Classification of Acute Kidney Injury

AKI is classified into three categories based on anatomic location: prerenal (impaired renal perfusion), intrarenal (direct kidney parenchymal damage), and postrenal (urinary tract obstruction), though prerenal and intrarenal causes account for over 97% of cases. 1

Prerenal AKI

Prerenal AKI results from decreased renal perfusion without structural kidney damage. Common causes include: 1, 2

Hypovolemia: hemorrhage, gastrointestinal losses, burns, diuretic overuse
Decreased cardiac output: heart failure, cardiogenic shock, arrhythmias
Systemic vasodilation: sepsis, anaphylaxis, cirrhosis with hepatorenal syndrome
Renal vasoconstriction: NSAIDs, ACE inhibitors/ARBs, hepatorenal syndrome
Renal artery occlusion: thrombosis, embolism, dissection

Intrarenal (Intrinsic) AKI

Intrarenal AKI involves direct damage to kidney structures: 1, 2

Acute tubular necrosis (ATN): ischemic (prolonged prerenal state, surgery) or nephrotoxic (aminoglycosides, contrast agents, myoglobin, hemoglobin)
Acute interstitial nephritis: drug-induced (beta-lactams, NSAIDs, PPIs), infection, autoimmune
Glomerulonephritis: post-infectious, lupus nephritis, ANCA-associated vasculitis, anti-GBM disease
Vascular: malignant hypertension, thrombotic microangiopathy, atheroembolic disease

Postrenal AKI

Postrenal AKI results from urinary tract obstruction (accounts for <3% of cases): 1

Ureteral obstruction: bilateral stones, retroperitoneal fibrosis, malignancy
Bladder outlet obstruction: benign prostatic hyperplasia, prostate cancer, neurogenic bladder
Urethral obstruction: strictures, blood clots

Definition and Diagnosis of AKI

AKI is defined by KDIGO criteria as: an increase in serum creatinine ≥0.3 mg/dL within 48 hours, OR an increase to ≥1.5 times baseline within 7 days, OR urine output <0.5 mL/kg/hr for 6 consecutive hours. 1, 3

AKI Staging

Stage	Serum Creatinine Criteria	Urine Output Criteria
Stage 1	1.5-1.9× baseline OR ≥0.3 mg/dL increase	<0.5 mL/kg/hr for 6-12 hours
Stage 2	2.0-2.9× baseline	<0.5 mL/kg/hr for ≥12 hours
Stage 3	≥3.0× baseline OR ≥4.0 mg/dL (with acute rise >0.3 mg/dL) OR initiation of RRT	<0.3 mL/kg/hr for ≥24 hours OR anuria for ≥12 hours

1, 3

Progression through AKI stages strongly correlates with increased mortality. 3 Even small increases in creatinine (≥0.3 mg/dL) independently associate with approximately four-fold increased hospital mortality. 3

BUN-Creatinine Ratio (BCR)

The BUN-Creatinine Ratio helps differentiate prerenal from intrarenal AKI: a ratio >20:1 suggests prerenal azotemia, while a ratio <15:1 suggests intrarenal disease (particularly ATN). 2, 4

Calculation

BCR = BUN (mg/dL) ÷ Serum Creatinine (mg/dL)

Normal ratio: 10:1 to 20:1

Interpretation

BCR >20:1: Prerenal azotemia (enhanced urea reabsorption with preserved tubular function)
BCR 10-20:1: Normal or mixed picture
BCR <10:1: Intrarenal disease (impaired urea reabsorption due to tubular damage)

Caveats: The BCR can be falsely elevated by gastrointestinal bleeding, high-protein diet, corticosteroids, or tetracyclines, and falsely decreased by liver disease, malnutrition, or pregnancy. 2, 4

Inadequate Urine Output

Oliguria is defined as urine output <0.5 mL/kg/hr for 6 hours, and anuria as <100 mL/24 hours or complete absence of urine for 12 hours. 1, 3

However, urine output measurement is less important than serum creatinine for AKI diagnosis, as changes may be physiologic and oliguria can occur without true AKI (e.g., cirrhosis with ascites). 1, 3

Emergency Hemodialysis Indications

The mnemonic "AEIOU" captures absolute indications for emergency dialysis: 5

A - Acidosis: Severe metabolic acidosis (pH <7.1) refractory to medical management
E - Electrolytes: Life-threatening hyperkalemia (typically >6.5 mEq/L with ECG changes) unresponsive to medical therapy
I - Intoxications: Dialyzable toxins (methanol, ethylene glycol, lithium, salicylates)
O - Overload: Severe volume overload with pulmonary edema refractory to diuretics
U - Uremia: Uremic complications (pericarditis, encephalopathy, bleeding)

Stage 3 AKI requiring renal replacement therapy represents the highest severity stage. 1

Hyperkalemia Management

Medications and Mechanisms

Immediate treatment priorities: cardiac membrane stabilization, intracellular potassium shift, and potassium removal from the body.

Cardiac Membrane Stabilization

Calcium gluconate 10% (10-20 mL IV over 2-5 minutes) or calcium chloride 10% (5-10 mL IV): Antagonizes cardiac effects of hyperkalemia without lowering potassium; onset within minutes, duration 30-60 minutes 5

Intracellular Shift (Temporary Measures)

Regular insulin (10 units IV) with dextrose (25-50g IV): Drives potassium into cells via Na-K-ATPase activation; onset 15-30 minutes, duration 4-6 hours 5
Albuterol nebulized (10-20 mg): Beta-2 agonist stimulates Na-K-ATPase; onset 30 minutes, duration 2-4 hours; less effective as monotherapy 5
Sodium bicarbonate (50-100 mEq IV): Shifts potassium intracellularly in metabolic acidosis; onset 30-60 minutes; controversial efficacy 5

Potassium Removal (Definitive Treatment)

Loop diuretics (furosemide 40-80 mg IV): Increases renal potassium excretion if kidney function adequate 5
Sodium polystyrene sulfonate (15-30g PO/PR): Cation exchange resin; onset hours; efficacy debated, risk of intestinal necrosis 5
Patiromer or sodium zirconium cyclosilicate: Newer potassium binders; onset hours to days 5
Hemodialysis: Most effective for severe, refractory hyperkalemia; removes 25-50 mEq/hour 5

ECG Changes in Potassium Disorders

Hyperkalemia (Progressive Changes)

ECG changes correlate with severity and occur sequentially: 5

Mild (5.5-6.5 mEq/L): Peaked, narrow T waves (earliest sign)
Moderate (6.5-8.0 mEq/L): Prolonged PR interval, flattened/absent P waves, widened QRS complex
Severe (>8.0 mEq/L): Sine wave pattern (pre-terminal rhythm), ventricular fibrillation, asystole

The presence of ECG changes indicates need for immediate treatment regardless of absolute potassium level. 5

Hypokalemia

ECG manifestations include: 5

U waves (most characteristic finding)
Flattened or inverted T waves
ST segment depression
Prolonged QT interval (actually QU interval)
Increased risk of arrhythmias: premature ventricular contractions, torsades de pointes

Potassium Deficit Calculation in Hypokalemia

Potassium deficit (mEq) = (Normal K⁺ - Measured K⁺) × Body weight (kg) × 0.4

Where 0.4 represents the estimated fraction of body weight as total body potassium distribution space. 5

Example: 70 kg patient with K⁺ = 2.5 mEq/L

Deficit = (4.0 - 2.5) × 70 × 0.4 = 42 mEq

Critical caveats:

This formula provides only an estimate; actual deficit may be higher due to ongoing losses 5
Maximum IV replacement rate: 10-20 mEq/hour via central line (40 mEq/L via peripheral line) to avoid cardiac complications 5
Recheck potassium after each 20-40 mEq replacement 5
Correct concurrent hypomagnesemia (prevents potassium repletion) 5

Hyponatremia Classification

Hyponatremia is classified by volume status and serum osmolality:

By Serum Osmolality

Hypotonic hyponatremia (<280 mOsm/kg): True hyponatremia
Isotonic hyponatremia (280-295 mOsm/kg): Pseudohyponatremia (hyperlipidemia, hyperproteinemia)
Hypertonic hyponatremia (>295 mOsm/kg): Hyperglycemia, mannitol

By Volume Status (Hypotonic Hyponatremia)

Hypovolemic Hyponatremia

Urine sodium <20 mEq/L (extrarenal losses):

Vomiting, diarrhea, third-spacing (burns, pancreatitis)

Urine sodium >20 mEq/L (renal losses):

Diuretics, salt-wasting nephropathy, cerebral salt wasting, adrenal insufficiency

Euvolemic Hyponatremia

Urine sodium >20 mEq/L:

SIADH (most common), hypothyroidism, adrenal insufficiency, psychogenic polydipsia, beer potomania

Hypervolemic Hyponatremia

Urine sodium <20 mEq/L:

Heart failure, cirrhosis, nephrotic syndrome

Urine sodium >20 mEq/L:

Advanced kidney disease

Mechanisms of Drug-Induced AKI

NSAIDs

NSAIDs cause AKI through multiple mechanisms: 1, 2

Afferent arteriolar vasoconstriction: Inhibition of prostaglandin synthesis (particularly PGE2 and PGI2) eliminates compensatory vasodilation, reducing glomerular perfusion pressure and GFR 2
Most problematic in states of prostaglandin dependence: Volume depletion, heart failure, cirrhosis, CKD, elderly patients 2
Acute interstitial nephritis: Immune-mediated hypersensitivity reaction (typically after weeks to months of use) 2
Papillary necrosis: With chronic use, particularly phenacetin-containing compounds 2

ACE Inhibitors/ARBs

ACE inhibitors and ARBs cause AKI by: 1, 2

Efferent arteriolar vasodilation: Block angiotensin II-mediated efferent arteriolar constriction, reducing intraglomerular pressure and GFR 2
Most problematic when GFR is angiotensin II-dependent: Bilateral renal artery stenosis, solitary kidney with stenosis, severe volume depletion, heart failure 2
Hyperkalemia: Reduced aldosterone secretion impairs renal potassium excretion 2

Both drug classes are particularly dangerous when combined (dual RAAS blockade) or used with diuretics (triple whammy with NSAIDs). 2

CKD Staging

CKD is staged by estimated GFR (eGFR) using equations such as CKD-EPI, present for >3 months: 1

Stage	Description	eGFR (mL/min/1.73m²)	Clinical Features
1	Kidney damage with normal GFR	≥90	Albuminuria, hematuria, structural abnormalities
2	Mild reduction in GFR	60-89	Usually asymptomatic
3a	Mild-moderate reduction	45-59	Increased cardiovascular risk
3b	Moderate-severe reduction	30-44	Anemia, bone disease may develop
4	Severe reduction	15-29	Prepare for renal replacement therapy
5	Kidney failure	<15 or dialysis	Uremic symptoms, requires RRT

CKD staging also incorporates albuminuria categories (A1: <30 mg/g, A2: 30-300 mg/g, A3: >300 mg/g) in the CGA classification system. 1

Renal Replacement Therapy Strategies

Three main modalities exist, each with specific indications:

Intermittent Hemodialysis (IHD)

Mechanism: Diffusion-based solute removal across semipermeable membrane over 3-4 hours 5
Indications: Hemodynamically stable patients, emergency situations requiring rapid solute removal (severe hyperkalemia, toxic ingestions) 5
Advantages: Rapid correction of electrolytes and acid-base, widely available 5
Disadvantages: Hemodynamic instability, dialysis disequilibrium syndrome 5

Continuous Renal Replacement Therapy (CRRT)

Mechanism: Continuous hemofiltration/hemodialysis over 24 hours 5
Indications: Hemodynamically unstable patients (septic shock), severe volume overload, cerebral edema risk 5
Advantages: Hemodynamic stability, precise fluid management, better for critically ill 5
Disadvantages: Requires ICU setting, anticoagulation, immobilization 5

Peritoneal Dialysis (PD)

Mechanism: Diffusion and osmosis across peritoneal membrane 5
Indications: Chronic dialysis, resource-limited settings, pediatric patients 5
Advantages: Hemodynamic stability, home-based, preserves residual renal function 5
Disadvantages: Slower solute clearance, contraindicated with abdominal surgery/peritonitis, requires intact peritoneum 5

Nephrotic Syndrome

Clinical Findings

The classic tetrad of nephrotic syndrome includes: 1

Heavy proteinuria: ≥3.5 g/24 hours (nephrotic-range proteinuria) 1
Hypoalbuminemia: Serum albumin <3.0 g/dL 1
Edema: Peripheral (legs, periorbital) and potentially anasarca 1
Hyperlipidemia: Elevated total cholesterol and LDL 1

Additional features include:

Hypercoagulability: Loss of anticoagulant proteins (antithrombin III, protein C/S), increased thrombosis risk 1
Increased infection risk: Loss of immunoglobulins 1
Lipiduria: Oval fat bodies, fatty casts on urinalysis 1

Nephrotic-Range Proteinuria Definition

Nephrotic-range proteinuria is defined as ≥3.5 g protein per 24 hours or urine protein-to-creatinine ratio ≥3.5 g/g (or ≥350 mg/mmol). 1

Diuretics: Classes and Mechanisms

Loop Diuretics

Mechanism: Inhibit Na-K-2Cl cotransporter in thick ascending limb of loop of Henle 5
Examples: Furosemide, bumetanide, torsemide 5
Effects: Most potent diuretics; cause hypokalemia, hypomagnesemia, metabolic alkalosis 5

Thiazide Diuretics

Mechanism: Inhibit Na-Cl cotransporter in distal convoluted tubule 5
Examples: Hydrochlorothiazide, chlorthalidone, metolazone 5
Effects: Moderate potency; cause hypokalemia, hyponatremia, hypercalcemia, metabolic alkalosis 5

Potassium-Sparing Diuretics

Mechanism: Block epithelial sodium channels (amiloride, triamterene) or antagonize aldosterone (spironolactone, eplerenone) in collecting duct 5
Examples: Spironolactone, eplerenone, amiloride, triamterene 5
Effects: Weak diuretics; cause hyperkalemia, metabolic acidosis 5

Carbonic Anhydrase Inhibitors

Mechanism: Inhibit carbonic anhydrase in proximal tubule, reducing bicarbonate reabsorption 5
Examples: Acetazolamide 5
Effects: Weak diuretics; cause metabolic acidosis, hypokalemia 5

Osmotic Diuretics

Mechanism: Increase tubular fluid osmolality, reducing water reabsorption throughout nephron 5
Examples: Mannitol 5
Effects: Increase intravascular volume initially; used for cerebral edema, rhabdomyolysis 5

Edema Pathophysiology: Starling Forces

Edema formation is governed by Starling forces across capillary membranes:

Net fluid movement = Kf [(Pc - Pi) - σ(πc - πi)]

Where:

Kf = capillary filtration coefficient (permeability)
Pc = capillary hydrostatic pressure
Pi = interstitial hydrostatic pressure
σ = reflection coefficient (protein permeability)
πc = capillary oncotic pressure
πi = interstitial oncotic pressure

Mechanisms of Edema

Increased Capillary Hydrostatic Pressure (↑Pc)

Heart failure: Venous congestion increases upstream capillary pressure 5
Venous obstruction: Deep vein thrombosis, venous insufficiency 5
Volume overload: Excessive sodium/water retention 5

Decreased Plasma Oncotic Pressure (↓πc)

Nephrotic syndrome: Urinary protein loss causes hypoalbuminemia 1, 5
Cirrhosis: Decreased hepatic albumin synthesis 5
Malnutrition: Inadequate protein intake 5
Protein-losing enteropathy: Intestinal protein loss 5

Increased Capillary Permeability (↑Kf)

Inflammation: Cytokine-mediated endothelial damage (sepsis, burns, allergic reactions) 5
ARDS: Pulmonary capillary leak 5

Lymphatic Obstruction

Lymphedema: Surgical removal of lymph nodes, filariasis, malignancy 5
Results in protein-rich interstitial fluid accumulation 5

In nephrotic syndrome specifically, the primary mechanism is decreased plasma oncotic pressure from hypoalbuminemia, though secondary sodium retention (via RAAS activation) contributes to edema perpetuation. 1

What are the classification, diagnosis, and management of acute kidney injury (AKI), including differentiation between pre-renal and renal AKI, indications for emergency hemodialysis, and treatment of electrolyte imbalances?

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