Acute pyelonephritis results from bacterial invasion of the renal parenchyma. Bacteria usually reach the kidney by ascending from the lower urinary tract. In all age groups, episodes of bacteriuria occur commonly, but most are asymptomatic and do not lead to infection. The development of infection is influenced by bacterial factors and host factors. 
Bacteria may also reach the kidney via the bloodstream. Hematogenous sources of gram-positive organisms, such as Staphylococcus, are intravenous drug abuse and endocarditis. Experimental evidence suggests that hematogenous spread of gram-negative organisms to the kidney is less likely unless an underlying problem exists, such as an obstruction. Little or no evidence supports lymphatic spread of uropathogens to the kidney.
Most bacterial data are derived from research with Escherichia coli, which accounts for 70-90% of uncomplicated UTIs and 21-54% of complicated UTIs (ie, UTIs that are secondary to anatomic or functional abnormalities that impair urinary tract drainage; are associated with metabolic disorders; or involve unusual pathogens). A subset of E coli, the uropathogenic E coli (UPEC), also termed extraintestinal pathogenic E coli (ExPEC), accounts for most clinical isolates from UTIs.
UPEC derives commonly from the phylogenetic groups B2 and D, which express distinctive O, K, and H antigens. UPEC genes encode several postulated virulence factors (VFs), including adhesins, siderophores, protectins, and toxins, as well as having the metabolic advantage of synthesizing essential substances.
Adhesins have specific regions that attach to cell receptor epitopes in a lock-and-key fashion. Mannose-sensitive adhesins (usually type 1 fimbriae) are present on essentially all E coli. They contribute to colonization (eg, bladder, gut, mouth, vagina) and possibly pathogenesis of infection; however, they also attach to polymorphonuclear neutrophils (PMNs), leading to bacterial clearance.
Mannose-resistant adhesins permit the bacteria to attach to epithelial cells, thereby resisting the cleansing action of urine flow and bladder emptying. They also allow the bacteria to remain in close proximity to the epithelial cell, enhancing the activity of other VFs.
The P fimbriae family of adhesins is epidemiologically associated with prostatitis, pyelonephritis (70-90% of strains), and sepsis. This family of adhesins is associated with less than 20% of asymptomatic bacteriuria (ABU) strains. The AFA/Dr family is associated with diarrhea, UTI, and particularly pyelonephritis in pregnancy. The S/F1C family is associated with neonatal meningitis and UTI.
Siderophores are involved in iron uptake, an essential element for bacteria, and possibly adhesion. Protectins and their contributions to virulence include the following:
Lipopolysaccharide (LPS) coatings: resist phagocytosis
Tra T and Iss: resist action of complement
Omp T: cleave host defense proteins (eg, immunoglobulins)
Toxins, which affect various host cell functions, include the following:
Cytotoxic necrotizing factor–1
Cytolethal distending toxin
Secreted autotransporter toxin
No single VF is sufficient or necessary to promote pathogenesis. Apparently, multiple VFs are necessary to ensure pathogenesis, although adhesins play an important role.
Asymptomatic bacteriuria strains
Bacterial strains that produce ABU may in some instances provide a measure of protection against symptomatic infections from UPEC and other organisms. On the other hand, ABU may also cause increased morbidity and mortality. Once bacteriuria is established, these strains appear to stop producing adhesins, allowing them to survive and persist without producing an inflammatory reaction.
As noted above, UPEC account for most uncomplicated pyelonephritis cases and a significant portion of complicated pyelonephritis cases. The following microorganisms are also commonly isolated:
This is the same spectrum of organisms cultured in cystitis. In 10-15% of symptomatic cystitis cases, cultures using routine methods remain negative, although the symptoms typically respond to antibiotic therapy. In some cases, cultures using selective media have grown Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum. These data cannot be extended to acute pyelonephritis, but they do illustrate the difficulties in isolating the causative organism.
Epithelial attachment and inflammatory response
Evidence suggests that the pathogenesis of pyelonephritis takes a 2-step path. First, UPEC attaches to the epithelium and triggers an inflammatory response involving at least 2 receptors, glycosphingolipid (GSL) and Toll-like receptor 4 (TLR4). In the mouse model, GSL is the primary receptor and TLR4 is recruited and is an important receptor for the release of chemokines. When TLR4 is genetically absent, an asymptomatic carrier state develops in the infected mice.
Second, as a result of the inflammatory response, chemokines (eg, interleukin-8 [IL-8], which is chemotactic for PMNs) are released and attach to the neutrophil-activating chemokine receptor 1 (CXCR1), allowing PMNs to cross the epithelial barrier into the urine. In children prone to pyelonephritis, for example, CXCR1 expression has been shown to be significantly lower than in control subjects.
Several other host factors militate against symptomatic UTI. Phagocytosis of bacteria in urine is maximized at pH 6.5-7.5 and osmolality of 485 mOsm; values deviating from these ranges lead to significantly reduced or absent phagocytosis. Other important factors are the flushing action of urine flow in the ureter and bladder, the inhibition of attachment of type 1 fimbriae E coli to uroepithelial cells by tubular cell–secreted Tamm-Horsfall protein, and the inhibition of attachment by some surface mucopolysaccharides on the uroepithelial cells.
Complicated UTI is an infection of the urinary tract in which the efficacy of antibiotics is reduced because of the presence of one or more of the following:
Structural abnormalities of the urinary tract
Functional abnormalities of the urinary tract
Metabolic abnormalities predisposing to UTIs
Recent antibiotic use
Recent urinary tract instrumentation
Obstruction is the most important factor. It negates the flushing effect of urine flow; allows urine to pool (urinary stasis), providing bacteria a medium in which to multiply; and changes intrarenal blood flow, affecting neutrophil delivery. Obstruction may be extrinsic or intrinsic. Extrinsic obstruction occurs with chronic constipation (particularly in children), prostatic swelling/mass (eg, hypertrophy, infection, cancer), and retroperitoneal mass.
Intrinsic obstruction occurs with bladder outlet obstruction, cystocele, fungus ball, papillary necrosis, stricture, and urinary stones. With increasing size of stone, the probability of stone passage decreases while the probability of obstruction increases. Nonetheless, stones as small as 2 mm have resulted in obstruction, while 8-mm stones have occasionally passed spontaneously.
Infectious stones, urease stones, or triple-phosphate stones composed of magnesium ammonium phosphate or struvite and apatite account for 10-15% of all urinary stones. They develop secondary to the action of urea-splitting organisms and can grow rapidly and branch out (ie, staghorn calculi).
If left untreated, staghorn calculi will destroy the kidney and may cause the death of the patient. Complications include azotemia, hydropyonephrosis, perinephric abscess, pyelonephritis (severe or end-stage), sepsis, and xanthogranulomatous pyelonephritis.
Incomplete bladder emptying may be related to medication (eg, anticholinergics). The spermicide nonoxynol-9 inhibits the growth of lactobacilli. Lactobacilli produce hydrogen peroxide, which protects the vaginal ecosystem against pathogens. Frequent sexual intercourse causes local mechanical trauma to the urethra in both partners.
Atrophic vaginal mucosa in postmenopausal women predisposes to the colonization of urinary tract pathogens and UTIs because of the higher pH (5.5 vs 3.8) and the absence of lactobacilli. Bacterial prostatitis (acute or chronic) produces bacteriuria, whereas nonbacterial prostatitis and pelviperineal pain syndrome (prostadynia) do not.
Unusual organisms include Mycoplasma, Pseudomonas, and urea-splitting organisms. Pseudomonas aeruginosa has several mechanisms that promote adherence, including alginate, other membrane proteins, pili, and surface-associated exoenzyme S.
Urea-splitting organisms produce urease, which hydrolyzes urea, yielding ammonia, bicarbonate, and carbonate; this leads to a more alkaline urine and allows crystal formation (staghorn calculus) from the supersaturation of carbonate apatite and struvite. Staghorn calculi continue to grow in size, leading to infection, obstruction, or both.
Complications of obstruction with superimposed infection include hydronephrosis, pyonephrosis, urosepsis, and Xanthogranulomatous pyelonephritis. Additionally, the pathogens can sequester in the struvite stones, protected from the host’s immune system. Proteus species are the most common urea-splitting organisms. E coli, Klebsiella, Pseudomonas, and Staphylococcus can also produce urease, however, and are sometimes involved in staghorn calculus formation.
Pregnancy produces hormonal and mechanical changes that predispose the woman to upper urinary traction infections. Hydroureter of pregnancy, secondary to both hormonal and mechanical factors, manifests as dilatation of the renal pelvis and ureters (greater on the left than on the right), with the ureters containing up to 200 mL of urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis. Complicated UTI can result from one or more diverse factors.
Diabetes mellitus produces autonomic bladder neuropathy, glucosuria, leukocyte dysfunction, microangiopathy, and nephrosclerosis; additionally, it leads to recurrent bladder instrumentation secondary to the neuropathy. Complicated UTIs in patients who have diabetes mellitus include the following:
Renal and perirenal abscess
For more information on this topic, see the Medscape Reference article Pathophysiology of Complicated Urinary Tract Infections.
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