The pathological finding of renal lesions in this case demonstrated not only the features of anti-GBM nephritis such as linear deposits of IgG and C3c along the GBM, but also those of AAV including endarteritis of interlobular artery. Based on these pathological findings, this case was diagnosed with both anti-GBM nephritis and AAV.
Patients with anti-GBM disease, also known as Goodpasture’s disease, often develop both RPGN and pulmonary hemorrhage; however, 30–40% have renal involvement alone [7]. The suspicion of anti-GBM disease can usually be easily validated by the detection of serum anti-GBM antibodies using either indirect immunofluorescence or direct enzyme-linked immunoassay; however, a definitive diagnosis is made by means of a renal biopsy. Optical microscopic findings in renal biopsies consistent with anti-GBM disease usually include crescentic glomerulonephritis, whereas immunofluorescence microscopy demonstrates the virtually pathognomonic finding of linear deposits of IgG along the GBM.
It has been suggested that both environmental factors such as lung infections, exposure to hydrocarbons, and smoking, combined with genetic factors may cause anti-GBM disease [8, 9]. Recent reports suggested the association between pulmonary tuberculosis infection and anti-GBM disease [10, 11]. These risk factors are believed to expose a cryptic epitope in the alveolar basement membrane thereby inducing an autoimmune response against the α3 chain of type IV collagen and the subsequent anti-GBM disease [12].
Compared with anti-GBM disease, pathological renal findings for AAV are characterized as necrotizing vasculitis predominantly in small vessels with few or no immune deposits and is associated with ANCAs specific for MPO or PR3 [13].
Several reports have described a role for ANCAs in the mechanism of GBM antibody production [2, 3]. ANCA has a strong membrane-disordering activity. An analysis of longitudinal sera collected prior to the onset of GBM nephritis indicated that as many as 40% of GBM nephritis patients have ANCA before anti-GBM antibodies are detected [14]. Thus, the presence of ANCA has been speculated to be partly responsible for the development of anti-GBM nephritis. Importantly, AAV exposes the NC1 domain of the α3 chain of type IV collagen in lesions of glomerular or alveolar basement membrane, which could result in the production of anti-GBM antibodies.
In this case study, it was not clear whether the glomerular lesion was caused by AAV because the renal biopsy revealed linear deposits of IgG and C3c predominantly along the GBM, which is evidence of anti-GBM nephritis rather than AAV. However, also in this case, the interstitial lesion was characterized as endarteritis of arterioles. Arterioles are considered to be one of the target vessels of AAV [13], and endarteritis of arterioles are not caused by anti-GBM nephritis because type IV collagen is not a constituent of an arteriole. Therefore, we suggest that both AAV and anti-GBM nephritis are responsible for the renal lesions in this patient.
Following the clinical course of the patient, serum ANCA were detectable before the onset of renal lesions, and anti-GBM antibodies became detectable later at the onset of GBM nephritis, suggesting that ANCA may have induced the development of anti-GBM antibodies in this patient similar to the previously cited reports. Taken together, both ANCAs and anti-GBM antibodies could have played an important role in the pathogenesis of renal lesions in this case.
In several studies, respiratory tract infections, including NTM or other infections, were associated with the development and increase of serum ANCA [15]. Recently, an increase in the occurrence of NTM has been reported in Japan [16], and MAC is considered to be the cause for most pulmonary NTM infections. It has been suggested that NTM infection is related to the development of AAV [5, 6]; however, the mechanism by which NTM induces ANCA production is not fully clarified.
Conversely, the mechanism of ANCA induction by Mycobacterium tuberculosis, which belongs to the genus mycobacterium along with NTM, is well known. Thus, M. tuberculosis stimulates the release of oxygen metabolites from neutrophils that are activated through interactions with the phenol glycolipids in the M. tuberculosis cell wall [17]. This activation most likely leads to the release of lysosomal enzymes from the neutrophils in the initial stages of the mycobacterial infection, and autoantibodies against the granular components of the infected cells are produced [18]. Thus, the mechanism by which ANCA production is induced by NTM infection may be similar to that induced by M. tuberculosis. As in this case, NTM infection may be involved in the pathogenesis of some cases of AAV. Therefore, it may be important to measure ANCA in NTM patients with abnormal urine findings.
In this case, histological findings of the renal biopsy showed no remaining normal glomeruli; 11 of 23 were fully sclerotic, 10 were cellular crescentic, and 2 were collapsed glomeruli. Renal biopsy findings showed few normal glomeruli and the renal lesions were determined to be those induced by anti-GBM antibodies rather than those of the AAV. At the time of diagnosis of GBM by the renal biopsy findings, it was considered that immunosuppressive therapy was not expected to improve renal function. Additionally, there was no organ manifestation of AAV or GBM disease other than renal lesions in this patient. In addition, rituximab had not been approved for GBM disease in Japan, therefore the Japanese guideline of RPGN did not recommend rituximab for GBM disease [19].
This patient was treated with multidisciplinary therapy which, unfortunately, did not improve the renal prognosis. The presence of both AAV and GBM nephritis in the renal lesions could be the reason. Although AAV was diagnosed relatively early as a cause of kidney damage, the diagnosis of GBM nephritis was delayed in this case. An early diagnosis of GBM nephritis complicated with AAV might have improved the renal prognosis. It is important to recognize that some cases of AAV are complicated by GBM nephritis, and this could have a strong impact on the renal prognosis as was seen in this case. The detection of anti-GBM antibodies at the time of diagnosis and during treatment of AAV with severe renal impairment would be beneficial in improving renal outcome.