Featured New InvestigatorMolecular imaging of the kidney in lupus nephritis to characterize response to treatment
Introduction
The short-term goal of lupus nephritis (LN) induction therapy is to achieve a clinical response, assessed mainly as a reduction in proteinuria and stabilization or improvement in kidney function. In human LN, the intrarenal molecular correlates of clinical response or nonresponse are not known, although such data are emerging in animal models of lupus.1, 2 Understanding the kidney's molecular response to treatment may have therapeutic implications. For example, it is becoming increasingly clear that a clinical renal response may not reflect histologic resolution of kidney injury.3 This raises the possibility that despite treatment and improvement of clinical signs of kidney injury, there may be ongoing activity of the intrarenal immune and inflammatory pathways that were engaged at the time of LN flare. Knowledge of these active pathways could facilitate maintenance therapy. Furthermore, patients who completely respond to treatment often develop chronic kidney damage, suggesting the activation of additional mechanisms of kidney injury, like fibrosis pathways, during therapy.4 Such mechanisms, if known may be amenable to treatment, and this could attenuate the development of chronic kidney disease in lupus. For patients who do not respond to conventional immunosuppressive therapy, it is reasonable to assume that certain intrarenal immune and inflammatory pathways are still active, but without identifying these pathways the choice of an alternative treatment regimen remains uninformed.
To characterize the molecular correlates of clinical renal responses, we have examined intra-renal gene expression in serial biopsies from a well-phenotyped LN cohort. Transcript expression of genes relevant to immunity and inflammation were measured in kidney biopsy material taken at the time of LN flare and after completion of induction therapy in patients who responded completely to induction and patients who did not respond to induction. Differentially-expressed transcripts in LN biopsies relative to normal kidney were identified, and changes in transcript expression between responders and nonresponders during treatment were compared.
Section snippets
Kidney biopsies
Kidney biopsies were done on 19 patients with proliferative (Class III or IV ± V) LN between 2007 and 2011. The biopsies had been archived after all clinical testing was completed. Biopsy 1 (Bx1) was done to diagnose LN flare and biopsy 2 (Bx2) was done after LN induction therapy was completed. Patients were segregated by clinical response and only those who achieved a complete clinical response (n = 5) or had a nonresponse (n = 4) were included in the analysis. Ten patients achieved a partial
Results
The clinical, demographic, and pathologic characteristics of the LN kidney biopsy cohort are provided in Table I. All patients were White and Hispanic. The median time between Bx1 and Bx2 was 13 months, with a range of 6–37 months. The median time between Bx1 and Bx2 in the CR group was 13 months (6–37) and the median time between Bx1 and Bx2 in the NR group was 12.5 months (6–28). The clinical variables and follow-up time between biopsies for each patient are provided in Table II. Although
Discussion
This is the first study to profile the expression of immune system genes in the kidneys of patients with LN before and after induction therapy, and associate changes in transcript expression with clinical responses to treatment. Several general observations emerged from this investigation. Most importantly, despite complete clinical remission after induction, intrarenal immune and inflammatory gene expression did not return to levels seen in normal kidneys, although most of these up- or
Acknowledgments
Conflicts of Interest: All the authors have read the journal's authorship agreement. Dr Rovin is a Scientific Advisor for Biogen Idec, Mallinckrodt, Centocor, Lilly, GlaxoSmithKline, Abbivie, and Genentech. Dr Rovin has received research funding from Biogen Idec and Malinckrodt. Dr Parikh has received a Research Fellowship Grant from Mallinckrodt and served as a Consultant for Alexion Pharmaceuticals. There are no other conflicts of interest to disclose.
This work was supported by NIDDK U01:
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Samir V. Parikh, MD, is an Assistant Professor in the Division of Nephrology at The Ohio State University Wexner Medical Center.
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Drs. Parikh and Malvar contributed equally to this work.