TUBERCULOSIS
AND
CHRONIC RENAL
FAILURE
Junior Resident Pulmonary Medicine
Magnitude Of The Problem:
 Patients with renal disease are at increased risk of tuberculosis (TB). This is
true for all patients with chronic kidney disease (CKD), 30 times higher
prevalence of TB in patients with CRF.
Yuan FH ,GuanLX, Zhao SJ Renal Fal 2005;27:149-53
It has been estimated patients undergoing dialysis have 10 to 12 fold higher
risk of developing TB compared to general population
Rutsky EA, Rostand SG Arch Intern Med 1980;140;57-61
The incidence of TB in Indian patients receiving Maintenance Hemodialysis
has been reported to be 3.7 to 13.3 percent .
Narula AS et al Indian J Nephrol 1991;1;67
Incidence of TB in renal transplant recepients has ranged from 1 to 4 % in
Northern Europe , 0.5 -1% in North America and nearly 5 to 10 % in India .
McWhinney N, Khan O, Williams G Br Surg 1981;68:408-11
Why increased incidence of TB in CKD patients
:Pathogenesis
The host response against intracellular pathogens, including Mycobacterium
tuberculosis, is determined by the type 1 helper T-cell response with the involvement of
interleukin (IL)-12, resulting in increased production of interferon (IFN)-c
UREMIA :
Acquired immuno deficiency state leading to excessive morbidity and
mortality related to infections.
Granulocyte functions like chemotaxis ,adherence and phagocytosis are
defective.
Decreased Interleukin 2 (IL2) production by activated T Helper Cells
A defect in the costimulatory function 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
Chatenoud L, Descamps-Latscha B: Immunological disturbances in uremia.In: Massry SG,
Glassock RJ (eds). Textbook of Nephrology, 4th ed. Philadelphia: Lippincott Williams &
Wilkins, 2001:1433–1438
HEMODIALYSIS :
Leucocyte chemotaxis has been shown to markedly diminished
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
Woeltje KF, Mathew A, Rothstein M, Seiler S, Fraser VJ: Tuberculosis
infection and anergy in hemodialysis patients. Am J Kidney Dis 31:848–852, 1998
IMMUNOSUPPRESSIVE THERAPY :
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
Other factors which might contribute to the decreased
immunity are
Malnutrition,
Vitamin D deficiency , and
Hyperparathyroidism
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 (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%)
Clinical Presentation of Tuberculosis
during Maintenance Hemodialysis
•Males nearly affected twice as commonly as compared to females
•Majority develop TB prior to initiation or with in short period from the
beigining of MHD, a time when effect of uraemia on immune status is still
pronounced
•Constitutional symptoms attributable to TB have been reported in 30 to 92
percent patients in various series
•Headache , chills and shortness of breath were less common (less than
30%)
•Almost 15 % presented with Pyrexia of Unknown Origin
•Malhotra et al (1981) pleural effusion in almost 50 % of cases in one study .
•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 include
Abdomen
Meninges
Bone and Joints
•Disseminated /Miliary TB ranged between 10 to 15 %
•Tuberculosis Peritonitis has been described in patients on Continuous
Ambulatory Peritoneal Dialysis
Clinical Presentation of Tuberculosis
following Renal Transplantation
Tuberculosis in
Renal Transplant
Patients
TB in Pre transplant
phase.. Having post
RT phase too
TB first time
following RT
Patient who develop TB following RT are usually younger .Male are more
often affected.
Past history of TB has been reported in 5.6 to 8.9 % patients in studies
reported in India.
Constitutional Symptoms are more often encountered in RT patients than
in patients on MHD
Lung is most common site RT patients who develop followed by abdomen
, pericardium , thalamus , bone and joints
Miliary TB has also been reported in 7 to 36 % of RT patients
PUO presentation is associated more commonly with RT patients
Abdominal TB more commonly during dialysis
Neurological TB more common after transplantation
Diagnosis
The diagnosis of TB is based on the finding of an acidfast 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.
Routine blood investigations including renal function test and sugar monitoring
to keep check on renal function and diagnose and keep underlying pathology
under scanner .
Paradoxically, and despite the high rate of anergy to intracutaneously
administered antigens in uremic patients, high rates of positive Mantoux
tests (6.1–19%) have been found in routine screening of dialysis patients
without a history of or 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
Recommendations
1. 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
2. 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.
3. The decision on chemoprophylaxis regimen should be made by the
thoracic or infectious disease physician after discussion with both the
patient and renal team
DIAGNOSIS OF LATENT TB INFECTION
The diagnosis of LTBI is based on information gathered from the medical
history, TST or IGRA result, chest radiograph, physical examination, 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
The current practice in most renal units is to give prophylaxis to all at-risk
transplant patients without assessment.
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.
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.
CHEMOPROPHYLAXIS
There are three potential chemoprophylaxis regimens:
Isoniazid for 6 months (6H),
Rifampicin plus isoniazid for 3 months (3RH)
Rifampicin alone for 4-6 months (4-6R).
Rifampicin and pyrazinamide for 2 months (2RZ) was a regimen used in
the USA but it was associated with a very high rate of hepatitis , with a
number of fatalities reported
The choice of regimen
6H [ Isoniazid for 6 months] , which has a lower hepatitis rate.
3RH which may have advantages in terms of shorter duration and thus
possibly better adherence and also less risk of drug resistance developing if
active disease is present.
4-6R which also has the disadvantage of a single agent but was better
tolerated than 9 months of isoniazid alone and can be used following contact
with isoniazid-resistant disease.
No chemoprophylaxis regimen is wholly effective; protective efficacies of
60-65% have been reported for 6H and of 50% for 3RH.
There is strong evidence that regimens longer than 6H have only very
minimal additional advantage at the cost of an increase in the risk of
hepatitis
ANTITUBERCULOSIS DRUGS IN CHRONIC KIDNEY
DISEASE
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.
The exact timing of administration in relation to dialysis and concomitant
use of immunosuppressive drugs following 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.
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 300mg
Renal Transplant Recipients 15 mg/kg max 900 mg 3X/week
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.Renal Failure
Siskind MS, Thienemann D, Kirlin L. Isoniazid-induced neurotoxicity in chronic dialysis
patients: report of three cases and a review of the literature. Nephron 1993;64:303e6.
Wang HY, Chien CC, Chen YM, et al. Encephalopathy caused by isoniazid in a patient
with end stage renal disease with extrapulmonary tuberculosis. Ren Fail 2003;25:135e8.
Rifampicin (R)
Rifampicin is also metabolised by the liver. Its inactive metabolite,
formylrifampicin, is excreted in the urine and its major metabolite, desacetylrifampicin, 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
Rekha VV, Santha T, Jawahar MS. Rifampicin-induced renal toxicity during
retreatment of patients with pulmonary tuberculosis. J Assoc Physicians India
2005;53:811-13
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 h 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
Ellard GA. Chemotherapy of tuberculosis for patients with renal impairment.
Nephron 1993;64:169e81. (2++)
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
Varughese A, Brater DC, Benet LZ, et al. Ethambutol kinetics in patients with
impaired renal function. Am Rev Respir Dis 1986;134:34e8. (2+).
Citron K. Ethambutol: a review with special reference to ocular toxicity.
Tubercle 1969;50(Suppl):32e6. (2++).
Aminoglycosides
Around 80% of streptomycin, kanamycin, amikacin and capreomycin 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. Approximately 40% of streptomycin, amikacin, capreomycin and
kanamycin 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.
As with ethambutol and pyrazinamide, 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 or 12-15 mg/kg 2-3 times/week.
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.
HOW TO CALCULATE CREATININE
CLEARANCE
Cockcroft and Gault equation:
CrCl = [(140 - age) x TBW] / (Scr x 72) (x 0.85 for females)
Where
CrCl is Creatinine clearance
TBW is Total Body Weight
Scr is Serum Creatininine
Stage 1 CKD: Normal creatinine clearance and function but urinary
tract abnormality, for example, polycystic kidney, structural
abnormality.
Stage 2 CKD: Creatinine clearance 60 to 90 ml/min
Stage 3 CKD: Creatinine clearance 30 to 60 ml/min
Stage 4 CKD: Creatinine clearance 15 to 30 ml/min
Stage 5 CKD: Creatinine clearance <15 ml/min with or without dialysis.
SECOND-LINE DRUGS USED IN THE MANAGEMENT OF
RESISTANT DISEASE
FLUOROQUINOLONES
•Both ofloxacin and ciprofloxacin are also 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 ciclosporin A and
displace it from the bound form, thus increasing its toxicity
Fish DN, Chow AT. The clinical pharmacokinetics of
levofloxacin. Clin Pharmacokinet 1997;32:101-19. (l+).
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.
Malone RS, Fish DN, Spiegel DM, et al. The effect of hemodialysis on
cycloserine, ethionamide, para-aminosalicylate, and clofazimine.
Chest 1999;116:984-90. (2+).
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 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
Clofazimine
Clofazimine is available on a named patient basis. It can accumulate in CKD
and causes skin and hair discolouration, photosensitivity and ocular
problems. Pharmaceutical advice should be sought.
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.
Patients with CKD not on dialysis
For patients with stages 4 and 5 CKD, dosing intervals should be increased to
three times weekly for ethambutol, pyrazinamide and the aminoglycosides.
Isoniazid (H), rifampicin (R) and pyrazinamide (Z) can be used in normal
doses in renal impairment. Controlled clinical trials have shown that three
times weekly treatment with pyrazinamide is therapeutically more effective
than daily administration.
Pyridoxine supplementation should be given with isoniazid to prevent the
development of peripheral neuropathy.
Ethambutol and the aminoglycosides have the disadvantage of renal
clearance, the need for increased dose intervals or reduced dosage and
drug monitoring.
HAEMODIALYSIS
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.
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 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.
3. Pyrazinamide should be administered immediately after haemodialysis or 4-6
h beforehand.
Ethambutol can be given at a dose of 15-25 mg/kg three times weekly for
patients on regular haemodialysis.
PERITONEAL DIALYSIS
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
Ahn C, Oh K-H, Kim K, et al. Effect of peritoneal dialysis on plasma and
peritoneal fluid concentrations of isoniazid, pyrazinamide and rifampicin. Perit
Dial Int 2003;23:362e7.
RENAL TRANSPLANTATION
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.
Rifampicin is the drug most likely to interfere with immunosuppressive treatment
by induction of a number of liver enzymes including uridine diphosphateglucuronosyltransferases, monoamine oxidases, glutathione S-transferases and
cytochrome P450.
The daily corticosteroid dose should be increased to twice the baseline dosage
in patients taking rifampicin.
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.
SUMMARY
1. Close cooperation between renal physicians and specialists in the
management of TB is strongly recommended.
2. 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
3. For patients with stages 4 and 5 CKD, dosing intervals should be increased
to three times weekly for ethambutol, pyrazinamide and the
aminoglycosides.
4. Treatment can be given immediately after haemodialysis to avoid premature
drug removal.
5. 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.
Dosing Recommendaations for adult patients
with reduced renal function and receiving
hemodialysis
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