ACUTE PYELONEPHRITISThe most frequent of all nephropathies

Experience based on 276 cases over 12 years

Alain MeyrierHôpital Georges Pompidou and Broussais

Université René Descartes, Paris

Pierre Rayer

P. Rayer

Pyelo -- renal pelvis

-- nephritis: renal infection

at autopsy

1836

CT scan

DMSA scintigraphy

2006Pyelonephritis

Ascending renal tissue suppuration and ischemia

Uropathogenic E. coli

Acute Pyelonephritis

Primary = in a normal urinary tract 250 000 cases per year per million in the US

Secondary = complication of:Vesico-ureteral refluxMegaureterPosterior urethral valvesProstatic obstruction

NephrolithiasisMedullary sponge kidneyRenal cystsIndwelling catheter

Major cause of end-stage renaldisease in the third world

Still a cause of chronic renalinsufficiency in Western

countries

Cystitis in normal female

Simple pyelonephritis

in normal female

Complicated pyelonephritis

in normal female

Complicated pyelonephritis

in male with prostatitis

Complicated pyelonephritis(Ureteral stone)

Signs and symptoms

TypicalLomboabdominal pain. Enlarged, tender kidneyHigh fever and shaking chillsCystitis often lackingESR >>> 20 mm CRP >>> 20 mg/LPyuria = leukocytes > 105/ml + bacteria > 106/ml

MisleadingPainless: diabetic, malnourished alcoholic (autonomous

neuropathy), elderlyHypothermia: sepsisAseptic bacteriuria: uroculture following treatment

Acute pyelonephritisEncounter between an aggressor and a host

1) The vulnerable hostChildMaleDiabeticPregnant womanMenopauseAlcoholicTransplant recipient

2) The aggressor: a uropathogenic strain

Enterobacteria, mostly E. coli and ProteusStaphylococcus saprophyticus

Commensal microorganisms responsiblefor community acquired pyelonephritis (%)

E. coli 71-89 E. coli 60

P. mirabilis 1,1-9,7 P. mirabilis 15

Klebsiella,Enterobacter 1-9,2Enterococcus 1-3,2S. saprophyticus 3-7Other 2-6

Klebsiella 20

Other 5

FIRST EPISODEOR REMOTE

RELAPSE

RELAPSEBY SHORT-TERM

REINFECTION

Bacteria responsible for hospital acquired pyelonephritis

Van Poppel & al, Infection, 16:337, 1988

Factors of uropathogenicity

1) Physico-chemical factors• Enterobacteriaceae are electronegative but their charge is insufficient to

be repelled by the electronegativity of the urothelium, and by the ions

adsorbed on their surface

• They require and use other virulence factors to adhere to the epithelial

cells, the renal tubules, Bowman's capsule and vessel walls

2) Factors independent of fimbriae

3) Fimbrial adhesion

UPEC = UPEC = UropathogenicUropathogenic E. ColiE. Coli

CrossCross--sectionsection ofof thethe humanhuman kidneykidney displayingdisplaying UPEC UPEC fimbrialfimbrial adhesinadhesin--bindingbinding sitessites

Source: Source: LaneLane MC & MC & MobleyMobley HLT KI, 2007; 72:19HLT KI, 2007; 72:19--2525

Factors of uropathogenicityE. coli

Factors independent of fimbriae- Serotype O: O1, O2, O4, O6, O7, O16, O18, O75 are

found in 28 % of the intestinal flora sampling and are responsible for 80 % of pyelonephritis, 60% of cystitisand 30% of asymptomatic bacteriuria

- Aerobactin: siderophore that allows acquisition of ironfrom the urothelium and the urine

- Hemolysin: cytotoxic to the urothelial cells- Resistance to serum bactericidal activity, allowing E. coli

encapsulation

Factors of uropathogenicityE. coli

Fimbrial, and bacterial membrane adhesins

Fimbriae (Pili) carry epitopes (adhesins), lectins that bind to oligosaccharide motifs of the urothelial (and other) cell membranes, especially galactose-galactose (Gal-Gal) sequences

They also recognize blood group epitopes such as P (hence: 'P-fimbriae') and M

Women who are non-secretor of some blood group antigens elaborateglycolipid Gal-globoside receptors and are more susceptible to E. coli adhesion

The P epitope is located at the tip of fimbriae and assumes a fibrillarstructure

Uropthogenic E. coli: pili ("fimbriae")

Transmission electron micrographs of UPEC expressing different fimbriae. (a and b) CFT073 fim L-ON, a mutant that constitutively expresses type 1 fimbriae. (c and d) CFT073 fim L-OFF, a mutant that is unable to express type 1 fimbria produces another type offimbriae. a and c are at 34 000 magnification, and b and d are at 64 000 magnification.

Source: Lane MC & Mobley HLT KI, 2007; 72:19-25

UPEC = Uropathogenic E. Coli

UPEC adhesion to epithelial cells

Scanning electronmicroscopy

UPEC

Stick to theurothelial cell

membrane

(Le (Le BouguenecBouguenec C & al, J Clin C & al, J Clin MicrobiolMicrobiol, 39:1738, 2001), 39:1738, 2001)

Fimbriae are not solely pathogenicthrough their adhesive properties

• Type 1 adhesins bind to mannose and elicithemagglutination

• Hemagglutination increases the inflammatoryresponse to infection

• In a murine model of pyelonephritis Dr -fimbriaebind to Bowman's capsule and tubular cellbasement membranes through the complement'Decay accelerating factor' and type IV collagen

Factors of uropathogenicityP. mirabilis

Mobley HLT & al Kidney Int 46:S129-36, 1994

Specific factors

Four types of adhesins. MR/P in the kidney and PMF in the bladder

Non specific factorsFlagellaeHemolysinUrease → NH3 urinary pH → struvite staghorn stones

Lessons from animal modelsRoberts JA AJKD 1991

Model: primate

1) Flushing UPEC into the ureter2) Renal vein blood:

ReninComplementThromboxane A2

3) Renal tissue histology:Edema, PMNs, haemorrhage, tubular necrosis, capillarythromboses

Ischemia

1

2

3

Lessons from animal modelsHill GS & Clark RL Invest Radiol 1972

Model: rabbit. Flushing of UPEC in the ureter

VascularVascular neopreneneoprene injectioninjectionHistologyHistology

Summary

• Gram negative pathogenic bacteria progress from theperineum to the urethra, the bladder and spread from themedulla outwards into the renal tissue

• They induce intense vasoconstriction, PMNs influx, capillary plugging, edema and hemorrhagic suffusions

• The involved areas are ischemic• Ischemia may lead to necrosis and walled off cavity

formation = abscess• Ischemia may induce papillary necrosis• The corresponding cortex may undergo sclerosis leaving

definitive cortical scars

Pyelonephritickidney removedsurgically as a salvage procedure in a diabetic.

Whitish areas * denote suppuration.

Arrows show abscess formation

*

Renal biopsy

Edema, inflammatory infiltrate * leukocyte casts in the tubules

*

Renal biopsy, human. Edema, PMNs, hemorrhagic suffusions

Imaging• Emergency CT enhanced helical CT scan may reveal a ureteral

calculus requiring immediate referral to the urologist. Sensitivity98%, specificity 100% (Fielding JR, Am J Radiol 71:1051-3, 1998). Absolute superiority over IVP

• Ultrasound examination: not for assessing obstruction (dilatation lacks in 20% of cases. Found in only 65%), but shows parenchymallesions and discloses abscesses > 1 cm

• CT scan: hypodense images indicating vasoconstriction in suppurative areas. Shows abscesses

• DMSA scintigraphy: when available, extremely sensitive, results in two hours. Inexpensive. The imaging technique of choice in children

• Gallium scan: rarely indicated nowadays

Ultrasound diagnosis of pyelonephritis

Pyélonéphrite vue en échographieUltrasound diagnosis of pyelonephritis

Abscess

Bilateral pyelonephritisHypodense radiating appearance of presuppurative areas

CT scan

Large nodular hypodense "nephronia" from medulla to cortex Note the perirenal edema *

*

CT scan

Juxta cortical hypodense area

in a swollen, edematous

kidney

CT CT scanscan

Left sided pyelonephritis. Large edematous kidney with twohypodense, ischemic areas

Cortical scars two months later

Further progression to chronic interstitial nephritis

Abscess

Pseudo-renal cancer: febrile, painless renal abscess in a malnourishedchronic alcoholic patient Note calcifying pancreatitis

Pseudorenal cancer: febrile, painless renal abscess in a malnourishedchronic alcoholic patient Note calcifying pancreatitis

Gallium scan beforetreatment

Gallium scan aftertreatment

****

*** ***RL

Clinically right sided PN. In fact, bilateral on scintigraphy

99mTc-DMSA scintigraphy

Scintigraphy

CT scan

Pyelonephritis in pregnancy

• Frequent• Heralded by asymptomatic bacteriuria• Occurring in a physiological state of

immunodepression• Difficult imaging (dilatation of the urinary tract is

physiological)• Dangerous: risk of contractions and premature

labor

Patterson & al

Kidney Int

45:571, 1994

Patterson & al

Kidney Int

45:571, 1994

VUR

The most commoncause ofpyelonephritis in children

Risk of renal growtharrest, cortical scars, chronicpyelonephritis

Best diagnostic procedure:

DMSA scintigraphy

Compound papillae

Diabetics

• Male + Obese + Poor glycemic control• Bladder autonomic neuropathy + Glycosuria +

Neutrophil phagocytic impairment• May be painless• Leads to hyperosmolarity and acidocetosis• Abscess formation and papillary necrosis• Rescue nephrectomy may be the last recourse

Necrosis and abscess formation

Papillary necrosis

Papilla recovered in the urine

Acute pyelonephritis

Young woman

No urologic disease

No compromisedbackground

"Simple" pyelonephritis

Apparentlybenign

Ten dayambulatory Rx

Apparentlysevere

Hospitalization

Male

Elderly

Diabetic

Pregnant

Child

Antibiotic treatmentNot advisable before sensitivity tests

• Ampicillin• Cotrimoxazole

Recommended first line regimen

70 % of community acquiredenterobacteriaceae are now resistant

Aminoglycoside 4 days

Fluoroquinolone 10 days

Pregnancy3rd generation β lactamin

Children

Aminoglycoside + 3rd generation β lactamin