Chronic Pyelonephritis

Chronic pyelonephritis is associated with progressive renal scarring, which can lead to end-stage renal disease (ESRD). For example, in reflux nephropathy, intrarenal reflux of infected urine is suggested to induce renal injury, which heals with scar formation.[5] In some cases, scars may form in utero in patients with renal dysplasia with perfusion defects. Infection without reflux is less likely to produce injury. Dysplasia may also be acquired from obstruction. Scars of high-pressure reflux can occur in persons of any age. In some cases, normal growth may lead to spontaneous cessation of reflux by age 6 years.

Factors that may affect the pathogenesis of chronic pyelonephritis are as follows: (1) the sex of the patient and his or her sexual activity; (2) pregnancy, which may lead to progression of renal injury with loss of renal function; (3) genetic factors; (4) bacterial virulence factors; and (5) neurogenic bladder dysfunction. In cases with obstruction, the kidney may become filled with abscess cavities (see Pyonephrosis).

In the United States, VUR may be present in 30-40% of children with UTIs. The prevalence rate of VUR in siblings of patients with chronic pyelonephritis is approximately 35%.[6] VUR and chronic pyelonephritis are less common in African-American children than in white children, with chronic pyelonephritis occurring 3 times more often in white children.[7] Chronic pyelonephritis is also twice as common in females as it is in males.

Chronic pyelonephritis occurs more often in infants and young children (younger than 2 y) than it does in older children and adults.

The Birmingham Reflux Study clearly showed that medical and surgical management are equally effective in preventing renal damage from VUR.[8] Almost all children should receive a trial of medical management.

Although most children with chronic pyelonephritis due to VUR may experience spontaneous resolution of reflux, approximately 2% can still progress to renal failure, and 5-6% can have long-term complications, including hypertension.[9]

Hypertension contributes to the accelerated loss of renal function in persons with chronic pyelonephritis. Reflux nephropathy is the most common cause of hypertension in children, occurring in 10-20% of children with VUR and renal scars. The resolution of reflux does not appear to correct hypertension.

Complications of chronic pyelonephritis can also include the following:

• Proteinuria
• Focal glomerulosclerosis
• Progressive renal scarring leading to end-stage renal disease ^[10]
• Xanthogranulomatous pyelonephritis (XPN) - May occur in approximately 8.2% of cases and in 25% of patients with pyonephrosis; XPN can be confused with renal cancer ^{[11, 12, 13, 14, 15, 16, 17]}
• Pyonephrosis - May occur in cases of obstruction
• Progressive renal scarring (reflux nephropathy)

Some children with chronic pyelonephritis may report the following:

• Fever
• Lethargy
• Nausea and vomiting
• Flank pain or dysuria

A change in bowel or urinary frequency may be present in children with vesicoureteral reflux (VUR).[18]

The following may be noted on physical examination:

• Hypertension
• Failure to thrive in young children
• Flank tenderness

The characteristic renal scars of vesicoureteral reflux (VUR) are often present at the time of the initial diagnosis of chronic pyelonephritis. New renal scars may develop in 3-5% of patients after the initial evaluation. The progression of renal scars is inversely related to the promptness with which specific antibiotic therapy is instituted. The presence of new scars often suggests the occurrence of breakthrough infections.

Urinalysis results may reveal pyuria. Obtain a urine culture, which often isolates gram-negative bacteria, such as Escherichia coli or Proteus species. A negative urine culture does not exclude a diagnosis of chronic pyelonephritis. Proteinuria may be present and is a negative prognostic factor for this chronic pyelonephritis. Serum creatinine and blood urea nitrogen (BUN) levels are elevated (azotemia).

Kidney biopsy specimens show focal glomerulosclerosis in advanced reflux nephropathy, while xanthogranulomatous pyelonephritis must be distinguished from renal malakoplakia based on the presence of inclusions called Michaelis-Gutmann bodies in the latter.

On an intravenous urogram, caliceal dilatation and blunting with cortical scars helps to establish the diagnosis of pyelonephritis. Ureteral dilatation and reduced kidney size also may be evident.

Voiding cystourethrogram (VCUG) findings may document the reflux of urine to the renal pelvis and ureteral dilatation in children with gross reflux.[20]  To strike the balance between obtaining high-quality images and minimizing radiation exposure, radiology departments should observe the “as low as (is) reasonably achievable” (ALARA) Image Gently guidelines.[21]

Radioisotopic scanning with technetium dimercaptosuccinic acid (DMSA) is the gold standard for detecting renal scars and is more sensitive than intravenous pyelography.[22]  

Cystoscopy findings show evidence of previous reflux at the ureteral orifices, even if VCUG images show no reflux because of the spontaneous cessation of reflux due to puberty.

Computed tomography (CT) scanning is the procedure of choice to help diagnose xanthogranulomatous pyelonephritis.[14, 23] Renal ultrasonographic images may show calculi, but ultrasonography is not a sensitive screening procedure for reflux nephropathy. However, many cases of VUR are suggested by prenatal ultrasonographic findings.

Contrast-enhanced voiding urosonography (CEVUS) has been found to be a sensitive, radiation-free imaging method for the diagnosis of VUR, however its precise role in the diagnosis of pediatric VUR remains to be established.[24]

In the child with vesicoureteral reflux (VUR) who is experiencing chronic pyelonephritis, the goals of management are as follows:

• Prevent recurring febrile urinary tract infections (UTIs)
• Prevent kidney injury
• Minimize the morbidity of treatment and follow-up

Preventive strategies include the administration of prophylactic antibiotics, endoscopic injection of dextranomer hyaluronic acid, and antireflux surgery.[4]  Selecting the treatment option for different grades of VUR  depends on the clinical presentation and kidney function.

According to a study by Su et al, risk factors for the development of breakthrough UTI in children with VUR who receive continuous antibiotic prophylaxis include younger age at the initial diagnosis of UTI (≤ 12 mo), bilateral VUR, and bladder and bowel dysfunction.[25]  

If symptomatic breakthrough UTI occurs during preventive therapy, a change in therapy is recommended. The clinical scenario (ie, VUR grade, degree of renal scarring, and evidence of bowel/bladder dysfuntion), as well as parental preferences, will guide the choice of alternative treatment. In the absence of new renal cortical abnormalities, a change in the antibiotic used for prophylaxis may be effective. Therapy with curative intent, including open surgery, offers protection against febrile UTI but is associated with morbidity. Endoscopic injection therapy may be less successful than open surgery in resolution of VUR.[4]

Continuous antibiotic prophylaxis (CAP) is often the initial treatment. Agents typically selected include amoxicillin, trimethoprim/sulfamethoxazole (Bactrim), trimethoprim alone, or nitrofurantoin. CAP should continue until puberty or until reflux resolves. 

Endoscopic Injections

Endoscopic injection have advantages over open surgery, including less postoperative pain and fewer bladder spasms and infections, and the absence of surgical scarring. Endoscopic injection can be performed in a shorter operation time, in an outpatient setting, and with minimal use of postoperative analgesics and is preferred as the first-line treatment for children with vesicoureteral reflux (VUR).[26]  

The American Urological Association (AUA) Vesicoureteral Reflux Guideline Update Committee analyzed data from 17,972 patients, and reported that the overall success rate of a single endoscopic treatment was 83.0%, compared to 98% success rates for open surgery.[4] When an injection treatment fails, open ureteral reimplantation may be needed to treat persistent VUR.[26]

Open Ureteral Reimplantation

Surgery entails the reimplantation of the ureters, with the creation of an adequate submucosal tunnel and detrusor support. Open reimplantation surgery may be a primary treatment or may be performed as second-line therapy after endoscopic injection failure. Studies have reported no adverse effect on success rates, operation time, or complications when open reimplantation follows endospic injection treatment.[26]

Laparoscopic Ureteral Reimplantation

Robot-assisted laparoscopic extravesical ureteral reimplantation has been proposed as a minimally invasive alternative to open ureteral reimplantation for correcting primary VUR in children. However, the current literature contains conflicting data regarding the safety and efficacy of this approach. In a multi-institutional review, a success rate of 87.9% was reported in a series of 260 patients who underwent robot-assisted laparoscopic extravesical ureteral reimplantation for primary VUR.[27]

Progressive kidney injury can be reduced by dietary protein restriction, while aggressive blood pressure control aids in slowing progression of kidney disease. Angiotensin-converting enzyme (ACE) inhibitors are particularly beneficial in treating hypertension.

Careful follow-up and monitoring of kidney function is beneficial. Vigorously treat a UTI or bacteriuria in a patient who is pregnant, to prevent acute kidney injury, preeclampsia, and abortion.[28]

Renal ultrasonography is recommended for siblings of patients with VUR.[29]  If an abnormality is found, then perform a voiding cystourethrogram (VCUG).

The 2010 American Urological Association (AUA) guidelines for management and screening of primary vesicoureteral reflux (VUR) in children were reconfirmed in 2017.  Key recommendations for initial management of children less than 12 months old include the following[4] :

• Voiding cystourethrogram for neonates with high-grade (Society of Fetal Urology grade 3 and 4) hydronephrosis, hydroureter, or an abnormal bladder on ultrasound (late-term prenatal or postnatal), or who develop a urinary tract infection (UTI) on observation.
• Continuous antibiotic prophylaxis (CAP) for VUR in patients with a history of a febrile UTI
• CAP for VUR grades III–V in patients with no history of febrile UTI identified through screening
• CAP may be offered for VUR grades I-II in patients with no history of UTI identified through screening

For children over one year old, several factors influence clinical outcome, including a greater likelihood of bowel and/or bladder dysfunction (BBD), lower probability of spontaneous resolution of VUR, lower risk of acute morbidity from febrile UTI, and a greater ability of the child to communicate complaint of symptoms of acute infection. Thus, the AUA notes that management decisions must take into account recognition of the clinical context (ie, age, VUR grade, presence of scarring, and parental preferences). The guidelines make the following treatment recommendations[4] :

• In the absence of BBD, recurrent febrile UTI, or renal cortical abnormaties, CAP is optional. Observational management without continuous antibiotic prophylaxis, with prompt initiation of antibiotic therapy for UTIs, may be also be considered. 
• CAP should be initiated in any child with VUR and BBD, recurrent febrile UTI, or renal cortical abnormaties.
• Surgical intervention, including both open and endoscopic methods, may be considered. 
• Following endoscopic injection of bulking agents, a postoperative voiding cystography should be performed
• With the occurrence of a febrile UTI following resolution or surgical treatment of VUR, evaluation for BBD or recurrent VUR is required.

The penicillins (amoxicillin) and first-generation cephalosporins are the drugs of choice for chronic pyelonephritis because of good activity against gram-negative rods and good oral bioavailability. In infants, the choice of antibiotics is either amoxicillin or a first-generation cephalosporin. In patients aged 3-6 months, therapy can be changed to sulfamethoxazole or nitrofurantoin. Older children and adults may be treated with trimethoprim-sulfamethoxazole (Bactrim).

Once one antibiotic is chosen, frequent changes in the antibiotic regimen are discouraged, to help prevent the development of resistance.

Class Summary

Antibiotic therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Amoxicillin (Moxatag)

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

Cephalexin (Keflex)

Cephalexin is a first-generation cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. It has bactericidal activity against rapidly growing organisms.

Trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS, Sulfatrim)

Trimethoprim/sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. Bacterial species it acts against include common urinary tract pathogens, except Pseudomonas aeruginosa.

Nitrofurantoin (Furadantin, Macrodantin, Macrobid)

This is a synthetic nitrofuran that interferes with bacterial carbohydrate metabolism by inhibiting acetylcoenzyme A. Nitrofurantoin is bacteriostatic at low concentrations (5-10 mcg/mL) and bactericidal at higher concentrations.