Clinical Trials Logo

Clinical Trial 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).


Clinical Trial 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. ;


Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


Related Conditions & MeSH terms


NCT number NCT01207297
Study type Interventional
Source Zhejiang University
Contact
Status Completed
Phase Phase 1
Start date March 2003
Completion date June 2010

See also
  Status Clinical Trial Phase
Completed NCT04087213 - Study of HemoCare™ Hemodialysis System for Home Nocturnal Dialysis in Patients With ESRD N/A
Completed NCT02207088 - Ombitasvir/ABT-450/Ritonavir and Dasabuvir With or Without Ribavirin in HCV Genotype 1-Infected Adults With Chronic Kidney Disease Phase 3
Not yet recruiting NCT03090828 - Economic Evaluation of an Education Platform for Patients With End-stage Renal Disease N/A
Completed NCT02237521 - The Effect of the Incretin Hormones on the Endocrine Pancreatic Function During Hyperglycemia in End-stage Renal Disease N/A
Withdrawn NCT01691196 - Inflammation in Peritoneal Dialysis Patients: Effect of Obesity
Completed NCT01394341 - Liraglutide Treatment to Patients With Severe Renal Insufficiency Phase 4
Active, not recruiting NCT00247507 - The Effects of Acetylcysteine on Alleviating Damage of Oxidative Stress in Hemodialysis Patients Phase 4
Completed NCT00307463 - Effects of Strict Volume Control in Hypertensive Hemodialysis Patients on Cardiac Structure and Chronic Inflammation Phase 4
Recruiting NCT00155363 - Effect of Different Hemodialysis Modality on Adiponectin,Vascular Function and Clinical Prognosis Phase 4
Completed NCT00234156 - The Effect of Fructose on Blood Fats in Dialysis Patients and Healthy Volunteers N/A
Completed NCT00586131 - Arterial pH and Total Body Nitrogen Balances in APD Phase 4
Active, not recruiting NCT05027074 - Global Study of MK-2060 (Anti-Factor XI Monoclonal Antibody) in Participants With End Stage Renal Disease Receiving Hemodialysis (FXI Hemodialysis Study) (MK-2060-007) Phase 2
Recruiting NCT04575077 - The Role of Hepcidin as a Biomarker to Predict Successful Renal Transplantation
Enrolling by invitation NCT05001009 - Goals of Care Conversations Study N/A
Completed NCT01756508 - Eculizumab for Prevention and Treatment of Kidney Graft Reperfusion Injury Phase 2
Recruiting NCT03862859 - The Danish Warfarin-Dialysis Study - Safety and Efficacy of Warfarin in Patients With Atrial Fibrillation on Dialysis Phase 4
Terminated NCT03661229 - Cardiovascular and Respiratory Assessment Using Biometric Signals in a Non-contact Monitoring Device N/A
Completed NCT03288922 - Protein-bound Toxin Removal Between Limited Blood Flow Super High-flux Online HDF and High-Efficiency Online HDF N/A
Completed NCT02572882 - Gut Microbiome and p-Inulin in Hemodialysis N/A
Completed NCT02360748 - A Plant Based High Protein Diet to Improve Nutritional Outcomes in Peritoneal Dialysis Patients N/A