NELL1-Associated Membranous Glomerulopathy After Hematopoietic Stem Cell Transplantation

Abstract

INTRODUCTION M embranous glomerulopathy (MGN) is among the most common glomerular diseases identified in adult patients with nephrotic syndrome. Traditionally, MGN is classified into primary and secondary forms depending on the clinical context (i.e., renallimited vs. associated with a systemic disorder), with a presumed secondary etiology identified in approximately 30% of cases. Since the discovery of phospholipase A2 receptor (PLA2R) as a major target antigen in primary MGN, multiple additional antigenic targets have been discovered. Most if not all of these antigens are expressed on podocytes, including thrombospondin type-1 domain-containing 7A and neural epidermal growth factor–like 1 (NELL1), both of which have been described in both primary MGN and in MGN in the setting of malignancy. The discovery of these and other new antigens has led some to advocate for classification based on the deposited antigen. In contrast to PLA2R-associated MGN where deposits are globally distributed and immunoglobulin G4 (IgG4)–dominant, NELL1-associated MGN is characterized by IgG1-dominant subepithelial deposits that are often segmental or segmental to global in distribution and can occur in association with malignancy. To date, there have been no reports of NELL1associated MGN in the setting of hematopoietic stem cell transplantation (HSCT) or with findings of tubular basement membrane (TBM) deposits. Herein, we report the first case of NELL1-associated segmental MGN with TBM deposits following allogeneic HSCT complicated by graft-versus-host disease (GVHD). CASE A 74-year-old White male presented with nephrotic syndrome. Past medical history included chronic myelomonocytic leukemia status post myeloablative haploidentical peripheral blood HSCT from his son 2 years prior, longstanding hypertension, and chronic kidney disease (predating HSCT; associated with 1þ proteinuria on urinalysis), uric acid nephrolithiasis, hyperlipidemia, benign prostatic hypertrophy, and gout. The patient’s post-HSCT course was complicated at 3 months by neutropenic fever, inguinal rash, and upper gastroesophageal symptoms, suspicious for GVHD and treated with sirolimus; 3 months later he developed oligoclonal large granular lymphocytosis that resolved with steroids. Throughout the posttransplantation course, the patient required occasional transfusions and was treated with filgrastim and romiplostim for granulocytopenia and thrombocytopenia. There was no evidence of recurrent chronic myelomonocytic leukemia. Nine months post-transplantation, the patient developed a painful, pruritic maculopapular rash involving the chest and back, with skin biopsy findings consistent with GVHD. The rash responded to steroids, which were subsequently discontinued. The patient was noted to have mild edema without hypoalbuminemia. Intravenous immunoglobulin was administered for low serum IgG levels. As the edema improved following furosemide therapy, no further workup was performed. One year later, in the setting of increasing edema, the patient was found to have nephrotic syndrome. At the time, the patient’s medications included intravenous Ig, tamsulosin,