Tacrolimus Versus Cyclophosphamide as Treatment for Lupus Nephritis
Condition: SLE; Lupus Nephritis; Renal Insufficiency; End-stage Renal Disease
MeSH terms: Kidney Failure, Chronic; Renal Insufficiency; Nephritis; Lupus Nephritis
Study type: Interventional
Phase: Phase 1

Summary: 
      In this comparative open-label cohort study, the investigators compared the efficacy and
      safety of tacrolimus (TAC)and cyclophosphamide (CYC) in the treatment of diffuse
      proliferative and membranous lupus nephritis with severe renal disease. Treatment of lupus
      nephritis (LN) with cyclophosphamide is effective, but retain a certain proportion of renal
      function exacerbations. Tacrolimus may be a suitable substitute treatment for CYC.

      Methods: Forty patients with diffuse proliferative or membranous were recruited for this
      trial, 45% of them had lower Ccr (<60mL/min/1.73m2), 10% had increased serum creatinine
      (>180µmol/L) and 67.5% had nephritic proteinuria (>3.5g/day). The investigators compared the
      efficacy and adverse effects of TAC (0.04-0.08 mg/kg/d) and prednisone for 12 months (TAC
      group) with pulse cyclophosphamide (750mg/m2 per month for six months) and prednisone
      followed by azathioprine (50mg/day）for 6 months (CYC group).
    

Detailed description: 
      Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. About 60% of SLE
      patients have renal disease, and patients with rapidly progressive destruction of renal
      parenchyma have significantly poorer prognosis. Drug therapies that employ corticosteroids,
      cyclophosphamide, and/or mycophenolate mofetil have improved patient outcomes, but a
      significant number of patients have refractory disease or cannot tolerate these drugs.
      Moreover, SLE patients who are partially responsive or resistant to treatment have
      significant morbidity，mortality, and exacerbations of renal function. Thus, in patients with
      lupus nephritis (LN), the two main causes of morbidity and mortality are treatment-related or
      patient-related. It has been suggested that new therapies be developed for SLE that more
      specifically target the relevant immunopathogenetic pathways, so as to achieve greater
      efficacy and reduce therapy-related toxicities ，and to save or protect renal function.

      Tacrolimus (TAC) is an immunosuppressive macrolide of the calcineurin inhibitor (CNI) group
      that is widely administered following organ transplantation. In 1989, Takabayashi K. et al.
      studied the effect of TAC on a murine model of SLE, and showed that it prolonged lifespan,
      reduced proteinuria, and prevented the progression of nephropathy, although it had no
      appreciable effect on the levels of anti-dsDNA antibodies. More recent small-scale studies
      have shown that TAC may be an effective treatment for nephritic syndrome and LN8-11. However,
      there is little clinical experience in the use of TAC for treatment of LN, especially for LN
      with severe renal disease, and limited knowledge of the comparative efficacy of TAC and other
      therapies.

      In this comparative open-label cohort study, we compared the efficacy and safety of TAC and
      CYC in the treatment of diffuse proliferative and membranous lupus nephritis with severe
      renal disease.

      LN is characterized by autoantibody-mediated vasculitis that may lead to rapid progression of
      multi-system and organ damage. The kidneys are often involved due to excretion of excessive
      urinary protein and/or rapidly progressive kidney injury, and end-stage renal disease may
      result. Treatment-related differences in the rates of renal failure may not be discernible
      early in the course of treatment, but there are definite advantages of rapid remission,
      effective prophylaxis against relapse, and prevention of renal failure.

      An intravenous pulse CYC regime has been the "gold standard" immunosuppressive regime for the
      treatment of LN. The activation of lymphocytes, production of autoantibody, and high
      expression of IFN-γ in the circulation and renal tissue are important indicators of renal
      injury in SLE. Previous clinical and animal studies have shown that TAC therapy inhibits
      T-lymphocyte activation, suppresses cytokine production in lymphocytes, suppresses
      antigen-induced monokine (TNF-α) production in macrophages, reduces interleukin-2 mRNA
      expression, decreases serum levels of IFN-γ and IFN-γ mRNA expression in the kidney and
      spleen, and decreases serum levels of IgG-class anti-DNA antibodies. A recent study also
      showed that TAC treatment affects B-cell antibody responses indirectly by interfering with
      T-helper cells.

      The risk of end-stage renal failure is particularly high in patients with diffuse
      proliferative glomerulonephritis. Despite the diverse and complex interplay of various
      causative factors in individual patients, two previous studies suggested that SLE patients
      who experience glomerulonephritis that does not diminish following treatment with
      conventional immunosuppressive therapies have increased risk for subsequent deterioration of
      renal function and poor long-term outcome. This suggests that there is an urgent need for
      alternative immunosuppressive therapies for treatment of SLE, and motivated our investigation
      of TAC. On the other hand, it is well know that calcineurin inhibitors (such as TAC) are
      associated with chronic nephrotoxicity. For example, Tse et al. showed that one of six
      patients developed chronic nephrotoxicity after 10 months of TAC therapy. As a calcineurin
      inhibitor, TAC has a lower potential for nephrotoxicity than cyclosporine.

      Opportunistic infection is a severe complication that can result from treatment of LN with
      immunosuppressive drugs.
    

Intervention name(s): Tacrolimus; cyclophosphamide
Intervention type(s): Drug; Drug
Intervention description(s): The calcineurin inhibitor is widely administered for organ transplantation，which establish the current method for lupus nephritis (LN).
20 patients with LN were self-assigned the therapy of TAC and prednisone for 12 months. The dosage was adjusted to achieve a whole blood TAC 12 h trough concentration.; 20 patients with LN were self-assigned the protolcol of intravenous cyclophosphamide (750mg/m2 per month)/prednisone for six months followed by azathioprine(100mg/day)/prednisone for six months.
Other intervention name(s): Prograf
Intervention MeSH terms: Cyclophosphamide; Tacrolimus
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lupus nephritis; tacrolimus; cyclophosphamide