Atypical Nonepidemic Diarrhea Negative Hemolytic Uremic Syndrome

Slide 1 · ATYPICAL HEMOLYTIC UREMIC SYNDROME

Nonepidemic / “diarrhea-negative” HUS

Mechanisms • Renal vascular morphology • Clinicopathologic differentiation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain the TMA phenotype and locate atypical HUS within its major causal groups.

Connect impaired complement regulation to glomerular endothelial injury and thrombosis.

Distinguish acute thrombotic lesions from chronic ischemic remodeling.

Compare aHUS with Shiga toxin-associated HUS and ADAMTS13-deficient TTP.

Slide 3 · Atypical HUS belongs to the TMA spectrum

Thrombotic microangiopathy

Shiga toxin–associated HUS

Atypical HUS / complement-mediated TMA

ADAMTS13-deficient TTP

Shared lesions do not imply shared initiating mechanisms

Slide 4 · TMA names a vascular injury pattern

Thrombi form in capillaries and/or arterioles across susceptible organ beds.

Tissue ischemia and organ dysfunction follow loss of microvascular perfusion.

Red cell destruction and platelet consumption are linked consequences.

TMA is a clinicopathologic pattern, not a single etiologic diagnosis.

Slide 5 · Four linked consequences of microvascular thrombi

Microvascular thrombi

RBC fragmentation + platelet use

Tissue ischemia

Organ dysfunction

Parallel consequences of narrowed or occluded microvessels

Slide 6 · Two dominant initiating routes in TMA

Endothelial injury

Platelet hyperactivation

Central in HUS

Shiga-like toxin in typical HUS

Excess complement in inherited aHUS

Central in TTP

ADAMTS13 deficiency

Ultralarge vWF multimers persist

Slide 7 · Why the renal microvasculature matters

Schematic — not a histologic image

Glomerular capillary and arteriolar thrombi compromise cortical perfusion.

Persistent or extensive vascular occlusion can produce cortical necrosis.

Chronic injury leads to glomerular and vascular scarring.

Slide 8 · The “atypical HUS” label covers different settings

Atypical HUS

Inherited complement-regulatory defects

Acquired anti-regulator autoantibodies

Other endothelial-injury associations

Mechanism and associated condition must be distinguished

Slide 9 · Complement activation needs host-cell safeguards

Alternative-pathway activation

Regulatory proteins restrain C3b / C3 convertase

Host endothelium is protected

Regulation limits complement damage to normal tissue

Slide 10 · Factor H protects cells from complement injury

Factor H is a circulating regulator of the alternative complement pathway.

It promotes cleavage and destruction of C3b.

It promotes turnover of C3 convertases, limiting continued activation.

Defective Factor H regulation allows damage to host microvascular endothelium.

Slide 11 · Factor H regulates the C3 amplification step

C3b and C3 convertase

Factor H–dependent downregulation

Reduced complement attack on host cells

Factor H acts as a brake, not as an initiating complement trigger

Slide 12 · Loss of Factor H function removes a vascular brake

Factor H abnormality

Insufficient convertase control

Excess complement activation

Endothelial injury

Pathogenetic model described for complement-mediated HUS

Slide 13 · Factor H is the most commonly cited regulator

More than half of affected patients have identifiable complement-regulatory mutations in the cited textbook account.

Factor H is the most common named regulator among those mutations.

The mutation-based fraction is a textbook observation—not a diagnostic cut-off.

Absence of an identified mutation does not negate the clinical TMA phenotype.

Slide 14 · Factor I is another complement regulator

Complement Factor I mutations among aHUS-associated defects.

This broadens the mechanism beyond a single gene or protein.

The shared downstream problem is inadequate restraint of complement activity.

The renal lesion remains TMA rather than a Factor I–specific histology.

Slide 15 · CD46 is a membrane-bound cofactor protein

CD46 is also termed membrane cofactor protein.

CD46 mutations among complement-regulatory defects in aHUS.

The role of cell-associated regulators complements circulating regulators.

Mutations converge on endothelial susceptibility to complement-mediated injury.

Slide 16 · Three named regulators, one pathogenic theme

Regulator

Description in source

Disease relevance

Factor H

Circulating regulator; C3b/C3 convertase control

Most commonly cited mutation

Factor I

Complement regulatory protein

Mutations associated with aHUS

CD46

Membrane cofactor protein

Mutations associated with aHUS

Slide 17 · Genetic architecture can modify disease onset

Multiple complement-regulatory mutations may coexist in a patient.

Multiple mutations with presentation at a younger age.

The observation supports a cumulative vulnerability model.

The source does not provide a penetrance estimate or an age threshold.

Slide 18 · Acquired autoantibodies can mimic regulatory loss

Autoantibody blocks regulator

Insufficient regulatory activity

Excess complement activation

TMA

An acquired mechanism can reproduce the downstream phenotype

Slide 19 · Inherited and acquired mechanisms converge

Inherited

Acquired

Mutation in regulatory protein

Examples: Factor H, Factor I, CD46

Mutations affect complement-regulatory proteins

Autoantibody blocks regulatory activity

Complement control becomes impaired

Similar downstream endothelial injury

Slide 20 · Complement-mediated TMA is endothelial disease

Complement overactivation

Glomerular endothelial damage

Platelet activation

Microvascular thrombi

Mechanistic order: Complement dysregulation precedes the platelet-rich lesion

Slide 21 · Endothelial injury shifts the vessel toward thrombosis

In HUS, endothelial injury appears to be the primary initiating event.

Damaged microvascular endothelium promotes platelet activation.

Platelet-rich occlusion reduces glomerular capillary blood flow.

Ultimately the clinical phenotype reflects the distribution and severity of thrombi.

Slide 22 · Microthrombi mechanically fragment erythrocytes

Narrowed capillary lumen

Increased shear stress on RBCs

Fragmented erythrocytes

Intravascular hemolysis

Schistocytes are a blood-smear manifestation of mechanical red cell trauma

Slide 23 · Why platelet counts fall

Endothelial injury

Platelet activation and adhesion

Platelet-rich thrombi

Consumptive thrombocytopenia

Consumption links vascular pathology to a systemic blood-count abnormality

Slide 24 · One complement defect produces three clinical axes

Complement-mediated microvascular thrombosis

Hemolytic anemia

Thrombocytopenia

Renal dysfunction

Slide 25 · The aHUS cascade: An integrated model

Regulatory mutation / autoantibody

Excess complement activity

Endothelial injury + thrombosis

Hemolysis, thrombocytopenia, ischemia

Original editable mechanism synthesis text

Slide 26 · Not every aHUS association is a complement mutation

Robbins also describes a group associated with heterogeneous conditions or exposures.

Antiphospholipid syndrome is one named association.

Pregnancy complications and postpartum renal failure are another setting.

Vascular renal disease, including systemic sclerosis, is also implicated.

Slide 27 · Antiphospholipid syndrome is an associated setting

Antiphospholipid syndrome among conditions associated with aHUS.

This belongs to the acquired endothelial-injury context of TMA.

An aPL-associated TMA should not automatically be labeled a proven inherited complement disorder.

Morphology alone cannot identify the causative association.

Slide 28 · Pregnancy can precede a TMA presentation

Pregnancy / delivery

Postpartum TMA may emerge

Endothelial injury + renal microthrombi

Acute kidney injury / renal failure

Onset from one day to several months after delivery

Slide 29 · Postpartum renal failure: Important uncertainty

The underlying pathogenic mechanism is described as unclear.

Some patients may carry a complement-regulatory mutation.

A grave prognosis, although milder cases can recover.

A pregnancy association does not by itself prove a complement gene defect.

Slide 30 · Systemic sclerosis is a vascular renal association

Systemic sclerosis is listed among vascular diseases affecting the kidney.

The association is part of the heterogeneous acquired-injury group.

Kidney microangiopathy may therefore be encountered outside primary regulator defects.

The microscopic TMA lesion cannot establish systemic sclerosis by itself.

Slide 31 · Other endothelial-injury contexts in the parent section

Associated setting

How it

Severe hypertension

Acquired endothelial injury associated with TMA

Chemotherapeutic or immunosuppressive drugs

Drug-associated endothelial injury

Radiation

An exposure associated with endothelial injury

Systemic sclerosis

Vascular disease affecting the kidney

Slide 32 · Etiologic categories should not be conflated

Complement-dysregulated aHUS

Other associated TMAs

Inherited regulatory mutations

Blocking anti-regulator antibodies

Complement is the primary described driver

Pregnancy-associated injury

Antiphospholipid syndrome

Systemic sclerosis, drugs, radiation, etc.

Slide 33 · Typical HUS: A different initiating insult

Most typical HUS cases follow Shiga-like toxin–producing intestinal infection.

Escherichia coli O157:H7 is the most commonly named strain.

Shigella dysenteriae may also cause a related syndrome.

The toxin is linked to endothelial injury and platelet activation.

Slide 34 · Typical HUS endothelial mechanism is not fully settled

One proposed pathway involves endothelial activation and altered vasoactive signaling.

Reduced nitric oxide and increased endothelin favor vasoconstriction.

Cytokine context may contribute to endothelial apoptosis.

Robbins explicitly acknowledges alternative mechanisms, including possible complement interaction.

Slide 35 · TTP: ADAMTS13 deficiency drives platelet activation

ADAMTS13 deficient

Ultralarge vWF remains uncleaved

Platelet activation / aggregation

Microthrombi

Different initiating event; Overlap in TMA consequences

Slide 36 · TTP can be acquired or inherited

Inhibitory autoantibodies are the most common ADAMTS13-deficiency cause.

Inherited inactivating ADAMTS13 mutations occur less commonly.

The resulting ultralarge vWF multimers can activate platelets.

This pathway is pathogenetically distinct from complement-mediated aHUS.

Slide 37 · Compare the three principal TMA mechanisms

Syndrome

Initiating mechanism

Emphasis

Typical HUS

Shiga-like toxin–related endothelial injury

Renal involvement prominent

Atypical HUS

Complement-regulatory defect or other endothelial injury

Chronic renal injury common

TTP

ADAMTS13 deficiency → ultralarge vWF

Neurologic signs often dominate

Slide 38 · ADAMTS13 distinguishes TTP from aHUS

Plasma ADAMTS13 levels as normal in aHUS cases with neurologic findings.

TTP instead involves inherited or acquired ADAMTS13 deficiency.

This comparison is mechanistically informative when syndromes overlap clinically.

No numerical activity threshold is provided in the cited textbook section.

Slide 39 · All HUS/TTP types share nonspecific morphology

Morphologic findings across HUS and TTP are indistinguishable.

Tissue changes differ primarily according to acuity and chronicity.

A renal thrombus supports TMA—not its specific molecular etiology.

Clinical and etiologic context is required for classification.

Slide 40 · Acute kidney: Subcapsular petechiae and necrosis

Cortex

Schematic — not a histologic image

Acute active TMA can yield subcapsular petechial hemorrhages.

Cortical necrosis may be patchy or diffuse.

The gross effect is downstream of microvascular ischemia.

Slide 41 · Cortical necrosis may be sharply delimited

Cortex

Schematic — not a histologic image

Massive ischemic necrosis is sharply limited to the renal cortex.

The underlying injury is loss of perfusion within cortical microvasculature.

Necrotic foci may alternate with relatively preserved cortex.

Slide 42 · Glomerular capillary thrombi are a core acute lesion

Schematic — not a histologic image

Capillary loops can be distended by intraluminal thrombi.

Obstruction reduces effective glomerular blood flow.

The depicted arrangement is a schematic, not a histologic specimen.

Slide 43 · Mesangial matrix destruction is termed mesangiolysis

Mesangial disruption

Schematic — not a histologic image

Acute injury disrupts mesangial matrix and damages mesangial cells.

Sufficient damage can produce collapse or loss of mesangial support.

Mesangiolysis coexists with capillary vascular injury in TMA.

Slide 44 · Arterioles and interlobular arteries may thrombose

Occluding thrombus

Schematic — not a histologic image

Occlusive thrombi can involve both arterioles and interlobular arteries.

The distribution extends beyond glomerular capillary loops.

Arterial occlusion magnifies cortical ischemia.

Slide 45 · Chronic TMA leaves renal cortical scars

Chronic lesions are especially common in atypical HUS.

The cortex shows variable scarring after persistent or recurrent injury.

Scarring records both the original ischemic insult and subsequent healing.

Chronicity adds irreversible structural damage to active microthrombosis.

Slide 46 · Chronic glomeruli may become shrunken

Schematic — not a histologic image

Glomerular shrinkage is part of the chronic TMA pattern.

Capillary wall thickening accompanies chronic glomerular remodeling.

These changes reflect sustained injury rather than an etiology-specific lesion.

Slide 47 · Double contours: Capillary-wall remodeling

Parallel wall outlines

Schematic — not a histologic image

Chronic disease may duplicate the glomerular basement membrane.

The source describes “double contours” or “tram tracks.”

Duplication is linked to capillary wall thickening and repair after injury.

Slide 48 · Concentric arterial wall expansion narrows lumina

Concentric wall expansion

Schematic — not a histologic image

Additional layers of cells and connective tissue thicken arterial walls.

Thickened walls progressively narrow the lumen.

Persistent vascular narrowing maintains renal hypoperfusion.

Slide 49 · Arteriolar hyalinosis can dominate chronic lesions

Thick hyaline wall

Schematic — not a histologic image

In chronic TMA, arteriolar walls may be thickened by hyalinosis.

Wall thickening contributes further to luminal narrowing.

Together with other vascular lesions, this perpetuates ischemic damage.

Slide 50 · Acute and chronic renal changes form a continuum

Acute / active

Chronic / reparative

Glomerular and arterial thrombi

Mesangiolysis

Petechiae; Cortical necrosis

Cortical scar; Small glomeruli

Double-contour capillary walls

Vascular thickening and hyalinosis

Slide 51 · Vascular injury can become self-reinforcing

Repeated endothelial injury

Thrombi + vascular remodeling

Persistent hypoperfusion

Scarring and renal failure

Temporal synthesis: Acute thrombosis evolves into chronic perfusion deficit

Slide 52 · RBC fragments are evidence of mechanical hemolysis

Narrow or thrombus-lined microvessels create shear stress on erythrocytes.

Peripheral blood may show fragmented cells (schistocytes).

Microangiopathic hemolysis is shared by several TMA disorders.

Schistocytes alone cannot identify the underlying TMA cause.

Slide 53 · Renal dysfunction is a vascular consequence

Glomerular thrombosis reduces filtration through affected capillary beds.

Arteriolar injury diminishes cortical perfusion.

Severe ischemia can produce cortical necrosis and renal failure.

Chronic hypoperfusion adds scarring and sustained loss of function.

Slide 54 · Neurologic symptoms do not automatically mean TTP

Some patients with aHUS develop neurologic manifestations.

Normal plasma ADAMTS13 in these aHUS cases with TTP deficiency.

TTP typically shows more prominent CNS involvement.

The entire clinical picture and mechanism must be considered together.

Slide 55 · Prognosis: Atypical HUS is often less favorable

Typical HUS

Atypical HUS

Following infection, many recover kidney function if injury is limited

Long-term renal damage remains possible

Genetic or persistent underlying conditions may remain active

Chronic lesions and difficult-to-remove triggers worsen outlook

Slide 56 · Etiology matters beyond a biopsy diagnosis

Establish TMA phenotype

Consider STEC-associated HUS

Assess ADAMTS13-deficient TTP

Evaluate complement and associated disorders

Teaching framework, not a clinical practice guideline or formal diagnostic algorithm

Slide 57 · Biopsy interpretation: Identify pattern, not subtype

Acute occlusive thrombi and mesangiolysis support active TMA.

Double contours, vascular thickening, and scarring suggest chronicity.

Neither acute nor chronic morphology alone establishes Factor H or CD46 defects.

Clinicopathologic correlation is mandatory for subtype attribution.

Slide 58 · Case 1: Complement-regulatory disease

Clinical reasoning exercise — hypothetical

A patient develops hemolysis, thrombocytopenia, and acute kidney dysfunction.

Review identifies a pathogenic complement-regulatory protein defect.

Question: What order of events links the defect to renal failure?

Teaching interpretation: Impaired complement control → endothelial injury → platelet-rich TMA → glomerular ischemia. Mechanistic application of the Robbins framework; Hypothetical case.

Slide 59 · Case 2: Delayed postpartum renal failure

Clinical reasoning exercise — hypothetical

Renal failure with a TMA phenotype appears weeks after delivery.

A complement-regulatory defect has not yet been established.

Question: What can be inferred from pregnancy timing alone?

Teaching interpretation: Postpartum TMA is a recognized association, but its mechanism may be uncertain. The timing does not prove a complement mutation; Hypothetical case.

Slide 60 · Case 3: Neurologic TMA and ADAMTS13

Clinical reasoning exercise — hypothetical

A patient has hemolysis, thrombocytopenia, neurologic symptoms, and renal injury.

Question: Does prominent neurologic involvement itself establish TTP?

Which mechanistic feature should be contrasted with aHUS?

Teaching interpretation: No. TTP is associated with ADAMTS13 deficiency; Normal plasma levels in aHUS. Hypothetical discrimination exercise; Not a management protocol.

Slide 61 · Integrated pathologic interpretation

Complement-regulatory failure is a major route to atypical HUS, but acquired endothelial-injury contexts also occur.

Endothelial damage → platelet-rich TMA → mechanical hemolysis, platelet consumption, and renal ischemia.

Acute thrombi/mesangiolysis and chronic double contours/vascular scarring are shared TMA morphologies.

Cause is assigned by clinicopathologic and mechanistic context—not by renal morphology alone.

Slide 62 · Textbook sources and lecture boundaries

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Ch 20, pp 853–855: Thrombotic microangiopathies, HUS, TTP.

Same text, Ch 3, p 82: regulatory proteins of complement, including Factor H.

Same text, Ch 14: hemolytic anemia due to red cell trauma.

Source-derived teaching interpretation; no chapter PDF or source figures were supplied for direct image verification.