Anti-TNF, Immunosuppression and
Renal Disease: Approaches in TB
Dr Heather Milburn
Consultant Respiratory Physician
Guy’s & St Thomas’ NHS Foundation Trust
READER IN Respiratory Medicine
KING’S College London
Relative risk of developing active TB
(Nice Guidelines, 2006/2011)
Clinical Condition
Relative Risk
Diabetes mellitus
Solid organ transplantation
2-4
20-74
Silicosis
30
Chronic renal failure/haemodialysis 10-25.3
Gastrectomy
Contact smear +ve TB
2.5
5-10
HIV
10
Anti-TNF therapy
Corticosteroids, MMF, tacrolimus,
ciclosporin, aza, mtx, rituximab…..
5
?
Difficulties in Management of TB & LTBI in Renal
Disease
• Risk: ethinic minorities inc risk both TB & CKD
• Screening: when? How? skin anergy; IGRA tests –
evaluation.
• Diagnosis: unusual presentations
• Treatment: timing; dosage; drug interactions.
Renal Disease – TB Risk
• Chronic Kidney Disease
- Acqu’d i/d state
- Functional abnorm N, T&B lympho,
monos, NK cells; vitamin D deficiency
- Risk 31.4 in China, ?UK
• Maintenance Haemodialysis
- Risk 10-25x (NICE 2006)
• Transplant
- Risk 100-400x (Europe & USA; ISC
?higher)
- NICE 2006 overall relative risk x37
Incidence of TB - CKD
• TB incidence UK 15/100,000; London 44.4/100,000
• Dialysis 1,187/100,000 (Moore et al 2002)
No. of
cases/100,000
1400
1200
1000
800
600
400
200
CAPD
Haemodialysis
Functioning
Transplant
Total
Transplants
General UK
Population
London
0
Palchaudhuri et al 2011
Uraemic Milieu
Intracellular Ca++
Zn deficiency
Malnutrition –
low albumin
Fe overload
Uraemic toxins –
guanidines, polyamines
neutrophil
Myeloperoxidase
O2 radicals
bacterial killing
bacterial virulence
Uraemic milieu
Renal replacement therapy
Vit D deficiency
C’ activation
IL1b
IL6
Monocyte/APC
Chronic inflammation
TNFa
IL12
costimulation
IL6/IL10 imbalance
T cell
IL6
TH1
differentiation
TH2
IL4
IFNg
Cellular immune
response
B cell
Humoral immune
response
Renal Disease – LTBI & Prophylaxis
• Who?
- All uraemic patients?
- Only those with particular risk?
• When?
- CKD?
- On dialysis?
- Pre-transplant?
- Post-transplant?
• How?
- TST?
- IGRA?
• What?
- 6/12 H
- 3/12 RH (drug interactions)
- 4-6/12 R (drug interactions)
Renal Disease – Method of Screening
• Pre-transplant
• TST – Anergy 30-50%
Drugs – pred, aza, 6-MCP, mtx,
cycloph, mycophenolate, ciclosp,
tacrolimus
• Interferon-g tests – evaluation?
• CXR
Bumbacea et al. Eur Respir J 2012;40:990-1013
IGRAs in Immunosuppression
CKD
Systematic Review of 30 studies (47):
• Predominantly HD
• Countries with low-mod TB prevalence
• 9 compared IGRAs with TST, 17 TST only, 4 other tests.
• cf +ve TST, +ve ELISA more strongly assoc with radiol evidence past TB (OR
4.29, CI 1.83-10.3, p=0.001) and contact with aTB (OR 3.36, CI 1.61-7.01,
p=0.001)
• cf –ve TST, -ve ELISA more strongly assoc with BCG (OR 0.30, CI 0.14-0.63,
p=0.002)
• Insufficient data to compare ELISPOT with TST or ELISA
• ELISA more strongly assoc with risk factors for LTBI in CKD than TST
(Rogerson et al., Am J Kidney Dis 2013)
Study design
Data set consisting of
• Mendel Mantoux skin-test
• T-SPOT.TB
• QuantiFERON-TB Gold In-Tube
Clinical data
• TB risk factors
• Level of immunosuppression
TBNET
Percentage of positive results
Similar percentages of
positive test results in all assays
CRF
40
30
26.3%
26.7%
27.1%
all
<5 years of dialysis
>5 years of dialysis
20
10
0
TBNET
Patients with
chronic renal
failure
Percentage of positive results
Similar percentages of
positive test results in all assays
CRF
40
30
all
<5 years of dialysis
>5 years of dialysis
20
10
TBNET
0
Patients with
chronic renal
failure
Agreement between the tests
K=0.3
2
neg
pos
K=0.2
8
neg
CRF
pos
neg
158
(60.3%)
35
(13.4%)
neg
155
(59.2%)
38
(14.5%)
pos
34 (13.0%)
35
(13.4%)
pos
36 (13.7%)
33
(12.6%)
K=0.5
2
neg
pos
TBNET
neg
167
(63.7%)
25 (9.5%)
pos
24 (9.2%)
46
(17.6%)
CRF
No association with TB exposure
crude
TBNET
age, sex, duration of
dialysis
OR
95% CI
OR
95% CI
1.2
0.6-2.2
1.1
0.6-2.3
1.3
0.7-2.3
1.2
0.6-2.3
1.2
0.6-2.5
1.3
0.6-2.6
BTS Recommendations 2010
• Screening for LTBI - Method:
Use IGRA with or without TST
• Who to screen:
Pre-transplant
Contacts
• Chemoprophylaxis:
6H if post transplant
3RH if pre transplant
4R if pre transplant
Drug Recommendations: Chemoprophylaxis
• H & R - normal doses in CKD.
• Long term use of isoniazid is not recommended.
• No evidence for prolonged chemoprophylaxis with
any of above.
• No evidence for lower doses - lower peak levels and
drug resistance.
Guidelines for management of TB & LTBI in CKD;Thorax 2010:65:559-70
Active TB
Routine Assessment:
• History – prev TB, Rx & time, recent contact
• Chronic cough, wt loss, sweats – CXR
• Sputum, ind sputum, FOB, EBUS
Presentation:
• Not always classic
• Extra pulmonary common – 30-50%; peritoneal
Investigation:
• Active TB suspected –fluid or tissue for culture & sensitivity testing;
histology
• Active pulm disease – isolate in negative pressure room
• Notify
• INVOLVE CHEST PHYSICIANS
40yr old white M
Peritoneal dialysis 1yr
Abdom pain, Cloudy dialysate, No cough
T 38, WCC 5.4, N 4.4, Ly 0.8, CXR unremarkable
Blood cultures –ve, MC&S of dialysate –ve
From Latvia, UK 1yr
Antibiotics 1/52
No improvement
Further specimens neg
Change antibiotics
No improvement
Abdo US – nodes and omental thickening
Biopsy – granulomata, no AFB seen, grew H resistant TB
Pharmacokinetics & Toxicity of first-line drugs in
CKD
• H: metabolised by liver
- neurotoxicity – give pyridoxine
- neuropsychiatric disturbance
- ototoxicity – rare and can occur in CKD
• R: metabolised by liver
- no signif increase tox
• Z: metabolised by liver
- uric acid retention – gout
• E: 80% excreted unchanged by kidneys
- ocular toxicity dose dependent
- increased efficacy normal dose less often
Treatment aTB
47yr old Black African, HD, sm+ PTB, dry wt 68kg
Management?
Not on open HD unit!
Medication:
Rifater 6 daily
Ethambutol 600mg daily
Renal Disease - Treatment
CKD Stage 1 normal function but structural abnormality
CKD Stage 2 Cr Cl 60-90mls/min; Stage 3 30-60mls/min;
Stage 4 15-30mls.min; Stage 5 <15mls/min.
• Dose
Do not reduce dose as leads to lower peak dose
- Iso, Rif, – normal doses; Give piridoxine
- PZA & E – normal doses for stages 1-3;
increased dose intervals in stages 4 & 5 CKD
and HD;
- Moxi – normal dose stages 1-3 & Tx; not suitable
3x/wk
Renal Disease - Treatment
• When?
- H & R daily or 3x/wk
- E & Z daily for stages 1-3, otherwise
3x/week; E peak & trough levels
- Z signif removed by dialysis
- 4-6hrs before haemodialysis or
immediately after
- Moxi daily 1-3 & Tx; not 3x/week
Peritoneal dialysis? – careful monitoring
Renal Disease - Treatment
• Duration
Standard 6/12 for fully sensitive
CNS – 1 year
• Immunosuppression
Rif interferes with most regimens.
Monitor levels
Double steroid doses
MMF, ciclosporin and tacrolimus dosages
adjustment
need
Drug recommendations…active TB
• Standard chemotherapy agents, standard
duration as per NICE guidelines
• Monitor peak & trough levels - Ethambutol and
aminoglycosides. Concern about over-and underdosing.
• CKD stage 4-5 or haemodialysis – increase dosing
intervals to 3 times weekly for E, Z &
aminoglycosides. Reduces risk of drug
accumulation and toxicity
BTS Guidelines Thorax 2010
TB in CKD - Summary
•
•
•
•
•
•
•
•
•
High risk of TB – partic non-UK born, EMGs
Screen pre-tx & those at particular risk
Usual chemoprophylaxis
aTB – extra-pulmonary, low index of suspicion
Medication – do not reduce dose but inc dosing interval (E, Z,
aminoglycosides Stages 4-5 & haemodialysis)
Increased risk drug resistance
Drug interactions - Rif
Drug monitoring
VIGILANCE!
»
BTS Guidelines Thorax 2010
Renal Impairment & TB:
Unanswered Questions
What are the rates of TB and LTBI in countries with
low background rate?
• What is the increased risk?
 How do the IgRA tests perform?
When to screen for LTBI?
 Which patients should receive chemoprophylaxis?
 Dosages, dose intervals, timing on HD?
Pharmacokinetics for patients on peritoneal dialysis?