American Journal of Therapeutics 0, 1–6 (2014)
Adult Post–Kidney Transplant Familial Atypical Hemolytic Uremic Syndrome Successfully Treated With Eculizumab: A Case Report and Literature Review Hassan Salameh, MD,1 Mohannad Abu Omar, MD,1 Ahmad Alhariri, MD,2 Sood Kisra, MD,1 Abdulraheem Qasem, MD,1 and Aref Bin Abdulhak, MD1*
Hemolytic uremic syndrome is the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. When not associated with enteric infection, it is classified as atypical hemolytic uremic syndrome (aHUS) and carries a worse outcome with high mortality rate and up to 50% of the survivors will end up with end-stage renal disease. Renal transplant was restricted to a very small percentage of patients due to high recurrence rate posttransplant that approaches 90%. Our case describes a posttransplant adult patient with familial aHUS whom was successfully treated with eculizumab. We also reviewed all other reported cases of adult posttransplant aHUS, both familial and sporadic, which were treated with eculizumab. In summary, eculizumab might expand the utility of renal transplant for patients with end-stage renal disease due to aHUS. Keywords: eculizumab, atypical hemolytic uremic syndrome, kidney transplant, familial
INTRODUCTION The triad of non-immune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure defines hemolytic uremic syndrome (HUS).1 HUS is usually associated with Shiga-like toxin–producing enteric bacteria, particularly enterohemorrhagic Escherichia coli. However, up to 10% of HUS cases are not associated with enteric infection and are classified as atypical hemolytic uremic syndrome (aHUS). The aHUS is extremely rare with an estimated annual incidence rate of z1–2 cases per million in the United States.2
1
Department of Medicine, School of Medicine, University of Missouri-Kansas City, Kansas City, MO; and 2Department of Pediatrics, Division of Medical Genetics, University of California San Francisco Medical Center, San Francisco, CA. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Medicine, School of Medicine, University of Missouri-Kansas City, 2301 Holmes St, Kansas City, MO 64108. E-mail: [email protected] 1075–2765 2014 Lippincott Williams & Wilkins
The aHUS is primarily a disease of children and young adult in which the majority of cases are sporadic and less than 20% familial. The aHUS has a poor prognosis, worse than that of enteric infection-related HUS, with a 10%–15% mortality rate during the acute phase and up to 50% of cases will progress to endstage renal disease (ESRD).3 Complement activation and/or dysregulation have been implicated to play a fundamental role in the pathogenesis of aHUS.4 Mutations in complement regulators [complement factor H (CFH), factor I (IF), membrane cofactor protein (MCP), and thrombomodulin], autoantibodies to CFH, and gain of function mutations in the complement components C3 and factor B (BF) have all been recently shown to play a role in the pathogenesis of aHUS.5 Until 2010, plasma therapy was the mainstay treatment for aHUS. However, when the patients reach ESRD, the option of kidney transplant comes into question. This option was limited by the overall risk of posttransplant recurrence of aHUS and graft loss in 50% and 90%, respectively. These risks were highly correlated with genetic mutations.1 In 2009, the Food and Drug Administration (FDA) has approved the use www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2
of the anti-C5 monoclonal antibody eculizumab for the treatment of aHUS. It was reported to be effective in patients with aHUS on native kidneys and to rescue or prevent posttransplant recurrence.6,7 The following case report describes an adult patient who developed aHUS post–kidney transplant and was successfully treated with eculizumab. We also briefly review the genetic mutations involved in aHUS, treatment options, and summarize the clinical features and outcomes of reported cases of adult post–kidney transplant aHUS patients who were treated with eculizumab.
CASE DESCRIPTION A 48-year-old African American male patient who had a post–cadaveric renal transplant was admitted to the hospital 3 months after transplant, complaining of right lower quadrant abdominal pain and found to have elevated creatinine level. He reported transplant incision site pain for 1 day before admission. The patient denied fever, diarrhea, altered mental status, change in urine output or color, or bleeding. The patient had his transplant due to ESRD secondary to hypertension and had a history of 2 left upper extremity arteriovenous fistulas. The patient’s family history is positive for aHUS due to a CFH gene mutations in 2 of his sons, 1 of them died at the age of 17 months secondary to the condition. Noteworthy is that the patient himself had no genetic testing for CFH gene mutations before transplant. At that time, the patient was maintained on the following medications: hydrochlorothiazide, metoprolol, amlodipine, mycophenolate, prednisone, trimethoprim/sulfamethoxazole, valacyclovir, and tacrolimus. On physical examination, the patient was conscious, alert, and oriented. Apart from a blood pressure of 147/85 mm Hg, other vital signs were normal. He was obese; his weight was 130 kg and height was 180 cm with a body mass index of 40 kg/m2. The patient was in no distress with no pallor, icterus, or cyanosis. He was not found to have any lymphadenopathy, skin rash, or mouth ulcers and the rest of his physical examination was not remarkable. Laboratory evaluation showed a platelet count of 41 3 103/mL, hemoglobin of 9.2 g/dL, and a white blood cell count of 6.5 x 103/mL. Schistocytes were evident on peripheral blood smear. The chemistry panel showed absolute reticulocyte count of 131000/mL (26000-105000/mL), LDH 2756 U/L, haptoglobin 4 ng/dL (40–240 ng/dL), creatinine 4 mg/dL, tacrolimus level 4.4 ng/dL (5–15 ng/dL), and an ADAMTS 13 activity more than 75%. American Journal of Therapeutics (2014) 0(0)
Salameh et al
The patient was treated with multidisciplinary team approach involving a nephrologist, hematologist, transplant surgeon, social services, and clinical pharmacist. Since admission, tacrolimus was discontinued because it is known to cause drug-induced thrombotic thrombocytopenic purpura, and the patient underwent a total of 7 sessions of plasma therapy. Platelet count and LDH normalized and hemoglobin remained stable but serum creatinine was still increasing. He had a kidney biopsy that showed thrombotic microangiopathy (TMA) with no evidence of acute rejection and a genetic testing revealed CFH gene mutation (p. Arg 1215Gln). At this point, the patient was started on eculizumab therapy with a dose of 900 mg per week for 4 weeks then 1200 mg at week 5 to be followed by 1200 mg every 2 weeks then after. Three months after eculizumab therapy, the patient’s hemoglobin level was back to his baseline of 12 mg/dL, and serum creatinine level significantly improved to his base line of 1.5 mg/dL at 6 months from starting therapy. Sixteen months later, the patient has stable kidney function, no recurrence of aHUS, and no side effect from eculizumab.
DISCUSSION HUS is defined by the triad of non-immune hemolytic anemia with erythrocyte fragmentation (schizocytes), thrombocytopenia, and renal dysfunction. The aHUS refers to the condition when it is not due to Shiga toxin–producing organisms rather to a disorder in the regulation of the complement alternative pathway.1 Common for all genes involved in the pathogenesis of aHUS is a role in the regulation of the activity of the alternative pathway of compliment amplification, C3 convertase. Inactivating mutations in genes encoding complement regulators (CFH, IF, and MCP), gain-offunction mutations in genes encoding the complement activators (C3 and BF), and mutations in the gene encoding thrombomodulin that modulates complement activation on cell surfaces have all been described in aHUS.4 The clinical phenotype of aHUS is distinctive for each genetic mutation and the type of mutation also has prognostic significance. CFH gene mutations are the commonest genetic mutations in patients with aHUS and have been described in up to 30% of patients.8 CFH gene mutation is known to be associated with very high risk of death or progression to ESRD of up to 75% and recurrence post–kidney transplant up to 95%.9 The majority of mutations are heterozygous missense mutations resulting in abnormal protein rather than quantitative abnormalities.4,5 Mutations are most commonly located in the exons encoding the C-terminal domain www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Reference Age, gender
Mutation
Protein
Familial versus sporadic
NI
NI
NI
32 yrs, female
17
42 yrs, female
18
37 yrs, Tyr475Ser female 32 yrs, male Glu1172Stop
19
Arg592Gln
C3
Familial
CFH
Sporadic
CFH
Sporadic
Therapeutic scheme
Duration of eculizumab
Follow-up and response
SR up to 14 mo after 9 mo after First attack: 2 wk 900 mg which she first attack induction during which developed aHUS then dose then she received PE secondary to stopped for PE EOD and eculizumab pneumonia and 5 mo and with 600 eculizumab was resumed for mg after resumed as 6 mo after each protocol without second session PE for 6 more mo attack for 2 wk after which the then 1200 graft was lost to mg every ATN secondary to 2 wk an endovascular procedure Second attack: Second attack: 14 mo after Tx the same day of admission 7 mo SR at 7 mo with 1 3 yrs after 9 mo of PE then Complete protocol episode of aHUS second Tx switched to due to a 6-d delay eculizumab in the ninth dose, because of which resolved intolerance with resumption to PE of eculizumab 6 wk after second 4d Single dose 1d SR at 8 mo Tx of 600 mg NR Complete 10 mo SR at 10 mo with First attack: 1 mo protocol Cr at baseline of after cocaine use 2.6 mg/dL treated with PE only Second attack: 2 mo after TX after cocaine use again First attack: 10 wk after second Tx
(Continued on next page)
3
American Journal of Therapeutics (2014) 0(0)
16
Time between Tx and aHUS
Time between recurrence and initiation of eculizumab
Post–Kidney Transplant Familial aHUS
www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Table 1. The general characteristics and outcome of the reported adult cases of post–kidney transplant aHUS that were given rescue therapy with eculizumab.
SR at 6 mo with baseline Cr at 2.7 mg/dL 6 mo
Second attack: 5 mo after second Tx
9 mo during which she was receiving PE First attack: 1 mo after first Tx NR NR NR 21
American Journal of Therapeutics (2014) 0(0)
ATN, acute tubular necrosis; Cr, creatinine level; EOD, every other day; NI, not identified; NR, not reported; PE, plasma exchange; SR, sustained remission; Tx, transplant.
SR at 7 mo 1d
Single dose of 600 mg Complete protocol NR 12 d after first Tx NI NI NI
22 yrs, female 34 yrs, female
Protein Mutation Reference Age, gender
20
Time between Tx and aHUS
Time between recurrence and initiation of eculizumab
Therapeutic scheme
Duration of eculizumab
Follow-up and response
Salameh et al
Familial versus sporadic
Table 1. (Continued) The general characteristics and outcome of the reported adult cases of post–kidney transplant aHUS that were given rescue therapy with eculizumab.
4
of the protein that mediates complement protection on the cell surface. Abnormal proteins fail to control complement activation at the glomerular endothelium leading to reduced ability to bind to platelets, which results in complement activation on the platelet surfaces with platelet activation and aggregation eventually leading to aHUS.10 MCP is a surface protein expressed on all cells except erythrocytes. MCP functions with IF (a plasma complement regulatory protein) to degrade C3b and C4b bound on the cell surface.3 MCP gene mutations account for 15% of cases of aHUS,3,4 whereas IF gene mutation is less common, reported in 2%–12% of aHUS patients.11,12 Mutations in the CD46 gene are the most common MCP encoding gene mutations resulting in decreased cell surface expression. All other gene mutations in MCP result in functionally inactive protein expression.13 The majority of IF gene mutations result in a quantitative defect.5 Thrombomodulin and BF gene defects are not as common as the previously mentioned gene defects. Noteworthy is that BF functions as an activator of complement rather than a regulator, and mutations in BF gene lead to increased complement activation, resulting in increased deposition of complement in the glomerular endothelial cells.14 Until recently, treatment of HUS generally is widely based on supportive measures and plasma therapy, either exchange or pheresis. Recommendations are to start empiric plasma therapy as early as possible preferably within 24 hours of presentation.15 First-line therapy should be plasmapheresis unless it cannot be performed within the first 24 hours, where plasma infusion should be given if the patient is not in volume overload, hypertensive, or showing symptoms of cardiac failure. Plasma therapy should be continued daily until platelet count, LDH, and hemoglobin levels are back to normal and the renal function has been improving for several days. If hemolysis persists or renal function does not improve after 3–5 daily plasma therapy sessions, the patient is regarded to be in uncontrolled TMA even if platelet counts improve. Data from International Registry of Recurrent and Familial HUS/TTP have shown that treatment with plasma therapy ensued complete hematological and renal recovery in only 5%, hematological recovery with renal sequelae in 58%, and death or ESRD in 37%.3 Uncontrolled TMA used to be an indication to remain on daily plasma therapy but recently eculizumab has become an FDA-approved alternative. When disease activity has been controlled with daily plasma therapy, the recommended subsequent frequency is 5 times a week for 2 more weeks then 3 times a week for 2 additional weeks. Due to the high frequency of www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Post–Kidney Transplant Familial aHUS
recurrence and renal sequel in patients with CFH mutation, plasma therapy should probably never be stopped.1 Eculizumab is a recombinant, humanized monoclonal antibody that binds to complement protein C5 and inhibits the production of the terminal complement components C5a and the membrane attack complex C5b-9. Prevention of terminal complement components inhibits complement-mediated TMA in aHUS patients. FDA has recently approved eculizumab for treatment of pediatric and adult patients with aHUS. Experience with eculizumab in treatment of post– kidney transplant aHUS in adults is very scanty with only 7 reported cases (including our case) in the literature.6 Table 1 shows the general characteristics and outcome of the reported adult cases of post–kidney transplant aHUS that were given rescue therapy with eculizumab. Most of the cases have very good outcome with initially remission in all patients. Two patients had subsequent relapses; the first patient had a relapse 5 months after stopping treatment secondary to a pneumonia episode and eventually lost her graft due to acute tubular necrosis.16 The second patient had a relapse after delaying 1 infusion by 6 days and improved later on with resumption of therapy.17 Anti-C5 therapy provides an opportunity for kidney transplants in patients with ESRD secondary to aHUS and may eliminate the need for combined kidney–liver transplant as the only curative intervention. Our case report is of an adult posttransplant familial aHUS successfully treated with eculizumab, although he has the worst prognostic genetic mutation (CFH gene mutation).
CONCLUSIONS The aHUS is a rare but often fatal disease associated with devastating sequelae, including ESRD. Kidney transplant was of limited utility in the treatment of ESRD in adult population from aHUS due to higher rate of recurrence and graft loss. However, limited experience with eculizumab in the treatment of adult post–kidney transplant patients with aHUS has shown a promising outcome in graft survival that may potentially increase the utility of kidney transplant in aHUS.
REFERENCES 1. Loirat C, Fremeaux-Bacchi V. A typical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. 2. Constantinescu AR, Bitzan M, Weiss LS, et al. Nonenteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43:976–982. www.americantherapeutics.com
5 3. 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. 4. Kavanagh D, Goodship TH. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. Hematology Am Soc Hematol Educ Program. 2011;2011: 15–20. 5. Kavanagh D, Goodship T. Genetics and complement in a typical HUS. Pediatr Nephrol. 2010;25:2431–2442. 6. Zuber J, Le Quintrec M, Krid S, et al. Eculizumab for a typical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12:3337–3354. 7. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in a typical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–2181. 8. Westra D, Volokhina E, van der Heijden E, et al. Genetic disorders in complement regulating genes in patients with atypical haemolytic uraemic syndrome (aHUS). Nephrol Dial Transplant. 2010;25:2195–2202. 9. Zuber J, Le Quintrec M, Sberro-Soussan R, et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;7:23–35. 10. Stahl AL, Vaziri-Sani F, Heinen S, et al. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood. 2008;111:5307–5315. 11. Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267–1279. 12. Kavanagh D, Kemp EJ, Mayland E, et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005; 16:2150–2155. 13. Richards A, Kathryn Liszewski M, Kavanagh D, et al. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol. 2007;44:111–122. 14. Roumenina LT, Jablonski M, Hue C, et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to a typical hemolytic uremic syndrome. Blood. 2009;114:2837–2845. 15. Taylor CM, Machin S, Wigmore SJ, et al. Clinical practice guidelines for the management of a typical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol. 2010;148:37–47. 16. Alachkar N, Bagnasco S, Montgomery R. Eculizumab for the treatment of two recurrences of a typical hemolytic uremic syndrome in a kidney allograft. Transpl Int. 2012; 25:e93–e95. 17. Chatelet V, Fremeaux-Bacchi V, Lobbedez T, et al. Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant. 2009;9:2644–2645. 18. Nurnberger J, Philipp T, Witzke O, et al. Eculizumab for a typical hemolytic-uremic syndrome. N Engl J Med. 2009;360:542–544. American Journal of Therapeutics (2014) 0(0)
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
6 19. Duran CE, Maduell FM, Campistol JM. Rescue therapy with eculizumab in a transplant recipient with atypical haemolytic uraemic syndrome. Clin Kidney J. 2012;5:28–30. 20. Larrea CF, Cofan F, Oppenheimer F, et al. Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation. 2010;89:903–904.
American Journal of Therapeutics (2014) 0(0)
Salameh et al 21. Legault D, Boelkins M. Successful treatment of aHUS recurrence and arrest of plasma exchange resistant TMA post-renal transplantation with the terminal complement inhibitor eculizumab. Paper presented at: 51st Annual meeting of the American Society of Hematology; December 5–8, 2009: Grand Rapids, MI. p. 2421.
www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Adult Post–Kidney Transplant Familial Atypical Hemolytic Uremic Syndrome Successfully Treated With Eculizumab: A Case Report and Literature Review Hassan Salameh, MD,1 Mohannad Abu Omar, MD,1 Ahmad Alhariri, MD,2 Sood Kisra, MD,1 Abdulraheem Qasem, MD,1 and Aref Bin Abdulhak, MD1*
Hemolytic uremic syndrome is the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. When not associated with enteric infection, it is classified as atypical hemolytic uremic syndrome (aHUS) and carries a worse outcome with high mortality rate and up to 50% of the survivors will end up with end-stage renal disease. Renal transplant was restricted to a very small percentage of patients due to high recurrence rate posttransplant that approaches 90%. Our case describes a posttransplant adult patient with familial aHUS whom was successfully treated with eculizumab. We also reviewed all other reported cases of adult posttransplant aHUS, both familial and sporadic, which were treated with eculizumab. In summary, eculizumab might expand the utility of renal transplant for patients with end-stage renal disease due to aHUS. Keywords: eculizumab, atypical hemolytic uremic syndrome, kidney transplant, familial
INTRODUCTION The triad of non-immune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure defines hemolytic uremic syndrome (HUS).1 HUS is usually associated with Shiga-like toxin–producing enteric bacteria, particularly enterohemorrhagic Escherichia coli. However, up to 10% of HUS cases are not associated with enteric infection and are classified as atypical hemolytic uremic syndrome (aHUS). The aHUS is extremely rare with an estimated annual incidence rate of z1–2 cases per million in the United States.2
1
Department of Medicine, School of Medicine, University of Missouri-Kansas City, Kansas City, MO; and 2Department of Pediatrics, Division of Medical Genetics, University of California San Francisco Medical Center, San Francisco, CA. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Medicine, School of Medicine, University of Missouri-Kansas City, 2301 Holmes St, Kansas City, MO 64108. E-mail: [email protected] 1075–2765 2014 Lippincott Williams & Wilkins
The aHUS is primarily a disease of children and young adult in which the majority of cases are sporadic and less than 20% familial. The aHUS has a poor prognosis, worse than that of enteric infection-related HUS, with a 10%–15% mortality rate during the acute phase and up to 50% of cases will progress to endstage renal disease (ESRD).3 Complement activation and/or dysregulation have been implicated to play a fundamental role in the pathogenesis of aHUS.4 Mutations in complement regulators [complement factor H (CFH), factor I (IF), membrane cofactor protein (MCP), and thrombomodulin], autoantibodies to CFH, and gain of function mutations in the complement components C3 and factor B (BF) have all been recently shown to play a role in the pathogenesis of aHUS.5 Until 2010, plasma therapy was the mainstay treatment for aHUS. However, when the patients reach ESRD, the option of kidney transplant comes into question. This option was limited by the overall risk of posttransplant recurrence of aHUS and graft loss in 50% and 90%, respectively. These risks were highly correlated with genetic mutations.1 In 2009, the Food and Drug Administration (FDA) has approved the use www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2
of the anti-C5 monoclonal antibody eculizumab for the treatment of aHUS. It was reported to be effective in patients with aHUS on native kidneys and to rescue or prevent posttransplant recurrence.6,7 The following case report describes an adult patient who developed aHUS post–kidney transplant and was successfully treated with eculizumab. We also briefly review the genetic mutations involved in aHUS, treatment options, and summarize the clinical features and outcomes of reported cases of adult post–kidney transplant aHUS patients who were treated with eculizumab.
CASE DESCRIPTION A 48-year-old African American male patient who had a post–cadaveric renal transplant was admitted to the hospital 3 months after transplant, complaining of right lower quadrant abdominal pain and found to have elevated creatinine level. He reported transplant incision site pain for 1 day before admission. The patient denied fever, diarrhea, altered mental status, change in urine output or color, or bleeding. The patient had his transplant due to ESRD secondary to hypertension and had a history of 2 left upper extremity arteriovenous fistulas. The patient’s family history is positive for aHUS due to a CFH gene mutations in 2 of his sons, 1 of them died at the age of 17 months secondary to the condition. Noteworthy is that the patient himself had no genetic testing for CFH gene mutations before transplant. At that time, the patient was maintained on the following medications: hydrochlorothiazide, metoprolol, amlodipine, mycophenolate, prednisone, trimethoprim/sulfamethoxazole, valacyclovir, and tacrolimus. On physical examination, the patient was conscious, alert, and oriented. Apart from a blood pressure of 147/85 mm Hg, other vital signs were normal. He was obese; his weight was 130 kg and height was 180 cm with a body mass index of 40 kg/m2. The patient was in no distress with no pallor, icterus, or cyanosis. He was not found to have any lymphadenopathy, skin rash, or mouth ulcers and the rest of his physical examination was not remarkable. Laboratory evaluation showed a platelet count of 41 3 103/mL, hemoglobin of 9.2 g/dL, and a white blood cell count of 6.5 x 103/mL. Schistocytes were evident on peripheral blood smear. The chemistry panel showed absolute reticulocyte count of 131000/mL (26000-105000/mL), LDH 2756 U/L, haptoglobin 4 ng/dL (40–240 ng/dL), creatinine 4 mg/dL, tacrolimus level 4.4 ng/dL (5–15 ng/dL), and an ADAMTS 13 activity more than 75%. American Journal of Therapeutics (2014) 0(0)
Salameh et al
The patient was treated with multidisciplinary team approach involving a nephrologist, hematologist, transplant surgeon, social services, and clinical pharmacist. Since admission, tacrolimus was discontinued because it is known to cause drug-induced thrombotic thrombocytopenic purpura, and the patient underwent a total of 7 sessions of plasma therapy. Platelet count and LDH normalized and hemoglobin remained stable but serum creatinine was still increasing. He had a kidney biopsy that showed thrombotic microangiopathy (TMA) with no evidence of acute rejection and a genetic testing revealed CFH gene mutation (p. Arg 1215Gln). At this point, the patient was started on eculizumab therapy with a dose of 900 mg per week for 4 weeks then 1200 mg at week 5 to be followed by 1200 mg every 2 weeks then after. Three months after eculizumab therapy, the patient’s hemoglobin level was back to his baseline of 12 mg/dL, and serum creatinine level significantly improved to his base line of 1.5 mg/dL at 6 months from starting therapy. Sixteen months later, the patient has stable kidney function, no recurrence of aHUS, and no side effect from eculizumab.
DISCUSSION HUS is defined by the triad of non-immune hemolytic anemia with erythrocyte fragmentation (schizocytes), thrombocytopenia, and renal dysfunction. The aHUS refers to the condition when it is not due to Shiga toxin–producing organisms rather to a disorder in the regulation of the complement alternative pathway.1 Common for all genes involved in the pathogenesis of aHUS is a role in the regulation of the activity of the alternative pathway of compliment amplification, C3 convertase. Inactivating mutations in genes encoding complement regulators (CFH, IF, and MCP), gain-offunction mutations in genes encoding the complement activators (C3 and BF), and mutations in the gene encoding thrombomodulin that modulates complement activation on cell surfaces have all been described in aHUS.4 The clinical phenotype of aHUS is distinctive for each genetic mutation and the type of mutation also has prognostic significance. CFH gene mutations are the commonest genetic mutations in patients with aHUS and have been described in up to 30% of patients.8 CFH gene mutation is known to be associated with very high risk of death or progression to ESRD of up to 75% and recurrence post–kidney transplant up to 95%.9 The majority of mutations are heterozygous missense mutations resulting in abnormal protein rather than quantitative abnormalities.4,5 Mutations are most commonly located in the exons encoding the C-terminal domain www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Reference Age, gender
Mutation
Protein
Familial versus sporadic
NI
NI
NI
32 yrs, female
17
42 yrs, female
18
37 yrs, Tyr475Ser female 32 yrs, male Glu1172Stop
19
Arg592Gln
C3
Familial
CFH
Sporadic
CFH
Sporadic
Therapeutic scheme
Duration of eculizumab
Follow-up and response
SR up to 14 mo after 9 mo after First attack: 2 wk 900 mg which she first attack induction during which developed aHUS then dose then she received PE secondary to stopped for PE EOD and eculizumab pneumonia and 5 mo and with 600 eculizumab was resumed for mg after resumed as 6 mo after each protocol without second session PE for 6 more mo attack for 2 wk after which the then 1200 graft was lost to mg every ATN secondary to 2 wk an endovascular procedure Second attack: Second attack: 14 mo after Tx the same day of admission 7 mo SR at 7 mo with 1 3 yrs after 9 mo of PE then Complete protocol episode of aHUS second Tx switched to due to a 6-d delay eculizumab in the ninth dose, because of which resolved intolerance with resumption to PE of eculizumab 6 wk after second 4d Single dose 1d SR at 8 mo Tx of 600 mg NR Complete 10 mo SR at 10 mo with First attack: 1 mo protocol Cr at baseline of after cocaine use 2.6 mg/dL treated with PE only Second attack: 2 mo after TX after cocaine use again First attack: 10 wk after second Tx
(Continued on next page)
3
American Journal of Therapeutics (2014) 0(0)
16
Time between Tx and aHUS
Time between recurrence and initiation of eculizumab
Post–Kidney Transplant Familial aHUS
www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Table 1. The general characteristics and outcome of the reported adult cases of post–kidney transplant aHUS that were given rescue therapy with eculizumab.
SR at 6 mo with baseline Cr at 2.7 mg/dL 6 mo
Second attack: 5 mo after second Tx
9 mo during which she was receiving PE First attack: 1 mo after first Tx NR NR NR 21
American Journal of Therapeutics (2014) 0(0)
ATN, acute tubular necrosis; Cr, creatinine level; EOD, every other day; NI, not identified; NR, not reported; PE, plasma exchange; SR, sustained remission; Tx, transplant.
SR at 7 mo 1d
Single dose of 600 mg Complete protocol NR 12 d after first Tx NI NI NI
22 yrs, female 34 yrs, female
Protein Mutation Reference Age, gender
20
Time between Tx and aHUS
Time between recurrence and initiation of eculizumab
Therapeutic scheme
Duration of eculizumab
Follow-up and response
Salameh et al
Familial versus sporadic
Table 1. (Continued) The general characteristics and outcome of the reported adult cases of post–kidney transplant aHUS that were given rescue therapy with eculizumab.
4
of the protein that mediates complement protection on the cell surface. Abnormal proteins fail to control complement activation at the glomerular endothelium leading to reduced ability to bind to platelets, which results in complement activation on the platelet surfaces with platelet activation and aggregation eventually leading to aHUS.10 MCP is a surface protein expressed on all cells except erythrocytes. MCP functions with IF (a plasma complement regulatory protein) to degrade C3b and C4b bound on the cell surface.3 MCP gene mutations account for 15% of cases of aHUS,3,4 whereas IF gene mutation is less common, reported in 2%–12% of aHUS patients.11,12 Mutations in the CD46 gene are the most common MCP encoding gene mutations resulting in decreased cell surface expression. All other gene mutations in MCP result in functionally inactive protein expression.13 The majority of IF gene mutations result in a quantitative defect.5 Thrombomodulin and BF gene defects are not as common as the previously mentioned gene defects. Noteworthy is that BF functions as an activator of complement rather than a regulator, and mutations in BF gene lead to increased complement activation, resulting in increased deposition of complement in the glomerular endothelial cells.14 Until recently, treatment of HUS generally is widely based on supportive measures and plasma therapy, either exchange or pheresis. Recommendations are to start empiric plasma therapy as early as possible preferably within 24 hours of presentation.15 First-line therapy should be plasmapheresis unless it cannot be performed within the first 24 hours, where plasma infusion should be given if the patient is not in volume overload, hypertensive, or showing symptoms of cardiac failure. Plasma therapy should be continued daily until platelet count, LDH, and hemoglobin levels are back to normal and the renal function has been improving for several days. If hemolysis persists or renal function does not improve after 3–5 daily plasma therapy sessions, the patient is regarded to be in uncontrolled TMA even if platelet counts improve. Data from International Registry of Recurrent and Familial HUS/TTP have shown that treatment with plasma therapy ensued complete hematological and renal recovery in only 5%, hematological recovery with renal sequelae in 58%, and death or ESRD in 37%.3 Uncontrolled TMA used to be an indication to remain on daily plasma therapy but recently eculizumab has become an FDA-approved alternative. When disease activity has been controlled with daily plasma therapy, the recommended subsequent frequency is 5 times a week for 2 more weeks then 3 times a week for 2 additional weeks. Due to the high frequency of www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Post–Kidney Transplant Familial aHUS
recurrence and renal sequel in patients with CFH mutation, plasma therapy should probably never be stopped.1 Eculizumab is a recombinant, humanized monoclonal antibody that binds to complement protein C5 and inhibits the production of the terminal complement components C5a and the membrane attack complex C5b-9. Prevention of terminal complement components inhibits complement-mediated TMA in aHUS patients. FDA has recently approved eculizumab for treatment of pediatric and adult patients with aHUS. Experience with eculizumab in treatment of post– kidney transplant aHUS in adults is very scanty with only 7 reported cases (including our case) in the literature.6 Table 1 shows the general characteristics and outcome of the reported adult cases of post–kidney transplant aHUS that were given rescue therapy with eculizumab. Most of the cases have very good outcome with initially remission in all patients. Two patients had subsequent relapses; the first patient had a relapse 5 months after stopping treatment secondary to a pneumonia episode and eventually lost her graft due to acute tubular necrosis.16 The second patient had a relapse after delaying 1 infusion by 6 days and improved later on with resumption of therapy.17 Anti-C5 therapy provides an opportunity for kidney transplants in patients with ESRD secondary to aHUS and may eliminate the need for combined kidney–liver transplant as the only curative intervention. Our case report is of an adult posttransplant familial aHUS successfully treated with eculizumab, although he has the worst prognostic genetic mutation (CFH gene mutation).
CONCLUSIONS The aHUS is a rare but often fatal disease associated with devastating sequelae, including ESRD. Kidney transplant was of limited utility in the treatment of ESRD in adult population from aHUS due to higher rate of recurrence and graft loss. However, limited experience with eculizumab in the treatment of adult post–kidney transplant patients with aHUS has shown a promising outcome in graft survival that may potentially increase the utility of kidney transplant in aHUS.
REFERENCES 1. Loirat C, Fremeaux-Bacchi V. A typical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. 2. Constantinescu AR, Bitzan M, Weiss LS, et al. Nonenteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43:976–982. www.americantherapeutics.com
5 3. 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. 4. Kavanagh D, Goodship TH. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. Hematology Am Soc Hematol Educ Program. 2011;2011: 15–20. 5. Kavanagh D, Goodship T. Genetics and complement in a typical HUS. Pediatr Nephrol. 2010;25:2431–2442. 6. Zuber J, Le Quintrec M, Krid S, et al. Eculizumab for a typical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12:3337–3354. 7. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in a typical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–2181. 8. Westra D, Volokhina E, van der Heijden E, et al. Genetic disorders in complement regulating genes in patients with atypical haemolytic uraemic syndrome (aHUS). Nephrol Dial Transplant. 2010;25:2195–2202. 9. Zuber J, Le Quintrec M, Sberro-Soussan R, et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;7:23–35. 10. Stahl AL, Vaziri-Sani F, Heinen S, et al. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood. 2008;111:5307–5315. 11. Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267–1279. 12. Kavanagh D, Kemp EJ, Mayland E, et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005; 16:2150–2155. 13. Richards A, Kathryn Liszewski M, Kavanagh D, et al. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol. 2007;44:111–122. 14. Roumenina LT, Jablonski M, Hue C, et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to a typical hemolytic uremic syndrome. Blood. 2009;114:2837–2845. 15. Taylor CM, Machin S, Wigmore SJ, et al. Clinical practice guidelines for the management of a typical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol. 2010;148:37–47. 16. Alachkar N, Bagnasco S, Montgomery R. Eculizumab for the treatment of two recurrences of a typical hemolytic uremic syndrome in a kidney allograft. Transpl Int. 2012; 25:e93–e95. 17. Chatelet V, Fremeaux-Bacchi V, Lobbedez T, et al. Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant. 2009;9:2644–2645. 18. Nurnberger J, Philipp T, Witzke O, et al. Eculizumab for a typical hemolytic-uremic syndrome. N Engl J Med. 2009;360:542–544. American Journal of Therapeutics (2014) 0(0)
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
6 19. Duran CE, Maduell FM, Campistol JM. Rescue therapy with eculizumab in a transplant recipient with atypical haemolytic uraemic syndrome. Clin Kidney J. 2012;5:28–30. 20. Larrea CF, Cofan F, Oppenheimer F, et al. Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation. 2010;89:903–904.
American Journal of Therapeutics (2014) 0(0)
Salameh et al 21. Legault D, Boelkins M. Successful treatment of aHUS recurrence and arrest of plasma exchange resistant TMA post-renal transplantation with the terminal complement inhibitor eculizumab. Paper presented at: 51st Annual meeting of the American Society of Hematology; December 5–8, 2009: Grand Rapids, MI. p. 2421.
www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
