When the Macrophage Eats and the Podocyte Leaks: Biopsy-Proven Podocytopathy in Hemophagocytic Lymphohistiocytosis

Introduction: Kidney injury in hemophagocytic lymphohistiocytosis (HLH) is typically tubular or thrombotic. Biopsy-proven minimal change disease (MCD) is exceedingly rare. Case Description: A 59-year-old man presented with fever, night sweats, and diarrhea. Laboratory testing revealed pancytopenia, ferritin 65,358 ng/mL, triglycerides 631 mg/dL, fibrinogen 96 mg/dL, and rapidly rising creatinine (up to 11.3 from baseline 1.0 mg/dL) with oliguria and 8 g/g proteinuria. Bone-marrow biopsy showed hemophagocytosis without clonal blasts, and flow cytometry confirmed polytypic lymphocytes. These findings that, together with high soluble IL-2R, satisfied HLH criteria in the setting of high-grade EBV viremia. The severity of nephrotic-range proteinuria prompted a kidney biopsy despite the patient’s critical illness. Light microscopy demonstrated acute tubular injury without endocapillary hypercellularity or immune deposits, and immunofluorescence was negative. Electron microscopy showed global, diffuse podocyte foot-process effacement and no hemophagocytic or immune-complex lesions. High-dose dexamethasone, intravenous immunoglobulin, rituximab, and subsequent IL-1 blockade (anakinra) were initiated to dampen the cytokine storm thought to underlie both HLH and secondary podocytopathy. Nonetheless, the patient remained dialysis-dependent. His course was complicated by retroperitoneal hemorrhage, angioinvasive aspergillosis, and refractory shock, culminating in death on day 24. Autopsy confirmed persistent HLH without alternative glomerular pathology. Discussion: Marked proteinuria in HLH should not be dismissed as “overflow” but triggers biopsy even in unstable patients, because unexpected glomerular lesions can alter management. The global podocyte injury supports an emerging concept of “cytokine-storm MCD,” in which IL-2 and IFN-γ excess directly injure podocytes. Outcomes hinge on rapid control of the hyperinflammatory state. Traditional MCD therapies are insufficient when the inciting cytokine surge persists. Earlier or broader cytokine-directed therapy may be necessary to preserve renal function and improve survival in this rare overlap syndrome.