What is the differential diagnosis of Thrombotic Microangiopathy (TMA) on renal biopsy?

Differential Diagnosis of Thrombotic Microangiopathy (TMA) on Renal Biopsy

When TMA is identified on renal biopsy, the differential diagnosis must systematically distinguish between primary TMA syndromes and secondary causes, as pathologic features alone cannot determine etiology and require integration with clinical, laboratory, and serologic data. 1

Primary TMA Syndromes

Thrombotic Thrombocytopenic Purpura (TTP)

• ADAMTS13 activity <10% is diagnostic of TTP, distinguishing it from all other TMA forms 2, 3, 4
• Test for both ADAMTS13 activity and anti-ADAMTS13 antibodies urgently when TMA is suspected 4
• Presence of anti-ADAMTS13 antibodies indicates immune-mediated (acquired) TTP, while their absence with low ADAMTS13 suggests congenital TTP 4
• The PLASMIC score (>5 points = high risk) can risk-stratify patients while awaiting ADAMTS13 results 2, 3, 4

Complement-Mediated TMA (Atypical HUS)

• Occurs with ADAMTS13 activity >10% and requires evaluation of the alternative complement pathway 2, 3
• Genetic testing should include: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 2
• Gene variants detected in 60% of cases; 40-50% have no identifiable mutation but can still be diagnosed with aHUS 2
• In children <1 year old, consider mutations in complement-unrelated genes (DGKE, WT1) and metabolic causes (MMACHC causing methylmalonic acidemia) 2
• Test for acquired autoantibodies: C3 nephritic factor (C3Nef) and anti-factor H antibody 2

Shiga Toxin-Producing E. coli HUS (STEC-HUS)

• Typically presents 4-5 days after onset of bloody diarrhea 2
• If diarrhea and HUS appear concomitantly or with very short prodrome, suspect aHUS rather than STEC-HUS 2
• Stool culture and Shiga toxin testing confirm diagnosis 5

Secondary TMA: Systemic Conditions

Lupus Nephritis with TMA

• TMA associated with antiphospholipid antibodies in lupus nephritis should be included within the primary diagnosis rather than as a secondary finding 2
• Test for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 2, 6
• Distinguish between three TMA mechanisms in SLE: antiphospholipid syndrome nephropathy, complement-mediated TMA, and TTP 2, 6
• Lupus nephritis biopsies may show both glomerular and arterial TMA involvement 7

Malignant Hypertension

• Most common etiology of TMA in native kidney biopsies (representing approximately 33% of cases in one series) 7
• Characterized by severe blood pressure elevation with advanced retinopathy 3
• Renal biopsies typically show isolated arterial changes without glomerular involvement 7
• Controlling blood pressure within 24-48 hours usually improves the TMA 3
• An MPGN pattern with neither immunoglobulin nor C3 deposits should raise suspicion for chronic TMA including malignant hypertension 2

Pregnancy-Associated TMA

• Postpartum TMA represents approximately 18% of native kidney TMA cases 7
• Shows isolated arterial changes on biopsy similar to malignant hypertension 7
• Has poor renal outcome frequently requiring renal replacement therapy 7
• Distinguish from preeclampsia/eclampsia based on timing and severity 1

Monoclonal Immunoglobulin-Associated TMA

• The monoclonal immunoglobulin may activate the alternative complement pathway, causing complement-mediated TMA 2
• Associated with multiple myeloma, Waldenström macroglobulinemia, or MGRS 2
• Requires correlation of kidney biopsy findings with serum/urine monoclonal protein studies 2
• Paraffin immunofluorescence may be needed to detect masked monoclonal deposits 2

Scleroderma Renal Crisis

• Part of the differential when MPGN pattern lacks immunoglobulin and C3 deposits 2
• Clinical features of systemic sclerosis guide diagnosis 1

Secondary TMA: Transplant-Related

Acute Antibody-Mediated Rejection

• Represents approximately 57% of TMA cases in transplant biopsies 7
• Requires C4d staining and donor-specific antibody testing for diagnosis 7

Calcineurin Inhibitor (CNI) Toxicity

• Accounts for approximately 43% of TMA in transplant biopsies 7
• Drug-mediated TMA diagnosis requires temporal relationship with CNI exposure 6
• Consider dose reduction or switch to mTOR inhibitor 6

Recurrent or De Novo aHUS in Transplant

• Renal transplantation may trigger aHUS recurrence or de novo disease 2
• Absence of marked thrombocytopenia or significant anemia should not exclude TMA diagnosis post-transplant (38% lack significant thrombocytopenia) 2

Secondary TMA: Drug-Induced

Common Offending Agents

• Calcineurin inhibitors (tacrolimus, cyclosporine) 6, 1
• Immune checkpoint inhibitors 4
• Chemotherapeutic agents 1
• Quinine, certain antibiotics 1

Critical Diagnostic Algorithm

Step 1: Confirm TMA on Biopsy

• Pathologic features include endothelial injury, mesangiolysis, glomerular capillary wall thickening with double contours, arteriolar mucoid intimal edema, and fibrin thrombi 8, 1
• Adopt the term "TMA features" when TMA-like changes accompany other glomerulopathies to prompt appropriate workup 8

Step 2: Assess for Systemic TMA

• Thrombocytopenia (<150,000/mm³ or 25% reduction) 2
• Microangiopathic hemolytic anemia: elevated LDH, reduced haptoglobin, elevated indirect bilirubin, negative Coombs test 2, 4
• Schistocytes on peripheral smear (>1%) 4
• Note: "Isolated renal TMA" can occur without systemic features, particularly in malignant hypertension and lupus nephritis 7

Step 3: Urgent ADAMTS13 Testing

• ADAMTS13 <10% = TTP; ADAMTS13 >10% = evaluate other causes 2, 3, 4
• Do not delay plasma exchange in adults with high clinical suspicion while awaiting results 4

Step 4: If ADAMTS13 >10%, Systematic Evaluation

• Blood pressure measurement and assessment for malignant hypertension 3
• Antiphospholipid antibody panel (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 2, 3
• Complement studies: C3, C4, genetic testing for complement regulatory proteins 2, 3
• Medication review for drug-induced causes 3, 6
• Stool studies if diarrheal prodrome (Shiga toxin, culture) 5
• Serum/urine protein electrophoresis and immunofixation for monoclonal gammopathy 2
• Pregnancy testing and timing if reproductive-age female 1

Step 5: Histologic Pattern Recognition

• Isolated arterial involvement: suggests malignant hypertension or postpartum TMA 7
• Both glomerular and arterial involvement: suggests aHUS or lupus nephritis with TMA 7
• MPGN pattern without immunoglobulin or C3: consider chronic TMA, transplant glomerulopathy, antiphospholipid syndrome, or malignant hypertension 2

Common Pitfalls to Avoid

• Do not assume absence of systemic features excludes TMA—isolated renal TMA occurs in malignant hypertension and lupus nephritis 7
• Do not rely on platelet count alone post-transplant—38% of transplant TMA cases lack significant thrombocytopenia 2
• Do not attribute TMA solely to hypertension without excluding primary causes—hypertension may be secondary to TMA rather than causative 7
• Do not delay genetic testing in aHUS—results inform prognosis, recurrence risk, and family counseling 2
• Do not overlook monoclonal gammopathy—always correlate biopsy with serum/urine studies when monoclonal protein detected 2