Beyond glomeruli in lupus nephritis: Impact of tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy on renal function decline – A systematic review and meta-analysis

Background To evaluate the prognostic impact of tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy on renal function decline in patients with lupus nephritis. Methods This systematic review and meta-analysis followed PRISMA and Cochrane guidelines and was registered in PROSPERO (CRD420251045672). PubMed, Embase, Web of Science, and Cochrane were searched for studies evaluating the association between tubulointerstitial histopathologic lesions in lupus nephritis and renal outcomes. Risk ratios were pooled using random-effects models. Prespecified subgroup analyses were conducted according to follow-up duration, and sensitivity analyses included leave-one-out testing and restriction to studies defining ≥25% tubulointerstitial involvement. Meta-regression was performed to explore study-level sources of heterogeneity. Risk of bias was assessed using the Newcastle–Ottawa Scale. Analyses were performed in RStudio. Results Twenty-one retrospective studies encompassing 3607 adult patients with lupus nephritis were included. Tubulointerstitial inflammation (TII) was associated with an increased risk of renal function decline (RR 2.22; 95% CI 1.75–2.82), as was interstitial fibrosis/tubular atrophy (IFTA) (RR 3.44; 95% CI 2.70–4.38). No significant difference was observed between TII and IFTA regarding renal outcomes (RR 0.78; 95% CI 0.59–1.03). In subgroup analyses stratified by follow-up duration, the association between TII and renal decline was stronger in studies with longer follow-up (>5 years), whereas IFTA conferred a consistently elevated risk across follow-up strata. Sensitivity analyses, including leave-one-out testing, confirmed the robustness of findings. Funnel plot symmetry and Egger’s test ( p = 0.9074) indicated no evidence of publication bias. Study-level meta-regression suggested that the association between TII and renal decline varied according to the distribution of proliferative glomerular classes, while the association for IFTA was not significantly modified by glomerular pattern. Conclusion This meta-analysis found that both interstitial fibrosis/tubular atrophy (IFTA) and tubulointerstitial inflammation (TII) are significantly associated with renal function decline in lupus nephritis, suggesting a worse prognosis. These findings highlight the prognostic relevance of tubulointerstitial lesions in lupus nephritis.