Etiology and Pathophysiology of Pyelonephritis

AIllerican Journal of Kidney Diseases

IF The National Kidney Foundation The Official Journal of

Vol XVII, No 1, January 1991

IN-DEPTH REVIEW

Etiology and Pathophysiology of Pyelonephritis James A. Roberts, MD • Escherichia coli is the most frequent cause of pyelonephritis. Its possible virulence factors include the ability to adhere and colonize the urinary tract, an imporant initiating factor in all urinary tract infections (UTls). 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 inhlbHor. 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. Thus, the prevention of end-stage renal disease that may occur from acute pyelonephritis during infancy depends on early diagnosis and rapid and effective antibiotic treatment. This will eradicate the bacteria and stop the destructive reperfusion damage and that associated with the inflammatory response. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Pyelonephritis; Escherichia coli; end-stage renal disease; reperfusion damage; respiratory burst of phagocytosis; bacterial adhesion; P fimbriae.

D

ENAL FAILURE probably does not occur ..&after acute pyelonephritis in the adult . However, chronic pyelonephritis has been reported as the cause in from 15 %1 to 25 %2 of children and young adults coming to end-stage renal disease, whether with or without vesicoureteral reflux. End-stage renal disease from bacterial infection is probably the result of damage from acute renal infection during childhood. When renal damage has been severe enough, the remnant kidney is insufficient to maintain the increased need for renal function occurring during adolescence. This results in glomerular hyperfiltration and hypertension of the remaining nephrons, as suggested by the studies of Brenner.3 This leads to progressive destruction of the remaining nephrons, with focal glomerulosde-

rosis and further tubulointerstitial disease. This may be similar to the progressive chronic renal failure of glomerulonephritis . 4 This report will review the mechanisms involved in the etiology of acute pyelonephritis , as well as those causing the renal damage that follows renal infections. From the Department of Urology. Delta Regional Primate Research Center, Covington, LA; and Tulane University School of Medicine, New Orleans, LA. Supported by Public Health Service Grants No. RRool64 and DK14681. Address reprint requests to James A. Roberts, MD , Department of Urology, Delta Primate Center, 18703 Three Rivers Rd, Covington, LA 70433. © 1991 by the National Kidney Foundation , Inc. 0272-6386/91 /1701-0001 $3.00/0

American Journal of Kidney Diseases, Vol XVII, No 1 (January), 1991 : pp 1-9

JAMES A. ROBERTS

2

BACTERIAL ADHESION

Enterobacteriaceae are the most frequent cause of pyelonephritis, Escherichia coli being the etiologic agent in over 80 %. Bacterial adhesion of fecal bacteria leads to colonization of the perineum or prepuce prior to ascending urinary tract infection (UTI) .56 The chemical structure of the cell membrane of these bacteria is a complex mosaic of both protein and carbohydrate molecules under strict genetic control. These molecules produce both adhesive (adhesins such as fimbriae) and antiadhesive (capsule, lipopolysaccharides) properties. 7 .8 Adhesion may occur because of nonspecific characteristics such as hydrophobicity, or more specific receptor-lectin interaction. These mechanisms have been described by the surface energy theory for the early physicochemical events that lead to adhesion to many surfaces 9 (Fig 1). The net negative charge of both bacteria and epithelial cells would be expected to at first attract, and then repel the cells as they approach each other. The forces of attraction are greatest when they are more than 10 nm apart. Closer than this, adsorbed ions on the surfaces tend to repel adhesion. Bacteria do not have enough kinetic energy to overcome Attraction

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this force; thus, attachment would not occur ifbacterial fimbriae or other surface adhesins were not present. Since the magnitude of the repulsive forces increases with the radius of the cell, fimbriae with a radius of 2 to 10 nm are not repelled as much as E coli, whose radius approaches 250 nm. Duguid et al called these appendages fimbriae,lo while Brinton has favored the name pili II for these nonflagellar bacterial appendages. While bacterial fimbriae promote specific carbohydrate interactions, they also make the bacteria more hydrophobic. Hydrophobicity promotes adhesion as the epithelial cells' surface is hydrophobic, and adhesion between the two displaces water, yielding a net-free energy decrease. However, fimbriae are not the only means of attachment, as carbohydrate polymers also can overcome the repulsive forces, as for example in the case of adherence of Salmonella. 12 While the ability of bacteria to adhere and colonize a mucosal surface is often dependent on the presence of receptors on epithelial cell surfaces, this interaction may be affected by soluble receptors in the urine. Thus, Tamm-Horsfall protein, which is secreted by proximal tubules , is present within the urine and can adhere to type 1 fimbriae of E coli, preventing adherence to mucous (glycosarninoglycans or glycoproteins) on the surface of urothelial cells. 13 FIMBRIAL ADHESION

Nonobstructive acute pyelonephritis is caused most often by P-fimbriated E coli, and has been reported in over 95% of children l4 -16 and 50% to 90% of adults. 17.18 These studies used methods designed to show mannose-resistant hemagglutination and specific agglutination of P receptorcoated particles. 19 Harber and Asscher have cast doubt on the importance of adherence, since they were unable to show the presence of fimbriae on bacteria obtained from the urine prior to culture. 20 This may be due to the fact that more than 108 bacteria per milliliter are necessary before agglutination can be seen. 19 Pere et ai, using monoclonal antibodies to P fimbriae, showed that only some of the bacteria in an infected urine expressed P fimbriae and that those with many P fimbriae were usually adherent to epithelial cells and would thus not be found free in the urine. 21 A more recent study using specific im-

3

PATHOGENESIS OF PYELONEPHRITIS

munofluorescence for P fimbriae confirms these finding s. 22 These studies thus contradict Harber and Asscher's negative results. P fimbriae are so named because they act as lectins for urothelial receptors, which are the P blood group antigens. 23.24 P fimbriae adhere to both squamous and urothelial cells by means of this specific urothelial glycolipid receptor, the minimal active moiety being a disaccharide a-galp-l-4-{3galp.25 P fimbriated E coli often also have other proposed virulence factors such as bacterial hemolysin, type 1 fimbriae, and aerobactin, and are resistant to serum bactericidal activity.26.27 A clonal theory has been advanced to explain the concomitant presence of these factors. 28.29 Thus, P fimbriation is probably not the only virulence factor important in the etiology of acute pyelonephritis. The sequential activation of bacterial phenotypic traits is possible by means of phase variation by which a change from the fimbriated state to the nonfimbriated state may occur when it is advantageous to the organism. 30 Thus , the ability to colonize the urinary tract may be in part due to type 1 fimbriae , while P fimbriae are necessary for adherence and colonization of the upper urinary tract. Studies in pigs, monkeys , and the BALB/c mouse have shown the importance of P fimbriae . All of these animals are known to have the same urothelial cell receptors for P-fimbriated E coli as man. In the pig, bladder infection in the presence or absence of either vesicoureteral reflux or P-fimbriated E coli was studied. It was found that chronic pyelonephritis (reflux nephropathy) correlated better with the presence of P fimbriae than with vesicoureteral reflux. 31 Studies in the BALBI c mouse by Hagberg et al showed that UTI was prolonged when the E coli contained both P and type 1 fimbriae than when the same bacteria, following genetic engineering to delete all genes for fimbriae, were inoculated. 32 The same mouse model was used in a study by O'Hanley et ai, wherein all virulence factors were deleted from the bacteria except for the presence of P fimbriae in one strain and type 1 fimbriae in another. 33 The strain with only type 1 fimbriae did not colonize the kidneys unless a very large volume was used for the bladder inoculum, while the P-fimbriated strain colonized the kidney with a small-volume inoculum. This suggests that vesicoureteral reflux (which is normally present in the mouse) allowed

renal infection with the normally nonnephropathogenic type 1 fimbriated E coli. Studies by Schaeffer et al in the same mouse strain showed that as the degree of fimbriation increased, so did the incidence of colonization. 34 Strains with only P fimbriae in this mouse model were less effective in renal colonization than those with both P and type 1 fimbriae. The studies by Domingue et al with the BALB/c mouse showed that E coli with P fimbriae were more frequently associated with invasive renal disease (pyelonephritis) than those with type 1 fimbriae. 35 However, renal disease occurred very occasionally, even from E coli with no fimbriae or other known virulence factors, again suggesting a facilitating effect of vesicoureteral reflux in ascending renal infection of the mouse. 36 Our studies in the monkey showed that P-fimbriated E coli would cause nonobstructive acute pyelonephritis after bladder inoculation, even in the absence of vesicoureteral reflux. 37 Proof of the importance of P fimbriae is found in studies of the BALB/c mouse, as well as in nonhuman primates. In both of these species, immunization with both homologous and heterologous purified P fimbriae protected against pyelonephritis following either a bladder (mouse) or renal (monkey) inoculation of P-fimbriated E coli. 33.38-40 In addition, studies by Svanborg-Eden et al showed that a receptor analogue in vitro would prevent adhesion of P-fimbriated E coli to human urothelial cells, and that experimental ascending UTI in the BALB/c mouse was inhibited by treatment of P-fimbriated E coli with the specific receptor molecule globotetrarose prior to bladder inoculation. 41 In the monkey, similar treatment of the bacteria with the soluble minimal receptor agalp-1-4-{3-galp-O-methyl significantly delayed the onset of pyelonephritis following ureteral inoculation. 42 We did not expect it to totally prevent disease, as only the first generation of P-fimbriated E coli would be affected by treatment with the receptor. HOST RECEPTOR DENSITY

Why many women have UTIs, but only a few develop pyelonephritis, is probably due to the known relative increase of urothelial receptors for P-fimbriated E coli in those prone to pyelonephritis. 17.43 An interesting theory first promulgated by Blackwell et al suggests that when women have

JAMES A. ROBERTS

4

fewer soluble receptor compounds (such as the blood group antigen) in their secretions (so-called nonsecretors), they will be more prone to infection. 44 It would seem likely that the secreted receptor in vaginal or urothelial mucous would compete with the cellular receptor for P fimbriae. Lomberg et al first thought that the PI antigen was important, as 75 % of all individuals carry it, whereas 97 % of patients with recurrent pyelonephritis do. However, their later studies showed that adherence to urothelial cells was independent of P blood group .45 In addition, Sheinfeld et al have shown that other substances on the mucosa, such as the A, B, 0, or Lewis blood group oligosaccharides usually found on the cells of secretors, may interfere with receptor-ligand interaction by means of steric hindrance. 46 BACTERIAL EFFECT ON URETERAL PHYSIOLOGY

After reaching the bladder, colonization of the ureter can occur from P-fimbriated E coli even in the absence ofvesicoureteral reflux. This was suggested by the early studies of Winberg et al 47 and the later ones of Winter et al,48 wherein only one third of the children with nonobstructive pyelonephritis had vesicoureteral reflux. Bacteria may ascend and colonize the ureter in the area of turbulent flow next to the mucosa, as probably occurred in the studies of Roberts et al using a monkey model, wherein infection of the bladder with Pfimbriated E coli led to acute pyelonephritis in the absence of vesicoureteral refluxY Bacterial colonization of the ureter affects ureteral peristalsis as shown by both Roberts 49 and Boyarsky et apo Indeed, it has been shown that the inflammatory effects of endotoxin are increased in infections caused by attaching strains of E coli, which adhere to urothelial cells by means of P fimbriae. 51 The endotoxin of E coli probably acts by affecting (Xadrenergic nerves within smooth muscle, as suggested by studies of the cat ureter. 52 When the E coli colonize the ureter and its function ceases, this produces ureteral dilation and a physiologic obstruction. This was first suggested by Michie, who found dilation of calyces, pelvis, and ureter in children with acute pyelonephritis, which disappeared as the infection was controlled. 53 Recent studies of larger numbers of children with acute pyelonephritis show significant ureteral dilation when compared with normal ureters , again sug-

gesting a bacterial effect on smooth muscle. 54 Dilation of the ureter and calyces would lead to a change in the shape of the renal papillae by which easy intrarenal reflux of the colonizing bacteria could occur at a low pressure. 55 Since receptors for P-fimbriated E coli are present in the collecting duct and proximal tubules,56 adhesion occurs and acute pyelonephritis ensues. ISCHEMIC EVENTS

Ischemia has been found to cause significant damage to the heart,57 gastrointestinal tract,58 and kidney in a unique way. 59 While ischemia itself may be damaging, it is during reperfusion that maximum damage appears to occur. In several organs, including the heart and gastrointestinal tract, it appears that reperfusion injury is to a great extent due to neutrophil-mediated damage from oxygen-free radicals. 57 .58 However, Paller has shown that renal injury from warm ischemia is not mediated by neutrophils , as their depletion following nitrogen mustard treatment did not prevent the damage in the rat. 59 Thus, the neutrophilic response following renal ischemia may be only a secondary response and the events following reperfusion the cause of damage. During ischemia, adenosine triphosphate (ATP) is used as the anoxic energy source leading to a buildup of hypoxanthine molecules. During reperfusion, the action of xanthine oxidase leads to the formation of uric acid and superoxide. This and other toxic oxygen radicals damage tissue by means of lipid peroxidation of cell membranes (Fig 2).60 Paller et al have shown that ischemic renal damage in the rat can be prevented by allopurinol, an inhibitor of xanthine oxidase. 61 Studies in the monkey by Patarroyo and Makgoba showed that within 1 minute of bacterial antigen (lipid A) reaching the renal tubules, complement activation occurs, and with production of C3 and C5b, chemotaxis begins. Adhesion of granulocytes to the endothelium is mediated by leukocyte adhesion molecules such as CDlla/Cd18. 62 This adhesion occurs before their penetration of the capillary walls to reach the interstitium and then the tubular spaces. Study of ipsilateral renal venous blood using an aggregometer showed granulocytic aggregation. These aggregates obstruct capillaries and produce renal ischemia, as shown by increased renin concentration in renal venous blood. 63 The renal damage occurring after renal inoculation with

5

PATHOGENESIS OF PYELONEPHRITIS

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E coli in the monkey can also be prevented by pretreatment with the allopurinol ,64 which stops the action of xanthine oxidase, and thus prevents the reperfusion damage following the ischemic event. DAMAGE FROM OXYGEN RADICALS DURING PHAGOCYTOSIS

The presence of bacterial adhesins brings the bacteria closer to the mucosal surface and increases the effect of the soluble lipopolysaccharide, particularly lipid A, which triggers the production of many acute phase reactants. Bacteria or some soluble products themselves act as chemoatractins. Many agents act as mediators of these reactions. 65 These include complement, tumor necrosis factor, and other lymphokines, particularly interleukin 1 and interleukin 6 . 66 Glauser et al first suggested that inflammatory events were responsible for renal damage following infection, as opposed to any direct effect of the bacteria themselves, by suppressing the acute inflammatory response with antibiotic therapy in the rat. 67 When the inflammatory response was prevented by decomplementation following cobra venom factor therapy in studies by Shimamura in the rat 68 and Roberts et al in the monkey,69 acute renal damage was prevented. The recent studies by Ormrod et al

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also show that renal damage from infection is due to neutrophil-mediated tissue damage. The extent of renal damage was directly correlated with numbers of neutrophils and could be modulated by treatment with corticosteroids. 70 In the monkey, the inflammatory response maximizes by 24 hours. Without treatment, by 48 hours there is loss of from 10% to 20% of the renal function. 71 Neutrophils that reach the tubular lumen become active phagocytes, the bacteria being opsonized by means of complement, activated to C3 and C5a by the alternative pathway. Receptors for C3 on neutrophils leads to activation, and phagocytosis then begins, the respiratory burst occurring within the phagosome, but also on the surface of the phagocyte. The antimicrobial mechanisms effective during phagocytosis have been reviewed by Klebanoff. 72 He shows that superoxide production may lead to production of other toxic radicals such as hydrogen peroxide, hydroxyl radical, singlet oxygen, and in the presence of halides and myeloperoxidase, a secondary toxic effect, all of which eradicate bacteria in the phagosome. McCord and Fridovich have pointed out in their review that all cells in the body have superoxide dismutase, which ameliorates the effect of these toxic free radicals of oxygen. 73 However,

JAMES A. ROBERTS

6

there is no superoxide dismutase in urine; thus, the respiratory burst acts unopposed, damaging both the neutrophils and tubular cells. Our studies in the primate showed that exogenous superoxide dismutase (SOD) prevents the renal damage.74 Despite its short half-life, the SOD was effective since it is totally excreted in the urine. Degranulation of the phagocytes begins at approximately the same time for the production of lysosomal enzymes, which assist in eradicating the bacteria, but which can also leak into the tubular lumen and cause further tubular damage (Fig 3) . PREVENTION OF CHRONIC PYELONEPHRITIS

Prevention of the disease by vaccination with P fimbriae or oral administration of the receptor or an analogue of the receptor to cause competitive inhibition of the receptor-ligand interaction is still under investigation. Studies in the BALB/c mouse and the monkey have shown that immunization with purified P fimbriae prevents pyelonephritis following inoculation with a homologous P-fimbriated E coli.32.33 While there was also an anti1

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body response to contaminating endotoxin, protection was shown to correlate with antibody titers to P fimbriae as opposed to the 0 antigen. Our studies of immunization with heterologous P fimbriae in the baboon have shown only partial protection; thus, a broadly active common vaccine against pyelonephritis may be difficult to obtain. However, Schmidt et al have shown that certain fimbrial peptides may be immunogenic epitopes, 75 and O'Hanley et aI, using the gene probe for the gal-gal binding adhesin and one for the hemolysin gene, have shown that the nucleotide sequence for hemolysin and P fimbriae in many heterologous strains seem to be the same. 76 Thus, a vaccine may well be possible for the prevention of disease from many fimbriated strains. Since ascending nonobstructive pyelonephritis occurs because of adhesion by P fimbriae , this vaccine will be designed to prevent bacteria from reaching the kidney. In pyelonephritis associated with obstruction or vesicoureteral reflux, it would be expected that bacteria would cause pyelonephritis with significant renal damage. Thus, in these cases a vaccine to P fimbiae would not be helpful. Indeed , in the presence of vesicoureteral reflux it has been shown that P fimbriation is not necessary for pyelonephritis to occur. 77 Both pyelonephritis and renal scars occur more frequently from non-P-fimbriated E coli in children with reflux. 78 Thus, when vesicoureteral reflux is present, reliance on prophylactic antibiotics until the reflux disappears should be stressed, as originally shown by Smellie and Normand. 79 Extensive genetic analysis of E coli for the genes necessary for the production of P fimbriae have been done in the laboratories of Staffan Normark. 80 .81 These explain the complex biogenesis of the formation of P fimbriae by E coli. It now appears that the tips of P fimbriae are the specific adhesins. Normark feels that using a combination of the peri plasmic transport protein and the tipassociated protein may well be the most important method to develop a vaccine against heterologous P fimbriae. 82 One difficulty will be in deciding who should be immunized . Individuals who are nonsecretors and thus have more receptors may well be candidates. Studies of children by Berg and Johansson showed that the infant kidney appears to be more vulnerable to the damaging effects of infection occurring during the first 3 years of life. 83 This reduction in

7

PATHOGENESIS OF PYELONEPHRITIS

renal function was not dependent on either the presence of or grade of vesicoureteral reflux, but rather correlated with infection. In a study of adults who had their first infection during infancy, Jacobson et al showed decreased renal function in all, hypertension in one third , and end-stage renal disease in 10%.84 Kaack et al have shown in the monkey that maternal immunization leads to passive immunization of their infants , with protective activity against experimental pyelonephritis. 85 Thus, if it can be shown that the nonsecretor status is a familial trait, maternal immunization for passive protection of the newborn at risk might even be considered. In the absence of preventive therapy, treatment is the only viable alternative. The study of Glauser et al in a rodent model showed that renal damage could be prevented with antibiotic therapy, if begun prior to suppuration (no later than 30 hours after infection).67 This has been supported by the more recent animal studies of Slotki and Asscher. 86 While they showed that therapy must begin within 24 hours to be protective, similar studies by Miller and Phillips showed that treatment could be delayed for up to 4 days after the onset of the infection and still be effective in preventing renal scarring.87 While the studies of Ransley and Risdon in the pig with vesicoureteral reflux and infection did not determine when treatment should be started, they did show that antibiotic treatment de-

creased renal damage even in the presence of reflux. 88 Studies in the monkey showed that renal damage could not be totally prevented when antibiotic therapy was delayed until 72 hours after infection. The addition of allopurinol to the antibiotic treatment gave additive protection probably by its effect on reperfusion damage. 71 Direct extrapolation of animal data to the clinical situation in man must be done carefully because of interspecies differences in both anatomy and immunological function. However, it appears that the studies in both animals and man show that early effective antibacterial therapy of acute pyelonephritis is vital to the prevention of chronic pyelonephritis, although exactly when this therapy must be begun to be effective has not been determined. Most patients who acquire the renal scars of chronic pyelonephritis had their first febrile infection within the first few years of life. Studies by both Winberg et al of infants 47 and Wi~ter et al 48 in children have shown that improper or delayed treatment of acute pyelonephritis is responsible for the renal scarring of chronic pyelonephritis (reflux nephropathy). The studies by Smellie et al show that this can occur in older children as well. 89 Thus, at present, the prevention of end-stage renal disease from acute pyelonephritis depends on early diagnosis and rapid and effective treatment to erradicate the bacteria and stop the destructive inflammatory response.

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