Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome

Abstract

Terminal complement inhibition is the standard of care for atypical hemolytic uremic syndrome (aHUS). The optimal duration of complement inhibition is unknown, although indefinite therapy is common. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 31 patients that started eculizumab for acute aHUS (and without a history of renal transplant). Twenty-five (80.6%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (interquartile range: 1.06, 9.70) months. Eighteen patients discontinued per protocol and 7 because of nonadherence. Of these, 5 (20%) relapsed; however, relapse rate was higher in the case of nonadherence (42.8%) vs clinician-directed discontinuation and monitoring (11.1%). Four of 5 patients who relapsed were successfully retreated without a decline in renal function. One patient died because of recurrent aHUS and hypertensive emergency in the setting of nonadherence. Nonadherence to therapy (odds ratio, 8.25; 95% confidence interval, 1.02-66.19; P = .047) was associated with relapse, whereas the presence of complement gene variants (odds ratio, 1.39; 95% confidence interval, 0.39-4.87; P = .598) was not significantly associated with relapse. Relapse occurred in 40% (2 of 5) with a CFH or MCP variant, 33.3% (2 of 6) with other complement variants, and 0% (0 of 6) with no variants (P = .217). There was no decline in mean glomerular filtration rate from the date of stopping eculizumab until end of follow-up. In summary, eculizumab discontinuation with close monitoring is safe in most patients, with low rates of aHUS relapse and effective salvage with eculizumab retreatment in the event of recurrence.

Graphical abstract

Figure 1.

Protocol for eculizumab discontinuation and monitoring. All 4 of the following criteria must be met before we discontinue eculizumab: resolved TMA, renal function normal or stable at new baseline, no active trigger (in patients that had an identified trigger), and patients desire to stop therapy and agree to monitoring plan. Monitoring is conduced as outlined. Home urine dipstick monitoring may also be used as an adjunct. We restart a C5 inhibitor (eculizumab or ravulizumab) in the case of recurrent TMA, in which case therapy is continued indefinitely or possibly temporarily during high-risk periods such as pregnancy, surgery, or flare of inflammatory disease. When long-term therapy is anticipated, we suggest ravulizumab rather than eculizumab.

Figure 2.

Cohort diagram.

Figure 3.

Clinical course after eculizumab cessation. (A) Patients that discontinued eculizumab on the physician-directed protocol. (B) Patients that discontinued or interrupted therapy due to nonadherence. (C) Patients that did not discontinue complement inhibition therapy. Origin of the x-axis is at initiation of eculizumab therapy for acute thrombotic microangiopathy. Duration of eculizumab therapy is indicated in blue, relapse is indicated in red, and relapse-free time off eculizumab therapy is indicated in green. Patient 23 (A) was briefly restarted on eculizumab in the setting of renal transplant. Patient 32 has switched to ravulizumab, and patients 51 and 55 are in the process of switching. D, death during follow-up.

Figure 4.

Change in eGFR categories from date of stopping eculizumab until end of follow-up. Data from 25 patients that discontinued eculizumab presented as n (%). eGFR categories are shown in milliliters per minute per 1.73 m². Green cells represent improvement from baseline to day 183, red cells represent worsening, and white cells represent no change.