Secondary Hemophagocytic Lymphohistiocytosis-Induced Podocytopathy with High-Risk APOL1 Alleles

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by a dysregulated inflammatory cascade resulting in widespread damage to various organ systems. HLH may occur due to genetic mutations (primary) or be triggered by other conditions (secondary), including malignancies, infections, and autoimmune diseases. Kidney involvement in HLH can occur due to multiple factors, such as hypoperfusion and immune-mediated nephritis. We present a case of secondary HLH triggered by a recurrent B-cell lymphoma in a patient with two high-risk APOL1 alleles, leading to acute kidney injury due to podocytopathy. Case Description: A 30-year-old Cameroonian man with a history of B-cell lymphoma, reportedly in remission, presented with fever, anasarca and diffuse abdominal pain. Serum creatinine was 4.55 mg/dL without prior kidney disease and urine spot protein to creatinine ratio of >4.4 g/g. Imaging showed a 3cm hepatic lesion and large echogenic kidneys. Kidney biopsy showed podocytopathy with focally prominent visceral epithelial cells, suggestive of collapsing glomerulopathy, and acute tubular injury. Anuria and severe metabolic acidosis led to dialysis initiation on day six. Further workup showed ferritin >100000 ng/ml and soluble CD25 >95000 pg/ml (normal <858). Hepatic biopsy confirmed recurrent B-cell lymphoma and bone marrow showed lymphoma and hemophagocytosis. He met HLH-2004 criteria (H-score 239). Unfortunately, despite chemotherapy, his condition deteriorated, and he passed away. Genetic testing showed homozygosity for APOL1 G1 risk allele. Discussion: This case demonstrates podocytopathy with collapsing glomerulopathy (CG) in a patient with secondary HLH and APOL1 G1 homozygosity. The two-hit model, where interferon-driven APOL1 overexpression accelerates CG during hyperinflammatory states, is well supported. Our case uniquely highlights malignancy-associated hypercytokinemia as a potent “second hit” alongside genetic susceptibility, and emphasizes cytokine-mediated podocyte injury across etiologies of HLH.