Rethinking the Benign Nature of Class II Lupus Nephritis
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Introduction
Class II lupus nephritis (LN) is considered clinically benign, yet up to 50% of patients progress to more severe disease and no molecular characterization exists. We aimed to define the single-cell landscape of Class II LN and identify cellular and transcriptional features associated with kidney outcome.
Methods
We performed single-cell RNA sequencing on kidney biopsies from 15 Class II LN patients (8 de novo, 7 regressed from prior proliferative or membranous disease) and 6 healthy controls, integrated with 155 LN and 30 healthy-control samples from the Accelerating Medicines Partnership in SLE spanning proliferative, membranous, and mixed LN. Findings were correlated with 52-week renal response and supported by urinary proteomics.
Results
Despite histologically minimal changes, Class II LN exhibited marked immune cell expansion comparable to proliferative and membranous LN, including CCL3+ CCL4+ intermediate monocytes producing TNF, FOLR2+ SIGLEC1+ macrophages producing TGF-beta and PDGF, and CD69+ CD8+ effector memory T cells producing IFN-gamma. Fibroblasts and myofibroblasts were significantly expanded and displayed divergent transcriptional programs: pro-fibrotic and inflammatory myofibroblast modules were associated with worse 52-week outcomes, while interferon-responsive and matrix-remodeling fibroblast programs were associated with improvement. Pathogenic and protective fibroblast populations received overlapping immune-derived signals, suggesting that fibroblast transcriptional state, rather than the identity of incoming signals, shapes the stromal response. Baseline chronicity index captured this stromal heterogeneity and was the clinical parameter most associated with outcome. Urinary proteomics aligned Class II with proliferative rather than membranous disease.
Conclusions
Class II LN harbors substantial molecular activity not captured by routine histology. Fibroblast transcriptional programs and baseline chronicity index are candidate correlates of kidney outcome that warrant validation in larger, prospectively followed cohorts.
Lay summary
Class II lupus nephritis is generally regarded as benign and is not specifically treated, yet up to half of patients later progress to more severe nephritis. To understand this discordance, we applied single-cell RNA sequencing to kidney biopsies from 15 patients with Class II disease and compared them with the full spectrum of lupus nephritis. Despite their mild histologic appearance, Class II kidneys showed immune infiltration comparable to proliferative disease, together with expanded fibroblast populations whose transcriptional programs differed between patients. These fibroblast programs, and the degree of chronic damage already present at biopsy, tracked with kidney outcomes at one year more closely than standard clinical measures. These findings indicate that Class II lupus nephritis carries greater molecular activity than its histology suggests, and that chronicity warrants closer attention in its assessment.
