==== Front Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.39737 Internal Medicine Nephrology Anti-glomerular Basement Membrane Disease After Diagnosis of Immunoglobulin A Nephropathy: A Case Report Muacevic Alexander Adler John R Matsuno Takahiro 1 Okumura Toshiya 2 1 Nephrology, Komatsu Sophia Hospital, Komatsu, JPN 2 Nephrology, Tonami General Hospital, Tonami, JPN Takahiro Matsuno takahiromorino31@yahoo.co.jp 30 5 2023 5 2023 15 5 e3973730 5 2023 Copyright © 2023, Matsuno et al. 2023 Matsuno et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from https://www.cureus.com/articles/160296-anti-glomerular-basement-membrane-disease-after-diagnosis-of-immunoglobulin-a-nephropathy-a-case-report Anti-glomerular basement membrane (anti-GBM) disease has one of the worst prognoses of nephritis and is rarely associated with other forms of glomerulonephritis. In this report, we present the case of a 76-year-old man who developed anti-GBM disease four months after being diagnosed with IgA nephropathy (IgAN). To our knowledge, although there have been several reports of IgAN combined with anti-GBM disease, there have been no cases in which we were able to confirm that the anti-GBM antibody titer changed from negative to positive over the disease course. This case suggests that even patients with previously diagnosed chronic glomerulonephritis, including IgAN, and an unusually rapid clinical course should be evaluated for the presence of autoantibodies to exclude overlapping autoimmune diseases. glomerulonephritis antibodies autoimmune disease immunoglobin a nephropathy anti-glomerular basement membrane disease ==== Body pmcIntroduction Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune disease characterized by positive anti-GBM antibodies and linear deposition of IgG along the GBM [1]. Due to its rarity, no definitive statement on the incidence of anti-GBM disease is available. In European populations, it is often said to be less than 1 per million, but this is not certain [2]. Complicated cases of this disease have been reported, including cases that were related to anti-neutrophil cytoplasmic antibody (ANCA) [3,4] and membranous nephropathy [5,6]. However, IgA nephropathy (IgAN) cases are rare [7]. Here, we report a case in which IgAN was diagnosed by renal biopsy; the patient was negative for anti-GBM antibodies at that time; approximately four months later, he was positive for anti-GBM antibodies, and rapidly progressive glomerulonephritis developed. Case presentation A 76-year-old Japanese man with hypertension who had been visiting his local doctor was referred to our hospital in June 2019 because of positive urine protein and occult blood. Urinalysis showed urinary protein 2+ and urinary occult blood 3+, and urinary sediment showed erythrocyte levels of 50-99/high power field (HPF). No red blood cell casts or white blood cell casts were observed. Blood tests showed a creatinine (Cr) level of 0.89 mg/dL (reference range: 0.65 to 1.09 mg/dL) and IgA levels of 450 mg/dL (reference range: 90 to 400 mg/dL). The patient was negative for Complement C3, anti-nuclear antibody (ANA), and ANCA. A renal biopsy was performed in July 2019. Light microscopy revealed 18 glomeruli, including two all-nodular sclerosing glomeruli. Five glomeruli with increased mesangial cells and substrates, as well as one fibrous crescent, were observed (Figure 1). Using the Oxford Classification of IgAN, the patient’s biopsy showed mesangial hypercellularity (M0: ≤50% of the glomeruli showing mesangial hypercellularity) and endocapillary hypercellularity (E1) without segmental sclerosis (S0), interstitial fibrosis/ tubular atrophy (T0), or crescents (C0). Immunofluorescence staining showed mesangial deposits of IgA (IgA: [++] mes), whereas electron microscopy showed deposits in the mesangial area, no thickening or thinning of the GBM, and no fracture (Figure 1). Accordingly, IgAN was diagnosed. The treatment plan was to continue with angiotensin II receptor blockers (ARB), which had been previously prescribed for hypertension. Figure 1 Histopathology of the renal biopsy (A) Mesangial cells and matrix were increased (PAS stain; 400x). (B) One fibrous crescent was observed (PAS stain; 400x). (C) No basement membrane doubling or spike formation was observed (PAM stain; 400x). (D) IgA was strongly deposited in the mesangium (IF). (E) Deposits were seen in the mesangial area. No thickening or thinning of GBM or tear image was observed (EM; 3000x). IgA: immunoglobulin A; PAS: periodic acid-Schiff; PAM: periodic acid-methenamine-silver; IF: immunofluorescence; EM: electron microscope Thereafter, the patient was followed up during outpatient visits. In November 2019, a fever of 37.5°C and general malaise were observed, and the patient visited our clinic without an appointment. Physical examination revealed lower leg edema. Urinalysis showed that his condition was worsening, and blood samples showed an elevated inflammatory response and a Cr of 5.18 mg/dL (Table 1). He was urgently admitted to our department for close examination and treatment of progressive renal dysfunction and elevated inflammatory response. Table 1 Laboratory findings on admission MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibodies; PR3-ANCA: proteinase-3-anti-neutrophil cytoplasmic antibodies; Cr: creatinine; Na: sodium; K: potassium; Cl: chloride; CRP: C-reactive protein; IgG: immunoglobulin G; IgA: immunoglobulin A; IgM: immunoglobulin M; ANA: anti-nuclear antibody; RBC: red blood cells; WBC: white blood cells Laboratory test Unit Patient’s laboratory values Reference ranges White blood cell /μL 10000 3300-8600 Hemoglobin g/dL 10.1 13.7-16.8 Plates /μL 34.9×104 15.8×104-34.8×104 Total protein g/dL 6.0 6.9-8.4 Albumin g/dL 2.4 3.9-5.2 Urea nitrogen mg/dL 57.5 8-21 Cr mg/dL 5.18 0.65-1.09 Na mEq/L 140 135-146 K mEq/L 4.1 3.7-4.8 Cl mEq/L 103 101-109 CRP mg/dL 13.7 <0.3 IgG mg/dL 1067 870-1700 IgA mg/dL 468 90-400 IgM mg/dL 76 33-190 C3 mg/dL 164 73-138 C4 mg/dL 33 11-31 CH50 U/mL 50 30-45 ANA SP 40 <40 MPO-ANCA EU <10 <10 PR3-ANCA EU <10 <10 Anti-GBM antibody titer U/mL 485.7 <3.0 Urinalysis 　 　   Protein 　 3+ Negative Blood 　 3+ Negative RBC /HF >200 Negative WBC /HF 5-9 Negative Worsening renal function was suspected to be an aggravation of the nephritis, and steroid pulse therapy was initiated as soon as the patient was admitted. Simultaneously, a urinary tract infection could not be completely excluded; therefore, the patient was treated with ceftriaxone 2 g/day. Prednisolone (PSL) 50 mg was started on the fifth day as post-treatment. On the eighth day, the anti-GBM antibody was found to be positive at 485.7 U/mL, and a diagnosis of anti-GBM disease was made. Plasma exchange (PE) therapy was initiated and performed seven times during a 14-day course. Hemodialysis was performed simultaneously. The anti-GBM antibody titer improved to 59.6 U/mL, but the patient remained positive for anti-GBM, and a second dose of steroid pulse therapy was administered on the eighth day. The patient was treated with cyclophosphamide; 150 mg was administered from the 19th day. His anti-GBM antibody titer increased again (136.5 U/mL), and a second course of PE was administered from the 30th day of the disease. On the 37th day, a blood sample was collected; pancytopenia progressed, and the drug was discontinued based on the suspicion of myelosuppression caused by cyclophosphamide. After the second course of PE, the anti-GBM antibody titer showed a gradual downward trend; therefore, PSL was tapered. From the 60th day, azathioprine 150 mg was added, and PSL was reduced to 20 mg. Thereafter, there were no apparent relapse findings, but renal function did not improve, and he required permanent hemodialysis. The patient was discharged home on the 78th day and remained on maintenance dialysis at our hospital after discharge (Figure 2). Figure 2 Clinical course mPSL: methylprednisolone; PE: plasma exchange; HD: hemodialysis; GBM: glomerular basement membrane; CRP: C-reactive protein; eGFR: estimated glomerular filtration rate Discussion Here, we report a case of anti-GBM disease complicated by IgAN approximately four months after diagnosis. Although several cases of anti-GBM nephritis associated with IgAN have been reported, no case has been reported in which the GBM antibody titer was negative at the time of IgAN diagnosis. The mechanism by which IgAN is complicated by anti-GBM diseases remains unclear. Various hypotheses have been proposed to explain the phenomenon. IgA-associated immune complexes promote immunological and inflammatory events that lead to GBM antigen exposure and anti-GBM antibody production [8]. Secondly, it has been hypothesized that abnormal IgA deposition along the GBM triggers the formation of new antigens, leading to the production of anti-GBM antibodies [9]. Other hypotheses propose that anti-GBM antibodies alter the permeability of GBM, allowing the deposition of circulating immune complexes on the mesangium [9]. However, it is difficult to prove whether the anti-GBM disease in these patients is an incidental complication or secondary to IgAN since no biomarkers have been identified to distinguish primary from secondary anti-GBM disease [10]. However, in the present case, IgAN was confirmed to be negative for anti-GBM antibodies at the time of diagnosis, and renal biopsy showed the aforementioned results, suggesting that IgAN occurred first and that anti-GBM nephritis occurred later. Thus, the final hypothesis may be negative. However, more cases need to be studied. It has been reported that the overall dialysis dependence rate of anti-GBM disease is 69% and that renal prognosis is relatively good (31%) only in patients with IgAN complications [11]. Unfortunately, the patient died due to renal failure and required maintenance dialysis. The reason for this was the high titer of the anti-GBM antibody. High titers of anti-GBM antibodies are reportedly associated with severe disease and poor renal prognosis [12]. The highest antibody titer reported thus far among patients with IgAN-associated anti-GBM disease is 258.3 U/mL, and the titer in the present case was almost twice that level. The rarity of this case is that the patient developed anti-GBM nephritis approximately four months after the diagnosis of IgAN. Furthermore, the anti-GBM antibody titer increased from negative to 485.7 U/mL during the four-month period, which was unprecedented. Even if IgAN has been diagnosed in the past, it should not be regarded simply as an acute exacerbation; other factors should also be thoroughly investigated. Conclusions Herein, we describe a case of IgAN followed by anti-glioblastoma nephritis. When renal function worsened, we first considered IgAN exacerbation. However, this was not the case. Even if the patient has already been diagnosed with chronic glomerulonephritis, including IgAN, autoantibodies should be confirmed again according to the clinical course. Human Ethics Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. ==== Refs References 1 The distribution of IgG subclass deposition on renal tissues from patients with anti-glomerular basement membrane disease BMC Immunol Qu Z Cui Z Liu G Zhao MH 19 14 2013 23586976 2 Anti-glomerular basement membrane disease Clin J Am Soc Nephrol McAdoo SP Pusey CD 1162 1172 12 2017 28515156 3 Comparison of anti-GBM antibodies in sera with or without ANCA J Am Soc Nephrol Hellmark T Niles JL Collins AB McCluskey RT Brunmark C 376 385 8 1997 9071706 4 Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis Am J Kidney Dis Rutgers A Slot M van Paassen P van Breda Vriesman P Heeringa P Tervaert JW 253 262 46 2005 16112043 5 Simultaneous anti-glomerular basement membrane and membranous glomerulonephritis: case report and literature review Clin Immunol Immunopathol Pettersson E Törnroth T Miettinen A 171 180 31 1984 6713739 6 Clinical and pathological features of anti-glomerular basement membrane disease associated with membranous nephropathy: an observational study Ren Fail Zhang S Li C Huang J 1904 1914 44 2022 36351876 7 IgA nephropathy and atypical anti-GBM disease: a rare dual pathology in a pediatric rapidly progressive glomerulonephritis Glomerular Dis Bajaj V Thakur S Barwad A Sinha A Bagga A Singh G 54 57 2 2022 36751265 8 Recurrence of anti-GBM antibody disease twelve years after transplantation associated with de novo IgA nephropathy Clin Nephrol Trpkov K Abdulkareem F Jim K Solez K 124 128 49 1998 https://europepmc.org/article/med/9524784 9524784 9 Concurrent antiglomerular basement membrane disease and immune complex glomerulonephritis Ren Fail Cui Z Zhao MH Wang SX Liu G Zou WZ Wang HY 7 14 28 2006 16526313 10 Development of anti-glomerular basement membrane glomerulonephritis during the course of IgA nephropathy: a case report BMC Nephrol Kojima T Hirose G Komatsu S 25 20 2019 30683055 11 Predicting outcome in patients with anti-GBM glomerulonephritis Clin J Am Soc Nephrol van Daalen EE Jennette JC McAdoo SP 63 72 13 2018 29162595 12 Anti-GBM disease: predictive value of clinical, histological and serological data Clin Nephrol Herody M Bobrie G Gouarin C Grünfeld JP Noel LH 249 255 40 1993 https://pubmed.ncbi.nlm.nih.gov/8281713/ 8281713