Dexamethasone to prevent kidney scarring in acute pyelonephritis: a randomized clinical trial

Urinary tract infection (UTI) is one of the most common bacterial infections in childhood and is associated with long-term complications such as kidney scarring and later arterial hypertension, proteinuria, pre-eclampsia, and chronic kidney disease [1, 2].

Both age and sex modulate UTI incidence. It is estimated that 8–10% of girls and 2–3% of boys will suffer from a symptomatic urinary infection before the age of 7 [3‐8]. Between 50 and 80% of patients with febrile UTI have acute pyelonephritis (APN) [9].

The pathogenesis of kidney scarring after APN is not completely understood. It is postulated that both acute kidney injury and scarring appear as a consequence of the inflammatory and immunological response triggered to eradicate kidney tissue infection through the activation of inflammatory mediators such as cytokines [10, 11]. The incidence of permanent kidney scarring after APN is highly variable (10–60%) [9, 12‐14].

Recently, animal and human studies proposed a blockade of the inflammatory cascade involved in kidney scarring as a therapeutic option. In animal models, the use of corticosteroids, anti-inflammatory drugs (ibuprofen), dapsone, or melatonin/oxytocin resulted in a significant reduction in kidney scarring and its long-term consequences, probably due to an inhibitory effect on neutrophilic infiltration [15‐19].

An important objective while treating patients with APN is to avoid permanent kidney damage. Therefore, any intervention that reduced kidney scarring would have a great impact, as it would decrease the incidence of chronic kidney failure or hypertension in adulthood. Previous results reported possible benefits of using corticosteroids that could lead to a change in the prognosis of APN patients [20‐22]. Among corticosteroids, dexamethasone is an outstanding candidate due to its greater potency, extensive clinical knowledge, and previous benefits observed in the treatment of other infections, such as meningitis, where it reduced permanent sequelae [23].

The scarce literature published in pediatric APN patients shows differing methodologies and results [20‐22]; thus, more trials are needed to establish well-based recommendations. Hence, our objective was to evaluate the effect of adjuvant dexamethasone treatment on kidney scarring after APN in children in a randomized clinical trial (RCT).

This study was a phase III, double-blind, placebo-controlled, multicentric RCT performed in children with APN. The study was conducted in 8 Spanish hospitals corresponding to the acronym of DEXCAR.

One hundred eighty-four patients were recruited between April 2013 and April 2018. After recruitment, 4 parents withdrew their consent; therefore, 180 infants were randomly allocated to receive dexamethasone (n = 92) or placebo (n = 88). Acute pyelonephritis was confirmed by DMSA and a positive urine culture in 116 infants (60 in the dexamethasone group and 56 in the placebo group). Ninety-one patients (49 and 42 in the dexamethasone and placebo groups, respectively) completed the follow-up and were finally analyzed. Figure 1 shows the flowchart of the study. Twenty-one infants were lost to follow-up (11 in the placebo group and 10 in the intervention one) and four had a second APN before the late DMSA examination (3 in the placebo and 1 in the intervention group). There were no differences between study groups in the number or the reasons for withdrawing (including UTI recurrence; 5.4% vs. 1.7% in placebo and intervention groups respectively, p = 0.5623).

Among the included 91 infants, 74% were females. The median age was 9 months (IQR 4–21 months, from 1 month to 11 years). Eighty percent of infants (n = 73) were younger than 2 years, and almost 63% (n = 57) were younger than 1 year. As expected, 98% of infections were caused by Escherichia coli. The empiric antibiotic therapy administered was gentamicin in 43% of patients (n = 39), amoxicillin-clavulanic acid in 29% (n = 26) and cephalosporin in 29% (n = 26). None of the patients had associated bacteremia or other complications including infection by resistant microorganisms. Abdominal ultrasound was abnormal in 11 patients (12%) (9 UTDs and 2 CAKUTs (double ureteral system in one patient and renal ectopy in the other)). Among patients with any UTD, none of them were classified in the high-risk group according to the new consensus classification (44% low risk and 56% moderate) [28].

Vesicoureteral reflux was confirmed in 12 patients (15% among the 83 who completed the VCUG assessment). All patients showed a coincidence of the APN with the reflux side. Reflux severity was classified as dilated (grades 3–5) in 4 patients.

Table 1 shows the patient characteristics by intervention group. Both groups were comparable in terms of age, sex distribution, fever before admission, basal blood analysis variables, germ, renal uropathy presence (VUR, CAKUT or UTD), and early REDSS. Although both study groups showed a similar % of patients with VUR, the number of patients classified as having dilated reflux (grades 3–5) tended to be higher in the dexamethasone group, without reaching statistical significance. Both groups were also comparable in terms of time delay between diagnosis and the beginning of study product administration (9.2 ± 7.8 vs. 8.5 ± 8.2 h for the dexamethasone and placebo groups, p = 0.531).

Early REDSS was directly correlated with differences in renal function between kidneys (r = 0.287, p = 0.008), showing an agreement of this score with functional loss in the affected kidney (analysis performed in the unilateral affected patients). REDSS also correlated with acute phase reactants (PCR: r = 0.320, p = 0.006 and PCT: r = 0.496, p < 0.001).

Overall, a kidney scar was observed in 20 patients (22% of included patients: 1 grade 4, 9 grade 2, and 10 grade 1). Kidney scarring was observed in 16% of infants younger than 1 year, 21% in those younger than 2, and 28% among children older than 2, but these differences were not statistically significant (p = 0.358). Table 2 shows the clinical and biochemical characteristics of patients according to kidney scar presence. Infants who developed kidney scarring showed a higher early REDSS compared to those who did not develop scarring (2.7 ± 1.1 vs. 2.1 ± 0.9 points in the scar present and absent groups, p = 0.030). There were no differences in any of the other studied variables (Table 2). Patients with VUR showed a threefold higher risk of developing a kidney scar, without reaching statistical significance (OR 3.19 (0.87–11.64, p = 0.08)).

The effect of the intervention on kidney scar development and severity is shown in Fig. 2. The incidence of kidney scarring was similar in both groups (22% and 21% in the dexamethasone and placebo groups, respectively, p = 0.907) (Fig. 2a). Treatment with dexamethasone did not enhance remission in kidney damage, nor did it enhance remission in all children (Fig. 2b) or in those with persistent kidney damage (Fig. 2c). The REDSS (both in the early and late phase) were similar between groups (early: 2.15 ± 1.05 vs. 2.26 ± 0.95 in the dexamethasone and placebo groups, p = 0.673; late: 0.41 ± 0.70 vs. 0.32 ± 0.66 in the dexamethasone and placebo groups, p = 0.848) (Fig. 2b). The kidney damage (REDSS) improved in most patients (94%) irrespective of the study group. Moreover, among those children with permanent scarring, the magnitude of the improvement was also independent of the treatment, as both dexamethasone and placebo groups showed a 42% reduction of REDSS (p = 0.988) (Fig. 2c). The dexamethasone group showed a significant reduction in fever days after clinic admission (0.9 ± 0.8 days vs. 1.7 ± 0.9 days, p < 0.001), but the maximal temperature reached was not different between the study groups.

We analyzed the possible effect of the treatment in those infants belonging to higher risk subgroups (i.e., age, diagnostic delay (measured as days of fever before admission), elevated acute phase reactants, UTD, or VUR) (Table 3). The incidence of kidney scarring was similar among the intervention groups in all the specific risk factors studied. These results were confirmed by logistic regression that assessed the effect of treatment adjusted by possible confounders. Kidney scar development was significantly modulated by early REDSS (β = 0.648, p = 0.023) and PCT values (β = 0.065 p = 0.027), whereas VUR grade showed a tendency to modulate kidney scar development (β = 0.545, p = 0.054). None of the other variables showed a significant relationship with kidney scar development, irrespective of the study treatment groups or adjustment by confounders.

Acute pyelonephritis can cause kidney scars and permanent kidney damage [2]. In our study, the presence of kidney scarring was observed in 20 patients (22%), with a slight tendency to a higher risk of scarring in patients older than 2 years or those with the presence of VUR, as previously observed [6, 13, 14, 22, 31]. Children with more extensive parenchymal involvement at admission had an increased risk of scarring (REDSS 2.7 ± 1.1 vs. 2.1 ± 0.9, p = 0.030).

Previous animal studies provided evidence for the efficacy of corticosteroids in preventing kidney scarring that was attributed to a decrease in inflammatory cytokines [15, 16]. Accordingly, a RCT performed in children with APN verified by DMSA demonstrated a protective effect of oral corticosteroids on scar development [20]. That RCT, which included patients with severe damage to the kidney parenchyma in the acute phase and a high risk of scarring, achieved an almost 50% reduction in the number of scars in the prednisolone group, which included only 18 infants. The number of children with scars was very high, since even in the group treated with corticosteroids it was 33%, clearly exceeding the 22% of children with scars in our trial. Our study, which included a larger number of patients with different degrees of parenchymal impairment, failed to demonstrate a protective effect of iv. dexamethasone treatment on kidney scarring. Other trials have investigated the effect of different doses of dexamethasone (both via oral or intravenous administration) on children with febrile UTI and failed to demonstrate a protective effect of corticosteroid administration (although they showed a trend towards a risk reduction) [21, 22]. The study by Shaikh et al. [22] had some important limitations, as they did not confirm APN by DMSA in the acute phase. Thus, the results could be masked by a different proportion of patients with APN, hiding the interpretation of the intervention. Furthermore, as the authors point out, they did not reach the desired sample size to prevent a loss of statistical power. It is true that in clinical practice, it is not common to perform a DMSA in the acute phase, but it does not allow us to draw completely valid pathophysiological conclusions. Finally, it is also worth mentioning that dexamethasone treatment was oral in Shaikh et al., and compliance was defined as 80% of doses administered as reported by parents (which does not exclude a misreporting effect in comparison with those trials performed with iv. treatment under hospitalization). Another trial, the study by Ghaffari et al. [21], shows important methodological inaccuracies and mainly aimed to demonstrate the relationship between permanent high levels of IL-6 and IL-8 during the acute phase of febrile UTI and the subsequent presence of kidney scars, irrespective of the received treatment. Actually, this study did not show a statistically significant protective effect of dexamethasone on kidney scarring, and if we analyze only the patients with APN demonstrated by DMSA, dexamethasone had the same effect in both groups (33% kidney scars); therefore, the data of Ghaffari et al. are very similar to our results.

Different prognostic factors have been postulated to increase the risk of kidney scarring after pyelonephritis [6, 13, 14, 32‐37]. We analyzed whether treatment with dexamethasone reduced the risk of scarring in specific high-risk patients, and the obtained ORs were not significant for these subgroups (i.e., age older 2 years, prolonged fever, VUR, elevated CRP, or magnitude of kidney damage in DMSA). The lack of signification could be affected by a loss of statistical power due to the limited sample size, especially in the subgroup analyses. The analysis of the magnitude of kidney damage allowed us to assess whether our results reproduced the protective effects observed by Huang et al. [20] in severe impairment-affected patients. In our patients, corticosteroids showed the same effect as placebo, reducing parenchymal damage and kidney scarring in both patients with mild and severe impairment (Fig. 2). It is also noteworthy that in infants with VUR, who could be considered the group with the highest risk of scarring, no effect could be demonstrated, possibly due to the small number of patients with dilated reflux in each intervention group.

Finally, we analyzed whether these factors could influence kidney scarring development regardless of corticosteroid treatment. We found that the presence of VUR and a higher early REDSS tended to be associated with kidney scarring, as both variables were increased among infants with kidney scarring (with a trend towards statistical significance, Table 2). These results were confirmed by logistic regression, as both variables modulated the presence of permanent scarring (p = 0.023 for REDSS at the early DMSA and p = 0.054 for VUR). These data confirm previous findings described in the literature and allow us to conclude that the results are in line with those described previously [6, 13, 33].

In summary, our study shows that dexamethasone plus antibiotics did not reduce the risk of scar formation in children with APN compared to antibiotic therapy alone. As other authors have shown, acute severity damage (evaluated in our study as early REDSS), PCT values, and the presence of VUR were independent risk factors for scar formation.