James A. Roberts

Etiology and Pathophysiology of Pyelonephritis

Escherichia coli is the most frequent cause of pyelonephritis. Its possible virulence factors include the ability to adhere and colonize the urinary tract, an important initiating factor in all urinary tract infections (UTIs). The importance of P fimbriae in this adhesion is stressed and the evidence for its importance in pyelonephritis is presented in epidemiologic studies of patients, as well as in animal studies. It appears that both host receptor density and the nonsecretor state is responsible for susceptibility to urinary tract infection. Vesicoureteral reflux can be responsible for ascending upper tract infection, but infection with P-fimbriated E coli may lead to ascending pyelonephritis without reflux because of the paralytic effect of lipid A on ureteral peristaltic activity. Renal ischemia leads to renal damage following infection by reperfusion damage due to the release of superoxide. Experimentally, this ischemic damage can be prevented by allopurinol, a xanthine oxidase inhibitor. The acute inflammatory response can produce renal damage because of the respiratory burst of phagocytosis, which while killing phagocytosed bacteria also damages renal tubules. An amelioration of the inflammatory response by treatment with superoxide dismutase or corticosteroids has been shown to modulate renal damage. Vaccination with P fimbriae has been shown experimentally to prevent the initiation of the disease. However, since vaccines are not clinically available, the clinical and animal studies on therapy of acute disease are stressed. Acute pyelonephritis during the first 3 years of life more often produced the renal damage that could lead to end-stage renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of pyelonephritis by immunization with P-fimbriae.

P-fimbriae have been found to be a virulence factor in both human and nonhuman primate urinary tract infections caused by Escherichia coli. This is because of bacterial adherence to urothelial cells which is mediated by adherence of fimbriae to a specific glycolipid receptor on the cell membrane of these cells. We purified P-fimbriae for immunization of monkeys. High titers of antifimbrial antibody protected against both acute and chronic pyelonephritis after renal inoculations of P-fimbriate Escherichia coli.

Immunology of pyelonephritis in the primate model. V. Effect of superoxide dismutase.

Ascending acute pyelonephritis was produced in monkeys by infusion of bacteria through a ureteral catheter to the point of intrarenal reflux. This led to a significant inflammatory response with death of renal tubular cells in the area of the tubular granulocytes and bacteria. We gave superoxide dismutase, and found that the inflammatory response was decreased and fewer tubular cells were killed. Ultrastructural change was also decreased in tubular cells adjoining phagocytosing neutrophils. This suggests that renal damage following a bacterial infection may be due to the production and release of superoxide into the tubular lumen during phagocytosis. We believe that it is the initial event which may lead to the eventual loss of renal tissue and function called chronic pyelonephritis.

Bacterial adherence to urethral catheters.

Closed sterile catheter drainage has markedly reduced the incidence of nosocomial urinary tract infections. Infections that occur during closed drainage must ascend by colonizing the catheter or urethra. Our study compared adherence by different bacterial species to different catheter surfaces. We found no bacteria adhering to the hydrophilic catheter surface. Of the gram-negative bacteria Proteus mirabilis showed the greatest adherence to the other catheters and it, like most bacteria, showed the most marked adherence to the red rubber catheter.

Treatment of Experimental Pyelonephritis in the Monkey

Previous studies show that chronic pyelonephritis and end stage renal disease may follow acute pyelonephritis in children and adolescents when improperly or inadequately treated. Our study shows that there is a significant decrease in renal function following untreated acute bacterial pyelonephritis due to nephron loss. The acute inflammatory response is responsible for much of the renal damage, although damage from renal ischemia is an additional significant factor. The present study used a combination of an antibiotic and a xanthine oxidase inhibitor (allopurinol) as compared to antibiotic therapy alone begun 72 hours after infection. Both were successful in eradicating the infection rapidly, but did not entirely prevent renal damage. Treatment prior to 72 hours thus is important. It appears that the combined treatment, designed to eradicate the bacteria as well as reduce the post-ischemic reperfusion damage and the phagocytic burst of phagocytosis is ideal, as this combined treatment was effective in preventing almost all renal damage and loss of renal function.

Experimental Pyelonephritis in the Monkey. VII. Ascending Pyelonephritis in the Absence of vesicoureteral Reflux

Six adult male nonrefluxing monkeys were experimentally infected by inoculation of P-fimbriated E. coli into the bladder. Eight control monkeys were inoculated with a non-P-fimbriated E. coli strain. Inoculation with the P-fimbriated E. coli resulted in marked leukocytosis, prolonged bacteriuria and loss of renal function with a 66 per cent incidence of pyelonephritis. Death secondary to bilateral pyelonephritis was seen in 2 monkeys inoculated with P-fimbriated E. coli. Pyelonephritis was not seen in any of the monkeys inoculated with non-P-fimbriated E. coli. The study shows that ascending pyelonephritis can occur in monkeys in the absence of vesicoureteral reflux.

Effects of sterile high pressure vesicoureteral reflux on the monkey.

We surgically produced high-grade sterile vesicoureteral reflux in infant monkeys by unroofing the intravesical ureter and partially ligating the bladder neck. Half of the monkeys developed a decrease in renal function and were found to have interstitial nephritis. We found that this was due to a high resting bladder pressure, which affected the function and structure of the ureter. Thus, when a functional obstruction occurs in the refluxing ureter, renal function may be lost even when the urine is sterile. This situation is like that occurring in the patient with posterior urethral valves.

Immunology of pyelonephritis in the primate model. VI. Effect of complement depletion.

The inflammatory response has been shown to be responsible for the renal damage from bacterial infection. Phagocytic events are responsible for damage to the host as well as the pathogen. In this study we evaluated the effect of complement depletion, in an attempt to decrease chemotaxis and opsonization and thus decrease phagocytosis. Acute renal damage was decreased from both a decrease in inflammatory cells and phagocytic events in the areas of bacterial inoculation.

Bacterial adherence in urinary tract infections: preliminary studies in a primate model.

SummaryEscherichia coli with both P and type 1 fimbriae caused vaginal colonization in the female green monkey, while only the P-fimbriated bacteria frequently caused ascending bladder infection. Bladder inoculation caused only short-lived bladder infection from type 1 fimbriatedE. coli, but those with P-fimbriae caused acute pyelonephritis even in the absence of vesicoureteral reflux. Thus, type 1 fimbriae ofE. coli, while causing vaginal colonization, did not often cause ascending infection in the non-compromised host as did P-fimbriated bacteria.ZusammenfassungEscherichia coli-Stämme mit P-und Typ-1-Fimbrien können bei weiblichen grünen Affen die Vagina besiedeln; aufsteigende Harnwegsinfektionen werden jedoch gehäuft nur von Stämmen verursacht, die P-Fimbrien tragen. Die Inokulation der Blase mit Typ-1-Fimbrien tragendenE. coli führte zu einer kurzzeitigen Blaseninfektion, P-Fimbrien tragende Stämme lösten hingegen eine akute Pyelonephritis aus, obwohl die Tiere keinen vesikoureteralen Reflux hatten. Im Gegensatz zu P-Fimbrien tragenden Stämmen lösten folglich Typ-1-Fimbrien tragendeE. coli in der Regel bei Tieren ohne Abwehrschwäche keine aufsteigende Infektion aus, obwohl sie sich in der Vagina ansiedelten.

The ultrastructure of acute pyelonephritis in the monkey.

P-fimbriated E. coli, which have specific receptors on urothelial cells for their fimbriae, were used to produce pyelonephritis. Using both scanning and electron microscopy, it was shown that the bacteria attached to ureteral epithelium by 12 hours after inoculation. They developed into a biolayer of bacteria covering the epithelium by 48 hours, but did not invade within that time. In the kidney, adherence was seen by 6 hours in collecting proximal and distal tubules. While many bacteria were seen, tubular epithelium remained normal through 24 hours. The inflammatory response was first seen at 48 hours. Phagocytosis was accompanied by mortal damage to both phagocytes and surrounding tubules. This was followed by bacterial invasion of the interstitium.