Anti-GBM diseases are rare spectrum of autoimmune disorders characterized by circulating anti-GBM antibodies that deposit in kidney and/or lung tissues, potentially resulting in kidney damage and/or pulmonary hemorrhage. The target antigen in this context is the non-collagenous domains of the α3(IV)NC1 and α5(IV)NC1 in the GBM [2, 4].

In the development of anti-GBM disease, the immunological characteristics of anti-GBM antibodies play a crucial role in its pathogenicity. This involves a gradual increase in titer, the progressive emergence and amplification of IgG1 subtypes, and a shift in target antigens recognized by the antibodies. Initially limited to α3(IV)NC1 and α5(IV)NC1, the antibodies eventually come to recognize all five target antigens from α1 to α5(IV)NC1 [9, 10]. Plasma exchange has proven effective in removing circulating antibodies, leading to the recovery of pulmonary hemorrhage and kidney function. Recently, there has been the identification of atypical anti-GBM disease, which presents some unique features. Despite revealing typical immunoglobulin deposition along the GBM lineage in kidney immunofluorescence, the serum tests negative for anti-GBM antibodies. Furthermore, the clinical manifestations, serologic and pathologic features, and prognosis of atypical anti-GBM disease differ from those of the typical variant, suggesting the possibility of distinct underlying pathogenic mechanisms [5, 6, 11].

Our patient exhibited pathological features such as diffuse and globular deposition of IgG along capillary loops, diffuse and homogeneously thickened basement membranes, crescent formation (62.5%), moderate-to-severe hyperplasia of mesangial cells, and the visible insertion of mesangial membranes. Additionally, nodular changes were evident in the form of double-track formation. Considering the clinical presentation alongside multiple negative laboratory indicators for anti-GBM antibodies, we concluded that the case involved atypical anti-GBM disease combined with membrane hyperplasia. The absence of electron-dense material in the ultrastructure excluded the possibility of membranoproliferative nephropathy in conjunction with crescent formation.

The linear IgG deposition in atypical anti-GBM disease may be due to an abnormal GBM or non-traditional characteristics of the antibody-binding sites [8, 12]. The phenomenon of “serum negativity” for anti-GBM antibodies could be explained by an “immunological sink,” wherein high-affinity antibodies are selectively sequestered from the circulation, leaving behind low-affinity antibodies undetectable by standard ELISA [13]. This hypothesis is indirectly supported by the fact that when anti-GBM disease was first identified in 1967, it was found that circulating anti-GBM antibodies increased rapidly when patients underwent bilateral nephrectomy [14].

Compared with typical anti-GBM disease, atypical anti-GBM disease develops more slowly. In this case, the patient’s kidney failure progressed slower than typical anti-GBM disease. This was primarily due to acute water and sodium retention from corticosteroids therapy, which was later withdrawn after fluid hemodialysis was restored with oral diuretics. Unlike the clinical presentation of classical anti-GBM disease, it is instead similar to a diabetic nephropathy grade III condition, where the blood creatinine is not high, but the urine output is not at normal levels [15].

Furthermore, the pathology of this case was compounded by membranous hyperplasia. Previous reports have shown that anti-GBM disease can also be associated with or secondary to other glomerulopathies, the most common of which is membranous nephropathy. It is hypothesized that these pre-existing glomerulonephritis may cause damage to the glomerular basement membrane structure, exposing the antigen which is originally in a masked state, inducing autoimmune reaction to produce autoantibodies, leading to the development of anti-GBM disease. In this case, the pathology happened to be combined with a manifestation of membranous hyperplasia as well. Previous reports have shown that anti-GBM disease can also be associated with or secondary to other glomerulopathies, the most common of which is membranous nephropathy. It is hypothesized that these pre-existing glomerulonephritides may cause damage to the glomerular basement membrane structure, exposing the antigen that is originally in a masked state, inducing an autoimmune reaction that produces autoantibodies, ultimately leading to the development of anti-GBM disease. In this case, we favored the pathological manifestation of membranous hyperplasia secondary to atypical anti-GBM nephropathy because no electron-dense material was observed in the ultrastructure, and this case is exceptionally rare. This case was similar to diabetic nephropathy grade III in both clinical presentation and pathology, and it was hypothesized that the two shared a common pathogenesis.

In the management of anti-GBM disease, timely and effective treatment is crucial for improving outcomes. The standard therapeutic strategy includes a combination of immunosuppression (usually with corticosteroids and cyclophosphamide) and plasmapheresis [1, 16]. The goal of immunosuppression is to dampen the immune response and reduce antibody production, while plasmapheresis aims to remove circulating anti-GBM antibodies from the plasma, thereby reducing their pathogenic impact on the kidneys and lungs [17]. For patients with atypical anti-GBM disease, as in our case, treatment decisions can be challenging due to the absence of circulating antibodies detectable by standard assays. However, the presence of organ involvement necessitates a similar approach to that of the typical form. Clinical symptoms and pathology of atypical anti-GBM disease differ from those of typical anti-GBM nephropathy with specificity. An accurate diagnosis based on pathology is essential for the appropriate management of acute and chronic lesions, guiding treatment decisions that may involve massive corticosteroid therapy and cyclophosphamide. Here, we reviewed a total of 20 case reports of pathology of atypical anti-GBM disease. Atypical anti-GBM disease shares similarities with typical anti-GBM disease in linear deposition of IgG. As shown in Table 2, a defining characteristic of atypical anti-GBM disease is negative serum anti-GBM antibodies. Cellular glomerular crescent, a histomorphological indicator of a rupture of glomerular capillaries, is the common pathological finding in both atypical anti-GBM disease and anti-GBM disease. As shows in Tables 2 and 75% (15/20) of atypical anti-GBM disease cases exhibit glomerular crescents. This phenomenon is usually a consequence of an intense immune attack involving cytotoxic elements, such as the complement membrane attack complex and extracellular histones, known as necroinflammation. Mesangial hyperplasia is more common in diabetic nephropathy [18], and it can be observed in 40% (8/20) of cases with atypical anti-GBM disease. If the blood glucose levels and screening of microalbuminuria are normal, it’s not considered diabetic nephropathy [15]. Membranoproliferative glomerulonephritis (MPGN) is identified by specific patterns of glomerular injury seen on a kidney biopsy. These patterns are characterized by distinct light microscopic changes, which include hypercellularity and thickening of the glomerular basement membrane (GBM) [19]. In this case, we observed the thickening of the glomerular basement membrane. However, since we didn’t observe the dense deposits by electron microcopy, MPGN was not considered. Thickening of the glomerular basement membrane is not a common phenomenon in atypical anti-GBM disease, with only 15% (3/20) observed. This highlights the importance of a comprehensive diagnostic approach that considers multiple factors.

In summary, although atypical anti-GBM disease shares similarities with typical anti-GBM disease in terms of immunofluorescence, where immunoglobulin is deposited linearly along the GBM, its clinicopathologic manifestations, response to treatment, and prognosis differ from those of typical anti-GBM disease. This suggests that it has a pathogenesis distinct from that of typical anti-GBM disease. Therefore, it is recommended to evaluate active and chronic lesions through pathology before deciding whether to pursue treatment involving massive corticosteroid therapy and cyclophosphamide.