Pathophysiology

Almost all UTIs are ascending in origin and are caused by bacteria in the GI tract that have colonized the periurethral area. After birth, the periurethral area, including the distal urethra, becomes colonized with aerobic and anaerobic microorganisms.[3] These organisms appear to function as a defense barrier against colonization by potential pathogens. Disturbance of the normal periurethral flora, such as may occur when an upper respiratory tract infection is treated with a broad-spectrum antibiotic, predisposes to colonization of the periurethral area by potential uropathogens. [4] Data from studies of women with recurrent UTIs support the concept that periurethral colonization with a uropathogen plays an important role in the pathogenesis of recurrent infections.[5,6] These findings have not been confirmed in children.[7] However, children recently treated with antibiotics do have an increased risk of a febrile UTI compared with children with a nonUTI febrile illness who did not have recent antibiotic exposure. [8] The pathophysiology of UTI reflects a complex interaction between virulence factors of the microorganisms and the host defense.[9] The perineal flora are normal inhabitants of the distal urethra. Urine in the proximal urethra, the urinary bladder, and more proximal sites within the urinary tract is normally sterile. Uropathogens must gain access to the urinary bladder and proliferate if infection is to occur. Bacteria in the distal urethra may gain access to the bladder because of turbulent urine flow during normal voiding, as a consequence of voiding dysfunction, or as a result of the use of instrumentation. In any case, normal voiding results in essentially complete washout of contaminating bacteria. Therefore, urinary bladder colonization does not usually occur unless bladder defense mechanisms are impaired or a virulent strain of bacteria has gained access to the bladder. In the absence of normal bladder emptying, there is proliferation of bacteria in bladder urine and the risk of a UTI. Even with normal bladder emptying, adherence to uroepithelial cells by virulent organisms such as PfimbriatedEscherichia coli may result in a UTI. P fimbriae (or pili) are organelles on E coli that mediate attachment to specific receptors on uroepithelial cells and impair washout of the bacteria.[10] The majority of UTIs in neurologically and anatomically intact children are caused by E

coli. Children with intestinal carriage of P-fimbriated E coli are at increased risk for UTI because of colonization of the periurethral area by these pathogens.[11]

Acute Pyelonephritis
UTI is a general term referring to infection (usually bacterial) anywhere in the urinary tract. It is generally accepted that infection of the upper urinary tract places the patient at risk for kidney damage, while lower UTI, although a cause of morbidity, does not cause renal damage. Acute pyelonephritis is characterized by systemic symptoms, such as fever, abdominal and/or back pain, vomiting and, at times, dehydration. The young infant with acute pyelonephritis may present with a febrile illness with no localized signs of infection. Until about 15 years ago, it was assumed that kidney damage caused by infection was almost always a result of ascent of bacteria from the urinary bladder because of vesicoureteric reflux (VUR).[12] Care of the child with a history of a febrile UTI centered on identification and management of VUR, often as if VUR was a specific disease. Current concepts of the role of VUR in the pathogenesis of kidney infection have changed as a result of studies in which imaging of the cortex of the kidney with dimercaptosuccinic acid or gluco- heptonate scans has been used to diagnose acute pyelonephritis. These studies have shown that some two thirds of children with acute pyelonephritis do not have demonstrable VUR; that is, they have nonreflux pyelonephritis.[12,13] The hypothesis to explain infection of the upper urinary tract in children who have imaging studies showing an absence of VUR is that P-fimbriated E coli and, presumably, other organisms that adhere to uroepithelial cells gain access to ureteral cells because of turbulent flow.[14] Virulent organisms that adhere to the ureteral mucosa cause an inflammatory response that alters the function of the ureter, permitting ascent of bacteria to the kidney. Renal scarring caused by acute pyelonephritis may occur in renal units with, as well as in those without, VUR.[13]This is evidence that it is renal parenchymal infection, rather than VUR, that is responsible for acquired renal scarring (in patients with unobstructed urinary tracts).

However, the infants and young children with an unobstructed urinary tract who are at highest risk for kidney damage caused by a UTI are those with reflux into renal papillae that permit intrarenal reflux, ie, focal pyelotubular backflow.[12] Intrarenal reflux has been observed in 5% to 15% of infants and young children with VUR, but it is unusual in those older than 5 years.[15]

Long-Term Consequences
The advent of intrauterine ultrasonography has brought about marked changes in our understanding of the renal consequences of UTIs. Studies of infants with intrauterine dilatation of the urinary tract have demonstrated that some children previously thought to have incurred kidney damage after a UTI had preexisting intrauterine renal damage.[16] Before the widespread use of intrauterine ultrasonography, these children had their first imaging studies of the urinary tract following a UTI. When kidney damage was found, it was assumed to have been acquired as a result of the UTI. Intrauterine renal damage associated with VUR has 2 distinct but not exclusive patterns.[17] Mild VUR with normal kidneys is found most frequently in female infants, while severe VUR with extensive kidney damage of fetal origin is seen almost exclusively in male infants. Epidemiologic studies show that chronic renal failure caused by kidney damage secondary to recurrent febrile UTIs has become rare in countries where widespread high-quality health care has been available for many years.[16] In countries where such health care has not been available, recurrent febrile UTIs in children without anatomic or neurologic abnormalities of the urinary tract account for 15% or more of patients with chronic renal failure. Congenital renal damage associated with intrauterine VUR or obstruction is a much more common cause of impaired renal function in children in developed countries than is renal scarring secondary to UTI.