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TB in CKD

TB in CKD. Dr. Ramprasad. Introduction. There is an increased incidence of tuberculosis (TB) in patients with end-stage renal disease (ESRD) as compared with the general population In absolute numbers, this observation is especially important in areas where the disease is endemic.

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TB in CKD

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  1. TB in CKD Dr. Ramprasad

  2. Introduction • There is an increased incidence of tuberculosis (TB) in patients with end-stage renal disease (ESRD) as compared with the general population • In absolute numbers, this observation is especially important in areas where the disease is endemic Seminars in Dialysis 2003; 16(1): 38–44

  3. Introduction • Approximately 1/3rd of the world population is infected with TB • Patients with ESRD undergoing chronic dialysis are 6-25 times more likely to develop TB compared to the general population mainly due to impaired cell-mediated immunity Physicians Academy 2011 ;5 (11): 139-43

  4. Introduction • The presentation of TB in uremic patients is often • Quite unusual and insidious, and • Diagnosis and management provide the treating physician with many special challenges Physicians Academy 2011 ;5 (11): 139-43

  5. Epidemiology Continued on next slide… Seminars in Dialysis 2003; 16(1): 38–44

  6. Epidemiology (Contd) Seminars in Dialysis 2003; 16(1): 38–44

  7. Pathogenesis • The host response against intracellular pathogens, including Mycobacterium tuberculosis, is determined by • Type 1 helper T-cell response with the involvement of interleukin (IL)-12, resulting in increased production of interferon (IFN)-γ • In uremia there is a decreased T-cell response, as indicated by • High rate of anergyto intracutaneouslyadministered antigens, reported to be as high as 32% and 40% Seminars in Dialysis 2003; 16(1): 38–44

  8. Pathogenesis • Reason for the decreased cellular immunity might • Defect in the costimulatoryfunction of antigen-presenting cells, and a • Persistent inflammatory state of monocytes, which is caused by the uremia per se, as well as by the dialysis treatment • Other factors which might contribute to the decreased immunity are • Malnutrition, vitamin D deficiency, and hyperparathyroidism Seminars in Dialysis 2003; 16(1): 38–44

  9. Risk Factors • In a retrospective analysis • Age • Asian and Native American race • Smoking • Reduced body mass index • Low serum albumin • Ischemic heart disease and • Anemiawere found as significant risk factors for dialysis patients to develop TB Nephrol Dial Transplant 2006; 21:3287-3292

  10. Risk Factors • Prospective multi-center clinical trial • Advanced age (>65 years) • Body mass index (underweight being more prone) • Diabetes mellitus • Tuberculin reactivity • Healed TB lesions on chest X-ray and • Time on dialysis were significant risk factors for development of TB • Those treated with dialysis <12 months presented significantly higher risk for TB BMC Nephrology 2009, 10: 36.

  11. Features • The symptomatology of TB is often confused with that of CKD leading to difficulty in early diagnosis and high mortality • Extra pulmonary TB in dialysis patients is more common and may be seen up to 77% of cases compared to the general population occurrence of 11.5% Physicians Academy 2011 ;5 (11): 139-43

  12. Features • All studies report an insidious onset of symptoms,with fever, anorexia, and loss of weight being the main complaints, mimicking uremic symptoms • Pien et al. found • Fever occurring in a mean of 72% of the cases (range 29–100%) • Malaise in a mean of 69% (range 29–100%), and • Weight loss in a mean of 54% (range 10–100%) • However, • Cough and hemoptysis, classic symptoms of TB in the general population, are less frequently reported in dialysis patients (mean 22% of cases; range 5–71%) Seminars in Dialysis 2003; 16(1): 38–44

  13. Features • The localization is often extrapulmonary, with percentages varying from 38% up to >80% • The nonspecific presenting symptoms together with the frequent extrapulmonary localization constitute risk factors for a delay in the diagnosis of TB, which unfortunately has been observed in several studies Seminars in Dialysis 2003; 16(1): 38–44

  14. Features • Within the extrapulmonarygroup • Tuberculous lymphadenitis and peritonitis are the most reported localizations; • Less frequently cases of • Military • Spine (Pott’s syndrome) • Cerebral and • Genitourinary TB have been reported Seminars in Dialysis 2003; 16(1): 38–44

  15. Features • The most common forms of presentation are • Lymphadenitis • Gastrointestinal • Bone, • Genitourinary • Peritonitis • Pleural effusion • Pericardial effusion • MiliaryTB and • Pyrexia of unknown origin Physicians Academy 2011 ;5 (11): 139-43

  16. Features • A special category represents the so-called • Occult or probable TB, which is defined as a • Strong suspicion of the disease with negative routine and invasive investigations, failure to respond to broad-spectrum antibiotics, and good response to empirical antituberculous therapy • Most reports include cases of occult TB in their series, up to a frequency of 21–50% in some studies Seminars in Dialysis 2003; 16(1): 38–44

  17. Diagnosis • The diagnosis of TB in dialysis patients is generally difficult because of frequent extrapulmonary involvement and nonspecific symptoms • A high degree of suspicion is needed in patients on dialysis with symptoms of fever, weight loss and/or lymphadenopathy • The diagnosis is confirmed by the isolation of acid-fast bacilli, the finding of typical caseatinggranulomaon biopsy or the growth of tubercle bacilli from the culture of the biopsy material Physicians Academy 2011 ;5 (11): 139-43

  18. Diagnosis • Tuberculin Skin Test (TST) • Infection with Mycobacterium tuberculosis is followed by delayed type hypersensitivity (DTH) • This reactivity is the basis of the TST which is used for the detection of TB infection in persons without symptoms • The previously sensitized CD4+ T lymphocytes are attracted to the skin test site where they proliferate and produce cytokines • Cases of active TB are often accompanied by strongly +veskin test reactions • The TST measures the DTH response to intradermal inoculation of tuberculin purified protein derivative (PPD), a crude mixture of >200 Mycobacterium tuberculosis proteins • A skin induration >10 mm in diameter is considered positive Physicians Academy 2011 ;5 (11): 139-43

  19. Diagnosis • Tuberculin Skin Test (TST) • However anergy to TST is prevalent in ESRD patients and is significantly higher than in the general population (44% versus 16%) • Because of its poor sensitivity a negative STS cannot be used to exclude the possibility of latent or active TB in dialysis patients • Booster TST (two consecutive tests within 7-14 days) with a higher dose of PPD (usually double) has been recommended in immunocompromised like dialysis patients to improve the sensitivity of TST Physicians Academy 2011 ;5 (11): 139-43

  20. Diagnosis • Tuberculin Skin Test (TST) • Doganet al found a positive test in 11.3% of 124 chronic hemodialysis patients whereas the second test added 12.1% more • The importance of TST despite its low sensitivity cannot be underestimated since a positive test forms an indication for TB prophylaxis in dialysis patients • A 6 month course of prophylaxis with isoniazid as 15 mg/kg dose 2 or 3 times per week has been recommended and up to 90% of treated patients enjoy long term protection from TB Physicians Academy 2011 ;5 (11): 139-43

  21. Diagnosis • The Interferon (IFN)-ϒ Release Assays (IGRAs): • Recently2 in vitro assays that measure T cell release of IFN-ϒ in response to stimulation with the highly tuberculosis specific antigens ESAT-6 and CFP-10 have become commercially available • QuantiferonTB Gold, a whole blood enzyme linked immunosorbent assay (ELISA) for measurement of IFN-ϒ and • T-SPOT TB, an enzyme linked immune spot (ELI spot) assay • These are more specific than the TST as a result of less cross reactivity due to BCG vaccination and sensitization to non-tuberculosis mycobacteria Physicians Academy 2011 ;5 (11): 139-43

  22. Clin J Am Soc Nephrol 2010; 5: 1114–1122

  23. Clin J Am Soc Nephrol 2010; 5: 1114–1122

  24. Continued on next slide… Clin J Am Soc Nephrol 2010; 5: 1114–1122

  25. Clin J Am Soc Nephrol 2010; 5: 1114–1122

  26. Diagnosis • The Interferon (IFN)-ϒ Release Assays (IGRAs): • For the diagnosis of active TB in dialysis patients the sensitivity and specificity of IGRAs using QFT-G were found to be 100% and 89.7% respectively. • The authors conclude that QFT test is a useful supplementary tool for the diagnosis of active tuberculosis even in dialysis patients • Negative and indeterminate test may be used to exclude for the presence of active TB Physicians Academy 2011 ;5 (11): 139-43

  27. Diagnosis • The Interferon (IFN)-ϒ Release Assays (IGRAs): • TST ,the classic diagnostic tool for the diagnosis of latent TB has several drawbacks including poor sensitivity(because of high prevalence of anergy in dialysis patients and specificity with false positive tests in vaccinated with Bacillus CalmetteGuerin (BCG). • So IGRAs should be used instead of TST for latent TB screening in dialysis patients Physicians Academy 2011 ;5 (11): 139-43

  28. Treatment • After 1993 the short course therapy consisting of Isoniazid (INH), Rifampicin (Rif), Pyrazinamide(PZA) and Ethambutol (Eth) or streptomycin for 2 months followed by only INH and Rif for another 4 months to complete a total 6 month therapy has been recommended for pulmonary as well as extra pulmonary TB • Except TB meningitis and children with military or bone/joint TB. Such cases require a therapy for 12 months Physicians Academy 2011 ;5 (11): 139-43

  29. Treatment • After 1993 the short course therapy consisting of Isoniazid (INH), Rifampicin (Rif), Pyrazinamide(PZA) and Ethambutol (Eth) or streptomycin for 2 months followed by only INH and Rif for another 4 months to complete a total 6 month therapy has been recommended for pulmonary as well as extra pulmonary TB • Except TB meningitis and children with military or bone/joint TB. Such cases require a therapy for 12 months Physicians Academy 2011 ;5 (11): 139-43

  30. Treatment • After 1993 the short course therapy consisting of Isoniazid (INH), Rifampicin (Rif), Pyrazinamide(PZA) and Ethambutol (Eth) or streptomycin for 2 months followed by only INH and Rif for another 4 months to complete a total 6 month therapy has been recommended for pulmonary as well as extra pulmonary TB • Except TB meningitis and children with military or bone/joint TB. Such cases require a therapy for 12 months Physicians Academy 2011 ;5 (11): 139-43

  31. Antituberculosis drugs in hemodialysis patients • Confusion exists regarding regimen, duration etc however, • Treatment duration should follow NICE guidelines (UK) namely, • 6 months for most cases of fully sensitive disease, with the exception of • TB involving the CNS when treatment should be for 1 year Thorax 2010;65:559e570

  32. Recommended doses of first-line drugs in CKD Thorax 2010;65:559e570

  33. Antituberculosis drugs in hemodialysis patients (Contd) • For patients on haemodialysis, dosing intervals should be increased to three times weekly to reduce the risk of drug accumulation and toxicity Thorax 2010;65:559e570

  34. Antituberculosis drugs in hemodialysis patients (Contd) • Treatment can be given immediately after haemodialysis to avoid premature drug removal • With this strategy there is a possible risk of raised drug levels of ethambutol and pyrazinamide between dialysis sessions. Alternatively, • Treatment can be given 4-6 h before dialysis, increasing the possibility of premature drug removal but reducing possible ethambutol or pyrazinamide toxicity • The choice of strategy may be influenced by a need to ensure adherence (when post dialysis offers the opportunity for directly observed therapy), practical issues (post dialysis for morning shift patients) and expected pharmacokinetics or drug interactions Thorax 2010;65:559e570

  35. Antituberculosis drugs in hemodialysis patients (Contd) • Both rifampicin and isoniazid may be given in their usual daily doses. • Haemodialysis removes a significant amount of pyrazinamide and the primary metabolite of pyrazinamide, pyrazinoic acid, accumulates in patients with renal failure Thorax 2010;65:559e570

  36. Antituberculosis drugs in hemodialysis patients (Contd) • Advice varies over whether reduction or spacing of the dose of pryazinamide is best for patients on haemodialysis • Variable doses of 25-30 mg/kg three times weekly or 40 mg/kg three times weekly have been recommended • The American guidelines generally recommend a change in dose frequency rather than dose level because, although toxicity may be avoided by reducing the dose, the peak serum concentrations may be too low, leading to suboptimal treatment Thorax 2010;65:559e570

  37. Mortality • The mortality rate of TB in dialysis patients is high ranging from 17-75% • In the USRDS analysis TB was independently associated with a 42% increased mortality • However, many studies have reported no or low mortality, possibly related to early diagnosis and treatment. Physicians Academy 2011 ;5 (11): 139-43

  38. Conclusions • There is an increased prevalence of TB among dialysis patients • The prognosis is very much dependent on early diagnosis and treatment • Nephrologists should therefore be awareof the unusual presentation and localization, and include TB in the differential diagnosis of any patient having nonspecific symptoms such as anorexia, fever, weight loss

  39. Conclusions • All efforts should then be made, including invasive investigations, to reach an early diagnosis, a major determinant of the outcome • However, if this is not possible or the result is negative and the diagnosis remains strongly suspected, an empirical trial with antituberculousmedication is justified, especially in endemic areas

  40. Thank YOU!

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