Anti-TNF, Immunosuppression and Renal Disease: Approaches
in TB
Dr Heather MilburnConsultant Respiratory Physician
Guy’s & St Thomas’ NHS Foundation TrustREADER IN Respiratory Medicine
KING’S College London
Relative risk of developing active TB(Nice Guidelines, 2006/2011)
Clinical Condition Relative Risk
Diabetes mellitus 2-4
Solid organ transplantation 20-74
Silicosis 30
Chronic renal failure/haemodialysis 10-25.3
Gastrectomy 2.5
Contact smear +ve TB 5-10
HIV 10
Anti-TNF therapy 5
Corticosteroids, MMF, tacrolimus, ciclosporin, aza, mtx, rituximab…..
?
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)
0
200
400
600
800
1000
1200
1400
CAPD Haemodialysis FunctioningTransplant
TotalTransplants
General UKPopulation
London
No. ofcases/100,000
Palchaudhuri et al 2011
398
1267
298
522
14.9
44
Uraemic Milieu
neutrophil
Fe overload
Zn deficiency
Intracellular Ca++
Malnutrition – low albumin
Uraemic toxins – guanidines, polyamines
Myeloperoxidase
O2 radicals
bacterial killing
bacterial virulence
Uraemic milieuRenal replacement therapy
IL1b
IL6
TNFa
C’ activation
Chronic inflammation
IL6/IL10 imbalance
Monocyte/APC
IL12
T cell
TH1 TH2
B cell
costimulation
Cellular immune response
Humoral immune response
IFNg
IL4
differentiationIL6
Vit D deficiency
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 ImmunosuppressionCKD
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
Similar percentages ofpositive test results in all assays
0
10
20
30
40
all<5 years of dialysis>5 years of dialysis
Perc
enta
ge o
f pos
itive
resu
lts
Patients with chronic renal failure
26.3% 26.7%
CRF
27.1%
TBNET
Similar percentages ofpositive test results in all assays
Patients with chronic renal failure
CRF
0
10
20
30
40
all<5 years of dialysis>5 years of dialysis
Perc
enta
ge o
f pos
itive
resu
lts
TBNET
Agreement between the tests
K=0.32
neg pos
neg158 (60.3%)
35 (13.4%)
pos 34 (13.0%)35 (13.4%)
K=0.28
neg pos
neg155 (59.2%)
38 (14.5%)
pos 36 (13.7%) 33 (12.6%)
K=0.52
neg pos
neg167 (63.7%)
25 (9.5%)
pos 24 (9.2%) 46 (17.6%)
CRF
TBNET
No association with TB exposure
crude 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
CRF
TBNET
BTS Recommendations 2010
• Screening for LTBI - Method:Use IGRA with or without TST
• Who to screen:Pre-transplantContacts
• Chemoprophylaxis:6H if post transplant3RH if pre transplant4R 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 TBRoutine Assessment:• History – prev TB, Rx & time, recent contact• Chronic cough, wt loss, sweats – CXR• Sputum, ind sputum, FOB, EBUSPresentation:• Not always classic• Extra pulmonary common – 30-50%; peritonealInvestigation:• 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 MPeritoneal dialysis 1yr
Abdom pain, Cloudy dialysate, No coughT 38, WCC 5.4, N 4.4, Ly 0.8, CXR unremarkableBlood cultures –ve, MC&S of dialysate –veFrom Latvia, UK 1yrAntibiotics 1/52No improvementFurther specimens negChange antibioticsNo improvementAbdo US – nodes and omental thickeningBiopsy – 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 68kgManagement?
Not on open HD unit!Medication:
Rifater 6 dailyEthambutol 600mg daily
Renal Disease - TreatmentCKD Stage 1 normal function but structural abnormalityCKD Stage 2 Cr Cl 60-90mls/min; Stage 3 30-60mls/min; Stage 4 15-30mls.min; Stage 5 <15mls/min.
• DoseDo 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
• DurationStandard 6/12 for fully sensitiveCNS – 1 year
• ImmunosuppressionRif interferes with most regimens.Monitor levelsDouble steroid dosesMMF, ciclosporin and tacrolimus dosages
need adjustment
Drug recommendations…active TB
• Standard chemotherapy agents, standard duration as per NICE guidelines
• Monitor peak & trough levels - Ethambutol and aminoglycosides. Concern about over-and under-dosing.
• 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?