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 inammatory 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, 2001:14331438

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 31:848852, 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 deciency , 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 29100%), and weight loss in a mean of 54% (range 10100%). However, cough and hemoptysis, classic symptoms of TB in the general population, are less frequently reported in dialysis patients (mean 22% of cases; range 571%)

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 nding of an acidfast bacilli-positive smear, positive culture of M. tuberculosis, and typical histopathologic ndings. Eorts 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 puried protein derivative (PPD) (Mantoux) skin test, which was found in 40100% 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 (6.119%) have been found in routine screening of dialysis patients without a history of or active TB. Thus, due to the frequent extrapulmonary presentation and nonspecic 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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