Anti-PLA2R antibody testing has improved the diagnosis and treatment of MN6,7,8. Anti-PLA2R antibodies are correlated with MN progression, remission, and recurrence. In a study by Bobart et al.2, among 101 SAb + patients without associated diseases or diabetes, all renal biopsies indicated the presence of MN. Only 12 patients (11.9%) showed copathologies, which did not significantly affect the diagnosis and treatment. In our study, among the 491 SAb + patients without associated diseases or diabetes, 1 patient was diagnosed with FSGS, 490 (99.8%) were diagnosed with MN, and 16 of them were diagnosed with AMN; additionally, 21.5% of patients with PMN exhibited additional biopsy findings. These results suggest that serum anti-PLA2R antibody testing is highly accurate for diagnosing MN in Chinese adults; however, additional biopsy findings were more frequent in the Chinese population than in the Western population2,10,11. Thus, the decision to replace renal biopsy with the serological antibody test in Chinese patients should be weighed against potential complications of the biopsy procedure.
As serum anti-PLA2R antibodies can spontaneously diminish over time, staining of glomerular deposits of PLA2R antigen (GAg) has been found to have higher sensitivity for diagnosing MN9. In a study by Peihong14, patients who were SAb − /GAg − were more likely to exhibit complete remission than those who were SAb − /GAg + or SAb + /GAg + . Recently, Luo et al.15,16 reported that a small subpopulation of SAb + patients with MN was negative for GAg. These patients showed higher SAb titers, worse clinicopathological manifestations and poorer treatment response and prognosis, indicating a distinct clinical subtype of PMN. The specific etiology and pathogenesis of SAb + /GAg − remain unknown, but SAb + /GAg − may occur when anti-PLA2R antibodies are not pathogenic or when epitopes are poorly accessible at the time of renal biopsy; it may also be a technical artifact16. In our study, 18 patients (4.0%) were negative for GAg. Although the GAg status did not affect clinical decisions regarding treatment, it may be explored further for prognosis.
In recent years, a new type of MN has been increasing in China. It is characterized by mesangial proliferation and electron-dense deposits at multiple sites. The immunofluorescence results of most of these patients demonstrate a “full house” pattern of MN, which indicates positivity for IgG, IgA, IgM, C3 and C1q, but without a definite etiology17. These cases have been referred to as atypical MN, lupus-like MN or “full house” MN. In our study, 9 of the 16 patients with AMN (3.3%) showed a “full house” pattern. Previous work18 suggested that this might be SLE confined to the kidney. However, follow-up studies19,20 demonstrated that extrarenal manifestations of SLE in these patients only occurred rarely or not at all. Sam et al.21 hypothesized that lupus-like MN might be a new type of MN whose baseline characteristics and prognosis fall between those of PMN and LN-MN. However, Jiang Z et al.17,19 conducted a study in the Chinese population and suggested that AMN is merely a pathological variant of MN because there was no difference in SAb titers, clinical manifestations and renal outcomes between patients with PMN and AMN. Thus, current evidence suggests that the diagnosis of AMN may not affect treatment decisions, but a renal biopsy could be helpful in distinguishing different types of MN. Further studies on AMN and its clinical consequences are warranted.
Two AMN patients were positive for HBsAg/HBcAg staining but were serologically negative for HBV-MN. The current prevalence of HBV infection in the general Chinese population is 5–6%, with approximately 70 million patients with chronic HBV infection22. Approximately 3–5% of patients with HBV develop kidney disease, with HBV-MN as the most common histological change23. Most patients with HBV-associated glomerulonephritis (HBV-GN) have a history of chronic HBV infection and are seropositive for HBsAg. However, our previous work and several other studies24,25,26 demonstrated that some HBV-GN patients (12–37.6%) are seronegative for HBV markers. This could be due to the delay in the recovery of glomerulonephritis relative to the resolution of HBV infection or to occult hepatitis B virus infection. We found similar treatment remission rates for HBV-MN and PMN in our previous study24. Moreover, HBV-GN remission was similar in both serum HBsAg + and HBsAg − patients25. Thus, HBsAg/HBcAg staining may be a crucial test in Chinese patients with MN.
In our study, 18 PMN patients (3.7%) had superimposed IgAN, which is also the most common renal pathological finding in Asians27. At our center5, the proportion of MN with IgAN was 1.3% in total renal pathology, which was higher than that reported in Western studies10,11. In some studies28,29,30,31, a small proportion of Chinese patients with MN also reported exhibiting IgAN. To date, the etiology of MN complicated by IgAN is unknown. This entity may be due to the superposition of two independent pathologies. However, some researchers28 have suggested that either PMN or IgAN can be a primary event that induces the occurrence of another kidney disease. In these studies28,29, patients with MN + IgAN displayed similar clinical features as MN patients but milder pathological lesions than IgAN patients. Furthermore, MN + IgAN patients showed similar treatment responses but higher cumulative incidence rates of remission than MN patients. In our study, mild mesangial proliferation with IgAN was more common, which is consistent with previous studies. We also found that the SAb titer was lower in PMN + IgAN patients, suggesting that there could be more MN variants in patients with mild seropositivity.
In our study, ORG (5.1%) was found to be the most common additional disease. Studies on the relationship between obesity and MN are scarce. Only one study32 demonstrated that obesity may play an essential role in mesangial lesions of PMN. Obesity has currently become an epidemic. ORG is strongly associated with CKD33, and patients with obesity are likely to develop drug-induced diabetes when treated with steroids or immunosuppressants, which are the mainstay for MN therapy. Therefore, a renal biopsy could be highly considered for SAb + patients with obesity.
In our study, patients with impaired GFR exhibited additional findings (76.3%) more frequently than those with preserved kidney function (P < 0.05). This is consistent with data reported by Bobart et al.2,10. ATI was the most common superimposed disease, followed by ATIN/SATIN, which could be the main cause of renal impairment in MN patients in our study. The presence of ATIN/SATIN and crescents in patients with a decreased GFR should prompt the consideration of more aggressive treatment. Moreover, the pathological grading of PMN was higher in the low-GFR group than in the normal-GFR group. However, previous studies34,35 demonstrated that creatinine clearance in PMN patients was related to the chronicity of renal pathology. Furthermore, the PMN stage determined via EM could not predict kidney survival. Thus, more studies are warranted to elucidate the significance of the PMN stage. For SAb + patients with renal insufficiency, renal biopsy can reveal the underlying cause of renal impairment.
We previously9 demonstrated that there is no difference in the specificity (97.3%) for diagnosing MN via ELISA using different cutoff values of 14, 20 and 40 RU/mL. However, the sensitivity was the highest when the cutoff value was 14 RU/mL. Porcelli et al.36 also suggested that 14 RU/mL is the optimal cutoff value. In contrast, Bobart et al. used a cutoff value of 20 RU/mL2,10. In our study, an 18-year-old patient with an SAb titer of 17 RU/mL had FSGS with clinical manifestations of nephrotic syndrome complicated by AKI. Similar results8,37 have been reported in other studies; SAb + patients with low SAb titers exhibited biopsy-proven FSGS. Although the relationship between FSGS and MN remains unclear, the lower titer of SAb in this patient did not seem to be pathogenic. A higher cutoff value of the SAb titer could help achieve an accurate diagnosis, and ELISA and indirect immunofluorescence techniques are comparable and complementary. It is best to perform a renal biopsy in a patient with a low SAb titer (< 20 RU/mL), especially in younger patients.
This study has some limitations. Although more patients were included in the current study than in the previous study, data were collected retrospectively from a single center and were limited to those available in the electronic medical records. Second, the lack of follow-up data limits the determination of the prognostic value of this test. This question is currently being addressed in our follow-up studies.
In summary, our study demonstrated that anti-PLA2R antibody testing has high accuracy for noninvasively diagnosing PMN in a large Chinese cohort. Compared with studies in Western populations2,10,11, we observed pathological variations in MN and complicating diseases more frequently in the Chinese population. Thus, an individualized approach should be employed when deciding whether to use antibody testing instead of renal biopsy to diagnose MN in Chinese patients. We recommend that in patients with nephrotic syndrome, preserved kidney function, positive serum anti-PLA2R antibody (≥ 20 RU/mL; ELISA), and no comorbidities, renal biopsy is not necessary for the diagnosis of MN. However, close observation and follow-up are warranted to monitor the emergence of new clinical manifestations, immunological seropositivity and poor treatment response in these patients. Furthermore, renal biopsy should be performed to avoid misdiagnosis or missed diagnoses.
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- Source: https://www.nature.com/articles/s41598-024-53445-x