COLLAPSING GLOMERULOPATHY AND HISTIOCYTIC INFLAMMATION IN A PATIENT WITH STXBP2 MUTATION.

Introduction:

A 4-year-old female presented with multiple episodes of vomiting and diarrhea, decreased activity, fatigue, and loss of appetite. She was febrile on admission and test for rhino/enterovirus positive. Evaluation showed evidence of nephrotic syndrome, transaminitis, hyperinflammatory state, and cytokine storm.

Methods:

A kidney biopsy was performed due to the presence of nephrotic syndrome. The biopsy was processed per usual protocol using, Light, Immunofluorescence and electron Microscopy (LM, IF, EM).

Results:

23 glomeruli were noted, 6-7 of which per section showed features of collapsing glomerulopathy with variable wrinkling/collapse of the glomerular capillary tufts (Fig: 1A and B), podocyte hyperplasia/ hypertrophy, prominent vacuoles and cytoplasmatic protein droplets. Renal tubules showed prominent intracytoplasmic protein and lysozyme droplets, and some with microcystic dilatation. The interstitium and some glomerular capillaries showed several large-sized, ovoid to spindle-shaped cells with prominent nuclei and eosinophilic cytoplasm with intracytoplasmic droplets. These cells were admixed with mixed inflammatory infiltrate including lymphocytes and rare trickling neutrophils. IF was negative for any immune complex deposition. IHC stains showed the large cells to stain with CD163 (Fig 2A) and PU.1 (Fig 2B) highlighting histiocyte lineage. Muramidase-positive lysozyme granules (Fig 2C) were noted in the tubular epithelial cells and histiocytes. EM showed severe foot process effacement, but no evidence of any electron-dense deposits. Concurrent Bone marrow biopsy and mesenteric lymph node biopsy were negative for the presence of any malignancy.

Conclusions:

A diagnosis of Hemophagocytic Lymphohistiocytosis (HLH) associated nephropathy was made. Further evaluation revealed the presence of STXBP2 mutation, which is associated with a predisposition to autosomal recessive familial HLH type 5. This missense mutation replaces glycine with serine, disrupting the biophysical properties of the STXBP2 protein molecule. She was treated with anakinra, steroids, and cyclosporine, as well as Tylenol for fever. At discharge she was afebrile, and with normal range vital signs, on amlodipine.

Clinically HLH presents with symptoms of extreme inflammation, prolonged fever, and hepatosplenomegaly. The diagnosis is made in the presence of other well-established lab data including hypertriglyceridemia, hypofibrinogenemia, Ferritin ≥500 μg/L, Soluble IL-2 receptor ≥2,400 U/mL etc. Activation of cytotoxic T-cells and macrophages causes phagocytosis of circulating cells, variable cytopenias, endocapillary proliferation, and crescents leading to active glomerulitis. Biological relatives (not tested in this patient) have a chance of being a carrier or at risk for HLH. The presence of concomitant autoimmune disease, infections, and/or malignancy may act as a second hit in the setting of a genetic predisposition. AKI exacerbates the comorbidity, thus highlighting the need for better understanding of the underlying mechanisms of kidney dysfunction.

High mortality (20-50%) is reported with HLH. Therefore, kidney biopsy should be considered early in the setting of HLH as a subset of patients may have pathologic findings other than ATI that could result in renal dysfunction and could potentially be amenable to clinical treatment.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.