|Year : 2018 | Volume
| Issue : 4 | Page : 852-862
|Heat shock protein 60 as a biomarker for acute kidney injury secondary to septic shock in pediatric patients, Egyptian multicenter experience
Mohamed A El-Gamasy1, Akram E El-Sadek2, Ahmed R Fakhreldin3, Ashraf Kamel4, Eman G Elbehery5
1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
2 Department of Pediatrics, Faculty of Medicine, Benha University, Benha, Egypt
3 Department of Pediatrics, Faculty of Medicine, Aswan University, Aswan, Egypt
4 Department of Pediatrics, Faculty of Medicine, Fayum University, Fayum, Egypt
5 Department of Clinical Pathology, Faculty of Medicine, Benha University, Benha, Egypt
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|Date of Submission||23-Jul-2017|
|Date of Decision||30-Aug-2017|
|Date of Acceptance||03-Sep-2017|
|Date of Web Publication||28-Aug-2018|
| Abstract|| |
Acute kidney injury (AKI) is an independent predictor of morbidity and mortality for critically ill children at pediatric Intensive Care Units (PICU). It is proposed that heat shock protein 60 (HSP60) may be either a biomarker or a co-factor of survival in PICU. The aim of this work is to assess plasma levels of HSP60 in critically ill pediatric patients with AKI secondary to septic shock within the first 24 h of admission. This study was carried out on 120 pediatric patients admitted to PICUs of four university hospitals. They were divided into Group 1 included 60 patients meeting the criteria of AKI Network and septic shock, the second group included 60 critically ill patients without AKI or septic shock and the third group was 60 healthy children as controls. HSP60 levels were measured in the plasma using a commercially available ELISA and difference between groups were analyzed with a Kruskal–Wallis one-way ANOVA. P <0.05 was considered significant. There was highly significant increase in plasma levels of HSP60 in Group 1 (median 25.85 ng/mL) compared to both Group 2 (median 6.15 ng/mL) and healthy controls (median 4.35 ng/mL) (P <0.001). At a cut-off value ≥10 ng/mL, HSP60 sensitivity for prediction of cases with AKI secondary to septic shock was 96.67% with specificity 86.67%, positive predictive value 87.9%, negative predictive value 96.3%, AUC 0.993. HSP60 levels are significantly elevated in pediatric patients in Group 1 when compared to Groups 2 and 3. Hence, HSP60 may play a role in the pathogenesis of sepsis in pediatric patients.
|How to cite this article:|
El-Gamasy MA, El-Sadek AE, Fakhreldin AR, Kamel A, Elbehery EG. Heat shock protein 60 as a biomarker for acute kidney injury secondary to septic shock in pediatric patients, Egyptian multicenter experience. Saudi J Kidney Dis Transpl 2018;29:852-62
|How to cite this URL:|
El-Gamasy MA, El-Sadek AE, Fakhreldin AR, Kamel A, Elbehery EG. Heat shock protein 60 as a biomarker for acute kidney injury secondary to septic shock in pediatric patients, Egyptian multicenter experience. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Nov 15];29:852-62. Available from: http://www.sjkdt.org/text.asp?2018/29/4/852/239651
| Introduction|| |
Sepsis is a clinical syndrome complicating severe infection that is characterized by systemic inflammatory response syndrome (SIRS), immune dysregulation, microcirculatory derangements, and end-organ dysfunction.
Critically ill pediatric patients mostly have prerenal causes of acute kidney injury (AKI) due to markedly diminished diastolic blood pressure and low serum albumin levels compared to the general pediatric population. The pathophysiology might be a loss of binding proteins related to protein extravasation from increased vascular permeability following SIRS, decreased synthesis, and hemodilution during active resuscitation.
AKI remains an independent predictor of morbidity and mortality for critically ill children despite advances in the provision of hospitalized care. Management of AKI is directed toward reversing the underlying cause and providing supportive care including avoidance of nephrotoxic medications, normalizing electrolytes and fluid status as well as maintaining hemodynamic stability and kidney perfusion with vasoactive medications and mechanical ventilation. AKI in Pediatric Intensive Care Unit (PICU) may be secondary to severe sepsis or septic shock resulting from renal hypoperfusion due to persistently low blood pressure. Extracellular heat shock protein 60 (HSP60) has been shown to act as potent stimulators of immune responses. When released into the extracellular milieu, HSP60 increases levels of CD4+CD25 cells and suppresses cytotoxic T lymphocytes. Increased cell surface expression of HSP60 serves as a danger signal for the immune system culminating in the stimulation of dendritic cells and, ultimately the induction of T cell-mediated anti-tumor immune responses.
We speculate that the cytoprotective and signaling properties of extracellular HSP60 may play a major role in the host response to sepsis. Accordingly, we hypothesized that increased HSP60 levels could also be detected in the plasma of children with septic shock and may correlate with the outcome as well. HSP 60 levels may increase either during stress or under pathologic conditions such as chronic inflammatory, autoimmune, and cardiovascular diseases. Previously reported studies have linked HSP60 to cardiovascular diseases, diabetes mellitus, stress response, cancer, and certain types of immunological disorders.,
The value of HSP60 as a marker in AKI has recently reported, as HSP 60 is expressed in podocytes, renal tubular cells of outer medulla and macrophages, The unique properties of HSP60s provide an important immunoregulatory function in human kidney whose expression on the inflammatory cell surface results in differentiation of specific regulatory pheno-types of HSP-specific T-lymphocytes (CD4+, CD25+, Th2, Tc1 cells). AKI results in a violation of HSP function, which can lead to a violation of local kidney self-defense mechanisms with resulting progressive tissue damage. Excess HSP60 is indicative of apoptosis of renal cells. HSP has been recently published as urinary bio-markers for AKI resulting from long-standing renal ischemia which may be secondary to septic shock or other causes of renal hypo-perfusion. In experimental toxic renal damage, the HSP60 expression increased in all cortical tubules correlating with the degree of the damage. HSPs are promising targets for the development of new approaches to the diagnosis and treatment of AKI.
The aim of this study was to compare between plasma levels of HSP60 of patients with AKI secondary to septic shock (Group 1) and these in critically ill pediatric patients without AKI or septic shock (Group 2) at PICU of four University hospitals; Tanta, Benha, Fayuom and Aswan University Hospitals to clarify the predictive value of serum levels of HSP60 for diagnosing AKI secondary to septic shock.
| Materials and Methods|| |
Design of the study and setting
This case–controlled study was conducted after approval from the Ethical Committee of the Faculty of Medicine of Tanta, Benha, Fayum and Aswan Universities and informed parental consents from all patients involved in the study, on 120 pediatric patients who were hospitalized at PICUs of Tanta, Benha, Fayum and Aswan University hospitals in the period from July 2016 to July 2017. Their ages ranged from three months to 12 years. They were 70 males and 50 females. The patients were classified into: Group 1 which included 60 pediatric patients with AKI secondary to septic shock. Group 2 which included 60 critically ill pediatric patients without AKI or septic shock. Sixty completely healthy subjects of comparable age and sex were served as controls (Group 3). They were 39 males and 21 females.
Pediatric patients with AKI aged from three months to 12 years with hospital admission more than 24 h. AKI was diagnosed when 0.3 mg/dL or 50% increase in serum creatinine (SCr) of reference range occurred within 48 h according to the AKI Network criteria for SCr. Septic shock was defined as severe sepsis with persistently low blood pressure despite the administration of intravenous fluids. SIRS is the presence of two or more of the following: abnormal body temperature, heart rate, respiratory rate or blood gas, or white blood cell count. Sepsis is defined as SIRS in response to an infectious process. Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction (manifesting as hypotension, elevated lactate, or decreased urine output). Septic shock is severe sepsis plus persistently low blood pressure despite the administration of intravenous fluids. Critical illness is any disease process which causes physiological instability leading to disability or death within minutes or hours, e.g., airway obstruction and other breathing problems; circulatory impairment or shock; severely altered central nervous system function and severe dehydration which requires urgent appropriate care.
Children who have congenital anomalies of kidney or urinary tract, patients transferred from another PICU and patients with chronic kidney diseases. Shock due to other cause not related to sepsis.
All patients and controls were subjected to through history taking (onset of AKI, sepsis or critical illness, duration of hospital admission, need and duration of mechanic ventilation, number of organ system failure and disease outcome), full clinical examination (especially weight and height for age percentiles according to Egyptian growth curves.
We assessed the severity of critical illness in the first 24 h of admission by Pediatric Risk of Mortality score III and the follow up was with the Sequential Organ Failure Assessment score. The routine laboratory tests were: Complete blood count (CBC) by ERMA BC 210, C-reactive protein (CRP) by Adiva Centaur CP/Immunoassay, Prothrombin time (PT) and activity by Sysmex CA 1500, SCr by kinetic assay using Kone Lab Prime 60I), some liver function tests [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] by Kone Lab Prime 60I), and plasma levels of HSP-60.
Samples were withdrawn within 24 h of admission. Seven milliliters of venous blood was drawn under aseptic conditions and distributed as follows:
- One milliliter of whole blood was taken in an EDTA vacutainer (violet cap) and mixed gently. This sample was used to measure CBC which was done for all samples by Sysmex KX-21N
- Three milliliters of blood were taken in citrated test tubes (blue cap), the samples were centrifuged at 1500 rpm for 15 min. The separated plasma was used for the assay of PT, International Normalized Ratio and partial thromboplastin time and HSP60, Plasma level of HSP60: was measured using human enzyme-linked immunosorbent assay (ELISA) (sandwich technique) kits provided by Sunred (Shanghai, China) (catalog No. 201-12-1775), with assay range 0.15–32 ng/mL
- Three milliliters of blood were taken in plain test tubes without anticoagulant (red cap) and left until coagulation. After coagulation, the samples were centrifuged at 1500 rpm for 15 min. The separated serum was used for the assay of ALT and AST and SCr. SCr was evaluated with the BioSystems reagent kit provided by BioSystems S.A. (Barcelona, Spain) by modified Jaffee reaction. Serum urea was determined by the enzymatic colorimetric test, using a Diamond kit, (Diamond Diagnostics, Holliston, USA) and CRP, Quantitative CRP CRP: serum was separated and analyzed using Turbox plus. Results were considered positive above 6 mg/L
- Blood culture: sterile acquisition by veni-puncture of 5 mL–1 mL of blood incubated for 72 h before considered negative.
Test principle for plasma levels of HSP
The kit uses a double-antibody sandwich ELISA to assay the level of human HSP60 in samples. HSP60 was added to monoclonal antibody Enzyme which is precoated with human HSP60 monoclonal antibody, incubation; then, add HSP60 antibodies labeled with biotin, and combined with Streptavidin-horseradish peroxidase to form immune complex; then incubation and washing again to remove the uncombined enzyme. Then Chromogen Solution A, B, were added, the color of the liquid changes into the blue, and at the effect of acid, the color finally becomes yellow. The chroma of color and the concentration of the human substance HSP60 of sample were positively correlated. Samples withdrawn within 24 h of admission.
| Statistical Analysis|| |
Data were fed to the computer and analyzed using IBM Statistical Package for Social Sciences (SPSS) software version 20.0 (IBM Corp., Armonk, NY, USA). Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, standard deviation, and median. Significance of the obtained results was judged at the 5% level.
The used tests were: Chi-square test for categorical variables, to compare between different groups. Fisher's Exact or Monte Carlo correction for correction for Chi-square when more than 20% of the cells have expected count <5. F-test (ANOVA) for normally quantitative variables, to compare between more than two groups, and post hoc test (Least Significant Difference) for pair wise comparisons. Mann–Whitney test for abnormally quantitative variables, to compare between two studied groups. Kruskal–Wallis test for abnormally quantitative variables, to compare between more than two studied groups. Receiver operating characteristic curve (ROC), the area under the ROC curve denotes the diagnostic performance of the test. The area more than 50% gives acceptable performance and area about 100% is the best performance for the test. The ROC curve allows also a comparison of performance between two tests, Kaplan-Meier and Cox regression was done for the significant relation with progression free survival and overall survival.
| Results|| |
[Table 1] summarizes demographic data of the studied groups; there is no statistically significant difference between studied groups as regard age, sex, or weight. [Table 2] shows that there was a highly statistically significance decrease in heart rate, systolic and diastolic blood pressure, and respiratory rate in group 1 than other two groups, while there was highly statistically significance increase in temperature and no statistically significant difference regarding vital signs in Group 2 when compared to Group 3. In our work, we studied some inflammatory markers of septicemia. [Table 3] shows a highly significant increase in TLC in group 1 when compared to other groups (Mean TLC was 19.98 ± 10.39 (1000/mm3) in Group 1 vs. 15.15 ± 6.03 (1000/mm3) in Group 2 vs. 12.71 ± 3.03 (1000/mm3) in Group 3) (P <0.001). There was highly significant decrease in HB, HCT, PLT in group 1 when compared to other groups. No statistically significantly difference between Group 2 and Group 3 regard CBC. [Table 4] shows no statistically significant difference between CRP (as another inflammatory marker of septicemia) in Group 1 when compared to Group 2 (mean CRP was 180.2 ± 77.3 (mg/dL) in Group1 vs. 77.73 ± 66.4 (mg/dL) in Group 2) (P = 0.75). [Table 5] shows highly significant increase in ALT and AST in Group 1 when compared to other groups.
In the present study, blood culture was positive in 46 children and negative in 14 children of Group 1. Klebsiella (14%), pseudomonas (13%), and Actinobacter (9.7%) were the most common organisms (36.7%), staph and strept (13.3%) and MRSA (13.3%), Candida (10%) and no growth (23.3%). While in Group 2 blood cultures were positive in 14 children and negative in 46 children, pseudomonas (7.7%), staph (3.5%), Candida (3.3%), no growth (76.6%). [Table 6] and [Figure 1] show that extracellular HSP60 plasma levels were significantly increased in Group 1 when compared with Group II or Group III (Mean HSP60 was 24.43 ± 5.14 (ng/mL) in Group1 vs. 5.71 ± 1.85 (ng/mL) in Group 2 vs. 4.49 ± 1.24 (ng/mL) in Group 3) (P <0.001). [Table 7] and [Figure 2] compared Receiver of Characteristics (ROC) curves for the validity of plasma levels of CRP and HSP60, respectively in the prediction of AKI secondary to septic shock.
|Table 6: Comparison between the three studied groups according HSP60 plasma levels (ng/mL).|
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|Figure 1: Comparison between the three studied groups according plasma levels of HSP 60.|
HSP60: Heat shock protein 60.
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|Table 7: Comparison between validity of HSP 60 and CRP to predict AKI secondary to septic shock.|
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|Figure 2: ROC curves for validity of CRP and HSP60 to predict patients with AKI secondary to septic shock.|
ROC: Receiver operating characteristic, CRP: C-reactive protein, HSP60: Heat shock protein 60, AKI: Acute kidney injury.
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This study shows that CRP at a cut-off value ≥112. CRP sensitivity for prediction of cases with septic shock was 75% with specificity 70.67%, positive predictive value (PPV) 94.7, negative predictive value (NPV) 25, area under curve (AUC) 0.819so no correlation with septic shock (p = 0.076).
This study shows that, at a cut-off value of >10 ng/mL, HSP60 sensitivity for prediction of cases with AKI secondary to septic shock was 96.67% with specificity 86.67%, PPV 87.9%, NPV 96.3%, AUC 0.993 with high sensitive correlation with AKI secondary to septic shock (P <0.001).
| Discussion|| |
This case–controlled study was performed to evaluate the plasma level of extracellular HSP60 in AKI secondary to septic shock and critically ill patients. The study was conducted on 120 pediatric patients who were divided into two groups: Group 1 of 60 children with AKI secondary to septic shock, Group 2 of 60 children critically ill patient without AKI or sepsis. Ages ranged from three months to 144 months (70 males and 50 females) and 60 healthy age-and sex-matched children as control group, their ages range from three to 112.8 months (39 males and 21 females). In this study, there was no statistically significant difference between studied groups as regard to age, sex, and weight.
Most of the previous studies had shown a predominance of males among patients with sepsis. This is in agreement with our study; we found that the male-to-female ratio among septic group had a predominance of males among patients with sepsis (63.3%) in Group 1 while (53.3%) in Group 2 and (65%) in Group 3.
A number of diagnostic tests can used in assessing pediatric patients suspected of sepsis. In spite of ease, availability, and cheapness of some laboratory indicators, such as CBC, CRP, and immature to total leukocytes (I/T) ratio in neonatal sepsis, they did not appear to have good sensitivity or specificity, especially if measured early in the course of sepsis. The standard method for diagnosing bacterial infection is the culture of body fluids, especially blood, however, bacterial cultures often require up to 72 h before the results are known and cannot identify many causative organisms due to misuse of antibiotics, especially in developing countries like Egypt.
In this study, we studied some inflammatory markers of septicemia. The findings of total leukocytic count (TLC) in Group 1 were significantly increased compared with Group 2 and Group 3, with mean level (1000/mm3) in Group I (19.98 ± 10.39), and Group II (15.15 ± 6.03), whereas in control group (12.71 ± -3.03) and this was concordant with the results of study done by Abou El-Ela et al.
CRP is a globulin that is produced by the hepatocytes in response to tissue injury, trauma, cellular degeneration, and infection. CRP level is normal at the onset and 8 h after infection by invasive bacteria, but becomes apparent within 24 h, peaks within two to three days, and remains elevated till infection is resolved.
In our study, CRP was positive in 80% of Group 1, 10% of Group 2 (critically ill patient) and 0% in Group III (healthy controls). There was a highly significant increase in positive cases in group 1 when compared to Group 2.
In our study, the findings of extracellular HSP60 levels in Group 1 (septic shock) were statistically significantly increased compared with Group 2 (critically ill patient without septic shock) and Group 3 (normal healthy patient), with mean ± SD level in Group 1 (24.43 ± 5.14) ng/mL, and Group 2 (5.71 ± 1.85) ng/mL, whereas in control group (4.49 ± 1.24) ng/mL. This was concordant with the results of Wheeler et al which showed that extracellular HSP60 levels are significantly greater in patients with septic shock compared with critically ill patient without sepsis and non critically ill patient.
This also concordant with the results of Gelain et al which showed that HSP60 and HSP70 levels are significantly greater in their patients with sepsis compared with healthy control patients.
Our study agree with the result of Habich et al, which showed that HSP27, HSP60, HSP70, and HSP90 were significantly increased in patients with sepsis.
Our study disagree with Hashiguchi et al which showed that HSP60 levels are significantly greater in critical ill patients (who exposed to severe trauma) than healthy control patient. They showed that extracellular HSP60 levels are significantly greater in patients with septic shock compared with critically ill patient without sepsis and non-critically ill patient. This also concordant with the result of Gelain et al which showed that HSP60 and HSP 70 levels are significantly greater in patients with sepsis compared with healthy control patients. Our study agrees with the result of Habich et al, which showed that HSP27, HSP60, HSP70, and HSP90 were significantly increased in patients with sepsis.
Our study disagree with Hashiguchi et al which showed that HSP60 levels are significantly greater in critical ill patients (who exposed to severe trauma) than healthy control patient.
This study shows that, at a cut-off value ≥10 ng/mL. HSP60 sensitivity for prediction of cases with AKI secondary to septic shock was 96.67% with specificity 86.67%, positive predictive value (PPV) 87.9%, negative predictive value (NPV) 96.3%, AUC 0.993 with high sensitive correlation with AKI secondary to Septic shock (P <0.001).
Regarding to this point, our results had a promising data than found by Enguix et al, who evaluated procalcitonin (PCT) as a diagnostic marker of bacterial sepsis in critically ill neo-nates and children and who compared results of PCT with those of CRP and serum amyloid A (SAA). Enguix et al, found that admission PCT was significantly higher in neonates and children with sepsis than in the other groups. In the neonates, AUC the ROC curve was 0.99 for PCT, 0.98 for SAA and 0.95 for CRP, while in the children AUC was 1 for PCT, 0.96 for SAA and 0.93 for CRP. Cut-off concentrations for optimum prediction of sepsis in their neonates were for PCT >6.1 ng/mL with diagnostic efficiency 93.8%), CRP >23.0 mg/L with diagnostic efficiency 89.7%, and SAA >41.3 mg/L with diagnostic efficiency 95.3% while in the children they were PCT >8.1 ng/mL with diagnostic efficiency 100%, CRP >22.1 mg/L with diagnostic efficiency 89.8% and SAA >67.2 mg/L with diagnostic efficiency 94.4%.
| Conclusion|| |
Although the blood culture is believed to be the gold standard for establishing the diagnosis of sepsis caused by systemic bacterial infection, it still has disadvantages of low sensitivity and delay in results reporting delay (24–72 h). False-positive results may be secondary to fastidious organisms, contamination of blood cultures by skin microbes such as Coagulase-negative Staphylococcus (CONS) or effects of maternal antibiotic treatment in neonatal sepsis. False-negative results may occur due to small specimen volumes or decrease the sensitivity of blood cultures. CRP has similar disadvantages so there is urge to find more sensitive and more specific biomarker for sepsis. This study concluded that plasma levels of extracellular HSP60 were significantly elevated in children with AKI secondary to septic shock compared to critically ill children without AKI or sepsis or compared to healthy controls. HSP60 had high validity for prediction of cases of AKI with septic shock (sensitivity was 96.67%, specificity was 86.67%, PPV 87.9%, NPV 96.3%, AUC 0.993. So, we could conclude that HSP60 might be playing a role in the pathogenesis of sepsis in children and could be used as diagnostic tool of AKI which occurred with septic shock.
| Recommendations|| |
It is recommended to measure plasma levels of HSP60 as it was proven to be a sensitive marker in diagnosis of AKI in septic shock. However in developing countries like Egypt, the cost remains a limiting factor for wide scale usage of these tests. We suggest further researches on wider scale for the potential physiopathological, diagnostic, prognostic and therapeutic roles of HSP60 in AKI secondary to sepsis in pediatric age.
| Acknowledgment|| |
We would like to thank our colleagues and nurses in PICU of Tanta, Benha, Fayum and Aswan University Hospitals, for our internship and for their wonderful cooperation for the study. We would like to express our gratitude to parents of our studied participants whose understand and help performance of this work.
Conflict of interest: None declared.
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Dr. Mohamed A El-Gamasy
Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Gharbia
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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