For The Treatment Of Membranous Nephropathy, These 5 Programs Are Commonly Used in Clinical Practice!

Membranous nephropathy is a glomerular disease, the most common of which is idiopathic membranous nephropathy (IMN). IMN is an organ-specific autoimmune podocyte disease in which the glomerular podocyte phospholipase A2 receptor (PLA2R) is the major target antigen [1].

The "membrane" of membranous nephropathy specifically, is the lining of the capillaries in the kidneys. The walls of the blood vessels are first attacked by the immune system, and after a period of time, the lesions appear and the urine protein leaks from the blood vessels.

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The onset of these diseases is slow and the process of complete remission of symptoms is slow. Patients with membranous nephropathy often feel confused due to long-term and repeated symptoms of proteinuria and edema. Membranous nephropathy has also become a very big challenge in the current clinical work nephropathy. This article gives an overview of the new progress in the treatment of membranous nephropathy in recent years, for readers to learn together!

Principles of immunosuppressive therapy in the treatment of membranous nephropathy

Not all patients with membranous nephropathy require immunosuppressive therapy. Immunosuppressive therapy is not required when the patient has proteinuria <3.5g/d and an estimated glomerular filtration rate>60ml/min/1.73m2[2]. Because many patients with membranous nephropathy have an excellent prognosis, with as many as 40% and more experiencing spontaneous remission, the use of immunosuppressive therapy in the absence of significant nephrotic syndrome complications provides no benefit and may even increase risk. It can be said that mild symptoms and the possibility of spontaneous remission are also "advantages" of membranous nephropathy.

Immunosuppressive therapy should be limited to patients who do not resolve spontaneously and are at risk for progressive renal impairment.

1 Classical immunotherapy for IMN: glucocorticoid + cyclophosphamide

We all know that for the treatment of proteinuria, hormones are one of the necessary drugs, which can play an anti-inflammatory effect. Many patients also use immunosuppressants such as cyclophosphamide in addition to hormones. These two partners are mainly because some patients with kidney disease use hormones alone. Once the drug is discontinued, it may cause the recurrence of kidney disease. Therefore, immunosuppressants must be added for combined therapy. .

This regimen provides patients with long-term and short-term benefits. In this program, all patients received non-immunosuppressive basic treatments such as blood pressure control, correction of dyslipidemia, preventive anticoagulation, and diuresis and detumescence.

Prednisone acetate tablets for immunotherapy 0.8-1 mg/(kg·d), the dose is reduced after 8 weeks of treatment and reduced to ≤0.5 mg/(kg·d) after 3-4 months of treatment, QD; cyclophosphamide for injection Amide is administered by intravenous drip in 150ml of body surface area 0.5g/m2+0.9% sodium chloride injection, once/month. 30 days as a course of treatment, continuous treatment for 6 courses [3].

However, hormonal side effects are large, and cyclophosphamide also has adverse reactions such as reproductive toxicity, bone marrow suppression, infection, and hemorrhagic cystitis, and nearly half of the patients are still not relieved, so this program is not ideal.

2 Treatment with calcineurin inhibitors (CNIs): escalating effects

CNIs belong to a large class of immunosuppressive drugs. For patients who are unwilling to accept glucocorticoid + cyclophosphamide or have contraindications to treatment, CNIs can be used for treatment. The currently used CNIs are mainly cyclosporine and tacrolimus.

▌ Glucocorticoid + cyclosporine therapy

The advantages of cyclosporine in the treatment of IMN are that the onset of action is fast, the curative effect is better than that of cyclophosphamide, and the adverse reactions are less and milder than that of cyclophosphamide. The disadvantage is that the overall response rate is not higher than that of cyclophosphamide and the short-term recurrence rate is significantly higher than that of cyclophosphamide.

The dose of cyclosporine: KDIGO guidelines recommend 3-5 mg/(kg d); however, domestic studies have shown that when cyclosporine less than 3-5 mg/(kg d) is used in the treatment of IMN, its efficacy is comparable to that greater than 3-5 mg/(kg d). (kg · d) similar. Therefore, for Chinese patients, the dose of cyclosporine may be less than 3 mg/(kg·d) more appropriate.

Considering that IMN is not an acute severe autoimmune disease and the nephrotoxicity of cyclosporine, Chinese experts suggest that low-dose cyclosporine can be given in the treatment of IMN. In the course of treatment, the dose is gradually reduced to the minimum dose, and the long-term maintenance is about 5.5 years, which can maintain long-term remission in patients with IMN and significantly reduce the recurrence rate [4].

Dosage of glucocorticoids: Domestic studies have shown that compared with medium-dose prednisone [0.4-0.5 mg/(kg·d)] + cyclosporine, the efficacy of low-dose prednisone + cyclosporine in the treatment of IMN is significantly decreased. Therefore, when using cyclosporine to treat IMN, domestic experts recommend moderate-dose prednisone combined therapy.

▌ Tacrolimus treatment

The immunosuppressive efficacy of tacrolimus is 10-100 times higher than that of cyclosporine, but its nephrotoxicity and effects on blood pressure, blood lipids, and endothelial function are weaker than those of cyclosporine. The disadvantage is that similar to cyclosporine, tacrolimus also has the problem of a high recurrence rate; the prominent adverse reactions of tacrolimus are abnormal glucose tolerance and new-onset diabetes; the price is more expensive.

Currently, tacrolimus has been reported to be superior, similar, or even inferior to cyclophosphamide in the treatment of IMN. Therefore, it is uncertain whether tacrolimus is superior to cyclophosphamide in the treatment of IMN.

Medication regimen: KDIGO guidelines recommend tacrolimus 0.05-0.075 mg/(kg·d). Some studies have shown that the efficacy of tacrolimus monotherapy is not inferior to cyclophosphamide + glucocorticoids. Therefore, the KDIGO guidelines recommend that tacrolimus not need to be combined with prednisone in the treatment of IMN.

However, some studies have also shown that the efficacy of tacrolimus combined with moderate doses of prednisone is significantly better than that of tacrolimus monotherapy. Therefore, unless there are contraindications to hormones, tacrolimus combined with moderate doses of hormones can generally be used to treat IMN.

The KDIGO guidelines recommend tacrolimus for the treatment of IMN with a course of 6 to 12 months. However, some studies have shown that long-term (24 months) treatment can maintain remission and reduce recurrence [5].

3 Mycophenolate mofetil therapy: appropriate combination

Available evidence suggests that mycophenolate mofetil monotherapy is ineffective for IMN. Therefore, the KDIGO guidelines do not recommend mycophenolate mofetil monotherapy. Even combined with hormone therapy, the efficacy is inferior to cyclophosphamide and CNIs. Experts believe that the value of mycophenolate mofetil in the treatment of IMN may be that it can be used in combination with other immunosuppressants to reduce the dosage of other immunosuppressants, thereby reducing adverse drug reactions and reducing the recurrence rate.

4 Monoclonal antibody therapy: improvement in remission rate

At present, a series of clinical studies have been carried out with rituximab in the treatment of IMN, which has established its status in the treatment of IMN. The consultation draft for the 2020 edition of the KDIGO guidelines lists rituximab as one of the mainstays of treatment for IMN. However, due to the high price, it may not be suitable as a first-line drug in my country at present. Second-line treatment only when cyclophosphamide or CNIs are ineffective or contraindicated.

A new meta-analysis shows that rituximab has a 67% response rate for IMN. Another randomized controlled study comparing rituximab and cyclosporine in IMN showed that at 12 months, the response rate with rituximab was no better than that with cyclosporine (52% vs 60%), but at 24 months, the response rate in the rituximab group was significantly higher than that in the cyclosporine group (60% vs 13%); Events were significantly lower in the cyclosporine group (17% vs 30%) [6].

5 Multi-target immunosuppressive combination therapy

The method is to combine a variety of immunosuppressants with different effects to treat IMN. The combination of several drugs not only reduces the dose of each drug and the accompanying adverse reactions but also exerts its own characteristics and has a synergistic effect. The current main regimen is glucocorticoid + CNIs + mycophenolate mofetil.

Foreign studies have shown that compared with the tacrolimus monotherapy group, the tacrolimus + mycophenolate mofetil regimen is significantly better than the tacrolimus monotherapy group in terms of remission rate and remission time. Nine patients with refractory IMN were treated with "prednisone + tacrolimus + mycophenolate mofetil". The results showed that 2 patients had complete remission, 3 had partial remission, and 4 had no effect. The effective rate was 55.6%.

Domestic clinical multi-target therapy (prednisone + tacrolimus + mycophenolate mofetil + tripterygium wilfordii) was given to treat refractory IMN, and the remission rate was 75.01%, which was significantly higher than that of the control group (prednisone + cyclophosphamide). ) with a remission rate of 53.57%. However, the observation was short (6 months), and the previous immunosuppression was unknown, so the influence of previous treatment could not be completely ruled out.

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