Urinary diversion and UTI: Adaptation of epithelial response - Rob Pickard Professor of Urology
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Urinary diversion and UTI: Adaptation of epithelial response Rob Pickard Professor of Urology Newcastle University r.s.pickard@ncl.ac.uk
My Talk • Epithelial – Bacterial interactions – Tolerance versus immune response • Ileal conduit – a surgically-fashioned epithelial paradox • The clinical problem • The laboratory investigation • The clinical application • Summary
Bacteria – Epithelium Interaction
Urinary Tract
Maintain sterility
•Surveillance Ureter
•Seek & destroy
•Immune response
•Innate
•Encourages virulence
GI – Tract
Symbiotic relationship
•Control Ileum
•Tolerance
•Arm’s length
•Discourage virulence
Escherichia coli (E. coli)
Bacterial adaption
The changing face of E. coli
• Planktonic
– ‘Floaters’ Asymptomatic bacteriuria
Changing genotype
(ABU)
• Motile
– Flagellin
• Invasive – Uropathogenic E. coli
(UPEC)
– Adhesion molecules
• Adhesins
• Pili
– Membrane digestion
• Hyalurinidase
Urinary surveillance
• Fluid flow – 5 ml/min
• pH < 7
• Antimicrobials
– Proteins
• Tamm Horsfall
• Lipocalin
• Lactoferrin
– Peptides
• Cathelicidin (LL-37)
• Alpha defensins (HD5)
• Beta defensins (BD1)
ABU
Epithelial Response UPEC
• Cell surface receptors
– Pathogen Recognition Receptors Outside
Toll - Like receptor 4 cell
• TLRs 4- LPS; 5 - flagellin
• Signal Transduction
Inside
– NFκB Adapter molecules
cell
– NOD2 Intermediaries
• Transcription
• Effectors NFB
Activation
– Anti-microbial peptides (AMP) leading to AMP
secretion
– Anti-microbial proteins
Cell Nucleus
– Cytokines
+Transcription factors gene (DNA) mRNA functional peptide
Ileal conduit – epithelial paradox
Joining the
bacterially–tolerant
ileal mucosa to the
Immune-active ureteric
mucosa
Constant bacterial threat
•Ileum
•Skin
What does the conduit do:
•Seek and destroy?
•Or tolerate?
The Clinical Question
Why do some people with
a urostomy get lots of
urinary infections and
others don’t?
Defining a urinary infection (CDC)
Symptomatic UTI
• Collection of symptoms
– ‘Flu-like’ feelings
– Fever
– Rigors
– Loin pain
• > 104/ml of 1 or 2 organisms in
catheterised specimen of urine
Asymptomatic bacteriuria
• > 104/ml of 1 or 2 organisms in
catheterised specimen of urine
• No symptoms
• May have changes in urine
– Cloudy
– Smelly
– Mucus ↑
UTIs – some are worse than
others!
• Simple
– Local symptoms
– Get better quickly
– May not need
antibiotics
• Fever/shivers
– Toxaemia
– Need antibiotics
• Bacteraemia
– Need IV antibiotics in
hospitalSymptomatic UTIs – How common
are they in people with urostomy?
•c80% have bacteriuria
•Symptomatic recurrent UTIs are common 20 -30%
•The problem continues over many yearsAre recurrent UTIs important?
Costs: Personal and health care
Miserable
Antibiotics don’t help much Loss of functioning renal tissue
& cause problemsThe Paradox
100 100
75 75
50 50
% People with
% People with urostomy
25 urostomy 25
0 0
Bugs Infection
in
urine
Is it the person or the bug?What may keep bacteria at bay?
Anti-microbial peptides (AMPs)
• Small protein molecules (15 – 30
ααs)
– Highly conserved
– Made by epithelia
• Constitutively
• Induced
– Bacteriocidal
• +ve charged segment – hydrophilic
• Non-charged segment – lipophilic
– defensins
– defensins
– CathelicidinOur Research 8/07 – 12/09
Aims
1. Are the AMPs present
and active in ileal
conduits?
Stoma clinic Freeman Hospital FMS Newcastle University
Participants
2. Do people with
urostomies who get 1. 10 People undergoing
recurrent symptomatic ileal conduit surgery
UTIs have reduced 2. 20 people with a conduit
amounts or activity of and no infections
AMPs? 3. 20 people with a conduit
and > 2 UTIs per yearOur Participants 17 people had recurrent UTIs –average People with recurrent UTIs ( ) reported Of 7 per year ( ) and 17 none ( ) had worse health than those without ( )
1. Results – id of AMPs
RNA level
Ileum
Ureter
*
Protein level *
HD5 - ileum BD1 - ureter HD5 - ureterResults - details
- defensin – BD1
- defensin – HD-5
18S RNA control
Only 2 AMPs were consistently constitutively expressed in both ureter and ileum
A new discovery – HD5 in the urinary tract - an exciting development!2. Change in AMP expression after
diversion3. rUTIs versus asymptomatic A. No difference in urinary activity against B. Organisms isolated from standard organism. rUTI more virulent C. High urinary activity against infecting D. High urinary activity in rUTI group organism in rUTI group against highly virulent UPEC strain
Our Conclusions
• Asymptomatic patients
– Adaptation of ureteral urothelium to a bacteria-tolerant phenotype
– Tolerance of bacterial colonization
– No evolutionary pressure towards virulent bacterial phenotype
• Patients with recurrent symptomatic UTIs
– Maintenance of aggressive antimicrobial response typical of the normal
urinary tract
– In response evolution of pathogens toward virulent phenotype
– Temporary clearance of pathogen at expense of infective symptoms
• Key role for HD-5?
– Expression increased significantly in ureter after diversion
– Trend toward greater ileal and ureteral HD-5 expression in rUTI group
• Next steps
– Comparative longitudinal analysis of HD-5 urinary content
– Related to phase of infection – clearance – re-infection
– Define therapeutic potentialWhat might this mean clinically?
Pathway modulation
• Host
– Epithelial recognition
– Signalling pathway
– Effector gene
transcription
– Effector interaction
• Bug
– Adaption
– Interaction with
environment
– Virulence factors
– Invasiveness
New drugsNeeded because of ↑ antibiotic resistance
Alternatives to antibiotics – Identify
asymptomatic patients and encourage less
antibiotic use through patient education
100 women with cystitis treated with 3 days antibiotics:
NHS patient decision aidCurrent alternatives
• High fluid intake
• Analgesia
• Urinary alkalinising agents x/
• Cranberry preparations x/
• Methenamine x/
• Pro-biotics x/
http://www.cks.nhs.uk/
Need more - urgentlySummary
• We know more about the
bugs
– Changing
phenotype/adaptatability
• We know more about the
host
– Defences
– Tolerance vs Response
• Need to put it together
– New treatments strategies
– Stratify risk
• Induce tolerance
• Induce/enhance responseAcknowledgements
The workers
• Dr Judith Hall
• Dr Claire Townes
• Ased Ali
• Marcelo Lanz
+
• Wendy Robson
• Marian Haskin/Liz Davis/Helen
Lake
• Kieran O’Toole
• Natasha Rigas
Funding
• Craig Robson
+
• The participants and urine
collectorsAny Questions?
Read more!?
• Ali et al J Urol 2009: 182;
21-28
• Townes et al Urology
2010: In press
• http://www.uroweb.org/fileadmin/EAUN/gu
idelines/EAUN_IU_Guidelines_EN_2009_
LR.pdf
• Sivick KE and Mobley HLT. Waging War
against Uropathogenic Escherichia coli:
Winning Back the Urinary Tract.
INFECTION AND IMMUNITY 2010;
78:568–585
• Weichhart et al. Current concepts of
molecular defence mechanisms
operative during urinary tract
infection. Eur J Clin Invest 2008; 38
(S2): 29–38You can also read
