Elsevier

Translational Research

Volume 182, April 2017, Pages 1-13
Translational Research

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

https://doi.org/10.1016/j.trsl.2016.10.010Get rights and content

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 intrarenal transcript expression were measured and correlated with response in a LN cohort that underwent serial kidney biopsies. The intrarenal 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 with normal controls (n = 4), and the change in expression was compared in each responder group and between groups. Compared with controls, the CR group had 21 and 28, whereas 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.

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:

References (27)

  • E. Buzhor et al.

    Reactivation of NCAM1 defines a subpopulation of human adult kidney epithelial cells with clonogenic and stem/progenitor properties

    Am J Pathol

    (2013)
  • M.A. Otten et al.

    The Fc receptor for IgA (FcalphaRI, CD89)

    Immunol Lett

    (2004)
  • C.C. Berthier et al.

    Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis

    J Immunol

    (2012)
  • R. Bethunaickan et al.

    Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice

    Arthritis Rheumatol

    (2014)
  • A. Alvarado et al.

    The value of repeat kidney biopsy in quiescent Argentinian lupus nephritis patients

    Lupus

    (2014)
  • A. Malvar et al.

    Histologic versus clinical remission in proliferative lupus nephritis

    Nephrol Dial Transplant

    (2015)
  • B.H. Hahn et al.

    American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis

    Arthritis Care Res

    (2012)
  • S.V. Parikh et al.

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

    Lupus Sci Med

    (2015)
  • V. Dave et al.

    Use of the nCounter system for the analysis of multiple RNA expression profiles in peripheral blood mononuclear cells

    Environ Mol Mutagen

    (2013)
  • Y. Golubeva et al.

    Laser capture microdissection for protein and NanoString RNA analysis

    Methods Mol Biol

    (2013)
  • E. Vaes et al.

    Statistical analysis of differential gene expression relative to a fold change threshold on NanoString data of mouse odorant receptor genes

    BMC Bioinformatics

    (2014)
  • M.A. Sartor et al.

    Intensity-based hierarchical Bayes method improves testing for differentially expressed genes in microarray experiments

    BMC Bioinformatics

    (2006)
  • L. Bao et al.

    C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

    Eur J Immunol

    (2005)
  • Cited by (32)

    • Molecular profiling of kidney compartments from serial biopsies differentiate treatment responders from non-responders in lupus nephritis

      2022, Kidney International
      Citation Excerpt :

      Some pathways are dysregulated in both the glomerular and TI compartments, such as the type 1 interferon pathway, which has a well-established role in the pathogenesis of SLE and LN.36,37 Using whole kidney biopsies in a separate LN cohort, we have previously shown that intrakidney interferon transcripts remain overexpressed in NR after treatment.38 This persistence of an interferon signature after treatment in NRs was confirmed in the current study of kidney compartments.

    • Intertwined pathways of complement activation command the pathogenesis of lupus nephritis

      2022, Translational Research
      Citation Excerpt :

      In the kidneys of patients with SLE who did not achieve a clinical response after standard 6 months of induction therapy, the expression of C3 and FD was increased by 80% and 122% compared to that before induction therapy, respectively. On the other hand, in the kidneys of patients with SLE who achieved a complete clinical response, the expression of many of the complement genes tended to normalize after treatment.110 These findings suggest that the alternative pathway may be a potential therapeutic target for refractory LN.

    • The lupus nephritis management renaissance

      2022, Kidney International
      Citation Excerpt :

      Transcriptional profiling of kidney tissue was used to characterize the molecular differences between LN patients who were complete renal responders and nonresponders after treatment. Nonresponders were patients who had neither a complete renal response or a partial response.112,113 On the basis of the first (diagnostic) kidney biopsy, patients who would not respond to therapy displayed more dysregulated genes than those who would become complete renal responders.

    • Kidney disease

      2021, Lahita’s Systemic Lupus Erythematosus
    • Moving Forward With Biologics in Lupus Nephritis

      2019, Advances in Chronic Kidney Disease
    View all citing articles on Scopus

    Samir V. Parikh, MD, is an Assistant Professor in the Division of Nephrology at The Ohio State University Wexner Medical Center.

    1

    Drs. Parikh and Malvar contributed equally to this work.

    View full text