| Abstract|| |
Children with nephrotic syndrome (NS) have a number of potential risk factors for the development of acute kidney injury (AKI) including intravascular volume depletion, infection, exposure to nephrotoxic medication, and renal interstitial edema. This study was aimed to determine the incidence of AKI in children hospitalized with a relapse of NS and its short-term outcome. This prospective observational study was conducted from February 2017 to January 2018 at a tertiary care teaching hospital. A total of 54 children and adolescents (1–18 years) hospitalized with a diagnosis of NS and relapse with/or without other complications were enrolled. Clinical data and examination were recorded. AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria and Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (p-RIFLE) classification. Children who developed AKI during the first two weeks of hospitalization were followed up till recovery or six weeks whichever was earlier to determine the outcome and factors predisposing to AKI. The mean age of the study population was 59.5 months and 35 (64.8%) patients were male. Of the 54 patients hospitalized, 42 (77.8%) were admitted with infection-associated relapses while 22.2% of children had relapse alone. Diarrhea and spontaneous bacterial peritonitis were the most common infections (26.1% each) followed by urinary tract infections in 19% and pneumonia in 14.3%. Twenty-three (42.6%) children developed AKI according to the KDIGO definition and 27 (50%) using the pRIFLE classification. Fourteen (60.9%) had stage 2 AKI while 21.7% had stage 3 AKI. Infections [odds ratio (OR) 1.24] and use of angiotensin-converting enzyme inhibitors (ACEI) (OR 2.3) were the most common predisposing factors for AKI. The mean recovery time for AKI was 7.34 days. Development of AKI was associated with prolonged hospital stay (12.57 vs.8.55 days P <0.01) and delayed recovery. At the end of follow-up all children recovered from AKI. The incidence of AKI in children hospitalized with complications of NS is high. While the occurrence of these AKI episodes may appear transient, a recurrence of such episodes may be detrimental to the long-term outcome of children with NS. Infections and the use of ACEI during relapses are risk factor for the occurrence of AKI.
|How to cite this article:|
Kumar R, Agrwal S, Mantan M, Yadav S. Acute kidney injury in children hospitalized with a relapse of nephrotic syndrome: A short-term outcome study. Saudi J Kidney Dis Transpl 2021;32:437-44
|How to cite this URL:|
Kumar R, Agrwal S, Mantan M, Yadav S. Acute kidney injury in children hospitalized with a relapse of nephrotic syndrome: A short-term outcome study. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 23];32:437-44. Available from: https://www.sjkdt.org/text.asp?2021/32/2/437/335456
| Introduction|| |
Nephrotic syndrome (NS) is a chronic disorder in children characterized by edema, nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia. The annual incidence of the condition is 2–7/100,000 in children under 15 years of age and its prevalence is 16/100,000., There is epidemiological evidence of a higher incidence of the condition in the Asian population.
The common complications of NS in childhood are recurrent infections, thrombosis, steroid toxicity and hypertension (HTN). Acute kidney injury (AKI) is less frequently seen. However, the incidence of AKI in children with NS appears to be increasing. While previous studies reported an incidence of less than 10%, a recent publication gives the figure as high as 58.6%., This could be due to the increasing use of drugs like cyclosporine and tacrolimus, especially for patients with a steroid-resistant course. Furthermore, the use of diuretics like furosemide and nephrotoxic antibiotics have been implicated for the causation of AKI in children hospitalized with NS. An increased incidence of AKI could also be due to lower thresholds of serum creatinine (SCr) now being used for making the diagnosis as compared to previous years when only severe acute renal failure got reported. Children with NS are at higher risk of developing AKI due to volume shift, infections, and use of nephrotoxic medications. There is evidence that episodes of AKI may predispose to the development of chronic kidney disease (CKD). As the children with NS are prone to recurrent episodes of AKI due to multiple relapses and infections there is a need to follow-up these cases of AKI to know if these episodes have any impact on disease outcome.
| Materials and methods|| |
This prospective observational study was done in the department of pediatrics of a tertiary care teaching hospital in northern India. The study was approved by the institutional ethical committee. Children aged 1–18 years hospitalized with a diagnosis of NS with a relapse alone and/or associated with other complications were included. Children admitted for biopsy, congenital NS, and those with established CKD were excluded.
After obtaining written informed consent from the guardian, the data regarding demographic characteristics, age at diagnosis, type of NS, presence of relapse, infection, complications, medication use (aminoglycosides, glycopeptides, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers, calcineurin inhibitors and non-steroidal anti-inflammatory drugs), their doses and duration were recorded. Anthropometry and physical examination were noted. Investigations including hematological (hemoglobin and total leukocyte counts) and biochemical (blood urea, SCr, albumin, and cholesterol) were done. SCr was estimated by modified Jaffe’s technique using the Beckman Coulter AU480 auto-analyzer which was isotope dilution mass spectroscopy calibrated for SCr value and modified Schwartz formula was used to calculate estimated glomerular filtration rate (GFR). Lowest SCr value in last three months if available or the value at admission was taken as the baseline. SCr was repeated twice weekly for initial two weeks and afterward weekly for those who developed AKI till resolution of AKI or six weeks whichever was earlier. The Kidney Disease Improving Global Outcomes (KDIGO) definition for AKI was used in the study and any increase in SCr by ≥0.3 mg/dL within 48 h or an increase in SCr to ≥1.5 times from baseline was considered as AKI. Furthermore, the pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (p-RIFLE) classification was used to classify AKI.
Outcome measures and data analysis
The primary outcome measure of the study was the occurrence of AKI in the study population during the first two weeks of hospitalization (KDIGO and pRIFLE classification). The secondary outcome measures were the risk factors for AKI, duration of AKI, duration of hospital stay, and outcome of hospitalization/AKI.
The collected data was transformed into variables, coded and entered in Microsoft Excel. Data were analyzed and statistically evaluated using Statistical Package for the Social Sciences (SPSS) version 17.0 (SPSS Inc, Chicago, Il, USA). Quantitative data were expressed in mean, standard deviation, or median and the difference between two comparable groups was tested by Student’s t-test (unpaired) or Mann–Whitney “U”-test, while qualitative data were expressed as percentage. The statistical differences between the proportions were tested by Chi-square test or Fisher’s exact test. A P <0.05 was considered statistically significant. Further, the Odds ratio and 95% confidence interval were used to quantify the risk factors. Univariate analysis was done and among those factors which were found to be significant with P ≤0.1 were entered further in multivariate analysis.
| Results|| |
Fifty-four children (64.8% males) were enrolled during the study period. The mean age at diagnosis of NS for the study population was 37.4 months and the mean age at enrolment was 59.5 months. Twenty-seven (50%) children presented with the first episode or an infrequently relapsing course of NS; 15 (27.8%) had steroid-resistant disease and the remaining had a frequently relapsing or steroid-dependent NS. Of the 54 children enrolled in study 42 (77.8%) were admitted with infection-associated relapses while 12 (22.2%) children were admitted for treatment of relapse alone (control of edema). The most common infections amongst these children were diarrhea in 11 (26.1%) patients, spontaneous bacterial peritonitis in 26.1% and urinary tract infections in 19%. Six (14.3%) patients were admitted with pneumonia, one had pulmonary tuberculosis (PTB) while another five (11.9%) had upper respiratory tract infections and skin infections were reported in 7.1%.
The mean SCr value on day 1 was 0.52 mg/dL and the highest Cr values were seen between day 1 and day 4, following which a declining trend was seen in mean SCr values. This decline was found to be significant with P-value being <0.05 between day 1 and day 10 [Table 1]. The mean GFR on day 1 was 94.22 mL/min/1.73 m2. A rising trend was seen in mean GFR values from the day of admission to values on the 10th day. This rise was found to be significant with P <0.05 between day 1 and day 7.
Of the 54 children enrolled, 23(42.6%) developed AKI using the KDIGO definition for AKI. Of these, a majority (60.9%) had stage 2 AKI while 21.7% had stage 3 AKI. The proportion of patients with stage 1 AKI was 17.4%.
While using the pRIFLE classification, 27 (50%) patients developed AKI. Most (44.4%) of the patients were in stage Injury (I) of the classification, followed by the Risk (R) category in 40.7%. A comparison between stage-wise distribution of the pRIFLE vs the KDIGO criteria showed that pRIFLE criteria were more sensitive in detecting AKI as compared to KDIGO though KDIGO criteria identified more patients with severe disease. The level of agreement between the pRIFLE and AKIN criteria was significant (kappa 0.513, P <0.001) [Table 2].
|Table 2: Level of agreement between pRIFLE and Kidney Disease Improving Global Outcomes staging of acute kidney injury.|
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The mean duration of onset of AKI was 1.9 days from the day of admission. The highest SCr values in 11 (47.8%) patients who developed AKI were observed on day 1. The mean recovery time for AKI was 7.3 ± 4.3 days. As the severity of AKI increased, recovery of AKI was delayed although this difference was not found to be statistically significant (P = 0.50). The mean length of hospital stay of patients with AKI was more (12.6 ± 5.4 days) than patients without AKI (8.6 ± 3.8 days) and the difference was statistically significant (P <0.01). As the severity of AKI increased length of hospital stay also increased.
A comparison of patients who developed AKI versus those who did not is given in [Table 3]. The children who developed AKI had lower hemoglobin levels compared to non AKI ones (P <0.05). Similarly, infections were more common in patients with AKI (P <0.01). The use of ACEI was more in AKI patients (P = 0.05) and the mean duration of hospital stay was also longer (P <0.01). None of the other risk factors, which could affect the development of AKI, were found to be significantly different between the two groups.
|Table 3: Comparison of patient parameters in acute kidney injury versus nonacute kidney injury patients.|
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| Discussion|| |
Children with NS require frequent hospitalizations, especially during relapses and are at an increased risk of AKI due to volume shifts, recurrent infections, and use of nephrotoxic medications. These recurrent AKI episodes may have a role in the development of CKD in future. Prevention of such episodes of AKI may have a significant effect on the outcome of the disease.
The mean age of onset of NS of the study population was 37.4 months and the age at enrolment was 59.4 months. Of the 54 children enrolled in the study, 46 (85.2%) were between two to 12 years of age. In a study done by William Wong in New Zealand in 2007, 81.6% of children were diagnosed between the ages of one to 10 years. Early childhood is the usual age of onset of NS. These patients often require hospitalizations during the initial years of the disease due to recurrent relapses and infections. The relapses decrease in number as the child grows older and permanent disease remission is often seen close to puberty.
Of the 54 children enrolled, 50% either had first episode of NS or an infrequently relapsing course. Another 22.2% were either steroid dependent or having a frequently relapsing NS, the remaining being steroid resistant. These results imply that hospitalizations are more common at the initial diagnosis when these children present with infections and bad relapses. Once they are on treatment with either steroids or other alternative agents the likelihood of relapses and infections decreases. Besides the proportion of patients with steroid sensitive disease was higher as has been seen in other studies as well. Another study on children less than 18 years of age with hospitalizations on NS showed that 73.2% of hospitalizations of patients with NS had a steroid-sensitive disease.
Of the 54 children enrolled almost 77.8% had a concomitant infection with the relapse. The reasons for hospitalization in children with NS are often for control of edema, treatment of infections, and other complications like thromboembolism. A previous study amongst 86 children with NS identified 101 hospital admissions. The common indications for hospitalization in the study population were major infections in 36.6%, severe ascites in 61.4%, scrotal edema in 37.7%, and vulval edema in 33.3%.
The commonest infections observed amongst the subjects in the present study were acute watery diarrhea (25.6%), spontaneous bacterial peritonitis (25.6%), urinary tract infections (18.6%), and pneumonia (14%). An Indian study in 246 children with NS observed 48 (19.6%) episodes of infections in 46 children. Most common infection observed were pneumonia (41.7%), followed by urinary tract infection (25%), septicemia (16.7%), spontaneous bacterial peritonitis (8.3%), cellulitis (4.2%), perinephric abscess (2.1%) and PTB (2.1%).
AKI occurred in 23 (42.6%) patients using the KDIGO definition and 27 (50%) using the pRIFLE criteria in the present study. Among patients with AKI according to KDIGO criteria 17.4% had stage 1 AKI, 60.9% stage 2 AKI and 21.7% had stage 3 AKI. According to pRIFLE classification, the category Risk (R) was present in 40.7%, Injury (I) in 44.4% and Failure (F) in 14.8% of subjects.
A retrospective study from North America in children below 18 years of age showed that AKI occurred in 58.6% of 336 children hospitalized with a diagnosis of NS. More than 50% episodes of AKI occurred after the first day of admission. Steroid-resistant NS, focal segmental glomerulosclerosis, infections, nephrotoxic medication exposure, and non-white race were all significantly associated with increased risk of AKI. Besides AKI was associated with a longer duration of stay in the hospital (P <0.001) and increasing need for ICU admission.
A retrospective study included 355 children below 18 years of age, admitted with a diagnosis of NS, and reported an incidence of 23.7% for AKI using the pRIFLE criteria. The common risk factors for the development of AKI were steroid dependant or steroid-resistant NS, infections, HTN, low serum albumin, and nephrotoxic medication exposure. They too found that mean time to recovery was increased as the severity of AKI increased.
Another prospective recently published study has shown a lower incidence of AKI of 16% in children hospitalized with NS using the KDIGO definition. The children enrolled in the study were less sick at admission as a majority were admitted for edema control (61.6%) alone and fewer had a concomitant infection while 77.8% of the children in the present study had an infection complicating the relapse.
Application of two different definitions resulted in a difference in the incidence of AKI. A comparison between different stages of AKI using pRIFLE versus KDIGO definition showed that the pRIFLE criteria were more sensitive in diagnosing AKI as compared to KDIGO (50% vs. 42.6% respectively) though KDIGO classified them as having more severe disease. It was noticed that KDIGO stage 1 was not equivalent to the pRIFLE R stage which explains why KDIGO missed four (7.4%) patients which were identified by pRIFLE. Classification of KDIGO stage 1 would be roughly equivalent to a decrease in eCrCl of more than 33%.
Similar findings were observed by Sutherland et al in a study done in 2015 amongst hospitalized children. The incidence of AKI according to pRIFLE and KDIGO was 51.1% and 40.3% respectively. These findings showed that pRIFLE was more sensitive for the identification of AKI compared to KDIGO and it identified even milder forms of AKI.
The mean recovery time from AKI was 7.3 days and as the severity of AKI increased, recovery of AKI was delayed although this difference was not found statistically significant. Similar findings have been observed in previous studies.,
We found that children receiving ACEI were more likely to develop AKI as compared to those not receiving them [odds ratio (OR) 2.30; 95% confidence interval (CI) 0.61–8.75]. This is significant because many children with steroid-resistant NS are continued on ACEI for prolonged periods. It would be prudent to discontinue these medications during relapse and infections.
While lower serum albumin has been shown to be a risk factor in previous studies the present study found similar albumin levels in both AKI and non AKI groups. Infection was found as a significant risk factor for the development of AKI (OR 1.24 and 95% 1.44–3.36). Another study in children with NS found that children with infections were twice as likely to develop AKI as those without (OR 2.20; 95% CI 1.44–3.36).
We did not find any significant difference in the development of AKI with the use of calcineurin inhibitors. Previous studies in children with NS found that the use of calcineurin inhibitors was associated with increased risk of AKI., The reason for this difference could be a smaller number of patients on CNI in the present study as a majority had a steroid-sensitive disease.
The use of nephrotoxic aminoglycosides was less in our study cohort possibly due to which we did not find any significant difference in the risk of AKI. This is primarily due to our policy of not using aminoglycosides as first-line antibiotics in children with NS. A comparison of other risk factors like hypovolemia, shock, need for vasopressor too was not significant.
As children with NS are predisposed to recurrent episodes of AKI, these episodes may lead to the development of CKD during the course of disease and can affect the final outcome of the disease. A recent prospective study in 119 children of NS with AKI reported that 45.4% of children did not recover from AKI and 41.2% progressed to different stages of CKD during the follow-up period.
To conclude 42.6% of the children hospitalized with a relapse of NS developed AKI in the present study using the KDIGO definition. All patients recovered from AKI at discharge indicating its transient and reversible nature Infections and ACEI were identified as significant risk factors for AKI. While the occurrence of these AKI episodes may appear transient and trivial, a recurrence of such episodes may be detrimental to the long-term outcome of children with NS. The impact of AKI in such situations needs to be studied in a larger group of patients.
Conflict of interest: None declared.
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Department of Pediatrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, University of Delhi, New Delhi
[Table 1], [Table 2], [Table 3]