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We present a case of a 67-year-old Caucasian male, with history of hypertension, obesity, and previous hepatitis B infection. He was diagnosed with chronic lymphocytic B leukemia in 2011, treated with rituximab, cyclophosphamide, and fludarabine. His disease progressed in 2014 and was treated with 6 cycles of R-CHOP. Then, in 2015 a hematopoietic stem cell transplant (HSCT) from a related donor (fludarabin/bussulfan conditioning regimen) was performed. Cyclosporine A and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis and lamivudine for hepatitis B reactivation prophylaxis. In 2017, he was considered in complete response and had complete chimerism. During follow-up, he developed mucosa and ocular GVHD after stopping GVHD-prophylaxis and steroids were started, iatrogenic diabetes arose which was treated with oral antidiabetics. He had also developed chronic kidney disease after the HSCT, with creatinine of 1,8mg/dL in 2019. At this time, he developed peripheral edema, proteinuria (+++) and red blood cells in urine sediment. In June 2020, he was referred to the nephrology clinic for study of nephrotic syndrome (NS) – table. A kidney biopsy was performed, revealing stage II membranous nephropathy (MN) and chronic thrombotic microangiopathy in electron microscopy, immunofluorescence was positive for IgG only, with no light chain restriction by immunohistochemistry; the chronicity index was 4/10.
After conservative measures for 6 months, NS persisted. Then, we decided to treat the patient with rituximab, 375mg/m2 weakly for 4 weeks, assuming secondary MN due to GVHD after HSCT. The patient completed only two doses – before the third dose, he developed severe sepsis and was admitted for antibiotics and intravenous immune globulin. Rituximab was halted due to high infection risk. Nevertheless, 6 months later, he achieved partial remission and complete response by 12 months (proteinuria <300mg/day). CD19-positive cells were below 20/microL 6 months after rituximab and 22/microL one year after with subsequent increase. Proteinuria recurred and rose above 1g/day 14 months after B-cell reconstitution (26 months after treatment). We agreed to not rechallenge the patient with rituximab due to previous serious infection complications and the absence of NS.
Protocadherin FAT1 (p-FAT1) associated membranous nephropathy after HSCT was first described in 2022 by Mayo Clinic team. A sample of our patient’s kidney biopsy was sent to that institution, where mass spectrometry was performed confirming the positivity of p-FAT1, corroborating secondary MN due to GVHD in the context of HSCT.
Our p-FAT1 positive MN patient was successfully treated with rituximab achieving complete remission. We speculate that a primary MN regimen (two doses of 1g of rituximab, fortnightly) is a reasonable choice to treat p-FAT1 positive MN, especially in patients not suitable for calcineurin inhibitors due to altered kidney function. Reconstitution of CD19+ cells appears to be a good marker of proteinuria recurrence, probably identifying when a patient should be re-treated, yet with considerable delay.
To the best of our knowledge, this is the first reported case (after the discovery series) of p-FAT1 positive MN secondary to HSCT that achieved complete remission of NS with rituximab.