Calmodulin inhibitor is effective in the treatment of lupus nephritis.

Lupus nephritis is a common renal damage in patients with systemic lupus erythematosus, which greatly increases the mortality of patients. At present, due to the treatment of LN, the remission rate of patients is low and the side effects are great. Therefore, finding new methods and drugs to treat LN has always been the focus of clinical and basic research of LN.

Cyclosporine (CSA) and tacrolimus (TAC) are calcineurin inhibitors (CNIs), which have been used in organ transplantation for many years. Recent studies show that CNIs has obvious therapeutic effect on LN, and it is superior to the current therapeutic drugs. However, some studies show that CNIs has obvious side effects and unknown long-term results in the treatment of LN. Therefore, there are still great differences about the application of central nervous system in the treatment of renal LN.

The latest issue of NDT magazine published a series of CNIs views on LN treatment in the form of special topics, which were divided into supporters, opponents and neutrals. This article will share with you the views of supporters expressed by ChiChiuMok of Tuen Mun Hospital in Hong Kong. Other views will be shared with you later.

Basic and pharmacological research of central nervous system

Basic research shows that CSA can reduce urine protein by stabilizing foot cytoskeleton protein. The results of mouse research show that TAC can reduce urine protein by stabilizing podocyte cytoskeleton protein and inhibiting podocyte apoptosis. In addition, TAC can also inhibit the expression of IFN- in glomerulus, inhibit the proliferation of mesangial cells and proteinuria.

Recent studies have also shown that P- glycoprotein, the product of multidrug resistance gene 1, is related to glucocorticoid resistance. CsA and TAC can obviously inhibit the production of P- glycoprotein. This may be an effective mechanism of CNIs in the treatment of hormone-resistant lupus nephritis.

The effect of TAC is 10~ 100 times that of CsA, and the side effects such as hypertension, hyperlipidemia, gingival hyperplasia and hirsutism are obviously reduced. Therefore, TAC may be a better choice for the treatment of LN.

Application of central nervous system in the treatment of proliferative lupus nephritis

1. Induction therapy

In a study of RCT, 40 patients with proliferative LN were randomly given CsA(45mg/kg/d) combined with high-dose glucocorticoid or intravenous cyclophosphamide (CTX, 10mg/kg) combined with high-dose glucocorticoid ***8 times. After 9 months of induction, there was no significant difference in renal remission rate between the two groups. After 7.7 years of follow-up, there was no significant difference in the incidence of renal damage and ESRD between the two groups.

Other small RCT studies showed that there was no significant difference between short-term TAC and intravenous CTX in patients with proliferative LN. A recent meta-analysis including five controlled studies showed that TAC was superior to CTX in complete renal remission and partial renal remission. Another RCT study compared the therapeutic effects of TAC and MMF on proliferative and membranous LN, and the results showed that TAC and MMF had similar therapeutic effects.

2. Maintenance treatment

Moroni et al. compared the effects of CsA(2.5~3.0mg/kg/d) and AZA(2mg/kg/d) in maintenance therapy. Follow-up for 4 years showed that the recurrence rate of CSA group was 65438 09%, and that of AZA group was 24%.

Treatment of membranous lupus by central nervous system

Austin et al. included 42 patients with membranous LN confirmed by pathology. Patients were randomly divided into three groups, each group received prednisone (1mg/kg/d) for 8 weeks, and then the dose was gradually reduced. Or prednisone combined with CTX(0.5~ 1g/m2, every other month 1 time); Or prednisone combined with CSA(5mg/kg/d). After 12 months of treatment, the complete remission rate and partial remission rate of CsA combined with prednisone were the highest (83%), followed by CTX combined with prednisone (60%) and prednisone alone (27%). But the recurrence rate of nephrotic syndrome in CsA group was higher than that in CTX group.

TAC-based combination therapy

A large RCT study in China involved 368 patients with lupus nephritis. The results showed that the 6-month complete remission rate of MMF( 1g/d) and TAC(4mg/d) was better than that of intravenous CTX. At the same time, other studies show that this scheme is also effective for recurrent LN.

Limitation of central nervous system in the treatment of lupus nephritis

At present, there is no long-term research result of TAC in treating LN. In addition, there is no study on TAC in the treatment of LN patients with renal insufficiency. The therapeutic window of TAC is narrow, so it is necessary to detect the blood concentration of patients.

CNIs has obvious side effects such as nephrotoxicity, infection and tumor. Nephrotoxicity of central nervous system includes acute and chronic nephrotoxicity. Acute nephrotoxicity is related to the patient's blood concentration.

At present, there are no studies on the incidence of chronic nephrotoxicity, CNIs dosage and systemic lupus erythematosus (SLE) activity in LN treatment.

More and more evidence shows that CNIs has the same or better curative effect as the current treatment scheme, and has no obvious reproductive toxicity, and is effective for patients who are ineffective in glucocorticoid and CTX treatment.

This is another choice for induction therapy of severe LN TAC. TAC can be considered to treat non-CTX. TAC can be used to treat young patients who want to preserve their fertility.