Pathophysiology of UTI and Dementia

UTI

Entry is normally by ascent from the urethra. The organisms that cause UTI’s are usually fecal organisms. Blood borne infections are infrequent usually leading to renal abscesses.

Host factors - Host factors important in protection from cystitis include the normal flow of urine and the constant sloughing of the epithelial cells lining the urinary tract. The kidneys are protected due to the presence of the ureterovesical valves that prevent reflux of urine from the bladder, and constant peristalsis of the ureters.

The larger number of UTI's seen in women is due to the much shorter urethra and the much closer association of the urethra to the anus. Sexual intercourse contributes to the increased number of UTI's seen in women. Celibate women have a lower frequency of bacteriuria.

Some women have been shown to have a much higher number of bacterial receptors on their uroepithelial cells leading to recurrent UTI’s. Any anatomic obstruction or neurological disorder leading to failure to completely eliminate urine from the bladder can lead to UTI. Men in their 50's and above have problems with prostate gland enlargement resulting in obstruction of the urethra followed by incomplete elimination of urine from the bladder and UTI's.

Bacterial factors - The ability of an organism to produce fimbriae (Type 1, P, S, and Dr) is important in that it enables the bacteria to attach to the uroepithelial cells and thereby avoid elimination. Uropathogenic strains of E coli can also resist killing by complement.

Human epithelial cells of the bladder and the kidney can internalize E coli cells. The Type 1 fimbriae are important in attachment of the bacteria to the host epithelial cells and in promoting reorganization of the epithelial cell’s intracellular cytoskeleton to then internalize the bacteria. Internalization of the bacterial cells in epithelial cell vacuoles enhances bacterial cell survival by providing protection from host immune defenses and allows the pathogen greater access to deeper tissues. Once internalized the bacteria can grow in the epithelial cell and form pod-like structures. Intracellular E coli can form a reservoir within the bladder mucosa that may serve as a source for recurrent acute infections (20% of all UTI’s).

The Type 1 fimbriae mediated internalization of E coli is rather slow and the rate of internalization can be increased by 10 fold if the bacteria have first been opsonized by complement component C3. Since uropathogenic E coli are resistant to killing by complement they can then use C3 to gain entry into the host epithelial cells. Not much complement is in the urine in normal conditions. However, during infection LPS from E coli may induce the production of cytokines in the kidney that then causes increased amounts of C3 to gain entrance into the bladder. C3 binds to the surface of the bacterial cells. This surface bound C3 then binds to human complement regulatory protein, CD46, on the surface of the epithelial cell. The CD46 protein then mediates internalization of E coli.

Spread to the kidney - Infection of the kidney is due to ascent from the lower urinary tract and so any factor leading to retrograde flow of the urine to the kidney will predispose the host to pyelonephritis. Such factors include:

1. Cystitis due to a strain of E coli that produces the mannose resistant pili that binds to the receptor for the P blood group found on epithelial cells and red blood cells.
2. Internalization of E coli in the proximal tubular epithelial cells of the kidney can also occur helping the bacteria avoid the immune response of the host. C3 bound to the surface of E coli cells appears to also be important in internalization of the bacteria in the kidney epithelial cells.
3. Reflux of urine to the kidney - usually due to incomplete development of ureterovesical valves.
4. Physiological malfunctions - disorders leading to poor emptying of the bladder. Changes during pregnancy leading to dilatation and decreased peristalsis of the ureters.
5. Urethral catheters - can serve as a conduit for the bacteria to ascend into the bladder and a source of bacteria for persistent infection.
6. Urinary tract stones - These stones serve as a place in which bacteria can escape antibiotics and cause further infections. Proteus sp. is an example of an organism, which can cause stone formation. Proteus sp. produce an enzyme called urease that splits urea to ammonia and carbon dioxide. This raises the pH of the urine and facilitates the formation of "struvite" calculi. A high pH in the urine is indicative of a Proteus infection.

Kidney damage is due to the ability of the organism to produce polysaccharide (which inhibits phagocytosis), alpha hemolysin and cytotoxic necrotizing factor 1 (causes tissue damage directly), endotoxin that contributes to inflammation and damage of renal parenchyma and internalization of the bacterial cells in kidney epithelial cells.

Dementia

Table 3
Classification of Some Dementias Classification Examples Characterized by β-amyloid abnormalities Alzheimer's disease Characterized by tau abnormalities Frontotemporal dementia (including Pick's disease) Corticobasal ganglionic degeneration Progressive supranuclear palsy Characterized by α-synuclein abnormalities Lewy body dementia Dementia in patients with Parkinson's disease Characterized by huntingtin abnormalities* Huntington's disease Vascular Lacunar disease Binswanger's disease Multi-infarct dementia Strategic single-infarct dementia Due to ingestion of drugs or toxins Alcohol-associated dementia Dementia due to exposure to heavy metals Due to infections Fungal: Dementia due to cryptococcosis Spirochetal: Dementia due to syphilis or Lyme disease Viral: HIV-associated dementia, postencephalitis syndromes Due to prions Creutzfeldt-Jakob disease Variant Creutzfeldt-Jakob disease Due to structural brain disorders Brain tumors Chronic subdural hematomas Normal-pressure hydrocephalus Due to other potentially reversible disorders Depression Hypothyroidism Vitamin B12 deficiency *Abnormalities include atrophy of caudate nucleus, degeneration of small cells, and decreased levels of γ-aminobutyric acid (GABA) and substance P.

Alzheimers

• Extracellular β-amyloid deposits, intracellular neurofibrillary tangles (paired helical filaments), and senile plaques develop, and neurons are lost
• Cerebrocortical atrophy is common, and use of cerebral glucose is reduced, as is perfusion in the parietal lobe, temporal cortices, and prefrontal cortex.
• Other common abnormalities include increased brain and CSF concentrations of the tau protein (a component of neurofibrillary tangles and β-amyloid) and reduced levels of choline acetyltransferase and various neurotransmitters (eg, somatostatin).