Kidney Tertiary Lymphoid Tissues and Poor Immunosuppressive Response in IgA Nephropathy

Abstract

Introduction: Ectopic lymphoid structures termed as tertiary lymphoid tissues (TLTs) are observed in certain kidney diseases, including IgA nephropathy (IgAN); however, clinical relevance of TLTs remains unclear.

Methods: This prospective cohort study included 845 Chinese patients with IgAN with proteinuria ≥ 1 g/d despite 3 months of optimized supportive care with renin-angiotensin system inhibitors. Patients received immunosuppression for a median of 22 months. Kidney interstitial TLTs, defined as lymphocyte aggregates, were counted using immunochemistry and staged by the absence (stage I) or presence of follicular dendritic cells (FDCs) (stage II) or germinal centers (GCs) (stage III). The outcome was response to immunosuppression, defined as no remission with up to 12 months of immunosuppression.

Results: Kidney interstitial TLTs were present in 429 of 845 patients with IgAN (50.8%), of whom 72 of 429 (16.8%) had TLTs at advanced stages (stage II or III). Compared with patients without TLTs, both the presence and stage of TLTs were associated with significantly increased risk of poor response to immunosuppression, with an adjusted odds ratio (95% confidence interval [CI]) of 3.07 (2.16-4.37), 2.97 (2.05-4.28), and 6.25 (3.39-11.53) in those with TLTs at any stage, stage I, and advanced stage, respectively. This grade association remained consistent across all prespecified subgroups. The stage and number of TLTs predicted poor response to immunosuppression with an area under receiver operating characteristic curve (AUC) of 0.81 (95% CI: 0.75-0.87). The AUC increased to 0.90 (95% CI: 0.87-0.94) when we combined TLTs with the clinical and glomerular macrophage data at biopsy.

Conclusion: The presence of interstitial TLTs at diagnosis was associated with poor response to immunosuppression in IgAN.

Keywords: IgA nephropathy; immunosuppression; response; tertiary lymphoid tissues.

Graphical abstract

Figure 1

Flowchart of enrollment and exclusion of the study cohorts. AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; GN, glomerulonephritis; IgAN, IgA nephropathy; RASi, renin-angiotensin system inhibitor.

Figure 2

Characteristics of tertiary lymphoid tissues in kidney from patients with IgAN. An overview of PAS-stained kidney tissues from a patient with IgAN revealing multiple lymphocyte infiltrates, as indicated by the (a) boxed areas, which were predominantly located under (b) the kidney capsule, (c) periglomerular region, or (d) surrounding blood vessels, and (e–g) were further confirmed as tertiary lymphoid tissues by CD3 and (h–j) CD20 immunohistochemistry staining. PAS, periodic acid-Schiff.

Figure 3

Representative photos of tertiary lymphoid tissues in renal tubulointerstitium in patients with IgA nephropathy. The stages of tertiary lymphoid tissues were determined by the expression patterns of CD3, CD20, CD21, and Ki67 using immunochemistry staining in sequential sections.

Figure 4

Maturation of kidney tertiary lymphoid tissues (TLT) and association with poor response to immunosuppressive therapy in IgA nephropathy. Schematic representation of kidney TLT maturation and its association with treatment response in patients with IgA nephropathy. The left panel shows morphological features of stage I (immature lymphocyte aggregates), stage II (organized aggregates with follicular dendritic cells), and stage III (advanced structures containing germinal center B cells). The right upper panel illustrates different types of immunosuppressive strategies administered to patients with IgA nephropathy. The right middle panel summarizes the proportion of patients responding to immunosuppressive therapy according to TLT stage (no TLT, stage I, advanced stage II and III). The lower right panel shows the adjusted odds ratio (95% confidence interval) for poor response across TLT stages. (Figure created with biorender.com).