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1. Tuberculosis in chronic kiDney disease dR. Gurumoorthy a d Resident, institute of nephrology, Mmc - rgggh

2. introduction Tuberculosis is caused by Mycobacterium tuberculosis TB continues to be a leading cause of infectious morbidity and mortality worldwide Since 1990, TB mortality and prevalence have decreased by 45% and 41%, respectively, but much work still needs to be done to eliminate this largely preventable and curable disease. The prevalence of CKD is estimated to be between 8% and 16% worldwide and appears to have increased in recent years.

3. Over the next decade, the global ESKD prevalence is predicted to rise sharply. The fastest growth is expected in low- and middle-income countries with growing economies, such as India and China, where elderly populations are expanding, health-care expenditure is increasing, and disease burden is shifting toward noncommunicable conditions such as diabetes and hypertension. T he link between active tuberculosis (TB) and chronic kidney disease (CKD) was fi rst reported in a 1974 case series involving dialysis patients Later, many s tudies have confirmed a 6.9- to 52.5-fold increased risk of TB in patients with chronic renal failure and on dialysis as compared to the general population

4. According to a recent global systematic review and meta-analysis, the incidence of TB in CKD patients was 3718/100,000 population. A pooled estimate revealed that patients on dialysis had 3.6 times the risk to develop TB compared to the general population. Transplant recipients also have an increased TB risk ranging from 3 to 24 times that of the general population. In a meta-analysis, the pooled unadjusted rate ratio for TB in renal transplant recipients was 11.4 compared with the general population Most cases are due to LTBI reactivation rather than new infection

5. Why increased incidence of tb in ckd ? Ckd is a immunodeficiency state Advanced CKD is associated with oxidative stress and in fl ammation, 25-hydroxyvitamin D de fi ciency, Hyperparathyroidism, and malnutrition, with evidence of functional abnormalities in a variety of immune cellsincluding B and T cells, neutrophils, monocytes, and natural killer cells. Changes in immunity begin as early as stage 3 CKD and worsen in later stages as kidney function deteriorates and waste products accumulate.

6. Uremia Granulocyte functions like chemostaxis , adherence, and phagocytosis are defective Decreased interleukin 2 production by activated t lymphocytes A defect in the co-stimulatory functions of APC’s Persistent inflammatory state of monocytes, caused by uremia per se, as well as by dialysis

7. hemodialysis A state of impaired cell-mediated immunity persists in dialysis and leaves patients susceptible to infectious complication Conventional cellulose membrane causes alternate complement pathway activation leading to changes in granulocyte cell adhesion molecules like CD11b, CD18, L- selectin, this correlate with leucopenia Impairment of phagocytosis is often encountered with cuprophane membrane

8. Post renal transplant Transplant recipients are also at high risk of active TB, related in part to post transplantation immunosuppressive medications (CNI, MMF) that speci fi cally target T cell – mediated immunity, which is critical to maintaining latency in patients with Mycobacterium tuberculosis infection

9. Clinical presentation The clinical presentation of TB in dialysis and kidney transplant patients is often insidious and atypical. Patients frequently present with systemic symptoms, such as fever, anorexia, and weight loss. Patients may present with extrapulmonary disease in as many as 60% to 80% of cases, with presentation including disseminated disease’ Common extrapulmonary sites are pleura, lymph node, abdomen and urinary tract, meninges, bones and joints.

10. Tb peritonitis P atients receiving peritoneal dialysis can have TB peritonitis which typically present with fever, abdominal pain, and cloudy dialysate lymphocyte or polymorphonuclear neutrophil predominance on peritoneal dialysis fl uid cytology testing. TB peritonitis should be considered in all cases of culture negative peritonitis or culture-positive peritonitis that is refractory to appropriate antibiotic treatment

11. Post transplant Patients who develop TB following transplant are usually younger Males are more commonly affected More constitutional symptoms Lung is the most common site followed by abdomen Pyrexia of unknown origin presentation is associated more commonly Neurological TB also more common Miliary TB - 7% to 36% in various studies

12. Diagnosis of ptb

13. Latent tb ( Ltbi ) Latent TB can be de fi ned as infection with M. tuberculosis at some earlier time with viable organisms remaining in a dormant state. The backbone of LTBI screening is the immune assay, which includes the traditional tuberculin skin test (TST) and the newer interferon gamma release assays (IGRAs). Screening all patients with advanced CKD or even only those on hemodialysis or peritoneal dialysis would be time-consuming, expensive and unlikely to be cost-effective. Set of people who will benefit are patients born abroad in areas of high prevalence, and those on immunosuppression or due to start immunosuppression for transplantation.

14. TST Time tested and cheaper higher rates of false-negative results in the ESKD population than in the general population false-positive TST can results in the context of previous B acillis Calmette-Guérin vaccination. IGRA More sensitive and specific But costly

15. Tuberculin skin test

16. Interferon gamma release assays

17. Chemoprophylaxis for ltbi Patients with LTBI and risk of developing active disease can be treated with chemoprophylaxis There are three potential chemoprophylaxis regimens: I soniazid for 6 months (6H) R ifampicin plus Isoniazid for 3 months (3RH) Rifampicin alone for 4 - 6 months (4-6R) T he choice of regimen is between 6H, which has a lower hepatitis rate, 3RH which may have advantages in terms of shorter duration and thus possibly better adherence

18. Diagnosis of active tb Radiological – Xray or CT Microscopy – modified ZN technique – Acid Fast bacilli Culture Molecular Diagnosis- CBNAAT/ TruNAAT / Line probe assays Histopathology – caseating granulomas with AFB

19. Patients with Ckd not on dialysis INH and Rifampicin can be used in normal doses Pyridoxine supplementation should be given with INH to prevent peripheral neuropathy For patients with stage 4 and 5 CKD, dosing intervals should be increased to three times weekly for Ethambutol, Pyrazinamide and Aminoglycosides Rifampicin can decrease blood level of commonly used antihypertensives like metoprolol and amlodipine, thereby patients can develop difficult to control hypertension

20. Esrd on dialysis INH and Rifampicin can be used in normal doses Hemodialysis removes significant amount of PYZ and the primary metabolite of PYZ, pyrazinoic acide , accumulates in patients with renal failure. Variable doses of 25-30mg/kg three times weekly have been recommended. Pyrazinamide should be administered immediately after dialsysis Ethambutol can be given at a dose of 15-25 mg/kg three times weekly after HD to avoid premature drug removal Pyridoxine supplementation

21. ESRD on CAPD Mechanism for drug removal differ between HD and PD so it cannot be assumed that recommendations for HD also apply to PD One study has shown that no dose adjustment is needed for INH, Rifampicin and PYZ for treatment in patients on CAPD Rifampicin has a HMW. Lipid solubility and protein binding capacity and these properties make it less dialysable through peritoneal membrane so that only minimal amounts are recovered in the dialysate, implying that oral therapy with Rifampicin may not be adequate for treatment of peritoneal TB Ahn and colleagues suggest intraperitoneal administration of Rifampicin should be considered when treating peritoneal TB

22. Renal transplantation Rifampicin can interact with immunosuppressive regimens, increasing the chance of graft rejection, and doses of MMF, Tacrolimus, and Cyclosporine will need adjustment Corticosteroid doses should be doubled in patients on Rifampicin Rifampicin is the drug most likely to interfere with immunosuppressive treatment by inducing number of liver enzymes including UDP – glucuronosyl transferases, monoamine oxidases, Glutathione S transferase, and CYP 450 Azathioprine sometimes can cause hepatotoxicity which has to differentiated from hepatotoxicity due to ATT drugs

23. REFERENCES TUBERCULOSIS AND CHRONIC KIDNEY DISEASE- AN EMERGING GLOBAL SYNDEMIC – KIDNEY INERNATIONAL BTS – GUIDELINES FOR PREVENTION AND MANAGEMENT OF MTB INFECTION IN ADULTS WITH RENAL DISEASE 2010

24. THANK YOU