Background Chronic renal impairment remains a feared complication of lupus nephritis (LN). Yet, little is known about mechanisms and markers of disease severity in the lupus kidney.
Methods We performed high-throughput transcriptomic studies (Illumina HumanHT12 v4 Expression Beadchips) on archived (- 80 degrees) kidney biopsies from 32 SLE patients and 8 controls (pre-transplant donors). Unsupervized clustering and differential gene expression studies were performed using GeneSpring software. Pathway analyses were carried on using DAVID and GSEA. Clinical and biological data were retrieved from the patients' medical records. Immunohistochemistry experiments (CD3, CD20, CD21) were performed on the same samples, and on an additional cohort of 37 SLE kidney biopsies. Syndecan-1 (SDC1) was used as a marker of renal tubular cell response to stress.
Results Compared to controls, LN samples overexpressed transcripts involved in interferon signature, apoptosis, chemokines, antigen presentation, T and B cell activation.
Unsupervized clustering studies isolated 14 SLE samples based on their gene expression features. These samples were characterized by a significantly lower estimated GFR at the time of biopsy (T0) (50.7 versus 97.4 ml/min/1.72m2), but also at follow-up (49.1 versus 85.8 ml/min/1.72m2) compared to the other SLE samples. Yet, apparent renal disease duration at T0, disease duration at last follow-up (median 91.5 versus 86 months), double-stranded DNA antibody titers at T0 and other relevant characteristics (histological scores, proteinuria, numbers of subsequent flares) were not different between both groups.
From a transcriptomic point of view, these 14 samples were characterized by the overexpression of transcripts and pathways involved in adaptive immune responses: antigen presentation, T cell differentiation and B cell activation.
Immunohistochemistry studies confirmed a significant association between the presence of CD3 and CD20 positive cells in the interstitial space and lower estimated GFR at baseline in the same, but also in an independent set of samples. The presence of CD3 and CD20 positive cells was also associated with lower SDC1 expression on renal tubular cells. Low SDC1 expression on renal tubular cells was strongly associated with impaired kidney function at baseline.
Conclusions LN kidney biopsy samples from patients with lower estimated GFR are characterized by the overexpression of transcripts pointing to the activation of a local antigen-dependent immune response. Activation of “second wave” immune effectors in the LN kidney is a known feature of the disease, and impacts kidney function through alterations in the function of renal tubular cells.
Acknowledgements The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115565, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies' in kind contribution
Disclosure of Interest None declared