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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
BRIEF COMMUNICATION  
Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1376-1387
Postdiarrheal hemolytic uremic syndrome in Egyptian children: An 11-year single-center experience


1 Pediatric Nephrology Unit, Mansoura University Children’s Hospital, Mansoura, Egypt
2 Nora Center for Pediatric Kidney Diseases and Kidney Transplantation, Soba University Hospital, Khartoum, Sudan

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Date of Web Publication29-Jan-2021
 

   Abstract 


Hemolytic-uremic syndrome (HUS) is a leading cause of childhood acute kidney injury (AKI) worldwide, with its postdiarrheal (D+HUS) form being the most common. Scarce data are available regarding D+HUS epidemiology from developing countries. This study aims to reveal the characterization of D+ HUS in Egyptian children. This is a retrospective study of all children with D+HUS admitted to a tertiary pediatric hospital in Egypt between 2007 and 2017. The study included epidemiological, clinical and laboratory data; management details; and outcomes. A cohort of 132 children aged 4months to 12 years was analyzed. Yearly incidence peaked in 2017, and spring showed the highest peak. All cases had a diarrheal prodrome that was bloody in 83% of the cases. Edema and decreased urine output were the most frequent presentations (50.3% and 42.4%, respectively). Escherichia coli was detected in 56 cases. Dialysis was performed in 102 cases. Eight patients died during acute illness, while five patients experienced long-term sequels. Lactate dehydrogenase (LDH) positively correlated with serum creatinine and negatively correlated with reticulocytic count. Univariate analysis showed that longer anuria duration, short duration between diarrheal illness and development of AKI (P = 0.001), leukocyte count above 20 × 109 cells/L (P ≤ 0.001), platelet count below 30 × 109 cells/L (P = 0.02), high LDH levels (P = 0.02) and hematocrit above 30% (P = 0.0001), need for dialysis (P = 0.03), and neurological involvement (P ≤ 0.001) were associated with unfavorable outcomes. This is the first report with a detailed insight into the epidemiology of D+HUS in Egyptian children. The incidence of D+HUS is increasing in our country due to increased awareness of the disease and the poor public health measures. Anuria duration, leukocyte count, and neurological involvement are predictors of poor outcome in the current work, and LDH is introduced as a marker of disease severity.

How to cite this article:
Eid R, Bakr A, Elmougy A, Zedan MM, Allam NA, Sarhan A, Hammad A, El-Refaey AM, Hamdy N. Postdiarrheal hemolytic uremic syndrome in Egyptian children: An 11-year single-center experience. Saudi J Kidney Dis Transpl 2020;31:1376-87

How to cite this URL:
Eid R, Bakr A, Elmougy A, Zedan MM, Allam NA, Sarhan A, Hammad A, El-Refaey AM, Hamdy N. Postdiarrheal hemolytic uremic syndrome in Egyptian children: An 11-year single-center experience. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Mar 2];31:1376-87. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1376/308349



   Introduction Top


Hemolytic-uremic syndrome (HUS) is a triad of thrombocytopenia, microangiopathichemo-lytic anemia, and acute kidney injury (AKI).[1] HUS leads to thickening of the arterioles and capillaries, endothelial swelling and detachment, thrombosis, and obstruction of the lumina of blood vessels in different organs.[2] HUS is usually classified in relation to the preceding diarrheal prodrome into diarrhea-positive HUS (D+HUS) equivalent to typical HUS and diarrhea-negative HUS (D-HUS) equivalent to atypical HUS (a-HUS). However, it was later identified that diarrhea cannot be the only factor differentiating D+HUS and a-HUS because diarrhea was reported to be the triggering factor in up to 30% of the cases of a-HUS.[3] Shiga toxin-producing Escherichia coli (STEC) is the most commonly reported cause of D+HUS. STEC O157:H7 has been the predominant strain for long time, however other serotypes are increasingly reported,[4],[5] and the term “STEC-HUS” has become the most accepted term for HUS secondary to infection with STEC[6] and represents 85%–90% of all childhood HUS.[7] HUS is the leading cause of childhood AKI in different countries, with its incidence being variably reported.[8],[9],[10] Extrarenal involvement occurs in approximately 20% of cases with STEC-HUS and is associated with higher mortality rates. Supportive measures are the main management for STEC-HUS, with about two-thirds of the D+HUS children needing renal replacement therapy.[11] STEC-HUS generally has a good prognosis, with 95% of the children recovering from the acute phase, however long-term renal sequelae have been reported with a mortality rate of 3%–5%, emphasizing the need for longterm follow-up for all D+HUS even those who recovered completely from the acute stage.[9],[12] Data regarding the epidemiology and outcome of D+HUS in children from developing countries are scarce, hence this study was conducted as the first study to report the detailed clinical, laboratory, and outcome characteristics of children with D+HUS in Egypt.


   Subjects and Methods Top


Study design

We conducted a retrospective study of children aged below18 years diagnosed with D+HUS in Mansoura University Children’s hospital, Egypt, from January 2007 to December 2017.

Inclusion criteria

D+ HUS was diagnosed with a prodrome of gastroenteritis with or without bloody stools followed by the presence of all of the following three findings: platelet count of <150,000/mm3, hemoglobin levels lower than the age-specific normal range and/or evidence of hemolysis [the presence of schistocytes, above-normal corrected reticulocytic count, above-normal serum lactate dehydrogenase levels (LDH)], and signs of AKI (serum creatinine above the age-specific normal range, microscopic hematuria, or a urinary protein-to-creatinine ratio above the age-specific normal limit). Hypertension was defined as average systolic blood pressure and/or diastolic blood pressure that is greater than the 95th percentile for sex, age, and height on three or more occasions. Hematuria was defined as ≥5 red blood cells/high-power field. Oliguria was defined by a urine output of <0.5 mL/kg/h in children <30 kg and <400 mL/day in children >30 kg during the first day of admission.

Estimated glomerular filtration rate was calculated by the original Schwartz formula.[13] Reticulocytic count was corrected for patients’ normal hematocrit for age. Unfortunately, specific tests for E. coli O157:H7 and Shiga toxin were not available in our country. To make the data consistent with past published data and more clinically useful, we present data using a cutoff of 20 × 109 cells/L for white blood cell (WBC) count, 30 × 109 cells/L for platelet count, and 30% for the hematocrit level. Renal biopsy was done in three cases: two of them due to persistent high serum creatinine for more than three months after disease onset, while the 3rd case was biopsied due to persistent non-nephrotic range proteinuria at 12 months after disease onset.

Patients were classified as having unfavorable outcome if they died during or after acute illness or if developed chronic renal failure or needed long-term therapies. While favorable outcome is defined as normal blood pressure, absence of proteinuria, and normal kidney functions. Patients who recovered completely and did not require dialysis were followed up for two years, while those dialyzed were followed up for five years. Chronic kidney disease (CKD) patients are on ongoing follow-up.


   Statistical Analysis Top


Data were analyzed with IBM SPSS Statistics for Windows version 25.0 (IBM Corp., Armonk, NY, USA). Qualitative data were described using number and percent. Association between categorical variables was tested using Chi-square test. P <0.05 was considered significant. We used univariate analysis to examine associations between each variable and patients’ outcome, followed by multivariable regression, including all single variables associated with unfavorable outcomes (P <0.05).


   Results Top


In an 11-year period, 132 cases of D+HUS were identified. Patients’ age ranged 4 to 148 months at diagnosis, with 50% of the patients aged one to three years. Seventy patients were female (53%), consanguinity was reported in 34 patients, and had a family history of HUS in a brother and a sister with their parents suffering bloody diarrhea at the same time but did not progress to HUS. Dairy products (mainly cow milk) and water were the most possible (by patients’ history) but not confirmed source of exposures. Spring season showed the highest number of cases (45.5%) followed by summer (24.2%) and April also had the highest number of cases (29 cases). Over 11 years, 2017 had the highest incidence with 20 cases [Figure 1]. All children had diarrheal prodrome with an interval ranging from five to 22 days between diarrhea onset and AKI diagnosis, and diarrhea was bloody in 110 cases. Fifty-five patients received antimicrobials during the diarrheal episode. All children had normal weight and height for age at the time of presentation and were previously healthy with no history of any chronic illnesses. Generalized edema was the most frequent presenting symptom (50.3%) followed by decreased urine output (42.4%). Central nervous system (CNS) manifestations were documented in eight cases at presentation and three patients during hospital stay including disturbed conscious level and convulsions. Hypertension was documented only in six cases. Ninety-eight patients were anuric at presentation, with anuria duration ranging five to 35 days (calculated in 90 patients who survived). Heart failure was reported in two cases and ventricular tachycardia in one case, while no long-term cardiac complications were reported.
Figure 1: Yearly distribution of cases and their management.

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Laboratory data for patients are presented in [Table 1]. E. coli was detected in 56 cases in stool cultures. Coombs’ test was negative in all patients, and only 29 patients showed hematocrit above 30% at the time of presentation. LDH levels are available only for 83 cases as it was not part of our laboratory workup before2013. [Figure 2] shows a positive correlation between creatinine and LDH and negative correlation between creatinine and corrected reticulocytic count. Peripheral blood film showed schistocytes in 120 patients. Biopsies of the two cases with persistent high creatinine showed diffuse glomerulosclerosis, while the 3rd case showed focal segmental glomerulosclerosis.
Figure 2: Scatter plot for creatinine against corrected reticulocytic count and LDH.
LDH: Lactate dehydrogenase.


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Table 1: Laboratory data of the studied patients.

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Conservative treatment included controlling blood pressure and correcting anemia, fluid, and electrolyte disturbances. All patients required blood transfusion at least once. Dialysis was initiated in 102 patients, out of them, 92 patients stopped dialysis after a duration ranging six to 37 days, while eight patients passed away and two patients developed ESRD and are still on dialysis so far. Volume overload was the most frequent indication for dialysis (92 patients) followed by uremic manifestations in six patients and intractable acidosis and hyperkalemia each in two patients. Hemodialysis (HD) was used in 53 patients, peritoneal dialysis (PD) in 45 patients, while four patients received both PD and HD due to failure of one modality. None of our patients received plasma transfusion or plasmapheresis. Hyperglycemia was reported in six patients and all were treated by PD, managed by insulin therapy, and recovered completely after stopping PD. Peritonitis was reported in two patients on PD, while catheter-related infection was reported only in one patient on HD. Two cases developed heart failure due to volume overload and one case developed ventricular tachycardia due to hyperkalemia. No antibiotics were given to the patients after admission except for those who developed peritonitis, catheter infection, or sepsis. Complete recovery was reported in 119 patients, and volume overload was the cause of death in five out of eight mortalities, two cases died because of sepsis, and one case by CNS hemorrhage with uncontrolled seizures. The hospital stay ranged from two to 72 days. Out of 119 completely recovered patients, 22 cases lost to follow-up before completing the scheduled follow-up period (2–5 years). No long-term CNS, cardiac, or gastrointestinal sequels were reported in all the survived patients. Univariate analysis showed that anuria duration, WBC count above 20 × 109 cells/L, platelet count below 30 × 109 cells/L, high LDH levels and hematocrit above 30% at presentation, short interval between diarrhea and AKI presentation, and neurological involvement were associated with unfavorable outcomes [Table 2], however no significant difference was found as a result of logistic regression when we tested significant factors of univariate analysis.
Table 2: Favorable and unfavorable outcomes associated variables in the studied patients.

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   Discussion Top


This study presents an 11 years’ experience with D+HUS from one of the largest pediatric nephrology centers in Egypt. In the current work, there was a slight female predominance, as sometimes[14],[15] but not always[16],[17] reported and the majority cases were aged below five years, which is consistent with that of many published studies[5],[14],[18],[19] [Table 3] except for the higher age reported in the Turkish outbreak in 2011.[20] There is a pattern of decreased incidence of STEC-HUS in older children, which may be explained by either increased anti-stx antibodies in adults[21] or a different expression of the stx receptors in the glomeruli in children.[22] In the current study, a whole family was reported to have bloody diarrhea at the same time, with two kids progressing to HUS. A similar incident was reported in Saudi Arabia[23] and Kuwait.[10] This is explained by the common source of infection or possible person-to-person transmission. However, as not all the affected family members developed HUS, this highlights the fact that the pathogenesis of HUS is affected by individual host factors such as age, sex, and genetic predisposition. Cow milk and water were the most probable sources of infection in the current study unlike other reports, in which consumption of undercooked ground beef or contact with a person with diarrhea were the major risk factors.[24]
Table 3: Comparison of the current study versus some published studies.

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There was an increase in the annual incidence of D+HUS during the 11-year observation period, as documented by the overall trend [Figure 1], although no epidemic was recorded. It could be argued that this is due to increased awareness of pediatricians regarding HUS. In the current study, 62% of the cases were reported in warm months. The seasonal predilection of D+HUS for these months is reported in many studies.[5],[17],[18],[19] Cattles, the major STEC reservoir, usually present a seasonal pattern of shedding, with an increase in warm weather.[25] The diarrheal prodrome is not always bloody in STEC-HUS. Diarrhea is almost always non-bloody at first and then it becomes bloody between one and five days after its onset in up to 80% of patients.[6] The reported number of bloody diarrhea is variable[5],[19] [Table 3]. This variability may be due to differences in pathogenic strains reported. In the current study, the interval between diarrhea onset and AKI presentation ranged from five to 22 days with a shorter interval associated with poor outcomes [Table 2]. This is consistent with that of many reports,[17],[19],[20] however Malla et al reported poor outcomes associated with duration of illness of more than 14 days before the onset of AKI.[26]

In the current study, antimicrobials received during diarrheal attack was one of the factors associated with unfavorable outcomes [Table 2]. Antibiotics might increase the risk of HUS by the release of Shiga toxin after injury of bacterial membranes.[9] The only antibiotics that showed some benefits regarding D+HUS cases are azithromycin used in the outbreak in Germany[27] and fosfomycin which resulted in a significantly decreased risk of HUS development when given to children with STEC infection.[28] Conflicting reports may be related to different strains, the class of antibiotic, and the time and duration of the antibiotic therapy.

LDH levels are not diagnostic for HUS but are used mainly in follow-up. LDH levels in our cohort are higher than that reported by Kawasaki et al;[29] and was one of the factors associated with unfavorable outcome, which was also previously reported.[20],[29] LDH is elevated in HUS mainly due to systemic microvascular involvement, rather than hemolysis.[30] A positive correlation between creatinine and LDH levels in the current work may be an indicator for severe disease. Corrected reticulocytic count was low in some patients despite evidenced hemolysis and a negative correlation between creatinine and corrected reticulocytic count, supporting the possibility of bone marrow suppression by uremia.[31]

In the current work, hyperglycemia was reported in six patients and all of them were undergoing PD. All patients were treated with insulin therapy and recovered totally after stopping PD, so hyperglycemia was related to PD not HUS. Diabetes mellitus (DM) incidence is variably reported in HUS cases.[9],[32] A systematic review in 2005 reported the incidence of DM during acute D+HUS in children to be 0%–15%.[33] Frequent monitoring of blood glucose during acute D+HUS is a must, especially for patients on PD. CNS involvement is common in acute childhood HUS and in the reported series, 17%–24% of the patients had developed seizures and 7%–40% developed coma,[18],[34],[35] which is much higher than that of our study (8.3%), which may be explained by the early initiation of dialysis and the frequent use of HD, which is associated with rapid correction of electrolyte and acid-base disturbances, hypertension, and uremia than PD. In the current study, no longterm cardiac complications were reported in the survived patients, while Lynn et al and Milford et al reported cardiomyopathy in1% and 2% of the HUS cases, respectively.[32]

There is no evidence that early dialysis affects clinical outcomes in children with D+HUS. As a result, the indications for dialysis in children with HUS are similar to those in children with other forms of AKI. In the current work, dialysis was required in 77% of patients, which is consistent with the findings of Ekinciet al study[19] but much higher than that of other reports.[14],[18],[29] In the current study, peritonitis was reported only in two cases, while Zambrano et al reported peritonitis in 11% of the studied cases.[14] In the current work, anuria duration calculated in 90 patients who survived was five to 35 days, while Schifferli et al reported anuria duration of eight (1–31) days.[36] Anuria at presentation and duration of anuria are among the most critical determinants of the outcome of D+HUS cases, however the exact duration of anuria that is associated with unfavorable outcomes is variably reported. Malla et al reported that mortality was 91% and 100% with anuria >3 to eight days and >8 days, respectively.[26] Other researchers used duration of oliguria and anuria to classify the severity of HUS and renal damage.[37] The mortality from D+HUS has fallen from 100% to <10% in the developed world. However, high mortality rates were also reported.[17],[26] Findings of Zhao et al were consistent with those of our results and reported pulmonary edema and multiorgan failure as the most common causes of D+HUS-related mortality.[42] In the current study, three patients developed CKD and two cases developed ESRD. HUS accounts for 3.6% of CKD cases in Egyptian children.[43]

WBC count above 20000× 109 cells/L and CNS involvement were the most associated unfavorable outcomes. This is consistent with those of most published studies.[17],[20],[23],[42] Leukocytosis in part reflects neutrophil activation resulting from monocyte release of the neutrophil chemoattractant interleukin 8; these neutrophils may then contribute to tissue damage. In in vitro experiments, stx binds to leukocytes and is transferred by them to endothelial cells.[42] Accordingly, stx also has been detected on the surface of circulating leukocytes of patients with HUS,[44] and in a murine HUS model, stx2 induced neutrophilia and neutrophil activation.[45] Hematocrit levels above 30% were associated with poor outcome, which may be explained by a widespread thrombotic microangiopathy that severely occludes microvascular flow, minimizing red blood cell fragmentation, reflecting a more fulminant insult.[46] Strikingly, all the 29 patients with high hematocrit levels required dialysis. Hematocrit is a measure of hydration status. It has been postulated that renal hypo-perfusion during the STEC infection phase increases the risk of HUS and that volume expansion before HUS evolves may diminish its occurrence or severity. In 2017, a systematic review provided evidence supporting the benefit of vigorous fluid repletion during the diarrheal phase of STEC infection to prevent or reduce the severity of HUS.[47] Higher LDH levels were reported in patients with unfavorable outcomes, which is scarcely reported previously as a risk factor for poor outcomes.[20],[29] Hypertension was reported in only six cases, which is much less than some reports by Milford et al;[32] and Lynn et al.[9] Hypertension was one of the variables associated with poor outcome, which is consistent with other reports.[14],[48] In the current study, age of patients (above and below 5 years), sex, and bloody versus non-bloody diarrhea showed no difference in the outcomes, while Jha et al reported significantly higher mortality in females,[17] Malla et al reported age below 18 months and above five years to be associated with poor outcomes[26] and Mody et al reported that all patients without bloody stools survived.[20]

Focal segmental glomerulosclerosis, diffuse mesangial proliferative glomerulonephritis, diffuse glomerulosclerosis, and minimal glomerular changes are the most frequent reported pathological findings following D+HUS.[37] Hyperfiltration injury of the remaining nephrons after acute HUS is a possible mechanism of deterioration of kidney function after initial recovery and development of different reported pathologies.[8]

Fully recovered patients are discharged home when they restore normal urine output, stopped dialysis for at least one week, and dialysis access was safely removed with stable hemoglobin and platelet count and fully active orally feeding and instructed to avoid household transmission of STEC. STEC continues to shed from the bowel of an infected individual up to one month after the resolution of symptoms, under-pinning the need for meticulous infection control and source isolation. In the UK, children aged under five years must not return to nursery/school until they have two negative stool cultures 24 h apart, while children older than 5 years must have 48 h of normal stool prior to returning to school.[49]

Points of strength of the current work lie in the fact that this is the first study that discusses the epidemiology, management experience, and outcome in a large number of Egyptian children with D+ HUS. The limitations of the current work lie in the fact that this is a singlecenter study and non-availability of specific microbiological and genetic studies for STEC and tests for detection of Shiga toxin.


   Conclusion Top


Despite the limitations, this is the first study on childhood D+HUS in Egypt establishing robust clinical, epidemiological, and outcome data. Anuria, leukocyte count above 20 × 109 cells/L, platelet count below 30 × 109 cells/L, LDH levels and hematocrit above 30% at presentation, short interval between diarrhea and AKI presentation, need for dialysis, and neurological involvement were associated with unfavorable outcomes. Finally, this study emphasizes the need for long-term follow-up to identify children at risk for long-term sequelae after initial apparent complete recovery of acute disease.


   Acknowledgments Top


The authors would like to thank Prof. Fatma El-hussieny Moustafa for pathological analysis of patients’ biopsies and Dr. Aya Ahmed Fathy for revising statistical analysis of the data.


   Ethics Approval Top


This study was reviewed and approved by Mansoura Faculty of Medicine Institutional Research Board (R.18.02.31).


   Consent for Publication Top


Written informed consent was obtained from the parents of the patient for possible use and publications of their data as part of hospital administrative work at the time of admission.


   Prior Publication Top


Part of this research was presented as poster presentation in The World Congress of Nephrology” Melbourne 2019” and only the abstract was published in Kidney International Reports journal.



 
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Correspondence Address:
Riham Eid
Pediatric Nephrology Unit, Mansoura University Children’s Hospital, Mansoura Faculty of Medicine, Mansoura
Egypt
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DOI: 10.4103/1319-2442.308349

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analysis
   Results
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   Acknowledgments
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