Frontiers in the management of AHUS – Organised by ALEXION PHARMACUTICALS, INC.

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the companies reviewed and approved the contents

Would you like to know more?

Atypical haemolytic uremic syndrome (aHUS) is a rare, life-threatening disease caused by complement dysregulation and presenting as thrombotic microangiopathy (TMA). Approval of the complement protein C5 inhibitor eculizumab in 2011 revolutionized treatment of aHUS, but clinical challenges remain. How do the extent and intricacies of complement involvement in aHUS pathophysiology influence diagnosis? How does clinical trial data translate into real-world use of a C5 inhibitor? And how should clinicians manage the complexities of aHUS in a kidney transplant setting? These challenges were discussed by Professor Hermann Haller, Dr Anja Gäckler and Dr Yahsou Delmas at a virtual symposium held during the 2021 ERA-EDTA fully virtual congress.

Complement C5 at the heart of aHUS

Hermann Haller, Germany

TMA is difficult to diagnose since it is a systemic disease, affecting multiple organs and systems. The first clinical symptoms include thrombocytopenia, microangiopathic haemolysis and fever. Up to 48% of aHUS cases also have central nervous system (CNS) findings, while up to 80% have impaired renal function. Patients may present with other conditions such as pregnancy or malignant hypertension, symptoms may occur at any age, and onset may be acute or more chronic with relapses.

Professor Haller emphasized that differential diagnosis of aHUS must include both predisposing or genetic molecular mechanisms and precipitating factors or external triggers. In some patients, genetic factors are so strong that it requires only a minor external trigger like a viral infection to precipitate aHUS, while a severe trigger in which the complement cascade is highly activated is required when there is only a minor genetic polymorphism.

Genetic analysis can provide important diagnostic clues, but Professor Haller considered the clinical diagnosis of aHUS to be more important and he advised against waiting for a genetic diagnosis before initiating treatment. This is because, the earlier C5 inhibition is started, the more likely it is that further damage from microangiopathy will be prevented and organ function will be preserved.

Professor Haller advised that discontinuation of the C5 inhibitor can only be considered if it is medically justified. Discontinuation is not recommended for patients who have lost a previous allograft. In other patients, discontinuation should be on a case-by-case basis, considering: the severity of the disease, whether there has been prolonged period of organ function normalization or stabilization; biopsy results; and TMA activity. Family history and genetic analysis are important, as is the risk of recurrence of conditions that amplify complement. Finally, if treatment is discontinued, close monitoring is essential and patient compliance should be checked and education regularly reinforced.

C5 inhibition in aHUS, from clinical trials to practical use

Anja Gäckler, Germany

Although highly effective in treating aHUS, eculizumab requires a standard regimen of intravenous infusions every two weeks in patients with a body weight of ≥10 kg. Ravulizumab is a long-acting, humanized monoclonal antibody that has been engineered from eculizumab to enable increased elimination half-life and allow an extended dosing interval from two to eight weeks, without sacrificing immediate and complete C5 inhibition.

Dr Gäckler outlined the results of the phase III trial of ravulizumab in adults, a multicentre, open, single-arm trial that included 56 complement-inhibitor naïve patients (aged ≥ 18 years, body weight ≥ 40 kg) who fulfilled diagnostic criteria for aHUS. Patients received meningococcal vaccination before or at the time of treatment; if vaccine was received less than two weeks before start of treatment, appropriate prophylactic antibiotics were given until two weeks after vaccination.

On the primary endpoint, complete TMA response was achieved in 30/56 patients (53.6%) during the initial evaluation period, with a median response time of 86.0 days. On hematologic endpoints, during the initial evaluation period 47 (83.9%) patients achieved platelet count normalization and lactate dehydrogenase (LDH) normalization was reached in 43 (76.8%) patients; further, a 25% improvement from baseline in serum creatinine was achieved by 33 patients (58.9%).

Renal function (eGFR) substantially improved from baseline, with a median increase of 29.0 (–13 to +108) ml/min) to day 183, increasing substantially by day 15. Dialysis was discontinued in 17/29 patients (59%) who were on dialysis at baseline. Of 27 patients not on dialysis at baseline, 21 (78%) remained off dialysis at the last available follow-up (which may have occurred after day 183). 95.8% (45/47) of patients showed improvement or preservation in renal function with regard to CKD stage, with 68% improving.

Dr Gäckler added that there were no unexpected adverse events (AEs), and most occurred within the first 26 weeks. Through all available follow-up, 20 patients (34.5%) experienced treatment-related AEs, most commonly headache, diarrhea, and vomiting. Serious AEs occurred in 33 patients (56.9%), most commonly hypertension and pneumonia. Three patients (5.2%) discontinued treatment and withdrew from the study because of an SAE (autoimmune haemolytic anaemia, intracranial haemorrhage, and immune thrombocytopenic purpura). No meningococcal infections or deaths related to the study drug occurred.

On the basis of the phase III trial, ravulizumab was approved in Europe in patients with aHUS and body weight ≥10 kg, who are complement inhibitor treatment-naïve, or have received eculizumab for at least three months with evidence of response. Originally presented in a 10mg/ml formulation, ravulizumab is now available in a 100mg/ml formulation, reducing the number of vials and infusion time required for dosing.

Complement inhibitor treatment is associated with an increased risk of infection with encapsulated bacteria. Dr Gäckler recommended that to minimize this risk, patients should be given information about Neisseria gonorrhoeae prevention, and vaccinated against meningococcal infection. Vaccination against Haemophilus influenzae and pneumococci should be given to patients aged <18 years and considered in those ≥18. Patients should always carry a safety card, and they should be educated about the signs of serious infection, especially meningitis.

Dr Gäckler has switched 12 patients with aHUS, including five kidney transplant patients, from eculizumab to ravulizumab. In general, patients were pleased with the reduced burden of treatment, and the medical staff report that administration of ravulizumab was simple and convenient.

aHUS and kidney transplant, a particular challenge

Yahsou Delmas, France

TMA is a complicated differential diagnosis in the setting of kidney transplantation. Dr Delmas explained that TMA aetiology may be cumulative, and may be related to medication (such as calcineurin (CNI) or mTOR inhibitors) and malignant hypertension. Transplant patients are at risk of infections, including Shiga toxin, which results in diarrhea in 30% of aHUS patients. Finally, the presentation of vitamin B9 and/or vitamin B12 deficiency can resemble that of TMA. She added that these aetiologies can act as triggers for complement-mediated aHUS, and a normal C5 does not rule out complement activation in transplant patients.

Prophylactic eculizumab improves post-kidney transplant outcomes in aHUS patients. Timing of initiation is important, as optimum survival is seen when eculizumab is introduced within one week of aHUS recurrence post-transplantation. Since patients with early recurrence post-kidney transplant have a very high risk of recurrence within two years of the next transplant, risk stratification is essential.

KDIGO proposes risk stratification based on the patient history and type of variant, with the highest risk seen in patients with a previous early recurrence, a pathogenic mutation and a gain-of-function mutation. In these patients, KDIGO recommends prophylactic eculizumab started on the day of surgery and continued after kidney transplantation. Prophylactic eculizumab or plasma exchange is recommended in moderate-risk patients without an unrelated mutation or persistent low anti-FH antibody. No prophylaxis is recommended in low-risk patients (<10% risk of recurrence) with an isolated MCP mutation and persistently negative FH antibodies.

Licensed dosing of eculizumab in kidney transplantation is 900mg/weekly for four weeks in the initial phase, followed by maintenance dosing of 1200mg every other week. Dr Delmas recommended monitoring residual complement blockade at the beginning of treatment or if there is insufficient response. Kidney transplant patients receiving a C5 inhibitor should receive the recommended vaccinations, education about infections, and a personalized card to ensure prompt medical attention in an emergency.

KDIGO recommends against discontinuing eculizumab in kidney transplant patients with aHUS except during intercurrent illness with an encapsulated organism. Eculizumab is first-line therapy if aHUS is diagnosed post-transplant. If acute renal failure necessitates dialysis restart, KDIGO recommends waiting six months before the next kidney transplant, as there may be late recovery with eculizumab. If clinicians do consider discontinuing eculizumab post transplantation, no hematologic TMA features should be present and extrarenal manifestations must be resolved.

In conclusion, early diagnosis of aHUS recurrence post-transplant is essential, as early prophylactic C5 inhibition gives the best outcomes. Patients with aHUS should be stratified for post-transplant risk of recurrence. Genetic background should be assessed, and patients should be protected by a living-donor transplant, if possible, a low dose of CNI and strict target blood pressure. Dr Delmas concluded that anti-C5 therapy has opened the door to good outcomes of kidney transplantation for aHUS patients, and we are in the era of personalized therapeutic strategies.

Further reading

Diagnosis of TMA

Campistol JM, et al. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia 2015;35:421-47

Norris M, Remuzzi G. Atypical hemolytic–uremic syndrome. N Engl J Med 2009; 361:1676-1687

Legendre CM, et al. Terminal complement inhibitor eculizumab in atypical hemolytic–uremic syndrome. N Engl J Med 2013;368:2169-81

From clinical trials to practical use

Sheridan S, et al. Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS One 2018;13(4):e0195909.

Rondeau E, et al. The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. Kidney Int 202097:1287-1296

aHUS and kidney transplantation

Le Quintrec M, et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.  Am J Transplant 2013;13:663-75

Goodship TH, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2017;91:539-551.

Zuber J, et al. Use of highly individualized complement blockade has revolutionized clinical outcomes after kidney transplantation and renal epidemiology of atypical hemolytic uremic syndrome. J Am Soc Nephrol 2019;30:2449-246