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 ConditionRelative Risk Diabetes mellitus2-4 Solid organ transplantation20-74 Silicosis30 Chronic renal failure/haemodialysis Gastrectomy2.5 Contact smear +ve TB5-10 HIV10 Anti-TNF therapy5 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 x (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) Palchaudhuri et al

Uraemic Milieu neutrophil Fe overload Zn deficiency Intracellular Ca++ Malnutrition – low albumin Uraemic toxins – guanidines, polyamines Myeloperoxidase O 2 radicals bacterial killing bacterial virulence

Uraemic milieu Renal replacement therapy IL1  IL6 TNF  C’ activation Chronic inflammation IL6/IL10 imbalance Monocyte/APC IL12 T cell TH1TH2 B cell costimulation Cellular immune response Humoral immune response IFN  IL4 differentiation IL6 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-  tests – evaluation? CXR

Bumbacea et al. Eur Respir J 2012;40:

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 , p=0.001) and contact with aTB (OR 3.36, CI , p=0.001) cf –ve TST, -ve ELISA more strongly assoc with BCG (OR 0.30, CI , 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 of positive test results in all assays Patients with chronic renal failure 26.3% 26.7% CRF 27.1% TBNET

Similar percentages of positive test results in all assays Patients with chronic renal failure CRF TBNET

Agreement between the tests  =0.3 2 negpos neg 158 (60.3%) 35 (13.4%) pos34 (13.0%) 35 (13.4%)  =0.2 8 negpos neg 155 (59.2%) 38 (14.5%) pos36 (13.7%) 33 (12.6%)  =0.5 2 negpos neg 167 (63.7%) 25 (9.5%) pos24 (9.2%) 46 (17.6%) CRF TBNET

No association with TB exposure crude age, sex, duration of dialysis OR95% CIOR95% CI CRF TBNET

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 mls/min; Stage mls.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 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?