commentary
4.
5.
6.
Noordzij M, Leffondre K, van Stralen KJ, Zoccali C, Dekker FW, Jager KJ. When do we need competing risks methods for survival analysis in nephrology? Nephrol Dial Transplant 2013; 28: 2670–2677. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987; 40: 373–383. Liu J, Huang Z, Gilbertson DT, Foley RN, Collins AJ. An improved comorbidity index for
7.
8.
outcome analyses among dialysis patients. Kidney international 2010; 77: 141–151. Couchoud C, Labeeuw M, Moranne O et al. A clinical score to predict 6-month prognosis in elderly patients starting dialysis for endstage renal disease. Nephrol Dial Transplant 2009; 24: 1553–1561. Steyerberg EW. Clinical Prediction Models, A Practical Approach to Development. Validation and Updating Statistics for Biology and Health. Springer: New York, 2009.
see clinical trial on page 1061
Managing atypical hemolytic uremic syndrome: chapter 2 Carla M. Nester1,2 Licht et al. present the 2-year follow-up data of the landmark trials studying the efficacy of eculizumab in the treatment of atypical hemolytic uremic syndrome (aHUS). They report sustained improvements in hematologic parameters, continued safety, and additional improvements in kidney function with extended treatment. This report adds a layer of comfort to our care of patients with this rare disease; however, it is unlikely to be the final chapter in the treatment of aHUS. Kidney International (2015) 87, 882–884. doi:10.1038/ki.2015.60
The management of atypical hemolytic uremic syndrome (aHUS), an ultra-rare disease frequently associated with alternate complement pathway dysregulation, has markedly changed with the regulatory approval of the anti-C5 agent eculizumab. Before 2011, the mainstay of treatment was plasma therapy. Early reports in complement factor H (FH)related aHUS suggested a therapeutic benefit from either plasma infusion or exchange. A closer look at additional data was not as reassuring. In a report by Noris and colleagues, plasma therapy resulted in complete or partial remission in 78% of aHUS episodes in children and 53% in adults. Despite 1 Stead Family Department of Pediatrics, University of Iowa, Iowa City, USA and 2Department of Internal Medicine, University of Iowa, Iowa City, USA Correspondence: Carla M. Nester, Rare Renal Disease Clinic, Carver College of Medicine, University of Iowa, 200 Hawkins Drive 4036BT, Iowa City 52242, Iowa, USA. E-mail: [email protected]
882
this, 48% of children and 67% of adults either died or reached end-stage kidney disease.1 Similar results have been obtained in other cohorts.2,3 To be clear, plasma therapy has not been formally studied; therefore we do not know whether it could be used more effectively and in whom. In the absence of further study, however, it appears that plasma therapy is reasonably effective at normalizing the hematologic parameters of thrombotic microangiopathy, but it is not uniformly effective at preventing the progression of renal disease. This knowledge, combined with an improved understanding of the role of complement in the pathogenesis of aHUS, set the stage for an anticomplement approach to the treatment of aHUS. Trial data documenting the efficacy of eculizumab were first reported in 2013.4 Licht et al.5 (this issue) now present the two-year follow-up data of those two trials. It is worth mentioning that the original trials were not randomized, controlled, or blinded. None-
theless, our enthusiasm for these data should not be dampened by these study design limitations. Randomized, controlled trials are a luxury often not afforded or expected for the rare diseases.6 Simply put, these trials may well be as good as it gets. In this detailed accounting, Licht et al.5 report that extended eculizumab treatment is both safe and well tolerated by patients. Not surprisingly, eculizumab continues to be effective at blocking terminal complement and sustaining normal hematologic parameters. Also reinforced by this report is the fact that extended eculizumab treatment is equally effective whether or not the cause of aHUS is known (for instance, through genetic mutation or autoantibody). The most striking update, however, is the apparent effect of extended eculizumab treatment on renal outcomes. Specifically, in an ad hoc analysis, the gains in kidney function previously noted in trial patients were not only maintained but were further improved during extension in the progressing aHUS cohort (trial 1). Given the severity of renal dysfunction often manifest in this disease and the related morbidity, this outcome is quite important and changes our expectations for recovery. Eculizumab has become the preferred treatment of aHUS in many settings, and this report provides evidence to support this approach. Despite this exciting report, there remain a number of questions that the trials were not designed to address but that are nonetheless important to clinicians. One of those questions is whether a dosing regimen shorter than 2 years would be equally effective. Without compromising renal or extrarenal health, can eculizumab be stopped once patients are in remission? Specific rationale aside, this concept is not foreign to the treatment of aHUS. Historically, clinicians have sought to stop therapy (for instance, plasma therapy) once disease is believed to be in remission.7,8 The reasons for considering a shorter treatment course for eculizumab specifically are not trivial. They include reducing the risk of meningococcal infection, Kidney International (2015) 87
commentary
minimizing the quality-of-life impact of twice-monthly intravenous administration, preventing immune side effects, and a logical preference to be fiscally responsible when treating this rare disease. Given the single-arm nature of the trials, these points cannot be addressed entirely by an analysis of the 2-year data. We can, however, glean partial answers to the first and second points from the follow-up data provided by Licht and colleagues.5 No meningo coccal infections occurred during the extension period, and quality-oflife data remained good. Accepting the limitations of small cohort studies, the follow-up data suggest that at least for these two points, benefit likely outweighs risk. A single patient was reported to have developed an antibody to eculizumab. This patient was not part of the extension period, and additional data on the effect of this antibody are not reported. Nonetheless, it appears that the risk for an immune response to the drug with extended dosing is low. Given the small cohort size and limited follow-up, vigilance for immune effects remains necessary.
The desire both to be fiscally responsible yet to achieve the best patient outcomes possible is a natural stance for physicians. With that in mind, the issue becomes whether similar patient outcomes could be achieved with shorter-duration treatment. Would trial 1 patients have had the same renal recovery had they been taken off eculizumab at 1 year? Not only does shorter treatment release the patient from drugrelated risks, it also decreases the cost of care (including both drug cost and infusion expense). The trials reported here cannot answer this question. Additional data from those patients who have been taken off the drug are required. Robust follow-up data are not available for trial patients who declined to enter the extension period. The authors state simply that with 8-week follow-up, none had a thrombotic microangiopathy event. Unfortunately, given that many aHUS patients have much longer periods between relapses, assuming that these patients are free from relapse would be incorrect. According to the eculizumab package insert (revised version, April 2014), a total of 18 aHUS patients in clinical
trials discontinued treatment. Thrombotic microangiopathy complications occurred in 5 (28%). Published case reports tell a similar story. Twenty-four eculizumab withdrawal cases have been published (Table 1). Treatment duration prior to stopping ranged from approximately 2 weeks to 19 months. Six of the 24 had relapsed at the time of publication (25%). Though FH-related or high-titer FH autoantibody-related disease accounted for the majority of those with relapse, one patient with a C3 mutation and one with no mutation also relapsed. Considering publication bias and the myriad of variables that go into case reports, we must remain cautious about conclusions. Still, the fact that no confirmatory trial is pending and the possibility that the logistics of any proposed trial may be prohibitive (that is, the cost and time to achieve balanced gene-specific arms and adequate follow-up) suggest that the outcomes of accumulated case reports are likely to influence practice. Undoubtedly, the best evidence would be obtained from a well-designed trial, and this is what we should advocate for. In current practice, however, we are either
Table 1 | Relapse status after eculizumab discontinuation Reported cause of aHUS
Treatment duration
Time to relapse
Anti-FH FH mutation FH, FI, THBD mutations FH mutation Unknown (Tx) C3 (Tx) Anti-FH (Tx) FH mutation FH mutation Anti-FH Anti-FH FH + FI mutation FI mutation FI mutation FI mutation FI mutation MCP mutation MCP mutation MCP mutation Not reported Unknown Unknown Unknown Unknown
0.4 months 9 months 14 months 5.5 months 12 months ~ 2.5 months 5.5 months 5 months 9 months 8 weeks 2.5 months 19 months 2 weeks 1.5 months 11.5 months 5.5 months 8 weeks 0.5 month 5 weeks 13 weeks 3 months 13.5 months 6 months 3 weeks
1 month 6 months ~ 1 month 1.5 months 5 months 6 days No relapse On HDa No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse On HDa
Reported relapse-free follow-up
Author
14.5 months 13 months ~ 9 months 7 months 8.5 months 22 months 4 months 22 months 10 months 15.5 months 7 months 13.5 months 9 months 6 months 12 months 6.5 months 12 months 12 months
Ardissino1 Carr2 Ardissino1 Ardissino1 Alachkar3 Chatelet4 Ardissino1 Fakhouri5 Chaudhary6 Fakhouri5 Ardissino1 Delmas7 Cayci8 Ardissino1 Ardissino1 Ardissino1 Fakhouri5 Ardissino1 Gulleroglu9 Beye10 Pu11 Ardissino1 Canigral12 Fakhouri5
Abbreviations: C3, complement C3; FH, factor H; FI, factor I; HD, hemodialysis; MCP, membrane cofactor protein; Tx, transplant. There have been 24 published reports of aHUS patients in whom eculizumab was stopped. Six of the 24 have relapsed (dark pink, native kidney; light pink, transplant kidney), the majority being related to FH dysregulation (either FH mutation or anti-FH antibody). a No relapse of extrarenal symptoms.
Kidney International (2015) 87
883
commentary
left with an extended treatment plan by default or forced to make assumptions based on our knowledge of the pathology of causal agents or on available case reports. Should we surmise that all patients with FH-mediated disease are destined to relapse, therefore the risk to organ health is too great to take them off protective therapy? Would C3 patients relapse if they were treated longer than 3 months? If relapse has not been reported in a given scenario, and the causal agent is not a major regulator of complement, can eculizumab be safely stopped, and if so, after what time period? What do we do with ‘unknowns’? If relapse occurs, will a rescue strategy with eculizumab be equally as organ preserving as continued dosing? Complicating the issue of treatment duration is our lack of knowledge of how to monitor for impending relapse. How do we identify that roughly 25% of patients before they suffer organ damage? Are the markers that were used to confirm remission in the trials sensitive enough to be organ protective? In the largest report of patients taken off eculizumab, home testing for hematuria was used to signal a potential relapse.9 Is this an appropriate strategy for the general aHUS population? Additional questions abound. Should we be monitoring complement during or after treatment? Are eculizumab drug
884
levels useful? Can patients with FH autoantibody forego eculizumab after plasma exchange and anticellular immune suppression, or would they also recover better with eculizumab treatment? None of these questions can be answered by the current trial data. Unfortunately, the number of unanswered questions has the potential to limit the general applicability of the trials to current clinical practice.
DISCLOSURE
The author declares no competing interests. REFERENCES 1.
2.
3.
CONCLUSION
The 2-year follow-up data presented by Licht et al.5 for the use of eculizumab in the treatment of aHUS have clinical importance for at least three reasons. They provide evidence of durable efficacy and safety of eculizumab using an every-2-weeks dosing schedule. They provide evidence for the effectiveness of anticomplement therapy regardless of genetic background. Importantly, as we move forward, they also remind us that the gold standard now in making treatment choices must include renal recovery. The trial data presented by Licht et al.5 clearly support the efficacy of eculizumab. We await now the next chapter— the one that tells us our limitations in how the drug can be used as we strive to provide the best care possible to patients with aHUS.
4.
5.
6.
7.
8.
9.
Noris M, Caprioli J, Bresin E et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5: 1844–1859. Fremeaux-Bacchi V, Fakhouri F, Garnier A et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013; 8: 554–562. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007; 18: 2392–2400. 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. Licht C, Greenbaum LA, Muus P et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 2015; 87: 1061–1073. Gerss JW, Kopcke W.. Clinical trials and rare diseases. Adv Exp Med Biol 2010; 686: 173–190. Ariceta G, Besbas N, Johnson S et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009; 24: 687–696. Taylor CM, Machin S, Wigmore SJ et al. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010; 148: 37–47. Ardissino G, Testa S, Possenti I et al. Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases. Am J Kidney Dis 2014; 64: 633–637.
Kidney International (2015) 87
4.
5.
6.
Noordzij M, Leffondre K, van Stralen KJ, Zoccali C, Dekker FW, Jager KJ. When do we need competing risks methods for survival analysis in nephrology? Nephrol Dial Transplant 2013; 28: 2670–2677. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987; 40: 373–383. Liu J, Huang Z, Gilbertson DT, Foley RN, Collins AJ. An improved comorbidity index for
7.
8.
outcome analyses among dialysis patients. Kidney international 2010; 77: 141–151. Couchoud C, Labeeuw M, Moranne O et al. A clinical score to predict 6-month prognosis in elderly patients starting dialysis for endstage renal disease. Nephrol Dial Transplant 2009; 24: 1553–1561. Steyerberg EW. Clinical Prediction Models, A Practical Approach to Development. Validation and Updating Statistics for Biology and Health. Springer: New York, 2009.
see clinical trial on page 1061
Managing atypical hemolytic uremic syndrome: chapter 2 Carla M. Nester1,2 Licht et al. present the 2-year follow-up data of the landmark trials studying the efficacy of eculizumab in the treatment of atypical hemolytic uremic syndrome (aHUS). They report sustained improvements in hematologic parameters, continued safety, and additional improvements in kidney function with extended treatment. This report adds a layer of comfort to our care of patients with this rare disease; however, it is unlikely to be the final chapter in the treatment of aHUS. Kidney International (2015) 87, 882–884. doi:10.1038/ki.2015.60
The management of atypical hemolytic uremic syndrome (aHUS), an ultra-rare disease frequently associated with alternate complement pathway dysregulation, has markedly changed with the regulatory approval of the anti-C5 agent eculizumab. Before 2011, the mainstay of treatment was plasma therapy. Early reports in complement factor H (FH)related aHUS suggested a therapeutic benefit from either plasma infusion or exchange. A closer look at additional data was not as reassuring. In a report by Noris and colleagues, plasma therapy resulted in complete or partial remission in 78% of aHUS episodes in children and 53% in adults. Despite 1 Stead Family Department of Pediatrics, University of Iowa, Iowa City, USA and 2Department of Internal Medicine, University of Iowa, Iowa City, USA Correspondence: Carla M. Nester, Rare Renal Disease Clinic, Carver College of Medicine, University of Iowa, 200 Hawkins Drive 4036BT, Iowa City 52242, Iowa, USA. E-mail: [email protected]
882
this, 48% of children and 67% of adults either died or reached end-stage kidney disease.1 Similar results have been obtained in other cohorts.2,3 To be clear, plasma therapy has not been formally studied; therefore we do not know whether it could be used more effectively and in whom. In the absence of further study, however, it appears that plasma therapy is reasonably effective at normalizing the hematologic parameters of thrombotic microangiopathy, but it is not uniformly effective at preventing the progression of renal disease. This knowledge, combined with an improved understanding of the role of complement in the pathogenesis of aHUS, set the stage for an anticomplement approach to the treatment of aHUS. Trial data documenting the efficacy of eculizumab were first reported in 2013.4 Licht et al.5 (this issue) now present the two-year follow-up data of those two trials. It is worth mentioning that the original trials were not randomized, controlled, or blinded. None-
theless, our enthusiasm for these data should not be dampened by these study design limitations. Randomized, controlled trials are a luxury often not afforded or expected for the rare diseases.6 Simply put, these trials may well be as good as it gets. In this detailed accounting, Licht et al.5 report that extended eculizumab treatment is both safe and well tolerated by patients. Not surprisingly, eculizumab continues to be effective at blocking terminal complement and sustaining normal hematologic parameters. Also reinforced by this report is the fact that extended eculizumab treatment is equally effective whether or not the cause of aHUS is known (for instance, through genetic mutation or autoantibody). The most striking update, however, is the apparent effect of extended eculizumab treatment on renal outcomes. Specifically, in an ad hoc analysis, the gains in kidney function previously noted in trial patients were not only maintained but were further improved during extension in the progressing aHUS cohort (trial 1). Given the severity of renal dysfunction often manifest in this disease and the related morbidity, this outcome is quite important and changes our expectations for recovery. Eculizumab has become the preferred treatment of aHUS in many settings, and this report provides evidence to support this approach. Despite this exciting report, there remain a number of questions that the trials were not designed to address but that are nonetheless important to clinicians. One of those questions is whether a dosing regimen shorter than 2 years would be equally effective. Without compromising renal or extrarenal health, can eculizumab be stopped once patients are in remission? Specific rationale aside, this concept is not foreign to the treatment of aHUS. Historically, clinicians have sought to stop therapy (for instance, plasma therapy) once disease is believed to be in remission.7,8 The reasons for considering a shorter treatment course for eculizumab specifically are not trivial. They include reducing the risk of meningococcal infection, Kidney International (2015) 87
commentary
minimizing the quality-of-life impact of twice-monthly intravenous administration, preventing immune side effects, and a logical preference to be fiscally responsible when treating this rare disease. Given the single-arm nature of the trials, these points cannot be addressed entirely by an analysis of the 2-year data. We can, however, glean partial answers to the first and second points from the follow-up data provided by Licht and colleagues.5 No meningo coccal infections occurred during the extension period, and quality-oflife data remained good. Accepting the limitations of small cohort studies, the follow-up data suggest that at least for these two points, benefit likely outweighs risk. A single patient was reported to have developed an antibody to eculizumab. This patient was not part of the extension period, and additional data on the effect of this antibody are not reported. Nonetheless, it appears that the risk for an immune response to the drug with extended dosing is low. Given the small cohort size and limited follow-up, vigilance for immune effects remains necessary.
The desire both to be fiscally responsible yet to achieve the best patient outcomes possible is a natural stance for physicians. With that in mind, the issue becomes whether similar patient outcomes could be achieved with shorter-duration treatment. Would trial 1 patients have had the same renal recovery had they been taken off eculizumab at 1 year? Not only does shorter treatment release the patient from drugrelated risks, it also decreases the cost of care (including both drug cost and infusion expense). The trials reported here cannot answer this question. Additional data from those patients who have been taken off the drug are required. Robust follow-up data are not available for trial patients who declined to enter the extension period. The authors state simply that with 8-week follow-up, none had a thrombotic microangiopathy event. Unfortunately, given that many aHUS patients have much longer periods between relapses, assuming that these patients are free from relapse would be incorrect. According to the eculizumab package insert (revised version, April 2014), a total of 18 aHUS patients in clinical
trials discontinued treatment. Thrombotic microangiopathy complications occurred in 5 (28%). Published case reports tell a similar story. Twenty-four eculizumab withdrawal cases have been published (Table 1). Treatment duration prior to stopping ranged from approximately 2 weeks to 19 months. Six of the 24 had relapsed at the time of publication (25%). Though FH-related or high-titer FH autoantibody-related disease accounted for the majority of those with relapse, one patient with a C3 mutation and one with no mutation also relapsed. Considering publication bias and the myriad of variables that go into case reports, we must remain cautious about conclusions. Still, the fact that no confirmatory trial is pending and the possibility that the logistics of any proposed trial may be prohibitive (that is, the cost and time to achieve balanced gene-specific arms and adequate follow-up) suggest that the outcomes of accumulated case reports are likely to influence practice. Undoubtedly, the best evidence would be obtained from a well-designed trial, and this is what we should advocate for. In current practice, however, we are either
Table 1 | Relapse status after eculizumab discontinuation Reported cause of aHUS
Treatment duration
Time to relapse
Anti-FH FH mutation FH, FI, THBD mutations FH mutation Unknown (Tx) C3 (Tx) Anti-FH (Tx) FH mutation FH mutation Anti-FH Anti-FH FH + FI mutation FI mutation FI mutation FI mutation FI mutation MCP mutation MCP mutation MCP mutation Not reported Unknown Unknown Unknown Unknown
0.4 months 9 months 14 months 5.5 months 12 months ~ 2.5 months 5.5 months 5 months 9 months 8 weeks 2.5 months 19 months 2 weeks 1.5 months 11.5 months 5.5 months 8 weeks 0.5 month 5 weeks 13 weeks 3 months 13.5 months 6 months 3 weeks
1 month 6 months ~ 1 month 1.5 months 5 months 6 days No relapse On HDa No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse No relapse On HDa
Reported relapse-free follow-up
Author
14.5 months 13 months ~ 9 months 7 months 8.5 months 22 months 4 months 22 months 10 months 15.5 months 7 months 13.5 months 9 months 6 months 12 months 6.5 months 12 months 12 months
Ardissino1 Carr2 Ardissino1 Ardissino1 Alachkar3 Chatelet4 Ardissino1 Fakhouri5 Chaudhary6 Fakhouri5 Ardissino1 Delmas7 Cayci8 Ardissino1 Ardissino1 Ardissino1 Fakhouri5 Ardissino1 Gulleroglu9 Beye10 Pu11 Ardissino1 Canigral12 Fakhouri5
Abbreviations: C3, complement C3; FH, factor H; FI, factor I; HD, hemodialysis; MCP, membrane cofactor protein; Tx, transplant. There have been 24 published reports of aHUS patients in whom eculizumab was stopped. Six of the 24 have relapsed (dark pink, native kidney; light pink, transplant kidney), the majority being related to FH dysregulation (either FH mutation or anti-FH antibody). a No relapse of extrarenal symptoms.
Kidney International (2015) 87
883
commentary
left with an extended treatment plan by default or forced to make assumptions based on our knowledge of the pathology of causal agents or on available case reports. Should we surmise that all patients with FH-mediated disease are destined to relapse, therefore the risk to organ health is too great to take them off protective therapy? Would C3 patients relapse if they were treated longer than 3 months? If relapse has not been reported in a given scenario, and the causal agent is not a major regulator of complement, can eculizumab be safely stopped, and if so, after what time period? What do we do with ‘unknowns’? If relapse occurs, will a rescue strategy with eculizumab be equally as organ preserving as continued dosing? Complicating the issue of treatment duration is our lack of knowledge of how to monitor for impending relapse. How do we identify that roughly 25% of patients before they suffer organ damage? Are the markers that were used to confirm remission in the trials sensitive enough to be organ protective? In the largest report of patients taken off eculizumab, home testing for hematuria was used to signal a potential relapse.9 Is this an appropriate strategy for the general aHUS population? Additional questions abound. Should we be monitoring complement during or after treatment? Are eculizumab drug
884
levels useful? Can patients with FH autoantibody forego eculizumab after plasma exchange and anticellular immune suppression, or would they also recover better with eculizumab treatment? None of these questions can be answered by the current trial data. Unfortunately, the number of unanswered questions has the potential to limit the general applicability of the trials to current clinical practice.
DISCLOSURE
The author declares no competing interests. REFERENCES 1.
2.
3.
CONCLUSION
The 2-year follow-up data presented by Licht et al.5 for the use of eculizumab in the treatment of aHUS have clinical importance for at least three reasons. They provide evidence of durable efficacy and safety of eculizumab using an every-2-weeks dosing schedule. They provide evidence for the effectiveness of anticomplement therapy regardless of genetic background. Importantly, as we move forward, they also remind us that the gold standard now in making treatment choices must include renal recovery. The trial data presented by Licht et al.5 clearly support the efficacy of eculizumab. We await now the next chapter— the one that tells us our limitations in how the drug can be used as we strive to provide the best care possible to patients with aHUS.
4.
5.
6.
7.
8.
9.
Noris M, Caprioli J, Bresin E et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5: 1844–1859. Fremeaux-Bacchi V, Fakhouri F, Garnier A et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013; 8: 554–562. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007; 18: 2392–2400. 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. Licht C, Greenbaum LA, Muus P et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 2015; 87: 1061–1073. Gerss JW, Kopcke W.. Clinical trials and rare diseases. Adv Exp Med Biol 2010; 686: 173–190. Ariceta G, Besbas N, Johnson S et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009; 24: 687–696. Taylor CM, Machin S, Wigmore SJ et al. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010; 148: 37–47. Ardissino G, Testa S, Possenti I et al. Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases. Am J Kidney Dis 2014; 64: 633–637.
Kidney International (2015) 87
