Membranous nephropathy associated with multicentric Castleman’s disease that was successfully treated with tocilizumab: a case report and review of the literature

Background Multicentric Castleman’s disease is a life-threatening disorder involving a systemic inflammatory response and multiple organ failure caused by the overproduction of interleukin-6. Although renal complications of Castleman’s disease include AA amyloidosis, thrombotic microangiopathy, and membranoproliferative glomerulonephritis, membranous nephropathy is relatively rare. We experienced a case of secondary membranous nephropathy associated with Castleman’s disease. Case presentation The patient was a 43-year-old Japanese man who had shown a high zinc sulfate value in turbidity test, polyclonal hypergammaglobulinemia, anemia, and proteinuria. A physical examination revealed diffuse lymphadenopathy, an enlarged spleen and papulae of the body trunk. A skin biopsy of a papule on the patient’s back showed plasma cells in the perivascular area and he was diagnosed with multicentric Castleman’s disease, plasma cell variant. Kidney biopsy showed the appearance of bubbling in the glomerular basement membranes in Periodic acid methenamine silver stain and electron microscopy revealed electron dense deposits within and outside the glomerular basement membranes. Since immunofluorescence study showed predominant granular deposition of IgG1 and IgG2, he was diagnosed with secondary membranous nephropathy associated with Castleman’s disease. He was initially treated with prednisolone alone, however his biochemical abnormalities did not improve. After intravenous tocilizumab (700 mg every 2 weeks) was started, his C-reactive protein elevation, anemia, and polyclonal gammopathy improved. Furthermore, his urinary protein level declined from 1.58 g/gCr to 0.13 g/gCr. The prednisolone dose was gradually tapered, then discontinued. He has been stable without a recurrence of proteinuria for more than 6 months. Conclusions Tocilizumab might be a treatment option for secondary membranous nephropathy associated with Castleman’s disease.

Case Report: A Rare Presentation of NSAID-Induced Secondary Membranous Nephropathy in a Pediatric Patient

Background: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, but it is responsible for <5% of nephrotic syndrome cases in children. MN has primary and secondary forms. Secondary MN is caused by viral infections, autoimmune diseases like lupus, or drugs. Non-steroid anti-inflammatory drug (NSAID)-induced secondary MN is rarely described in the pediatric population. Thus, the clinical presentation and time to recovery are vastly unknown in the pediatric subgroup.Clinical Presentation: We report a case of a 15-year-old female who presented with acute onset of nephrotic range proteinuria, significant hypoalbuminemia, hyperlipidemia, and lower extremity edema related to the presence of nephrotic syndrome. She had a history of ibuprofen use periodically for 6 months before presentation because of menstrual cramps and intermittent lower abdominal pain. After the presentation, we performed a renal biopsy that reported stage 1–2 MN, likely secondary. The phospholipase A2 receptor (PLA2R) antibody on the blood test and PLA2R immune stain on the renal biopsy sample were negative. We performed a comprehensive evaluation of the viral and immune causes of secondary MN, which was non-revealing. She had stopped ibuprofen use subsequent to the initial presentation. She was prescribed ACE inhibitor therapy. After 6 months of ACE inhibitor treatment, the proteinuria had resolved.Conclusion: Proteinuria can last for several weeks when NSAID induces secondary MN and nephrotic syndrome. With the widespread use of NSAIDs prevalent in the pediatric community, further studies are needed to evaluate and study the role of NSAIDs in this condition.

P023 Secondary membranous nephropathy in a patient with a background of rheumatoid arthritis treated with biosimilar etanercept

Background/Aims There is a growing number of reports of the development of autoimmune processes related to TNF-targeted therapies. This relationship is much more established with the originator biologics as they have been in clinical use for longer, but data for biosimilar safety is still emerging. Here we describe a case of an 80-year-old gentleman with a background of rheumatoid arthritis who developed membranous nephropathy secondary to Benepali®. Methods An 80-year-old Caucasian gentleman with a background of seropositive rheumatoid arthritis, diagnosed at the age of 35 years, was maintained in a clinical remission on oral methotrexate 15 mg weekly, until 2017, when his disease started to flare. At that time, his treatment was switched to sulfasalazine, but due to ongoing high disease activity, this was changed again in December 2018 to methotrexate with Benepali®. His rheumatoid arthritis was controlled with these disease-modifying anti-rheumatic drugs (DMARDs) and his blood test monitoring including full blood count, liver and renal profile (eGFR 80 ml/min/1.73m2) remained normal during the first seven months of treatment. In June 2019, his eGFR deteriorated to 46 and methotrexate was held. Despite this, his eGFR continued to worsen to 28 in July. At that point his Benepali® was discontinued and he was referred to the renal physicians. Results He was normotensive (blood pressure 120/68) and had no dependent oedema. A renal tract ultrasound scan showed normal appearing (with a couple of simple cysts) 10.7/9.4 cm kidneys. Urine dipstick showed 2+ blood and 2+ protein, urine protein:creatinine ratio was 138 mg/mmol (normal ≤ 23) and serum albumin 31 g/L (normal ≥ 34). Serum electrophoresis, HIV and Hepatitis PCRs and serum anti-phospholipase A2 receptor antibody were negative. Renal biopsy confirmed stage I to II membranous nephropathy with mild focal segmental glomerulosclerosis. Reassuringly his renal function and proteinuria continued to improve off Benepali® and both returned to normal a few months after stopping this agent. Conclusion This is the case of an 80-year-old gentleman who developed membranous nephropathy eight months after commencing etanercept biosimilar - Benepali® - for rheumatoid arthritis. Although attribution to a single agent is challenging, we believe that it is likely Benepali® was the main attributing factor for the development of membranous nephropathy. The temporal relationship between the initiation of Benepali® and the subsequent development of biopsy proven membranous nephropathy along with the resolution following withdrawal of Benepali® supports drug-related renal injury. Although TNF inhibitor-induced renal injury is uncommon, this case highlights the need for physicians to maintain a high level of suspicion if a patient on a TNF inhibitor, including biosimilars, develops proteinuria and renal injury. Disclosure L. Sammut: None. T. Leach: None. L. Yalakki: None.

Takayasu’s arteritis and secondary membranous nephropathy: an exceptional association

The association between Takayasu’s arteritis and membranous nephropathy is uncommon. We present the case of a 46-year-old man with Takayasu’s arteritis treated over 10 years by a multidisciplinary medical team. He had an atrophic left kidney due to arterial stenosis, with a basal creatinine of 1.59 mg/dL (140.55 µmol/l). Three years ago, he presented with full nephrotic syndrome, uncontrolled blood pressure, creatinine increases to 4.5 mg/dL (basal: 1.59 mg/dL), severe hypoalbuminaemia (1.4 g/dL) and albuminuria of 24.6 g per day. He underwent percutaneous biopsy of the right kidney that showed membranous nephropathy with negative PLA2R1 and positive IgG 1, 3 and 4 subclasses. After therapy with oral prednisone and cyclophosphamide, the patient’s kidney function improved, without recurrence of disease after 3 years of follow-up. Here, we present this extremely uncommon association of Takayasu’s arteritis and membranous nephropathy.

Secondary Membranous Nephropathy. A Narrative Review

Membranous nephropathy (MN) is a common cause of proteinuria and nephrotic syndrome all over the world. It can be subdivided into primary and secondary forms. Primary form is an autoimmune disease clinically characterized by nephrotic syndrome and slow progression. It accounts for ~70% cases of MN. In the remaining cases MN may be secondary to well-defined causes, including infections, drugs, cancer, or autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), urticarial vasculitis, sarcoidosis, thyroiditis, Sjogren syndrome, systemic sclerosis, or ankylosing spondylitis. The clinical presentation is similar in primary and secondary MN. However, the outcome may be different, being often related to that of the original disease in secondary MN. Also, the treatment may be different, being targeted to the etiologic cause in secondary MN. Thus, the differential diagnosis between primary and secondary MN is critical and should be based not only on history and clinical features of the patient but also on immunofluorescence and electron microscopy analysis of renal biopsy as well as on the research of circulating antibodies. The identification of the pathologic events underlying a secondary MN is of paramount importance, since the eradication of the etiologic factors may be followed by remission or definitive cure of MN. In this review we report the main diseases and drugs responsible of secondary MN, the outcome and the pathogenesis of renal disease in different settings and the possible treatments.

Idiopathic multicentric Castleman disease with Sjögren’s syndrome and secondary membranous nephropathy: a case report and review of the literature

Background Idiopathic multicentric Castleman disease (iMCD) is an uncommon lymphoproliferative disorder and lacks treatment consensus. Herein, we report a case of iMCD complicated with Sjögren’s syndrome (SS) and secondary membranous nephropathy (SMN). Case presentation A 45-year-old female with dry mouth for 3 months and anasarca and proteinuria for 2 months was admitted. She also experienced chest tightness, wheezing, fever, weight loss, moderate proteinuria and hypoalbuminemia. A computed tomography (CT) scan revealed a tissue mass in the thymus area and enlarged multiple lymph nodes. Her symptoms did not improve after resection of the thymus mass. The pathological findings were “reactive hyperplasia of the mediastinal lymph nodes and thymic hyperplasia”. Lymph node biopsy findings confirmed iMCD with human herpes virus-8 (HHV-8) negativity. Based on anti-nuclear antibody (ANA) 1:320, anti-SSA and anti-SSB antibody positivity, salivary flow less than 0.1 ml/min and lip biopsy with focal lymphocytic sialadenitis, SS was diagnosed. Kidney biopsy showed secondary membranous nephropathy with endocapillary cell proliferation and infiltration of plasma cells and lymphocytes in the tubulointerstitium. Serum interleukin-6 (IL-6) levels were significantly increased, and therapy with tocilizumab (anti-IL-6 receptor antibody) worked well. The combination of cyclophosphamide (CyS) with methylprednisolone (MP) maintained satisfactory remission. Conclusions Our case of iMCD with SS and SMN is rare. There is a need for increased awareness of the disease to avoid unnecessary procedures and misdiagnoses. IL-6 was extremely high, and there was a rapid response to anti-IL-6 receptor agents. The combination of CyS with MP maintained complete remission.

Case Review of lgG4-Related Disease Patient with Combined Tubulointerstitial Nephritis and Membranous Nephropathy Coexisting with Cholangiocarcinoma: Case Report

Immunoglobulin G4-related disease (IgG4-RD) has recently been recognized as an autoimmune disorder involving multiple organs. The kidney is a represented organ with a wide range of renal manifestations. The authors report a case of an 83-year-old Thai male with combined IgG4 tubulointerstitial nephritis and membranous nephropathy coexisting with cholangiocarcinoma. The patient presented with proteinuria, acute renal failure, eosinophilia, hypocomplementemia, and high serum IgG4 concentration. The diagnosis was IgG 4-related tubulointerstitial nephritis and membranous nephropathy on renal biopsy, with negative immunohistochemistry for anti-phospholipase A2 receptor antibodies. Magnetic resonance imaging (MRI) abdomen showed two wedge shaped arterial enhancing lesions of liver. Liver biopsy revealed adenocarcinoma, compatible with cholangiocarcinoma. Proteinuria and renal failure were resolved with initial steroid treatment. Meanwhile, IgG4-related membranous nephropathy should be considered in the differential diagnosis for patients with proteinuria. Potentially, IgG4-RD may be rarely associated with carcinoma development. However, further studies are recommended to ratify and confirm the association between IgG4-RD and incidence of malignancies. Keywords: IgG4-related disease, Membranous nephropathy, Secondary membranous nephropathy, Tubulointerstitial nephritis, Cholangiocarcinoma

P0092GEMPREDICT: AN HISTOLOGICAL AND BIOLOGICAL COMBINED CRITERIA TO DIAGNOSE PRIMARY MEMBRANOUS NEPHROPATHY

Background and Aims Membranous nephropathy (MN) is a frequent cause of nephrotic syndrome of non-diabetic origin in adults, and a leading cause of end stage renal disease. Its origin is primary in up to 80% of cases but can also be secondary to underlying diseases such as cancer, lupus or other systemic disease, infections or drugs. Important recent advances have been made in our understanding of primary MN physiopathology with the identification of various antibodies such as PLA2R, THSD7A, Exostosin 1,2 suggesting autoimmunity. However, distinction between primary and secondary MN remains difficult and can lead to numerous and expensive complementary exams and postpone treatment. Some authors (Cambier, Ronco, CJASN 2012) proposed an algorithm based on histological and biological features in order to distinguish primary from secondary MN. Yet this algorithm has never been tested. The main objective of our study was to evaluate the efficiency of a combined histological and biological criterion in order to establish the diagnosis of primary MN. Method We conducted a pluricentric retrospective cohort study in Northern France. All patients with histological proved membranous nephropathy between January 2010 and December 2016 were included. All kidney biopsies were re-analysed in order to specify the predominant IgG subclass and PLA2R staining. The combined criterion was considered present if: PLA2R was detected (in biopsy or serum), with no endocapillary proliferation and an IgG4 subclass predominance (or co-predominance) on kidney biopsy. The gold standard to diagnose primary MN was the exclusion of other causes of MN after biological and radiological investigation, in particular the absence of cancer detected after at least 2 years of following. We tested the sensitivity, specificity, and predictive values of this combined criterion in order to diagnose primary MN. Results 173 patients were included. 66 (38.2%) patients were women. At the time of diagnosis mean age was 52.1 years old (SD: 17.4), mean albumine and creatinine were respectively 25.2 g/L (9.02) and 14 mg/L (17.7). Mean protein to creatinine ratio was 5.75 g/g. 119 (68.8%) patients had primary membranous nephropathy. Secondary membranous nephropathy were due to lupus, other auto immune disease and cancer in respectively 25 (14.5%), 14 (8.0%), and 15 (8.0%) cases. 59 patients had a positive combined criterion. Sensitivity of the criterion was: 0.50 [95%CI: 0.40-0.59], Specificity was: 0.90 [95%CI: 0.80-0.98] compared to a specificity of 0.50 [95%CI 0.34-0.54] for single criterion PLa2R on biopsy. Negative predictive value was 0.45 [95%CI: 0.31-0.59] and positive predictive value was 0.92 [95%CI: 0.84-0.99]. Histological features associated with primary membranous nephropathy were: no extracapillary proliferation (p=0.003), presence of PLA2R (p<0.001), IgG4 predominant staining (p<0.001) and low Ig1 staining (2.24 + in secondary MN versus 1.86 + in MN) p=0.011. Conclusion Our histological combined criterion had a high specificity: 0.90 [95%CI 0.80-0.98] and positive predictive value 0.92 [95%CI: 0.84-0.99]. Presence of this combined criterion could allow the clinician to reduce the number of complementary analyses and help conclude faster to the primary etiology of the MN.