Management of tb in ckd

1. Management of TB in
CKD Patients
Tarek Mohamed El Tantawy
Nephrology Consultant
MD, MSc Nephrology – Ain Shams University
Egyptian Nephrology Fellowship Trainer – MNGH
Secretary-General of the Dakhlia Nephrology Group
HQM – Cambridge
1/23/2016 DNG - Nabaroh

2. Outlines
• Introduction
• Why increased incidence of TB in CKD patients
• Pathogenesis
• Clinical Presentation of TB in CKD patients
• Diagnosis of TB in CKD patients
• Anti -TB drugs in CKD patients
- First line
- Second line
• Conclusions
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3. Introduction
• Tuberculosis (TB), caused mostly by Mycobacterium
tuberculosis, is a major global health problem.TB is more
common in patients with chronic kidney disease (CKD),
especially when associated with anatomic abnormalities or
immunosuppression.
• In some endemic areas, TB has been reported to occur in up
to 9% of patients receiving hemodialysis, 9% of renal allograft
recipients, and 12% of children with nephrotic syndrome.
• Genitourinary TB occurs in about 5% of active TB cases. It is
almost always secondary to a symptomatic or asymptomatic
primary lesion in the lung.
• Renal involvement may also occur as a complication of miliary
(septicemic) TB.
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4. Why increased incidence of TB in
CKD patients
UREMIA :
• Granulocyte functions like chemotaxis ,adherence and
phagocytosis are defective.
• Decreased Interleukin 2 production by activated T
Helper cells.
• A defect in the costimulatory function of antigen-
presenting cells.
• Persistent inflammatory state of monocytes, which is
caused by the uremia per se, as well as by the dialysis
treatment.
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5. Why increased incidence of TB in
CKD patients
HEMODIALYSIS
• Conventional cellulose membrane causes alternate complement
pathway leading to changes in granulocyte cell adhesion molecules
CD11b ,CD18 and L - selectin , this correlate with leucopenia.
• Impairment of phagocytosis is often encountered with cuprophane
membrane.
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6. Why increased incidence of TB in
CKD patients
POST – KIDNEY TRANSPLANTATION:
• Immunosuppression with tacrolimus or mycophenylate mofetil
is, however, associated with the development of TB earlier in
the post-transplant period and in younger patients predisposing
to infection as cell mediated and humoral immunity got
affected.
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7. Why increased incidence of TB in
CKD patients
Other factors which might contribute to the
decreased immunity are :
• Malnutrition.
• Vitamin D deficiency.
• Hyperparathyroidism.
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8. Pathogenesis
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9. Clinical Features
• 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, malaise in a mean of 69%, and weight loss in a
mean of 54%.
• However, cough and hemoptysis, classic symptoms of TB
in the general population, are less frequently reported in
dialysis patients (mean 22% of cases).
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10. Clinical Presentation of TB during
Maintenance HD
• Males nearly affected twice as commonly as compared to females.
• Majority develop TB prior to initiation or within short period from the
beginning of MHD, a time when effect of uremia on immune status is
still pronounced.
• Constitutional symptoms attributable to TB have been reported in 30 to
92 % patients in various series.
• Headache , chills and shortness of breath were less common (< 30%).
• Almost 15 % presented with Pyrexia of Unknown Origin.
• Malhotra et al; pleural effusion in almost 50 % of cases in one study.
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11. Clinical Presentation of TB during
Maintenance HD
• Lung is the most common site of involvement in patients on MHD,
Pulmonary TB ranged from 40 to 92 %.
• Lymph Node involvement has been found to be most common extra
pulmonary site of TB on MHD 15 to 30 %.
• Other extra pulmonary involvement (granulomatous infiltrates)
include :
Abdomen and Urinary tract
Meninges
Bone and Joints
• Disseminated / Miliary TB ranged between 10 to 15 %
• Tuberculosis Peritonitis has been described in patients on CAPD.
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12. Clinical Presentation of Tuberculosis
following Renal Transplantation
• Patient who develop TB following RTx are usually younger
• Males are more often affected.
• Constitutional Symptoms are more often encountered in RTx
patients than in patients on MHD.
• Lung is most common site in RTx patients who develop followed
by abdomen , pericardium , thalamus , bone and joints.
• Miliary TB has also been reported in 7 to 36 % of RTx patients.
• Pyrexia of unknown origin presentation is associated more
commonly with RTx patients.
• Neurological TB more common after transplantation.
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13. Diagnosis
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14. Diagnosis
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15. Diagnosis
• The diagnosis of TB is based on the finding of an acid-fast
bacilli-positive smear, positive culture of M. tuberculosis,
and typical histopathologic findings.
• Efforts should be made to obtain appropriate materials for
culture, which should include sensitivity testing.
• The diagnosis of TB is hampered by the common
occurrence of a negative purified protein derivative (PPD)
(Mantoux) skin test, which was found in 40 –100% of the
cases.
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16. Diagnosis
• Paradoxically, and despite the high rate of anergy to intracutaneously
administered antigens in uremic patients, high rates of positive
Mantoux tests (PPD) 6 –19% have been found in routine screening of
dialysis patients without a history of active TB.
• Thus, due to the frequent extrapulmonary presentation and
nonspecific symptomatology, a high index of suspicion is
required, coupled with a need for invasive procedures, including
liver, bone, lymph node, and peritoneal biopsies
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17. Recommendations
• All patients with chronic kidney disease (CKD) considered at risk for
tuberculosis (TB) should have a history of prior TB or TB contact
sought, any history of prior TB treatment checked (including drugs
taken and treatment duration), an appropriate clinical examination, a
chest x-ray.
• Any patient with CKD with an abnormal chest x-ray consistent with
past TB, or previous history of extrapulmonary TB but who has
previously received adequate treatment should be monitored regularly
and considered for referral to and assessment by a specialist with an
interest in TB, either a thoracic or infectious diseases physician.
• The decision on chemoprophylaxis regimen should be made by the
thoracic or infectious disease physician after discussion with both the
patient and renal team.
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18. Diagnosis of Latent TB Infection
• The diagnosis of LTBI is based on information gathered from the
medical history, physical examination, chest radiograph, TST or
Interferon-Gamma Release Assays (IGRA) and in certain
circumstances, sputum examinations.
Timing of screening
• For patients with CKD, there is no evidence on when or how to
screen for LTBI. Screening all patients with advanced CKD or
even only those on haemodialysis or peritoneal dialysis would be
time-consuming, expensive and unlikely to be cost-effective.
• A significant proportion of patients will be receiving prophylaxis
without evidence of LTBI. Chemoprophylaxis could be offered to
those with LTBI before transplantation, precluding the need for
post-transplant prophylaxis.
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19. Interferon-Gamma Release Assays (IGRAs) are whole-blood tests that
can aid in diagnosing Mycobacterium tuberculosis infection.
They do not help differentiate latent tuberculosis infection (LTBI) from
tuberculosis disease.
Two IGRAs that have been approved by the U.S. Food and Drug
Administration (FDA) are commercially available in the U.S:
QuantiFERON®-TB Gold In-Tube test (QFT-GIT);
T-SPOT®.TB test (T-Spot)
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20. Method of screening
• All patients with CKD, on haemodialysis or CAPD and prior to renal
transplantation should have a chest x-ray and abnormalities
investigated.
• Most patients will have normal x-rays and the response to tuberculin or
TB-specific antigens will be needed for screening for LTBI in
appropriate patients.
• The TST is unreliable in patients with advanced CKD and in those on
immunosuppressive agents. A positive test may be useful but a
negative result cannot be assumed to be a true negative.
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21. Chemoprophylaxis
• The pharmacological properties of antituberculosis drugs
determine how their levels are likely to be influenced by renal
failure, clearance during dialysis and also their interaction with
immunosuppressive drugs used in patients undergoing renal
transplantation.
• Treatment duration should, however, follow guidelines, 6
months for most cases of fully sensitive disease, with the
exception of TB involving the CNS when treatment should be for
1 year.
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22. Isoniazid (H)
• Isoniazid is metabolised by the liver into less active compounds
which are then excreted by the kidneys. The most recent evidence
available suggests that isoniazid is dialysable in only very small
amounts and most clearance occurs from hepatic metabolism.
• Pharmacokinetic studies of isoniazid in renal failure, however, suggest
that even though the half-life of isoniazid is increased by about 45% in
slow acetylators, this does not lead to significant adverse events
necessitating dosage reduction, and therapeutic drug monitoring is not
thought to be necessary.
• Furthermore, there is evidence to suggest that administering isoniazid
in reduced doses may lead to reduced potency and risk the
development of resistance.
• Stage 1-3 of CKD Isoniazid 300 mg
Stage 4-5 of CKD Isoniazid 300 mg
Renal Transplant Recipients 15 mg/kg max 900 mg 3X/week
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23. Isoniazid (H)
Side Effects of Isoniazid
1. Neurotoxicity : grand mal seizures (with no prior history), depressive
psychosis, confusion, nightmares, hallucinations, peripheral
neuropathy, twitching and dizziness. Encephalopathy was also
reported in 3 of 48 dialysis patients with TB
2. A few of those receiving dialysis also experienced significant
gastrointestinal adverse effects (jaundice, nausea and vomiting).
3. Ototoxicity has been described over a 10-year period in seven patients
with CKD receiving isoniazid together with other drugs but not
aminoglycosides.
4. High anion gap metabolic acidosis.
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24. Rifampicin (R)
• Rifampicin is also metabolised by the liver. Its inactive metabolite,
formylrifampicin, is excreted in the urine and its major metabolite,
desacetyl-rifampicin, is excreted in bile.
• Urinary excretion accounts for very little of its elimination from the body,
with only about 10% of a given dose being found unchanged in the
urine. Rifampicin does not appear in significant amounts in dialysate.
• Reported side effects for rifampicin do not appear to occur with
significantly increased frequency in patients with CKD or on dialysis,
although rifampicin has been cited as a rare cause of acute renal
failure.
• As such, there is widespread agreement that the dose of rifampicin
need not be altered in renal impairment and that drug levels need not
be monitored (450 – 600 mg / day).
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25. Pyrazinamide (Z)
• Pyrazinamide is metabolised in the liver. Only 3-4% is renally
excreted in unaltered. Although the pharmacokinetics of the drug are
unaltered initially in patients with renal failure, one study of its
elimination found much higher levels detectable for up to 48 hours
after administration. Owing to its effect on uric acid retention, this may
lead to hyperuricaemia and gout.
• Pyrazinamide and its metabolites are significantly eliminated from the
body by haemodialysis, 45% appearing in the dialysate. No data are
available for peritoneal dialysis.
• Due to possible delayed elimination of the drug and its metabolite, the
dosage interval should be altered in stages 4 and 5 CKD and in
patients on haemodialysis . There are no clear data for peritoneal
dialysis
• 20 -35 mg/kg per dose three timer per week
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26. Ethambutol (E)
• Around 80% of Ethambutol is excreted unchanged by the kidneys.
• In patients with renal failure, excretion of Ethambutol was
significantly reduced following the usual dose of 15 mg/kg.
• It is renally excreted and ocular toxicity is largely dose-dependent.
Ethambutol has been detected in dialysate.
• It has improved efficacy when administered in high doses less often
than in a daily lower dose. Serum monitoring should be done and
trough levels should be less than 1.0 mg/ml at 24 h post-dose without
dialysis.
Recommendation : 15-25 mg/kg per dose three times per week
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27. Aminoglycosides
• Streptomycin, Kanamycin, Amikacin and Capreomycin: around
80% are excreted unchanged in the urine without having undergone
significant metabolism.
• Streptomycin causes significant vestibular toxicity but less
nephrotoxicity compared with the other aminoglycosides.
• There is an increase in elimination time with increasing age and
declining renal function.
• Streptomycin, Kanamycin, Amikacin and Capreomycin:
approximately 40% are removed by haemodialysis when these drugs
are given just before haemodialysis.
– The American Thoracic Society (ATS) recommends 12-15
mg/kg/dose 2 or 3 times/week for all of these drugs.
– Drug levels should be monitored.
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28. Aminoglycosides
• Streptomycin:
The dosing interval should be increased rather than the dose
decreased as the drugs exhibit concentration dependent bactericidal
action, and lower doses may reduce drug efficacy.
• It is preferable to give Streptomycin twice or thrice weekly without
decreasing the usual dose.
• 15 mg/kg (max 1 g daily). Dose is reduced in <50 kg and >40 years to
max 500 to 750 mg daily.
• Peak plasma concentrations of Streptomycin should be between 15
and 40 mg/ml and trough concentrations <3-5 mg/ml or <1 mg/ml in
CKD or those >50 years.
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30. Second-Line Drugs Used in The
Management of Resistant Disease
Fluoroquinolones
• Ofloxacin and Ciprofloxacin are dependent on renal clearance
and doses should be reduced accordingly.
• Other Fluoroquinolones undergo some degree of renal
clearance which varies from drug to drug.
• Levofloxacin undergoes greater renal clearance than
Moxifloxacin.
• Fluoroquinolones decrease the metabolism of Cyclosporin A
and displace it from the bound form, thus increasing its toxicity
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31. Second-Line Drugs Used in The
Management of Resistant Disease
Cycloserine
• Up to 70% of Cycloserine is excreted by the kidney and 56%
removed by haemodialysis.
• Given that dose-related neurological and psychiatric side effects
of Cycloserine have been reported in up to 50% of patients,
dose adjustment in the setting of renal failure is recommended.
• The ATS recommends increasing the dose interval and suggests
250 mg once daily or preferably 500 mg 3 times/week.
• Again, it should be given after haemodialysis to avoid under-
dosing and monitored for neurotoxicity.
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32. Second-Line Drugs Used in The
Management of Resistant Disease
Para-amino salicylic acid (PAS)
• A modest amount of PAS (6.3%) is cleared by haemodialysis but its
metabolite, acetyl-PAS, is substantially removed.
• 8-12 g/day in two or three divided doses twice weekly should be
adequate.
Ethionamide/ prothionamide
• Ethionamide and Prothionamide are not cleared by the kidneys nor
are they removed by haemodialysis, so no adjustment to dosing is
needed.
• 15 to 20 mg/kg/day (maximum 1g ; usually 500 to 750 mg) in single
daily dose or two divided dose.
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33. Second-Line Drugs Used in The
Management of Resistant Disease
Clofazimine
Clofazimine is available on a named patient basis. It can accumulate
in CKD and causes skin and hair discolouration, photosensitivity and
ocular problems.
• The normal dose is 100-300 mg daily and this should be reduced to
three times weekly in patients with CKD and those on dialysis.
Linezolid
• A higher incidence of blood disorders and optic neuropathy has been
reported if Linezolid is used for longer than 28 days, making its use in
the management of TB difficult.
• Linezolid is a reversible non-selective monoamine oxidase inhibitor
and patients should avoid eating tyramine-rich foods such as cheese
and products containing yeast.
• The normal dose is 600 mg every 12 h.
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34. Patients with CKD not on dialysis
• Isoniazid (H), Rifampicin (R) can be used in normal doses in renal
impairment.
• Pyridoxine supplementation should be given with Isoniazid to
prevent the development of peripheral neuropathy.
• For patients with stages 4 and 5 CKD, dosing intervals should be
increased to three times weekly for Ethambutol, Pyrazinamide and
the Aminoglycosides.
• Ethambutol and the Aminoglycosides have the disadvantage of
renal clearance, the need for increased dose intervals or reduced
dosage and drug monitoring.
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35. Patients with ESRD on Hemodialysis
1. Both Rifampicin and Isoniazid may be given in their usual daily Doses
2. Haemodialysis removes a significant amount of Pyrazinamide and the
primary metabolite of Pyrazinamide , pyrazinoic acid, accumulates in
patients with renal failure. Advice varies over whether reduction or
spacing of the dose of Pyrazinamide is best for patients on
haemodialysis. Variable doses of 25-30 mg/kg three times weekly have
been Recommended. Pyrazinamide should be administered
immediately after haemodialysis.
3. Ethambutol can be given at a dose of 15-25 mg/kg three times weekly
after haemodialysis to avoid premature drug removal.
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36. Patients with ESRD on PD
• Mechanisms for drug removal differ between haemodialysis and
peritoneal dialysis so it cannot be assumed that recommendations for
haemodialysis also apply to peritoneal dialysis.
• One study has shown that no dose adjustment is needed for
Isoniazid, Rifampicin or Pyrazinmide for the treatment of systemic or
pulmonary TB in patients on CAPD.
• Rifampicin has a high molecular weight, lipid solubility and protein
binding capacity and these properties make it less dialysable through
the 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
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37. Renal Transplantation Patients
• Rifampicin in particular can interact with immunosuppressive
regimens, increasing the chance of graft rejection, and doses of
mycophenolate mofetil, tacrolimus and cyclosporine will need
adjustment.
• Corticosteroid doses should be doubled in patients receiving
Rifampicin.
• Rifampicin is the drug most likely to interfere with immunosuppressive
treatment by induction of a number of liver enzymes including uridine
diphosphate - glucuronosyl transferases, monoamine oxidases,
glutathione S - transferases and cytochrome P450.
• Once Rifampicin has been stopped, liver enzyme induction
usually takes 2 weeks to return to normal.
• Azathioprine sometimes causes hepatotoxicity, which has to be
differentiated from the hepatotoxicity due to antituberculosis
drugs.
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38. Conclusions
• Close cooperation between renal physicians and specialists in the
management of TB is strongly recommended.
• Active TB should be excluded in patients with CKD by appropriate
investigations in patients who have an abnormal chest x-ray or a history
of prior pulmonary or extrapulmonary TB that has been either
inadequately or not previously treated. Chemoprophylaxis should be
given
• For patients with stages 4 and 5 CKD, dosing intervals should be
increased to three times weekly for Ethambutol, Pyrazinamide and the
Aminoglycosides.
• Treatment can be given immediately after haemodialysis to avoid
premature drug removal.
• Rifampicin in particular can interact with immunosuppressive regimens,
increasing the chance of graft rejection, and doses of mycophenolate
mofetil, tacrolimus and ciclosporin may need adjustment. Corticosteroid
doses should be doubled in patients receiving Rifampicin.
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40. THANK YOU
Tarek Mohamed El Tantawy
Nephrology Consultant
MD, MSc Nephrology – Ain Shams University
Egyptian Nephrology Fellowship Trainer – MNGH
Secretary-General of the Dakhlia Nephrology Group
HQM – Cambridge
1/23/2016 DNG - Nabaroh