CTLA-4 Haploinsufficiency Presenting with IgA Nephropathy

Introduction: The regulatory mechanisms governing activation and inhibition of the immune response are orchestrated by key molecules. Derangements in CTLA-4 activity can lead to loss of T cell suppression with a resulting hyperinflammatory state, with manifestations of recurrent infections, lymphoproliferation, cytopenias, and liver/lung infiltration. Case Description: A 25yr South Asian Woman with CTLA4 immune dysregulation syndrome, managed with monthly abatacept (anti CD80/CD86) and IVIg infusions for 5 years, presented with new onset cytopenia, hypertension, acute kidney injury, Cr 3 mg/dL (baseline 1 mg/dl), proteinuria of 1 g/g and an active urine sediment with acanthocytes, red blood cell casts. Serologic workup and cultures were negative. Kidney biopsy showed IgA Nephropathy (IgAN) with 25% crescentic lesions. The etiology of the IgAN was most likely secondary to her immune dysregulation syndrome, given the concomitant cytopenias and profound upregulation of inflammatory markers, rather than the effect of drug-induced IgAN. Therefore the immunosuppression was escalated. Kidney function initially stabilized, but worsened again, progressing to oliguric AKI-D. She was started on pulse steroids and IV cyclophosphamide. She continues to be dialysis dependent despite these therapies. Discussion: CTLA-4 haploinsufficiency has been rarely linked with kidney disease, with only a few reports of interstitial nephritis. Our case is the first report of CTLA-4 immune dysregulation associated with glomerulonephritis (GN). Studies have shown that CTLA-4 polymorphisms have a predisposition for GN. This patient’s presentation with other autoimmune diseases (cytopenias) and upregulation of systemic inflammatory markers such as CD19 and IL2, it was thought to be more an escape from the abatacept immune regulation, rather than caused by it. This case highlights the first reported IgAN associated with CTLA-4 immune dysregulation syndrome.