Urinary B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL): potential biomarkers of active lupus nephritis

Abstract

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) help in B cell activation, maintenance and plasma cell survival. B cell infiltration has been demonstrated in kidneys of patients with lupus nephritis (LN). Serum levels of BAFF and APRIL have shown inconsistent relationships with lupus disease activity. We evaluated urinary levels of BAFF and APRIL as biomarker for LN. Thirty-six patients with proliferative lupus nephritis (AN), 10 with active lupus without nephritis (AL) and 15 healthy controls (HC) were studied. APRIL and BAFF levels were measured in both serum and urine using enzyme-linked immunosorbent assay (ELISA). Urine levels were normalized for urinary creatinine excretion. Urine levels were correlated with conventional disease activity markers and histology. Levels were reassessed in 20 AN patients at 6 months after treatment with cyclophosphamide. Urinary APRIL (uAPRIL) and BAFF (uBAFF) levels were raised significantly in AN. uAPRIL, but not uBAFF, correlated moderately with renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in AN (r = 0·36, P < 0·05). On receiver operator curve (ROC) analysis, uBAFF and uAPRIL showed an area under the curve (AUC) of 0·825 and 0·781, respectively, in differentiating between nephritis and non-nephritis, which performed better than low C3, C4 and raised anti-dsDNA antibodies. There was no correlation of serum levels with uBAFF (r = 0·187, P = 0·261) and uAPRIL (r = 0·114, P = 0·494). uAPRIL levels reduced after treatment (mean 125 pg/mg to 36 pg/mg, P < 0·05). uBAFF levels reduced in 16 responders while two of four non-responders had increase in levels. Thus, uBAFF and uAPRIL are potential biomarkers of proliferative lupus nephritis.

Dendritic cells’ characteristics in patients with treated systemic lupus erythematosus

“…In a previous study, we have shown that there were no significant differences in serum levels of BAFF in SLE patients when compared to healthy controls, while the APRIL levels were even significantly decreased (Wardowska et al, 2020). As we suggested earlier, it is also possible that an increased APRIL gene expression in B cells of SLE patients (Wardowska et al, 2020), as well as in mDCs, as demonstrated here, is the result of feedback in response to urinary protein loss which is a phenomenon often described in SLE (Phatak et al, 2017).…”

Expression of BAFF, APRIL, and cognate receptor genes in lupus nephritis and potential use as urinary biomarkers

“…Therefore, it is necessary to identify non-invasive biomarkers that can be easily obtained and reflect current renal inflammation [ 34 ]. Over the last two decades, many clinical studies have demonstrated the presence of molecules associated with B-cell activation in the serum [ 29 , [35] , [36] , [37] ] and kidney tissues [ 24 , 26 , 28 , 38 ] of active LN patients. One study demonstrated that serum BAFF level was lower in SLE patients with nephrotic-range proteinuria than in SLE patients with less severe proteinuria.…”

“…Furthermore, the selective blockade of BAFF prevents the development of LN in mice [ 23 ]. B-cell infiltration has also been demonstrated in the kidneys of proliferative LN patients [ 24 ], resulting in elevated renal BAFF and APRIL that can be detected in urinary sediment [ 25 ], suggesting potential utility of these factors as urinary disease biomarkers.…”

“…Several animal model studies have demonstrated pathogenic roles for BAFF, APRIL, and their receptors in SLE and LN, and human clinical studies have demonstrated immunohistochemical expression of BAFF in glomeruli and tubular epithelial cells [ [24] , [25] , [26] , [27] , [28] , [29] ]. However, there are many obvious advantages of urinary detection.…”

Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

“…Several putative novel serum and urine biomarkers have been studied in LN. [104][105][106][107] These candidate markers must be studied in a prospective fashion, ideally in clinical trials. It is likely that biomarker panels will be required to accurately stratify risk, predict flare, determine treatment, monitor response to treatment, and predict prognosis.…”