Thrombotic Renovascular Disorders¶

Chapter 329 | Part 9: Disorders of the Kidney and Urinary Tract

KEY CLINICAL POINTS¶

Thrombotic microangiopathy (TMA) is characterized by endothelial injury, platelet/ hyaline thrombi, and microangiopathic hemolytic anemia (MAHA) with thrombocytopenia and schistocytes.
Hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are prototypes of microangiopathic hemolytic anemia (MAHA), with distinct etiologies and pathophysiology.
Complement dysregulation (e.g., factor H deficiency) and ADAMTS13 deficiency are central to atypical HUS (aHUS) and TTP, respectively.
Renal vein thrombosis is a critical differential in patients with acute kidney injury, with risk factors including nephrotic syndrome, hypercoagulable states, and venous stasis.
Management of TMA includes plasma exchange, anticoagulation, and targeted therapies (e.g., eculizumab, caplacizum, rituximab) depending on the underlying cause.

1. DEFINITION & OVERVIEW¶

Thrombotic microangiopathy (TMA) is a pathologic lesion characterized by endothelial cell injury in terminal arterioles and capillaries, with platelet/hyaline thrombi causing partial/complete occlusion. TMA is associated with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and schistocytes. Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are prototypical TMA disorders. Renal involvement is common, with features such as glomerular collapse, cortical necrosis, and focal segmental glomerulosclerosis.

Table 329-1: Criteria for Establishing Microangiopathic Kidney Injury Associated with Hematopoietic Stem Cell Transplantation¶

Criteria	Description
>4% schistocytes in the blood	RBC fragmentation and at least 2 schistocytes per high-power field
Concurrent increase in LDH above baseline	De novo, prolonged, or progressive thrombocytopenia
Negative direct and indirect Coombs test	Decrease in haptoglobin concentration
Decrease in hemoglobin or increased RBC transfusion requirement	Concurrent renal and/or neurologic dysfunction

1.1 Thrombotic Microangiopathy (TMA)¶

TMA is defined by endothelial injury, platelet/hyaline thrombi, and MAHA. It can occur in various contexts, including TTP, HUS, cancer-associated TMA, and antiphospholipid syndrome (APLS).

1.2 Renal Involvement¶

Renal manifestations include glomerular collapse, cortical necrosis, and focal segmental glomerulosclerosis. TMA in the kidney is often associated with acute kidney injury, hypertension, and proteinuria.

2. EPIDEMIOLOGY¶

TMA is a rare but severe condition with varying prevalence depending on the underlying cause. Hemolytic-uremic syndrome (HUS) and TTP are more common in children and adults, respectively. Cancer-associated TMA is linked to malignancies, while antiphospholipid syndrome (APLS) is more prevalent in women. Scleroderma renal crisis occurs in 12% of patients with diffuse systemic sclerosis. HELLP syndrome affects 0.2–0.9% of pregnancies, with higher rates in severe preeclampsia.

2.1 HUS/TTP¶

HUS is more common in children (<5 years), while TTP is more prevalent in adults. Atypical HUS (aHUS) can present in adulthood with neurologic involvement.

2.2 Cancer-Associated TMA¶

Cancer-associated TMA is linked to solid and hematologic malignancies. It is more common in patients with advanced malignancies and poor prognosis.

2.3 APLS and Scleroderma¶

APLS is more prevalent in women, with a 3:1 female-to-male ratio. Scleroderma renal crisis occurs in 12% of diffuse systemic sclerosis patients.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

TMA arises from endothelial injury, platelet activation, and microvascular thrombosis. Key mechanisms include complement dysregulation (aHUS), ADAMTS13 deficiency (TTP), endothelial damage (cancer, HIV, sickle cell disease), and hypercoagulable states (APLS, nephrotic syndrome).

3.1 Complement Dysregulation¶

Atypical HUS (aHUS) is caused by complement dysregulation (e.g., factor H deficiency, mutations in CFH, CFHR1/3). This leads to uncontrolled C3 convertase formation and glomerular injury.

3.2 ADAMTS13 Deficiency¶

TTP is caused by ADAMTS13 deficiency (congenital or acquired), leading to ultra-large von Willebrand multimers and microvascular thrombosis.

3.3 Endothelial Injury¶

Endothelial damage from infections (e.g., Shiga toxin-producing E. coli), toxins, or autoimmune conditions (e.g., HIV, sickle cell disease) triggers TMA.

4. CLINICAL FEATURES¶

Clinical features include MAHA (thrombocytopenia, schistocytes), acute kidney injury, hypertension, proteinuria, and neurological symptoms (e.g., encephalopathy, seizures). HELLP syndrome presents with hemolysis, elevated liver enzymes, and thrombocytopenia. Scleroderma renal crisis is marked by acute kidney injury, hypertension, and normal urine sediment.

4.1 HUS/TTP¶

HUS: Diarrhea, abdominal pain, neurological symptoms (e.g., encephalopathy). TTP: Neurologic symptoms, fever, renal failure, and thrombocytopenia.

4.2 HELLP Syndrome¶

Hemolysis, elevated liver enzymes, thrombocytopenia, and fetal demise. Often associated with preeclampsia or eclampsia.

4.3 Scleroderma Renal Crisis¶

Acute kidney injury, abrupt hypertension, normal urine sediment, and retinopathy/encephalopathy.

5. DIFFERENTIAL DIAGNOSIS¶

Differential diagnoses include other causes of MAHA (e.g., disseminated intravascular coagulation, drug-induced TMA), acute kidney injury from other etiologies (e.g., glomerulonephritis, interstitial nephritis), and systemic vasculitis. HELLP syndrome must be differentiated from preeclampsia and aHUS.

5.1 HUS vs. TTP¶

HUS: Diarrhea, abdominal pain, more common in children. TTP: Neurologic symptoms, fever, more common in adults.

5.2 HELLP vs. Preeclampsia¶

HELLP: Thrombocytopenia, elevated liver enzymes, and fetal demise. Preeclampsia: Hypertension, proteinuria, but no thrombocytopenia or elevated liver enzymes.

6. INVESTIGATIONS & DIAGNOSIS¶

Diagnostic workup includes CBC, peripheral blood smear (schistocytes), renal function tests, urinalysis, and specific tests for complement factors (e.g., C3, C4, factor H), ADAMTS13 activity, and antiphospholipid antibodies. Flow cytometry and genetic testing may identify mutations in CFH, CFHR1/3, or ADAMTS13.

6.1 Laboratory Tests¶

CBC, peripheral blood smear, LDH, creatinine, urinalysis, ADAMTS13 activity, complement factors (C3, C4), antiphospholipid antibodies, and genetic testing for CFH/CFHR mutations.

6.2 Imaging¶

Doppler ultrasound, CT angiography, or MRI for renal vein thrombosis. Renal biopsy may be required for scleroderma renal crisis or aHUS.

7. MANAGEMENT & TREATMENT¶

Management depends on the underlying cause. TTP and aHUS are treated with plasma exchange, corticosteroids, and targeted therapies (e.g., eculizumab, caplacizumab). Cancer-associated TMA requires treatment of the underlying malignancy. APLS is managed with anticoagulation (warfarin, DOACs), and scleroderma renal crisis is treated with ACE inhibitors.

7.1 TTP and aHUS¶

Plasma exchange, corticosteroids, and eculizumab/caplacizumab. For cTTP, plasma transfusion is critical. For iTTP, rituximab or C5 inhibitors may be used.

7.2 Cancer-Associated TMA¶

Treatment of the underlying malignancy, with supportive care for renal failure. Avoid ACE inhibitors in patients with severe renal impairment.

8. PROGNOSIS & COMPLICATIONS¶

Prognosis varies by condition. TTP has a mortality rate >90% without treatment. Scleroderma renal crisis has a 30% survival rate with ACE inhibitors. HELLP syndrome has a mortality rate of 7.4–34%. Complications include renal failure, cerebral infarction, and fetal demise.

8.1 TTP¶

Without treatment, mortality exceeds 90%. With modern therapy, 20% die within the first month from microvascular complications.

8.2 Scleroderma Renal Crisis¶

Mortality rate drops to 30% at 3 years with ACE inhibitors. Nearly two-thirds may require dialysis, with 50% recovery of renal function.

8.3 HELLP Syndrome¶

Mortality rate of 7.4–34%. Complications include maternal and fetal mortality, liver rupture, and pulmonary edema.

9. SPECIAL CONSIDERATIONS¶

Special considerations include pregnancy (HELLP syndrome, APLS), pediatric populations (Mesoamerican nephropathy, STEC HUS), and elderly patients (scleroderma renal crisis). HIV-related TMA is more common in women with low CD4+ counts. Sickle cell nephropathy requires monitoring for hypertension and proteinuria.

9.1 Pregnancy¶

HELLP syndrome and APLS are pregnancy-related. Management includes prompt delivery and anticoagulation. ACE inhibitors are contraindicated in pregnancy.

9.2 Sickle Cell Disease¶

Sickle cell nephropathy is associated with hyposthenuria, hematuria, and papillary necrosis. ACE inhibitors reduce proteinuria but may worsen renal function.

10. KEY POINTS & CLINICAL PEARLS¶

Key points: TMA is a clinical syndrome with diverse etiologies (e.g., HUS, TTP, APLS). Diagnosis requires ruling out other causes of MAHA. Treatment is tailored to the underlying mechanism (e.g., plasma exchange for TTP, eculizumab for aHUS). Renal vein thrombosis requires anticoagulation and management of underlying conditions. Early recognition and intervention are critical to improve outcomes.