Management of Tuberculosis in Chronic Kidney Disease (CKD)

Introduction

• Uraemia-induced acquired immunodeficiency
• Immunosuppressive therapy post-transplantation
• Bioincompatibility of dialysis membranes (with older cuprophane membranes)

Principles of Management

1. Pharmacokinetics of anti-TB drugs in renal impairment
2. Drug removal during haemodialysis
3. Drug interactions with immunosuppressives (in RT recipients)

Pharmacology of First-line Anti-TB Drugs in CKD

1. Isoniazid (INH)

• 96% of administered isoniazid is recoverable in urine as unchanged drug + metabolites
• In anuric patients: half-life is unaltered in rapid acetylators; increases by ~40% in slow acetylators
• In slow acetylators with severe renal impairment: 5–6 mg/kg ≡ daily dose of 7–9 mg/kg in normal subjects
• Recommendation: Normal daily dose (300 mg or 5 mg/kg) should be given — no dose reduction required
• Reducing INH to 150 mg/day is unjustified; doses <200 mg/day significantly decrease therapeutic response
• Vitamin B6 (pyridoxine) 10–20 mg/day should be given prophylactically in all CKD patients on INH

2. Rifampicin

• Primarily hepatically metabolised; only ~14% excreted unchanged in urine
• Renal impairment has negligible effect at 450 mg, modest effect at 600 mg
• Recommendation: Rifampicin up to 600 mg/day does not require dose reduction at any stage of CKD
• Caution: In non-dialysed CKD patients, rifampicin can cause acute renal failure or deterioration in renal function — administer cautiously

3. Pyrazinamide (PZA)

• Only 3–4% excreted unchanged in urine; half-life 6–10 hours
• Metabolites may accumulate in renal failure
• Recommendation: Treat with thrice or twice weekly 40–60 mg/kg pyrazinamide rather than daily dosing (controlled trials show thrice-weekly is more effective)

4. Ethambutol (EMB)

• ~80% excreted unchanged in urine — major dose reduction required in renal failure
• Recommended dosage in renal failure: 5–10 mg/kg/day or 15–25 mg/kg per dose thrice weekly (not daily)
• Risk of irreversible blindness in ESRD — close ophthalmological monitoring mandatory
• If a 4th drug is needed (in addition to RHZ), streptomycin is preferred over ethambutol (drug levels easier to monitor)

5. Streptomycin

• ~80% excreted unchanged in urine (by glomerular filtration)
• Significant correlation between degree of renal failure and serum streptomycin levels
• Recommendation: Give twice or thrice weekly (not daily); do not decrease the usual dose
• Drug trough level should be measured and must not exceed 4 mg/L

Dosing Recommendations (Table 28.4)

All medications should be given AFTER haemodialysis on days of dialysis to avoid drug removal during the procedure and to facilitate directly observed therapy (DOT).

Second-line Drugs in CKD

• Kanamycin, Amikacin, Capreomycin: Renally excreted — dosing interval must be increased; given just prior to HD removes ~40% of dose, so give AFTER HD
• Ethionamide: Not cleared by kidneys, not removed by HD — no dose adjustment required
• Para-aminosalicylic acid (PAS): Moderately cleared by HD (6.3%); acetyl-PAS substantially removed — twice daily 4 g is adequate
• Cycloserine: Primarily renal excretion; cleared by HD (56%) — increase dosing interval; give after HD to avoid under-dosing
• Fluoroquinolones: Vary in renal clearance; levofloxacin undergoes greater renal clearance than moxifloxacin — dose adjustment needed; note that manufacturer dosing recommendations for ESRD may not apply to TB treatment
• Monitor serum drug concentrations in patients with renal insufficiency taking cycloserine, ethambutol, or injectable agents

Treatment of TB in Patients on Dialysis (MHD)

• Treatment is imperative as soon as diagnosis is confirmed or strongly suspected
• Isoniazid and rifampicin form the backbone of treatment
• INH 200–300 mg/day does not cause significant toxicity in adult patients with renal failure
• Pyridoxine (Vitamin B6) should be administered prophylactically
• Rifampicin should be used cautiously in non-dialysed CKD (risk of acute interstitial nephritis)
• Under RNTCP (Government of India): Daily standard anti-TB treatment is advocated for all patients including those with renal failure, MHD, or post-RT
• No consensus exists on duration of anti-TB treatment in CKD — this requires further study
• Possibility of impaired drug absorption in comorbidities (e.g., diabetic gastroparesis) should be kept in mind

Treatment of TB in Renal Transplant Recipients

Key Drug Interactions:

1. Rifampicin + Corticosteroids: Rifampicin induces hepatic enzymes metabolising corticosteroids → steroid dose must be increased to ~1.5 times the baseline during rifampicin therapy
2. Rifampicin + Tacrolimus/Cyclosporine: Rifampicin increases hepatic metabolism of tacrolimus → significant reduction in tacrolimus blood levels → risk of graft rejection; tacrolimus blood levels must be monitored and dose adjusted
3. Rifampicin + Antihypertensives: Significant interaction leading to loss of blood pressure control after rifampicin initiation; most patients require increased antihypertensive doses; risk of hypertensive crisis — close BP monitoring mandatory
4. Azathioprine: Can cause hepatotoxicity — must be differentiated from anti-TB drug-induced hepatotoxicity

Special Considerations:

• After successful RT, renal function becomes normal — dosage modifications used during MHD phase are no longer needed
• No recommendation to decrease immunosuppressive medications if TB develops post-RT
• Rifampicin-sparing protocols have been tried in RT recipients to decrease monitoring burden and drug interaction costs, but require validation

Duration of Treatment:

• Under RNTCP/DOTS: 6 months (standard)
• Extended to 9 months for extrapulmonary TB (EPTB) or 12 months for TB meningitis
• Some studies have used treatment for 12 months or more in RT patients
• Short-course chemotherapy efficacy not well studied in this population

Management of Latent TB Infection (LTBI) in CKD

Diagnosis of LTBI:

• Tuberculin skin test (TST): Often negative/unreliable in MHD and post-RT patients
  • TST positive in only 10.5% of CKD patients on MHD in North India
  • Should NOT be used as the sole criterion to prescribe TB prophylaxis in endemic areas
• Interferon-Gamma Release Assays (IGRAs):
  • QuantiFERON Gold In-Tube (QFT-GIT) tests positive in 35.6% vs. TST in 17.2% of HD patients
  • Poor agreement between the two tests
  • BCG vaccination and past TB history do not seem to affect either test in HD patients
  • Role of IGRAs is promising but needs further exploration

Treatment of LTBI:

• ATS guidelines recommend targeted treatment of LTBI in CKD/MHD (RR 10–25.3) and RT recipients (RR 37)
• This strategy is most relevant in low-transmission countries (USA); less clear in high-TB-burden countries like India
• Isoniazid prophylaxis in MHD (Indian RCT): Showed some degree of protection, but dropout rates and breakthrough TB in treatment group made the result statistically insignificant
• Isoniazid prophylaxis pre-RT (Indian prospective RCT): TB developed in 16.7% isoniazid group vs. 32.7% control group — significant reduction if isoniazid started early
• Isoniazid prophylaxis post-RT: 11.1% vs. 25.8% (control) developed TB; RR 0.36 — trend not statistically significant
• WHO's END-TB strategy advocates a national policy for LTBI treatment in high-risk groups (CKD, RT recipients) after ruling out active TB

Timing Before RT:

• No controlled trials exist, but 4–6 weeks of adequate anti-TB treatment is likely sufficient before surgery, especially with good clinical response

Prognosis and Therapeutic Response

• Cure rate: 50–80% in studies with clear outcome reporting
• TB-related mortality: ~10% in RT patients; overall mortality varies 7.7–75%
• Anti-TB drug-induced hepatotoxicity occurs in ~20% of RT patients
• Major determinants of outcome:
  1. Extent of disease at diagnosis
  2. Treatment regimen
  3. Drug sensitivity of mycobacteria
  4. Patient compliance
• MDR-TB in CRF and post-RT settings needs more systematic study

Key Points Summary for Exam