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

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 6months. 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 3months after tacrolimus therapy. Renal response was assessed according to ACR response criteria after 3 and 6months 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 3months, and 11 patients achieved renal response (7 PR and 4 CR) at 6months 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 3months (p < 0.001) and to 0.80 (0.19-1.30) at 6months (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 3months 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.