Contributed by Gaurav Kattel, MBBS, MD and Parmjeet S. Randhawa, MDFINAL DIAGNOSIS
Focal Segmental Glomerulosclerosis, not specified with EBV (Epstein Barr Virus) associated interstitial nephritis.
DISCUSSION
The patient had several risk factors for focal segmental glomerulosclerosis (FSGS), which explained the proteinuria. FSGS is a diverse syndrome that arises after podocyte injury from diverse causes. HIV infection and obesity are risk factors associated with FSGS. APO-L1(Apolipoprotein L1) genetic variants have also been associated with FSGS and is seen commonly in individual of Sub-Saharan African descent. APO-L1 status was not known for this patient but approximately one third of FSGS in the United States is associated with APO-L1 variants[1]. Although an attenuated form of the disease could not be excluded, HIV associated nephropathy was unlikely since collapsing lesions were not seen, and tubular microcystic change was not a very prominent finding. Moreover, the patient was on anti-retroviral drugs and had an undetectable viral load for many years. In-situ hybridization for COVID-19 RNA was also negative, and the patient did not receive oxygen or steroids for his respiratory symptoms.
Electron microscopy showed tubulo-reticular inclusions and electron dense deposits in the mesangial compartment and in the tubular basement membranes. The appearances suggested immune complex glomerulonephritis of infectious or autoimmune origin. Immunofluorescence did not show any staining for IgG or IgA but mesangial staining for IgM, C1q and C3 was present in glomeruli that also showed segmental sclerosis. These glomerular changes were occurring in the setting of advanced interstitial fibrosis tubular atrophy and glomerulosclerosis, which reflected severe chronic kidney disease.
The diffuse tubulointerstitial nephritis may have been the morphologic correlate for the elevated serum creatinine. Most often this inflammation is a manifestation of infection or drug reaction [2, 3]. HIV infection can per se result in a plasma cell rich infiltrate or a CD8 dominant diffuse interstitial lymphocytosis in the interstitial compartment. Another confounding factor in this biopsy was the presence of EBER RNA positive cells. This suggested an element of Epstein-Barr virus associated interstitial nephritis, possibly as a part of a systemic viral syndrome with tonsillitis, lymphadenitis, splenomegaly and hepatitis. Alternately, the Epstein-Barr virus infected cells could have reflected an increase in circulating viral load and represented a risk factor for the development of lymphoproliferative disease[4, 5].
EBV is widespread in individuals where it exists as an asymptomatic latent infection. They are subjected to T cell mediated immune control and individuals with profound T cell impairment are at an elevated risk of developing an EBV-positive B-lymphoproliferative disease[5]. Classically seen in two immunocompromised settings (stem cell/solid organ transplant recipients and HIV positive patients), these EBV-positive B-lymphoproliferative lesions are often oligoclonal in origin and present at different sites[6]. An oligoclonal/polyclonal B cell expansion with antibody formation and immune complex deposition could explain the electrodense deposits in the electron micrograph. In HIV positive patients, the lesion may resemble post-transplant lymphoproliferative disorder that appears as polymorphic lymphoid proliferations[7]. These lesions are less common than in the post-transplant setting, accounting for less than 5% of HIV-associated lymphomas. Like other HIV-related non-Hodgkin lymphomas, their mean age at presentation is 38 years. They may present at nodal and extra nodal sites and conform to the criteria of polymorphic B-cell post-transplant lymphoproliferative disorder. The infiltrates have a range of lymphoid cells, from small cells (often with plasmacytoid features) to immunoblasts, with scattered large, bizarre cells expressing CD30. EBV is often present, but some cases are EBV-negative. A clonal B-cell population is present in most cases, and there may be an oligoclonal background, suggesting variable numbers of clonal cells within a polymorphic background[7]. Thus, serial monitoring for Epstein-Barr virus DNA is usually considered in such circumstances to rule out the development of an EBV-positive B-lymphoproliferative disease.
REFERENCES
Contributed by Gaurav Kattel, MBBS, MD and Parmjeet S. Randhawa, MD
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