ANCA Vasculitis Treatment in the Dialysis Patient

ANCA vasculitis is a multisystem small vessel vasculitis with a high rate of morbidity (including kidney failure) and mortality. The treatment of ANCA vasculitis requires induction immunosuppression with cyclophosphamide or rituximab and maintenance with glucocorticoids and rituximab. The use of high-dose immunosuppression is required for disease control, but it can contribute to patient mortality through severe infections, hematologic toxicity, osteopenia, and higher risk of malignancy (1). The challenge of vasculitis management is to balance the risk of treatment toxicity with the risk of vasculitis relapse.

Patients who require KRT for kidney involvement of ANCA vasculitis notoriously have poor long-term outcomes. A subgroup analysis of the MEPEX study showed that only 43% of patients who required dialysis at the time of diagnosis were able to come off dialysis at 1 year (2). Furthermore, in that patient population, 25% of the cohort died and 32% remained dialysis dependent at 1 year. Retrospective cohort studies, including a previous study of patients in the national Renal Epidemiology and Information Network (REIN) registry and a study from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), have shown that patients who have been determined by their nephrologist to have chronic kidney failure have much lower rates of kidney recovery after dialysis initiation at approximately 5% (3,4). Fortunately, after patients are established on maintenance dialysis, there appears to be a low rate of vasculitis relapse (<10%), and immunosuppression may be safely tapered faster than the recommended 2-year maintenance period due to the lower relapse rate (5).

The DIAVAS study is a retrospective cohort study that seeks to understand the long-term outcomes of 229 patients with AAV initiated on dialysis from 2008 to 2012 as part of the REIN registry in France. Although data from this study population have been previously published (3), in this issue of CJASN, Kauffman et al. are now able to link the patients to national health service (SNDS) data on vasculitis activity and treatment (5). The main study outcomes were the proportion of patients remaining in remission off immunosuppression over time (defined by the use of <7.5 mg of prednisone per day), overall survival on dialysis (with transplant as a competing risk), and cause of death. They also followed complications, including serious infection, cardiovascular events, and vasculitis relapse. Patients were followed until kidney transplantation, death, loss to follow-up, kidney recovery, or the end of the study (December 2017).

Although information on immunosuppressive induction regimens was not available, the authors presume that patients in this cohort would have received cyclophosphamide induction therapy and azathioprine maintenance. Additionally, data on the use of plasmapheresis were not discussed in the paper.

Overall, the authors found the incidence of relapse to be low after dialysis initiation, with only 3% of patients experiencing a vasculitis relapse at 1 year and 13% of patients experiencing a vasculitis relapse at 5 years. Among patients in remission off immunosuppression, 12% relapsed over the study period at a median of 18 months after long-term dialysis initiation. The annual incidence of relapse in the study cohort was significantly lower after patients started on dialysis compared with the duration of their vasculitis before dialysis initiation (57 per 100 versus 7 per 100 patient-years). This is comparable with previous relapse rates seen in retrospective cohort studies (6). Those who experienced a relapse were more likely to be off immunosuppression at the time of their relapse (78%), and among those who relapsed, there was a high mortality rate (59%) from infections (seven patients), vasculitis complications (four patients), cardiovascular events (three patients), and malignancy (two patients).

Over time, the proportion of patients with inactive vasculitis increased with each year after dialysis initiation. Although the incidence of vasculitis flares was lower in patients on dialysis, the rates of infections and cardiovascular events were significantly higher after dialysis initiation (infection: 16 versus 35 per 100 patient-years; cardiovascular events: 13 versus 34 per 100 patient-years).

When looking at differences between patients with granulomatosis with polyangiitis (GPA) versus myeloperoxidase patterns of ANCA vasculitis, patients with GPA were less likely to be in remission at the time of dialysis initiation. There was no difference in the incidence of vasculitis relapse or survival on dialysis; however, patients with GPA vasculitis were more likely to develop an infection over the study period, which may be related to the higher rates of active vasculitis and, therefore, immunosuppression at the time of dialysis initiation.

This study demonstrates the risk of immunosuppressive therapies for patients with ANCA vasculitis on dialysis, with infection being a leading cause of death. Additionally, one must consider that there may be a higher risk of severe complications of immunosuppression during a vasculitis relapse than from the vasculitis itself. This speaks to the need for further randomized trials for alternative treatment regimens with more optimal safety profiles.

Some of the strengths of this study include the understanding of the clinical trajectory in a large, real-world population starting at the time of dialysis initiation. This gives a more realistic understanding of the risks of immunosuppressive therapy than in a clinical trial, which may select for healthier patients. Additionally, the linkage of the REIN registry with NHS data allows the authors to investigate important clinical parameters, including the use of immunosuppression and other clinical outcomes. The authors used a comprehensive definition of vasculitis relapse by including patients with any immunosuppression and details from hospital admissions with a diagnosis of ANCA vasculitis; therefore, the likelihood of an uncaptured vasculitis flare in this cohort is low.

The limitations of the study include data lacking on induction immunosuppression and the use of plasmapheresis. Also, recent studies are demonstrating the merits of lower immunosuppression protocols, which will hopefully reduce some of the toxicity of therapy, including the risk of infections, and would not be reflected in this study cohort that presumably received cyclophosphamide induction therapy.

Several randomized controlled trials have been recently published to help establish new treatment protocols for ANCA vasculitis, and it will be important to reassess long-term outcomes in patients who have been treated with newer regimens. The PEXIVAS study used a 2×2 study design to demonstrate that a rapid taper of glucocorticoids and withholding plasmapheresis were noninferior to a slow taper and plasmapheresis (7). The subgroup analysis showed a potential benefit for plasmapheresis in patients with the worst kidney function at the time of diagnosis (Cr >5.6 mg/dl or requiring dialysis), although this was not statistically significant.

The latest therapies to be tested for ANCA vasculitis are complement inhibitors, due to recent understanding of the role of alternative complement pathway activation in neutrophil activation and migration (8). The recently published ADVOCATE trial is a phase 3 randomized controlled trial comparing Avacopan (a C5a receptor inhibitor) with standard glucocorticoid therapy in addition to treatment with cyclophosphamide/azathioprine or rituximab induction therapy. The study demonstrated noninferiority for the clinical end point and may provide an option for a steroid-sparing regimen for patients in the future (9). Additional anti-C5a therapies are currently being studied in phase 2 trials. Finally, an upcoming randomized clinical trial from France will be investigating whether complete withdrawal of immunosuppression in patients with ANCA vasculitis on dialysis is noninferior to standard of care, and it will provide further insight into how quickly immunosuppression can be tapered after a patient starts KRT. Overall, these trials show that it is an exciting time for clinicians who treat patients with ANCA vasculitis and that new treatment guidelines with less toxicity may be on the horizon.

In conclusion, there are important considerations for the management of patients with ANCA vasculitis who are started on hemodialysis. First, the risk of ongoing immunosuppression must be weighed against the patient’s risk of vasculitis relapse, which appears to be low after dialysis initiation. Additionally, dialysis likely contributes to a higher risk of infection due to concomitant immunosuppressive effects of kidney failure and the exposure to potential infections, including bloodstream and abdominal infections. Unless there is a strong clinical suspicion that a patient will have kidney recovery after dialysis initiation, immunosuppression can likely be tapered safely. If a patient does have a vasculitis flare after dialysis initiation, then less–immunosuppressive treatment protocols should be considered (including the lower-dose glucocorticoid regimen from the PEXIVAS study) to offset the risk of a potentially fatal infection. Hopefully, the upcoming randomized trial from France will provide more clarity on the appropriate window to reduce immunosuppression.

Disclosures

J. Radhakrishnan reports consultancy agreements with Angion Biomedica, Aurinia Pharmaceuticals, Equillium Bio, Reata Pharmaceuticals, Reistone Biopharma, Sanofi Genzyme, and Travere Therapeutics; receiving research funding from Bayer and Travere Therapeutics; receiving honoraria from Angion Biomedica, Aurinia Pharmaceuticals, Equillium Bio, GlaxoSmithKline, Reata Pharmaceuticals, Reistone Biopharma, Sanofi Genzyme, and Travere Therapeutics; and serving as a scientific advisor or member of Kidney International and Kidney International Reports. The remaining author has nothing to disclose.

Funding

None.