Context: Hemolytic uremic syndrome (HUS), being more prevalent in infants and children, is recognized by a triad of acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. It is classified according to the underlying disorders, such as infection, systemic, metabolic disorder, or complement dysregulation. It has a high rate of morbidity and mortality. Many types of treatment, such as conservative management, plasma exchange, regular plasma infusion, and even a new expensive medication, "Ecluzimab", have been suggested. The aim of this systematic review is to estimate the incidence and prevalence of HUS (according to diarrhea positive or negative samples). In addition, the study will investigate the clinical presentation and the outcome of Iranian patients. Evidence Acquisition: The following data bases will be explored for articles published between years 1985 and 2016, PubMed, EMBASE, OVID, SCOPUS,Web of Sciences, Google Scholar, Google, barakatkns.com, MagIran, SID, dociran, PDFiran, and ganj.irandoc. Besides, all online university databases will be searched for theses and abstracts of local or international congresses; a manual search will be performed to identify pertinent cross references. Systematic reviewor meta-analysis, longitudinal and cohort studies, crosssectional, case-control, and epidemiological studies will be included in this review. Relevant conference proceedings, theses or unpublished data will also be considered. The retrieved data should comprise of proportions, incidence, prevalence, geographical distribution, mortality and morbidity rates (i.e. dialysis and central nervous system involvement). A meta-analysis will be performed if 3 similar studies are found. If sufficient data is extracted, subgroup analysis will be performed for age, gender, acute kidney injury, dialysis, and death. Results: The results of the current study could have implications for health policies, practice, research, and medical education: The data could improve clinical and health care decisions, allow estimation of the number of patients that require new medication, and could direct future research design in this field. Â© 2018, Journal of Comprehensive Pediatrics

Hooman, N.

Hosseini, S.

Jahangiri, F.

Sadeghian, M.

eprints Iran University of Medical Sciences

J Compr Ped. In Press(In Press):e56080.Published online 2017 November 27.doi: 10.5812/compreped.56080.Review ArticleThe Prevalence and Incidence of Atypical Hemolytic UremicSyndrome in Iran: A Systematic Review and Meta-Analysis ProtocolStudyNakysa Hooman,1,* Mahnaz Sadeghian,2 Fariba Jahangiri,3 and Soudabeh Hosseini41Ali-Asghar Clinical Research Development Center, Iran University of Medical Sciences, Tehran, Iran2Department of Pediatric Gastroenterology, Ali-Asghar Children Hospital, Iran University of Medical Sciences, Tehran, Iran3Department of Pediatric Surgery, Ali-Asghar Children Hospital, Iran University of Medical Sciences, Tehran, Iran4Department of Laboratory, Ali-Asghar Children Hospital, Iran University of Medical Sciences, Tehran, Iran*Corresponding author: Nakysa Hooman, N197, Ali-Asghar Children’s Hospital, Vahid Dasgerdi St, Tehran, Iran. Tel: +98-212222041, Fax: +98-2122220063, E-mail:hooman.n@iums.ac.irReceived 2017 June 24; Revised 2017 August 25; Accepted 2017 November 06.AbstractContext: Hemolytic uremic syndrome (HUS), being more prevalent in infants and children, is recognized by a triad of acute kidneyinjury, microangiopathic hemolytic anemia, and thrombocytopenia. It is classified according to the underlying disorders, such asinfection, systemic, metabolic disorder, or complement dysregulation. It has a high rate of morbidity and mortality. Many types oftreatment, such as conservative management, plasma exchange, regular plasma infusion, and even a new expensive medication,“Ecluzimab”, have been suggested. The aim of this systematic review is to estimate the incidence and prevalence of HUS (accordingto diarrhea positive or negative samples). In addition, the study will investigate the clinical presentation and the outcome of Iranianpatients.Evidence Acquisition: The following data bases will be explored for articles published between years 1985 and 2016, PubMed, EM-BASE, OVID, SCOPUS, Web of Sciences, Google Scholar, Google, barakatkns.com, MagIran, SID, dociran, PDFiran, and ganj.irandoc. Be-sides, all online university databases will be searched for theses and abstracts of local or international congresses; a manual searchwill be performed to identify pertinent cross references. Systematic review or meta-analysis, longitudinal and cohort studies, cross-sectional, case-control, and epidemiological studies will be included in this review. Relevant conference proceedings, theses or un-published data will also be considered. The retrieved data should comprise of proportions, incidence, prevalence, geographical dis-tribution, mortality and morbidity rates (i.e. dialysis and central nervous system involvement). A meta-analysis will be performed if3 similar studies are found. If sufficient data is extracted, subgroup analysis will be performed for age, gender, acute kidney injury,dialysis, and death.Results: The results of the current study could have implications for health policies, practice, research, and medical education: Thedata could improve clinical and health care decisions, allow estimation of the number of patients that require new medication, andcould direct future research design in this field.Keywords: Hemolytic- Uremic Syndrome, Atypical Hemolytic Uremic Syndrome, Diarrhea Prodrom Positive HUS1. ContextHemolytic uremic syndrome (HUS) is defined bythrombocytopenia, acute kidney injury, and microangio-pathic hemolytic anemia. Historically, it was identified bya positive diarrhea and negative HUS. Atypical hemolyticuremic syndrome (aHUS) is an old terminology used fordescribing non-infectious-induced HUS in infants andchildren (1). Gaining an understanding of the concealedmechanisms and pathophysiology, different etiologies,including bacteria or viral infections, metabolic disorders,vacuities, medication, and complement dysregulationhave been identified (2-5).Hemolytic uremic syndrome is one of the leadingcauses of acute kidney injury in Iranian children (6, 7). De-layed improvement of kidney function has been reported(8). This was found in approximately one third of caseswho died (9, 10). Furthermore, HUS affects various organsand there is a few studies on morbidity in Iranian children:i.e. cholelithiasis presented with obstructive jaundice (11),delayed dilated cardiomyopathy responded to inotropicagents and diuretics (12), and diffuse brain ischemia (13),Gastrointestinal perforation, intussusceptions, and gan-grene lead to surgical exploration (14).Copyright © 2017, Journal of Comprehensive Pediatrics. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided theoriginal work is properly cited.Hooman N et al.The overall incidence of diarrhea negative HUS is 0.5to 2.1 per 100000 per years (15, 16). The incidence rate ofHUS /1000000 person-years was reported as 2.7 in the US,2.1 in United Kingdome, and 2.1 in Canada (17). Europeanregistry of aHUS reported a pediatric prevalence of 3.3 casesone million individuals (18). Karimi et al. reported a declin-ing incidence of HUS in Southwest of Iran with an annualincidence of 8 cases per one million children younger than15 years in 1993 to 1.1 in 2003 (19). The overall mortality rateof HUS in Iran is high, between 19.5% and 35% (20).2. Research Question and Analytic FrameworkThe proportion, prevalence, and incidence of HUS (Dpositive and negative HUS) in Iran will be estimated in thisreview. Moreover, the etiology and final outcome of HUSwill be studied.3. Protocol and RegistrationThe protocol has been registered with the interna-tional prospective register of systematic reviews ( PROS-PERO) (21), registration number CRD42017059086 , and ap-proved by the ethics committee of Iran University of Medi-cal Sciences, number code: 96-02-225-31405. The PreferredReporting Items for systematic review and meta-analysis (PRISMA)-Protocols statement was followedthrough the study.4. Eligibility CriteriaAll patients with hemolytic uremic syndrome or renalbiopsy indicating typical pathological findings of throm-botic microangiopathy (TMA) will be included. The defi-nition of hemolytic uremic syndrome is microangiopathichemolytic anemia, thrombocytopenia, and acute renal fail-ure. All cases with atypical (diarrhea negative), diarrheapositive hemolytic uremic syndrome, and TMA will beincluded. Microangiopathic hemolytic anemia is identi-fied by hemoglobin of less than the lower limit of nor-mal for age, high reticulocyte count, elevated level of lac-tic dehydrogenase (LDH) when the coombs test is nega-tive. Thrombocytopenia is defined by platelet count of lessthan 150000/micro liters, and renal injury is delineated byserum creatinine of more than the upper limit of normalfor age. This study will include systematic reviews or meta-analysis, longitudinal and cohort studies, cross-sectional,case-control, and epidemiological studies. Pertinent con-ference proceedings, theses or unpublished data will alsobe evaluated. Experimental studies, narrative reviews, andcase reports, and thrombotic thrombocytopenic purpurawill be excluded.5. Types of ParticipantsThe outcome of interest is the proportion of aHUS, finaloutcome including end stage renal disease (ESRD), morbid-ity, or death.6. Data Source and Search StrategyThe following data bases will be searched for publishedarticles, PubMed, EMBASE, Google Scholar, Google, OVID,SCOPUS, Web of Sciences, barakatkns.com, MagIran, SID,dociran, PDFiran, and ganj.irandoc. Moreover, databasesof each medical university in Iran will be searched for rel-evant theses and records. In order to obtain missed data, amanual search will be performed for cross references, theabstracts of international, regional, or local congresses.The authors will be contacted to obtain more details in caseof missing information and to collect unpublished datafrom known Iranian investigators pundit in HUS. Studiesissued between January 1985 and January 2016 will be con-sidered. Before the final analyses the researchers will re-peat the search for recent admissible studies to be coveredin the review.7. Provisional Search Strategy for PubmedAtypical hemolytic uremic syndrome “(Mesh) AND“Iran”(Mesh)/”Hemolytic-Uremic Syndrome”(Mesh)) AND“Iran”(Mesh)/”Thrombotic Microangiopathies”(Mesh)AND “Iran”(Mesh)/ (“glomerulonephritis”(MeSH Terms)OR “glomerulonephritis”(All Fields)) AND “Iran”(Mesh).“acute kidney injury”(MeSH Terms) OR Acute renal fail-ure, “renal insufficiency, chronic”(MeSH Terms), chron-ic”(MeSH Terms) OR chronic renal disease, “renal dialy-sis”(MeSH Terms) OR “dialysis”(MeSH Terms).The comparable Persian terms for the above quotedwords will be used to survey the articles in Iraniandatabase.8. Study SelectionAfter the preliminary pilot search, NH, MS, and FJ willindependently review the abstracts and articles to selectsuitable studies. Disagreement between reviewers will besolved by consensus or by NH. The STROBE statement willbe used to assess the quality of studies and their eligibil-ity as previously explained (22, 23). The researchers willuse PRISMA flowchart to present the process of article se-lection.2 J Compr Ped. In Press(In Press):e56080.Hooman N et al.9. Data Extraction and Risk of Bias AssessmentThe researchers have designed a structured data ab-straction form and one author will extract data that includ-ing authors’ name, title of study, journal, year, volume,number, page; language of study, center of study, type ofstudy, period of study, sample size, patient information(age, disease and gender), the region of study, length of fol-low up, outcome (recovery, HUS, death and unreported),and funding sources.Three reviewers will independently assess the risk ofbias by using the tool developed by Hoy et al. (22-24). Dis-agreement between reviewers will be solved by consensusor by the third author (NH).10. Data Synthesis and Statistical AnalysisThe authors will consider performing meta-analyseswhen at least 3 studies of low or medium risk of bias ex-ist and have similar population, design, and outcomes.The researchers are aware of the probable biases of meta-analyses that include a small number of articles; beforecalculating a pooled summary estimate in a meta-analysis,the researchers will carefully consider the heterogeneityacross studies. An anecdotal synthesis of the data will begiven. The researchers will calculate point prevalence andincidence. If studies could be assembled, the researcherswill pool results for studies that have used the same tech-nique and the same outcome. A random-effects meta-analysis and risk ratios for binary outcomes will be used.The researchers will calculate 95% confidence intervals.If the studies cannot be clustered, both the Chi-squaretest (P value of 0.1 set for clinical significance) and the I-squared statistic will be used to evaluate heterogeneity be-tween the studies in effect measures (I-squared value ofmore than 50% indicates substantial heterogeneity) (25).The researchers will investigate the potential causes forheterogeneity. Funnel plots and Kendall’s test will be usedto gauge publication bias.If data are sufficient, the researchers will conductsubgroup-analyses testing for differences between agegroups (children-adults), regions, diarrhea positive andnegative, acute kidney injury, and chronic kidney disease.11. DiscussionThis protocol aims at investigating the incidence ofhemolytic uremic syndrome and its subtypes in Iran. Thereview will focus on morbidity (chronic kidney disease andESRD) and mortality.There are currently no figures of HUS incidence orprevalence in Iranian children. The epidemiological studyof HUS would help promote laboratory methods to accel-erate the most accurate diagnosis of the underlying dis-ease, as different types of HUS have various pathogenesisand management (26).Delay in diagnosis and treatment has a crucial impacton quality of life and increases the risk of morbidity andmortality (27, 28).No surveillance strategy has been conducted to detectshiga-toxin in suspicious diarrhea cases in Iran so far. Cor-rect and on time diagnosis is decisive for appropriate man-agement and follow up. In addition, a few centers in Iranafford to measure complement component to detect atyp-ical HUS due to complement dysregulation. However, re-lying on this approach per se has its limitations and draw-backs. The panel is not complete yet and a normal resultdoes not eliminate neither inherited nor acquired comple-ment dysregulation type of HUS. An accurate diagnosis isparamount to reduce morbidity with on time treatmentusing novel medication that inhibit terminal component.The findings of this systematic review will be published ina peer-reviewed journal and presented in conferences. Thissystematic review and meta-analysis will estimate the fre-quency of HUS (D+ or D-) in Iran. This figure could helpclinical and health care administrative processes. Further-more, it could assist with the unfolding of the path forforthcoming research design and direction in this field.12. Implication for Health Policy, Practice, Research,and Medical EducationThe proposed research could improve clinical andhealth care decisions, allow estimation of patients requir-ing new medication, and direct future research design inthis field.AcknowledgmentsThis work was supported by the center for inter-national scientific studies and collaborations (CISSC),ID number 376 dated the 1st June 2016. Website:http://www.cissc.ir/FootnoteConflict of Interest: None.References1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. NEngl J Med. 2014;371(19):1847–8. doi: 10.1056/NEJMc1410951. [PubMed:25372103].J Compr Ped. In Press(In Press):e56080. 3Hooman N et al.2. Loirat C, Noris M, Fremeaux-Bacchi V. Complement and the atyp-ical hemolytic uremic syndrome in children. Pediatr Nephrol.2008;23(11):1957–72. doi: 10.1007/s00467-008-0872-4. [PubMed:18594873].3. Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, etal. 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The prevalence and incidence of atypical hemolytic uremic syndrome in Iran: A systematic review and meta-analysis protocol study

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The prevalence and incidence of atypical hemolytic uremic syndrome in Iran: A systematic review and meta-analysis protocol study

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