Molecular imaging of the kidney in lupus nephritis to characterize response to treatment

Abstract

The consequences of treatment for the kidney at the molecular level have not been explored in human lupus nephritis (LN). In this investigation, changes in intra-renal transcript expression were measured and correlated with response in a LN cohort that underwent serial kidney biopsies. The intra-renal transcript expression of 19 patients with proliferative LN (Class III or IV) was measured at diagnostic biopsy (Bx1) and after induction therapy was completed (Bx2) using Nanostring® technology. Patients were segregated by clinical response into complete responders (n=5, CR) or nonresponders (n=4, NR). Transcript expression for each biopsy was compared to normal controls (n=4) and the change in expression was compared in each responder group and between groups. Compared to controls, the CR group had 21 and 28 while NR had 45 and 103 differentially-expressed transcripts at Bx1 and Bx2, respectively. The profiles of these differentially-expressed genes indicated that the type I and II interferon, alternative complement and T cell signaling pathways discriminated CR from NR. Comparing the change in transcript expression from Bx1 to Bx2 revealed a 5-gene signature that differentiated NR from CR and included increased IL1RAP and FCAR in NR and increased NCAM1 in CR. In summary, molecular imaging of serial kidney biopsies from LN patients shows several immune and inflammatory pathways that are dysregulated in the kidneys during active disease that may serve as therapeutic targets to improve clinical response. This approach to LN biomarker development may facilitate personalized medicine in LN and improve long-term kidney outcomes.

Dysregulated heme oxygenase-1low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons

“…We hypothesized that local inflammatory conditions of LN are responsible for the discrepancy between CD163/CMAF positivity and HO-1 expression in glomerular Mϕ. In the present study, we focused on effects of IFN-α on mRNA expression of both molecules in human monocyte-derived M2-like Mϕ generated in vitro , because type I IFN and the related genes are upregulated in patients with LN, including the renal tissues as a so-called IFN signature [ 1 , 3 , 30 ].…”

Tubulointerstitial damage predicts end stage renal disease in lupus nephritis with preserved to moderately impaired renal function: A retrospective cohort study

“…Further studies are needed to determine if early treatment with MMF in these patients may be beneficial to prevent TID. Novel approaches including molecular imaging, cell distance mapping, functional magnetic resonance imaging, as well as integrative biology approaches are being developed to identify early inflammatory changes, biomarkers and response to treatment in lupus nephritis [52–55]. …”

Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis

“…In line with our own results, they reported that transcripts associated with leucocyte infiltration, T cell activation, complement pathway and interferon signature increased between baseline and follow-up in non-responders. 32 In the present study, we instead used an unbiased analytical approach, grouping the samples based on their molecular characteristics rather than predefined clinical categories, resulting in the identification of a link between T and B cell infiltration and activation, tubular damage and decreased renal function in LN. Tubulointerstitial lesions were previously already identified as a prognostic marker in LN.…”