention of nitrogenous and other waste products normally cleared by the kidneys. • KDIGO Criteria: → Increase in serum creatinine (SCr) of ≥0.3 mg/dL within 48 h → OR increase in SCr ≥1.5 times from baseline over 7 days → OR urine output <0.5 mL/kg per h for 6 h • Clinical vs. Structural: → AKI is a clinical diagnosis, not a structural one. → A patient may have AKI with or without injury to the kidney parenchyma (the term 'AKI' can be a misnomer if parenchymal injury is absent). → Severity ranges from asymptomatic and transient changes in GFR to overwhelming and rapidly fatal derangements in volume regulation, waste excretion, and acid-base balance.

Staging of AKI Severity (Table 321-1)¶

• Stage 1: → SCr: 1.5–1.9 times baseline OR ≥0.3 mg/dL increase → Urine Output: <0.5 mL/kg per h for 6–12 h • Stage 2: → SCr: 2.0–2.9 times baseline → Urine Output: <0.5 mL/kg per h for ≥12 h • Stage 3: → SCr: 3.0 times baseline OR increase to ≥4.0 mg/dL → OR initiation of renal replacement therapy (RRT) → OR, in patients <18 years of age, decrease in eGFR to <35 mL/min per 1.73 m² → Urine Output: <0.3 mL/kg per h for ≥24 h OR Anuria for ≥12 h

EPIDEMIOLOGY¶

• Incidence: → Complicates 5–7% of acute-care hospital admissions. → Complicates up to 30% of ICU admissions. → Growth: Increased >4-fold in the US since 1988; estimated yearly incidence is 500 per 100,000 population (higher than the incidence of stroke). • Morbidity: → Morbidity of AKI in those admitted to the ICU exceeds 50% in many studies. • Long-term Implications: → Increased risk for development or worsening of chronic kidney disease (CKD). → Increased risk for future cardiovascular disease.

ETIOLOGY & PATHOPHYISIOLOGY¶

• General Classification (Figure 321-1): → Prerenal, Intrinsic (Glomerular, Tubulointerstitium, Vascular), and Postrenal. • Prerenal Azotemia: → Cause: Inadequate renal perfusion (hypovolemia, decreased cardiac output, etc.). → Pathophysiology: No parenchymal damage; rapidly reversible once hemodynamics are restored. → Autoregulation Mechanisms: → Afferent dilation & Efferent constriction (via Angiotensin II) maintain GFR. → Tubuloglomerular feedback: Decreased solute to macula densa → afferent dilation. → Risk Factors for Prerenal AKI: → Age, hypertension, atherosclerosis (impair autoregulation). → Drugs: NSAIDs (block prostaglandins → afferent constriction); ACE-I/ARB (block AngII → efferent dilation). → Combination of NSAIDs + ACE-I/ARB poses high risk for prerenal azotemia. → SGLT-2 Inhibitors: Do not increase AKI risk; may have a protective effect. • Intrinsic AKI: → Causes: Sepsis, ischemia, and nephrotoxins (Figure 321-3). → ATN: Often the result of prolonged prerenal azotemia leading to tubular cell necrosis. → Note: Histological evidence of 'necrosis' is often lacking in sepsis/ischemia; inflammation, apoptosis, and altered regional perfusion are key drivers. • Sepsis-Associated AKI: → Occurs in >50% of cases of severe sepsis. → Mechanisms: Endothelial damage, microvascular leukocyte adhesion, thrombosis, increased interstitial pressure, and activation of reactive oxygen species. • Ischemia-Associated AKI (Figure 321-4, 6): → Renal Medulla: Most hypoxic region; outer medulla is highly vulnerable. → S3 segment of proximal tubule: Highly dependent on oxidative metabolism. → Mechanisms of GFR reduction: → Backleak of filtrate across damaged tubular epithelium. → Mechanical obstruction from necrotic debris. → Vasoconstriction due to endothelin, adenosine, Angiotensin II, etc.\ • Nephrotoxin-Associated AKI (Figure 321-5): → Contrast Agents: Risk higher in CKD/diabetes; peak at 3–5 days post-exposure. → Aminoglycosides: Cause tubular necrosis; can be nonoliguric (10–30% of cases). → Amphotericin B: Causes renal vasoconstriction and direct tubular toxicity; associated with polyuria, hypomagnesemia, hypocalcemia, and nongap metabolic acidosis. → Acyclovir: Risk of crystalluria/obstruction at high doses or in hypovolemia. → Chemotherapeutic Agents: Cisplatin/Carboplatin (tubular necrosis); Ifosfamide (type II RTA, polyuria, hypokalemia). → Endogenous Toxins: → Myoglobin (Rhabdomyolysis): Risk from crush injury, seizures, etc. → Hemoglobin (Hemolysis). → Uric Acid: Tumor Lysis Syndrome (TLS) → high uric acid (>15 mg/dL) → tubular precipitation. → Myeloma Light Chains: Glomerular damage and tubular toxicity. → Other: IgA, ANCA, Lupus, etc. (see Table 321-2). • Postrenal AKI: → Cause: Obstruction from renal pelvis to urethra (Figure 321-7). → Sites: Bladder outlet obstruction, bilateral pelvoureteral obstruction. → Factors: Stones, tumors, enlarged prostate.

Autoregulation Mechanisms (Figure 321-4)¶

• Normal Condition: → Afferent dilation + Efferent constriction (Angiotensin II) → Maintain GFR. • NSAID Effect: → Block prostaglandins → Afferent vasoconstriction → Lowered capillary pressure → Low GFR. • ACE-I/ARB Effect: → Block Angiotensin II → Efferent vasodilation → Lowered capillary pressure → Low GFR (especially in renal artery stenosis).

CLINICAL FEATURES¶

• Symptoms/Signs: → Often asymptomatic until significant waste accumulation. → Clinical signs of volume depletion (tachycardia, hypotension) in prerenal cases. • Complications: → Hyperkalemia, metabolic acidosis, volume overload, and uremia.

DIFFERENTIAL DIAGNOSIS¶

• Prerenal vs. Intrinsic vs. Postrenal (Table 321-2): → Prerenal: → Clinical: History of fluid loss, heart failure, NSAID/ACE-I use. → Lab: BUN/Cr ratio > 20; FeNa < 1%; hyaline casts; Urine SG > 1.018; Osmolality > 500 mOsm/kg. → Intrinsic (Ischemia/Sepsis): → Clinical: Sepsis, hypotension. → Lab: Granular casts, RTE cell casts; FeNa typically > 1%. → Nephrotoxins: → Endogenous: Myoglobin (Rhabdomyolysis), Hemoglobin, Uric Acid (Tumor Lysis Syndrome), Myeloma light chains. → Exogenous: Contrast, Aminoglycosides, Amphotericin B, etc. → Other Intrinsic Causes: - Tubulointerstitial nephritis (TINU, Lupus, Viral infections). - Atheroembolic disease (Aorta manipulation, Retinal plaques). - Vasculitis, Malignant hypertension, TTP/HUS.

DIAGNOSTIC APPROACH¶

Initial Assessment:
Evaluate clinical context (Sepsis? Volume depletion? Obstruction?).
Laboratory Evaluation:
Serum Creatinine, BUN, Electrolytes, Acid-Base status.
Urine analysis: Specific gravity, osmolality, and microscopy.
Urinary Sediment Interpretation (Figure 321-6):
Step 1: Initial Assessment of Sediment:
[Urinary sediment in AKI] → Is the sediment "Normal or few RBCs/WBCs or hyaline casts"?
YES → Outcome: Prerenal, Postrenal, Arterial thrombosis or embolism, Preglomerular vasculitis, HUS or TTP.
NO (Abnormal) → Proceed to specific component analysis:
RBCs / RBC casts → Outcome: GN, Vasculitis, Malignant hypertension, Thrombotic microangiopathy.
WBCs / WBC casts → Outcome: Interstitial nephritis, GN, Pyelonephritis, Allograft rejection, Malignant infiltration of the kidney.
RTE cells / RTE casts / Pigmented casts → Outcome: ATN, Tubulointerstitial nephritis, Acute cellular allograft rejection, Myoglobinuria, Hemoglobinuria.
Granular casts → Outcome: ATN, GN, Vasculitis, Tubulointerstitial nephritis.
Eosinophiluria → Outcome: Allergic interstitial nephritis, Atheroembolic disease, Pyelonephritis, Cystinuria, Glomerulonephritis.
Crystalluria → Outcome: Acute uric acid nephropathy, Calcium oxalate (ethylene glycol), Drugs or toxins (acyclovir, sulfonamides, amoxicillin).
Imaging:
Evaluate for obstruction (e.g., ultrasound or CT of the urinary tract).

MANAGEMENT & TREATMENT¶

General Management (Table 321-3):
Hemodynamics: Optimize via volume resuscitation and vasopressors; maintain MAP > 65 mmHg.
Nephrotoxins: Eliminate agents (NSAIDs, ACE-I, ARB, aminoglycosides, etc.) as soon as possible.
Nutrition: Provide 20–30 kcal/kg per day (preferably enteral).
Renal Replacement Therapy (RRT): Initiate when indicated by clinical criteria.
Specific Issues (Table 321-5):
Rhabdomyolysis: Aggressive IV fluids; consider forced alkaline diuresis.
Tumor Lysis Syndrome: Aggressive IV fluids and allopurinol or rasburicase.
Volume Overload: Salt/water restriction, diuretics, ultrafiltration.
Hyponatremia:
Restriction of enteral free water intake; minimize hypotonic solutions (e.g., D5W).
Hypertonic saline is rarely necessary in AKI; Vasopressin antagonists are not needed.
Hyperkalemia:
Prompt reduction of potassium intake.
Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs.
Loop diuretics to promote urinary potassium loss.
Potassium-binding molecules (sodium zirconium cyclosilicate) or ion-exchange resins (patiromer, sodium or calcium polystyrene sulfonate).
Insulin and glucose; Inhaled beta-agonist therapy.
Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium.
Metabolic Acidosis: Sodium bicarbonate if pH < 7.2 to keep serum bicarbonate > 15 mmol/L.
Hyperphosphatemia: Restriction of dietary phosphate; use binders (calcium acetate, sevelamer, aluminum hydroxide).
Hypocalcemia: Calcium carbonate or calcium gluconate if symptomatic.
Hypermagnesemia: Discontinue Mg2+ containing antacids.
Hyperuricemia:
Acute treatment is usually not required except in the setting of tumor lysis syndrome.
Drug Dosing:
Careful monitoring of dosages and frequency; adjust for degree of renal failure.
Note: Serum creatinine concentration may overestimate renal function in the non-steady state characteristic of patients with AKI.

Prerenal Management¶

• Restore volume and perfusion. → Stop offending agents (NSAIDs, ACE-I/ARB) if contributing to hypotension.

Intrinsic Management¶

• Treat underlying cause (e.g., antibiotics for sepsis, fluids for ischemia). → Discontinue nephrotoxins. → Manage metabolic complications (Hyperkalemia, Acidosis).

Postrenal Management¶

• Relieve obstruction (e.g., stent, stone removal, catheter placement).

COMPLICATIONS & PROGNOSIS¶

• Prognosis: → High mortality in sepsis-associated AKI. → Long-term risk of CKD and cardiovascular disease.

SPECIAL POPULATIONS¶

• Hepatorenal Syndrome (HRS): → Diagnosis of exclusion in liver disease. → Type 1 has a particularly poor prognosis. → Triggered by volume depletion or spontaneous bacterial peritonitis.

KEY PEARLS & HIGH-YIELD POINTS¶

• SGLT-2 Inhibitors: Do not increase AKI risk; may be protective. → Contrast Agents: Risk is primarily in patients with pre-existing CKD or heart failure. → Aminoglycosides: Can cause nonoliguric AKI (10–30% of cases). → Amphotericin B: Associated with polyuria and hypomagnesemia. → Acyclovir: Risk of crystalluria/obstruction at high doses or in hypovolemia. → Rhabdomyolysis: Requires aggressive fluids and consideration of alkaline diuresis. → Tumor Lysis Syndrome: Requires allopurinol or rasburicase. → Hyperkalemia Management: Calcium gluconate/chloride (1 g) is for stabilization, not lowering potassium.

Reference Tables¶

TABLE 321-1 Staging of Acute Kidney Injury Severity STAGE 1¶

Harrison's 22e, p.2372

STAGE	SERUM CREATININE	URINE OUTPUT
1	1.5–1.9 times baseline OR ≥0.3 mg/dL (≥26.5 μmol/L) increase	<0.5 mL/kg per h for 6–12 h
	2.0–2.9 times baseline
3	3.0 times baseline OR increase in serum creatinine to ≥4.0 mg/dL (≥353.6 μmol/L) OR initiation of renal replacement therapy OR, in patients <18 years of age, decrease in eGFR to <35 mL/min per 1.73 m2	<0.3 mL/kg per h for ≥24 h OR Anuria for ≥12 h

TABLE 321-2 Major Causes, Clinical Features, and Diagnostic Studies for Prerenal and Intrinsic Acute Kidney Injury…¶

Harrison's 22e, p.2379

ETIOLOGY	CLINICAL FEATURES	LABORATORY FEATURES	COMMENTS
Prerenal azotemia	History of poor fluid intake or fluid loss (hemorrhage, diarrhea, vomiting, sequestration into extravascular space); NSAID/ ACE-I/ARB; heart failure; evidence of volume depletion (tachycardia, absolute or postural hypotension, low jugular venous pressure, dry mucous membranes), decreased effective circulatory volume (cirrhosis, heart failure)	BUN/creatinine ratio above 20, FeNa <1%, hyaline casts in urine sediment, urine specific gravity >1.018, urine osmolality >500 mOsm/kg	Low FeNa, high specific gravity and osmolality may not be seen in the setting of CKD, diuretic use; BUN elevation out of proportion to creatinine may alternatively indicate upper GI bleed or increased catabolism. Response to restoration of hemodynamics is most diagnostic.
	Sepsis, sepsis syndrome, or septic shock; overt hypotension not always seen in mild to moderate AKI	Positive culture from normally sterile body fluid or other test confirming infection; urine sediment often contains granular casts, renal tubular epithelial cell casts
Ischemia- associated AKI	Systemic hypotension, often superimposed upon sepsis and/or reasons for limited renal reserve such as older age, CKD	Urine sediment often contains granular casts, renal tubular epithelial cell casts; FeNa typically >1%
Nephrotoxin-Associated AKI: Endogenous
	Traumatic crush injuries, seizures, immobilization	Elevated myoglobin, creatine kinase; urine heme positive with few red blood cells
Hemolysis	Recent blood transfusion with transfusion reaction	Anemia, elevated LDH, low haptoglobin	FeNa may be low (<1%); evaluation for transfusion reaction
	Recent chemotherapy	Hyperphosphatemia, hypocalcemia, hyperuricemia
Multiple myeloma	Age >60 years, constitutional symptoms, bone pain	Monoclonal spike in urine or serum electrophoresis; elevated serum free light chains, low anion gap; anemia	Bone marrow or renal biopsy can be diagnostic
Nephrotoxin-Associated AKI: Exogenous
	Exposure to iodinated contrast	Characteristic course is rise in SCr within 1–2 d, peak within 3–5 d, recovery within 7 d
Tubular injury	Aminoglycoside antibiotics, cisplatin, tenofovir, vancomycin, zoledronate, ethylene glycol, aristolochic acid, and melamine (to name a few)	Urine sediment often contains granular casts, renal tubular epithelial cell casts. FeNa typically >1%.	Can be oliguric or nonoliguric
Other Causes of Intrinsic AKI
	Variable (Chap. 326) features include skin rash, arthralgias, sinusitis (AGBM disease), lung hemorrhage (AGBM, ANCA, lupus), recent skin infection or pharyngitis (poststreptococcal), thrombotic microangiopathies including those related to drugs, such as cocaine, anti-VEGF agents, genetic abnormalities of the complement pathways	ANA, ANCA, Anti-GBM antibody, hepatitis serologies, cryoglobulins, blood culture, complement abnormalities, ASO titer (abnormalities of these tests depending on etiology)
Tubulointerstitial nephritis	Drugs are responsible for about 75% of the biopsy-proven acute interstitial nephritis, which involves tubules in most cases. Examples of causes include antibiotics, PPIs, immune checkpoint inhibitors. Non-drug-related causes include tubulointerstitial nephritis-uveitis (TINU) syndrome, lupus, viral infection (e.g., COVID, HIV, hantavirus), and Legionella infection.	Eosinophilia, sterile pyuria; often nonoliguric	Urine eosinophils have limited diagnostic accuracy; kidney biopsy may be necessary
	Neurologic abnormalities and/or AKI; recent diarrheal illness; use of calcineurin inhibitors; pregnancy or postpartum; spontaneous	Schistocytes on peripheral blood smear, elevated LDH, anemia, thrombocytopenia
Atheroembolic disease	Recent manipulation of the aorta or other large vessels; may occur spontaneously or after anticoagulation; retinal plaques, palpable purpura, livedo reticularis, GI bleed	Hypocomplementemia, eosinophiluria (variable), variable amounts of proteinuria	Skin or kidney biopsy can be diagnostic
	History of kidney stones, prostate disease, obstructed bladder catheter, retroperitoneal or pelvic neoplasm	No specific findings other than AKI; may have pyuria or hematuria

TABLE 321-3 Management of Acute Kidney Injury General Issues 1. Optimization of systemic and renal hemodynamics through…¶

Harrison's 22e, p.2383

General Issues
1. Optimization of systemic and renal hemodynamics through volume
  resuscitation and judicious use of vasopressors
  2. Maintain mean arterial pressure >65 mmHg
  3. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs, NSAIDs,
  aminoglycosides, chemotherapeutic agents, checkpoint inhibitors,
  antibiotics) if possible
  4. Sufficient protein and calorie intake (20–30 kcal/kg per day) to avoid negative
  nitrogen balance. Nutrition should be provided by the enteral route if oral
  intake is not possible.
  5. Initiation of renal replacement therapy when indicated
Specific Issues
1. Nephrotoxin-specific
  a. Rhabdomyolysis: aggressive intravenous fluids; consider forced alkaline
  diuresis
  b. Tumor lysis syndrome: aggressive intravenous fluids and allopurinol or
  rasburicase
  2. Volume overload
  a. Salt and water restriction
  b. Diuretics
  c. Ultrafiltration
  3. Hyponatremia
  a. Restriction of enteral free water intake, minimization of hypotonic
  intravenous solutions including those containing dextrose
  b. Hypertonic saline is rarely necessary in AKI. Vasopressin antagonists are
  generally not needed.
  4. Hyperkalemia
  a. Restriction of dietary potassium intake
  b. Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs
  c. Loop diuretics to promote urinary potassium loss
  d. Potassium-binding molecules (sodium zirconium cyclosilicate) or ion-
  exchange resins (patiromer, sodium or calcium polystyrene sulfonate)
  e. Insulin and glucose to promote entry of potassium intracellularly
  f. Inhaled beta-agonist therapy to promote entry of potassium intracellularly
  g. Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium
  5. Metabolic acidosis
  a. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L)
  b. Renal replacement therapy
  6. Hyperphosphatemia
  a. Restriction of dietary phosphate intake
  b. Phosphate binding agents (calcium acetate, sevelamer hydrochloride,
  aluminum hydroxide—taken with meals)
  7. Hypocalcemia
  a. Calcium carbonate or calcium gluconate if symptomatic
  8. Hypermagnesemia
  a. Discontinue Mg2+-containing antacids
  9. Hyperuricemia
  a. Acute treatment is usually not required except in the setting of tumor lysis
  syndrome (see above)
  10. Drug dosing
  a. Careful attention to dosages and frequency of administration of drugs,
  adjustment for degree of renal failure
  b. Note that serum creatinine concentration may overestimate renal function
  in the non-steady-state characteristic of patients with AKI