Unveiling the Second Hit: Cytomegalovirus-Induced Collapsing Glomerulopathy in a Patient with Lupus

Introduction: Collapsing glomerulopathy (cGN) is a histological type of focal segmental glomerulosclerosis (FSGS) best described in association with human immunodeficiency virus (HIV). It has been increasingly seen in association with drugs, autoimmune disease, viruses (SARS-CoV2), and in rare cases, with cytomegalovirus (CMV). We present the case of a patient with lupus found to have cGN in the setting of CMV viremia. Case Description: A 33-year-old African American female with a history of biopsy-proven Class V lupus maintained on hydroxychloroquine and mycophenolate, presented with 1 week of dyspnea and fevers. Lab investigations revealed Serum Creatinine (Cr) of 2.7 mg/dL (baseline 1.1mg/dL), pancytopenia, low C3 (80mg/dL), and C4 (7mg/dL) with negative dsDNA. Urinalysis showed 5-10 RBC. Spot urine Protein/Cr ratio was 10 gm/gm. Her clinical course was complicated by diarrhea and worsening acute kidney injury (AKI) requiring dialysis. The etiology of AKI was initially thought to be a lupus flare, and a kidney biopsy was done. Biopsy showed podocyte hyperplasia, collapse of the underlying glomerular tuft with segmental glomerulosclerosis, 40% interstitial fibrosis, and tubular atrophy. No evidence of an active immune complex-mediated process was noted. Viral studies were positive for CMV (CMV DNA 1,310,085 IU/ml). The patient was started on high-dose steroids and valganciclovir while other immunosuppression was held. Discussion: cGN represents a variant of FSGS typically presenting with severe nephrosis and AKI. In our case, CMV likely acted as a ‘second hit’ with a possible underlying high-risk APOL-1 gene mutation, given her ancestry. The mechanism driving development of cGN has been proposed to be mediated by an interferon-chemokine pathway. Second hits such as HIV or SARS-CoV2 activate an inflammatory cascade that interacts with high-risk APOL-1 variants to precipitate cGN. Lupus has been associated with high interferon activity and thus may be another predisposing factor. CMV overall, remains a rare cause for cGN. While flares and class switching are sound differentials for AKI in lupus patients, this case highlights the importance of testing for CMV and considering cGN as a cause for AKI, especially in patients with African American ancestry. It further emphasizes the importance of ruling out opportunistic infections before preemptively adding more immunosuppression.