- Email: [email protected]
Eculizumab in children with hemolytic uremic syndrome
commentary
7. Hu MC, Shiizaki K, Kuro-o M, et al. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–533. 8. Mencke R, Harms G, Mirkovic K, et al. NIGRAM Consortium. Membrane-bound Klotho is not
expressed endogenously in healthy or uraemic human vascular tissue. Cardiovasc Res. 2015;108:220–231. 9. Six I, Okazaki H, Gross P, et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS One. 2014;9:e93423.
Eculizumab in children with hemolytic uremic syndrome David Kavanagh1 and Kate Smith-Jackson1 Greenbaum et al. report the first prospective trial of eculizumab in pediatric atypical hemolytic uremic syndrome. As in adult trials, eculizumab appears effective and no serious safety signals were reported. There is the first suggestion of a dichotomy in response to treatment with a trend toward poorer outcome in those without complement abnormalities. This group, however, had worse renal function at presentation, and it remains to be seen whether this represents true non-response or merely late presentation. Kidney International (2016) 89, 537–538; http://dx.doi.org/10.1016/j.kint.2015.12.039 ª 2016 International Society of Nephrology
see clinical trial on page 701
T
he discovery of the role of the alternative pathway of complement in the pathogenesis of aHUS has led to a revolution in the treatment of the disease. Most individuals with aHUS have a latent genetic predisposition in the complement system (CFH, CFI, CD46, C3, CFB mutations).1 Following a triggering stimuli, such as infection, disease manifests acutely with microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Extrarenal manifestations are occasionally seen, although it is unclear whether these are a direct consequence of complement activation or the thrombotic microangiopathy process or the consequences of disease such as severe hypertension and uremia. 1 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
Correspondence: David Kavanagh, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. E-mail: [email protected] Kidney International (2016) 89, 529–538
In 2013 Legendre et al.2 published the landmark study demonstrating that complement blockade with eculizumab in adult patients with aHUS was effective. In this issue of Kidney International, Greenbaum et al.3 (2016) report the first prospective trial of eculizumab in pediatric aHUS (<18 years), with the efficacy mirroring that seen in the adult trial. As in the adult study, this is a nonrandomized uncontrolled trial; however, this does not detract from its utility. The high morbidity and mortality rates described historically in aHUS1 mean that the data are still informative. Overall the study population is representative of previously reported cohorts with w45% having a rare genetic variant in a complement gene or factor H autoantibody. The individual breakdown of mutation type revealed a slightly higher proportion of CD46 variants in relation to CFH variants than in the reported literature.1 There were no reported episodes of meningococcal sepsis in the trial.
In clinical practice, in both paroxysmal nocturnal hemoglobinuria and aHUS, meningococcal sepsis has been reported, prompting many centers to recommend long-term antibiotic prophylaxis in addition to vaccination. Although only 64% of patients reached the primary end point of complete thrombotic microangiopathy response (platelet and lactate dehydrogenase normalization with a >25% plasma creatinine reduction), latepresenting individuals with irretrievable renal impairment who have a complete resolution of the microangiopathic hemolytic anemia and thrombocytopenia cannot reach this end point. In keeping with this, the group that did not reach the primary end point had worse renal function at presentation compared to those who did respond.3 Nevertheless it is intriguing to note that in those with a rare genetic variant in the complement system or an autoantibody to factor H, all had an improvement in estimated glomerular filtration rate $15 ml/min per 1.73 m2; however, 27% of individuals without an identified complement abnormality failed to show an improvement in estimated glomerular filtration rate. This raises the possibility of a subgroup of non–complement-mediated aHUS that does not respond to eculizumab. With the increased scrutiny of wider clinical practice, such a group may reveal itself. It will be important to differentiate between non-responders and late presenters. It is interesting that in this cohort there was 1 individual who was subsequently demonstrated to have mutations in DGKE. The exact mechanism of action of these mutations is unclear, and no definitive link to the complement system has yet to be elucidated. In the initial report by Lemaire et al.,4 individuals had recurrent aHUS while on treatment with eculizumab. In this study the individual with the DGKE mutations achieved complete thrombotic microangiopathy response. It is too early to be clear as to the utility of complement blockade 537
commentary
in this subgroup, as it appears these individuals have a spontaneously remitting and relapsing disease that progresses over many years to endstage renal failure. This work by Greenbaum et al.3 completes the first stage of the journey from the initial description of mutations in CFH to the successful use of the complement inhibitor eculizumab in both adults and children. Many questions still remain to be answered. First among them is the optimal duration of treatment. There is currently no evidence to justify lifelong therapy. In this study 2 individuals withdrew from eculizumab treatment without documented relapse of symptoms.5,6 Unsurprisingly, in a few individuals with underlying complement abnormalities there has been evidence of disease recurrence, although eculizumab reintroduction led to normalization of renal function.5,6 Clinical trials comparing continuous versus disease-driven intermittent treatment are required to determine the best regime. These should be stratified by mutation type, as certain mutations (e.g., CD46) have a good prognosis even without treatment.7
538
Additionally, the trials of eculizumab have so far excluded potential secondary causes of aHUS, such as thrombotic microangiopathy associated with bone marrow transplantation.8 As alluded to above, even in individuals with complement mutations, disease requires a trigger to manifest. As such, it can be unclear whether these triggers have a direct effect or have a role only in the context of an underlying complement mutation. Genetic characterization and clinical trials of eculizumab in these secondary cohorts will be required before recommending its use in these cases. In summary, eculizumab appears effective in treating both adult and pediatric aHUS. It remains to define the optimal treatment regimen to minimize the infectious complications of terminal pathway complement blockade. Such a strategy will also minimize the financial impact of this highly expensive monoclonal antibody on those few countries that can afford eculizumab. DISCLOSURE
Newcastle University has received fees for consultancy work undertaken by DK for Biomarin Pharmaceuticals & Syncona. All the authors declared no competing interests.
ACKNOWLEDGMENT
DK is a Wellcome Trust intermediate clinical fellow. REFERENCES 1. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33:508–530. 2. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–2181. 3. Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89:701–711. 4. Lemaire M, Fremeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531–536. 5. Sheerin NS, Kavanagh D, Goodship TH, Johnson S. A national specialised service in England for atypical haemolytic uraemic syndrome—the first year’s experience. QJM. 2016;109:27–33. 6. Ardissino G, Possenti I, Tel F, et al. Discontinuation of eculizumab treatment in atypical hemolytic uremic syndrome: an update. Am J Kidney Dis. 2015;66:172–173. 7. Phillips EH, Westwood JP, Brocklebank V, et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost. 2016;14:175–185. 8. Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant associated thrombotic microangiopathy [e-pub ahead of print]. Blood. 24 November 2015. pii: blood-2015-08-663435, http://dx. doi.org/10.1182/blood-2015-08-663435.
Kidney International (2016) 89, 529–538
7. Hu MC, Shiizaki K, Kuro-o M, et al. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–533. 8. Mencke R, Harms G, Mirkovic K, et al. NIGRAM Consortium. Membrane-bound Klotho is not
expressed endogenously in healthy or uraemic human vascular tissue. Cardiovasc Res. 2015;108:220–231. 9. Six I, Okazaki H, Gross P, et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS One. 2014;9:e93423.
Eculizumab in children with hemolytic uremic syndrome David Kavanagh1 and Kate Smith-Jackson1 Greenbaum et al. report the first prospective trial of eculizumab in pediatric atypical hemolytic uremic syndrome. As in adult trials, eculizumab appears effective and no serious safety signals were reported. There is the first suggestion of a dichotomy in response to treatment with a trend toward poorer outcome in those without complement abnormalities. This group, however, had worse renal function at presentation, and it remains to be seen whether this represents true non-response or merely late presentation. Kidney International (2016) 89, 537–538; http://dx.doi.org/10.1016/j.kint.2015.12.039 ª 2016 International Society of Nephrology
see clinical trial on page 701
T
he discovery of the role of the alternative pathway of complement in the pathogenesis of aHUS has led to a revolution in the treatment of the disease. Most individuals with aHUS have a latent genetic predisposition in the complement system (CFH, CFI, CD46, C3, CFB mutations).1 Following a triggering stimuli, such as infection, disease manifests acutely with microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Extrarenal manifestations are occasionally seen, although it is unclear whether these are a direct consequence of complement activation or the thrombotic microangiopathy process or the consequences of disease such as severe hypertension and uremia. 1 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
Correspondence: David Kavanagh, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. E-mail: [email protected] Kidney International (2016) 89, 529–538
In 2013 Legendre et al.2 published the landmark study demonstrating that complement blockade with eculizumab in adult patients with aHUS was effective. In this issue of Kidney International, Greenbaum et al.3 (2016) report the first prospective trial of eculizumab in pediatric aHUS (<18 years), with the efficacy mirroring that seen in the adult trial. As in the adult study, this is a nonrandomized uncontrolled trial; however, this does not detract from its utility. The high morbidity and mortality rates described historically in aHUS1 mean that the data are still informative. Overall the study population is representative of previously reported cohorts with w45% having a rare genetic variant in a complement gene or factor H autoantibody. The individual breakdown of mutation type revealed a slightly higher proportion of CD46 variants in relation to CFH variants than in the reported literature.1 There were no reported episodes of meningococcal sepsis in the trial.
In clinical practice, in both paroxysmal nocturnal hemoglobinuria and aHUS, meningococcal sepsis has been reported, prompting many centers to recommend long-term antibiotic prophylaxis in addition to vaccination. Although only 64% of patients reached the primary end point of complete thrombotic microangiopathy response (platelet and lactate dehydrogenase normalization with a >25% plasma creatinine reduction), latepresenting individuals with irretrievable renal impairment who have a complete resolution of the microangiopathic hemolytic anemia and thrombocytopenia cannot reach this end point. In keeping with this, the group that did not reach the primary end point had worse renal function at presentation compared to those who did respond.3 Nevertheless it is intriguing to note that in those with a rare genetic variant in the complement system or an autoantibody to factor H, all had an improvement in estimated glomerular filtration rate $15 ml/min per 1.73 m2; however, 27% of individuals without an identified complement abnormality failed to show an improvement in estimated glomerular filtration rate. This raises the possibility of a subgroup of non–complement-mediated aHUS that does not respond to eculizumab. With the increased scrutiny of wider clinical practice, such a group may reveal itself. It will be important to differentiate between non-responders and late presenters. It is interesting that in this cohort there was 1 individual who was subsequently demonstrated to have mutations in DGKE. The exact mechanism of action of these mutations is unclear, and no definitive link to the complement system has yet to be elucidated. In the initial report by Lemaire et al.,4 individuals had recurrent aHUS while on treatment with eculizumab. In this study the individual with the DGKE mutations achieved complete thrombotic microangiopathy response. It is too early to be clear as to the utility of complement blockade 537
commentary
in this subgroup, as it appears these individuals have a spontaneously remitting and relapsing disease that progresses over many years to endstage renal failure. This work by Greenbaum et al.3 completes the first stage of the journey from the initial description of mutations in CFH to the successful use of the complement inhibitor eculizumab in both adults and children. Many questions still remain to be answered. First among them is the optimal duration of treatment. There is currently no evidence to justify lifelong therapy. In this study 2 individuals withdrew from eculizumab treatment without documented relapse of symptoms.5,6 Unsurprisingly, in a few individuals with underlying complement abnormalities there has been evidence of disease recurrence, although eculizumab reintroduction led to normalization of renal function.5,6 Clinical trials comparing continuous versus disease-driven intermittent treatment are required to determine the best regime. These should be stratified by mutation type, as certain mutations (e.g., CD46) have a good prognosis even without treatment.7
538
Additionally, the trials of eculizumab have so far excluded potential secondary causes of aHUS, such as thrombotic microangiopathy associated with bone marrow transplantation.8 As alluded to above, even in individuals with complement mutations, disease requires a trigger to manifest. As such, it can be unclear whether these triggers have a direct effect or have a role only in the context of an underlying complement mutation. Genetic characterization and clinical trials of eculizumab in these secondary cohorts will be required before recommending its use in these cases. In summary, eculizumab appears effective in treating both adult and pediatric aHUS. It remains to define the optimal treatment regimen to minimize the infectious complications of terminal pathway complement blockade. Such a strategy will also minimize the financial impact of this highly expensive monoclonal antibody on those few countries that can afford eculizumab. DISCLOSURE
Newcastle University has received fees for consultancy work undertaken by DK for Biomarin Pharmaceuticals & Syncona. All the authors declared no competing interests.
ACKNOWLEDGMENT
DK is a Wellcome Trust intermediate clinical fellow. REFERENCES 1. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33:508–530. 2. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–2181. 3. Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89:701–711. 4. Lemaire M, Fremeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531–536. 5. Sheerin NS, Kavanagh D, Goodship TH, Johnson S. A national specialised service in England for atypical haemolytic uraemic syndrome—the first year’s experience. QJM. 2016;109:27–33. 6. Ardissino G, Possenti I, Tel F, et al. Discontinuation of eculizumab treatment in atypical hemolytic uremic syndrome: an update. Am J Kidney Dis. 2015;66:172–173. 7. Phillips EH, Westwood JP, Brocklebank V, et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost. 2016;14:175–185. 8. Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant associated thrombotic microangiopathy [e-pub ahead of print]. Blood. 24 November 2015. pii: blood-2015-08-663435, http://dx. doi.org/10.1182/blood-2015-08-663435.
Kidney International (2016) 89, 529–538