Interventions for Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: A Systematic Review of Randomized Controlled Trials

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1 Interventions for Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: A Systematic Review of Randomized Controlled Trials Mini Michael, MBBS, FRACP, MM(Clin Epi), 1 Elizabeth J. Elliott, MBBS, MD, FRACP, 2,3,4 Jonathan C. Craig, MBChB, FRACP, PhD, MM(Clin Epi), 5,6 Greta Ridley, PhD, 4 and Elisabeth M. Hodson, MBBS, FRACP 5 Background: Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are related conditions with similar clinical features of variable severity. The objective of this systematic review is to evaluate the benefits and harms of available interventions for HUS and TTP. Selection Criteria for Studies: MEDLINE (1966 to June 2006), EMBASE (1980 to June 2006), the Cochrane Central Register, conference proceedings, and reference lists were searched to find randomized controlled trials (RCTs) of any intervention for HUS or TTP in patients of all ages selected for inclusion for this systematic review. Interventions: Trials that compared an intervention with placebo, an intervention with supportive therapy, or one or more different interventions for HUS or TTP. Outcomes: For TTP trials, failure of remission at 2 weeks or less and at 1 month or longer, all-cause mortality rate, and relapse rate. For HUS trials, all-cause mortality, chronic reduced kidney function, and persistent proteinuria or hypertension at last follow-up. Results: For TTP in adults, we found 6 RCTs of 331 patients. Two trials compared plasma infusion with plasma exchange using fresh frozen plasma and showed failure of remission at 2 weeks (2 trials, 140 patients; relative risk, 2.87; 95% confidence interval, 1.41 to 5.84), and all-cause mortality (relative risk, 1.91; 95% confidence interval, 1.09 to 3.33) occurred more frequently in the plasma infusion group. Three trials compared plasma exchange using cryosupernatant plasma with plasma exchange using fresh frozen plasma, and a meta-analysis of these trials showed no difference. Seven RCTs in 476 young children with postdiarrheal HUS have been conducted. None of the evaluated interventions (fresh frozen plasma transfusion, heparin with or without urokinase or dipyridamole, Shiga toxin binding protein, and steroid) were superior to supportive therapy alone for any outcomes. Limitations: Limitations of this review include the small number and suboptimal quality of reporting of included trials, possibility of publication bias, small number of participants with atypical HUS, and failure to report results for patients with atypical and typical HUS separately. Conclusions: No additional therapy has been shown to increase efficacy over plasma exchange for TTP. No intervention has been shown to be superior to supportive therapy in patients with postdiarrheal HUS. Am J Kidney Dis 53: by the National Kidney Foundation, Inc. INDEX WORDS: Hemolytic uremic syndrome; thrombotic thrombocytopenic purpura; systematic review. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are related conditions with similar clinical features of variable severity. Clinical and pathological features of TTP and HUS often overlap, 1 leading some to recommend the term TTP-HUS. Although TTP and HUS can affect many of the same organ systems, the frequency with which they do so differs markedly, and the detailed histopathologic features of the lesions of TTP and HUS are distinct. 2 In the late 1990s, some studies showed that these disorders can be differentiated by the high incidence of severe deficiency of the von Willebrand factor cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospodin) in patients with From the 1 Renal Section/Department of Pediatrics, Texas Children s Hospital/Baylor College of Medicine, Houston, TX; 2 Discipline of Paediatrics and Child Health, University of Sydney; 3 Centre for Evidence Based Paediatric Gastroenterology and Nutrition; 4 Australian Paediatric Surveillance Unit; and 5 Centre for Kidney Research, Cochrane Renal Group, The Children s Hospital at Westmead; and the 6 School of Public Health, University of Sydney, Sydney, Australia. Received February 25, Accepted in revised form July 30, Originally published online as doi: /j.ajkd on October 28, Address correspondence to Mini Michael, MBBS, FRACP, MM(Clin Epi), Renal Section/Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, MC , Houston, TX mmichael@bcm.tmc.edu 2009 by the National Kidney Foundation, Inc /09/ $36.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 53, No 2 (February), 2009: pp

2 260 clinically diagnosed TTP. 3-5 The high diagnostic value of finding severe ADAMTS13 deficiency in patients with TTP subsequently was challenged by other studies, including 2 prospective cohort studies 6,7 that reported the protease was severely deficient in only a variable proportion of patients, ranging from as little as 18% to 71%. TTP occurs with an estimated annual incidence of 3.7 cases/million 8 and is more common in females, with a peak incidence occurring in the fourth decade. 9 The mortality rate of patients with TTP exceeds 90% without therapy. 10 With the advent of plasma-based therapy, there has been a dramatic improvement in long-term survival, which now approaches 80% HUS usually affects young children and has been classified in several ways. The most common typical form is associated with diarrhea caused by infection with a Shiga toxin producing Escherichia coli or Shigella dysenteriae. This form accounts for at least 95% of HUS cases in children 15,16 and may cause sporadic or epidemic disease. E coli O157:H7 is the strain most commonly associated with HUS worldwide; however, there is considerable geographic variation. The atypical forms of HUS, which may show autosomal dominant or recessive inheritance, are less common. 17 Some patients with a family history of HUS show persistently low levels of complement, caused by a homozygous deficiency of complement factor H. 18 Their disease runs a chronic relapsing course, often complicated by hypertension and reduced kidney function, and exacerbations may be precipitated by intercurrent illness. The overall incidence of HUS in children younger than 5 years ranges from 1.1 to 5.8/ 100, Death or end-stage renal disease (ESRD) occurs in about 12% of patients with diarrhea-associated HUS. 25 Morbidity and mortality are greater in patients with atypical HUS than diarrhea-associated disease. The clinical course of HUS appears to depend on cause and age. Children with postdiarrheal HUS generally do well. The mainstay of treatment for patients with HUS is supportive therapy, and for patients with TTP, plasma-based therapies. However, there is no consensus on the role of specific therapies, many of which have been proposed for these diseases. No systematic review of the literature for interventions for HUS or TTP has been published. In this review, we aim to identify interventions evaluated by randomized controlled trial (RCT) in patients with HUS and TTP and evaluate their effectiveness for relevant clinical outcomes, including failure of remission, death and other severe complications, relapse, ESRD, and persistent renal impairment. METHODS Objectives The aim of this review is to evaluate the benefits and harms of different interventions for HUS and TTP in patients of all ages. We aim to assess the interventions for HUS and TTP separately. Criteria for Considering Studies for This Review Michael et al Types of Studies Studies eligible for inclusion in the review were all RCTs and quasi-rcts (trials in which allocation to treatment group was obtained by alternation, eg, use of alternate medical records, date of birth, or other predictable methods) that had compared an intervention with placebo, an intervention with supportive therapy, or one or more different interventions for HUS or TTP. Types of Participants Inclusion Criteria. Trials that included previously healthy patients of all ages fulfilling the diagnostic criteria for either HUS or TTP were included. HUS was defined as acute onset of renal impairment (oliguria or anuria with increased serum urea and creatinine levels), thrombocytopenia (platelet count / L), and microangiopathic hemolytic anemia (hemoglobin 10 g/dl with microscopic evidence of fragmented red blood cells in a peripheral-blood smear; platelet count expressed in 10 3 / L and 10 9 /L is equivalent; hemoglobin in g/dl may be converted to g/l by multiplying by 10). TTP was defined as acute onset of central nervous system abnormalities in association with thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal impairment (with a variable range of severity). Studies in which 75% or more of participants had renal impairment and/or central nervous system abnormalities, thrombocytopenia, and microangiopathic hemolytic anemia were eligible for inclusion in this review. Exclusion Criteria. Trials that included patients with septicemia, known chronic renal failure, collagen or vascular disorders, or preexisting malignant hypertension were excluded. Types of Interventions Interventions compared with placebo or supportive therapy including dialysis (hemodialysis or peritoneal dialysis) or a comparison of 2 or more interventions were examined. Interventions examined included heparin, aspirin/dipyridamole, prostanoids, ticlopidine, vincristine, fresh frozen plasma (FFP) infusion, plasmapheresis with FFP or cryosupernatant

3 Interventions for HUS and TTP: A Systematic Review 261 plasma, systemic corticosteroids, Shiga toxin binding agents, or immunosuppressive agents. Types of Outcome Measures For patients with TTP, the principal outcome of interest was failure of response to therapy, ie, failure of remission at 2 weeks or less and at 1 month or longer. Other outcomes of interest included all-cause mortality and relapse rates during the follow-up period ( 2 months). For patients with HUS, the principal outcome of interest was all-cause mortality. Other outcomes of interest included ESRD, kidney biopsy changes (cortical necrosis, glomerular thrombotic microangiopathy, and arterial thrombotic microangiopathy), persistent proteinuria, hypertension, and chronic reduced kidney function (glomerular filtration rate 80 ml/min/1.73 m 2 ) at last follow-up (glomerular filtration rate in ml/min/1.73 m 2 may be converted to ml/s/1.73 m 2 by multiplying by ). Other outcomes of interest in both groups of patients (TTP and HUS) were extrarenal manifestations of disease. Adverse effects of treatment, such as bleeding, opportunistic infections, and allergic reactions to the intervention, were also of interest. The definition of response or remission rate was that defined by the trial investigators. This usually was improvement in platelet count greater than / L for 3 consecutive days with or without resolution of hemolysis and normalization of serum creatinine level. Proteinuria was defined as the presence of 2 or greater protein on urinalysis or greater than 4 mg/m 2 /h of protein in a 24-hour urine sample. Hypertension was defined as systolic and diastolic blood pressure greater than the 95th centile for age and height. Search Strategy for Identification of Studies We searched MEDLINE (1966 to June 2006) and EMBASE (1980 to June 2006) using optimally sensitive search strategies developed by the Cochrane Collaboration for the identification of trials 26 (Item S1; provided as online supplementary material available with this article at Trials were considered without language restriction. The Cochrane Renal Group Specialised Register and Cochrane Central Register of Controlled Trials were also searched. Medical subject heading terms and text words used were haemolytic uraemic syndrome, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Other sources searched include reference lists of textbooks, reviews, previous trials, and conference proceedings of the International Pediatric Nephrology Association, American Society of Nephrology, International Congress of Nephrology, and European Dialysis and Transplantation Association. Studies in languages other than English were translated and included, and duplicate publications of the same trial were identified through reading the articles in question and contacting the investigators, if necessary. The Cochrane Renal Group Trials Search Coordinator ensured that all relevant trials had been identified. Methods of the Review Selection of Trials, Data Extraction, and Quality Assessment Three reviewers (M.M., E.J.E., and G.R.) independently screened titles and abstracts of the literature search and assessed trial eligibility against defined inclusion criteria. This process favored overselection to include all relevant trials. The full article was retrieved if there was uncertainty or the abstract was not available. Any disagreement about article selection was resolved through discussion. From all included trials, 3 reviewers extracted data by using a standardized form. Study date and place, participant characteristics, intervention (type of treatment, dose, duration, and cointerventions), comparator, and primary and secondary outcomes of interest were recorded. When appropriate, investigators of primary studies were contacted for clarification of data and to obtain missing information. Any discrepancies in data extraction were resolved in discussion. When results of a study were published more than once, the most complete data were extracted from all sources and used in the analysis only once. The reviewers assessed the quality of included trials independently without blinding to authorship or journal of publication by using the checklist developed for the Cochrane Renal Group. Discrepancies were resolved by consensus. The quality items assessed were allocation concealment, intention-to-treat analysis, completeness of follow-up, and blinding of investigators, participants, and outcome assessors Statistical Assessment For dichotomous outcomes, results were expressed as relative risk (RR) with 95% confidence interval (CI). Data were pooled by using a random-effects model when appropriate; however, the fixed-effects model was also analyzed to ensure robustness and susceptibility to outliers. Weighted mean difference with 95% CI was used when continuous scales of measurement were used to assess the effects of treatment. Statistical heterogeneity was analyzed by using the Cochran Q test on N-1 df, using 0.1 and the I 2 statistic. 30 There were insufficient studies to explore possible sources of variability. All analyses were undertaken using Review Manager 4.2 (RevMan Development Team, Copenhagen, Denmark). RESULTS Description of Studies Of 771 articles identified by using an extensive literature search, after review of the title and abstracts by 2 reviewers, 688 were excluded (Fig 1). Reasons for exclusion were nonrandomized design, case reports, noninterventional studies, and duplicate publications. Of 83 full-text articles reviewed, 15 eligible trials were identified Of these, 6 trials 31,32,37-39,43 compared different interventions in patients with TTP and were included. Nine trials compared different interventions in children with HUS, of which 7 trials 33-36,40-42 were included. Two of the 9 HUS trials identified were published in only abstract form and were excluded because insufficient outcome data were available. 44,45

4 262 Michael et al Figure 1. Flow chart shows number of citations retrieved by individual searches and number of trials included in the review. Abbreviations: APT, antiplatelet therapy; CPP, cryoprecipitate poor plasma; CSP, cryosupernatant plasma; FFP, fresh frozen plasma; HUS, hemolytic uremic syndrome; PE, plasma exchange; RCT, randomized controlled trial; TTP, thrombotic thrombocytopenic purpura. Study Characteristics Characteristics of the population and interventions in included studies are listed in Tables 1 and 2. TTP Trials Of 6 included trials of interventions for TTP 31,32,37-39,43 (331 patients), 1 trial (35 patients) included patients with HUS or TTP (age, 18 to 80 years), and insufficient data were provided to enable us to separate these groups. 39 Because all patients included in this trial were older than 18 years, it is likely that most had TTP or atypical HUS; thus, this trial was included with TTP trials for the purpose of this review (Table 1). In these 6 trials, the main comparator (control) treatment was plasma exchange (PE) using FFP. In 3 trials 38,39,43 (116 patients), PE with FFP was compared with cryosupernatant plasma or cryoprecipitate poor plasma (CPP). For ease of description in the remainder of the text, CPP will be used to represent cryosupernatant plasma and cryoprecipitate poor plasma. In 2 trials 32,37 (143 patients), PE using FFP was compared with plasma infusion with FFP (PI), and in these trials, both treatment and control groups also received antiplatelet therapy (APT), namely aspirin and dipyridamole. In 1 trial 31 (72 patients), the effectiveness of APT was tested; the control group received PE using FFP plus steroid, and the treatment group received PE using FFP plus steroid plus APT for 15 days. Patients who responded by achieving remission from the APT group received ticlopidine for 1 year. For 5 of the 6 trials, the follow-up period was longer than 6 months. HUS Trials Of 476 patients in the 7 included trials evaluating interventions for HUS, 33-36,40-42 most were young children with postdiarrheal (typical) HUS ( 70% in 3 trials, 34,36,41 100% in 2 trials, 35,40 and not reported in 2 trials 33,42 ). None of these studies reported outcomes separately for children with typical and atypical HUS. In all HUS

5 Table 1. Characteristics of Population and Intervention of Included TTP Trials Reference (year, country) Age (y) Control Intervention Definition of CR Bobbio-Pallavicini et al 31 (1997, Italy) Henon 32 (1992, France) Rock et al 37 (1991, Canada) Rock et al 38 (2005, Canada) Rothele et al 39 (2000, Germany) Zeigler et al 43 (2001, United States) Men, ; women, Men, 35 (19-62); women, 39 (18-57) Men & women, Not given Men & women, 18-80; because all 18 y, this trial included as a TTP trial for this SR Control, 38 (28-53); intervention, 45 (35-51) PE: 1 volume with FFP 7-10 sessions; Mpred: 2 mg/kg/d IV PE: FFP 15 ml/kg albumin 45 ml/kg for 4 d APT: aspirin (10 mg/kg/d) dipyridamole (10 mg/kg/d); if CR, continue APT PE: 1.5 volume with FFP for 3 d, then 1 volume for further 4 d APT: dipyridamole 400 mg/d & aspirin 325 mg/d orally for 2wk PE: 1.5 volume with FFP for 2 sessions, then 1 volume for 5 d optional APT PE: FFP 50 ml/kg, 5-10 PE over 7-14 d MPred 1.5 mg/kg orally or IV for 5 d, then tapered over 2 wk PE: FFP 60 ml/kg for 7-14 d MPred 1.5 mg/kg/d tapered over 2 wk As in control arm: ASA orally or LS IV 10 mg/kg/d dipyridamole 3 mg/kg/d orally or 0.4 mg/kg/d IV for 15 d For patient CR: ticlopidine 500 mg/ d orally 1 y FFP transfusions: 15 ml/kg/d 4d plus APT as in control arm (if CR, continue APT) FFP transfusion: 30 ml/kg/d 1d followed by 15 ml/kg/d for further6doruntil an event APT as in control arm PE: 1.5 volume with CSP for 2 sessions, then 1 volume for 5d optional APT PE: CSP 50 ml/kg, 5-10 PE over 7-14 d MPred 1.5 mg/kg orally or IV for 5 d, then tapered over 2wk PE: cryoprecipitate poor plasma 60 ml/kg for 7-14 d MPred 1.5 mg/kg/d tapered over 2 wk Platelets / L; reticulocytes / L; LDH 300 U/L; BUN 50 mg/dl; Cr 1.2 mg/dl Normalization of all clinical and biological abnormalities Platelets / L for 2 consecutive d with no neurological deterioration Platelets / L for 2 consecutive d No. of Patients (control/intervention) Follow-up (mo) 72 (37/35) (19/19) PR: intervention, 1 excluded due to death before treatment; control, 1 due to wrong diagnosis 103 (51/51) PR: intervention, 1 excluded due to wrong diagnosis (24/28) 6 Platelets / L 35 (15/20) 24 Platelets / L 29 (13, 14) PR: 2 from intervention excluded: 1 DIC and 1 HIV, which were exclusion criteria Note: Age expressed as mean SD or median (range). Platelet count expressed in 10 3 / L and 10 9 /L is equivalent. BUN in mg/dl may be converted to mmol/l by multiplying by 0.357; creatinine in mg/dl may be converted to mol/l by multiplying by Abbreviations: ASA, acetylsalicylic acid; APT, antiplatelet therapy; BUN, blood urea nitrogen; Cr, creatinine; CR, complete remission; CSP, cryosupernatant plasma; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; HIV, immunodeficiency virus; IV, intravenous; LDH, lactate dehydrogenase; LS, lysine salicylate; Mpred, methylprednisolone; PE, plasma exchange; PR, postrandomization; SR, systematic review; TTP, thrombotic thrombocytopenic purpura. 6 1 Interventions for HUS and TTP: A Systematic Review 263

6 Table 2. Characteristics of Population and Intervention of Included HUS Trials Reference (year, country) Age (y) Control Intervention Definition of CR No. of Patients (control, intervention) Follow-up (mo) 264 Loirat et al 33 (1984, France) Loirat et al 34 (1988, France) Perez et al 35 (1998, Argentina) Rizzoni et al 36 (1988, Italy) Trachtman et al 40 (2003, United States) Van Damme-Lombaerts et al 41 (1988, Belgium) Vitacco et al 42 (1973, Buenos Aires) Majority 3 y 2.3 (0.2-13) (87% diarrhea associated) Control, 1.1 ( ); intervention, 1.1 ( ) (100% diarrhea associated) 2.5 ( ) (72% diarrhea associated) 4.2 ( ) (100% diarrhea associated) (26 were 2y) (85% diarrhea associated) 1.0 ( ) (patients with severe disease including ARF, HT, CNS, GI complications) Supportive therapy including PD if required Supportive care including PD if required Placebo supportive therapy (dialysis type not specified) Supportive therapy (dialysis type not specified) Placebo supportive therapy including PD if required Supportive therapy: blood transfusion, blood pressure control, and PD if required Supportive therapy including PD if required Urokinase heparin* supportive therapy FFP transfusion 10 ml/ kg for 7 d supportive care Mpred 5 mg/kg/d 4 /d for7d supportive therapy FFP transfusion: 30 ml/ kg on d 1, then 10 ml/ kg until remission or d supportive therapy Synsorb-Pk 500 mg/kg/d as 3 /d for 7 d supportive therapy As in control heparin IV to keep APTT 2 normal and dipyridamole IV 1 mg/ kg/d until remission As in control heparin IV to keep coagulation time 3 initial value 9d Platelets / L Not included as a study outcome Not included as a study outcome Platelets / L and Hb & Hct stabilized Not included as a study outcome Platelets / L Not included as a study outcome 33 (18/15) (40/39) (47/45) 2 wk PR: 1 each from control & intervention excluded 32 (15/17) (49/96) 2 PR: 5 from intervention withdrew either before no treatment or after 1 dose 58 (28/30) (20/10) 2 Note: Age expressed as mean SD or median (range). Platelet count expressed in 10 3 / L and 10 9 /L is equivalent. Abbreviations: APTT, activated partial thromboplastin time; ARF, acute renal failure; CNS, central nervous system; CR, complete remission; FFP, fresh frozen plasma; HUS, hemolytic uremic syndrome; GI, gastrointestinal; Hb, hemoglobin; Hct, hematocrit; HT, hypertension; IV, intravenous; Mpred, methylprednisolone; PD, peritoneal dialysis; PR, postrandomization. *Urokinase, 5,000 U CTA/kg for 1 hour, followed by 4,400 U CTK/kg for 47 hours; and heparin, 400 UI/kg/24 h and dose adjusted to keep Howell s time twice that of control. Three patients with sudden deterioration received heparin and were excluded from this review because of no random allocation. Michael et al

7 Interventions for HUS and TTP: A Systematic Review 265 trials, supportive therapy plus a specific intervention (treatment group) was compared with supportive therapy alone (control group). Supportive therapy generally included control of fluid and electrolyte imbalance, use of dialysis if required, control of hypertension, and blood transfusion as required. In 5 of the 7 trials, peritoneal dialysis was used when dialysis was indicated, but in 2 trials, type of dialysis used was not specified. A range of interventions were trialed, including heparin with or without urokinase or dipyridamole (3 trials, 121 patients), FFP infusion (2 trials, 111 patients), methylprednisolone (1 trial, 94 patients), and Shiga toxin binding agent called Synsorb-Pk (Synsorb Biotech Inc, Calgary, Alberta; 1 trial, 150 patients). Study Quality Trial quality was variable (Table 3). For TTP trials, allocation concealment was unclear in 2 (33%) and adequate in 4 trials (67%). Blinding of participants, investigators, and outcome assessors was not stated in any of the 6 trials. In 2 trials (33%), intention-to-treat analysis was used. Between 0% and 10% of participants were lost to follow-up in 5 trials (83%), and 49%, in 1 trial (17%). For HUS trials, allocation concealment was unclear in 2 (29%) and adequate in 5 trials (71%). Participants and investigators were blinded in 2 trials (29%), but blinding was not reported in 5 trials (71%). The outcome assessor was blinded in 1 trial (14%), but not reported in 5 trials (86%). Intention-to-treat analysis was used in 5 trials (71%). Only 0% to 5% were lost to follow-up in all 7 trials (100%). Outcomes TTP Trials Three trials 36,37,41 (116 patients) compared the use of PE using CPP with PE using FFP (Fig 2). There was no significant difference between PE using FFP and PE using CPP for any of the 4 outcomes, such as failure of remission at less than 2 weeks (1 trial, 52 patients; RR, 1.29, 95% CI, 0.41 to 4.03), failure of remission at 1 month (1 trial, 45 patients; RR, 0.80; 95% CI, 0.18 to 3.54), all-cause mortality (3 trials, 97 patients; RR, 0.59; 95% CI, 0.20 to 1.80), and relapse rate (2 trials, 39 patients; RR, 1.06; 95% CI, 0.49 to 2.27). There was no significant heterogeneity between studies for these outcomes. In 2 TTP trials 30,35 (140 patients), PI plus APT was compared with PE using FFP plus APT (Fig 3). Failure of remission at less than 2 weeks was significantly higher in the treatment (PI) group (2 trials, 140 patients; RR, 1.48; 95% CI, 1.12 to 1.96). In addition, all-cause mortality was significantly higher in the PI group (2 trials, 140 patients; RR, 1.91; 95% CI, 1.09 to 3.33). Failure of remission rate at 1 month (2 trials, 72 patients; RR, 1.50; 95% CI, 0.93 to 2.42) and relapse rate (2 trials, 99 patients; RR, 0.34; 95% CI, 0.10 to 1.15) were not significantly different between the control and treatment groups. There was no significant heterogeneity between studies for any of these reported outcomes. Table 3. Quality of Included Studies Reference Allocation Concealed Patients Lost to Follow up (%) Blinding of Participants, Investigators Blinding Outcome Intention to Treat Bobbio-Pallavicini et al, Yes 0 NS NS Yes Henon, Unclear 0 NS NS No Rock et al, Yes 1 NS NS No Rock et al, Yes 0 NS NS Yes Rothele et al, Yes 49 NS NS No Zeigler et al, Unclear 7 NS NS No Loirat et al, Unclear 0 NS NS Yes Loirat et al, Yes 0 NS NS Yes Perez et al, Yes 2 Yes NS No Rizzoni et al, Yes 0 NS NS Yes Trachtman et al, Yes 3 Yes NS No Van Damme-Lombaerts et al, Yes 0 NS NS Yes Vitacco et al, Unclear 0 NS NS Yes Abbreviation: NS, not stated.

8 266 Michael et al Figure 2. Thrombotic thrombocytopenic purpura (TTP) trials. Effect of plasma exchange (PE) using cryoprecipitate poor plasma (CPP) versus PE using fresh frozen plasma (FFP) shows no difference in (A) all-cause mortality and (B) relapse rate in patients with TTP. Abbreviations: CI, confidence interval; CSP, cryosupernatant plasma; RR, relative risk. In 1 trial, 31 the effect of APT was tested in patients with TTP (meta-analysis not shown). Aspirin and dipyridamole were used for 15 days, and patients in the treatment arm who had experienced remission were then treated with ticlopidine for 1 year. Both the treatment and control groups received PE using FFP and steroid. There was no significant difference between the 2 groups with regard to failure of remission at 2 weeks (1 trial, 72 patients; RR, 0.99; 95% CI, 0.56 to 1.73) and/or at 1 month (1 trial, 23 patients; RR, 0.38; 95% CI, 0.09 to 1.70), allcause mortality rate (1 trial, 72 patients; RR, 0.35; 95% CI, 0.10 to 1.20), and relapse rate (1 trial, 60 patients; RR, 0.29; 95% CI, 0.06 to 1.33). Adverse effects of treatment were not reported equally in all trials and were reported in only 2 of the 6 TTP trials. In 1 trial 31 that used APT, 4 patients from the APT arm (n 35) had transient worsening of preexisting bleeding. In addition, 2 patients from ticlopidine group (n 32) developed severe erosive gastritis that resolved with medical treatment. In 1 trial 37 in which PI was compared with PE, 6 patients in the PE group (n 51) and 5 patients in PI group (n 51) reported no complications. The remaining patients from both groups all experienced minor complications, including nausea, hypotension, tachycardia, tachypnea, dizziness, chills, or edema. In addition, 8 of these had bleeding and 4 patients in each group had seizures during the procedure. HUS Trials In 3 trials, 33,41,42 anticoagulation therapy was used (heparin alone in 1 trial, heparin and urokinase in 1 trial, and heparin and dypyridamole in 1 trial; meta-analysis not shown). In all these trials, the treatment and control groups received supportive therapy. There was no significant difference between groups for any of the primary or secondary outcomes, including all-cause mortality (3 trials, 121 patients; RR, 1.13; 95% CI, 0.43 to 2.95), neurological events (1 trial, 58 patients; RR, 0.53; 95% CI, 0.17 to 1.63), and proteinuria (1 trial, 30 patients; RR, 0.33; 95% CI, 0.04 to 2.85) or hypertension (2 trials, 84 patients; RR, 0.31; 95% CI, 0.01 to 7.30) at the last follow-up. However, the incidence of bleeding (adverse effect) was significantly greater in the group that received anticoagulation therapy compared with supportive therapy alone (3 trials, 124 patients; risk difference, 0.35, 95% CI, 0.25 to 0.45; Fig 4). Because 1 of these 3 trials had no events (bleeding), the relative frequency was not estimable. Hence, the scale was changed to an absolute risk scale to show the difference in event rates. It is important to show the significant differences in bleeding rates between the 2 inter-

9 Interventions for HUS and TTP: A Systematic Review 267 Figure 3. Thrombotic thrombocytopenic purpura (TTP) trials. Effect of plasma infusion (PI) and antiplatelet therapy (APT) versus plasma exchange (PE) using fresh frozen plasma (FFP) versus APT shows no difference in (A) failure of remission at less than 2 weeks, (B) failure of remission at more than 2 weeks to 6 months, (C) all-cause mortality, and (D) relapse rate in patients with TTP. Abbreviations: CI, confidence interval; RR, relative risk. ventions under study; however, the imprecision caused by zero event rates should be considered when interpreting this result. There was significant heterogeneity between studies for this outcome ( , 1 df,i %). In 2 trials 34,36 (117 patients), FFP infusion was compared with supportive therapy (Fig 5). There was no significant difference between the 2 groups for any of the outcomes of interest. One trial 35 (94 patients) compared steroids with placebo, and there was no significant difference between the 2 groups for any of the outcome measures of interest. One trial 40 compared Shiga toxin binding agent (Synsorb-Pk) and placebo (145 patients). There was no significant difference between the 2 groups for any of the outcome measures of interest. Adverse effects of treatment were reported in 5 trials. As reported, rates of bleeding were significantly greater in patients receiving anticoagulation. In 1 trial 35 that compared supportive therapy plus steroid with supportive therapy and placebo, the number of cases of peritonitis was similar between groups. In 1 trial 34 in which PI was compared with supportive therapy, PI had to be stopped after 7 days in 1 child because of

10 268 Michael et al Figure 4. Hemolytic uremic syndrome (HUS) trials. Anticoagulation therapy (AC) using heparin with or without dipyridamole or urokinase and supportive therapy (ST) versus supportive therapy alone shows significantly increased risk of bleeding in patients in the anticoagulation group. Abbreviations: CI, confidence interval; RD, risk difference. cardiac overload. This trial also reported non-a non-b hepatitis in 2 children from the control group, but none from PI group. DISCUSSION This is the first systematic review of RCTs in the literature evaluating interventions for HUS or TTP. We have shown that PE using FFP is more effective than PI in patients with TTP and that other interventions provide no significant additional benefit over PE using FFP with regard to reducing any of the outcomes of interest (failure of remission, all-cause mortality, and relapse rate) from any of the interventions tested in RCTs (PE using CPP, PI and APT, or PE using FFP and APT). PE using CPP in 3 trials conferred no advantage over PE using FFP for outcomes of interest. Although use of CPP may incur additional cost, none of the trials compared the difference in cost involved with the use of CPP as opposed to FFP. One trial that used APT reported a slightly increased risk of bleeding and gastritis in the APT group, but no significant difference for any of the 4 outcomes of interest. Based on results of this systematic review, PE using FFP remains the primary treatment of choice for patients with TTP. Alternative therapies conferred no additional benefit, but increased risk. Current practice is to initiate PE using FFP for TTP that is currently diagnosed in patients with the presence of thrombocytopenia and microangiopathic hemolytic anemia without alternative explanation. 46 Some patients with TTP require prolonged PE to prevent a fatal outcome and achieve a sustained remission. In these patients, adjunct treatments including such immunosuppressive agents as corticosteroids, vincristine, cyclophosphamide, azathioprine, or cyclosporine A, high-dose intravenous immunoglobulin, staphylococcal protein A, immunoadsorption, or splenectomy have been used with variable results However, we found no RCT testing the effectiveness of any of these interventions. Use of rituximab, an anti-cd20 monoclonal antibody, has shown promise in a small prospective cohort study of patients with acute refractory and severe relapsing TTP related to anti-adamts13 antibodies. 50 The Transfusion Medicine/Haemostasis Clinical Trials Network from North America has initiated an RCT comparing the effectiveness of early use of rituximab versus placebo in addition to PE and glucocorticoids. 51 For HUS in young children, we found that FFP, anticoagulation therapy, steroids, and Shiga toxin binding agent conferred no advantage over supportive therapy alone for any of the outcomes: all-cause mortality, neurological/extrarenal events, ESRD, kidney biopsy changes or proteinuria, and hypertension at last follow-up. Adverse effects were reported in 5 of the 7 included trials, and bleeding was significantly greater with anticoagulation therapy in the 3 trials that compared its effectiveness. In the majority of the trials (5 of 7 trials), peritoneal dialysis was used when dialysis therapy was indicated. This contrasts with current practice in the majority of North American centers, where the preferred mode is hemodialysis or continuous venovenous hemodiafiltration for the management of acute renal failure. 52 Our findings likely reflect the age of the trials included in the review because 5 of the 7 trials were published before 1990 and 1 was published before It is important to note that 5 of the 7 HUS trials predominantly included children with postdiar-

11 Interventions for HUS and TTP: A Systematic Review 269 Figure 5. Hemolytic uremic syndrome (HUS) trials. Effect of plasma infusion (PI) and supportive therapy (ST) versus supportive therapy alone shows no difference in (A) all-cause mortality, (B) dialysis dependence at 6 weeks, (C) proteinuria at last follow-up, and (D) hypertension at last follow-up in patients with HUS. Abbreviations: CI, confidence interval; RR, relative risk. rheal HUS ( 70% in 3 trials, 100% in 2 trials, and not reported in 2 trials), and that no study reported outcomes separately for children with diarrhea-associated (typical) and atypical HUS. It has been suggested in the literature that atypical cases have a worse outcome. In 2 trials in which FFP infusion was compared with supportive therapy, there was no significant difference between the treatment and control groups for any of the outcomes of interest. However, the majority ( 70%) of patients in both trials had postdiarrheal HUS, which usually remits with supportive therapy. The effectiveness of PE was tested in a small trial 44 that was not included in this systematic review because it was published in only abstract form and data regarding outcomes of interest for this review were not available. This trial failed to show a superior response on incidence of recurrence or ESRD in their small subset of high-risk patients. Based on results of this systematic review, supportive therapy (including blood transfusion, control of fluid and electrolyte imbalance, dialysis when indicated, and control of hypertension) remains the preferred management for patients with postdiarrheal HUS. However, we identified

12 270 only a small number of trials, many of them old and none comparing the effectiveness of different types of dialysis (peritoneal dialysis, hemodialysis, or continuous venovenous hemodiafiltration) in patients with acute renal failure caused by HUS. We found no RCT that evaluated the effectiveness of any intervention, including PI or PE, in patients with atypical HUS, who may have a more chronic and relapsing course and present with features similar to TTP. Atypical HUS is not a homogeneous condition, but has several different causes and is a rare disease. Hence, multicenter trials in well-characterized patients would be required to evaluate specific treatments. Limitations of this review include the small number, suboptimal method quality, and age of included trials; the possibility of publication bias; the small number of participants with atypical HUS; and the failure to separate atypical and typical HUS in recruitment and reporting of trials. ACKNOWLEDGEMENTS The authors thank Narelle Willis, Review Group coordinator of the Cochrane Renal Group, Ruth Mitchell, Trials Search coordinator of the Cochrane Renal Group, and Sunita Chauhan, Research Librarian at the Centre for Evidence Based Paediatrics, Gastroenterology and Nutrition, Sydney, Australia, for their help with this study, which was carried out for the Cochrane Collaboration. Abstract of this review was presented as poster at the 14th Congress of the International Pediatric Nephrology Association in August Support: This study was undertaken as part of the thesis work for the Master of Medicine (Clinical Epidemiology) program undertaken by Mini Michael, and we acknowledge the support of a scholarship received for her from the Centre for Clinical Research Excellence in Renal Medicine, Sydney, Australia, to undertake this program. Dr Elliott is supported by a National Health and Medical Research Council of Australia Practitioner Fellowship (No ). The Cochrane Renal Group receives financial support from several sources, including government and industry. These funds go into a general fund managed by the Children s Hospital at Westmead. These funds are used to support key activities, including hand searching, the development of a trials registry, training and support for reviewers conducting reviews, and consumer participation in the group. Those contributing funds have no rights of authorship or publication. The authors of the review retain the right to interpretation of the results and the right to publish. Financial Disclosure: None. SUPPLEMENTARY MATERIAL Item S1: Electronic search strategies: Database search terms. Note: The supplementary material accompanying this article (doi: /j.ajkd ) is available at www. ajkd.org. REFERENCES Michael et al 1. Kaplan BS: Thrombotic microangiopathy: A proposal for a new terminology for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. J Nephrol 8:3-4, Hosler GA, Cusanamo AM, Hutchins GM: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. Arch Pathol Lab Med 127: , Furlan M, Robles R, Galbusera M, et al: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 339: , Tsai H-M, Lian ECY: Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 339: , Bianchi V, Robles R, Alberio L, et al: von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: A severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood 100: , Torok TJ, Holman RC, Chorba TL: Increasing mortality from thrombotic thrombocytopenic purpura in the United States Analysis of national mortality data, Am J Hematol 50:84-90, Terrell DR, Williams LA, Vesely SK, Lammle B, Hovinga JA, George JN: The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: All patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost 3: , Amorosi EL, Ultmann JE: Thrombotic thrombocytopenic purpura: Report of 16 cases and review of literature. Medicine (Baltimore) 45: , Vesely SK, George JN, Lämmle B, et al: ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: Relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 102:60-68, Allford SL, Hunt BJ, Rose P, Machin SJ: Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology: Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 120: , Byrnes JJ, Khurana H: Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med 297: , Bukowski RM, Hewlett JS, Harris JW: Exchange transfusion in the treatment of thrombotic thrombocytopenic purpura. Semin Hematol 13: , Rock G, Shumak KH, Sutton DM, Buskard NA, Nair RC: Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Br J Haematol 94: , Sacher R, Moake J: Solvent detergent-treated plasma versus fresh frozen plasma in patients with TTP. Transfusion 36:63S, 1996 (suppl 95)

13 Interventions for HUS and TTP: A Systematic Review Ruggenenti P, Noris M, Remuzzi G: Thrombotic microangiopathy, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Kidney Int 60: , Remuzzi G: The hemolytic uremic syndrome. Kidney Int 47:2-19, Kaplan BS, Kaplan P: Hemolytic uremic syndrome in families, in Kaplan BS, Trompeter R, Moake J (eds): Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. New York, NY, Marcel-Netter, 1992, pp Taylor CM: Hemolytic uremic syndrome and complement factor H deficiency: Clinical aspects. Semin Thromb Haemost 27: , Elliott EJ, Robins-Browne RM, O Loughlin EV, et al. Nationwide study of haemolytic uraemic syndrome: Clinical microbiological, and epidemiological features. Arch Dis Child 85: , Rowe PC, Orrbine E, Wells GA, McLaine PN: Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to The Canadian Pediatric Kidney Disease Reference Centre. J Pediatr 119: , Milford DV, Taylor CM, Gutteridge B, Hall SM, Rowe B, Kleanthous H: Haemolytic uraemic syndromes in the British Isles : Association with verocytotoxin producing Escherichia coli. Part 1: Clinical and epidemiological aspects. Arch Dis Child 65: , Martin DL, MacDonald KL, White KE, Soler JT, Osterholm MT: The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota. N Engl J Med 323: , Garg AX, Suri RS, Barrowman N, et al: Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: A systematic review, meta-analysis, and metaregression. JAMA 290: , Decludt B, Bouvet P, Mariani-Kurkdjian P, et al: Haemolytic uraemic syndrome and Shiga toxin-producing Escherichia coli infection in children in France. Epidemiol Infect 124: , Neuhaus T, Calonder S, Leumann E: Heterogeneity of atypical haemolytic uraemic syndromes. Arch Dis Child 76: , Dickersin K, Scherer R, Lefebvre C: Identifying relevant studies for systematic reviews. BMJ 309: , Hollis S, Cambell F: What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 319: , Moher D, Pham B, Jones A, et al: Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 352: , Schultz KF, Chalmers I, Hayes RJ, Altman DG: Empirical evidence of bias. JAMA 301: , Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 327: , Bobbio-Pallavicini E, Gugliotta L, Centurioni R, et al: Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomised multicenter trial by the Italian Cooperative Group for TTP. Haematologica 82: , Henon P: Thrombotic thrombocytopenic purpura: Clinical results of a French controlled trial. Transfus Sci 13:63-72, Loirat C, Beaufils E, Sonsino N, et al: Treatment of haemolytic uraemic syndrome in children with urokinase. Arch Fr Pediatr 41:15-19, Loriat C, Sonsino E, Hinglais N, Jais JP, Landais P, Fermanian J: Treatment of the childhood haemolytic uraemic syndrome with plasma. A multicentre randomized controlled trial. The French Society of Paediatric Nephrology. Pediatr Nephrol 2: , Perez N, Spizzirri F, Rahman R, Suarez A, Larrubia C, Lasarte P: Steroids in hemolytic uremic syndrome. Pediatr Nephrol 12: , Rizzoni G, Claris-Appiani A, Edefonti A, et al: Plasma infusion for hemolytic-uremic syndrome in children: Results of a multicenter controlled trial. J Paediatr 112: , Rock GA, Shumak KH, Buskard NA, et al: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 325: , Rock G, Anderson D, Clark W, et al: Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet. Br J Haematol 129:79-86, Rothele E, Krumme B, Rump LC: Design of the prospective randomised study for the treatment of patients with thrombotic microangiopathy. Ther Apher 4: , Trachtman H, Cnaan A, Christen E, et al: Effect of an oral Shiga toxin-binding agent on diarrhoea-associated haemolytic uraemic syndrome in children; A randomised controlled trial. JAMA 290: , Van Damme-Lombaerts R, Proesmans W, Van Damme B, et al: Heparin plus dipyridamole in childhood hemolyticuraemic syndrome: A prospective randomized study. J Pediatr 113: , Vitacco M, Sanchez Avalos J, Gianantonio CA: Heparin therapy in the haemolytic uraemic syndrome. J Pediatr 83: , Zeigler ZR, Shadduck RK, Gryn JF, et al: Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic prupura (TTP). J Clin Apher 16:19-22, Muller-Wiefel DE, Bulla M, Klare B, Balzar R, Bambauer R, Tonshoff B: Efficacy of therapeutic plasma exchange in haemolytic uraemic syndrome in childhood (abstracts, European Dialysis and Transplant Association- European Renal Association XXVIth Annual Congress, Göteborg, Sweden, June 1989): Nephrol Dial Transplant 4:446A, 1989 (abstr) 45. Thomson PD, Milnor LS: A randomly selected trial of vitamin E in the haemolytic uraemic syndrome (HUS). Proceedings of Xth International Congress of Nephrology 98 (Abstracts), London, July 26-31, George JN: Thrombotic thrombocytopenic purpura. N Engl J Med 354: , 2006

14 Durand JM, Lefevre P, Kaplanski G, et al: Vincristine for TTP. Lancet 340: , Udvardy M, Rak K: Cyclophosphamide for chronic relapsing TTP. Lancet 336: , Crowther MA, Heddle N, Hayward CP, et al: Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Ann Intern Med 125: , Fakhouri F, Vernant JP, Veyradier A, et al: Efficiency of curative and prophylactic treatment with rituximab in Michael et al ADAMTS13-deficient TTP: A study of 11 cases. Blood 105: , George JN, Woodson RD, Kiss JE, Kojouri K, Vesely SK: Rituximab therapy for TTP: A proposed study of the Transfusion Medicine/Hemostatsis Clinical Trials Network with a systematic review of rituximab therapy for immune mediated disorders. J Clin Apher 21:49-56, Maxvold N, Bunchman TE: Renal failure and renal replacement therapy. Crit Care Clin 19: , 2003