What is the issue?
Primary membranous nephropathy (PMN) is an autoimmune disease, where the body's immune system attacks the kidneys. The term "primary" is used to describe membranous nephropathy that is not caused by another disease in the body. PMN is a leading cause of nephrotic syndrome in adults. Nephrotic syndrome is a condition, where the membrane of the kidney is damaged and becomes permeable for proteins. Primary membranous nephropathy is diagnosed through findings in a kidney biopsy and the presence of nephrotic syndrome.
PMN is not harmful in about one-third of patients, who will have a spontaneous "complete remission", which means that the disease will resolve by itself. However, about another one third will experience spontaneous remission but will have some protein in the urine that continues with normal kidney function. These patients usually only require supportive treatments that do not interact with the immune system. Without treatment, about 15% to 50% of patients progress to end-stage kidney disease (ESKD) within 10 years.
In some patients, PMN can be severe or continues to get worse even after using 6 months of supportive treatments. In these patients, extra treatment that dampens the activity of the immune system may be used to reduce damage to the kidney. It is not clear which of these treatment(s) is the most helpful and what side effects can occur. Therefore, the duration and intensity of immunosuppressive treatment need to be balanced against possible side effects. There are different classes of drugs used in immunosuppressive therapy. These drugs may or may not be combined with corticosteroids (drugs based on the body's stress response hormone cortisol).
What did we do?
We searched the Cochrane Kidney and Transplant specialised register up to 1 April 2021. We have combined studies to compare different treatment regimens with immunosuppressive therapy to assess which treatments help to treat patients with PMN and nephrotic syndrome with the least side effects.
What did we find?
This review identified sixty-five studies with 3807 patients. Different types of immunosuppressive treatment include alkylating agents (cyclophosphamide and chlorambucil), calcineurin inhibitors (tacrolimus and cyclosporine), antimetabolites (mycophenolate mofetil, azathioprine), biologicals (e.g. rituximab) and adrenocorticotropic hormone. These drugs may or may not be combined with corticosteroids (e.g. prednisone), which also suppresses the immune system. After combining the results of available studies together, we found that compared with no treatment, supportive treatment or steroids alone, the use of immunosuppressive treatment probably reduced the number of patients who progressed to ESKD by about 40% and increased the number of patients that achieved complete remission. However, immunosuppressive treatment may lead to more adverse events, which can cause treatment to be stopped or lead to the patients needing to go to hospital.
The different drugs that can be used in the immunosuppressive treatment were also examined in our review. We found that alkylating agents probably increases complete remission but may lead to more adverse events. We are uncertain whether alkylating agents increase infection or cancer. Based on the currently available evidence, the effectiveness of using calcineurin inhibitors is still unclear, but there is low certainty of the evidence, that CNI may lead to similar remission rates compared to alkylating agents.
Furthermore, other treatment options such as mycophenolate mofetil, adrenocorticotropic hormone, rituximab and others have only been examined in a few studies. There is not enough data to draw final conclusions on the use of these treatments in adults with PMN and nephrotic syndrome.
Conclusions
The treatment of patients with PMN and nephrotic syndrome with immunosuppressive therapy compared to no treatment or supportive therapy alone probably protects the kidney but may increase side effects. A combination of immunosuppressive therapy with steroids may decrease disease activity and the use of alkylating agent combined with steroids probably has the short-term and long-term benefits of limiting damage to the kidney. Other therapies such as calcineurin inhibitors, mycophenolate mofetil, rituximab and adrenocorticotropic hormone have less certainty regarding their safety and effectiveness from these studies.
This updated review strengthened the evidence that immunosuppressive therapy is probably superior to non-immunosuppressive therapy in inducing remission and reducing the number of patients that progress to ESKD. However, these benefits need to be balanced against the side effects of immunosuppressive drugs. The number of included studies with high-quality design was relatively small and most studies did not have adequate follow-up. Clinicians should inform their patients of the lack of high-quality evidence.
An alkylating agent (cyclophosphamide or chlorambucil) combined with a corticosteroid regimen had short- and long-term benefits, but this was associated with a higher rate of adverse events.
CNI (tacrolimus and cyclosporin) showed equivalency with alkylating agents however, the certainty of this evidence remains low.
Novel immunosuppressive treatments with the biologic rituximab or use of adrenocorticotropic hormone require further investigation and validation in large and high-quality RCTs.
Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Without treatment, approximately 30% of patients will experience spontaneous remission and one third will have persistent proteinuria. Approximately one-third of patients progress toward end-stage kidney disease (ESKD) within 10 years. Immunosuppressive treatment aims to protect kidney function and is recommended for patients who do not show improvement of proteinuria by supportive therapy, and for patients with severe nephrotic syndrome at presentation due to the high risk of developing ESKD. The efficacy and safety of different immunosuppressive regimens are unclear. This is an update of a Cochrane review, first published in 2004 and updated in 2013.
The aim was to evaluate the safety and efficacy of different immunosuppressive treatments for adult patients with PMN and nephrotic syndrome.
We searched the Cochrane Kidney and Transplant Register of Studies up to 1 April 2021 with support from the Cochrane Kidney and Transplant Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Randomised controlled trials (RCTs) investigating effects of immunosuppression in adults with PMN and nephrotic syndrome were included.
Study selection, data extraction, quality assessment, and data synthesis were performed using Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Sixty-five studies (3807 patients) were included. Most studies exhibited a high risk of bias for the domains, blinding of study personnel, participants and outcome assessors, and most studies were judged unclear for randomisation sequence generation and allocation concealment.
Immunosuppressive treatment versus placebo/no treatment/non-immunosuppressive treatment
In moderate certainty evidence, immunosuppressive treatment probably makes little or no difference to death, probably reduces the overall risk of ESKD (16 studies, 944 participants: RR 0.59, 95% CI 0.35 to 0.99; I² = 22%), probably increases total remission (complete and partial) (6 studies, 879 participants: RR 1.44, 95% CI 1.05 to 1.97; I² = 73%) and complete remission (16 studies, 879 participants: RR 1.70, 95% CI 1.05 to 2.75; I² = 43%), and probably decreases the number with doubling of serum creatinine (SCr) (9 studies, 447 participants: RR 0.46, 95% CI 0.26 to 0.80; I² = 21%). However, immunosuppressive treatment may increase the number of patients relapsing after complete or partial remission (3 studies, 148 participants): RR 1.73, 95% CI 1.05 to 2.86; I² = 0%) and may lead to a greater number experiencing temporary or permanent discontinuation/hospitalisation due to adverse events (18 studies, 927 participants: RR 5.33, 95% CI 2.19 to 12.98; I² = 0%). Immunosuppressive treatment has uncertain effects on infection and malignancy.
Oral alkylating agents with or without steroids versus placebo/no treatment/steroids
Oral alkylating agents with or without steroids had uncertain effects on death but may reduce the overall risk of ESKD (9 studies, 537 participants: RR 0.42, 95% CI 0.24 to 0.74; I² = 0%; low certainty evidence). Total (9 studies, 468 participants: RR 1.37, 95% CI 1.04 to 1.82; I² = 70%) and complete remission (8 studies, 432 participants: RR 2.12, 95% CI 1.33 to 3.38; I² = 37%) may increase, but had uncertain effects on the number of patients relapsing, and decreasing the number with doubling of SCr. Alkylating agents may be associated with a higher rate of adverse events leading to discontinuation or hospitalisation (8 studies 439 participants: RR 6.82, 95% CI 2.24 to 20.71; I² = 0%). Oral alkylating agents with or without steroids had uncertain effects on infection and malignancy.
Calcineurin inhibitors (CNI) with or without steroids versus placebo/no treatment/supportive therapy/steroids
We are uncertain whether CNI with or without steroids increased or decreased the risk of death or ESKD, increased or decreased total or complete remission, or reduced relapse after complete or partial remission (low to very low certainty evidence). CNI also had uncertain effects on decreasing the number with a doubling of SCr, temporary or permanent discontinuation or hospitalisation due to adverse events, infection, or malignancy.
Calcineurin inhibitors (CNI) with or without steroids versus alkylating agents with or without steroids
We are uncertain whether CNI with or without steroids increases or decreases the risk of death or ESKD. CNI with or without steroids may make little or no difference to total remission (10 studies, 538 participants: RR 1.01, 95% CI 0.89 to 1.15; I² = 53%; moderate certainty evidence) or complete remission (10 studies, 538 participants: RR 1.15, 95% CI 0.84 to 1.56; I² = 56%; low certainty evidence). CNI with or without steroids may increase relapse after complete or partial remission. CNI with or without steroids had uncertain effects on SCr increase, adverse events, infection, and malignancy.
Other immunosuppressive treatments
Other interventions included azathioprine, mizoribine, adrenocorticotropic hormone, traditional Chinese medicines, and monoclonal antibodies such as rituximab. There were insufficient data to draw conclusions on these treatments.