Thrombotic Renovascular Disorders¶
Chapter 329 | Part 9: Disorders of the Kidney and Urinary Tract · Part 9 – Renal & Urinary Tract Disorders · Chapter 329
Key Clinical Points¶
- TMA is characterized by endothelial cell injury in terminal arterioles/capillaries, platelet/hyaline thrombi, MAHA, thrombocytopenia, and schistocytes.
- TTP is defined as MAHA with ADAMTS13 activity <5–10%; iTTP is autoantibody-mediated, while cTTP (Upshaw-Schülman syndrome) is a congenital deficiency.
- STEC HUS is caused by Shiga toxins (Stx1/Stx2) binding to the glycolipid receptor globotriaosylceramide (Gb3), primarily affecting children <5 years old.
- aHUS results from complement dysregulation (low C3, normal C4), often due to Factor H deficiency; treated with eculizumab or ravulizumab.
- Scleroderma renal crisis features 'onion-skinning' intimal proliferation; ACE inhibitors are first-line therapy, reducing 3-year mortality from >90% to 30%.
- HELLP syndrome is distinguished from non-preeclampsia by an LDH:AST ratio of 13:1 (vs. 29:1) and ADAMTS13 activity of 30–60% (vs. <10% in TTP).
- APLS 'triple positive' status carries high risk; Warfarin (INR 2–3) is preferred over DOACs for arterial events.
- Renal vein thrombosis is often on the left, frequently bilateral (2/3), and is nearly 100% detectable via CT angiography.
- Sickle cell nephropathy involves vasa recta occlusion and prostaglandin dependence; ACE inhibitors reduce proteinuria; gene therapies were approved Dec 2023.
- Drug-induced TMA typically does not respond to plasma exchange; management focuses on discontinuing the agent and potentially using C5 inhibitors.
1. DEFINITION & OVERVIEW¶
• Thrombotic Microangiopathy (TMA): ◦ Definition: A pathologic lesion characterized by endothelial cell injury in terminal arterioles and capillaries. ◦ Histopathology: Includes swollen endocapillary cells (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis, and a membranoproliferative pattern in the glomerulus. ◦ Clinical Features: Typically accompanied by microangiopathic hemolytic anemia (MAHA) with thrombocytopenia and schistocytes.
• Hemolytic-Uremic Syndrome (HUS) & Thrombotic Thrombocytopenic Purpura (TTP): ◦ These are the prototype conditions for MAHA. ◦ HUS: More common in children; often associated with hemorrhagic diarrhea. ◦ TTP: More common in adults; historically associated with more neurologic complications. ◦ Note: Differentiation is now based on specific pathophysiology and etiology rather than just clinical presentation.
• Other TMA Variants: ◦ Sleroderma renal crisis (characterized by 'onion-skinning' intimal proliferation). ◦ Antiphospholipid syndrome (APLS). ◦ HELLP syndrome. ◦ Drug-induced TMA (two mechanisms: endothelial damage vs. autoantibody-mediated). ◦ Cancer-associated TMA. ◦ HIV-related TMA. ◦ Sickle cell nephropathy. ◦ Renal vein thrombosis.
2. EPIDEMIOLOGY¶
• STEC HUS: ◦ Primarily affects children <5 years old; however, adults are also susceptible (e.g., 2011 Northern Europe outbreak).
• TTP: ◦ More common in adults. ◦ Incidence is >9 times higher among blacks than nonblacks. ◦ iTTP incidence is ~3 times higher among women than men (approx. 2.9 cases/10^6 patients in the US).
• Scleroderma Renal Crisis: ◦ Occurs in 12% of patients with diffuse systemic sclerosis. ◦ Occurs in only 2% of those with limited systemic sclerosis.
• HELLP Syndrome: ◦ Occurs in 0.2–0.9% of all pregnancies. ◦ Occurs in 10–20% of women with severe preeclampsia.
• Antiphospholipid Syndrome (APLS): ◦ Leading cause of stroke in patients <45 years old.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• STEC HUS Pathogenesis: ◦ Mechanism: Shiga toxins (Stx1 and Stx2) bind to the glycolipid receptor globotriaosylceramide (Gb3) on renal microvasculature. ◦ Downstream Effects: Binding induces inflammatory cytokines (IL-8, MCP-1, SDF-1) and chemokine receptors (CXCR4, CXCR7) → platelet aggregation and microangiopathy. ◦ Alternative Path: Streptococcus pneumoniae can cause HUS via neuraminidase activity on platelets/endothelial cells.
• aHUS & Complement Dysregulation: ◦ Result of complement dysregulation (congenital or acquired). ◦ Markers: Low C3, normal C4 (indicative of alternative pathway activation). ◦ Factor H: Most common defect; >70 mutations identified. Factor H competes with factor B to prevent C3bBb formation and acts as a cofactor for factor I. ◦ DEAP HUS: Autoimmune variant involving autoantibodies to factor H, often associated with an 84-kb deletion of the CFHR1/CFHR3 locus.
• TTP Pathophysiology: ◦ Mechanism: Accumulation of ultra-large multimers of von Willebrand factor due to lack or reduced activity of protease ADAMTS13. ◦ Definition: MAHA associated with ADAMTS13 activity <5–10%. ◦ iTTP: Acquired via autoantibody against ADAMTS13 (IgG or IgM). ◦ cTTP (Upshaw-Schülman syndrome): Congenital deficiency of ADAMTS13; may present in infancy or adulthood (especially during pregnancy).
• Drug-Induced TMA: ◦ Type 1 (Endothelial Damage): Caused by chemotherapeutic agents (e.g., bortezomib, mitomycin C, gemcitabine) or immunosuppressives (cyclosporine, interferon, sirolimus, tacrolimus). Usually dose-dependent. ◦ Type 2 (Autoantibody-mediated): e.g., Quinine; not dose-dependent; more common in women.
• Cancer-Associated TMA: ◦ Mechanism: Tumor cell obstruction in microvasculature → cell fragmentation and platelet consumption.
• HIV-Related TMA: ◦ Associated with advanced AIDS and low CD4+ counts. ◦ Note: ADAMTS13 activity is NOT reduced; renal biopsy is required to rule out other concurrent diseases.
• Sickle Cell Nephropathy: ◦ Cause: Occlusion of vasa recta in the renal medulla due to HbS polymerization. ◦ Response: Kidney increases blood flow/GFR via prostaglandins; nonsteroidal NSAIDs may significantly reduce GFR.
4. CLINICAL FEATURES¶
• STEC HUS: ◦ Diarrhea (often bloody) preceding MAHA within 1 week in >80% of cases. ◦ Common: Abdominal pain, cramping, vomiting; fever usually absent. ◦ Neurologic: Dysphasia, hyperreflexia, blurred vision, encephalopathy, agraphia.
• TTP: ◦ Pentad: MAHA, thrombocytopenia, neurologic symptoms, fever, renal failure. ◦ Note: <5% of patients with iTTP exhibit the full pentad.
• Scleroderma Renal Crisis: ◦ Triad: AKI, abrupt hypertension, normal urine sediment. ◦ Other: Retinopathy, encephalopathy, pulmonary edema (from salt/water retention).
• HELLP Syndrome: ◦ Symptoms: Hemolysis, elevated liver enzymes, low platelets. ◦ Complications: Subcapsular hepatic hematomas, placental abruption, vision loss.
• Cancer-Associated TMA: ◦ Distinctive features: Bone pain and respiratory symptoms.
• HIV-Related TMA: ◦ Presentation: MAHA, thrombocytopenia, renal failure.
• Sickle Cell Nephropathy: ◦ Symptoms: Hyposthenuria, hematuria, papillary necrosis; proteinuria (20–30%).
• Renal Vein Thrombosis: ◦ Symptoms: Flank pain, tenderness, hematuria, rapid decline in renal function, or asymptomatic.
5. DIFFERENTIAL DIAGNOSIS¶
• HUS vs TTP: ◦ HUS: More common in children; associated with hemorrhagic diarrhea. ◦ TTP: More common in adults; higher incidence of neurologic complications.
• HELLP vs TTP: ◦ LDH:AST ratio: 13:1 (HELLP) vs 29:1 (non-preeclampsia). ◦ ADAMTS13 activity: <30–60% (HELLP) vs <10% (TTP).
• Scleroderma Renal Crisis vs Malignant Hypertension: ◦ Histologically indistinguishable; both feature fibrinoid necrosis and thrombosis.
• Cancer-Associated TMA vs TTP: ◦ Cancer-associated: More bone pain/respiratory symptoms; no response to PEX or steroids.
• HIV-Related TMA vs TTP: ◦ HIV-related: ADAMTS13 activity is NOT reduced; requires biopsy to rule out other renal diseases.
6. INVESTIGATIONS & DIAGNOSIS¶
• General Laboratory Workup: 1. CBC (Hb, platelets, reticulocytes) and LDH/Haptoglobin for hemolysis. 2. Coombs test (direct/indirect) to rule out autoimmune hemolysis. 3. ADAMTS13 activity: <5–10% confirms TTP. 4. Complement levels: Low C3, normal C4 indicates aHUS. 5. LDH:AST ratio: 13:1 suggests HELLP; 29:1 suggests non-preeclampsia.
• Imaging for Renal Vein Thrombosis: 1. Doppler ultrasonography (more sensitive than standard ultrasound). 2. CT angiography (CTA) → nearly 100% sensitive.
• Renal Biopsy: 1. Required for HIV-related TMA to differentiate from other renal diseases. 2. Used when thrombocytopenia allows the procedure.
• Specialized Criteria (Table 329-1): Criteria for HSCT-TMA include: 1. >4% schistocytes in the blood. 2. De novo, prolonged, or progressive thrombocytopenia. 3. A sudden and persistent increase in LDH. 4. Decrease in haptoglobin concentration.
• APLS Diagnosis: 1. Identify 'triple positive' (lupus anticoagulant, anti-β2GPI, anticardiolipin).
7. MANAGEMENT & TREATMENT¶
• TTP Treatment: 1. Plasma exchange. 2. Steroids/Immunosuppression (for iTTP).
• aHUS Treatment: 1. C5 inhibitors (e.g., eculizumab, ravulizumab).
• STEC HUS Treatment: 1. Supportive care (standard for HUS).
• Drug-Induced TMA Treatment: 1. Discontinue the offending agent. 2. If refractory: Trial of C5 inhibitors.
• Scleroderma Renal Crisis Treatment: 1. ACE inhibitors (First-line therapy).
• APLS Treatment: 1. Warfarin (INR 2–3) preferred over DOACs for arterial events.
• HELLP Syndrome Treatment: 1. Delivery is the key management step.
• Cancer-Associated TMA Treatment: 1. Treat underlying malignancy (no PEX or steroids).
• Sickle Cell Nephropathy Treatment: 1. ACE inhibitors to reduce proteinuria.
• Renal Vein Thrombosis Treatment: 1. Anticoagulation.
8. PROGNOSIS & COMPLICATIONS¶
• TTP Mortality: High without treatment; risk of neurologic damage.
• HSCT-TMA Mortality: 1. 75% mortality within 3 months. 2. Plasma exchange benefit is limited in <25% of cases.
• Scleroderma Renal Crisis Prognosis: 1. ACE inhibitors reduce mortality from >90% to 30% at 3 years.
• HELLP Syndrome Mortality: High risk of pulmonary edema, bleeding, and fetal demise.
• Sickle Cell Nephropathy Progression: 1. Progresses to renal failure if proteinuria is in the nephrotic range.
9. SPECIAL CONSIDERATIONS¶
• Pregnancy (HELLP/TTP): 1. HELLP: 20% occur before week 28; 30% occur postpartum. 2. TTP can be triggered by pregnancy; check for APLS history.
• HSCT-TMA: 1. Use Table 329-1 criteria (Schistocytes >4%, LDH increase, Haptoglobin decrease).
• Cancer: 1. Cancer-associated TMA: No role for PEX or steroids; treat primary malignancy.
• HIV: 1. Renal biopsy required to differentiate from other renal diseases.
• Scleroderma: 1. ACE inhibitors are critical for survival in renal crisis.
• Sickle Cell: 1. Prostaglandin dependence; NSAIDs may reduce GFR significantly.
• Renal Vein Thrombosis: 1. CTA is nearly 100% sensitive for diagnosis.
10. KEY PEARLS & CLINICAL TRAPS¶
• TTP Diagnosis: Must check ADAMTS13 activity (<5–10%). • HELLP vs TTP: Use LDH:AST ratio (13:1 in HELLP) and ADAMTS13 levels (30–60% in HELLP vs. <10% in TTP). • Scleroderma Crisis: ACE inhibitors are the cornerstone of treatment. • Drug-Induced TMA: Stop the drug first; PEX is often ineffective. • Renal Vein Thrombosis: CTA is nearly 100% sensitive for diagnosis. • APLS: Warfarin (INR 2–3) is preferred over DOACs for arterial events.
Reference Tables¶
TABLE 329-1 Criteria for Establishing Microangiopathic Kidney Injury Associated with Hematopoietic Stem Cell…¶
Harrison's 22e, p.2445
| INTERNATIONAL WORKING GROUP |
BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK TOXICITY COMMITTEE |
|---|---|
| >4% schistocytes in the blood | RBC fragmentation and at least 2 schistocytes per high-power field |
| A sudden and persistent increase in LDH |
Negative direct and indirect Coombs test |
| Decrease in haptoglobin concentration |