Background
Acute pyelonephritis (APN) in pediatric patients may lead to kidney scarring and is listed as one of the important causes of permanent kidney damage [
1,
2]. Acquired scarring because of APN seems to be more common in girls and usually is associated with lower-grade vesicoureteral reflux (VUR) and better outcomes [
3]. Kidney scarring may lead to hypertension, proteinuria, and the risk of chronic kidney disease increases when high-grade VUR background is present [
1,
2,
4,
5]. The incidence of kidney scarring after one febrile urinary tract infection (UTI) is reported to range from 2.8% to 15%, with the percentage rising to 28.6% after three or more febrile UTIs [
5,
6]. Risk factors for kidney scarring are multiple APN episodes, high-grade VUR, bacterial virulence, and delay of treatment with antibiotics, especially in infants with non-specific UTI signs [
7,
8]. Adequate antibiotic treatment is the most efficient treatment option for UTI, but it may not be sufficient to prevent kidney scarring [
9].
Corticosteroids may have a role in reducing kidney scar formation and urine cytokine levels [
10]. Cytokines may predict the severity of kidney damage, playing a key role in kidney scarring after APN as they represent the mediators of an inflammatory process in response to an infection [
11‐
14]. A few studies have attempted to examine the hypothesis that corticosteroids may affect cytokine response and decrease kidney damage after APN, with promising results [
12,
15]. Recent randomized controlled studies (RCTs) and a meta-analysis demonstrated that a short period of adjuvant corticosteroids may decrease the risk of kidney scar formation after APN [
10,
13,
14]. These results and minimal adverse events make adjuvant corticosteroid administration to antibiotics a promising future treatment option for children with pyelonephritis.
We conducted a systematic review and meta-analysis to clarify the role of adjuvant administration of corticosteroids to antibiotic treatment for kidney scar prevention after APN in pediatric patients.
Discussion
Our meta-analysis evaluated the effectiveness of adjuvant corticosteroids to adequate antibiotic treatment in the reduction of kidney scar formation after APN/UTI in the pediatric population. The results of our meta-analysis showed that adjuvant corticosteroids to antibiotics led to a statistically significant reduction in kidney scarring incidence after APN/UTI in pediatric patients, without raising the risk of prolonged hospitalization, bacteremia, or recurrence of UTI.
UTI pathogens play a key role in inflammation, with the activation of local and systematic routes after the bacterial invasion [
12]. Animal studies have shown that the activation of cytokines during APN can cause damage to the kidney tissue leading to kidney dysfunction [
12,
24]. Kidney scarring is the result of the acute inflammation process and although APN is treated with adequate and aggressive antibiotic treatment, there is a high risk of kidney scar formation [
12,
25,
26]. Anti-inflammatory agent administration in animal studies has shown statistical significance in the reduction of kidney scarring after APN [
25,
27,
28]. Corticosteroids are one of the most used anti-inflammatory agents and the most studied option for kidney scar prevention after APN [
29].
A few studies have investigated the effects of corticosteroids for the prevention of kidney scarring after pediatric APN or UTI [
10,
12‐
15,
22,
23]. Meena et al. conducted the first meta-analysis to assess the efficacy and safety of adjuvant corticosteroids for preventing kidney scar formation in children with APN [
10]. They included 529 randomized subjects from three RCTs drawing the conclusion that corticosteroids are effective in kidney scarring reduction compared with placebo.
We conducted an extended literature search based on the available literature in the main medical electronic databases (PubMed/MEDLINE and Scopus) with no limitations regarding publication year and language. Our meta-analysis included only well-designed, placebo-controlled RCTs that focused on the pediatric population. Additionally, the analysis was performed with the help of the most recent RoB 2.0 tool and the review procedure was done in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [
17,
20]. Moreover, our meta-analysis was characterized by low heterogeneity for all outcomes assessed. Finally, only one study was evaluated to be at “some concerns” with all remaining studies evaluated to be at “low risk of bias” in the quality assessment.
The main advantages of the present systematic review and meta-analysis include the larger population number of included pediatric patients (5 RCTs with 693 randomized patients who met the inclusion criteria of the meta-analysis and 498 patients who completed the study follow-up). We also investigated the effectiveness of corticosteroids based on the corticosteroid of use (dexamethasone).
Our meta-analysis had also some limitations that have to be acknowledged. Corticosteroids used in the RCTs of our analysis do not belong to the same classes, with one study [
14] including methylprednisolone and the other four [
13,
15,
22,
23] dexamethasone as the corticosteroid of choice. According to the “Coopman classification,” methylprednisolone belongs to class A and dexamethasone to class B corticosteroids [
30]. They were also administered via different routes (intravenous or oral) and for different day courses (3-day or 4-day courses). Other limitations are that the total number of subjects who completed the study is relatively small (
n = 498 children) and that the diagnosis of APN was not confirmed with DMSA in all RCTs, and therefore in three of them [
13,
15,
23], the UTI episodes cannot be recorded with certainty as APN. Ghaffari et al. was the only study that evaluated the modification of interleukin levels in the urine, which can be helpful in the estimation of treatment response [
15]. Finally, the outcomes of our meta-analysis are limited due to the incompatibility of the possible comparisons between the study outcomes of different RCTs; thus, adverse events and inflammation marker trends before and after co-intervention with corticosteroids could not be thoroughly evaluated.
The subgroup that received dexamethasone did not reach any significant result in kidney scarring reduction. It is believed that this result was influenced by the dynamics of the studies, as that of Huang et al. was the only RCT that led to a significant reduction of kidney scarring after methylprednisolone administration [
14]. This study was not included in the subgroup of dexamethasone administration. When all RCTs were included in the meta-analysis
, Huang et al. received a large weighting (32.5%), influencing the result. In conclusion, differences in corticosteroid classes may have a key role in these results.
As reported by the results of our meta-analysis, corticosteroids—a well-known and routinely used, inexpensive, and relatively safe agent in moderate short-course dosages—could lead to the reduction of the risk of kidney scarring in children with APN, without causing any serious adverse effects. Although there are data that support corticosteroid administration in kidney scarring prevention, current evidence is still insufficient. Further RCTs should evaluate the benefit of corticosteroids in fever duration after their initiation, urinary interleukins, and other serum/urine biomarker levels before and after the intervention and a variety of adverse events.
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