C3 glomerulopathy in the native kidney: eculizumab

This evidence summary considers the best available evidence for using eculizumab to treat people with C3 glomerulopathy in their own, native kidneys. Use of eculizumab to treat C3 glomerulopathy in people who have had a transplant is considered in the associated evidence summary on prevention of recurrence of C3 glomerulopathy post-transplant: eculizumab.

The searches performed for this evidence summary found no RCTs assessing eculizumab for treating people with C3 glomerulopathy in their native kidneys. Limited evidence was found from a small open‑label study (Bomback et al. 2012, n=6 [3 with native kidneys]) and 12 full case reports of 17 single cases. A further 10 reports (15 cases) were identified but are available only as conference abstracts and have been excluded from the evidence summary due to significant limitations in the reporting of findings.

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 (2 with DDD and 1 with C3GN) had their native kidneys. No statistical analysis was performed because of the small number of participants. Results were mixed. In the first person with DDD, proteinuria improved and remained consistently low throughout treatment, and improvements were seen on renal biopsy. Renal function did not improve in the second person with DDD, who subsequently withdrew from treatment at 40 weeks. In the third person, who had C3GN, renal function improved with eculizumab over the first 24 weeks; however, it worsened again over the second 24 weeks. Deterioration was also seen on biopsy in this person.

An initial response to treatment was also seen in a case with DDD reported by Berthe-Aucejo et al. (2014), with improvement in serum albumin and normal sC5b‑9 (soluble membrane attack complex, an indicator of activation of the terminal complement cascade). However, these subsequently deteriorated after 2 months' treatment and proteinuria was unchanged after 3 months' treatment. Similarly, Haffner et al. (2015), reported improvements in serum albumin and proteinuria and normalisation of eGFR in a person with C3GN, but mycophenolate subsequently needed to be reintroduced after 16 weeks following a further increase in proteinuria. Follow‑up biopsy was not reported in these cases.

A patient with C3GN described by Besbas et al. (2014) saw no improvements on treatment and still had proteinuria after receiving eculizumab for 10 months. Follow‑up biopsy was not reported.

Proteinuria improved and other measures of renal function such as serum creatinine, serum albumin or estimated glomerular filtration rate improved or were stable in 5 cases with C3GN reported by Inman et al. (2015), Kerns et al. (2013), Le Quintrec et al. (2015) (2 cases) and Payette et al. (2015). The case described by Inman et al. (2015) discontinued dialysis. Improvements or stability were seen on renal biopsy in 3 of the cases (Le Quintrec et al. 2015 [2 cases] and Payette et al. 2015). Follow‑up biopsy was not reported in the other 2 cases (Inman et al. 2015 and Kerns et al. 2013).

Similarly, proteinuria improved and other measures of renal function improved or stabilised in 9 cases with DDD reported by Daina et al. (2012), Oosterveld et al. (2015) (5 cases), Ozkaya et al. (2014), Rousset-Rouviere et al. (2014) and Vivarelli et al. (2012). Kidney function did not always return to normal, with various degrees of chronic kidney disease remaining. However, 3 cases no longer needed dialysis (Rousset-Rouviere et al. 2014 and Oosterveld et al. 2015 [2 cases]). Improvements were seen on biopsy in the case reported by Vivarelli et al. (2012). No improvements were seen in 1 case in Oosterveld et al. (2015). Follow‑up biopsy was not reported for the other 7 cases.

Renal function deteriorated in 6 cases (5 with DDD and 1 with C3GN) when eculizumab was stopped and subsequently improved again when treatment was restarted (Bomback et al. 2012, Oosterveld et al. 2015 [3 cases] Payette et al. 2015 and Vivarelli et al. 2012).

The number of case reports was too small to assess adverse effects; however, none were reported in any of the cases.

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 20 people. Case reports are subject to bias and confounding and provide only low quality evidence for interventions. In addition, it is possible that cases in which eculizumab was unsuccessful are under reported in the literature (publication bias).

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 soluble 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, in terms of patient‑oriented outcomes such as the need for dialysis or kidney transplantation, 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.