Characterising the immune profile of the kidney biopsy at lupus nephritis flare differentiates early treatment responders from non-responders

INTRODUCTION: The kidney biopsy is used to diagnose and guide initial therapy in patients with lupus nephritis (LN). Kidney histology does not correlate well with clinical measurements of kidney injury or predict how patients will respond to standard-of-care immunosuppression. We postulated that the gene expression profile of kidney tissue at the time of biopsy may differentiate patients who will from those who will not respond to treatment. METHODS: The expression of 511 immune-response genes was measured in kidney biopsies from 19 patients with proliferative LN and 4 normal controls. RNA was extracted from formalin-fixed, paraffin-embedded kidney biopsies done at flare. After induction therapy, 5 patients achieved a complete clinical response (CR), 10 had a partial response (PR) and 4 patients were non-responders (NRs). Transcript expression was compared with normal controls and between renal response groups. RESULTS: A principal component analysis showed that intrarenal transcript expression from normal kidney, CR biopsies and NR biopsies segregated from each other. The top genes responsible for CR clustering included several interferon pathway genes (STAT1, IRF1, IRF7, MX1, STAT2, JAK2), while complement genes (C1R, C1QB, C6, C9, C5, MASP2) were mainly responsible for NR clustering. Overall, 35 genes were uniquely expressed in NR compared with CR. Pathway analysis revealed that interferon signalling and complement activation pathways were upregulated in both groups, while BAFF, APRIL, nuclear factor-κB and interleukin-6 signalling were increased in CR but suppressed in NR. CONCLUSIONS: These data suggest that molecular profiling of the kidney biopsy at LN flare may be useful in predicting treatment response to induction therapy.