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## Amit X. Garg; Rita S. Suri; Nick Barrowman; et al. 

# Meta-analysis, and Meta-regression Hemolytic Uremic Syndrome: A Systematic Review, Long-term Renal Prognosis of Diarrhea-Associated

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. 2003;290(10):1408. JAMA Sharon Parmet et al. 

## Food-Borne Illnesses . 2003;290(10):1379. JAMA Richard L. Siegler. 

## Postdiarrheal Shiga Toxin–Mediated Hemolytic Uremic Syndrome . 2003;290(10):1337. JAMA Howard Trachtman et al. 

## Uremic Syndrome in Children: A Randomized Controlled Trial Effect of an Oral Shiga Toxin–Binding Agent on Diarrhea-Associated Hemolytic

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## REVIEW



# Long-term Renal Prognosis of Diarrhea-Associated Hemolytic Uremic Syndrome A Systematic Review, Meta-ana lysis, and Meta-regre ssion

Amit X. Garg, MD, MA Rita S. Suri, MD Nick Barrowman, PhD Faisal Rehman, MD Doug Matsell, MD M. Patricia Rosas-Arellano, MD, PhD Marina Salvadori, MD R. Brian Haynes, MD, PhD William F. Clark, MD 

# T HE HEMOLYTIC UREMIC SYN



## drome (HUS) is a disordercharacterized by acute hemolytic anemia, thrombocytopenia, and renal insufficiency. HUS, especially in children, is a main cause ofacute renal failure worldwide. The incidence of HUS is increasing, 1 

## with current estimates of 1 case per 50000 patient-years for those younger than 18
years. 2 

## Ninety percent of childhoodcases of HUS are associated with diarrhea and gastroenteritis and are due to Shiga toxin–producing Escherichia coli

. 3 

## This typical form of diarrheaassociated HUS causes toxin mediated vascular endothelial cell damage and inthe kidney causes thrombotic occlusion of capillary lumens, glomerular endothelial cell swelling, apoptosis of glomerular and tubular cells, and extensive cortical necrosis. 4



## With improved recognition andsupportive care, more patients are surviving the acute phase of diarrheaAuthor Affiliations are listed at the end of this article. Corresponding Author and Reprints: Amit X. Garg,MD, Walkerton Health Study, Division of Nephrology, London Health Sciences Centre, Westminster Campus, 800 Commissioners Rd E, London, Ontario, Canada N6A 4G5 (e-mail: Amit.Garg@lhsc.on.ca). 

### Context The long-term renal prognosis of patients with diarrhea-associated hemolytic uremic syndrome (HUS) remains controversial. Objectives To quantify the long-term renal prognosis of patients with diarrheaassociated HUS and to identify reasons for different estimates provided in the literature.
Data Sources We searched MEDLINE and Experta Medica (EMBASE) bibliographic databases and conference proceedings, and we contacted experts until February 2003. We also searched the Institute for Scientific Information index and reference lists of all studies that fulfilled our eligibility criteria. The search strategy included the terms hemolytic-uremic syndrome

, purpura , thrombotic thrombocytopenic

, Escherichia coli O157

, longitudinal studies

, kidney diseases

, hypertension , and proteinuria Study Selection Any study that followed up 10 or more patients with primary diarrheaassociated HUS for at least 1 year for renal sequelae.
Data Extraction Two authors independently abstracted data on study and patient characteristics, renal measures, outcomes, and prognostic features. Disagreements were resolved by a third author or by consensus. Data Synthesis Forty-nine studies of 3476 patients with a mean follow-up of 4.4 years(range, 1-22 years at last follow-up) from 18 countries, 1950 to 2001, were summarized. At the time of recruitment, patients were aged 1 month to 18 years. In the different studies, death or permanent end-stage renal disease (ESRD) ranged from 0% to 30%, with a pooled incidence of 12% (95% confidence interval [CI], 10%-15%). A glomerular filtration rate lower than 80 mL/min per 1.73 m 2 

### , hypertension, or proteinuria was extremely variable and ranged from 0% to 64%, with a pooled incidence of 25% (95% CI, 20%-30%). A higher severity of acute illness was strongly associatedwith worse long-term prognosis. Studies with a higher proportion of patients with central nervous system symptoms (coma, seizures, or stroke) had a higher proportion of patients who died or developed permanent ESRD at follow-up (explaining 44% of the between-study variability, P =.01). Studies with a greater proportion of patients lost to follow-up also described a worse prognosis (P =.001) because these patients were typically healthier than those followed up. One or more years after diarrhea-associated HUS, patients with a predicted creatinine clearance higher than 80 mL/min per 1.73 m 2 

### , no overt proteinuria, and no hypertension appeared to have an excellent prognosis.
Conclusions Death or ESRD occurs in about 12% of patients with diarrheaassociated HUS, and 25% of survivors demonstrate long-term renal sequelae. Patients lost to follow-up contribute to worse estimates in some studies. The severity ofacute illness, particularly central nervous system symptoms and the need for initial dialysis, is strongly associated with a worse long-term prognosis.

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## associated HUS. An accurate estimateof the long-term renal prognosis is critical for patient counseling, follow-up,and monitoring. It informs the feasibility of future clinical trials, and guides the necessity of screening after large population outbreaks of Shiga toxin– producing E coli gastroenteritis. However, the long-term renal prognosis ofdiarrhea-associated HUS remains controversial, with markedly different results reported in various studies. Thisreview was conducted to better quantify prognosis and to identify reasons for different estimates provided in the world’s literature.

METHODS Research Questions 

## The primary questions of this review were: (1)What is the incidence of death or end-stage renal disease (ESRD) or a glomerular filtration rate (GFR) lower than 80 mL/min per 1.73m 2 

## , hypertension, or proteinuria at least 1 year afterdiarrhea-associated HUS; (2)Whichfactors are associated with a worse longterm prognosisinindividual studies; and(3) Which factors (such as secular differences, methodological quality, baseline patient characteristics, and initial treatments) are associated with a worse long-term prognosis at the study level.The last question was tested in metaregression and the a priori hypotheses were a worselong-term prognosis would be evident in more recent studies (morechildren surviving severe disease), studies with longer follow-up, studies with more loss to follow-up, 5-8 

## and studieswith more patients with severe acute illness. Secondary questions included (1) Are patients with a less severe initialinfection still at appreciable risk of longterm renal disease, and (2) Do patients develop renal disease after apparent renal recoveryfrom diarrhea-associated HUS.

Included Studies

## Case series, cohort studies, and randomized controlled trials were included if 2 among the reviewing group (A.X.G, R.S.S., F.R., D.M., M.P.R., M.S., or W.F.C.) had agreed independently that an article (1) described a study population of 10 or more patients withprimary diarrhea-associated HUS (idiopathic or infection associated), (2) followed up patients for at least 1 year (because the natural history of the disease is an improvement of GFR over the first
year9,10 

## ), and (3) reported 1 or more renal outcomes (proteinuria, hypertension, renal insufficiency, or ESRD). A third reviewer (A.X.G., R.S.S., or D.M.) resolved disagreements about whether a study should be included.

Finding Relevant Studies 

## An independent review of citations from MEDLINE (OVID 1966 to February 2003) and Experta Medica (EMBASE, 1980 to February 2003) bibliographic databases was conducted (A.X.G. and F.R.). Full-text articles were retrieved ifany of the authors considered any citation potentially relevant. The searchstrategy, developed with an experienced librarian, used terms most sensitive for identifying studies of prognosis 11 

## and was pilot tested and modified with known relevant articles. The search strategy included the terms hemolyticuremic syndrome

, purpura , thrombotic thrombocytopenic

, Escherichia coli O157

, longitudinal studies

, kidney diseases

, hypertension , and proteinuria (completestrategies available on request). Supplementary methods of finding studies included a review of relevant article bibliographies, a review of articles citingrelevant articles in the Institute for Scientific Information index, a review ofAmerican Society of Nephrology meeting abstracts, and information provided by primary study authors.

Data Abstraction From Studies

## Two of the reviewing group, using created forms, independently abstracteddata on study and patient characteristics, renal measures, outcomes, and prognostic features. Disagreements were resolved by a third reviewer or by consensus. Non-English/non-Frencharticles were an exception to this process, and a single reviewer (A.X.G.), with the help of a language translator, abstracted necessary data from Dutch,German, Japanese, Polish, Portuguese, and Spanish articles. Attempts were made to contact primary authorsof all relevant studies to confirm the accuracy of abstracted data and to provide additional missing data.

Statistical Analysis 

## The primary outcomes of this review were death or permanent ESRD, and a GFR lower than 80 mL/min per 1.73 m2



## ,hypertension, or proteinuria at followup. For one study, 12 

## original data provided by the study author was categorized according to criteriafor this review.Confidenceintervals (CIs)for single proportions were derived using the Wilson score method. 13 

## We used  2 

## tests to assess between-study heterogeneity. Anapproach based on generalized estimating equations, which accounted for thewithin-study and between-study variability (random effects modeling), wasused to derive pooled estimates of proportions and their variances. 14 

## Estimates were computed using Excel. Overall, each study contributed a weight between 1% and 9%for any estimate. For each study, we assessed 8 measures of quality. We selected a priori not to use an existing quality scale or to create ourown scale.We assessed 2 of the most important measures in the meta-regression analyses—percentage lost to follow-up and whether the method of renal assessment was reported.

Inmeta-regression, thefollowing prognostic factors were considered at thestudy level: the mean age of patients; duration of follow-up; the mid point yearof the study; whether the method of renal assessment was reported; the proportion of patients who presented withcentral nervous system (CNS) symptoms (coma, seizures, or stroke); the proportion of patients who received acute dialysis, plasma infusion or exchange, or corticosteroids; and the proportion who were lost to follow-up. Additionally, for the outcomes of GFR lower than 80 mL/ min per 1.73 m2 

## , hypertension, or proteinuria, the proportion of patients experiencing the competing event of death or permanent ESRD was considered. To examine the impact of these factors onstudy outcomes, exploratory metaLONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

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## regressions were conducted using logistic normal random effects models using SAS PROC NLMIXED (SAS Inc, Cary, NC). Values for some factors were notavailablefor some studies. For eachmetaregression, only studiesfor which allfactors were available were included in the analysis. The explanatory ability of eachmeta-regression model was summarized as the proportion of betweenstudy variability explained on the logit scale. Univariate meta-regression was used for each outcome and each factor. Factors found to be significant at the
P =.10 level were included in multivariate meta-regression models. Factorsfound to be nonsignificant in a multivariate model were subsequently removed. To generate best-fitlinesinmetaregression graphs, an approximatecorrection was used to convert conditional means from the logistic normal model into marginal mean curves. 15



## RESULTS Study Selection

## From screening more than 3384 citations, 124 full-text articles were retrieved, and 49 articles were included in this review. The agreement beyondchance between 2 independent reviewers in the reviewing group for citationscreening, article inclusion, and data abstraction was good ( range, 0.56-0.74 on 20 different measures). The reasonsfor article exclusion were the study’s follow-up was less than 1 year, reportingof renal outcomes was unclear, selection of population for follow-up wasnonrepresentative, inception of a cohort of patients with HUS was unclear, population included a large proportion of recognized secondary causes of HUS, or patients seemed to have beendescribed in other articles already included in this review. (Excluded articles are available on request.) A singleadult study was excluded from this review. 16 

## Of the 49 articles, we contacted 45 primary authors, 25 of whom provided additional information and confirmed the accuracy of abstracteddata. All included studies were considered representative of patients with typical diarrhea-associated HUS. Results of patients with recognized secondary forms of HUS were excluded when data were abstracted and analyzed. From solely reading the primary reports, wefound occasional ambiguity about the reported cause of HUS. Exclusion of 9 studies with such ambiguity from ouranalyses did not change the summary estimates provided in this review. 10,17-24



### Study Description 

## The 49 studies included 3476 patients living in 18 different countries who were followed up for a mean (SD) of 4.4 (4.2) years. The mean range of follow-up was1 to 22 years. The studies were conducted between 1950 and 2001 (TABLE 

## 1

, TABLE 

## 2 , and F IGURE 

## 1 ). 5-10,12,17-58 

## Fiftytwo percent of patients were female, and themean age was 2.4 years (range, 0.1-18 years at recruitment into studies). Seven studies were associated with outbreaks of Shiga toxin-producing E coli , the source was uncertain for 2 studies, 28,38

## and the others were associated with municipal water, 58 

## radish sprouts, 57 

## hamburgers, 8 

## raw ground beef, 12,59 

## and fermented sausage. 56 

## During the last 15 years, identification of Shiga toxin– producing E coli in study reports did notappreciably improve. With the exception of outbreaks, only 14% of all patients had E coli O157:H7 confirmed by either stool culture, antibody-to-stool verotoxin, or serological testing.

Methodological Quality Assessment 

## Three study designs were clinical trials of urokinase and heparin47 

## and plasma exchange or infusions 50,51 

## with the remaining being case-series and cohortstudies. (We considered nonrandomized trials with historical control groupsto be cohort studies [Table 1].) Excluding the 3 clinical trials from this review did not change the main study results.When assessing quality, 43% wereprospective, 73% described consecutive HUS patients at an institution, 56% defined cutoff values for the diagnosisof HUS, 71% described important baseline characteristics (such as demographic and exposure characteristics),69% described treatments used during acute HUS, 16% described treatments used during follow-up, 61% usedclear methods for defining and reporting renal outcomes, and 47% measured all patients at the same follow-up time or used statistical methodsthat adjusted for varying lengths of follow-up. On average, 21% of patients were lost to follow-up (range, 0% to 59%), and 64% of studies either had lessthan 10% lost to follow-up or described the characteristics of those lost to follow-up.

Renal Function Assessment

## When described, proteinuria, hypertension, low GFR, and combinations ofthese were defined and measured in different ways in the primary studies. Different definitions of proteinuria used in the primary studies included a randomurine dipstick (albustix, labstix, multistix) of at least 0.1 g/L (trace, 0.3 g/L [1 + 

## ] or 1.0 g/L [  2 + 

## ]), 9,23 

## or an earlymorning urine protein-to-creatinine ratio of at least 177 mg/g (  20 mg/ mmol) 5,38 

## or at least 265 mg/g (  30 mg/mmol), 56 

## or a random urine albumin-to-creatinine ratio of at least 177 mg/g (  20 mg/mmol), 58 

## a 24-hour urine protein of at least 100 mg/d, 150 mg/ d, 18,20,24 

## 200 mg/d, 25,42 

## 250 mg/d, or 300 mg/d, 23,31,44 

## or a 24-hour urine protein of at least 100 mg/m 2 

## of body surface

area. 33,35 

## Definitions of hypertension included the use of antihypertensive medications, 27,54 

## 1 blood pressure measurement higher than the 90th, 6 

## 95th, 9,12,25,33,42,50 

## 97th, or 99th8 

## percentile, or 10 mm Hg above the 95th23 

## or 97th percentile, 51 

## using various population norms defined by age, 17,39 

## sex, 56 

## weight and/or height. 5 

## Definitions of decreased GFR included an elevated serum creatinine level, GFR estimated from predictive equations, 60 

## 24-hour urine creatinine clearance, measured GFR using injected inulin, 23 

## iothalamate, 8 

## technetium diethylenetriamine pentaacetic acid, 7 

## or EDTA, 9,41 

## with usual cutoff points of abnormality of less than 80 mL/min per 1.73 m2 

## of body surface

area. 9 

## In this review, the expression longterm renal sequelae refers to a low GFR (usually  80 mL/min per 1.73m 2 

## ), LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

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### Table 1. Characteristics of Long-term Renal Prognosis Studies of Diarrhea-Associated Hemolytic Uremic Syndrome (HUS) *

Source Primary Location No. of Patients Years of HUS Presentation Study Design Prospective Study Patient Age, Mean (Range), y Patients Requiring Acute Dialysis, % Gagnadoux et al, 25 1996 Paris, France 96 1950-1978 Cohort No 1 (0.2-4) 67 Gianantonio et al, 22 1968 Buenos Aires, Argentina 123 1957-1965 Cohort Yes 1 (0.6-2) . . . Janssen et al, 19 1974 Brussels, Belgium 20 1957-1972 Cohort No 1 (0.1-7) 70 Dolislager and Tune, 26 1978 Stanford, United States 45 1962-1975 Cohort No 4 (0.2-14) . . . Donckerwolcke et al, 27 1979 Utrecht, the Netherlands 72 1964-1977 Cohort No 3 (0.5-11) 69 de Jong and Monnens, 20 1988 Nijmegen, the Netherlands 96 1965-1977 Cohort Yes 3 (0.1-8) . . . McLean et al, 28 1966 Rhyl, Wales 10 1963 Case series Yes 2 (0.1-8) 10 Fitzpatrick et al, 29 1991 London, England 103 1966-1985 Cohort No 2 (0.2-14) 85 Riella et al, 30 1976 Seattle, United States 18 1967-1973 Cohort No 5 (0.1-14) 17 Blahova et al, 31 2002 Prague, Czech Republic 57 1967-1997 Cohort No 3 (0.3-14) 65 Sorrenti and Lewy, 32 1978 Chicago, United States 19 1968-1975 Cohort No 4 (0.5-16) 84 Spizzirri et al, 33 1997 La Plata, Argentina 312 1968-1984 Cohort No 1 (0.2-6) . . . Cordero et al, 34 1990 Santiago, Chile 154 1968-1989 Cohort No 1 (0.2-9) 39 Donckerwolcke et al, 35 1973 The Netherlands and Belgium 49 1970-1971 Cohort Yes 3 (0.1-12) . . . Kelles et al, 36 1994 Leuven, Belgium 95 1970-1982 Cohort Yes 2 (0.1-14) . . . Gusmano et al, 37 1987 Genoa, Italy 92 1970-1985 Cohort Yes 2 (0.1-14) 86 Coad et al, 38 1991 Birmingham, England 74 1970-1987 Cohort No 3 (0.3-13) 59 Siegler et al, 39 1996 Salt Lake City, United States 265 1970-1993 Cohort No 3 (0.1-18) 47 Gillor et al, 21 1986 Cologne, Germany 31 1971-1982 Cohort Yes 4 (0.5-9) 100 Tonshoff et al, 23 1994 Heidelberg, Germany 89 1971-1988 Cohort Yes 3 (0.1-12) 69 Campos et al, 17 1982 Minneapolis, United States 26 1972-1979 Cohort No 5 (2-16) 92 Sheth et al, 40 1988 Milwaukee, United States 43 1972-1985 Cohort No 3 (0.5-9) 63 Hughes et al, 41 1991 Glasgow, Scotland 79 1972-1988 Cohort No 3 (0.2-14) 75 Zurowska et al, 42 2000 Gdansk, Poland 196 1972-1999 Cohort No . . . 83 Monnens et al, 18 1978 Rotterdam, the Netherlands 35 1973-1977 Cohort Yes 3 (1-7) . . . Diekmann, 43 1980 Munster, Germany 26 1973-1978 Cohort Yes 4 (0.5-11) 81 Wende-Fischer et al, 10 1996 Hannover, Germany 61 1973-1989 Cohort No 5 (0.3-15) 80 Imoberdorf et al, 44 1993 Bern, Switzerland 42 1973-1991 Cohort No 1 (0.1-13) 38 O’Brien et al, 6 1994 New Haven, United States 45 1974-1989 Cohort No . . . . . . Vermylen et al, 45 1988 Brussels, Belgium 53 1975-1987 Cohort Yes 2 (0.1-14) 47 Loirat et al, 46 1993 Paris, France 147 1975-1991 Cohort No 1 (0.1-16) 76 Huseman et al, 9 1999 Berlin, Germany 165 1976-1995 Cohort Yes 2 (0.2-11) 82 O’Regan et al, 7 1989 Montreal, Canada 50 1977-1982 Cohort No . . . . . . Loirat et al, 47 1984 Paris, France 33 1978-1980 Trial Yes 3 (0.1-16) 91 Mizusawa et al, 48 1996 Brisbane, Australia 55 1979-1995 Cohort No 2 (0.2-13) 64 Guyot et al, 49 1986 Nantes, France 37 1980-1985 Cohort No 2 (0.2-7) 59 Rizzoni et al, 50 1988 Padova, Italy 32 1981-1985 Trial Yes 2 (0.3-6) 100 Loirat et al, 51 1988 Paris, France 79 1983-1985 Trial Yes 2 (0.2-13) 84 Al-Eisa and Al-Hajeri, 52 2001 Safat, Kuwait 14 1985-2000 Cohort No 2 (1-3) 79 Miyazaki, 53 1994 36 centers, Japan 122 1986-1990 Cohort No 4 (1-6) 19 Small et al, 5 1999 Nottingham, England 114 1986-1996 Cohort Yes 3 (0.2-15) 72 Brichard et al, 54 1993 Brussels, Belgium 33 1987-1991 Cohort No 3 (0.2-14) 61 Ramos et al, 55 2001 Janeiro, Portugal 16 1989-2000 Cohort No 3 (0.8-14) 50 Ogborn et al, 12 1998 Arviat, Canada 21 1991 Cohort No 6 (0.8-14) 19 Brandt et al, 8 1998 Seattle, United States 37 1993 Cohort Yes 5 (1-15) 57 Litalien et al, 24 1999 Ottawa, Canada 38 1994-1996 Cohort Yes 4 (0.5-7) 37 Henning et al, 56 1998 Adelaide, Australia 20 1995 Cohort Yes 5 (0.5-12) 90 Yoshioka et al, 57 1999 Osaka, Japan 15 1996 Cohort Yes 8 (6-10) 33 Salvadori et al, 58 2002 Walkerton, Canada 22 2000 Cohort Yes 5 (1-16) 36

* Studies are arranged chronologically based on the initiation of study enrollment. Ellipses indicate not reported. 

### LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

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### Table 2. Long-term Renal Prognosis Studies of Diarrhea-Associated Hemolytic Uremic Syndrome

Source * Follow-up, Mean (Range), y Lost to Follow-up, % Died or Had ESRD at Follow-up, % No. of Patients With Renal

Testing GFR  80 mL/min per 1.73 m 2
, Hypertension, or Proteinuria, %† Hypertension, %† Proteinuria, %† GFR, mL/min per 1.73 m 2 , %†

60-80 30-59 5-29 Gagnadoux et al 25 15 (10-25) 35 25 38 37 21 11 8 8 0
Gianantonio et al 22 3 (1-8) 19 22 73 58 15 25 18 33 4
Janssen et al 19 3 (0.2-12) 10 15 15 27 7 13 . . . . . . . . . Dolislager and Tune 26 4 (1-12) 4 7 40 8 5 8 5 0 0
Donckerwolcke et al 27 1 3 21 55 . . . 11 7 . . . . . . . . . de Jong et al 20 10 5 19 73 . . . 14 6 4 4 1
McLean et al 28 2 0 10 9 0 0 0 0 0 0 Fitzpatrick et al 29 8 (5-21) 7 8 88 39 3 31 13 5 1
Riella et al 30 3 (0.4-7) 0 6 17 6 6 . . . 0 6 0
Blahova et al 31 7 (1-27) 0 12 50 40 8 40 26 2 12 Sorrenti and Lewy32 5 (1-8) 0 16 16 13 6 13 0 6 6 Spizzirri et al 33 13 (10-20) 59 4 114 35 15 35 10 5 4
Cordero et al 34 22 45 8 73 . . . 3 . . . . . . . . . . . .
Donckerwolcke et al 35 1 2 16 40 23 10 . . . . . . . . . . . .
Kelles et al 36 10 5 11 80 35 11 8 . . . . . . . . .
Gusmano et al 37 1 (0.5-11) 3 11 79 10 . . . 4 5 3 3
Coad et al 38  1 0 18 61 18 8 8 0 10 0 Siegler et al 39 4 (0.3-17) 52 5 115 43 11 17 17 . . . . . .
Gillor et al 21 1 0 29 22 23 23 . . . . . . . . . . . .
Tonshoff et al 23 2 (1-17) 15 30 67 52 . . . . . . 12 . . . . . . Campos et al 17 3 (0.5-7) 0 12 23 13 9 . . . 4 0 4
Sheth et al 40 . . . (1-13) 0 14 37 . . . . . . . . . . . . . . . . . . Hughes et al 41 4 (0.3-14) 16 13 59 25 7 10 . . . . . . 2
Zurowska et al 42 11 (2-27) 24 28 94 64 18 21 18 4 3
Monnens et al 18 2 0 0 33 . . . 24 24 3 3 3
Diekmann 43 2 (1-6) 8 27 17 35 6 38 . . . . . . . . .
Wende-Fischer et al 10 5 (4-13) 30 28 26 38 19 12 . . . . . . . . .
Imoberdorf et al 44 1 17 19 27 22 7 15 . . . . . . . . .
O’Brien et al 6 6 (1-15) 36 13 23 4 0 4 0 0 0 Vermylen et al 45 . . . (0.5-7) 4 0 51 2 0 2 0 0 0
Loirat et al 46  1 17 6 113 33 . . . . . . . . . . . . . . .
Huseman et al 9 5 (2-13) 13 12 123 20 . . . . . . 11 2 . . . O’Regan et al 7 7 (5-11) 26 . . . 37 62 0 19 27 30 0
Loirat et al 47 2 (1-4) 0 9 30 7 7 27 3 3 0
Mizusawa et al 48 5 (3-16) 7 5 49 8 6 8 0 8 0 Guyot et al 49 2 (0.6-5) 5 11 31 16 10 6 3 0 0
Rizzoni et al 50 2 (. . .) 0 0 32 . . . 6 6 . . . . . . . . .
Loirat et al 51 1 13 10 61 . . . 10 20 . . . . . . . . . Al-Eisa and Al-Hajeri 52 5 (1-15) 0 21 11 18 18 18 0 0 18 Miyazaki 53 3 (1-5) 4 10 105 7 6 7 . . . . . . . . .
Small et al 5 1 18 4 92 42 16 22 21 5 1
Brichard et al 54 3 (0.7-4) 0 0 33 6 0 6 0 0 0
Ramos et al 55 5 (0.5-11) 0 6 16 6 0 . . . 6 0 0 Ogborn et al 12 4 0 14 18 17 17 0 0 0 0
Brandt et al 8 2 (1-3) 16 5 29 21 3 17 0 0 0
Litalien et al 24 1 26 3 27 30 . . . 33 7 19 0 Henning et al 56 2 0 5 19 26 26 26 11 16 0
Yoshioka et al 57 1.5 0 0 15 7 0 0 7 0 0 Salvadori et al, 58 2002 1 18 5 16 19 19 19 13 0 0 Abbreviations: ESRD, end-stage renal disease; GFR, estimated glomerular filtration rate. Ellipses indicate not reported.

* Studies are arranged chronologically, based on the initiation of study enrollment. †A summary of the various study definitions for a GFR lower than 80 mL/min per 1.73 m 2 , hypertension, and proteinuria are presented in the “Methods” section. 

### LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

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### Figure 1. Proportion of Patients With Sequelae From Diarrhea-Associated Hemolytic Uremic Syndrome

Incidence, % 0 20 10 50 30 40 70 60 80 Incidence, % 1962 Dolislager and Tune, 261978 Donckerwolcke et al, 271979 de Jong and Monnens, 201988 McLean et al, 281966 Fitzpatrick et al, 291991 Riella et al, 301976 Blahova et al, 31 2002 Sorrenti and Lewy, 321978 Spizzirri et al, 331997 Cordero et al, 341990

1970 Donckerwolcke et al, 351973 Kelles et al, 361994 Gusmano et al, 371987 Coad et al, 381991 Siegler et al, 391996 Gillor et al, 21 1986 Tonshoff et al, 231994 Campos et al, 171982 Sheth et al, 401988 Hughes et al, 41 1991 Zurowska et al, 422000 Monnens et al, 181978 Diekmann, 431980 Wende-Fischer et al, 101996 Imoberdorf et al, 441993 O’Brien et al, 61994

1975 Vermylen et al, 451988 Loirat et al, 461993 Huseman et al, 91999 O’Regan et al, 71989 Loirat et al, 471984 Mizusawa et al, 481996

1980 Guyot et al, 491986 Rizzoni et al, 501988 Loirat et al, 51 1988

1985 Al-Eisa and Al-Hajeri, 522001 Miyazaki, 531994 Small et al, 51999 Brichard et al, 541993 Ramos et al, 552001

1991 Ogborn et al, 121998 Brandt et al, 81998 Litalien et al, 241999 Henning et al, 561998 Yoshioka et al, 571999

2000 Salvadori et al, 582003

0 20 10 50 30 40 Overall Pooled Estimate 1950 Gagnadoux et al, 251996 Gianantonio et al, 221968 Janssen et al, 191974 First Year of Study

Recruitment Source GFR < 80 mL/min per 1.73 m 2 , Hypertension, or Proteinuria Death or Permanent ESRD

0 20 10 50 30 40 70 60 80 0 20 10 50 30 40

Presented are the proportions of patients who died or developed permanent end-stage renal disease (ESRD), or developed a glomerular filtration rate (GFR) lower than 80 mL /min per 1.73 m 2 , hypertension, or proteinuria, at an average last follow-up of 4 years (range, 1-22 years). Point estimates are provided with 95% confidence intervals and overall pooled estimates.

The 49 studies are arranged chronologically from first year of study recruitment. A total of 2372 patients without permanent ESRD had renal function assessed at last follow-up. One study of estimates of death or ESRD and 7 studies of estimates of renal function were excluded due to missing information. A summary of th e various study definitions for a GFR lower than 80 mL/min per 1.73 m 2 , hypertension, and proteinuria are presented in the “Methods” section. 

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## hypertension, or overt proteinuria at last follow-up, as assessed in the individual studies. Similarly, renal recovery refers to a normal GFR (usually  80 mL/ min per 1.73m2

## ) and no evidence of hypertension or overt proteinuria as assessed in the individual studies.

Long-term Renal Prognosis

## For all outcomes, the variability between studies was larger than would beexpected by chance (significant heterogeneity, P  .001). Given the large between-study variability with wideranging heterogeneity (Figure 1), mathematically pooled results should be interpreted with caution. However such results are provided because they represent current best evidencefor clinical care andguide sample-size calculations for future epidemiological studies. Death or permanent ESRD rangedfrom 0% to 30% (death, 0%-23%; permanent ESRD, 0%- 17%; TABLE 

## 3 and Figure 1). The mathematical pooled estimate of the incidence of death or permanent ESRD was 12% (95% confidenceinterval [CI], 10%-15%; death 9%, [95% CI, 7%-11%; permanent ESRD, 3% [95% CI, 2%-5%]),with the majority of cases occurring during the acute phase of HUS.

At a minimum of 1 year of followup, 2372 patients without permanentESRD had an assessment of renal function. Renal sequelae ranged from 0% to64% (Table 3 and Figure 1). The majority of studies did not differentiate whether these were persistent findingsafter acute HUS or whether they developed after apparent initial renal recovery. The pooled estimate of renal sequelae was 25% (95% CI, 20%-30%). The pooled estimate of the incidence of a GFR of 60 to 80 mL/min per 1.73 m 2 

## was 8% (95% CI, 5%-11%); of 30 to 59 was 6% (95% CI, 3%-8%); of 5 to 29 was 1.8% (95% CI, 0.8%-3%), hypertension was 10% (95% CI, 8%-12%), and proteinuria was 15% (95% CI, 10%-20%).

Prognostic Features 

## A number of prognostic features were describedin theindividual studies.Many of the primary study authors described an association between an increasedseverity of acute illness (greater infection or host response) and worse longterm prognosis, including an elevated white blood cell count higher than 20  10 3 

## /μL with neutrophilia, 29,38 

## a highserum creatinine or urea concentration, 53 

## central nervous system symptoms (reduced consciousness, coma, stroke, or seizures), * 

## ischemic colitis, 33,49 

## and hypertension. 9,10,23,36,44,48,53 

## Lower and prolonged levels of anemiaand thrombocytopenia were inconsistently associated with both worse 8 

## and improved38 

## outcomes. Compared with patients with oliguria of 8 days or less (an approximate urine output less than 300 mL/m 2 

## per day), those with oliguria of greater than 8 days or anuria of 1 to 8 days, and thosewith anuria ofgreater than 8 days had a step-wise worseningof prognosis.†Alonger duration of dialysis was associated with worse prognosis, and no patient achieved full renal recovery when dialysis therapy exceeded 4 weeks. 5,23,29,41,42 

## Similarly after 3 weeks,the longer the duration of hospitalization, the worse the outcome. 56



## Certain studies examined the significance of renal biopsy near acute illness. Those with cortical necrosis or arterial thrombotic microangiopathydemonstrated a worse prognosis compared with patients with isolated glomerular lesions. 23,25,46 

## In patients with isolated glomerular lesions, those withmore than 50% glomerular involvement had a worse prognosis. 46



## Younger ages (on average  2-5 years old) 10,24,31,33 

## and female sex38 

## had an inconsistent effect on results. One study suggested a worse prognosis with HUS during winter. 38 

## Increased C-reactive protein 53 

## and cytokine levels (IL-6, IL10, IL-1, Ra) 24 

## were associated with worse prognosis.

With respect to treatment, living no further than 100 km (62.5 miles) from a tertiary center, 42 

## and early recognition and treatment including dialysis 10,42 

## were associated with better prognosis. Better outcomes were notconsistently achieved with streptokinase 18,43 

## or plasma exchange. 21,40,50,51



### Prognostic Features in Meta-regression

## At the study level, severity of acute illness was associated with worse longterm prognosis in both univariate and multivariate analyses. Studies with a higher proportion of patients with CNS symptoms (coma, seizures, or stroke) had a higher proportion of patients who died or who developed permanentESRD, explaining 44% of the betweenstudy variability ( P =.01; F IGURE 

## 2 ).Similarly, studies with a higher proportion of patients requiring acute dialysis had a higher proportion of patients who died or developed permanentESRD, explaining 10% of the betweenstudy variability ( P =.02), and had a higher proportion of patients with long- * References 10, 23, 33, 36, 41, 44, 49, 53. †References 9, 18, 20, 22, 23, 26, 33, 46, 48. 

### Table 3. Pooled Analyses of 3476 Total Patients and 2372 Patients With Renal Testing at Follow-up *

Variable Patients Who Died or Had ESRD at Follow-up (n = 3476) GFR  80 mL/min per 1.73 m 2
, Hypertension, or Proteinuria Hypertension Proteinuria GFR, mL/min per 1.73 m 2

60-80 30-59 5-29 Pooled average (95% CI), % 12 (10-15) 25 (20-30) 10 (8-12) 15 (10-20) 8 (5-11) 6 (3-8) 1.8 (0.8-3)

Range, % 0-30 0-64 0-26 0-40 0-27 0-33 0-18 Abbreviations: CI, confidence interval; ellipses, not reported; ESRD, end-stage renal disease; GFR, estimated glomerular filtration rate.

* Averages were pooled using a random-effects model. Most deaths or ESRD reported at last follow-up occurred during the acute stage of hemolytic uremic syndrome. A summary

of the various study definitions for a GFR lower than 80 mL/min per 1.73 m 2 , hypertension, and proteinuria are presented in the “Methods” section. 

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## term renal sequelae, explaining 15% of the between study variability (P  .001; F IGURE 

## 3 ).

Study level factors such as a higherproportion of patients of older age, female sex, receiving corticosteroids, and factors such as the years in which the study was conducted and whether the study reported careful methods of renalfunction assessment were not associated with worse outcomes. Similarly,studies with a lower proportion of patients with death or ESRD did not demonstrate a higher proportion of patientswith renal sequelae at follow-up. In univariate but not multivariate analyses, studies with a longer follow-up timedemonstrated a higher proportion of patients with long-term renal sequelae.

However, in both univariate and multivariate analyses, studies with a higher proportion of patients lost to follow-updemonstrated a higher proportion of patients with long-term renal sequelae, explaining 28% of the between-study variability (P =.001; F IGURE 

## 4 ). When the analysis was limited to the 30 studies with better than 90% follow-up, with a meanfollow-up of 3.6 years (range, 1-10 years), the pooled estimate of death or permanent ESRD was 11% (95% CI, 8%- 14%) and renal sequelae was 17% (95%CI, 12%-22%). Studies with a higher proportion of patients receiving plasma infusion or exchange had a lower proportion of patients who died or developed permanent ESRD, explaining 8% of the between study variability (P =.03), and a lower proportion of patients with renal sequelae, explaining 28% of the between-study variability, P =.03; F IGURE 

## 5 ). Visually this trend seemed to be influenced by a small number of studies. 45,52,54



### Sequelae After Milder Forms of Diarrhea-Associated HUS

## A few studies have suggested that patients with less severe forms of HUS, including those with a preserved urine output, may still demonstrate renal sequelae at follow-up. 23,25 

## For example, 2 of 5 patients with acute diarrhea-associated HUS andmild renalimpairment (normal urineoutput, no dialysis) demonstrated hypertension and proteinuria at longterm follow-up. 25 

## Similarly 5 of 18 patients with acute diarrhea-associated HUSand normal urine output later developed long-term renal sequelae including chronic renal failure. 23



### Renal Disease After Apparent Renal Recovery

## In studies of patients who develop longterm renal sequelae, the majority of studies did not differentiate patients who apparently completely recovered after theacute illness from those who demonstrated persistent renal abnormalities. Four studies that did differentiate these states using a single-screening test of clearance suggested that 8% to 61% of those who seemed to have a normal GFR after diarrhea-associated HUS (assessedeither by a normal serum creatinine concentration 7 

## or a calculated 33 

## or measured GFR  80 mL/min per 1.73 m2

## ) 5,9 

## went on to develop a GFR lower than 80 mL/min per 1.73m 2 

## , hypertension, orproteinuria during long-term followup. Similarly, a single study suggested that a quarter of those who recovered with an absence of proteinuria (  250mg of protein per day) went on to developrenal sequelae during long-term followup. 33 

## On the other hand, 4 studies that considered 3 measures of renal health in combination suggested that no one whorecovered with an absence of hypertension, an absence of dipstick proteinuria, and a calculated or measured GFR higher than 80 mL/min per 1.73m2 

## developedfuture renal sequelae, 5,22,23,26 

## recognizing these studies are limited by follow-up times of less than 5 years.

Figure 2. Studies With a Higher Proportion of Patients With Central Nervous System Symptoms (Coma, Seizures, or Stroke)

15

10

5 20 25 30 35

0

0 20 100 40 60 80 Patients With Acute Central Nervous System Symptoms, %Patients Who Died or DevelopedPermanent ESRD, %

These studies had a higher proportion of patients with death or permanent end-stage renal disease (ESRD) at follow-up, explaining 44% of the between-study variability ( P =.01). The area of each circle is proportional to the number of patients in each study. Curve is best-fit line from meta-regression. See “Methods” section.



### Figure 3. Studies With a Higher Proportion of Patients Who Required Acute Dialysis

15

10

5 20 25 30 35

0

0 20 100 40 60 80 Patients Receiving Acute Dialysis, % Death or Permanent ESRDPatients, %

30

20

10 40 50 60 70

0

0 20 100 40 60 80 Patients Receiving Acute Dialysis, %

GFR < 80 mL/min per 1.73 m 2

, Hypertension, or Proteinuria

These studies had a higher proportion of patients with death or permanent end-stage renal disease (ESRD) at follow-up, explaining 10% of the between-study variability ( P =.02), and a higher proportion of patients with a glomerular filtration rate (GFR) lower than 80 mL /min per 1.73 m 2 , hypertension, or proteinuria at last followup, explaining 15% of the between-study variability ( P  .001). The area of each circle is proportional to the number of patients in each study. Curves are best-fit lines from meta-regression. See “Methods” section. 

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## COMMENT Studies of diarrhea-associated HUS arehighly variable in their methodological rigor, methods of renal assessment, and estimates of long-term prognosis. For this reason, the long-term renal prognosis of diarrhea-associatedHUS remains controversial. As highlighted in this review, the incidence of death or permanent ESRD ranged from 0% to 30% in the primary studies, and 0% to 65% of patients demonstratedlong-term renal sequelae. Our mathematical pooled estimates based on existing studies suggest an average of 4years after experiencing diarrheaassociated HUS, 9% of patients die (most during the acute phase of illness), an additional 3% develop permanentESRD, and 25% demonstrate renal sequelae. Severity of the acute illness, especially the presence of CNS symptoms, is strongly associated with worse long-term outcome. These symptoms of coma, seizures, or stroke may be dueto ischemic thrombotic microangiopathy, concurrent hypertension, or metabolic alterations of hyponatremia and hypocalcemia. 61 

## The need for initial dialysis was also strongly associated with worse outcome. No one achieved fullrenal recovery when dialysis therapy exceeded 4 weeks.

Some studies have confirmed longterm sequelae even after milder forms of diarrhea-associated HUS. 22,24 

## The natural history of diarrhea-associated HUS is often an improvement of GFR (approximately 25 mL/min per 1.73m 2 

## over the first year9,10

## ). Thus it seems prudent to screen patients at least once forsilent renal disease a year after acute diarrhea-associated HUS. As the sole method of characterizing patients free of disease, a nuclear GFR higher than 80 mL/min per 1.73m 2 

## after recovery is an inadequate screening test. However,those who demonstrate a predicted creatinine clearance higher than 80 mL/ min per 1.73m 2



## , 60 

## no overt proteinuria (  1 + 

## or 0.3 g/L on dipstick), and no hypertension (based on population reference values), a potentially easily implemented cost-effective screening strategy, appear to have an excellent prognosis during early follow-up. 5,22,23,26



## Similar to other renal insults, it is theorized that diarrhea-associated HUScan lead to a critical reduction in nephron number, with unsustainable remnant single-nephron hyperfiltration 62 

## and progressive renal disease. 63 

## However, these results confirm that the relationship between longer follow-up time and worse prognosis is in partcomplicated by a high number of patients lost to follow-up in some studies. Patients lost to follow-up contribute to worse estimates of long-term prognosis because they are typicallyhealthier than those followed up. Further prognostic studies should adhere to the methodological quality criteriaoutlined in this review, and particularly should strive for less than 10% ofpatients lost to follow-up. Different definitions for surrogate outcomes of proteinuria, low GFR, and hypertension performed at different follow-up timescomplicate the interpretation and utility of results from many of the primary studies and the summary results of this review. A uniformly adopted time and method of measurement, withspecified cutoff levels that have been associated with death or ESRD in prospective studies of children, 64 

## would beadvantageous. Further characterization of prognostic factors and novel methods of screening patients after diarrhea-associated HUS, althoughcritical for clarifying pathophysiology, 6,9,65,66 

## may prove difficult to applyclinically. Rather, improving the detection of Shiga toxin–producing E coli Figure 4. Studies With a Higher Proportion of Patients Lost to Follow-up

30

20

10 40 50 60 70

0

0 20 100 40 60 80 Patients Lost to Follow-up, %Patients Who DemonstratedRenal Sequelae, %

These studies had a higher proportion of patients with renal sequelae at last follow-up, explaining 28% of the between-study variability ( P =.001). The area of each circle is proportional to the number of patientsin each study. Curve is best-fit line from metaregression. See “Methods” section.



### Figure 5. Studies With a Higher Proportion of Patients Who Received Acute Plasma Infusion or Exchange

15

10

5 20 25 30 35

0

0 20 100 40 60 80 Patients Receiving Acute Plasma Infusion or Exchange, % Death or Permanent ESRDPatients, %

30

20

10 40 50 60 70

0

0 20 100 40 60 80 Patients Receiving Acute Plasma Infusion or Exchange, % GFR < 80 mL/min per 1.73 m 2

, Hypertension, or Proteinuria

These studies had a lower proportion of patients who died or developed permanent end-stage renal disease (ESRD), explaining 8% of the between-study variability (P =.03), and a lower proportion with renal sequelae (glomerular filtration rate [GFR]  80 mL/min per 1.73 m 2 , hypertension, or proteinuria) at last follow-up, explaining 28% of the between-study variability (P =.03). Visually, this trend seemed to be influenced by a small number of studies. 45,52,54 

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## as the cause of diarrhea-associated HUS,which has been limited even in studies during the last 15 years, seems necessary for the proper characterization of future cohorts. In addition, given thatlong-term sequelae have been described after milder forms of diarrheaassociated HUS, 23,25 

## research examining the incidence of renal disease after toxigenic E coli gastroenteritis seems essential.

Future therapeutic studies may consider a preventive approach to the medical consequences of Shiga toxin– producing E coli , including increased sanitation, surveillance, assessment, reporting, and possibly bovine and human vaccination. 67,68 

## Avoidance ofantibiotics and antimotility agents during gastroenteritis 69,70 

## and the role of protective antibodies 71 

## and oral synthetic verotoxin-receptor analogs attached to chromosorb 72 

## remain to be clarified.Early recognition and referral to a specialized medical care center experienced in the critical care of acute diarrhea-associated HUS seems to be a particularly important strategy. 42 

## Corticosteroids, antiplatelet agents, anticoagulant therapy, and thrombolyticsduring the acute phase of diarrheaassociated HUS are not clearly effective. 47,73 

## Careful blood pressure controland renin-angiotensin system blockade may be particularly beneficial for those who demonstrate renal sequelae after diarrhea-associated HUS. With an event rate of 12% death or permanent ESRD at 4years, this review confirms that multicenter,multinational, clinical trials with thousands of patients are requiredfor adequate statistical power to demonstrate the benefits of any therapy on these outcomes.

A therapy that may warrant this level of attention in future clinical trials isplasma exchange. Sixteen studies included in this review described a portion of patients treated with infusion or exchange. However smaller and possibly underpowered trials of plasmahave not shown efficacy in diarrheaassociated HUS. 49,50 

## These metaregression results of the potential benefits of plasma areintriguing, recognizing their interpretation is complicated bytheir observational nature, analytic limitations, 74 

## trends influenced by a small number of studies, 45,52,54 

## and an absence of risk benefit assessment. Publication biases (in which studies withlarger efficacy are more likely to be reported) may also exist. In summary, death or ESRD occursin about 12% of patients 4 years after diarrhea-associated HUS, and 25% of survivors demonstrate long-term renal sequelae. The severity of acute illness, particularlyCNS symptoms and the needfor initial dialysis, is strongly associated with a worse long-term prognosis. Patients lost to follow-up contribute to worse estimates in some studies.

Author Affiliations: Divisions of Adult and PediatricNephrology (Drs Garg, Suri, Rehman, Matsell, RosasArellano, Haynes, and Clark) and Pediatric InfectiousDiseases (Dr Salvadori), University of Western Ontario, London; Thomas C. Chalmers Centre for Systematic Reviews, Ottawa, Ontario (Dr Barrowman);and Department of Clinical Epidemiology and Biostatistics and Department of Medicine, McMaster University, Hamilton, Ontario (Drs Garg and Haynes).Dr Garg is also now with the Department of Epidemiology and Biostatistics, University of Western Ontario, and the Lawson Health Research Institute, London, Ontario. Author Contributions: Review concept and design : Garg, Suri. Acquisition of data : Garg, Suri, Rehman, Matsell, Rosas-Arellano, Salvadori, Clark. Analysis and interpretation of the data : Garg, Suri, Barrowman, Matsell, Rosas-Arellano Haynes, Clark. Drafting of manuscript : Garg.Critical revision of the manuscript for important intellectual content : Garg, Suri, Barrowman, Rehman, Matsell, Rosas-Arellano, Salvadori, Haynes, Clark. Statistical expertise : Barrowman, Garg. Obtained funding : Garg, Matsell, Salvadori, Haynes, Clark. Administrative, technical, or material support : Garg, Suri, Rosas-Arellano. Review supervision : Garg. Funding/Support: This review study was supportedby the Ontario Ministry of Health and the Kidney Foundation of Canada. Dr Garg was supported by a Canadian Institutes of Health Research/Kidney Foundation of Canada Fellowship Award. Acknowledgment: We thank Ruby Gordon who provided administrative help, and Tom Flemming, who helped with the searches involved in the review. We thank Stephen Walter, PhD, Achilleas Thoma, MD, andDeborah Cook, MD, for statistical and methodological advice. We thank Juan Carlos, MD, Eva Manazzoni, and Grace Vermeulen, RN, for language translations. Finally we thank the 25 authors of included studies who generously confirmed and provided information and performed additional analyses for this review.

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