**5. Pathogenesis of UTI in diabetics**

The chance of occurrence of UTIs in diabetic patients used to increase many folds due to several factors. Multiple potential mechanisms unique to diabetes may cause increased risk of UTI in diabetic patients. Elevated renal parenchymal glucose levels create a positive environment for the growth and multiplication of microorganisms, which is one of the precipitating factors of pyelonephritis and renal problem such as emphysematous pyelonephritis. Several problems in the immune system, including humoral, cellular, and innate immunity, may help in the pathogenesis of UTI in diabetic patients [12–14]. Lower urinary interleukin-6 and interleukin-8 levels were found in diabetic patients with UTI. An outline of process involved in pathogenesis of urinary tract infection in diabetic patients is mentioned in **Figure 1**.

Some suggested host related mechanisms include [15]:


#### **5.1. Presence of glycosuria**

The presence of glycosuria is responsible for the growth of different microbial strains. Among all *E. coli* is the major cause for the condition of UTI [15]. The bacteria isolated from diabetic patients with a UTI are similar to the bacteria found in nondiabetic patients with a complicated UTI. As in uncomplicated UTIs, *E. coli* causes the majority of infections. For example, one study reported *E. coli* to be the causative uropathogen in 47% of the UTIs in diabetic patients and in 68% of the UTIs in nondiabetic patients. Non-*E. coli* uropathogens found in patients with diabetes, include *Enterobacter* spp., *Klebsiella* spp., *Proteus* spp., Group B *Streptococci,* and *Enterococcus faecalis* [16].

Geerlings et al. [17] in their study reported that urine samples with glucose concentrations between 100 and 1000 mg/dL, which comes in the range of moderate to severe glucosuria, were responsible for enhanced bacterial growth after 6 h, compared with normal urine.

*E. coli* gain access to the urinary tract by the mechanism which reflects an exceptional ability to adapt to an environment very different from the gut. They need to alter their metabolism [18],

**Figure 1.** Process involved in pathogenesis of UTI in patients with diabetes.

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**Figure 1.** Process involved in pathogenesis of UTI in patients with diabetes.

Various types of UTI in patients with diabetes include

• Complicated lower UTI (including catheter-associated UTI)

48 Microbiology of Urinary Tract Infections - Microbial Agents and Predisposing Factors

The chance of occurrence of UTIs in diabetic patients used to increase many folds due to several factors. Multiple potential mechanisms unique to diabetes may cause increased risk of UTI in diabetic patients. Elevated renal parenchymal glucose levels create a positive environment for the growth and multiplication of microorganisms, which is one of the precipitating factors of pyelonephritis and renal problem such as emphysematous pyelonephritis. Several problems in the immune system, including humoral, cellular, and innate immunity, may help in the pathogenesis of UTI in diabetic patients [12–14]. Lower urinary interleukin-6 and interleukin-8 levels were found in diabetic patients with UTI. An outline of process involved in

The presence of glycosuria is responsible for the growth of different microbial strains. Among all *E. coli* is the major cause for the condition of UTI [15]. The bacteria isolated from diabetic patients with a UTI are similar to the bacteria found in nondiabetic patients with a complicated UTI. As in uncomplicated UTIs, *E. coli* causes the majority of infections. For example, one study reported *E. coli* to be the causative uropathogen in 47% of the UTIs in diabetic patients and in 68% of the UTIs in nondiabetic patients. Non-*E. coli* uropathogens found in patients with diabetes, include *Enterobacter* spp., *Klebsiella* spp., *Proteus* spp., Group B *Streptococci,* and *Enterococcus faecalis* [16]. Geerlings et al. [17] in their study reported that urine samples with glucose concentrations between 100 and 1000 mg/dL, which comes in the range of moderate to severe glucosuria, were responsible for enhanced bacterial growth after 6 h, compared with normal urine.

*E. coli* gain access to the urinary tract by the mechanism which reflects an exceptional ability to adapt to an environment very different from the gut. They need to alter their metabolism [18],

pathogenesis of urinary tract infection in diabetic patients is mentioned in **Figure 1**.

• Asymptomatic bacteriuria

• Uncomplicated pyelonephritis

**i.** Presence of glycosuria

**iii.** Immune dysfunction

**5.1. Presence of glycosuria**

• Complicated pyelonephritis/urosepsis

**5. Pathogenesis of UTI in diabetics**

Some suggested host related mechanisms include [15]:

**ii.** Increased adherence to uroepithelial cells

• Acute cystitis

ascend against the flow of urine, and adhere to the epithelial layer. *E. coli* that successfully invade the urinary tract harbor a specific factor that enables them to survive. These strains of *E. coli* are commonly named uropathogenic *E. coli* (UPEC). Flagellae are thread-like structures which provide *E. coli* with the ability to move. It has been found to bind to TLR5 [19] and is of importance for the immune response to *E. coli* in UTI in mice [20]. A critical step for UPEC is adhesion to avoid being washed out with the urine and the first step in a series of events leading to infection. The type-1 fimbriae are adhesion factors studied in great detail and are critical for adhesion and invasion of UPEC into bladder cells [21, 22]. They are equipped with a protein on the tip called FimH, which is responsible for the interaction with the host cell [23]. It binds to several structures on uroepithelial cells, the most important being uroplakin IA that coats the facet cells of the bladder [24]. They also bind to β-integrin, which triggers cytoskeleton rearrangement leading to bacterial internalization [25]. In renal epithelial cells, complement factor 3, which is secreted by epithelial cells during infection, can link with type 1 fimbriae to form a complex that interacts with CD46 to promote internalization. Other fimbriae like P fimbriae are connected with kidney infection, since they bind to glycosphingolipids on kidney epithelial cells [26].

interleukin-8 and interleukin-6 in women suffering from diabetes have been shown to correlate with a lower urinary WBCs count that may contribute to the increased incidence of UTIs

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If UPEC comes in contact with the epithelium, within minutes, the antimicrobial peptide cathelicidin is secreted and acts on the bacteria. Within hours, cytokines and chemokines are produced and their signaling will start to fix professional immune cells to the site of infection. The bacteria on the other hand will try to circumvent the immune defense in different ways. One is to enter the cell cytoplasm and form intracellular bacterial communities (IBCs) in order to "hide" from the immune response [29]; another is to down regulate the immune response with different modes of signaling. Depending on the number of bacteria, the host status, and the virulence factors they carry, the bacteria will either survive in the urinary tract or be

If this first line of defense against pathogens entering the urinary tract fails, an inflammatory response is initiated. Attachment to the bladder uroepithelial cells by bacterial fimbriae allows for close contact between host and pathogen. Trans-membrane signaling through TLRs leads to the production of inflammatory mediators such as chemokines with subsequent recruitment of professional immune cells to the infectious focus. Chemokine IL-8 is required for

When the inflammatory response subsides, bacteria may still be left in the bladder epithelium. Bacteria that form IBCs can escape the different steps in host defense and treatment with antibiotics will be less efficient because of poor antibiotic penetration into the IBCs. From the IBC, bacteria can be expelled from the cells by a TLR4 mediated mechanism or in mature IBCs, and bacteria form filamentous structures and then separate from the cell to colonize adjacent cells. The cells may also be exfoliated, allowing the underlying immature cells to be exposed to further UPEC invasion. Here, they can turn into quiescent intracellular reservoirs (QIRs) for weeks, only to re-emerge to cause recurrent infections. Pyelonephritis may develop if the bacteria ascend further in the urinary tract. In the kidney, bacteria may cause damage of tissue and reach the blood circulation, causing septicemia, commonly called urosepsis. This

UTIs are classified based on laboratory data, clinical symptoms, and microbiological findings. Practically, UTIs have been divided into uncomplicated and complicated UTIs and sepsis. The present guidelines give an outline of a tentative improved system of classification of UTI based on various factors as follows: (Guidelines on Urological Infections by European

increases the mortality from 0.3% in pyelonephritis to 7.5–30% in urosepsis [31].

**i.** Classification based on grade of severity of infections and symptoms

in this patient group [28].

eliminated and washed out with the urine [29].

neutrophil recruitment and activation in the urinary tract [30].

**6. Classification of urinary tract infection**

**ii.** Classification based on underlying risk factors

**iii.** Classification based on anatomical level of infection

Association of Urology)

Flagella provide the bacteria with mobility and may interact with the superficial bladder cell through TLR5. Further adhesion is provided by type 1 fimbriae binding to uroplakin 1A or β1-integrin, which also promote internalization into the cell. Complement secreted upon bacterial infection binds to the bacteria and promotes interaction with the bladder through CD46. In the kidney, P fimbriae of the bacteria bind to glycosphingolipids on the surface of renal epithelial cells. Bacterial invasion is further promoted by TLR4 and TLR5.

#### **5.2. Increased adherence to uroepithelial cells**

The uroepithelium is having a very important property of flexibility by which it will allow filling and emptying of the bladder and at the same time impermeable to fluid and able to cope with the varying pH, osmolality, and toxicity, for example, high ammonium concentration. It is composed of different layers of cells with the umbrella or facet cells lining the lumen are multinuclear, large cells with uroplakin facing the urine. Uroplakins are proteins contributing to the impermeability of the epithelium but can also act as a receptor for type 1 fimbriae on the uropathogenic *E. coli* [27].

The important step in the pathogenesis of UTIs is the adherence of uropathogens to the bladder mucosa. Therefore, adhesins (fimbriae) are important virulence factors. Although virulence factors have been distinguished best in *E. coli* (the most common uropathogen), many same principles may be applicable to other Gram-negative uropathogens, for example, Klebsiellae. Type 1 fimbriae mediate the adherence of glycoprotein receptors (uroplakins) on the uroepithelial cells to *E. coli*, whereas P fimbriae bind to glycolipid receptors in the kidney [25].

#### **5.3. Immune dysfunction**

It is observed that hyperglycemic environment alters immune function in patients with diabetes. Several aspects of immunity may be affected, including polymorphonuclear leukocyte function and adhesion, phagocytosis, and chemotaxis. This may play a part in the pathogenesis of urinary tract infections in patients with diabetes. Lower urinary concentrations of interleukin-8 and interleukin-6 in women suffering from diabetes have been shown to correlate with a lower urinary WBCs count that may contribute to the increased incidence of UTIs in this patient group [28].

If UPEC comes in contact with the epithelium, within minutes, the antimicrobial peptide cathelicidin is secreted and acts on the bacteria. Within hours, cytokines and chemokines are produced and their signaling will start to fix professional immune cells to the site of infection. The bacteria on the other hand will try to circumvent the immune defense in different ways. One is to enter the cell cytoplasm and form intracellular bacterial communities (IBCs) in order to "hide" from the immune response [29]; another is to down regulate the immune response with different modes of signaling. Depending on the number of bacteria, the host status, and the virulence factors they carry, the bacteria will either survive in the urinary tract or be eliminated and washed out with the urine [29].

If this first line of defense against pathogens entering the urinary tract fails, an inflammatory response is initiated. Attachment to the bladder uroepithelial cells by bacterial fimbriae allows for close contact between host and pathogen. Trans-membrane signaling through TLRs leads to the production of inflammatory mediators such as chemokines with subsequent recruitment of professional immune cells to the infectious focus. Chemokine IL-8 is required for neutrophil recruitment and activation in the urinary tract [30].

When the inflammatory response subsides, bacteria may still be left in the bladder epithelium. Bacteria that form IBCs can escape the different steps in host defense and treatment with antibiotics will be less efficient because of poor antibiotic penetration into the IBCs. From the IBC, bacteria can be expelled from the cells by a TLR4 mediated mechanism or in mature IBCs, and bacteria form filamentous structures and then separate from the cell to colonize adjacent cells. The cells may also be exfoliated, allowing the underlying immature cells to be exposed to further UPEC invasion. Here, they can turn into quiescent intracellular reservoirs (QIRs) for weeks, only to re-emerge to cause recurrent infections. Pyelonephritis may develop if the bacteria ascend further in the urinary tract. In the kidney, bacteria may cause damage of tissue and reach the blood circulation, causing septicemia, commonly called urosepsis. This increases the mortality from 0.3% in pyelonephritis to 7.5–30% in urosepsis [31].
