Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: a non-randomized prospective cohort study

Abstract

Treatment of lupus nephritis (LN) with cyclophosphamide (CYC) is effective but retains a certain severe adverse effect. Tacrolimus (TAC) may be a suitable treatment for LN. Forty patients with diffuse proliferative or membranous LN were recruited for this non-randomized open-label study - 67.5% (27/40) had nephrotic proteinuria (>3.5 g/day) and 50.0% (20/40) had low estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73m(2)). We compared the efficacy and adverse effects of TAC (0.04-0.08 mg/kg/d)/prednisone for 12 months (TAC group, n = 20) with intravenous CYC (750 mg/m(2) per month)/prednisone for six months followed by azathioprine (Aza) (100 mg/day)/prednisone for six months (CYC group, n = 20). The TAC target concentration was 6-8 ng/mL or 4-6 ng/mL, respectively, when induction or maintenance therapy was required and 4.0 ng/mL for patient with renal insufficiency. In the TAC group, mean urinary protein excretion decreased significantly from 5.00 ± 1.91 g/day at baseline to 2.54 ± 1.68 g/day after two weeks of therapy (P < 0.001), compared with the CYC group (4.9 ± 19.4 g/day), P = 0.001, and 65.0% (13/20) achieved partial remission at one month, compared with the CYC group (0/20), P < 0.001. The incidence of complete remission (CR) was significantly higher in the TAC group than in the CYC group (55.0% vs.15.0% by five months, P = 0.008, and 75.0% vs.40.0% by 12 months, P = 0.025, respectively). The significant improvement in serum anti-dsDNA and systemic lupus erythematosus (SLE) disease activity index (DAI) was in the TAC group relative to the CYC group at 12 months (P = 0.031, P = 0.003, respectively). The eGFR improved in the TAC group from 59.90 ± 23.64 mL/min/1.73m(2) at baseline to 93.75 ± 28.52 mL/min/1.73m(2) after 12 months, P = 0.001. In the CYC group, two patients developed end-stage renal disease (ESRD), three patients experienced serious pneumonia, and one patient died. Our preliminary study showed TAC is a safe and effective treatment for LN with severe renal disease, and with less-severe adverse events compared with CYC followed Aza therapy. Further larger sample studies are needed to confirm our conclusion.

Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus

“…These drugs not only bind to P-gp and inhibit its activity but also downregulate P-gp expression by inhibiting IL-2 synthesis. Recently, few studies and even a meta-analysis have highlighted the efficacy of tacrolimus in proliferative lupus nephritis and reported its superiority over CYC in induction and even during maintenance therapy [35][36][37][38][39][40]. Another recent study, in which CYC refractory lupus nephritis patients have been effectively treated with low-dose tacrolimus [41], gives strength to our concept to use specific P-gp inhibitors.…”

Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network meta-analysis of randomized controlled trials

“…However, eight of the 17 studies were excluded because they contained duplicate data, [25][26][27] non-RCT data, [28][29][30] or no outcome data. 31 Figure 1).…”

Successful Treatment of Class IV+V Lupus Nephritis with Combination Therapy of High-dose Corticosteroids, Tacrolimus and Intravenous Cyclophosphamide

“…The efficacy of tacrolimus for LN was established in a randomized con- trolled trial conducted in Japan (10) and confirmed in a systematic review (11). In addition, tacrolimus has been reported to be safer than IVCY (12). We herein report a case of refractory LN that was successfully treated with a combination of tacrolimus and IVCY, despite neither of these agents demonstrating any efficacy when administered separately.…”