IgG4-RKD is any form of renal involvement in IgG4-RD [
4]. Its typical manifestation is TIN with multiple organ damage [
5,
7], which can be accompanied by a chronic or rapid progressive decline in renal function [
9,
10]. Only a small number of IgG4-RKD patients have disease that involved only the glomeruli and that was initially manifested as nephrotic syndrome, and approximately 7% of IgG4-RD patients have undergone renal biopsy [
11]. The number of patients with disease recurrence accompanied by IgG4-TIN is even smaller.
Our current patient had an initial disease manifestation of MN, which manifested as nephrotic syndrome. The disease was alleviated after treatment but relapsed upon drug withdrawal, and renal insufficiency was very serious. After the second renal biopsy, a pathological diagnosis of IgG4-TIN with MN was made. Comparison of the results of the two renal biopsies confirmed that the MN found during the first attack was also associated with IgG4-RKD. Thus, IgG4-RKD can be initially manifested as MN, followed by TIN. IgG4-RD is a cause of secondary MN [
4]. This extremely rare form of IgG4-RKD features initial involvement of renal glomeruli, followed by the renal interstitium as the disease progresses. While IgG4-RKD with TIN as its initial manifestation will not be missed, IgG4-RKD with MN as its initial manifestation can be easily overlooked. Therefore, this special form of IgG4-MN should be considered to be a differential diagnosis in patients presenting with MN, to ensure the early identification of IgG4-RD and avoid a missed diagnosis and delayed treatment.
How can this early identification of IgG4-MN in patients with MN be achieved? First, MN patients often have multi-system injuries, in which the possibility of IgG4-RKD involvement should be identified. In our current case, during the first disease attack, the patient had unexplained binocular chronic lacrimal gland inflammation. He also had exophthalmos, epiphora, and congestive conjunctiva. Chronic dacryocystitis is an infection of the lacrimal sac that is typically associated with nasolacrimal duct obstruction [
12], which was an important clinical clue. Second, laboratory tests showed that renal dysfunction progressed slowly in the patient. If patients with MN have AKI after recurrence or during treatment, a change in the pathological type should be considered after factors such as pre-renal azotemia, thrombosis, and medications are ruled out. A second renal biopsy should be performed to avoid a missed diagnosis of IgG4-MN. The typical laboratory findings of IgG4-MN include hyper-IgG-emia, hyper-IgG4-emia, and hyper-IgE-emia [
4]. In our current case, although the total IgG level was not high, the relative level of IgG4 was markedly elevated, which might be caused by proteinuria and massive loss of IgG in the patient. Although the relative serum levels of IgG and IgG4 were not high, the proportion of IgG4 was high over the total IgG, which was also highly suggestive of IgG4-MN. The serum anti-M-type phospholipase A2 receptor (PLA2R) is typically positive in primary MN patients, but it is negative in patients with MN secondary to IgG4-RD [
13‐
15]. A meta-analysis showed that the sensitivity and specificity of serum anti-PLA2R antibody were 68 and 97% in the differential diagnosis of primary MN and secondary MN, respectively [
16]. In our current case, PLA2R was negative during both attacks. Thus, patients with PLA2R-negative MN should be further examined to identify IgG4-RKD and other secondary MN. In addition, primary MN has similar pathological findings to IgG4-MN. The typical renal pathological features of IgG4-RKD include renal interstitial fibrosis and focal lymphoplasmacytic infiltration, during which eosinophil infiltration, tubulitis, and inflammatory cell infiltration of the renal capsule can be observed. Immunohistochemistry shows interstitial IgG4+ plasma cell infiltration (> 10/hpf), and IgG4-positive plasma cells account for more than 40% of IgG+ plasma cells [
13,
15]. Clinicians treating MN patients presenting with inflammatory cell infiltration and tubule-interstitial injury also require special staining to facilitate the early detection of IgG4-RKD. While IgG-RKD can also be treated using the standard combination of immunosuppressant and steroid therapy [
9,
10], it has a higher recurrence rate than MN [
17], and delayed treatment will increase the risk of renal failure [
18]. The differences between primary MN and IgG4-MN are summarized in Table
2.
Table 2
Differences between primary MN and IgG4-MN
Laboratory tests | Renal function | Often normal | Often abnormal |
Serum IgG4 | Often not elevated | (Absolute or relative values) often elevated |
Serum IgE | Often not elevated | Often elevated |
PLA2R | Often positive | Negative |
Pathology | Pathological IgG subtypes | Various | Mainly IgG4 |
Interstitial damage | Without plasma cell infiltration and often without interstitial damage | With plasma cell infiltration and often with interstitial damage |
Treatment protocol | Hormone dosage | Typically adequate (Prednisone dose that was 1–2 mg/kg/d) | Generally medium and small dose (Prednisone dose that induced was 30–40 mg/d) |
Withdrawal of hormone | Hormone are withdrawn regularly, and will be stopped when the condition is alleviated | Maintenance is required |
TIN is the most common initial manifestation of IgG4-RKD, whereas IgG4-RKD with MN as its initial manifestation is much rarer. In patients with MN accompanied by multi-system damage, impaired renal function, elevated IgG4 (absolute or relative value), negative PLA2R, and/or renal interstitial plasma cell infiltration, the possibility of IgG4-RKD should be carefully assessed.