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JAMA. 2003;290(10):1360-1370 (doi:10.1001/jama.290.10.1360) 

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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REVIEW

Long-term Renal Prognosis of

Diarrhea-Associated Hemolytic

Uremic Syndrome

A Systematic Review, Meta-analysis, and Meta-regression

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 SYNdrome (HUS) is a disorder

characterized by acute hemolytic anemia, thrombocytopenia, and renal insufficiency. HUS, especially in children, is a main cause of

acute 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 childhood

cases 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 in

the 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 and

supportive 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 m2

, 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 associated

with 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 m2

, 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 of

acute illness, particularly central nervous system symptoms and the need for initial dialysis, is strongly associated with a worse long-term prognosis.

JAMA. 2003;290:1360-1370 www.jama.com

See also pp 1337 and 1379

and Patient Page.

1360 JAMA, September 10, 2003—Vol 290, No. 10 (Reprinted) ©2003 American Medical Association. All rights reserved.

Downloaded from www.jama.com by guest on September 15, 2009 
associated HUS. An accurate estimate

of 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 of

diarrhea-associated HUS remains controversial, with markedly different results reported in various studies. This

review 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 1.73m2

, hypertension, or proteinuria at least 1 year after

diarrhea-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 (more

children surviving severe disease), studies with longer follow-up, studies with

more loss to follow-up,5-8 and studies

with more patients with severe acute illness. Secondary questions included (1)

Are patients with a less severe initial

infection 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 with

primary 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 if

any of the authors considered any citation potentially relevant. The search

strategy, developed with an experienced librarian, used terms most sensitive for identifying studies of prognosis11 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 (complete

strategies available on request). Supplementary methods of finding studies included a review of relevant article bibliographies, a review of articles citing

relevant articles in the Institute for Scientific Information index, a review of

American 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 abstracted

data on study and patient characteristics, renal measures, outcomes, and

prognostic features. Disagreements

were resolved by a third reviewer or by

consensus. Non-English/non-French

articles 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 authors

of 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. An

approach based on generalized estimating equations, which accounted for the

within-study and between-study variability (random effects modeling), was

used 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 our

own 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 the

study level: the mean age of patients; duration of follow-up; the mid point year

of the study; whether the method of renal assessment was reported; the proportion of patients who presented with

central 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 on

study outcomes, exploratory metaLONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, September 10, 2003—Vol 290, No. 10 1361

Downloaded from www.jama.com by guest on September 15, 2009 
regressions were conducted using logistic normal random effects models using

SAS PROC NLMIXED (SAS Inc, Cary,

NC). Values for some factors were not

availablefor some studies. For eachmetaregression, only studiesfor which allfactors were available were included in the

analysis. The explanatory ability of each

meta-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. Factors

found to be nonsignificant in a multivariate model were subsequently removed. To generate best-fitlinesinmetaregression graphs, an approximate

correction 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 beyond

chance between 2 independent reviewers in the reviewing group for citation

screening, article inclusion, and data abstraction was good (range, 0.56-0.74

on 20 different measures). The reasons

for article exclusion were the study’s follow-up was less than 1 year, reporting

of renal outcomes was unclear, selection of population for follow-up was

nonrepresentative, 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 been

described 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 abstracted

data. 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, we

found occasional ambiguity about the reported cause of HUS. Exclusion of 9

studies with such ambiguity from our

analyses 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 was

1 to 22 years. The studies were conducted between 1950 and 2001 (TABLE 1,

TABLE 2, and FIGURE 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 not

appreciably 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 infusions50,51 with the remaining being case-series and cohort

studies. (We considered nonrandomized trials with historical control groups

to be cohort studies [Table 1].) Excluding the 3 clinical trials from this review did not change the main study results.When assessing quality, 43% were

prospective, 73% described consecutive HUS patients at an institution, 56%

defined cutoff values for the diagnosis

of 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% used

clear methods for defining and reporting renal outcomes, and 47% measured all patients at the same follow-up time or used statistical methods

that 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 less

than 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 of

these were defined and measured in different ways in the primary studies. Different definitions of proteinuria used in

the primary studies included a random

urine 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/m2 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,9,41with 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 1.73m2

),

LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

1362 JAMA, September 10, 2003—Vol 290, No. 10 (Reprinted) ©2003 American Medical Association. All rights reserved.

Downloaded from www.jama.com by guest on September 15, 2009 
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

©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, September 10, 2003—Vol 290, No. 10 1363

Downloaded from www.jama.com by guest on September 15, 2009 
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 m2

,

Hypertension,

or Proteinuria, %†

Hypertension,

%†

Proteinuria,

%†

GFR, mL/min

per 1.73 m2

, %†

60-80 30-59 5-29

Gagnadoux et al25 15 (10-25) 35 25 38 37 21 11 8 8 0

Gianantonio et al22 3 (1-8) 19 22 73 58 15 25 18 33 4

Janssen et al19 3 (0.2-12) 10 15 15 27 7 13 . . . . . . . . .

Dolislager and Tune26 4 (1-12) 4 7 40 8 5 8 5 0 0

Donckerwolcke et al27 1 3 21 55 . . . 11 7 . . . . . . . . .

de Jong et al20 10 5 19 73 . . . 14 6 4 4 1

McLean et al28 2 0 10 9 0 0 0 0 0 0

Fitzpatrick et al29 8 (5-21) 7 8 88 39 3 31 13 5 1

Riella et al30 3 (0.4-7) 0 6 17 6 6 . . . 0 6 0

Blahova et al31 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 al33 13 (10-20) 59 4 114 35 15 35 10 5 4

Cordero et al34 22 45 8 73 . . . 3 . . . . . . . . . . . .

Donckerwolcke et al35 1 2 16 40 23 10 . . . . . . . . . . . .

Kelles et al36 10 5 11 80 35 11 8 . . . . . . . . .

Gusmano et al37 1 (0.5-11) 3 11 79 10 . . . 4 5 3 3

Coad et al38 1 0 18 61 18 8 8 0 10 0

Siegler et al39 4 (0.3-17) 52 5 115 43 11 17 17 . . . . . .

Gillor et al21 1 0 29 22 23 23 . . . . . . . . . . . .

Tonshoff et al23 2 (1-17) 15 30 67 52 . . . . . . 12 . . . . . .

Campos et al17 3 (0.5-7) 0 12 23 13 9 . . . 4 0 4

Sheth et al40 . . . (1-13) 0 14 37 . . . . . . . . . . . . . . . . . .

Hughes et al41 4 (0.3-14) 16 13 59 25 7 10 . . . . . . 2

Zurowska et al42 11 (2-27) 24 28 94 64 18 21 18 4 3

Monnens et al18 2 0 0 33 . . . 24 24 3 3 3

Diekmann43 2 (1-6) 8 27 17 35 6 38 . . . . . . . . .

Wende-Fischer et al10 5 (4-13) 30 28 26 38 19 12 . . . . . . . . .

Imoberdorf et al44 1 17 19 27 22 7 15 . . . . . . . . .

O’Brien et al6 6 (1-15) 36 13 23 4 0 4 0 0 0

Vermylen et al45 . . . (0.5-7) 4 0 51 2 0 2 0 0 0

Loirat et al46 1 17 6 113 33 . . . . . . . . . . . . . . .

Huseman et al9 5 (2-13) 13 12 123 20 . . . . . . 11 2 . . .

O’Regan et al7 7 (5-11) 26 . . . 37 62 0 19 27 30 0

Loirat et al47 2 (1-4) 0 9 30 7 7 27 3 3 0

Mizusawa et al48 5 (3-16) 7 5 49 8 6 8 0 8 0

Guyot et al49 2 (0.6-5) 5 11 31 16 10 6 3 0 0

Rizzoni et al50 2 (. . .) 0 0 32 . . . 6 6 . . . . . . . . .

Loirat et al51 1 13 10 61 . . . 10 20 . . . . . . . . .

Al-Eisa and Al-Hajeri52 5 (1-15) 0 21 11 18 18 18 0 0 18

Miyazaki53 3 (1-5) 4 10 105 7 6 7 . . . . . . . . .

Small et al5 1 18 4 92 42 16 22 21 5 1

Brichard et al54 3 (0.7-4) 0 0 33 6 0 6 0 0 0

Ramos et al55 5 (0.5-11) 0 6 16 6 0 . . . 6 0 0

Ogborn et al12 4 0 14 18 17 17 0 0 0 0

Brandt et al8 2 (1-3) 16 5 29 21 3 17 0 0 0

Litalien et al24 1 26 3 27 30 . . . 33 7 19 0

Henning et al56 2 0 5 19 26 26 26 11 16 0

Yoshioka et al57 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 m2

, hypertension, and proteinuria are presented in the “Methods” section.

LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

1364 JAMA, September 10, 2003—Vol 290, No. 10 (Reprinted) ©2003 American Medical Association. All rights reserved.

Downloaded from www.jama.com by guest on September 15, 2009 
Figure 1. Proportion of Patients With Sequelae From Diarrhea-Associated Hemolytic Uremic Syndrome

Incidence, %

0 10 20 30 40 50 60 70 80

Incidence, %

1962 Dolislager and Tune,26 1978

Donckerwolcke et al,27 1979

de Jong and Monnens,20 1988

McLean et al,28 1966

Fitzpatrick et al,29 1991

Riella et al,30 1976

Blahova et al,31 2002

Sorrenti and Lewy,32 1978

Spizzirri et al,33 1997

Cordero et al,34 1990

1970 Donckerwolcke et al,35 1973

Kelles et al,36 1994

Gusmano et al,37 1987

Coad et al,38 1991

Siegler et al,39 1996

Gillor et al,21 1986

Tonshoff et al,23 1994

Campos et al,17 1982

Sheth et al,40 1988

Hughes et al,41 1991

Zurowska et al,42 2000

Monnens et al,18 1978

Diekmann,43 1980

Wende-Fischer et al,10 1996

Imoberdorf et al,44 1993

O’Brien et al,6 1994

1975 Vermylen et al,45 1988

Loirat et al,46 1993

Huseman et al,9 1999

O’Regan et al,7 1989

Loirat et al,47 1984

Mizusawa et al,48 1996

1980 Guyot et al,49 1986

Rizzoni et al,50 1988

Loirat et al,51 1988

1985 Al-Eisa and Al-Hajeri,52 2001

Miyazaki,53 1994

Small et al,5 1999

Brichard et al,54 1993

Ramos et al,55 2001

1991 Ogborn et al,12 1998

Brandt et al,8 1998

Litalien et al,24 1999

Henning et al,56 1998

Yoshioka et al,57 1999

2000 Salvadori et al,58 2003

0 10 20 30 40 50

Overall Pooled Estimate

1950 Gagnadoux et al,25 1996

Gianantonio et al,22 1968

Janssen et al,19 1974

First Year of Study

Recruitment Source

GFR <80 mL/min per 1.73 m2 Death or Permanent ESRD , Hypertension, or Proteinuria

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

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 m2

, 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 the various

study definitions for a GFR lower than 80 mL/min per 1.73 m2

, hypertension, and proteinuria are presented in the “Methods” section.

LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, September 10, 2003—Vol 290, No. 10 1365

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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 be

expected by chance (significant heterogeneity, P.001). Given the large between-study variability with wide

ranging heterogeneity (Figure 1), mathematically pooled results should be interpreted with caution. However such results are provided because they represent

current best evidencefor clinical care and

guide 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 permanent

ESRD had an assessment of renal function. Renal sequelae ranged from 0% to

64% (Table 3 and Figure 1). The majority of studies did not differentiate

whether these were persistent findings

after 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 m2

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 increased

severity of acute illness (greater infection or host response) and worse longterm prognosis, including an elevated

white blood cell count higher than

20103

/μL with neutrophilia,29,38 a high

serum 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 anemia

and thrombocytopenia were inconsistently associated with both worse8 and

improved38 outcomes. Compared with

patients with oliguria of 8 days or less

(an approximate urine output less than

300 mL/m2 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 worsening

of 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 microangiopathy

demonstrated a worse prognosis compared with patients with isolated glomerular lesions.23,25,46 In patients with

isolated glomerular lesions, those with

more 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

protein53 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 dialysis10,42 were associated with better prognosis. Better outcomes were not

consistently achieved with streptokinase18,43 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 permanent

ESRD, explaining 44% of the betweenstudy variability (P=.01; FIGURE 2).

Similarly, studies with a higher proportion of patients requiring acute dialysis had a higher proportion of patients who died or developed permanent

ESRD, 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 m2

,

Hypertension,

or Proteinuria Hypertension Proteinuria

GFR, mL/min per 1.73 m2

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 m2

, hypertension, and proteinuria are presented in the “Methods” section.

LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

1366 JAMA, September 10, 2003—Vol 290, No. 10 (Reprinted) ©2003 American Medical Association. All rights reserved.

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term renal sequelae, explaining 15% of

the between study variability (P.001;

FIGURE 3).

Study level factors such as a higher

proportion 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 renal

function 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 patients

with renal sequelae at follow-up. In univariate but not multivariate analyses,

studies with a longer follow-up time

demonstrated 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-up

demonstrated a higher proportion of patients with long-term renal sequelae, explaining 28% of the between-study variability (P=.001; FIGURE 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;

FIGURE 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 urine

output, no dialysis) demonstrated hypertension and proteinuria at longterm follow-up.25 Similarly 5 of 18 patients with acute diarrhea-associated HUS

and 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 the

acute 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 (assessed

either by a normal serum creatinine concentration7 or a calculated33 or measured GFR 80 mL/min per 1.73 m2

)5,9

went on to develop a GFR lower than 80

mL/min per 1.73m2

, hypertension, or

proteinuria 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 develop

renal 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 who

recovered 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 40 60 80 100

Patients With Acute Central

Nervous System Symptoms, %

Patients Who Died or Developed

Permanent 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 40 60 80 100

Patients Receiving Acute Dialysis, %

Death or Permanent ESRD

Patients, %

30

20

10

40

50

60

70

0

0 20 40 60 80 100

Patients Receiving Acute Dialysis, %

GFR <80 mL/min per 1.73 m2,

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 m2

, 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.

LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, September 10, 2003—Vol 290, No. 10 1367

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COMMENT

Studies of diarrhea-associated HUS are

highly 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-associated

HUS 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 demonstrated

long-term renal sequelae. Our mathematical pooled estimates based on existing studies suggest an average of 4

years after experiencing diarrheaassociated HUS, 9% of patients die

(most during the acute phase of illness),

an additional 3% develop permanent

ESRD, 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 due

to 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 full

renal 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 1.73m2

over the first year9,10). Thus it seems prudent to screen patients at least once for

silent 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 1.73m2 after recovery is an

inadequate screening test. However,

those who demonstrate a predicted creatinine clearance higher than 80 mL/

min per 1.73m2

, 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 HUS

can lead to a critical reduction in nephron number, with unsustainable remnant single-nephron hyperfiltration62

and progressive renal disease.63 However, these results confirm that the relationship between longer follow-up

time and worse prognosis is in part

complicated 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 typically

healthier than those followed up. Further prognostic studies should adhere

to the methodological quality criteria

outlined in this review, and particularly should strive for less than 10% of

patients lost to follow-up. Different definitions for surrogate outcomes of proteinuria, low GFR, and hypertension

performed at different follow-up times

complicate 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, with

specified cutoff levels that have been associated with death or ESRD in prospective studies of children,64 would be

advantageous. Further characterization of prognostic factors and novel

methods of screening patients after

diarrhea-associated HUS, although

critical for clarifying pathophysiology,6,9,65,66 may prove difficult to apply

clinically. 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 40 60 80 100

Patients Lost to Follow-up, %

Patients Who Demonstrated

Renal 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 patients

in 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 40 60 80 100

Patients Receiving Acute Plasma

Infusion or Exchange, %

Death or Permanent ESRD

Patients, %

30

20

10

40

50

60

70

0

0 20 40 60 80 100

Patients Receiving Acute Plasma

Infusion or Exchange, %

GFR <80 mL/min per 1.73 m2,

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 m2

, 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

LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

1368 JAMA, September 10, 2003—Vol 290, No. 10 (Reprinted) ©2003 American Medical Association. All rights reserved.

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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 that

long-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 of

antibiotics and antimotility agents during gastroenteritis69,70 and the role of protective antibodies71 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 thrombolytics

during the acute phase of diarrheaassociated HUS are not clearly effective.47,73 Careful blood pressure control

and 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 required

for 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 is

plasma exchange. Sixteen studies included in this review described a portion of patients treated with infusion

or exchange. However smaller and

possibly underpowered trials of plasma

have not shown efficacy in diarrheaassociated HUS.49,50 These metaregression results of the potential benefits of plasma areintriguing, recognizing

their interpretation is complicated by

their 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 with

larger efficacy are more likely to be reported) may also exist.

In summary, death or ESRD occurs

in 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 need

for 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 Pediatric

Nephrology (Drs Garg, Suri, Rehman, Matsell, RosasArellano, Haynes, and Clark) and Pediatric Infectious

Diseases (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 supported

by 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, and

Deborah 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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LONG-TERM RENAL PROGNOSIS OF DIARRHEA-ASSOCIATED HUS

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