Corticosteroids for renal scar prevention in children with acute pyelonephritis

Abstract

Question Acute pyelonephritis in children is of great concern and I usually refer these patients to a pediatrician or send them to the emergency department owing to the risk of renal scarring. Are steroids an acceptable treatment to reduce risk of scarring?

Answer Several agents have been studied in an effort to prevent renal scar formation following acute pyelonephritis in children. Use of corticosteroids, in conjunction with standard therapy for acute pyelonephritis, shows promising findings. However, evidence is very limited and steroids should not be offered on a regular basis as part of treatment.

Pediatric urinary tract infections (UTIs) result in more than 1.1 million (0.7%) physician office visits by children annually in North America.¹ A 2008 meta-analysis² found that the prevalence of UTIs is 7% among febrile infants younger than 24 months of age and 7.8% among children younger than 19 years of age with urinary symptoms, with or without fever. Circumcision reduces the prevalence of UTIs in male infants, especially during the first 3 months of life (prevalence of 2.4% in circumcised and 20.1% in uncircumcised boys). Nevertheless, in boys 6 to 12 months old, the prevalence rates decline to 0.3% and 7.3% in circumcised and uncircumcised boys, respectively.² This large difference might possibly be due to sampling error, associated with difficulty in obtaining a clean sample owing to foreskin retraction.³ Prevalence among girls varies with age (Table 1).² Escherichia coli is the most common bacteria responsible for pediatric UTIs (80% of cases).⁴

Table 1.

Prevalence rates of UTIs in female infants younger than 24 months old

AGE, MO	PREVALENCE RATES, %
0–3	7.5
3–6	5.7
6–12	7.3
12–24	2.1

UTI—urinary tract infection.

Data from Shaikh et al.²

Acute pyelonephritis is an infection of the upper urinary tract that might lead to renal scarring potentially followed by hypertension and renal function impairment.⁵ The overall incidence of renal scarring is estimated at 42% (26.5% in Australia to 49.0% in Asia).⁶

Renal scarring is reported to be a result of renal parenchymal inflammation. Bacterial infection activates neutrophils and macrophages, and those migrate to the inflammation site. Phagocytosis leads to release of cytokines like interleukins (1, 6, and 8), metabolites of arachidonic acid, and noxious inflammatory mediators such as oxygen radicals and lysosomal enzymes. This results in tissue damage and scar formation.⁷ Renal scarring can be detected by dimercaptosuccinic acid (DMSA) renal scintigraphy several weeks to months after the infection.⁸

Conflicting findings have been published in regard to the value of antibiotics, an important treatment for pyelonephritis, when evaluating their contribution to prevent scarring in children.^9–12 A recent study from Greece provided confirmation that delay in treatment initiation of 72 hours or more is a risk factor for permanent renal scar formation in children with febrile UTI.¹³

Corticosteroids,^14,15 nonsteroidal anti-inflammatory drugs,¹⁶ vitamin A,¹⁷ vitamin E,¹⁸ combination of vitamin C and E,¹⁹ melatonin,²⁰ mesenchymal stem cells,²¹ and montelukast²² were all studied in both animals and humans as potential therapies to reduce renal inflammation and scar formation, with limited success.

Corticosteroids for renal scar prevention

A rat study from Turkey illustrated that the combination of ceftriaxone with either a nonsteroidal anti-inflammatory drug (eg, ketoprofen) or a corticosteroid (eg, methylprednisolone) in acute pyelonephritis decreased subsequent renal scar formation diagnosed by both follow-up DMSA scan and histopathologic evaluation.¹⁴ This positive finding was also seen in a human study that assigned 84 Taiwanese children younger than 16 years of age, with a first episode of acute pyelonephritis, to receive either an antibiotic with oral methylprednisolone for 3 days or antibiotics with placebo.¹⁵ A DMSA scan 6 months later revealed a lower percentage of children who had renal scarring in the treatment group compared with the placebo group (33% vs 60%, respectively; P < .05). The median cortical defect volume was also decreased in the treatment group compared with placebo (0 vs 1.5 mL, respectively; P < .01).

Finally, as cytokines play a considerable role in renal scar formation following acute pyelonephritis, previous studies have demonstrated that subsequent formation of renal scarring after acute pyelonephritis can be predicted by measuring urine cytokine levels.²³ Sharifian et al⁷ concluded that dexamethasone, in conjunction with antibiotics, significantly (P < .05) reduced urine cytokines (interleukins 6 and 8) and serum creatinine ratios at presentation and at 72 hours following treatment in children aged 3 months to 10 years with acute pyelonephritis admitted to a children’s hospital. Thirty-four children were treated with ceftriaxone in combination with dexamethasone for 3 days, compared with 20 children in a control group that received ceftriaxone alone. The difference between cytokine-creatinine ratios in initial and follow-up urine samples was significant in the case group (P < .001) but not in the control group. This result suggests that dexamethasone use in acute pyelonephritis might have a role in preventing renal scarring by reducing urine cytokines concentrations.

Conclusion

Corticosteroids are effective as an adjunctive therapy in addition to standard treatment of children with acute pyelonephritis, in order to prevent subsequent renal scarring. However, research is extremely limited, especially in children, and more studies are needed to confirm these findings before steroids can be used in practice as an acceptable treatment to reduce risk of scarring.

PRETx Pediatric Research in Emergency Therapeutics

Child Health Update is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (www.pretx.org) at the BC Children’s Hospital in Vancouver, BC. Dr Sakulchit is a member and Dr Goldman is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine.

Do you have questions about the effects of drugs, chemicals, radiation, or infections in children? We invite you to submit them to the PRETx program by fax at 604 875-2414; they will be addressed in future Child Health Updates. Published Child Health Updates are available on the Canadian Family Physician website (www.cfp.ca).