Renal vasculitis causes damage to the small blood vessels inside the kidneys and - when untreated - can lead to a rapid loss of kidney function. Therapies that block the immune system to switch off the vasculitis process are available but can lead to serious infections and other long-term complications. The Cochrane Review of treatments to induce and maintain disease remission for renal vasculitis was updated in January 2020 and we asked lead author, Giles Walters from Canberra Hospital in Australia to bring us up-to-date with the findings.
Monaz: Hello, I'm Monaz Mehta, editor in the Cochrane Editorial and Methods department. Renal vasculitis causes damage to the small blood vessels inside the kidneys and - when untreated - can lead to a rapid loss of kidney function. Therapies that block the immune system to switch off the vasculitis process are available but can lead to serious infections and other long-term complications. The Cochrane Review of treatments to induce and maintain disease remission for renal vasculitis was updated in January 2020 and we asked lead author, Giles Walters from Canberra Hospital in Australia to bring us up-to-date with the findings.
Giles: As Monaz said, renal vasculitis leads to inflammation of small blood vessels and can cause permanent kidney failure and death. Before effective treatments, mortality from renal vasculitis was often 80% within 12 months. Now, with modern therapies, 80% of affected people survive beyond 5 years. As renal vasculitis is caused by an immune reaction to blood vessels, most treatments act to suppress the immune system. Historically, treatment has centered around steroids and cyclophosphamide with plasma exchange added when severe kidney failure is present. More recently, other drugs have been shown to be probably equivalent to cyclophosphamide under certain conditions. Once treatment induces disease remission, the intensity of treatment is scaled back and longer-term, less potent therapies are used to maintain the remission.
Despite recent developments, more than one in ten people with severe renal vasculitis still die in the first year after their diagnosis, and half of these deaths are caused by treatment side-effects, making it important to identify treatments are as safe and effective as possible.
In the 2008 Cochrane Review, 13 studies were available involving 700 adults. By 2015, we could include 31 studies involving over 2200 adults, and now, for the 2020 review, there are 40 studies with nearly 3800 patients. However, despite this progress, the studies collectively still had important design limitations which continue to give us low confidence in some results.
Plasma exchange was studied in about 900 people, and a major addition to the review is the initial data from the PEXIVAS study, the largest ever trial in vasculitis. At the time of our update, data at 6 and 12 months were not available but the published survival data supports the previous studies in showing that when added to usual therapies, plasma exchange may reduce the risk of developing total kidney failure with the need for dialysis at 12 months being halved. However, there is no evidence that it affects mortality or the incidence of serious infections.
PEXIVAS also tested two different steroid dosing regimens and showed that a lower total dose of steroids is equally effective whilst resulting in fewer infections. Other studies, involving nearly 300 people, found that intravenous pulse cyclophosphamide may lead to disease relapse more often than continuous oral cyclophosphamide, but whether pulse or continuous cyclophosphamide had different impacts on death, need for dialysis or severe infection was very uncertain.
Evidence for the anti-CD20 monoclonal antibody, rituximab, was of higher quality. This drug was probably equivalent to cyclophosphamide, leading to most patients achieving disease remission by 6 months, without evidence that serious infection rates were increased. Mycophenolate is similar to cyclophosphamide as a therapy for inducing remission, but whether remission is sustained and relapse can be avoided by mycophenolate is still unclear.
Finally, when considering maintenance therapies, azathioprine was as effective as cyclophosphamide, but mycophenolate mofetil is still not proven as effective compared to azathioprine. This appears to be inconsistent with the increasing data on the effectiveness of mycophenolate as an induction agent. Multiple agents have been tested and shown to be effective in maintenance, including azathioprine, mycophenolate, rituximab, leflunomide and methotrexate. An important new study also tested the need for longer maintenance therapy and showed that, compared to two years of treatment, continuing treatment for four years dramatically reduced the risk of relapse.
To sum up, adults with renal vasculitis and severe kidney failure are less likely to need dialysis when plasma exchange is added, but there is little information about its impact on death or infection. Continuous cyclophosphamide reduces disease relapse, rituximab and mycophenolate are viable alternative induction agents, lower doses of steroids can be safely used to reduce risk of infection, azathioprine is equivalent to cyclophosphamide for maintaining remission and needs to be continued for at least four years from diagnosis.
Looking to the future, studies are now needed that focus on the impact of the various induction therapies on subsequent risk of relapse, new therapies such as alternative anti-CD20 antibodies and complement inhibitors.
Monaz: You can find full details of this review and watch for future updates by going online to Cochrane library dot com, and searching for 'renal vasculitis'.