Stefania Salardi

Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission.

Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS.

Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin–producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored. METHODS: All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted. RESULTS: Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01). CONCLUSIONS: Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes.

Skin Involvement in Atypical Hemolytic Uremic Syndrome

Skin involvement in atypical hemolytic uremic syndrome (aHUS) is very uncommon and therefore often unrecognized as a specific symptom of aHUS. We describe 3 cases of patients with aHUS who developed skin lesions that completely recovered when disease-specific treatment was established. These cases suggest that in individuals with aHUS, when skin lesions of unknown origin occur, the possibility that they are due to thrombotic microangiopathy should be considered.

Cryptic Activity of Atypical Hemolytic Uremic Syndrome and Eculizumab Treatment

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease often related to uncontrolled complement activation. The use of eculizumab has changed the management and the outcome of aHUS, becoming the frontline treatment of the acute disease and for the prevention of relapses. We report the case of a male patient with aHUS due to complement factor H gene mutation who was shifted from plasmatherapy to eculizumab for preventing disease relapses. The shift to eculizumab was associated with a significant decrease in proteinuria, revealing disease activity otherwise unsuspected, being the classic criteria of disease activity (platelet, haptoglobin, LDH, schistocytes), all in the normal range. The condition of proteinuria as the only sign of thrombotic microangiopathy activity is here designated as “cryptic activity of aHUS.”

Acquired Complement Regulatory Gene Mutations and Hematopoietic Stem Cell Transplant–Related Thrombotic Microangiopathy

Hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA) is a severe complication whose pathophysiology is unknown. We describe 6 patients in which the disease was associated with complement regulatory gene abnormalities received from their respective donors. It is suggested that mutated and transplanted monocyte-derived cells are responsible for production of abnormal proteins, complement dysregulation, and, ultimately, for the disease. This observation might have important drawbacks as far as HSCT-TMA pathophysiology and treatment are concerned.

Prepartum Eculizumab for prevention of atypical hemolytic uremic syndrome: A case report

Background: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) often caused by complement disregulation for which pregnancy and delivery are common triggers. The disease is associated with a poor prognosis both for the mother and the fetus. Case: A 30-year-old women with a membrane cofactor protein (MCP) gene mutation and two previous aHUS episodes, presented at 23 weeks of pregnancy with no signs of active TMA. Pregnancy proceeded uneventfully and a single dose of Eculizumab was given 24 hours prior to delivery. The patient gave birth to a healthy baby, did not develop TMA and had no side effects. Conclusion: A single prepartum Eculizumab dose may be a cost-effective and safe strategy to face the high risk of relapse in pregnancy-associated aHUS. Correspondence to: Gianluigi ARDISSINO, Center for HUS Control, Prevention and Management, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milano, Italy, Phone: +39 0255032300; Fax: +39 0255032451; E-mail: ardissino@italkid.org