What is the differential diagnosis for a 50-year-old male with retroviral infection, severe anemia, impaired renal function, and leg swelling?

Differential Diagnosis for HIV-Infected Patient with Severe Anemia, Renal Impairment, and Leg Swelling

The most critical differential diagnoses to consider in this 50-year-old HIV-positive male with severe anemia (Hb 6.5 g%), leukopenia, acute kidney injury (creatinine 2.9), and unilateral leg swelling are: HIV-associated thrombotic microangiopathy (TMA), HIV-associated nephropathy (HIVAN), parvovirus B19-induced pure red cell aplasia, and HIV immune complex glomerulonephritis. 1, 2

Primary Hematologic Differentials

HIV-Associated Thrombotic Microangiopathy

• TMA should be the first consideration given the triad of severe anemia, renal dysfunction, and potential microangiopathic process 1, 3, 2
• Obtain peripheral blood smear immediately to identify schistocytes (>1% supports TMA diagnosis) 3, 4, 5
• Check platelet count urgently—thrombocytopenia combined with hemolytic anemia and renal failure strongly suggests TMA 3, 4, 2
• Measure LDH, haptoglobin, indirect bilirubin, and reticulocyte count to confirm hemolysis 3, 5
• Order ADAMTS13 activity level stat to exclude thrombotic thrombocytopenic purpura (TTP), which requires immediate plasma exchange 3, 5
• HIV-associated TMA occurs independently of CD4 count and can present even with undetectable viral loads 2

Parvovirus B19-Induced Pure Red Cell Aplasia

• This diagnosis is critical because it is highly treatable with intravenous immunoglobulin and predominantly occurs in advanced immunodeficiency 6, 7
• The combination of severe normocytic anemia with absent or extremely low reticulocytes in an afebrile HIV patient without renal dysfunction suggests B19-PRCA 6, 7
• Order parvovirus B19 DNA PCR on serum or bone marrow—serological methods (IgM/IgG) are unreliable in HIV patients due to lack of antibody production 6, 7
• Bone marrow biopsy showing PRCA with giant pronormoblasts confirms diagnosis 6, 8
• Most patients with CD4+ counts ≤100 cells/mm³ relapse within 6 months after initial IVIg therapy and require maintenance treatment 6

Drug-Induced Bone Marrow Suppression

• Zidovudine causes dose-dependent bone marrow suppression leading to anemia and leukopenia 9, 6
• Ganciclovir (used for CMV prophylaxis/treatment) causes significant myelosuppression 1
• Trimethoprim-sulfamethoxazole (Pneumocystis prophylaxis) can cause cytopenias 1
• Review all current antiretroviral and prophylactic medications 1

Renal-Based Differentials

HIV-Associated Nephropathy (HIVAN)

• HIVAN with collapsing focal segmental glomerulosclerosis remains prevalent despite antiretroviral therapy and can present with acute kidney injury 1
• Obtain urinalysis looking for proteinuria (typically nephrotic-range in HIVAN) and microscopic hematuria 1
• Check spot urine protein-to-creatinine ratio 1
• Kidney biopsy is essential when feasible to distinguish HIVAN from other HIV-related kidney diseases, as pathological diagnosis guides therapy 1
• APOL1 high-risk variants (G1, G2) are strong predictors of HIVAN in patients of African ancestry 1

HIV Immune Complex Glomerulonephritis

• The spectrum includes IgA nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, and lupus-like GN 1, 2
• These conditions can occur even with undetectable viral loads and adequate antiretroviral therapy 1
• Check complement levels (C3, C4, CH50) to evaluate for complement-mediated disease 1, 4
• Obtain cryoglobulins, as cryoglobulinemic glomerulonephritis can occur with HIV 1
• Hepatitis C coinfection increases risk of immune complex disease—check HCV antibody and RNA if positive 1

Acute Tubular Necrosis from Sepsis

• Given the six-week fever history and previous cellulitis treatment, ongoing infection with sepsis-induced ATN is possible 1
• Check procalcitonin and C-reactive protein to assess for bacterial infection 1
• Blood cultures should be obtained if fever persists 1
• Consider occult infections: tuberculosis, disseminated fungal infections, or bacterial endocarditis 1

Additional Critical Differentials

Hemophagocytic Lymphohistiocytosis (HPS)

• HPS presents with fever, cytopenias, hepatosplenomegaly, and can occur with viral infections (CMV, EBV, HHV-6/8) or opportunistic infections in HIV patients 1
• Check ferritin (markedly elevated), triglycerides, fibrinogen (low), and soluble IL-2 receptor 1
• Bone marrow biopsy shows hemophagocytosis 1
• This carries poor prognosis and requires urgent recognition 1

Opportunistic Infections Causing Cytopenias

• CMV infection commonly causes anemia and can involve multiple organ systems including kidneys 1
• Check CMV PCR (viral load) in blood 1
• Disseminated Mycobacterium avium complex (MAC) causes fever, anemia, and cytopenias 1
• Consider mycobacterial blood cultures 1

Medication-Induced Thrombotic Microangiopathy

• Calcineurin inhibitors (if patient received transplant or other indication) can cause TMA 1, 5
• Review complete medication history for quinine, certain antibiotics, and chemotherapy agents 5

Diagnostic Algorithm

Immediate Priority Tests (Stat):

1. Peripheral blood smear for schistocytes and red cell morphology 3, 5
2. ADAMTS13 activity level 3, 5
3. Complete blood count with differential and platelet count 3, 5
4. Reticulocyte count 3, 5
5. LDH, haptoglobin, indirect bilirubin 3, 5
6. Direct antiglobulin test (Coombs) to exclude immune hemolysis 3

Urgent Tests (Within 24 Hours):

1. Parvovirus B19 DNA PCR 6, 7
2. Urinalysis with microscopy and urine protein-to-creatinine ratio 1
3. Complement levels (C3, C4, CH50) 1, 4
4. Cryoglobulins 1
5. CMV PCR (viral load) 1
6. Blood cultures if febrile 1
7. Hepatitis B and C serologies 1

Consider Based on Initial Results:

1. Kidney biopsy if proteinuria present or TMA suspected 1, 2
2. Bone marrow biopsy if reticulocyte count extremely low or pancytopenia unexplained 6, 8, 7
3. Ferritin, triglycerides, fibrinogen, soluble IL-2 receptor if HPS suspected 1
4. Mycobacterial blood cultures if prolonged fever 1

Critical Pitfalls to Avoid

• Do not delay plasma exchange if ADAMTS13 activity returns <10%—this is life-saving for TTP 3, 5
• Do not rely on parvovirus B19 serology (IgM/IgG)—use DNA PCR only, as HIV patients often lack antibody response 6, 7
• Do not transfuse platelets in suspected TMA unless life-threatening bleeding occurs, as this may worsen thrombosis 3, 5
• Do not attribute all findings to "HIV-related anemia of chronic disease" without excluding treatable causes 6, 7
• Do not assume undetectable viral load excludes HIV-specific kidney disease—HIVAN and immune complex GN occur despite adequate antiretroviral therapy 1