Clinical bottom line
IgG4-related tubulointerstitial nephritis (IgG4-TIN) is a distinct immune-mediated kidney disease characterized by infiltration of IgG4-positive plasma cells and fibrosis, often responsive to corticosteroids. However, a subset of patients with refractory or relapsing disease may not achieve sustained remission with steroids alone. Emerging evidence suggests that anti-tumor necrosis factor (anti-TNF) therapies could represent a promising adjunctive treatment option for refractory IgG4-TIN, potentially improving renal outcomes and reducing steroid exposure. This evidence remains preliminary and hypothesis-generating, warranting further clinical validation.
What the evidence shows
IgG4-related kidney disease (IgG4-RKD) primarily manifests as tubulointerstitial nephritis with characteristic histopathologic features including storiform fibrosis, dense lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, and often elevated serum IgG4 levels (Nagata et al., 2016; Cornell et al., 2010). Corticosteroids remain the first-line therapy and typically induce remission; however, relapse rates are notable, and some cases demonstrate steroid resistance or intolerance (Buglioni et al., 2022).
The pathogenesis of IgG4-TIN involves complex immune dysregulation with a prominent role for Th2 and regulatory T-cell cytokines, but emerging data implicate proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) in sustaining renal inflammation and fibrosis (Yamaguchi et al., 2016). This mechanistic insight has led to exploration of anti-TNF agents as potential therapeutic adjuncts.
Although randomized controlled trials are lacking, case reports and small case series have described the use of anti-TNF therapies such as infliximab or adalimumab in refractory IgG4-RKD with encouraging results. These reports indicate that anti-TNF treatment may reduce renal inflammation, improve renal function, and allow steroid tapering in patients unresponsive to conventional immunosuppression (Buglioni et al., 2022). The evidence remains limited but suggests a potential role for anti-TNF agents in selected refractory cases.
Caveats and uncertainty
The current evidence supporting anti-TNF therapy in IgG4-TIN is largely anecdotal and derived from small observational reports rather than controlled trials. The rarity of IgG4-TIN and heterogeneity in clinical presentation complicate robust assessment of treatment efficacy. Additionally, the long-term safety and optimal dosing regimens of anti-TNF agents in this population are unknown.
IgG4-RKD can overlap with other renal pathologies, including membranous nephropathy and ANCA-associated glomerulonephritis, which may confound interpretation of treatment response (Hatta et al., 2013; Su et al., 2017). Moreover, the immunopathology of IgG4-TIN is complex, and TNF-α may not be the dominant driver in all patients, limiting generalizability.
Given these uncertainties, anti-TNF therapy should be considered experimental and reserved for refractory cases after multidisciplinary evaluation. Prospective studies and clinical trials are needed to define patient selection criteria, efficacy, and safety profiles.
How this may change practice
For nephrologists managing IgG4-TIN, awareness of anti-TNF agents as a potential adjunctive therapy in refractory or relapsing disease may expand therapeutic options beyond corticosteroids and conventional immunosuppressants. In patients with persistent renal inflammation despite standard treatment, anti-TNF therapy could be discussed in specialized centers with experience in IgG4-RKD.
This approach may help reduce cumulative steroid exposure and associated toxicity, potentially improving long-term renal outcomes. However, clinicians should exercise caution, given the limited evidence base, and closely monitor for infectious complications and other adverse effects associated with anti-TNF agents.
Future incorporation of anti-TNF therapies into treatment algorithms will depend on emerging clinical trial data and consensus guidelines. Meanwhile, individualized risk-benefit assessment and shared decision-making remain paramount.