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Anti-TNF, Immunosuppression and Renal Disease: Approaches in TB

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).

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Anti-TNF, Immunosuppression and Renal Disease: Approaches in TB

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  1. 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

  2. Relative risk of developing active TB(Nice Guidelines, 2006/2011)

  3. 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.

  4. 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

  5. Incidence of TB - CKD • TB incidence UK 15/100,000; London 44.4/100,000 • Dialysis 1,187/100,000 (Moore et al 2002) 1267 522 398 298 14.9 44 Palchaudhuri et al 2011

  6. Uraemic Milieu Intracellular Ca++ Zn deficiency Malnutrition – low albumin Fe overload Uraemic toxins – guanidines, polyamines neutrophil Myeloperoxidase O2 radicals bacterial killing bacterial virulence

  7. Uraemic milieu Renal replacement therapy Vit D deficiency C’ activation IL1b IL6 TNFa Chronic inflammation Monocyte/APC IL12 costimulation IL6/IL10 imbalance T cell differentiation IL6 TH1 TH2 IL4 IFNg B cell Cellular immune response Humoral immune response

  8. 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)

  9. 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

  10. Bumbacea et al.Eur Respir J 2012;40:990-1013

  11. 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)

  12. 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

  13. CRF Similar percentages ofpositive test results in all assays 27.1% 26.7% 26.3% Patients with chronic renal failure TBNET

  14. CRF Similar percentages ofpositive test results in all assays Patients with chronic renal failure TBNET

  15. CRF Agreement between the tests TBNET

  16. CRF No association with TB exposure TBNET

  17. 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

  18. 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

  19. 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

  20. 40yr old white MPeritoneal 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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 intervalsto 3 times weekly for E, Z & aminoglycosides. Reduces risk of drug accumulation and toxicity BTS Guidelines Thorax 2010

  27. 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

  28. 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?

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