Acute kidney Injury

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"acute kidney injury"[MeSH Terms] AND management

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Acute Kidney Injury (AKI)

Definition

Acute kidney injury is a clinical syndrome defined by a rapid decline in the kidney's ability to clear waste products, occurring within approximately 1 week of an injurious stimulus. The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) criteria are the current gold standard:

AKI is defined by ANY ONE of the following:

Rise in serum creatinine (sCr) by ≥0.3 mg/dL within 48 hours, OR
Rise in sCr to ≥1.5 times baseline within 7 days, OR
Urine output <0.5 mL/kg/hour for ≥6 hours

The term "Acute Kidney Disease" (AKD) was introduced by KDIGO to capture cases where creatinine rises evolve over periods longer than 7 days and thus do not meet the formal AKI definition. - NKF Primer on Kidney Diseases, 8e

KDIGO Staging

Stage	Serum Creatinine	Urine Output
1	1.5-1.9x baseline OR ≥0.3 mg/dL increase	<0.5 mL/kg/h for 6-12 hrs
2	2.0-2.9x baseline	<0.5 mL/kg/h for ≥12 hrs
3	≥3.0x baseline OR sCr ≥4.0 mg/dL OR initiation of KRT	<0.3 mL/kg/h for ≥24 hrs OR anuria ≥12 hrs

Patients receiving kidney replacement therapy (KRT) are considered to have met Stage 3 criteria regardless of the creatinine level at the time of KRT initiation. - Goldman-Cecil Medicine, Table 106-1

The earlier RIFLE classification used a funnel-like staging system (Risk, Injury, Failure, Loss, ESKD) that preceded KDIGO but applied similar creatinine and urine output thresholds.

Epidemiology

~20-25% of hospitalized adults have an elevated serum creatinine
Up to 45% of ED admissions present with elevated sCr
55-65% of ICU patients develop AKI
Community-acquired AKI: annual incidence <1%
Prerenal azotemia accounts for 40% of hospital-acquired and 60-70% of community-acquired AKI cases
Intrinsic AKI is present in 5-6% of ED admissions and up to 60% of ICU patients
Intrinsic AKI requiring dialysis has increased substantially over the past three decades
Goldman-Cecil Medicine, p. 1241

Three Anatomic Categories

1. Prerenal AKI (60-70% of cases)

Mechanism: Decreased renal blood flow/perfusion without structural kidney damage.

Causes:

True volume depletion: Limited oral intake, fever/sweating, burns, diarrhea, diuretics, hemorrhage
Effective volume depletion: Heart failure, liver failure/cirrhosis, nephrotic syndrome
Medications reducing GFR: NSAIDs, ACE inhibitors, angiotensin receptor blockers, cyclosporine, radiocontrast agents

Key features:

BUN:Creatinine ratio >20:1 (increased urea reabsorption due to low effective arterial volume)
FENa <1% in oliguric patients (intact tubular sodium reabsorption)
Rapidly reversible with volume repletion within hours
Urinary biomarkers of tubular injury not particularly elevated

FENa can be influenced by diuretics; in such cases, FEurea <35% is more reliable. - NKF Primer, p. 346

2. Intrinsic AKI (25-40% of cases)

An abrupt, sustained decline in function due to structural kidney damage - cannot be readily reversed for days to weeks.

Subtypes and frequencies:

Tubular cell injury (80-90% of intrinsic AKI):
- Ischemic/ATN: Ischemia, reperfusion, inflammation, coagulation (e.g., sepsis, major surgery, cardiogenic shock)
- Toxic ATN: Endogenous toxins (myoglobin, hemoglobin, uric acid crystals, calcium oxalate) or exogenous (radiocontrast, aminoglycosides, vancomycin, amphotericin B, cisplatin, tacrolimus, cyclosporine)
Acute Interstitial Nephritis (5-10%): Drug-induced (sulfonamides, penicillins, cephalosporins, NSAIDs, PPIs, checkpoint inhibitors), infections (Legionella, leptospirosis, SARS-CoV-2), autoimmune (SLE, Sjögren's)
Acute Glomerulonephritis (<5%): Rapidly progressive GN, vasculitis

Molecular pathobiology: Activation of inflammatory, ischemic, and coagulation pathways; slow resolution due to vasoconstriction, tubular damage, cell death, and interstitial edema. Urinary biomarkers (NGAL, IL-18, KIM-1, TIMP-2, IGFBP7) are prominently elevated. - Goldman-Cecil Medicine, p. 1242

3. Postrenal AKI (5-10% of cases)

Mechanism: Obstruction of urine flow from kidneys to urethra.

Causes:

Men: Benign prostatic hypertrophy (most common), bladder outlet obstruction
Both sexes: Nephrolithiasis, pelvic malignancy, retroperitoneal fibrosis, neurogenic bladder
Children: Congenital anatomic abnormalities

Relieving the obstruction can restore kidney function, but prolonged obstruction leads to tubular damage and may not be fully reversible.

Pathophysiology of AKI (ATN)

The proximal tubule and medullary thick ascending limb are most vulnerable due to high metabolic activity and limited oxygen supply (the medullary-cortical oxygen gradient). Following ischemia:

Depletion of ATP → loss of cell polarity → detachment of tubular epithelial cells
Cells form casts obstructing tubular flow → back-leak of filtrate
Intense afferent arteriolar vasoconstriction (tubuloglomerular feedback via macula densa)
Endothelial activation → inflammation, neutrophil and monocyte infiltration
Reparative phase involves upregulation of genes for cell-cycle regulation, growth factors (KIM-1, NGAL), and cytokines

Diagnosis and Evaluation

Serum Creatinine - Limitations

sCr is widely available but has important limitations:

Reflects GFR only at steady-state; there is a 24-72 hour lag before sCr stabilizes after an acute injury
Influenced by age, sex, muscle mass, and catabolic state
Volume resuscitation dilutes sCr, masking true AKI severity (the FACTT trial demonstrated fluid-corrected sCr identified more AKI cases)
In the elderly and malnourished, lower creatinine generation means sCr rises more slowly even with severe injury

Urine Studies

Test	Prerenal	ATN
FENa	<1%	>2%
FEUrea	<35%	>50%
Urine Na	<10 mEq/L	>40 mEq/L
Urine Osmolality	>500 mOsm/kg	<350 mOsm/kg
Urine sediment	Normal/hyaline casts	Muddy brown granular casts, tubular cells
BUN:Cr ratio	>20:1	~10-15:1

Urinary electrolytes should not be used in isolation - they are influenced by diuretics, sepsis, cirrhosis, and the phase of AKI when obtained. - NKF Primer, p. 347

Novel Biomarkers

Biomarker	Source	Use
NGAL (Neutrophil Gelatinase-Associated Lipocalin)	Distal tubule	Early ATN detection (rises within hours)
KIM-1 (Kidney Injury Molecule-1)	Proximal tubule	Ischemic/toxic tubular injury
IL-18	Proximal tubule	Predicts AKI progression and long-term mortality; AUC ~0.74-0.76 in cardiac surgery
TIMP-2 × IGFBP7	Tubular cells	Cell-cycle arrest markers; FDA-cleared for AKI risk prediction
Cystatin C	All nucleated cells, freely filtered	Earlier GFR marker than creatinine
α1-Microglobulin	Proximal tubule reabsorption	AUC ~0.86 for predicting need for RRT

Brenner and Rector's The Kidney, 2-Volume Set

Management

General Principles (Goldman-Cecil Medicine, p. 1243)

"Treatments involve removal of offending stimuli, correcting any obstruction, and supportive care to address volume depletion and electrolyte disturbances."

1. Identify and Treat the Cause

Discontinue nephrotoxins (NSAIDs, aminoglycosides, contrast, ACE inhibitors if prerenal)
Relieve urinary obstruction (Foley catheter, ureteric stent, percutaneous nephrostomy)
Treat sepsis aggressively (source control, antibiotics, hemodynamic support)
Treat AIN with steroids when drug-induced and offending agent removed

2. Fluid and Hemodynamic Management

Prerenal AKI: IV fluids (isotonic crystalloids preferred); target euvolemia
Avoid fluid overload - associated with worse outcomes in AKI
Vasopressors in septic shock to maintain MAP ≥65 mmHg
Balanced crystalloids (e.g., lactated Ringer's) are preferred over normal saline to reduce hyperchloremic acidosis and AKI risk

3. Electrolyte Management

Hyperkalemia: Dietary restriction, sodium bicarbonate, calcium gluconate (membrane stabilization), insulin/dextrose, kayexalate, dialysis if severe
Metabolic acidosis: Sodium bicarbonate if pH <7.2 or HCO3 <15
Hyperphosphatemia: Dietary restriction, phosphate binders
Hyponatremia/hypervolemia: Fluid restriction

4. Nutritional Support

Standard caloric needs (20-25 kcal/kg/day non-catabolic; 25-30 in hypercatabolic)
Protein: 0.8-1.0 g/kg/day (non-dialysis); 1.0-1.5 g/kg/day if on RRT

5. Drug Dosing Adjustments

Renally cleared drugs must be dose-adjusted (antibiotics, anticoagulants, antivirals)
Avoid NSAIDs, contrast, aminoglycosides when possible

6. Renal Replacement Therapy (RRT)

Indications (AEIOU):

Acidosis refractory to medical management
Electrolyte disturbance (hyperkalemia) not responding to treatment
Ingestion/intoxication
Overload (fluid overload refractory to diuretics)
Uremic symptoms (encephalopathy, pericarditis, coagulopathy, nausea/vomiting)

Modalities:

Intermittent Hemodialysis (IHD): Hemodynamically stable patients; more efficient solute removal
Continuous RRT (CRRT): Hemodynamically unstable patients; preferred in ICU
Peritoneal dialysis: Alternative when vascular access not available

Timing of RRT: Multiple RCTs have shown that in patients with KDIGO Stage 3 AKI, delayed initiation (watchful waiting) showed no increase in mortality compared to early initiation, and patients with delayed dialysis often had earlier diuresis and fewer adverse events. - Goldman-Cecil Medicine, p. 1349

Complications of AKI

Complication	Mechanism
Hyperkalemia	Reduced K+ excretion + tissue breakdown
Metabolic acidosis	Reduced H+ excretion, reduced HCO3 reabsorption
Hyperphosphatemia	Reduced phosphate excretion
Volume overload/pulmonary edema	Reduced urine output
Uremia	Accumulation of urea and other uremic toxins
Hyponatremia	Water retention exceeding Na retention
Anemia	Reduced EPO production
Infection	Immune dysregulation, indwelling catheters
AKI-CKD progression	~25-50% of severe AKI survivors develop CKD

Prognosis and AKI-to-CKD Transition

About 1/3 of hospitalized patients with AKI resolve within 24 hours, ~60% by 48 hours, and ~70% by 72 hours
ATN carries a higher risk of CKD progression than non-ATN AKI
Severe AKI requiring dialysis carries ~40-60% in-hospital mortality in ICU settings
Each episode of AKI independently increases the risk of CKD, ESRD, cardiovascular events, and all-cause mortality
Long-term follow-up with nephrology is essential after hospitalized AKI

Prevention

Identify high-risk patients early (CKD, elderly, diabetic, volume-depleted, septic)
Minimize nephrotoxin exposure; use N-acetylcysteine + hydration for contrast nephropathy
Optimize hemodynamics before major surgery
Use balanced crystalloids rather than normal saline for resuscitation
Biomarker-guided (TIMP-2 × IGFBP7) protocols may allow preventive care bundles in high-risk surgical patients

Key Sources:

Goldman-Cecil Medicine International Edition, Ch. 106 - Acute Kidney Injury, p. 1241-1243
NKF Primer on Kidney Diseases, 8e, Ch. 31 - Acute Kidney Injury Definition, p. 346-348
Brenner and Rector's The Kidney, 2-Volume Set - AKI Biomarkers and Pathophysiology chapters
Sabiston Textbook of Surgery, 14e - KDIGO Criteria Table 26.4, p. 449
Frameworks for Internal Medicine - AKI Categories, p. 448

cause of aki in detail with rational

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Causes of AKI - In Detail with Rationale

AKI causes are divided into three anatomic categories, each with a distinct pathophysiologic basis:

Major causes of AKI - Harrison's classification

CATEGORY 1: PRERENAL AKI (40-80% of all AKI)

Core Rationale

Prerenal AKI arises from inadequate renal plasma flow and intraglomerular hydrostatic pressure to support normal glomerular filtration - without any structural damage to the kidney itself. The kidney parenchyma is intact; the problem is upstream. Because no tissue is destroyed, it is fully reversible within hours of restoring perfusion. - Harrison's Principles of Internal Medicine, 22e

Normal Autoregulatory Defense (Why Prerenal AKI Has a Threshold Effect)

The kidney defends GFR through three autoregulatory mechanisms:

Myogenic reflex: Afferent arteriole dilates in response to reduced perfusion pressure
Prostaglandins (PGI2, PGE2): Vasodilate the afferent arteriole under hypoperfusion
Angiotensin II: Preferentially vasoconstricts the efferent arteriole to maintain glomerular capillary pressure
Tubuloglomerular feedback: Macula densa senses low solute delivery → afferent arteriole dilates → maintains GFR

These compensatory responses maintain GFR until mean arterial pressure falls below ~80 mmHg, at which point GFR drops steeply and AKI ensues.

Causes of Prerenal AKI with Rationale

A. True Hypovolemia (Reduced Circulating Blood Volume)

Cause	Mechanism
GI losses (vomiting, diarrhea, NGT drainage)	Fluid lost from the gut → reduced intravascular volume → low renal perfusion pressure
Hemorrhage	Direct loss of blood volume → reduced MAP → reduced afferent arteriolar pressure
Burns	Massive plasma leak into burn wound (third-space loss) → reduced effective circulating volume
Diuretic overuse	Forced sodium and water excretion → reduced intravascular volume
Insensible losses (fever, sweating)	Increased free water loss not replaced → hypovolemia
Pancreatitis/Peritonitis	Third-space fluid sequestration into inflamed cavity → decreased effective circulating volume

Rationale: All of these reduce the effective blood volume reaching the kidneys. The reduced afferent arteriolar pressure triggers the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. While angiotensin II initially helps by constricting the efferent arteriole, once perfusion falls below the autoregulatory threshold, GFR falls.

B. Reduced Cardiac Output (Effective Arterial Hypovolemia)

Cause	Mechanism
Myocardial infarction	Pump failure → low cardiac output → low renal perfusion pressure
Cardiomyopathy / Congestive Heart Failure	Despite fluid overload, the effective arterial volume (volume perceived as filling the vascular tree) is low → RAAS and SNS activation → renal vasoconstriction
Valvular disease (severe aortic stenosis, mitral stenosis)	Low forward flow → reduced MAP and renal perfusion
Cardiac tamponade/massive PE	Obstructive shock → reduced cardiac output

Rationale: In heart failure, the kidneys "see" underfilling of the arterial tree (low effective arterial volume) despite total body sodium and water excess. This triggers intense RAAS activation and ADH release. The kidneys retain sodium and water (worsening edema) while GFR falls - a vicious cycle. The term "cardiorenal syndrome" describes this bidirectional interaction. - Rosen's Emergency Medicine

C. Decreased Effective Arterial Volume (Distributive States)

Cause	Mechanism
Liver failure / Cirrhosis	Splanchnic vasodilation (from nitric oxide) → underfilling of systemic circulation → compensatory RAAS/SNS activation → renal vasoconstriction → hepatorenal syndrome
Nephrotic syndrome	Profound hypoalbuminemia → low oncotic pressure → fluid escapes to interstitium → reduced effective circulating volume
Sepsis (early/distributive)	Massive peripheral vasodilation → profound drop in SVR → decreased effective perfusion pressure despite high cardiac output
Anaphylaxis	Extreme vasodilation and capillary leak → acute distributive shock → reduced renal perfusion

Special note - Hepatorenal Syndrome: This represents the extreme end of cirrhotic prerenal physiology. Intense splanchnic vasodilation causes compensatory renal vasoconstriction via RAAS, ADH, and endothelin. The kidney itself is normal - when transplanted into a healthy recipient, it functions perfectly. It is defined by urine sodium <10 mEq/L, absence of proteinuria, and failure to respond to volume expansion.

D. Impaired Renal Autoregulation (Drug-Induced Prerenal AKI)

This is one of the most clinically important and avoidable causes:

NSAIDs (including COX-2 inhibitors)

Normal state: Renal prostaglandins (PGI2, PGE2) play a minor role in renal blood flow
Hypoperfused state: Prostaglandins become critically important for maintaining afferent arteriolar dilation
NSAIDs block COX-1/COX-2 → prostaglandin synthesis inhibited → afferent vasoconstriction → GFR falls
Risk is highest in elderly, CKD, CHF, cirrhosis, or volume-depleted patients

ACE Inhibitors / ARBs

Angiotensin II normally maintains GFR under hypoperfusion by constricting the efferent arteriole
ACE-I/ARBs block this → efferent arteriole dilates → glomerular capillary hydrostatic pressure drops → GFR falls
Critical scenario: Bilateral renal artery stenosis - GFR is entirely dependent on efferent vasoconstriction; ACE-I/ARB causes precipitous GFR loss
Also important: combined NSAID + ACE-I use ("triple whammy" with diuretic) dramatically increases AKI risk

Cyclosporine / Tacrolimus (Calcineurin inhibitors)

Cause intense afferent arteriolar vasoconstriction → reduced GFR
This is a hemodynamic (prerenal-type) effect, distinct from their chronic nephrotoxicity

SGLT-2 inhibitors lower intraglomerular pressure by reducing proximal tubule sodium reabsorption, but recent studies show a protective effect against AKI - probably through reduction in hyperfiltration injury and anti-inflammatory effects. - Harrison's Principles, 22e

CATEGORY 2: INTRINSIC (RENAL) AKI

Core Rationale

Intrinsic AKI involves structural damage to the kidney parenchyma - tubules, interstitium, glomeruli, or blood vessels. Unlike prerenal AKI, restoring perfusion does NOT immediately reverse function because cells have been destroyed. Recovery requires cellular regeneration, which takes days to weeks.

Intrinsic Renal Failure - Anatomy and Causes

2A: TUBULAR INJURY - Acute Tubular Necrosis (ATN) - 80-90% of Intrinsic AKI

The S3 segment of the proximal tubule (pars recta) and the medullary thick ascending limb are the most vulnerable because:

They have the highest metabolic demand (ATP-intensive active transport)
They exist in the most hypoxic zone of the kidney (renal medulla has a naturally low pO2)
They cannot switch to anaerobic glycolysis under ischemia

i. Ischemic ATN

Causes: Prolonged prerenal azotemia, cardiogenic shock, septic shock, aortic cross-clamping, major surgery, hemorrhagic shock, burns

Pathophysiology - Step by Step:

ATP depletion → failure of Na-K-ATPase → cells swell, lose polarity
Cytoskeletal disruption → loss of brush border → tubular cells detach into lumen
Detached cells + cellular debris form casts → tubular obstruction → raised intratubular pressure → backpressure on glomerulus → GFR falls
Backleak of filtrate across denuded, leaky tubular epithelium → net fluid absorption is impaired
Afferent arteriolar vasoconstriction (from tubuloglomerular feedback - macula densa senses increased distal solute delivery due to failed proximal reabsorption) → further reduces GFR
Inflammatory cascade: Neutrophils and monocytes infiltrate the interstitium → cytokine release (TNF-α, IL-1, IL-6) → endothelial injury → microvascular thrombosis → worsens medullary ischemia
Reactive oxygen species (ROS) from mitochondrial dysfunction cause lipid peroxidation, cell membrane damage, and apoptosis

"Transient ischemia alone in a normal kidney is usually not sufficient to cause severe AKI, as evidenced by the relatively low risk of severe AKI even after total interruption of renal blood flow during suprarenal aortic clamping or cardiac arrest." Prerenal azotemia and ischemic ATN represent a continuum. - Harrison's Principles, 22e

ii. Sepsis-Associated AKI (most common cause of ATN in ICU)

Pathophysiology:

Renal vasoconstriction: Activation of RAAS, sympathetic nervous system, vasopressin, and endothelin
Paradox: In early sepsis, renal blood flow may actually be normal or even high, yet GFR falls - suggesting altered intrarenal microvascular distribution (shunting away from medullary tubules)
Endothelial damage → increased leukocyte adhesion and migration → microvascular thrombosis → tubular ischemia
Cytokine storm: TNF-α, IL-1, IL-6, IL-8 → direct tubular toxicity, increased permeability
Reactive oxygen species from activated neutrophils and macrophages → oxidative tubular damage
Sepsis may also cause AIN (see below)

iii. Exogenous Nephrotoxins

Radiocontrast Agents (Contrast-Induced AKI)

Mechanism 1 - Renal medullary ischemia: Contrast causes intense intrarenal vasoconstriction via endothelin, adenosine, and reduced nitric oxide → medullary hypoxia (S3 segment and thick ascending limb most affected)
Mechanism 2 - Direct tubular cytotoxicity: Contrast agents are directly toxic to tubular epithelial cells via reactive oxygen species and apoptosis
Timeline: SCr rises at 24-48 hours, peaks at 3-5 days, typically resolves within 1 week
Risk factors: CKD, diabetes, volume depletion, high contrast volume, heart failure, NSAID/ACE-I use
Prevention: IV fluid hydration with isotonic saline before and after, minimize contrast dose, use iso-osmolar agents

Aminoglycosides (Gentamicin, Tobramycin, Amikacin)

Freely filtered at glomerulus → concentrated in proximal tubular cells (via megalin receptor)
Accumulate in lysosomes → phospholipidosis → lysosomal rupture → mitochondrial dysfunction → cell death
Non-oliguric AKI in 10-30% of courses, even at therapeutic levels
Onset: typically 5-7 days into therapy (can appear even after stopping)
Causes hypomagnesemia (tubular Mg wasting) as an early sign
Once-daily dosing reduces nephrotoxicity compared to multiple daily doses

Amphotericin B

Binds ergosterol (and cholesterol) in tubular cell membranes → pores form → tubular cell lysis
Also causes intense afferent arteriolar vasoconstriction → ischemia
Causes distal RTA, hypokalemia, hypomagnesemia, and nephrotoxic ATN

Vancomycin

Tubular injury, especially when trough levels are high
Can crystallize in tubules causing intratubular obstruction
Synergistically nephrotoxic with aminoglycosides and piperacillin-tazobactam

Cisplatin and other Platinum Chemotherapeutics

Enter proximal tubular cells via organic cation transporters
Form platinum-DNA adducts in tubular cell nuclei → apoptosis and necrosis
Non-oliguric AKI; also causes hypomagnesemia (tubular Mg wasting), hypokalemia

iv. Endogenous Nephrotoxins

Myoglobin (Rhabdomyolysis)

Causes: Crush injury, prolonged immobilization, seizures, statin toxicity, extreme exertion, heat stroke, drugs (cocaine, ecstasy), hypokalemia, hypothyroidism

Triple mechanism of renal damage:

Cast formation: Myoglobin precipitates with Tamm-Horsfall protein in acidic, concentrated urine → obstructive casts in distal tubules → tubular obstruction
Direct proximal tubular cytotoxicity: At pH ≤5.6, myoglobin dissociates into ferriheme + free iron → ferriheme causes lipid peroxidation → oxidative cell death in proximal tubules
Intrarenal vasoconstriction: Myoglobin scavenges nitric oxide (a potent renal vasodilator) → net vasoconstrictive effect; also activates endothelin-1, thromboxane A2, and RAAS

All three mechanisms are worsened by volume depletion and aciduria - hence the rationale for aggressive isotonic saline (± bicarbonate to alkalinize urine) as treatment. - Rosen's Emergency Medicine

Hemoglobin (Hemolysis - Pigment Nephropathy)

Mechanism is analogous to myoglobin-induced ATN
Causes: Transfusion reactions, G6PD deficiency, TTP/HUS, malaria, snake envenomation
Hemoglobin cast formation in distal tubules + proximal tubular direct toxicity via heme iron

Uric Acid Crystals (Acute Urate Nephropathy)

Context: Tumor Lysis Syndrome (after cytotoxic therapy for high-burden tumors - lymphoma, leukemia) or spontaneous (Burkitt's, ALL)
Massive cell death → huge purine load → uric acid overproduction → uric acid precipitates in collecting ducts and distal tubules (poorly soluble at acidic pH)
Causes: tubular obstruction → anuria; also intrarenal vasoconstriction
Treatment: rasburicase, allopurinol, IV hydration, urine alkalinization

Myeloma Cast Nephropathy ("Myeloma Kidney")

Light chains (Bence Jones proteins) filtered at glomerulus → co-precipitate with Tamm-Horsfall protein in distal tubules → obstruct tubules
Light chains also directly toxic to proximal tubule cells (endocytosis → lysosomal injury)
Volume depletion, contrast, hypercalcemia, and NSAIDs dramatically worsen myeloma AKI

Calcium Oxalate Crystals

Ethylene glycol ingestion → oxalic acid → calcium oxalate crystals → tubular obstruction
Also in primary oxaluria, after jejunoileal bypass

2B: ACUTE INTERSTITIAL NEPHRITIS (AIN) - 5-10% of Intrinsic AKI

Core Rationale: An immune-mediated inflammatory reaction in the renal interstitium, not primarily the tubules. Pathologically shows interstitial edema and inflammatory infiltrate (T lymphocytes, macrophages, ± eosinophils) with relative preservation of glomeruli.

Causes:

1. Drug-Induced (most common ~75%)

Mechanism: Drugs act as haptens or directly trigger a T-cell-mediated delayed hypersensitivity reaction against tubular antigens
Key drugs:

Drug Class	Examples
Beta-lactam antibiotics	Penicillin, methicillin, cephalosporins
Sulfonamides	TMP-SMX
Fluoroquinolones	Ciprofloxacin
Rifampin	-
NSAIDs	Any NSAID (can also cause nephrotic syndrome simultaneously)
Proton pump inhibitors	Omeprazole, pantoprazole (now a leading cause)
Diuretics	Furosemide, thiazides
Checkpoint inhibitors	Ipilimumab, nivolumab, pembrolizumab (~5% of treated patients)
Allopurinol	-

Classic triad (present in only ~1/3 of cases): Fever + rash + eosinophilia - absence does NOT exclude AIN.

2. Infection-Associated AIN

Mechanism: Direct infection or immune-complex deposition
Legionella pneumophila, Leptospira, Streptococcus, Mycobacterium tuberculosis, CMV, EBV, SARS-CoV-2, Hantavirus

3. Autoimmune / Systemic Disease

Sjogren's syndrome, SLE, sarcoidosis (granulomatous AIN), tubulointerstitial nephritis-uveitis (TINU) syndrome, IgG4-related disease

2C: ACUTE GLOMERULONEPHRITIS - <5% of Intrinsic AKI

Core Rationale: Immune-mediated inflammation directly in the glomerulus → reduced filtration surface area + increased glomerular capillary permeability. GFR falls because glomerular inflammation causes:

Proliferation of mesangial, endothelial, or epithelial cells → physically narrows the capillary lumen
Fibrin deposition → occludes capillary loops
Inflammatory cells → release cytokines/ROS damaging the filtration barrier

Rapidly Progressive GN (RPGN) - most severe form:

Type	Mechanism	Cause
Type I - Anti-GBM	Antibodies vs. collagen IV in GBM → linear IgG deposits	Goodpasture's syndrome (lung + kidney)
Type II - Immune complex	Immune complex deposition → complement activation → inflammation	Post-streptococcal GN, lupus nephritis, IgA nephropathy (cresentic), endocarditis
Type III - Pauci-immune (ANCA)	ANCA-mediated neutrophil activation → vessel wall destruction	GPA (Wegener's), MPA, EGPA (Churg-Strauss)

Clinical clues: Hematuria with red cell casts, proteinuria (often 1-3 g/day), hypertension, edema. Absence of red cell casts, hematuria, and significant proteinuria effectively excludes GN.

2D: VASCULAR CAUSES - Large and Small Vessel Disease

Intrinsic Renal Failure - Anatomy and Causes diagram

Large Vessel Disease

Cause	Mechanism
Renal artery occlusion (thromboembolism, dissection, vasculitis)	Abrupt cessation of arterial inflow → cortical ischemia/infarction
Renal vein thrombosis	Venous congestion → reduced net filtration pressure → AKI (particularly in nephrotic syndrome, hypercoagulable states)
Abdominal compartment syndrome	Raised intra-abdominal pressure → renal vein and inferior vena cava compression → venous hypertension → reduced perfusion pressure
Aortic dissection	Involvement of renal artery ostia → ischemic AKI

Small Vessel and Microvascular Disease

Cause	Mechanism
TTP (Thrombotic Thrombocytopenic Purpura)	ADAMTS13 deficiency → uncleaved vWF multimers → platelet aggregation → microthrombi in glomerular capillaries → microangiopathic hemolytic anemia + AKI
HUS (Hemolytic Uremic Syndrome)	Shiga toxin (E. coli O157:H7) → endothelial injury in renal microvasculature → microthrombi in glomeruli → triad: hemolytic anemia + thrombocytopenia + AKI (predominant in children)
Malignant Hypertension	Extremely high BP → fibrinoid necrosis of arterioles → ischemic glomerular injury + tubular ischemia
Atheroembolic AKI	Cholesterol crystals embolize (after aortic catheterization or anticoagulation) → lodge in small renal arteries → local inflammation + ischemia; subacute onset; livedo reticularis, eosinophilia
Scleroderma Renal Crisis	Intense arteriolar spasm + endothelial proliferation → critical renal ischemia → malignant HTN + AKI
HELLP Syndrome / Preeclampsia	Endothelial dysfunction + microangiopathy in pregnancy → glomerular endotheliosis + platelet thrombi
Vasculitis (ANCA, PAN)	Necrotizing inflammation of arterioles → fibrinoid necrosis → ischemic glomerular injury

CATEGORY 3: POSTRENAL AKI (5-10% of all AKI)

Core Rationale

Obstruction at any level of the urinary tract causes a retrograde rise in intratubular pressure that opposes glomerular filtration. Initially afferent arteriole dilates (hyperemia), but within hours, intrarenal vasoconstriction from angiotensin II, thromboxane A2, and vasopressin causes GFR to fall. The key insight: obstruction must be bilateral (or unilateral in a solitary functioning kidney) to cause AKI.

Pathophysiology of Obstruction

Acute obstruction → ↑ intratubular pressure → opposes net filtration pressure → GFR falls
Phase 1 (0-2 hrs): Compensatory afferent arteriolar dilation (prostaglandin-mediated) → increased renal blood flow
Phase 2 (2-5 hrs): Efferent arteriolar vasodilation → reduced filtration pressure
Phase 3 (>5 hrs): Afferent arteriolar vasoconstriction (angiotensin II, thromboxane A2, endothelin) → marked reduction in RBF and GFR
Prolonged obstruction → tubular atrophy + interstitial fibrosis → permanent CKD

Causes by Level

Intrarenal (Collecting Duct Level)

Crystal precipitation: Uric acid (tumor lysis), calcium oxalate (ethylene glycol), phosphate (bowel prep), acyclovir, sulfonamides, methotrexate, indinavir
Myeloma proteins (see above)

Ureteral (Bilateral or Solitary Kidney)

Nephrolithiasis (most common cause of bilateral ureteral obstruction in young patients)
Retroperitoneal fibrosis (idiopathic or secondary to drugs - methysergide, beta-blockers; associated with AAA)
Pelvic/retroperitoneal malignancy (cervical, bladder, prostate, lymphoma, metastases)
Sloughed renal papillae (diabetes, analgesic nephropathy, sickle cell disease)
Surgical ligation of ureter
Blood clots

Bladder

Benign prostatic hypertrophy - most common cause of postrenal AKI in older men
Prostate cancer
Neurogenic bladder (diabetic autonomic neuropathy, spinal cord injury, MS)
Anticholinergic drugs (tricyclics, antihistamines, antipsychotics) → bladder atony
Bladder carcinoma
Blood clots, bladder stones

Urethra

Urethral stricture (post-infectious, post-traumatic)
Phimosis (in children)
Obstructed urinary catheter (most preventable cause in hospital)

"Obstruction is an eminently reversible cause of AKI and should be considered in every patient with newly discovered azotemia." - Rosen's Emergency Medicine

A post-obstructive diuresis can occur after relief - the kidneys excrete retained salt, water, and urea; patients need careful IV fluid replacement to avoid volume depletion worsening AKI.

Summary Table: Distinguishing the Three Categories

Feature	Prerenal	Intrinsic (ATN)	Postrenal
BUN:Cr	>20:1	~10-15:1	Variable
FENa	<1%	>2%	Variable
Urine Na	<10 mEq/L	>40 mEq/L	Variable
Urine osmolality	>500	<350	Variable
Urine sediment	Normal / hyaline casts	Muddy brown granular casts, tubular cells	Normal or RBC casts if stone
Response to fluids	Rapid reversal	No immediate reversal	No reversal until obstruction relieved
Kidney size on US	Normal	Normal	Bilateral hydronephrosis
Biomarkers (NGAL, KIM-1)	Low	Very elevated	Low-moderate

Key Sources:

Harrison's Principles of Internal Medicine, 22e (2025) - Chapter 321, Prerenal Azotemia and Ischemia/Nephrotoxin-Associated AKI
Rosen's Emergency Medicine - Chapters 83 and 116 (Rhabdomyolysis)
Goldman-Cecil Medicine International Edition - Chapter 106, Intrinsic AKI
Frameworks for Internal Medicine - Chapter 33, AKI Categories
Smith and Tanagho's General Urology, 19e - Postrenal Kidney Injury

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