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Tacrolimus induces remission in refractory and relapsing lupus nephritis by decreasing P-glycoprotein expression and function on peripheral blood lymphocytes

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Abstract

P-glycoprotein (P-gp)-mediated efflux of corticosteroids (CS) may contribute to treatment unresponsiveness in Lupus Nephritis (LN) patients. Tacrolimus is a P-gp inhibitor and hence, may overcome this resistance. We aimed to study the response to tacrolimus, along with the expression and function of P-gp on peripheral blood lymphocytes (PBL) in patients with refractory and relapsing proliferative Lupus Nephritis. We enrolled 12 refractory/relapsing LN patients and treated them with corticosteroids and tacrolimus for 6 months. Expression and function of P-gp on PBL was measured by flow cytometry (as relative fluorescence index, RFI and Rhodamine dye efflux assay) before and 3 months after tacrolimus therapy. Renal response was assessed according to ACR response criteria after 3 and 6 months of tacrolimus therapy. 8 out of 12 refractory/relapsing LN patients achieved renal response (5 partial response, PR and 3 complete responses, CR) as early as 3 months, and 11 patients achieved renal response (7 PR and 4 CR) at 6 months from start of tacrolimus therapy. Proteinuria decreased from median urine protein creatinine ratio (UPCR) of 2.80 (2.00–3.40) at baseline to 1.20 (0.66–1.73) at 3 months (p < 0.001) and to 0.80 (0.19–1.30) at 6 months (p < 0.01). There was significant decrease in P-gp expression [RFI, 3.33 (2.87–4.97) vs 2.03 (1.25–3.86), p < 0.05) and P-gp function (RFI, 55.7 (29.7–84.1) vs 26.8 (16.1–37.0), p < 0.01) after 3 months of tacrolimus therapy. Tacrolimus achieves renal response in refractory/relapsing proliferative LN patients which may be partly related to overcoming P-glycoprotein mediated treatment unresponsiveness.

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Acknowledgements

Part of this work had been presented during Annual American College of Rheumatology meeting in 2017, Abstract number 1920, Gupta V, Edavalath S, Rai MK, Singh H, Chaturvedi S, Agarwal V. Tacrolimus Induces Remission in Refractory and Relapsing Lupus Nephritis By Decreasing P-Glycoprotein Expression and Function on Peripheral Blood Lymphocytes [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/tacrolimus-induces-remission-in-refractory-and-relapsing-lupus-nephritis-by-decreasing-p-glycoprotein-expression-and-function-on-peripheral-blood-lymphocytes/. Accessed November 11, 2021, and at the Annual conference of the Indian Rheumatology Association in 2018, Abstract number PB0005: Anuja A, Rai MK, Misra DP, Agarwal V. Tacrolimus may regulate the pathogenic Th17 cells in lupus nephritis refractory patients [abstract]. Indian J Rheumatol 2018; 13(suppl 6).

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No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

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  1. Sukesh Edavalath and Mohit Kumar Rai have contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Clinical Immunology & Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India

    Sukesh Edavalath, Mohit Kumar Rai, Vikas Gupta, Ravi Mishra, Durga Prasanna Misra, Latika Gupta & Vikas Agarwal

  2. Department of Rheumatology, Dayanand Medical College & Hospital, Ludhiana, India

    Vikas Gupta

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  1. Sukesh Edavalath
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by SE, MKR, VG, RM, DPM and LG. The first draft of the manuscript was written by VA, VG and DPM and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Vikas Agarwal.

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The study was approved by the Institutional Ethics Committee SGPGI, approval number 2014–84-DM-77 dated 27-Mar-2014.

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Edavalath, S., Rai, M.K., Gupta, V. et al. Tacrolimus induces remission in refractory and relapsing lupus nephritis by decreasing P-glycoprotein expression and function on peripheral blood lymphocytes. Rheumatol Int 42, 1347–1354 (2022). https://doi.org/10.1007/s00296-021-05057-1

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