**1. Introduction**

Urinary tract infections (UTIs) are significant problem in infants and children and may be associated with renal scarring, which can cause serious long-term complications particularly hypertension and renal failure. The common characteristic of all UTIs is a significant growth of bacteria in the urinary tract. Uropathogenic Escherichia coli (*E*. *coli*) is the primary causa‐ tive agent of UTIs.

Symptomatic UTIs can be classified into infections limited to the lower urinary tract and in‐ fections of the upper urinary tract. Marked individual differences in susceptibility to UTIs have been known for decades. Through different molecular interactions bacteria may trigger epithelial cell responses, cause cell detachment and invade or kill cells by apoptosis. The in‐ dividual inflammatory response determines severity of acute pyelonephritis (APN) as well as differences in response to UTI among individuals. It is suggested that APN occurs more readily in high responders. Level of individual inflammatory response could be a key of enigma why some patients with APN develop renal scarring and progressive kidney dam‐ age whereas others do not.

Identification of new markers underlying APN and affecting its treatment is essential for de‐ signing interventions that would minimize tissue damage. Research of individual genetic background of inflammatory response suggests the significance of proinflammatory cyto‐ kine genes and polymorphisms of these genes. Such polymorphisms can occur either in reg‐ ulatory or in coding regions of genes. They may affect the level of inflammation by enhancing transcription of certain cytokines' genes and thus increasing production of these

© 2013 Zivkovic et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cytokines. Changes in genes' expression as well as presence of certain alleles associated with disease phenotype support the hypothesis that genetic factors could modify susceptibility to acute pyelonephritis and post-infectious renal damage.

**2. Acute Pyelonephritis (APN) in children and genetic susceptibility to APN**

Genetic Factors Underlying Susceptibility to Acute Pyelonephritis and Post-infectious Renal Damage

http://dx.doi.org/10.5772/52852

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Urinary tract infections (UTIs) are common among children of all ages including infants. UTI is defined as a penetration of microorganisms, mainly *E. coli*, into the tissue of urina‐ ry tract, which is marked by significant bacteriuria (>105 bacteria per 1ml of urine) [1]. UTIs are classified into three categories: upper UTI- acute pyelonephritis, lower UTIacute cystitis and asymptomatic bacteriuria (ABU). The upper UTI, or acute pyelonephri‐ tis (APN), represents bacterial infection of renal parenchyma, which may cause various inflammatory lesions. Post-infectious renal scarring is the most serious complication fol‐ lowing APN in children, with an estimated incidence of 10-65% [1-2]. Vesico-ureteral re‐ flux (VUR) may also play an important role in renal damage [3]. VUR is suggested to be a weak predictor of permanent renal damage in children hospitalized with UTI [4] but it is also known that the grade of VUR positively correlates with likelihood of renal scarring [5]. Extensive renal scarring leads to renal insufficiency and hypertension [6-7]. Early diag‐ nosis of APN and follow up to identify renal scarring after the first APN are thus very important. The primary distinction of APN is based on clinical manifestations and indirect laboratory testing of inflammatory markers such as C-reactive protein (CRP) serum levels, peripheral white blood cells' (WBC) count etc. However, these tests are unreliable in acute phase of pyelonephritis. The 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy is a gold‐ en standard method for detection of acute renal inflammatory lesions specific for diagno‐ sis of APN as well as for the follow-up detection of renal cortical scars [8-9]. Detection of permanent renal parenchymal defects following APN is ultimate for long-term prognosis of kidney function. The incidence of renal defects correlates inversely with the time inter‐ val between pyelonephritis and the scintigraphic study and stabilizes 4-6 months follow‐ ing acute disease. DMSA scintigraphy is based on binding of 99mTc-DMSA to renal parenchyma cells and therefore provides means of distinguishing APN from lower UTI and evaluating persistent DMSA uptake defects after the initial infection in children [8- 10]. Given that DMSA exposes the patients to radiation, this procedure is not regularly

Uropathogenic *Escherichia coli* is the most common causative agent (80%) of uncomplicated UTIs although other enteric organisms have been identified as well [11]. After colonization of the urethra and ascent to the bladder, bacteria bind to glycosphingolipid and glycopro‐ tein receptors on the urinary tract epithelium and penetrate into tissue of urinary tract [12]. They express a number of virulence determinants that contribute to successful colonization of the urinary tract [13]. Many pathogenic microorganisms use host cell surface oligosac‐ charides including glycosphingolipids (GSLs) as receptors to attach to uroepithelial cells. The attachment of *E. coli* is mediated trough expression of flagellin and ascending of *E. coli* to the upper urinary tract and dissemination of bacteria within the host are enabled through a flagellum-mediated motility [14-16]. These actions, along with the lipid A moiety of lipo‐ polysaccharide (endotoxin), have been shown to enhance activation of the host inflammato‐ ry response. Cytokines mediate this response [7,17-19]. Neutrophils are the first cells that

used to diagnose APN.

**2.1. Bacterial virulence and uroepithelial contact**

Several mechanical forces including urine flow and voiding, mucus shedding, and epithelial cell sloughing are important in minimizing UTI incidence. Bacterial adherence to the epithe‐ lium triggers defense responses. One of these is innate immunity response, which is impor‐ tant for uropathogenic *E. coli* recognition and immunomobilization. The innate immunity response is mediated by toll-like receptors (TLR4, TLR5, TLR11), adhesion molecules (E-se‐ lectin, ICAM-1, PECAM-1) and secreted factors such as cytokines (TNF-alpha, IL-1beta, IL-6, G-CSF, IL-17) and chemokines (CXCL1, CXCL2, CXCL3, CXCL8, CCL4). These molecules have been detected in mammalian bladder upon infection. Therefore, polymorphisms in genes coding for these molecules have been recognized as genetic susceptibility factors for UTIs. Neutrophils are the most abundant early responders to infection, while the anti‐ gen(Ag)-presenting macrophages, dendritic cells and innate-like lymphocytes (such as gam‐ ma delta T cells) have been implicated in the UTI host defense.

The cytokine response is essential for antibacterial defense of the urinary tract. Interleu‐ kin-8 (IL-8) is a potent chemoattractant responsible for neutrophil infiltration into the urinary tract. It was reported that neutrophils of children with recurrent pyelonephritis had lower expression of IL-8 receptor (CXCR1) than neutrophils of healthy controls. In‐ terleukin-6 (IL-6) is one of the pro-inflammatory cytokines, which stimulates production of all acute-phase proteins thus contributing to acute-phase response and systemic in‐ flammation. High serum or urine levels of IL-6 have been found in children with UTIs, particularly in children with APN compared to those with lower UTI. It was also indi‐ cated that urine and serum levels of cytokines could be observed as markers of renal damage as well as tools for monitoring the development and outcome of APN. Urine analysis has been extensively used by clinicians to diagnose various renal diseases. Ad‐ vances in technology of molecular biology enable analyses of genes' expression levels in urine sediment. These expression studies have a potential to improve the diagnosis of APN by detecting urinary gene expression profiles, which are specific for patients with APN.

Besides susceptibility to UTIs, of great therapeutic importance is susceptibility to post-infec‐ tious renal damage in APN patients. This kidney damage susceptibility has the genetic com‐ ponent. Among the candidate genes are those coding for molecules like growth factors (TGF-β1, VEGF), which play important roles in processes characteristic for the tissue dam‐ age and scarring such as cell proliferation and accumulation of extracellular matrix. Angio‐ tensin II, main effector of the renin-angiotensin system, is also considered a growth factor involved in all phenomena of renal tissue damaging and scar formation.

Here we will review the roles of candidate genes' polymorphisms and expression in sus‐ ceptibility to APN and post-infectious renal scarring, in order to summarize the existing re‐ sults and point out to further possible directions for research in this field.
