Pediatric Pyelonephritis

UTIs are generally ascending in origin and caused by perineal contaminants, usually bowel flora. However, in neonates, infection is assumed to be hematogenous in origin rather than ascending. This feature may explain the nonspecific symptoms associated with UTI in these patients. After the neonatal period, bacteremia is generally not the source of infection; rather, UTI or pyelonephritis is the cause of the bacteremia.

Bacterial pathogens are the most common cause of pyelonephritis. Bacterial sources of pyelonephritis include the following:

• Escherichia coli - This is by far the most common organism, causing more than 90% of all cases of acute pyelonephritis

• Extended-spectrum beta-lactamase–producing E coli is becoming more frequent[2]

• Klebsiella oxytoca and species

• Proteus species

• Enterococcus faecalis and species

• Gram-positive organisms, including staphylococcal species and group B Streptococcus- These are rare causes of acute pyelonephritis

Risk factors

High-grade vesicoureteral reflux (VUR) may increase the risk for pyelonephritis, and VUR has been reported in as many as 33% of children with acute pyelonephritis. Congenital or acquired anomalies, including dysplasia, hypoplasia, and obstruction, increase the risk for UTI, VUR, and pyelonephritis. Even in the absence of urinary tract abnormalities, cystitis may result in VUR or worsen preexisting VUR and lead to pyelonephritis. VUR increases the risk for and size of renal cortical lesions, although clinically significant lesions can develop in the absence of VUR.

Delayed or incomplete voiding, as seen with neurogenic bladder, obstruction, or dysfunctional voiding increases the risk for urinary stasis and overgrowth of colonizing bacteria. Constipation may impair bladder emptying, leading to stasis and ascending infection.

Catheterization may increase the risk of introducing periurethral bacteria into the bladder. Clean intermittent catheterization leads to colonization of the bladder that might lead to pyelonephritis if stasis allows any infection to ascend.

Boys who are uncircumcised have a risk of UTI that is 2.2% higher than that of circumcised boys. The risk of acute pyelonephritis is not established.

Sexual activity may cause urethral inflammation, lead to bladder colonization, and increase the risk for acute pyelonephritis.

Familial inheritance of susceptibility to pyelonephritis may be related to chemokine receptor inheritance. Host genetic factors that promote inflammation contribute to renal scarring. Interleukin (IL)-8 and CXCR1 polymorphisms, ACE insertion/deletion (ACE I/D) gene polymorphism, and tumor necrosis factor-[alpha] polymorphism have been identified as potential mediators to tissue fibrosis and subsequent renal scarring following acute pyelonephritis.[3]

United States statistics

The prevalence of pyelonephritis varies by age and sex. About 60-65% of children with febrile UTIs have acute pyelonephritis, as defined by presence of abnormalities of the renal cortex on dimercaptosuccinic acid (DMSA) scan.[4] In general, 2.7-4.1% of children younger than 2 years who have fever also have UTI, even if another source is identified. UTI is present in 17% of white girls younger than 2 years with fever (temperature >39°C).

Race-, sex-, and age-related demographics

The prevalence of urinary infection is 5-fold greater in white children than in black children and 2-fold greater than in children of other races.

The prevalence of UTI in uncircumcised males is 8 times greater than it is in circumcised males in the first year of life. In addition, the incidence of UTI is higher in uncircumcised male infants than in female infants. After age 12 months, UTIs are more frequent in girls than in boys.

In neonates, infection is generally hematogenous in origin. Girls younger than 11 years have a 3-5% risk of infection. For boys younger than 11 years, the risk is 1%. Febrile infants are more likely (6-8%) to have UTI as a source of fever than they are to be bacteremic (< 1%).[5] Children aged 1-5 years have a 3-fold increased risk of acute pyelonephritis on DMSA scanning compared with infants, whereas children older than 5 years have a 4.5-fold greater risk of acute pyelonephritis when evaluated for febrile UTI.

Most cases of pyelonephritis respond readily to antibiotic treatment without further sequelae. Permanent renal scars develop in 18-24% of children after acute pyelonephritis. Treatment within 5-7 days from the onset significantly reduces the formation of renal scars.

For patients with severe cases or chronic infections, appropriate treatment, imaging, and follow-up help to prevent long-term sequelae.

VUR often resolves without permanent damage. Recurrent pyelonephritis in the setting of VUR may be an indication for ureteral reimplantation.

Morbidity/mortality

Acute mortality is uncommon and is related to sepsis. Generalized bacteremia or sepsis may develop from pyelonephritis. In patients younger than 2 years with acute pyelonephritis, 8-10% have bacteremia.

Acute renal parenchymal injury occurs in 20-90% of children with acute pyelonephritis. About 40% of these children have long-term renal scarring, which may lead to hypertension and renal insufficiency. Risk factors for renal scarring include young age, treatment delay, infection by P-fimbriated E coli and VUR. Treatment of pyelonephritis within the first 5-7 days after onset is necessary to prevent renal damage.

Impaired renal tubular function and secondary pseudohypoaldosteronism may develop in infants with pyelonephritis. Infants may develop hyperkalemia and hyponatremia.

Complications

Dehydration is the most common acute complication of pyelonephritis. Intravenous (IV) fluid replacement is necessary in severe cases. Acute pyelonephritis may lead to renal abscess formation.[6]  Long-term complications include renal parenchymal scarring,[7]  hypertension, decreased renal function, and, in severe cases, renal failure. Renal scarring with long-term renal insufficiency is a significant concern.[8]

Signs and symptoms of urinary tract infection (UTI) and pyelonephritis vary with the age of the patient. Neonates often present with nonspecific symptoms of jaundice, hypothermia or fever, poor feeding, vomiting, and failure to thrive. Neonates, especially male newborns, may develop hyponatremia and hyperkalemia as a result of secondary pseudohypoaldosteronism.

Infants and young children aged 2 months to 2 years often present with nonspecific symptoms of fever lasting longer than 48 hours, as well as with poor feeding, vomiting, and diarrhea. Their urine may be malodorous[9] ; hematuria may be noted.

Preschoolers and school-age children present with fever for greater than 48 hours. They may complain of abdominal pain or flank pain. Vomiting, diarrhea, and anorexia may be present. Their urine is typically malodorous, and hematuria may be noted. Voiding-related symptoms including enuresis, dysuria, urgency, and frequency, may occur but need not be present.

Adolescents are most likely to present with the classic adult symptoms of fever, often with chills, rigors, and flank pain. They may have abdominal and suprapubic pain, along with voiding-related symptoms of frequency, dysuria, and hesitancy. Their urine is most often malodorous, and hematuria is variably present.

Because many symptoms of pyelonephritis are nonspecific, complete physical examination is necessary to exclude other causes of the patient's symptoms. Specific findings are as follows.

General appearance

Most infants and children are uncomfortable and appear ill. Older children and adolescents may be mildly to moderately ill.

Vital signs

Fever may be present, with body temperature of more than 38°C, and often more than 39°C. Tachycardia may be present, secondary to fever and pain. Blood pressure is usually normal. Hypertension should raise concern for clinically significant obstruction or renal parenchymal disease. Hypotension may occur if sepsis and shock are present.

Abdominal findings

Abdominal pain may be present. A mass may indicate obstruction, hydronephrosis, or another anatomic abnormality. Suprapubic pain may be present. A palpable bladder indicates obstruction or functional difficulty in starting or completing voiding.

Adolescent girls may have right upper quadrant pain similar to that observed in patients with cholecystitis.

Back findings

Tenderness in the costovertebral angle (CVA), back, or flank is likely to be present in older children and adolescents. Sacral dimple or birthmarks overlying the spine may be associated with an underlying anomaly of the spinal cord. Vertebral abnormalities may be evident.

Genitourinary findings

Assess for irritation, pinworms, vaginitis, trauma, or signs of sexual abuse. A bulging hymen suggests an imperforate hymen and urethral obstruction.

Neurologic findings

Weak lower extremities or diminished reflexes may be signs of spinal-cord dysfunction, and they may be associated with a neurogenic bladder.

It is prudent to order urinalysis (and urine culture in those with abnormal findings) in all febrile boys younger than 6 months and febrile girls younger than 24 months with fever lasting more than 48 hours. Female adolescents who present with symptoms of UTI, pyelonephritis, and/or vaginitis and who are sexually active must be evaluated for pregnancy and sexually transmitted diseases.

An increased blood urea nitrogen (BUN) and/or creatinine level should raise the suspicion for hydronephrosis or renal parenchymal disease.

Urine must be collected with proper technique to be useful for diagnosing cystitis or acute pyelonephritis. Suprapubic bladder aspiration should be performed in uncircumcised male patients in whom the urethral meatus is not visible, as well as in infants with periurethral irritation.

Bladder catheterization is the appropriate technique for obtaining a urine sample in most infants and young children. In neonates, suprapubic bladder aspiration may be used. A clean-catch, midstream urine sample may be obtained in children who can cooperate and void on request.

A specimen collected by using sterile bag may be used for urinalysis but not for urine culture. A urine specimen that is positive for nitrite, leukocyte esterase, or blood may indicate UTI. Microscopic examination of an unspun sample that contains more than 10 white blood cells (WBCs) per high-powered field or any bacteria is highly predictive of a positive urine culture. Red blood cell (RBC) or WBC casts suggest underlying renal parenchymal disease. Epithelial cells suggest skin contamination. A normal result from urinalysis does not exclude pyelonephritis.[10]

Urine cultures must be obtained in all children with suspected pyelonephritis. Treatment should not be commenced on the basis of urinalysis results, and normal urinalysis findings do not exclude an infection. Acute pyelonephritis may be present even if urine cultures demonstrate no growth.

A clean-catch urine specimen with more than 100,000 colony-forming units (CFUs) of a single organism is considered diagnostic of a UTI. Organisms, such as Lactobacillus, Staphylococcus, or Corynebacterium species, may not be clinically relevant.

Cultures showing more than 100,000 CFUs of a single organism obtained by means of transurethral catheterization are 95% sensitive and 99% specific for UTI. Specimens growing 104 CFUs may be consistent with infection, but the test should be repeated if infection is not likely and if treatment has not yet commenced.

Cultures from bagged urine specimens are useful only if no growth is observed. Bagged urine specimens result in a false-positive rate of 85%. Before treatment is started on the basis of results from a bagged-specimen test, a catheterized or suprapubic specimen should be obtained.

Structural abnormalities of the urinary tract may be associated with infections secondary to multiple organisms or unusual gram-negative bacteria, such as Pseudomonas aeruginosa.

Lertdumrongluk et al investigated whether urine heparin binding protein (UHBP), a cytokine released from activated neutrophils, was a useful diagnostic tool for acute pyelonephritis (APN) and concluded that UHBP is a valid adjunctive diagnostic tool for aiding clinicians in making rapid treatment decisions for APN.[11]

Some patients may have electrolyte abnormalities, which may be secondary to vomiting or diarrhea.

Secondary pseudohypoaldosteronism may develop, with impaired renal tubular function, in infants with pyelonephritis. Mild hyponatremia and hyperkalemia may be present. Infants with underlying urinary-tract anomalies have an increased risk of this electrolyte imbalance, which resolves when the infection is treated.

An elevated WBC count is nonspecific and does not help in distinguishing lower UTI from upper UTI. In the presence of a febrile UTI, however, an erythrocyte sedimentation rate (ESR) of more than 30 mm/h is highly predictive of acute pyelonephritis.

C-reactive protein (CRP) levels are correlated with parenchymal defects on DMSA scanning. Elevated CRP concentrations are sensitive, but nonspecific, markers of renal parenchymal involvement in the febrile infant and child with UTI. CRP values may be used to distinguish bladder colonization from acute pyelonephritis in a febrile child with bacteriuria and a neurogenic bladder.

Procalcitonin is an acute inflammatory marker with a sensitivity of 70-95% and a specificity that approaches 90% for renal involvement in infants and children with febrile UTI. Although less sensitive than CRP, procalcitonin is more specific for the diagnosis of acute pyelonephritis. Procalcitonin values are better correlated with long-term renal scarring than is CRP.[12, 13]

Procalcitonin levels near 0.5 ng/mL may not consistently correlate with acute pyelonephritis. As procalcitonin levels increase, the severity of renal lesions on DMSA increases. Higher levels of procalcitonin predict VUR in infants and children at the onset of pyelonephritis.[14]

Serum and urinary IL-6 and IL-8 are correlated with renal involvement in infants and children with UTI with high sensitivity (81-88%) and acceptable specificity (78-83%). These markers are not reliable in neonates with suspected acute pyelonephritis.

A Cochrane review aimed to determine whether procalcitonin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) can replace the acute DMSA scan in the diagnostic evaluation of children with UTI. The review found that the ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. The review also reported that the procalcitonin test seems better suited for ruling in pyelonephritis, however, the study could not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.[15]

A study reviewed 138 children with pediatric UTIs to compare the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) with procalcitonin, C-reactive protein, and white blood cells for predicting acute pyelonephritis. The study reported that at the best cutoff values of all the biomarkers examined for diagnosing acute pyelonephritis, plasma NGAL level had the highest sensitivity (86%), specificity (85 %), positive predictive value (81%), and negative predictive value (89%). The study also found that 117 ng/ml was the optimal NGAL cutoff value.[16]

A study by Lee et al that retrospectively analyzed the data of 177 infants with febrile UTI reported that higher D-dimer levels can also be used as an inflammatory marker for acute pyelonephritis.[17]

Radiographic studies are generally not indicated to diagnose acute pyelonephritis. Studies may be indicated, however, if the child's condition does not respond to treatment as expected and if colonization must be distinguished from infection in the patient with chronic bacteriuria.

Guidelines from the American Academy of Pediatrics recommend imaging after first febrile UTIs in infants and young children to identify abnormalities that may predispose them to recurrent infection or renal scarring.[18]

In children who have not had ultrasonography performed in the prenatal period, this study may be useful to exclude congenital malformations but is otherwise not helpful in the evaluation of acute pyelonephritis. Renal ultrasonography is useful for determining the size and shape of the kidneys but is generally poor for visualizing nondilated ureters. In addition, it does not provide information regarding renal function.

Renal ultrasonography has low sensitivity (50%) in detecting acute pyelonephritis, although focal abnormalities on ultrasonography, combined with a CRP level of more than 70 mg/L, may be predictive of renal scarring.

Findings on power Doppler ultrasonography have been correlated with DMSA findings of acute pyelonephritis. Renal ultrasonography is useful in the diagnosis of urolithiasis, hydronephrosis, hydroureter, ureteroceles, and bladder distention.[19]

VCUG

Voiding cystourethrography (VCUG) is useful for visualizing the urethral and bladder anatomy and for the detecting VUR. Following a second febrile UTI, VCUG may be performed after 3-4 days of therapy to ensure that bladder irritability has resolved and that the urine is sterilized. The voiding phase is needed to evaluate for VUR and posterior urethral valves.

Consistent with new recommendations, VCUG is no longer required as a mandatory part of the evaluation of children with their first febrile urinary tract infection,[20] although it may be of benefit for infants with abnormal 6-month follow-up DMSA scans.[21]

Nuclear cystography

This study is good for evaluating the bladder and detecting VUR. However, it does not permit adequate evaluation of the urethra and is therefore not used for an initial evaluation of the urologic anatomy.

Cystography has only about 1% of the radiation dose of fluoroscopic study. Cystography may be used for serial follow-up studies.

Nuclear cortical scanning depicts tubular damage and scarring. It provides information regarding the general size of the kidneys; however, it does not provide detailed information regarding the collecting system. DMSA scanning is not necessary to evaluate or follow up most episodes of acute pyelonephritis, although DMSA has a sensitivity of more than 90% in detecting changes that are suggestive of acute pyelonephritis. Radiation exposure to the patient undergoing this procedure is low.

This study most frequently involves the use of technetium-99m (99m Tc) DMSA to depict renal cortical scarring. The volume of the initial defect is useful in predicting the development of renal scars.

Follow-up DMSA scans performed more than 6 months after acute pyelonephritis resolves are useful to detect permanent renal scarring. Studies performed less than 6 months after acute pyelonephritis may reveal residua of the original infection rather than permanent scars.

DMSA scans can help in determining the cause of fever in children with chronic bacteriuria, such as patients with spinal-cord injury and those who undergo clean intermittent catheterization.

CT scanning

Enhanced computed tomography (CT) scanning may be useful in distinguishing acute pyelonephritis from other causes of fever. However, increased radiation exposure makes CT scanning a less favorable study in children, especially because ultrasonography is generally adequate in defining the anatomic structure. [#WorkupProcedures]

MRI

Gadolinium-enhanced magnetic resonance imaging (MRI) scans are correlated with DMSA scans in detecting renal parenchymal defects and are effective in distinguishing acute inflammation from scars. MRI is superior to nuclear scintigraphy in distinguishing acute inflammation from chronic scars. MR cystography may be useful in evaluating VUR. Sedation is generally required in MRI.[22, 23]

Routine supportive care in pyelonephritis includes adequate hydration, analgesia, and the use of antipyretics. IV fluid replacement and parenteral antibiotics are indicated for children unable to take medication and fluids orally. IV therapy may be continued until the child can receive oral medication and fluids. Septic or toxic patients require hospitalization for treatment.

Treatment with fluids and oral antibiotics may be given on an outpatient basis if children are not vomiting and not markedly ill.[24]

The optimal duration of therapy is not well studied, although recommended treatment is in the range of 7-14 days. Some studies have shown that recurrent infection rates increase with short courses of treatment.

Deterrence and prevention

A study noted that in children with or without primary nonsevere reflux, prophylaxis does not reduce the rate of recurrent febrile UTIs after the first episode and thus is no longer recommended.[25, 26]

A study by Lee et al compared the effectiveness of probiotic and antibiotic prophylaxis or no-prophylaxis in infants with pyelonephritis and normal urinary tract. The study found that the incidence of recurrent UTI in the probiotic group was 8.2%, 20.6% in the no-prophylaxis group and 10.0% of the antibiotic group.[27]

Consultations

Consultations are typically not required at the time of presentation. A urologist should be consulted for an infant or child with obstruction or a clinically significant anomaly of the urinary tract. Consultation with an infectious diseases specialist is necessary only if an unusual or resistant organism is identified. Consult a nephrologist when patients have impaired renal function.

The results of urine cultures ultimately dictate the choice of antibiotics.[28] Because E coli causes more than 95% of all cases of acute pyelonephritis in children, initial treatment should be based on regional susceptibility to this pathogen. Because of high resistance rates to amoxicillin, initial treatment should include a cephalosporin, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole (TMP-SMZ), or aminoglycoside.[29, 30, 31]

Initial therapy with IV antibiotics for 3-4 days followed by oral therapy to complete a 10-14 day course is equivalent to 10-14 days of IV therapy.

Initial oral therapy with cefixime or amoxicillin-clavulanate is equivalent to IV ceftriaxone for 3 days followed by oral therapy. Rates of renal scarring are equal in children treated orally or intravenously, although further study is needed to determine whether a subgroup of children with dilating VUR may have high rates of renal scarring if treated with oral antibiotics. Further studies are needed to ensure that currently available antibiotics have the same efficacy. The results of one study noted that children with a high risk of renal scar formation realized a reduced occurrence and/or severity of renal scarring with antibiotic therapy combined with oral methylprednisolone sodium phosphate (1.6 mg/kg/d for 3 d).[32]

A single dose of ceftriaxone given intramuscularly (IM) followed by oral therapy offers no advantage over 10 days of oral therapy alone. Hospitalization is required in similar numbers because of vomiting.

IV gentamicin may be dosed daily, rather than 3 times a day, for children who require IV treatment or who are infected with multiresistant organisms.

Hospitalization is necessary for pyelonephritis in any of the following situations:

• Toxicity or sepsis

• Signs of urinary obstruction or significant underlying disease

• Inability to tolerate adequate oral fluids or medications

• Infants and children younger than age 2 years with febrile UTI, presumed pyelonephritis

• All infants younger than age 3 months

Patients treated exclusively in the outpatient setting should be reevaluated in 48 hours to ensure adequate hydration and an appropriate response to therapy. For a first infection, perform renal ultrasonography. Manage constipation and voiding dysfunction. Recommendations for imaging following febrile UTI are in flux.[33, 34]

As previously stated, most cases of pyelonephritis respond readily to antibiotic treatment without further sequelae. Antibiotic therapy should be started after the urinalysis and culture have been performed, with the results of urine culture ultimately dictating the choice of antibiotics.[28] A 7- to 14-day course of antibiotics is recommended. Special attention is needed when dosing antibiotics in neonates and in infants born prematurely.

Class Summary

Empiric antibiotics should be chosen to cover E coli and Enterococcus, Proteus, and Klebsiella species.

Cefixime (Suprax)

Cefixime is a third-generation cephalosporin with broad, gram-negative activity. The drug arrests cell-wall development. Tablets are no longer available in United States; a suspension is available from Lupin Pharmaceutical.

Gentamicin

This is an aminoglycoside antibiotic for gram-negative coverage. Gentamicin is administered parenterally and may be coadministered with ampicillin.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity; it has decreased efficacy against gram-positive organisms. Ceftriaxone arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin with a gram-negative spectrum; it has decreased efficacy against gram-positive organisms. Cefotaxime arrests bacterial cell ̶ wall synthesis.

TMP-SMZ (BactrimDS, Septra DS)

TMP-SMZ inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. It exerts antibacterial activity against common urinary tract pathogens.

Amoxicillin and clavulanic acid (Augmentin, Amoclan)

This is an amino penicillin with a beta-lactamase inhibitor. It is for infants and children over age 3 months, base dosing on amoxicillin content. Because of different amoxicillin–clavulanic acid ratios in the 250-mg (250 mg/125 mg) versus 250-mg chewable tablet (250 mg/62.5 mg), do not use the 250-mg tablet until the child weighs more than 40 kg.

Amoxicillin (Moxatag)

Amoxicillin interferes with the synthesis of cell-wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Ampicillin

Ampicillin has bactericidal activity against susceptible organisms. It is administered parenterally and is used in combination with gentamicin or cefotaxime. Ampicillin is an alternative to amoxicillin when patients are unable to take medication orally.

Ciprofloxacin (Cipro, Proquin)

Ciprofloxacin is a fluoroquinolone that inhibits bacterial deoxyribonucleic acid (DNA) synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Ciprofloxacin has no activity against anaerobes. Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms have disappeared.

Ceftolozane/tazobactam (Zerbaxa)

Indicated for children aged birth and older with complicated urinary tract infections (cUTI), including pyelonephritis, caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.