In a 27‑year‑old man with abdominal pain, weakness, pallor, pancytopenia, severe azotemia, metabolic acidosis, hypertension, indirect hyperbilirubinemia, markedly elevated aspartate aminotransferase, and normal abdominal ultrasound, what is the most likely diagnosis and appropriate management?

Thrombotic Microangiopathy (TMA) with Severe Renal Failure

Most Likely Diagnosis

This patient most likely has thrombotic microangiopathy (TMA), specifically atypical hemolytic uremic syndrome (aHUS) or malignant hypertension-induced TMA, given the constellation of pancytopenia, severe azotemia, indirect hyperbilirubinemia, markedly elevated AST, metabolic acidosis, and hypertensive episodes despite normal kidney size on imaging. 1

---

Diagnostic Reasoning

Key Clinical Features Supporting TMA

• Pancytopenia with hemolytic anemia – The combination of anemia, thrombocytopenia, and indirect hyperbilirubinemia indicates microangiopathic hemolytic anemia (MAHA), the hallmark of TMA 1

• Markedly elevated AST (>1000 IU/mL typical) – In TMA, AST elevation reflects both hemolysis (red cell AST release) and hepatic ischemia from microvascular thrombosis; this pattern mimics acute hepatitis but occurs without primary liver disease 2

• Severe azotemia with normal-sized kidneys – Creatinine values of 613→972→646→873 µmol/L (approximately 7-11 mg/dL) with preserved cortical thickness indicate acute intrinsic renal injury rather than chronic kidney disease 1

• Metabolic acidosis – Results from both renal failure (impaired acid excretion) and tissue hypoperfusion from microvascular thrombosis 3

• Hypertensive episodes – Malignant hypertension can trigger secondary TMA, or conversely, TMA itself causes severe hypertension through renal microvascular injury and renin-angiotensin activation 1

• No improvement with antibiotics and dialysis – The failure to respond to leptospirosis treatment and supportive care points away from infection and toward a primary microangiopathic process 1

---

Differential Diagnosis: TMA Subtypes

Atypical Hemolytic Uremic Syndrome (aHUS)

• Most likely in a young adult with acute TMA, severe renal failure, and no diarrheal prodrome 1

• Characterized by complement dysregulation leading to uncontrolled alternative pathway activation on endothelial surfaces 4

• Presents with the triad of MAHA, thrombocytopenia, and acute kidney injury – exactly matching this patient's presentation 1

• ADAMTS13 activity is preserved (>10%), distinguishing it from thrombotic thrombocytopenic purpura (TTP) 1

Malignant Hypertension-Induced TMA

• Should be considered given the documented hypertensive episodes 1

• Typically presents with extreme hypertension (systolic >200 mmHg), hypertensive retinopathy, relatively higher platelet counts (>30,000/µL), and preserved ADAMTS13 activity 1

• Responds to aggressive blood pressure control alone without plasma exchange or complement blockade 1

• However, this patient's persistent severe azotemia despite dialysis and the degree of pancytopenia suggest primary TMA (aHUS) rather than purely hypertension-driven disease 1

---

Immediate Diagnostic Workup

Essential Laboratory Tests

• Peripheral blood smear – Look for schistocytes (fragmented red cells), which confirm microangiopathic hemolysis 1

• ADAMTS13 activity and inhibitor – If activity <10%, diagnose TTP; if >10%, consider aHUS or secondary TMA 1

• Direct Coombs test – Should be negative in TMA (distinguishes from autoimmune hemolytic anemia) 1

• Haptoglobin – Expect undetectable levels due to intravascular hemolysis 1

• Lactate dehydrogenase (LDH) – Markedly elevated (often >1000 IU/L) from both hemolysis and tissue ischemia 1

• Reticulocyte count – Elevated, reflecting bone marrow response to hemolysis 1

• Serum creatinine and BUN trends – Already documented as severely elevated and worsening 5

Complement Studies (for aHUS)

• Serum C3 and C4 levels – May be low in complement-mediated aHUS 4

• Genetic testing for complement mutations – CFH, CFI, MCP, C3, CFB, THBD genes (results take weeks but guide long-term management) 4

Exclude Secondary Causes

• Stool culture and Shiga toxin assay – Rule out typical HUS (though no diarrhea makes this unlikely) 1

• HIV, hepatitis B/C, autoimmune serologies (ANA, anti-dsDNA) – Exclude infection-associated or autoimmune TMA 1

• Pregnancy test – Exclude HELLP syndrome or pregnancy-related TMA (though patient is male) 6

• Drug history review – Certain medications (quinine, cyclosporine, tacrolimus) can trigger TMA 1

---

Immediate Management

First-Line Therapy: Complement Blockade with Eculizumab

For suspected aHUS, initiate eculizumab (Soliris®) immediately without waiting for genetic confirmation, as delay worsens renal outcomes and mortality. 4

• Eculizumab is a humanized monoclonal antibody that blocks terminal complement (C5), preventing formation of the membrane attack complex 4

• Dosing regimen for adults:

  • Induction: 900 mg IV weekly × 4 weeks
  • Maintenance: 1200 mg IV at week 5, then 1200 mg every 2 weeks thereafter 4

• Meningococcal vaccination is mandatory before starting eculizumab (or give antibiotic prophylaxis if treatment cannot be delayed) 4

• Expected response: Platelet count recovery within 1-2 weeks, LDH normalization, and stabilization or improvement in renal function 4

• Duration of therapy: Continue indefinitely in most cases, as discontinuation risks relapse 4

Supportive Care

• Continue hemodialysis for severe azotemia, hyperkalemia, and metabolic acidosis until renal function recovers 1

• Blood pressure control – Target systolic <140 mmHg with ACE inhibitors or calcium channel blockers (avoid abrupt drops that worsen renal perfusion) 1

• Red cell transfusions – For symptomatic anemia (hemoglobin <7 g/dL or hemodynamic instability) 1

• Platelet transfusions – Avoid unless life-threatening bleeding, as platelets may worsen microvascular thrombosis 1

• Correct metabolic acidosis – Sodium bicarbonate if pH <7.15-7.20 with hemodynamic instability 3

• Avoid nephrotoxic agents – NSAIDs, aminoglycosides, contrast dye 1

Plasma Exchange (PLEX) Consideration

• If ADAMTS13 results are pending and TTP cannot be excluded, initiate daily plasma exchange (1.5 plasma volumes) with fresh frozen plasma replacement 1

• Once ADAMTS13 activity returns >10%, discontinue PLEX and focus on complement blockade 1

• PLEX alone is ineffective for aHUS and delays definitive therapy 1

---

Distinguishing aHUS from Malignant Hypertension-Induced TMA

Feature	aHUS	Malignant HTN-Induced TMA
Blood pressure	Variable, may be elevated	Extreme (systolic >200 mmHg) [1]
Hypertensive retinopathy	Absent or mild	Severe (papilledema, hemorrhages) [1]
Platelet count	Often <50,000/µL	Typically >30,000/µL [1]
ADAMTS13 activity	>10%	>10% [1]
Response to BP control	Minimal	Rapid improvement [1]
Renal biopsy	Thrombotic microangiopathy	Acute tubular necrosis + TMA [1]

In this patient, the severity of pancytopenia, persistent renal failure despite dialysis, and lack of documented extreme hypertension favor primary aHUS over secondary TMA. 1

---

Prognosis and Long-Term Management

Without Treatment

• Mortality or end-stage renal disease (ESRD) in >50% of aHUS patients within the first year 4

• Renal recovery is unlikely once dialysis-dependent for >3 months without complement blockade 4

With Eculizumab

• Approximately 90% achieve hematologic remission (platelet count >150,000/µL, LDH normalization) 4

• 60-70% achieve dialysis independence if treatment is started early 4

• Lifelong therapy is typically required, as discontinuation leads to relapse in 20-30% of cases 4

Monitoring

• Weekly CBC, LDH, creatinine during induction phase 4

• Every 2 weeks during maintenance therapy 4

• Annual complement genetic testing results guide family counseling and transplant planning 4

---

Critical Pitfalls to Avoid

• Do not delay eculizumab while awaiting genetic confirmation – Irreversible renal damage occurs within days to weeks 4

• Do not rely on plasma exchange alone for aHUS – It is ineffective and delays definitive therapy 1

• Do not assume leptospirosis or infection is the cause when antibiotics fail – Consider TMA in any patient with unexplained hemolytic anemia, thrombocytopenia, and acute kidney injury 1

• Do not attribute AST elevation solely to liver disease – In TMA, AST >1000 IU/L reflects hemolysis and microvascular ischemia, not hepatitis 2

• Do not overlook meningococcal vaccination – Eculizumab increases meningococcal infection risk 1000-2000-fold; vaccination is mandatory 4

• Do not stop eculizumab prematurely – Relapse risk is high, and repeat episodes cause cumulative renal damage 4

---

Summary Algorithm

1. Confirm TMA diagnosis: Peripheral smear (schistocytes), LDH, haptoglobin, reticulocyte count 1
2. Measure ADAMTS13 activity: If <10%, treat as TTP with PLEX; if >10%, proceed to step 3 1
3. Assess blood pressure and retinal exam: If extreme hypertension + severe retinopathy, aggressively control BP and monitor for improvement 1
4. If no improvement with BP control or if primary TMA suspected, initiate eculizumab immediately 4
5. Ensure meningococcal vaccination (or antibiotic prophylaxis) 4
6. Continue dialysis, transfuse RBCs as needed, avoid platelet transfusions unless bleeding 1
7. Monitor CBC, LDH, creatinine weekly during induction 4
8. Plan for lifelong eculizumab therapy and genetic counseling 4