Prevention of recurrence of C3 glomerulopathy post-transplant: eculizumab

This evidence summary considers the evidence for using eculizumab to prevent recurrence of C3 glomerulopathy in people who have had a kidney transplant. Use of eculizumab to treat C3 glomerulopathy in people who have not had a transplant is outside the scope of the evidence summary, as is use to prevent antibody‑mediated rejection of a transplanted kidney.

The searches performed for the evidence summary found no studies or case reports of eculizumab to prevent recurrence of C3 glomerulopathy after a kidney transplant. A small open‑label study (n=6, 3 post‑transplant) and 7 reports of single cases who had recurrence of C3 glomerulopathy post‑transplant and were using eculizumab to prevent progression of the disease were found.

Bomback et al. (2012) performed a prospective single‑arm open‑label pilot study of eculizumab for treating 6 people with C3 glomerulopathy, of whom 3 (1 with DDD and 2 with C3GN) had recurrent disease after kidney transplantation. Stable renal function and improvements on renal biopsy were seen in 1 person with recurrence of DDD and 1 person with recurrence of C3GN. Improvement in serum creatinine but no changes on biopsy were seen in the second person with recurrence of C3GN.

An open‑label study (Gurkan et al. 2013) reported treatment of 1 person who experienced C3GN post‑transplant. Eculizumab only partially prevented progression of C3GN in this case. Renal function initially improved but proteinuria subsequently deteriorated, and worsening disease was seen on biopsy.

Le Quintrec et al. (2015) discussed 3 cases who received eculizumab for C3 glomerulopathy, 1 of whom had received a kidney transplant. In this person, eculizumab treatment was associated with improvement in renal function and improvements on biopsy for up to 28 months.

McCaughan et al. (2012) reported a case with recurrent DDD post‑transplant who was treated with eculizumab. Renal function improved immediately following treatment and was sustained for 11 weeks. Follow up biopsy was not reported.

Sanchez-Moreno et al. (2014) described treatment with eculizumab in a case with recurrent DDD post‑transplant. Renal function improved and became normal following treatment, over 30 months. Biopsy showed no progression of DDD.

Three case reports are available as abstracts only, providing limited information. Ariceta et al. (2013) reported that eculizumab improved renal function and caused remission of disease on biopsy in a case with recurrent DDD post‑transplant. Dorje et al. (2014) found that eculizumab was ineffective in a case with recurrence of C3GN post‑transplant. Jordan et al. (2013) reported that 1 case with recurrent C3GN did not improve with eculizumab treatment and lost his transplanted kidney.

The number of case reports was too small to assess adverse effects; however, none were reported in the majority of cases. The case described by Jordan et al. (2013) experienced herpes zoster infection.

According to the summary of product characteristics, the most common adverse reaction reported in 302 people with PNH and aHUS (the licensed indications) in clinical trials and in postmarketing reports was headache (occurring in more than 1 in 10 people, mostly in the initiation phase). The most serious adverse reaction was meningococcal sepsis (occurring in between 1 in 10 and 1 in 100 people). To reduce the risk of meningococcal infection, all patients must be vaccinated before receiving eculizumab and revaccinated according to current medical guidelines. However, vaccination may not be sufficient to prevent infection. Other common adverse effects seen in between 1 in 10 and 1 in 100 people include aspergillus infection, bacterial and viral infection, thrombocytopenia, leukopenia, haemolysis and anaphylaxis.

This evidence review includes information on only 10 people. Case reports are subject to bias and confounding and provide only low quality evidence for interventions. Although eculizumab improved or stabilised signs of C3 glomerulopathy in most cases, improvements in both renal function and biopsy were not always found, only a partial response was seen in 1 case and eculizumab was ineffective in 2 further cases. In addition, it is possible that cases in which eculizumab was unsuccessful are under reported in the literature.

C3 glomerulopathy is a heterogeneous condition associated with many different abnormalities in the alternative complement system pathway, and the degree of C5 convertase dysregulation varies between individuals. Therefore, people may not universally respond to eculizumab therapy. It is currently unclear whether it is possible to identify who will respond to eculizumab treatment using genetic and antibody testing for complement abnormalities. It has been proposed that elevated C5b‑9 levels, an increase in or appearance of C5b‑9 deposits in the kidney, and the presence of marked inflammatory changes on biopsy might be predictors of response to treatment. Longer, larger, statistically powered and adequately controlled studies are needed to better evaluate eculizumab for treating C3 glomerulopathy post‑transplant, in terms of outcomes such as patient survival, graft survival, adverse effects and quality of life. However, rare diseases present challenges in optimal study design.

In people in whom eculizumab is effective, long‑term treatment may be necessary (as recommended in aHUS and PNH) because eculizumab does not address the underlying complement abnormality, but merely prevents downstream formation of C5b-9. Bomback (2014a) notes that whether the drug is considered lifelong therapy is influenced by the high cost of eculizumab treatment and the potential for infection with prolonged use. Different doses of eculizumab were used in the cases and the optimal regimen for people with recurrence of C3 glomerulopathy is unclear.