Acute Tubular Injury Necrosis

Slide 1 · Acute Tubular Injury / Necrosis

Pathogenesis • morphology • clinicopathologic course

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish ATI from the historical term acute tubular necrosis.

Relate ischemic and toxic exposures to vulnerable nephron segments.

Explain tubular, vascular and inflammatory contributors to decreased GFR.

Recognize characteristic morphologic and clinical evolution.

Connect epithelial regeneration with functional recovery.

Slide 3 · ATI denotes a functional and structural injury spectrum

Acute kidney injury occurs with tubular epithelial dysfunction.

Necrosis is common but is not required for the diagnosis.

Ischemia and toxins are the dominant initiating categories.

Three linked observations · schematic

Insult

Ischemic or toxic exposure

Response

Tubular dysfunction ± cell death

Effect

Reduced GFR; Acute renal impairment

Slide 4 · Why “injury” is more precise than “necrosis”

“Acute tubular necrosis” is the historical term.

Reversible epithelial abnormalities may exist without overt necrosis.

The term ATI avoids claiming morphology that may not be present.

Comparison · conceptual

ATI

ATN

Preferred pathologic term

Includes sublethal injury

Necrosis not obligatory

Historical designation

Implies epithelial necrosis

Can be misleading when necrosis absent

Slide 5 · Clinical dysfunction need not match tissue appearance

Tubular injury can impair renal function even when necrosis is limited.

The intensity of histologic abnormalities may not mirror clinical severity.

Interpret tubular morphology in the clinical setting.

Mechanistic sequence · schematic

Tubular epithelial dysfunction

Impaired transport + intrarenal hemodynamics

Reduced filtration, despite variable necrosis

Slide 6 · ATI is a major cause of hospitalized AKI

ATI as the most common cause of acute kidney injury.

It accounts for approximately half of hospitalized AKI cases in the source.

The etiologic setting helps identify the relevant mechanism.

Three linked observations · schematic

Hospital AKI

Multiple possible mechanisms

ATI

About 50%

Context

Often shock or toxin exposure

Slide 7 · What determines reversibility?

Magnitude and duration of the insult influence outcome.

Patchy epithelial damage often leaves surviving cells able to repair.

Severe systemic illness may dominate prognosis despite renal repair potential.

Mechanistic sequence · schematic

Insult magnitude + duration

Extent of epithelial and vascular injury

Regeneration possible if injury resolves

Slide 8 · Tubular recovery requires living epithelial precursors

Viable epithelial cells can proliferate after injury.

New cells differentiate and re-epithelialize denuded segments.

Locally produced growth factors and cytokines contribute to repair.

Mechanistic sequence · schematic

Preserved viable epithelial cells

Proliferation + differentiation

Restored epithelial continuity

Slide 9 · Two major etiologic patterns

Ischemic ATI follows inadequate organ perfusion.

Nephrotoxic ATI follows exposure to tubular toxins.

A single patient can have both mechanisms.

Comparison · conceptual

Ischemic

Nephrotoxic

Hypoperfusion

Hypotension or shock

Outer-medullary vulnerability

Drugs or poisons

Direct tubular exposure

Prominent proximal injury with many toxins

Slide 10 · Clinical contexts of ischemic ATI

Severe trauma and acute pancreatitis are examples.

Marked hypotension or shock commonly accompanies the insult.

The shared event is inadequate blood flow to peripheral organs.

Mechanistic sequence · schematic

Severe systemic event

Reduced effective organ perfusion

Ischemic tubular injury

Slide 11 · Shock links systemic hypoperfusion to AKI

Renal oxygen delivery falls during circulatory compromise.

Tubular transport persists as an energy-intensive process.

Tubular injury and vasoconstriction together depress GFR.

Mechanistic sequence · schematic

Shock / hypotension

Tubular oxygen deficit + renal vascular changes

Reduced GFR and urine output

Slide 12 · Nephrotoxic drugs: Examples

Gentamicin is listed as a nephrotoxic agent.

Radiographic contrast agents are also included.

Toxin-related tubular damage may interact with hemodynamic injury.

Three linked observations · schematic

Gentamicin

Medication exposure

Contrast agents

Imaging-related exposure

Tubular injury

Nephrotoxic pattern

Slide 13 · Environmental and chemical nephrotoxins

Mercury is an example of a heavy-metal toxin.

Carbon tetrachloride is an example of an organic solvent.

Specific agents can produce distinctive tubular morphologies.

Mechanistic sequence · schematic

Heavy metals / organic solvents

Tubular toxin uptake or exposure

Epithelial injury; Sometimes distinctive changes

Slide 14 · Hemoglobinuria can combine ischemia and toxicity

Mismatched blood transfusions and hemolytic crises are examples.

Released hemoglobin reaches the nephron in the source context.

The text presents pigment-associated injury as potentially mixed.

Mechanistic sequence · schematic

Hemolytic crisis

Hemoglobinuria

Ischemic + nephrotoxic ATI mechanisms

Slide 15 · Myoglobinuria connects muscle injury to ATI

Skeletal muscle injury can cause myoglobinuria.

It is another example of mixed ischemic and nephrotoxic ATI.

Consider the antecedent systemic injury when interpreting AKI.

Mechanistic sequence · schematic

Skeletal muscle injury

Myoglobinuria

Combined tubular insult

Slide 16 · Real-world insults may not respect two categories

Pure ischemic and pure toxic forms are useful teaching patterns.

Hemolysis and muscle injury can combine mechanisms.

The histologic pattern should not be interpreted without exposures.

Comparison · conceptual

Teaching pattern

Clinical overlap

Ischemic

Nephrotoxic

Canonical segment preference

Shock + nephrotoxins

Pigment-associated crises

Variable mixed morphology

Slide 17 · High transport demand predisposes tubules to ischemia

Proximal cells have substantial metabolic and oxygen demands.

Active solute reabsorption depends on intact epithelial transport.

Oxygen deprivation rapidly impairs tubular function.

Mechanistic sequence · schematic

Intensive reabsorptive work

High oxygen requirement

Sensitivity to ischemia

Slide 18 · Proximal cells can concentrate injurious substances

Tubular epithelial surfaces contact filtrate extensively.

Active ion and organic-acid transport facilitates exposure.

Reabsorptive processes may concentrate toxins within cells.

Mechanistic sequence · schematic

Tubular transport / reabsorption

Concentration of some toxic solutes

Direct epithelial injury

Slide 19 · Why the outer medulla is a critical target

The proximal straight tubule is vulnerable.

The thick ascending limb also requires considerable energy.

Injurious perfusion changes can impair oxygen delivery to both.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

Proximal straight tubule

INJURY

Thick ascending limb

INJURY

Distal convoluted tubule

Collecting duct

Slide 20 · Segment-specific susceptibility predicts morphology

Ischemia preferentially affects proximal straight and ascending limbs.

Many toxins chiefly damage proximal convoluted tubules.

Distal segments may contain cellular debris and casts.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

INJURY

Proximal straight tubule

Thick ascending limb

Distal convoluted tubule

Collecting duct

Slide 21 · Two linked processes drive ATI

Tubular epithelial cell injury impairs filtration indirectly.

Persistent disturbance of intrarenal blood flow lowers filtration.

The two processes amplify each other.

Three linked observations · schematic

Epithelium

Loss of cell integrity and transport

Blood flow

Renal vasoconstriction and ischemia

GFR

Combined decline in filtration

Slide 22 · Loss of tubular cell polarity is an early response

Normal epithelial transport proteins have polarized localization.

Ischemia redistributes these proteins to inappropriate membranes.

The resulting transport defect may precede epithelial necrosis.

Mechanistic sequence · schematic

Ischemic epithelial stress

Loss of basolateral–luminal polarity

Abnormal transcellular ion transport

Slide 23 · Na⁺/K⁺-ATPase mislocalization impairs sodium handling

The textbook specifically identifies Na⁺/K⁺-ATPase.

Ischemia moves it from the basolateral toward the luminal surface.

Abnormal ion transport increases sodium delivery downstream.

Mechanistic sequence · schematic

Normal basolateral Na⁺/K⁺-ATPase

Ischemic redistribution toward lumen

Impaired proximal Na⁺ reabsorption

Slide 24 · Distal sodium delivery becomes a feedback signal

Reduced proximal sodium reabsorption raises distal sodium delivery.

Distal sodium sensing engages tubuloglomerular feedback.

This feedback influences the afferent arteriole and filtration.

Mechanistic sequence · schematic

Less proximal Na⁺ reabsorbed

More Na⁺ delivered distally

Tubuloglomerular feedback activated

Slide 25 · Tubuloglomerular feedback can lower GFR

The source describes afferent arteriolar vasoconstriction.

The resulting fall in glomerular blood flow decreases GFR.

A transport defect therefore produces a hemodynamic consequence.

Mechanistic sequence · schematic

Increased distal Na⁺ signal

Afferent arteriolar constriction

Reduced GFR

Slide 26 · Injured tubular cells recruit inflammatory cells

Ischemic tubules express cytokines and chemotactic molecules.

Leukocytes are recruited to the injured region.

Inflammatory cells may contribute to subsequent tubular damage.

Mechanistic sequence · schematic

Injured tubular epithelium

Cytokine / chemotactic signals

Leukocyte recruitment and additional injury

Slide 27 · Tubular epithelial detachment creates a second lesion

Damaged cells lose attachment to basement membranes.

Cells enter and accumulate within tubular lumens.

This creates the substrate for luminal obstruction.

Tubule cross-section · schematic only; Not a micrograph

Detached epithelial cells

Slide 28 · Cellular debris contributes to cast formation

Sloughed epithelial cells remain within the tubular lumen.

Debris and casts occupy distal nephron segments.

Cast-related obstruction contributes to reduced urine flow.

Tubule cross-section · schematic only; Not a micrograph

Luminal debris/cast

Slide 29 · Obstruction increases intratubular pressure

Sloughed cells and casts impede tubular flow.

Increased pressure opposes normal filtration downstream.

The functional consequence is an additional decrease in GFR.

Mechanistic sequence · schematic

Epithelial sloughing / casts

Tubular outflow obstruction

↑ intratubular pressure → ↓ GFR

Slide 30 · Damaged epithelium allows filtrate backleak

Filtrate may escape from the damaged tubular lumen.

Leaked fluid enters the interstitial compartment.

Backleak limits effective urine formation.

Tubule cross-section · schematic only; Not a micrograph

Filtrate leak across damaged epithelium

Slide 31 · Interstitial fluid accumulation perpetuates injury

Backleak causes interstitial edema.

Raised interstitial pressure impairs regional microperfusion.

Additional tubular ischemia can result.

Mechanistic sequence · schematic

Tubular filtrate backleak

Interstitial edema / pressure rise

Further regional ischemic damage

Slide 32 · Intrarenal vasoconstriction directly lowers filtration

Reduced renal microvascular flow is central to ischemic ATI.

Glomerular blood flow declines as intrarenal vessels constrict.

Oxygen delivery to vulnerable tubules falls further.

Three linked observations · schematic

Constriction

Reduced renal vascular caliber

Glomerulus

Reduced blood flow and GFR

Medulla

Reduced oxygen delivery

Slide 33 · The renin–angiotensin system participates in vasoconstriction

The textbook implicates the renin–angiotensin system.

Renal hypoperfusion engages vasoconstrictor pathways.

This contributes to persistent reductions in perfusion.

Mechanistic sequence · schematic

Decreased renal perfusion

Renin–angiotensin activation

Intrarenal vasoconstriction

Slide 34 · Endothelial dysfunction alters vasoactive balance

Sublethal endothelial injury increases endothelin release.

The source describes reduced nitric oxide and prostacyclin.

The altered balance favors intrarenal vasoconstriction.

Comparison · conceptual

Vasoconstrictor

Vasodilators

Endothelin

Release increases

Promotes narrowing

Nitric oxide

Prostacyclin (PGI₂)

Production decreases

Slide 35 · Hemodynamic and epithelial injury amplify one another

Reduced microvascular flow worsens tubular ischemia.

Injured epithelia send feedback signals and obstruct flow.

The combined effects sustain a decline in GFR.

Mechanistic sequence · schematic

Ischemia and epithelial injury

Feedback + obstruction + backleak

Lower GFR and worsening oxygen supply

Slide 36 · A glomerular component is possible but less established

The source notes some evidence for a direct glomerular effect.

Ischemia or toxins may decrease the ultrafiltration coefficient.

This is presented as a possibility, not the principal mechanism.

Mechanistic sequence · schematic

Ischemia or nephrotoxic exposure

Possible reduction of glomerular Kf

Additional reduction in GFR

Slide 37 · The GFR decline has several simultaneous causes

Tubuloglomerular feedback narrows afferent arterioles.

Obstruction and backleak compromise tubular flow.

Microvascular vasoconstriction limits renal blood supply.

Three linked observations · schematic

Feedback

Distal Na⁺ → arteriolar response

Tubular flow

Obstruction + filtrate backleak

Perfusion

Vascular constriction → reduced GFR

Slide 38 · Ischemic necrosis is characteristically patchy

Short damaged stretches alternate with preserved tubules.

The nephron may contain substantial intervening intact segments.

This helps explain the capacity for repair.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

Proximal straight tubule

INJURY

Thick ascending limb

INJURY

Distal convoluted tubule

Collecting duct

Slide 39 · The ischemic pattern favors two nephron segments

Proximal straight tubules are especially vulnerable.

Ascending limbs of the loop of Henle are also affected.

Necrosis is typically discontinuous rather than confluent.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

Proximal straight tubule

INJURY

Thick ascending limb

INJURY

Distal convoluted tubule

Collecting duct

Slide 40 · Toxic injury often centers on proximal convoluted tubules

Many toxins produce extensive proximal convoluted tubular necrosis.

Some toxic injuries also affect distal tubules and ascending limbs.

The specific distribution varies by agent.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

INJURY

Proximal straight tubule

Thick ascending limb

Distal convoluted tubule

Collecting duct

Slide 41 · Ischemic and toxic patterns are not identical

Distribution, not merely presence of necrosis, is informative.

Ischemic injury tends to be discontinuous in specific segments.

Some nephrotoxins cause more extensive proximal injury.

Comparison · conceptual

Ischemic ATI

Toxic ATI

Patchy lesions

Proximal straight segment

Ascending limb

Often prominent PCT necrosis

Agent-dependent specificity

May involve ascending limb

Slide 42 · Necrosis is one manifestation of epithelial injury

Tubular epithelial abnormalities vary in extent and severity.

Severe injury may produce overt epithelial necrosis.

Absence of dramatic necrosis does not exclude functional ATI.

Tubule cross-section · schematic only; Not a micrograph

Basement membrane and tubular lumen

Slide 43 · Tubulorrhexis denotes basement membrane rupture

The morphology description includes focal tubular rupture.

Injured segments may lose basement membrane integrity.

Preserved segments provide a scaffold for subsequent repair.

Mechanistic sequence · schematic

Severe focal epithelial injury

Tubular basement membrane rupture

Tubulorrhexis in some segments

Slide 44 · Sloughed epithelial cells appear within the lumen

Necrotic cells detach from the basement membrane.

Luminal cellular debris is a conspicuous lesion in examples.

This structural injury also has an obstructive consequence.

Tubule cross-section · schematic only; Not a micrograph

Detached epithelial cells

Slide 45 · Distal tubules and collecting ducts contain casts

Luminal casts are described in both major ATI patterns.

The distal convoluted tubule and collecting duct are common sites.

Casts provide a morphological correlate of impaired tubular flow.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

Proximal straight tubule

Thick ascending limb

Distal convoluted tubule

CASTS

Collecting duct

CASTS

Slide 46 · Ischemic ATI also affects the interstitium and vasa recta

Interstitial edema is a common associated finding.

Leukocytes may accumulate in dilated vasa recta.

These abnormalities reflect injury beyond epithelial cells alone.

Three linked observations · schematic

Tubule

Segmental epithelial damage

Interstitium

Edema and pressure

Vasa recta

Dilation with leukocytes

Slide 47 · Regeneration has identifiable morphologic features

Reparative lining cells may be flattened.

Hyperchromatic nuclei and mitotic figures can be present.

With complete repair, recognizable damage may disappear.

Tubule cross-section · schematic only; Not a micrograph

Re-epithelialization with surviving cells

Slide 48 · Mercuric chloride can produce distinctive toxic changes

Affected cells may contain large acidophilic inclusions.

Severely injured cells become necrotic and desquamate.

Some detached cells subsequently calcify.

Mechanistic sequence · schematic

Mercuric chloride exposure

Acidophilic epithelial inclusions

Necrosis, desquamation ± calcification

Slide 49 · Ethylene glycol injury can show crystal-associated damage

Proximal cells may become ballooned or vacuolated.

Hydropic change is part of the described pattern.

Calcium oxalate crystals can occur in tubular lumens.

Mechanistic sequence · schematic

Ethylene glycol toxicity

Ballooning / hydropic or vacuolar change

Luminal calcium oxalate crystals

Slide 50 · Histologic severity has imperfect clinical correlation

The source explicitly cautions against morphologic–clinical equivalence.

Marked renal dysfunction can occur with limited visible necrosis.

Reported tissue changes must be integrated with renal function.

Comparison · conceptual

Histology

Clinical course

Pattern and distribution

Necrosis or epithelial change

Casts / interstitial edema

GFR impairment

Oliguria and uremia

May be disproportionately severe

Slide 51 · Successful repair can erase visible injury

In surviving tubules, epithelial proliferation repopulates surfaces.

Tubular continuity and differentiation recover over time.

Eventually, there may be no residual histologic damage.

Mechanistic sequence · schematic

Focal tissue injury

Surviving cells proliferate

Regenerated tubular epithelium

Slide 52 · The classic clinical course has three phases

The illustrative course into initiation, maintenance, and recovery.

Clinical evolution is variable rather than universally stereotyped.

Functional recovery may lag behind improving urine output.

Initiation

Inciting event

↓ early GFR

Maintenance

Sustained oliguria

Uremic complications

Recovery

Rising urine volume

Functional restoration

A classic pattern; Individual clinical courses vary.

Slide 53 · Initiation follows the precipitating event

An initial period of about 36 hours.

A modest fall in urine output and rise in BUN may be evident.

Transient hypoperfusion and falling GFR can explain early oliguria.

Initiation

Inciting event

↓ early GFR

Maintenance

Sustained oliguria

Uremic complications

Recovery

Rising urine volume

Functional restoration

A classic pattern; Individual clinical courses vary.

Slide 54 · Maintenance features persistent oliguria

The source gives an illustrative urine output of 40–400 mL/day.

Urine flow remains markedly decreased during this period.

Salt and water retention contribute to the clinical burden.

Initiation

Inciting event

↓ early GFR

Maintenance

Sustained oliguria

Uremic complications

Recovery

Rising urine volume

Functional restoration

A classic pattern; Individual clinical courses vary.

Slide 55 · Maintenance produces systemic metabolic complications

Blood urea nitrogen continues to rise.

Hyperkalemia and metabolic acidosis may develop.

Uremic manifestations reflect sustained renal failure.

Three linked observations · schematic

Retention

Salt, water and nitrogenous products

Electrolytes

Hyperkalemia

Acid–base

Metabolic acidosis

Slide 56 · Recovery begins with increasing urine volume

The source describes progressive diuresis, sometimes to 3 L/day.

Urine production may recover before full transport function.

A rising urine output is therefore not synonymous with complete repair.

Initiation

Inciting event

↓ early GFR

Maintenance

Sustained oliguria

Uremic complications

Recovery

Rising urine volume

Functional restoration

A classic pattern; Individual clinical courses vary.

Slide 57 · Early recovery may cause substantial solute loss

Damaged tubules still reabsorb sodium and potassium inefficiently.

Large volumes of water and solutes may be lost in urine.

This explains why the diuretic phase requires attention to losses.

Mechanistic sequence · schematic

Filtration begins to improve

Tubules still transport poorly

Water + Na⁺ + K⁺ urinary losses

Slide 58 · Biochemical recovery can lag behind diuresis

Blood urea nitrogen and creatinine gradually normalize.

Tubular concentrating capacity improves progressively.

Different aspects of nephron function recover at different rates.

Mechanistic sequence · schematic

Urine volume increases

Tubular concentrating ability returns

BUN and creatinine approach baseline

Slide 59 · Residual functional defects may outlast acute injury

Subtle tubular impairment may persist for months.

The textbook also notes increased infection vulnerability during recovery.

Most patients reaching recovery ultimately regain function.

Initiation

Inciting event

↓ early GFR

Maintenance

Sustained oliguria

Uremic complications

Recovery

Rising urine volume

Functional restoration

A classic pattern; Individual clinical courses vary.

Slide 60 · Outcome depends on the initiating insult

Magnitude and duration determine how much epithelium survives.

Reversal of the cause supports regeneration.

Concurrent organ injury changes the prognosis substantially.

Mechanistic sequence · schematic

Severity + duration of insult

Preserved repair capacity and insult removal

Recovery probability / clinical outcome

Slide 61 · Renal repair and patient survival are distinct outcomes

Nephrotoxic ATI may resolve if other organs are not severely damaged.

High renal recovery among survivors of the precipitating event.

Sepsis, extensive burns, and multiorgan failure greatly worsen survival.

Comparison · conceptual

Localized toxin insult

Multiorgan shock

Cause removed

Other organs preserved

Renal recovery often expected

Sepsis / major burns

Persistent systemic injury

Mortality may be high

Slide 62 · Interpret prognosis figures in their clinical context

The source states 95% recovery with supportive care among patients who survive the precipitating event.

It also reports mortality exceeding 50% in some severe shock or multiorgan failure settings.

These figures describe different groups and endpoints; Do not compare them directly.

Three linked observations · schematic

95%

Renal recovery among those surviving inciting event (source)

>50%

Mortality may occur with severe multiorgan shock (source)

Interpretation

Different denominators and outcomes

Slide 63 · Application: Hypotension with new oliguria

A patient becomes hypotensive after major trauma.

Urine output subsequently falls and renal indices worsen.

Ischemic ATI is a plausible mechanism in this source-based scenario.

Mechanistic sequence · schematic

Major trauma + hypotension

Ischemic tubular and vascular injury

Oliguria with reduced GFR

Slide 64 · Application: Interpreting a toxic exposure

A patient develops AKI after exposure to a tubular toxin.

Predominant proximal convoluted tubular injury would fit many toxic patterns.

The exact morphologic picture depends on the offending agent.

Segmental involvement · original schematic, not an anatomical scale

Proximal convoluted tubule

INJURY

Proximal straight tubule

Thick ascending limb

Distal convoluted tubule

Collecting duct

Slide 65 · Application: Increasing urine output after ATI

A recovering patient begins to produce large urine volumes.

Persistent tubular transport defects may cause water and electrolyte losses.

Diuresis must be interpreted as a phase of recovery, not instant normalization.

Initiation

Inciting event

↓ early GFR

Maintenance

Sustained oliguria

Uremic complications

Recovery

Rising urine volume

Functional restoration

A classic pattern; Individual clinical courses vary.

Slide 66 · Synthesize the mechanism before reading the biopsy

The initiating context suggests ischemic, toxic, or mixed ATI.

Tubular transport changes and hemodynamics explain reduced GFR.

Morphology may support ATI without closely predicting severity.

Mechanistic sequence · schematic

Clinical insult and exposures

Tubular + hemodynamic mechanisms

Functional AKI ± variable histologic injury

Slide 67 · Three central pathology conclusions

ATI need not contain widespread tubular necrosis.

Sodium transport disruption, obstruction, backleak, and vasoconstriction reduce GFR.

Renal recovery relies on survival and regeneration of tubular epithelium.

Three linked observations · schematic

Definition

Injury ≠ obligatory necrosis

Mechanism

Epithelial + vascular

Recovery

Regeneration if insult resolves

Slide 68 · Primary reference and source limitations

Robbins, Cotran & Kumar

Pathologic Basis of Disease, 11th edition (2026)

Chapter 20 — The Kidney

Lecture coverage: acute tubular injury/necrosis and closely adjacent mechanism text.

Original source chapter PDF and authentic figure assets were not provided. All illustrated pathology is explicitly schematic.