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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 2  |  Page : 407-414
Acute kidney injury in dengue among hospitalized children: A prospective view


1 Department of Pediatrics, VMMC and Safdarjung Hospital, New Delhi, India
2 Department of Biochemistry, VMMC and Safdarjung Hospital, New Delhi, India

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Date of Submission13-Oct-2018
Date of Decision04-Dec-2018
Date of Acceptance06-Dec-2018
Date of Web Publication09-May-2020
 

   Abstract 


Dengue viral infection (DVI) has emerged as one of the most common arthropod borne diseases and is more prevalent in the tropical countries. It has varied clinical spectrum ranging from undifferentiated fever to severe hemorrhagic fever and shock with multi-organ dysfunction. Acute kidney injury (AKI) is lesser known complication in DVI. Although studies report varying reports of AKI in DVI among children, exact incidence is not known as most of the studies are retrospective. Hospital-based observational study in 105 children with DVI requiring admission was studied for the occurrence of AKI along with clinical course and outcome. AKI Network (AKIN) criteria were used to define AKI. The IBM SPSS Statistics software version 21.0 was used for the statistical analysis. Of 105 children with dengue, six (5.71%) cases developed AKI. All six cases had urine output <0.5 mL/kg/h for ≥12 h. Out of six cases with AKI, four had raised serum creatinine (SCr) ≥0.3 mg/dL at admission. One child had normal SCr level at admission which got deranged over the next 12 h, one child had oliguria ( <0.5 mL/kg/h) for about 24 h though the renal function was not deranged. Out of six children with AKI, three (50%) in Stage III and three had AKI Stage II as per the AKIN criteria. Children with AKI (Group A) differed significantly from those without AKI (Group B) in having blood pressure <3rd centile (P = 0.0023), tachycardia P = 0.008), hyponatremia and hypokalemia (P <0.001 and P = 0.029, respectively) and poor outcome 6% mortality in Group B compared to 66.67% in Group A) with P = 0.001. AKI is not a common complication of DVI but if develops it may lead to significant morbidity and mortality among pediatric age group.

How to cite this article:
Poddar S, Sharma S, Kaur C, Chellani HK. Acute kidney injury in dengue among hospitalized children: A prospective view. Saudi J Kidney Dis Transpl 2020;31:407-14

How to cite this URL:
Poddar S, Sharma S, Kaur C, Chellani HK. Acute kidney injury in dengue among hospitalized children: A prospective view. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 May 25];31:407-14. Available from: http://www.sjkdt.org/text.asp?2020/31/2/407/284015



   Introduction Top


Dengue viral infection (DVI) is caused by RNA virus from genus Flavivirus and has emerged as one of the most common arthropod borne diseases in the last few decades transmitted by mosquito belonging to Stegomyia family.[1] It is more prevalent in the tropical countries and its incidence has increased by many folds in the last few decades due to population travel epidemiology.[2] Today about 2.5 billion people (40% of the world’s population), live in areas with risk of dengue transmission and children are most vulnerable group with maximum morbidity and mortality.[3][4] It has varied clinical spectrum ranging from undifferentiated fever to severe hemorrhagic fever with shock and multi-organ dysfunction. Acute kidney injury (AKI) is lesser studied’ but serious complication of DVI. AKI implies abrupt (within 48 h) reduction in kidney function defined as either absolute increase in serum creatinine (SCr) by ≥0.3 mg/dL or a percentage increase by ≥50% from baseline or reduction in urine output (less than 0.5 mL/kg/h) for ≥6-12 h.[5] Incidence of AKI in DVI has been found to show wide variation mainly due to the variable study population taken’ time of study and the severity of dengue infection. Moreover’ most of the studies are retrospective in nature. In childhood population’ incidence is reported from 0.9% to 13.4%; however most of the studies are retrospective.[6],[7],[8],[9],[10]As problem of dengue infection is turning into epidemic form’ its complications including AKI is expected to increase accordingly. Therefore’ this study was undertaken with primary objective to know incidence’ presentation’ and outcome of AKI in dengue infection.


   Methods Top


This was hospital-based observational study done at tertiary care center in north India between June 2016 and December 2017 for 18 months and included febrile children with suspected dengue infection from one to 12 years of age presenting in outpatient department or emergency requiring hospitalization in indoor department. Children with known structural/anatomical abnormality of genitourinary system’ children with known chronic kidney disease and those in whom SCr level (baseline value) was not measured at admission’ were excluded from the study. According to a study done by Kuo et al’[11] prevalence of AKI in DVI was 5.5%; therefore, sample size was calculated to be 90 taking confidence level (z) of 95% and 5% margin of error(e) with formula: n = z[2] x p(1 -p) e[2] where n = required sample size, z = confidence level at 95%, p = estimated prevalence of children with SE e = margin of error 5%. All febrile children in the age group of one to 12 years with suspected dengue[4] requiring hospitali- zation were included. Detailed history and examination were done. On admission complete blood count, SCr level, dengue NS1 antigen (if fever <5 days), IgM antibodies against dengue virus (fever ≥5 days) were sent along with other relevant investigations. Monitoring of urine output was done by the measurement of urine volume in toilet trained children, while nontoilet trained/sick children were catheterized under aseptic precautions. Vital parameters [pulse rate, blood pressure (BP), temperature, and respiration] were monitored regularly. After reports of DVI (IgM/ NS1Ag) were received, positive cases were enrolled in the study after taking informed written consent. Those with documented oliguria (UO <0.5 mL/kg/h) or raised SCr with respect to age and gender or both were included in the group of AKI patients with DVI (Group A). In cases where SCr level was normal at admission, its level was monitored every 24 h up to 7th day of fever - if there was elevation in the level of SCr by 0.3 mg/dL in absolute value or ≥50% in respect to baseline value (SCr on day 0 of admission) then they were also included in Group A. Others without any rise in SCr level or documented oliguria were included as DVI cases without AKI (Group B or controls). Both groups followed for clinical presentation, course, and outcome while following the standard treatment protocol. Fluid management was done in both groups according to the standard protocol. Among those who had dengue shock syndrome (DSS), 10 cases required inotrope support also. Three children out of six who had AKI and required inotrope support expired. No nephrotoxic medication was given to them. [Figure 1] shows the flow of study cases. SCr level was measured on fully automated chemistry analyzer (ADVIA 2400) using commercially available kit for the same at Clinical Biochemistry Unit, Department of Biochemistry at Institute. For dengue serology, serum was separated and tested for NS1 Ag by ELISA and for IgM antibody by IgM Antibody Capture ELISA (MAC ELISA) as per the manufacturer’ s instructions. AKI classification was done as per AKI Network (AKIN) criteria (2007).[12]
Figure 1: Flow of study subjects.

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   Statistical Analysis Top


Categorical variables such as age, gender, and clinical presentation were presented in number and percentage (%) and laboratory parameters such as hematocrit, platelet count, total leukocyte count, and serum electrolytes were presented as mean ± standard deviation. Groups with and without AKI were compared using the Chi-square test/Fisher’s exact test. A value of P <0.05 was considered statistically signi-ficant. The data were entered in MS EXCEL spreadsheet, and analysis was performed using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA).


   Results Top


A total of 105 children with laboratory proven dengue was included in the study. The median age of presentation was seven years with minimum age of one year and maximum 12 years. The male-female ratio was 1:1.25. Among dengue patients, 58 (55.24%) had fever for <5 days, whereas 47 (44.76%) had fever ≥5 days. Headache (80%) was the next most common clinical feature followed by abdominal pain (78.10%), myalgia (61.9%), and arthralgia (60%), respectively. Hepatomegaly was found in 20% of children and almost the same number (19%) had hemorrhagic manifestations. Urine output was decreased in six (5.71%), and splenomegaly was the least common observation found in four (3.81%) cases. Twelve children (11.4%) presented with features of shock [Table 1].
Table 1: Demographic and clinical profile of patients hospitalized with dengue fever.

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Out of 105 children with dengue, six (5.71%) cases developed AKI. All six cases had urine output <0.5 mL/kg/h for ≥12 h. Four cases had raised SCr≥0.3 mg/dL at admission. One child had normal SCr level at admission which got deranged over the next 12 h and another had oliguria ( <0.5 mL/kg/h) for about 24 h although SCr was not deranged. Overall, out of six cases with AKI, three (50%) were in Stage III and three had AKI Stage II as per AKIN criteria [Figure 2].
Figure 2: Pie diagram showing frequency distribution of AKI in the study population.

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On comparing two groups, children with AKI (Group A) and those without AKI (Group B) with regard to demographic and clinical characteristics, the median age of children developing AKI was 6.5 years with a minimum age of two years and maximum age of nine years and the male-female ratio was 1:1. This difference in mean age and gender in both groups was not significant (P = 0.636 and P = 1, respectively). Similarly, there was no significant difference in two groups regarding clin-

ical features such as headache, arthralgia, myalgia, rash, vomiting, abdominal pain, hemorrhagic manifestation, hepatomegaly, etc., (P≥0.05). However, Group A and B differed significantly in terms of the presence of tachycardia (P = 0.008). BP was <3rd percentile (for age, gender, and height) in total 12 cases. Among six cases with AKI, three (50%) had BP <3rd centile, whereas out of 99 children who did not develop AKI, nine (9.09%) had BP <3rd centile (P = 0.0023) [Table 2].
Table 2: Comparison of demographic and clinical profile between Group A (cases) and Group B (controls).

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On comparing laboratory parameters, there was no statistical difference in mean values of hematocrit, total leukocyte count and platelet count between two groups; however, mean serum sodium as well as serum potassium values were significantly low in cases with AKI (Group A) P <0.001 and P = 0.029, respectively) [Table 3].
Table 3: Comparison of laboratory parameters in children with acute kidney injury (Group A) and without acute kidney injury (Group B).

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Overall, mortality among dengue cases was 9.52% (10 out of 105). Of these, among 99 cases without AKI, six (6%) expired, whereas among six cases with AKI four (66.67%) expired. The difference in the outcome of cases with and without AKI was statistically significant (P = 0.001) [Table 4].
Table 4: Outcome of dengue cases with and without acute kidney injury.

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   Discussion Top


The peculiarity of DVI is the lack of cross-immunity with different serotypes. Rather, second infection with different serotype predisposes to more severe manifestations with many complications such as hemorrhage, shock, MODS, and AKI.[1],[2] There are the paucity of data in the pediatric population regarding AKI in DVI.[6],[7],[8],[9],[10] In this observational study, the median age of admitted children with dengue was seven years, with the majority in the age group of six to 10 years and slight female preponderance (55.24%). Most of the previous studies in children have reported age of presentation in DVI to be between five and 10 years.[10],[13],[14],-15 In DVI besides fever and other associated features like headache, rash, myalgia, arthralgia, etc., presence of abdominal pain, hepatomegaly, hemorrhagic manifestations, persistent vomiting, etc., are red alerts defined as warning signs in the WHO 2009 criteria.[3] In this study, around 20% of children had warning signs in the form of hemorrhage and hepatomegaly; although, abdominal pain was reported in a relatively higher percentage (78%). Twelve children (11.4%) presented with features of shock and this proportion is more or less similar to the previous reports.[15],[16]

Six children (5.7%) had documented urine output <0.5 mL/kg/h of more than or equal to 12 h and qualified for AKI as per AKIN criteria (increase in SCr by ≥0.3 mg/dL or UO <0.5 mL/kg/h for ≥6 h).[12] Among them, four (66.67%) cases had raised SCr level (1 case on the day of admission and 3 cases on follow-up test). Three cases each (50%) of AKI were in Stage II and III, respectively. Most studies report the incidence of AKI in dengue infection in the pediatric age group to be much lower ranging from 0.2% to 3.6%.[6][7][9] compared to the adult population, where the higher incidence of AKI in DVI is reported (3.3%-35.7%).[11],[17],[18],[19],[20] However, Bunnag and Kalayanarooj[8] in their study among 59 children with DSS, reported AKI in 10% and in another recent study by Basu and Roy[10] incidence of AKI was found to be 13.4% among children with DVI. Reported variation in the previous studies may be due to the reason that most of the mentioned studies are retrospective in nature, have mixed population (adults as well as children), and also vary in the criteria used for AKI as well as the severity of DVI. In the current study, on comparing two groups, i.e., Group A(with AKI) and Group B (without AKI) with regard to demographic and clinical characteristics, the difference in mean age in both groups as well as gender was not significant P = 0.636 and 1, respectively). Similarly, there was no significant difference in two groups regarding clinical presentation (P≥0.05, however, tachycardia (with respect to age and gender) was observed significantly more in children with AKI (83.33%) compared to 26.26% in those without AKI (P = 0.008). Tachycardia is an important indicator of impending shock and maybe a significant factor for the development of AKI. In a retrospective analysis by Basu and Roy[10] in 97 children with DVI, mean age, gender, and clinical presentation did not significantly vary between two groups, i.e., with and without AKI (P ≥0.05) suggesting that occurrence of AKI cannot be predicted on the basis of clinical presentation in children with DVI, however close monitoring of patients with respect to their vital signs including increasing pulse rate may be more important in predicting adverse outcome.

BP was found to be another important factor associated with the development of AKI as 50% had BP <3rd percentile among the AKI cases compared to 9% among those who did not develop AKI (P = 0.0023). Previous studies are also in agreement that low blood pressure or hypotension is a major risk factor for developing AKI.[10],[11],[19] Basu and Roy observed that vasopressor support was required in 70% of AKI cases and 14% of non-AKI cases (P = 0.001).[10] Kuo et al found that DSS was correlated to development AKI P = 0.001).[11] Similarly, Mehra et al also concluded the requirement of inotropes (P <0.001) was important factor for the development of AKI in dengue.[19]

In this study, thrombocytopenia and raised hematocrit was present in 67.7% and 83% of AKI cases, respectively, which was significantly higher in respect to the non-AKI group, however, mean values for hematocrit and platelet count did not vary significantly between two groups(P = 0.20 and P = 0.26 respectively). In the study by Mehra et al, showed a similar finding that thrombocyto- penia was present in 70% cases of AKI with dengue, which was significant.[19] But Khalil et al concluded that thrombocytopenia is not a risk factor for AKI (P = 0.12).[17] In this study, both serum sodium and potassium levels were significantly low among dengue cases developing AKI (P <0.05) which is similar to the observation made in other studies as well.[7],[8],[9],[10] Although in the study by Mallhi et al[21] difference was not statistically significant (P = 0.11 and P = 0.67 respectively), Basu and Roy observed significant hyponatremia as well as hypokalemia among cases with AKI (P <0.05) similar to Vachvanichsanong and McNeil and Lumpaopong et al.[9],[10],[22] Although exact patho- genesis of DVI in causing AKI is not known but appears to be complex mechanism involving direct viral cytopathic invasion, immune complex-mediated injury, rhabdomyolysis, thrombotic microangiopathy with the hemo- lytic uremic syndrome and as part of multi- organ dysfunction in an advanced infection leading to vasomotor nephropathy and maybe the reason for variable presentation, severity, laboratory parameters, and outcome.[23],[24],[25],[26],[27] Severe dengue being an medical emergency, it is difficult to study prospectively the mechanism and pathophysiology in cases developing AKI, as main emphasis is on early correction of fluid and electrolyte balance.

Looking at the outcome, mortality was quite high among AKI cases (66.67%) compared to 6.06% among those without AKI and is similar to previous studies.[6],[10],[11],[17],[18] Basu and Roy showed that the seven days survival rate was 61% among renal failure patients as compared to 96.4% in the nonrenal failure group (P <0.001).[10] Kuo et al also showed that mortality is correlated with poor renal function and renal failure patients had higher mortality of 28.6% than the nonrenal failure group (1.2%) (P <0.001).[11] Khalil et al showed mortality of 11.3% among AKI group compared to none in non-AKI group.[17]


   Conclusion Top


To conclude, AKI is not a common complication of DVI, but if develops it may lead to significant morbidity and mortality among the pediatric age group. DSS is an important risk factor for the development of AKI in dengue. Hence, one should be vigilant in Dengue patients regarding progression to AKI as early diagnosis and intervention alter the prognosis significantly.


   Limitations Top


The study period included dengue cases during a single monsoon season, as a result did not show the trend of natural disease and its outcome over the years. Being a seasonal infection, not only the disease prevalence is different every year but also the severity varies.

As the study was done at a tertiary care center, early fluid management was done in cases of dengue. It prevented the disease to progress to severe complications like shock, multiorgan failure, and AKI. Hence, the natural disease course could not be assessed due to ethical issues.


   Acknowledgment Top


The authors would like to thank all patients and their guardians without whom the work would have been impossible.

Conflict of interest: None declared.



 
   References Top

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Goldstein SL, Zappitelli M. Evaluation and management of children with acute kidney injury in children. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Emma F, Goldstein SL, editors. Pediatric Nephrology. Berlin- Heidelberg: Springer; 2016. p. 2139-67  Back to cited text no. 5
    
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Vachvanichsanong P, McNeil E. Electrolyte disturbance and kidney dysfunction in dengue viral infection.Southeast Asian J Trop Med Public Health 2015;46Suppl 1:108-17  Back to cited text no. 9
    
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Adam AS, Pasaribu S, Wijaya H, Pasaribu AP. Clinical profile and warning sign finding in children with severe dengue and non-severe dengue. IOP Conf Series Earth Environ Sci 2018;125:012038  Back to cited text no. 16
    
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Khalil MA, Sarwar S, Chaudry MA, et al. Acute kidney injury in dengue virus infection.Clin Kidney J 2012;5:390-4  Back to cited text no. 17
    
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Mehra N, Patel A, Abraham G, Reddy YN, Reddy YN. Acute kidney injury in dengue fever using Acute Kidney Injury Network criteria: Incidence and risk factors. Trop Doct 2012;42:160-2  Back to cited text no. 19
    
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Basu G, Chrispal A, Boorugu H, et al. Acute kidney injury in tropical acute febrile illness in a tertiary care centre-RIFLE criteria validation. Nephrol Dial Transplant 2011;26:524-31  Back to cited text no. 20
    
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Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. Incidence, characteristics and risk factors of acute kidney injury among dengue patients: A retrospective analysis. PLoS ONE 2015;10:E013846  Back to cited text no. 21
    
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Lumpaopong A, Kaewplang P, Watanaveeradej V, et al. Electrolyte disturbances and abnormal urine analysis in children with dengue infection. Southeast Asian J Trop Med Public Health 2010;41:72-6  Back to cited text no. 22
    
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Wiersinga WJ, Scheepstra CG, Kasanardjo JS, deVries PJ, Zaaijer H, Geerlings SE. Dengue fever-induced hemolytic uremic syndrome. Clin Infect Dis 2006;43:800-1  Back to cited text no. 23
    
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Bhargava V, Gupta P, Kauntia R, Bajpai G. Dengue fever-induced thrombotic microangio- pathy: An unusual cause of renal failure. Indian J Nephrol 2017;27:321-3  Back to cited text no. 24
    
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Avasthi G, Prashant B, Rahul K, Vinay S. A case of immune complex mediated acute kidney injury occurring in the first few days of dengue fever. J Clin Case Rep 2012;2:2  Back to cited text no. 25
    
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Davis JS, Bourke P. Rhabdomyolysis associated with dengue virus infection. Clin Infect Dis 2004;38:e109-11  Back to cited text no. 26
    
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Correspondence Address:
Shobha Sharma
Department of Pediatrics, VMMC and Safdarjung Hospital, New Delhi
India
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DOI: 10.4103/1319-2442.284015

PMID: 32394913

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