Pediatric Infectious Disease 2012 April–June

Review Article
Volume 4, Number 2; pp. 57–60

Tuberculosis in nephrotic syndrome and chronic kidney disease:

an appraisal
S Gaur1, Arpana Iyengar2

ABSTRACT

Tuberculosis (TB) affects man at all ages with its protean manifestations and children with renal diseases are no
exception to it. Owing to altered immune status in nephrotic syndrome and chronic kidney disease (CKD), TB can be
a very common co-morbid condition in endemic nation like India. The onset can be very insidious and subtle mimick-
ing the primary condition especially in CKD and the diagnosis remains a challenge. A high index of suspicion usually
guides the clinician to diagnose the condition. The basic modalities of diagnosis remain same as in general popula-
tion yet the results have to be interpreted in the light of primary renal condition. The article tries to envisage the
diagnosis and management of TB in children with concomitant CKD and nephrotic syndrome.
Keywords: Anti-tuberculous drugs, chronic kidney disease, Mantoux test, nephrotic syndrome, tuberculosis

INTRODUCTION Tuberculosis and Nephrotic Syndrome

Children with renal disease are at high-risk to develop
infections and in this context tuberculosis (TB) is no excep-
tion especially in the developing world.1 Depressed immu-
nity due to the disease process, need for long-term high-dose
immunosuppression, and chronicity of the clinical course
of renal disease seem to be the major factors that determine
the vulnerability to TB. This justifies the fact that children
with nephrotic syndrome and glomerular diseases including
lupus nephritis, membranoproliferative disease, and immu-
noglobulin A nephropathy need screening for TB. Similarly,
children with chronic kidney disease (CKD) and recipients
of renal transplantation need constant monitoring for TB.
On the other hand, the spectrum of primary renal TB,
though not a common problem in children, includes sterile
pyuria, chronic pyelonephritis, cystitis, interstitial nephritis,
abscess, and amyloidosis.2
This article would deal with two important disease enti-
ties relevant to pediatricians caring for children with renal
disease and TB: nephrotic syndrome and CKD.
Children with nephrotic syndrome are prone to develop
infections due to reduced cell-mediated immunity, impaired-
T-lymphocyte function, and use of corticosteroids or immu-
nosuppressive medications. Tuberculosis may occur at or
after the onset of nephrotic syndrome interfering with the
response to steroid therapy and/or accelerate the progres-
sion of renal failure in these patients.3,4 Screening for TB
prior to initiating corticosteroid therapy is an important step
in the management of children with nephrotic syndrome.5
The overall prevalence of TB in nephrotic syndrome is
variable as reported in Indian studies, 9.3% by Gulati et al.,6
5% by Senguttuvan et al.,7 and 6% by Kala et al.8 This is
much higher than the 1% prevalence in the general popula-
tion.1 A six fold increase in the prevalence of mycobacterial
infection was found in the nephrotic children with focal
segmental glomerulosclerosis compared with minimal
change in a South African study.8
• Challenges: Diagnosing TB in children with nephrotic
syndrome is a challenge due to the following reasons: skin

1
Fellow, 2Associate Professor, Department of Pediatric Nephrology, St. John’s Medical College and Hospital, Bangalore – 560034, India.
Correspondence: Dr. Arpana Iyengar, email: arpanaiyengar@gmail.com
doi: 10.1016/S2212-8328(12)60024-1

ISSN: 2212-8328 Copyright © 2012. The Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
58 Pediatric Infectious Disease 2012 April–June; Vol. 4, No. 2
responses to common antigens and recall response to
common antigens are decreased during relapses making
Mantoux test an unreliable indicator of TB with a low
diagnostic yield. Erythrocyte sedimentation rate (ESR)
is known to be elevated and serves as a supportive
marker in diagnosing TB. However, ESR is known to be
raised above normal values in the state of relapse in
nephrotic syndrome due to elevated fibrinogen levels.9
Besides a high index of clinical suspicion, there is a need
to look for more reliable markers of TB in children with
nephrotic syndrome.
• Evaluation: The evaluation for TB in children with the
first episode of nephrotic syndrome comprises clinical
examination followed by Mantoux test (positivity defined
as > 10 mm induration at 72 hours), ESR, isolation of acid-
fast bacilli, chest radiograph, and screening parents/or
any suspected contact. History and clinical examination
takes precedence. In the study6 conducted by Gulati et al.,
of the various diagnostic criteria, a history of persistent
cough, fever, or exposure to a case of TB and chest radi-
ograph was most useful. Only 28.5% of the children had
a positive Mantoux test. Prior Bacille Calmette-Guérin
(BCG) vaccination did not prevent the subsequent occur-
rence of TB, including tubercular meningitis. This is in
contrast to previous observations which have postulated
that BCG vaccination protects against the severe dissemi-
nated form of TB.1
• Clinical spectrum: Among 28 children with nephrotic
syndrome, Gulati reported pulmonary involvement as
the commonest presentation (22/28), followed by tuber-
cular lymphadenitis (n = 2), tubercular meningitis (n = 2),
and occult TB (n = 2). Twenty-seven children developed
TB following a mean duration of 2.2 + 1.1 years following
initiation of immunosuppressive therapy. There was a
significantly higher prevalence of patients who received
frequent courses of steroids in the TB group than those
in the non-infected group. Children with TB had signifi-
cantly lower total protein and serum albumin and higher
serum cholesterol than children with no infectious
complications.
• Management: An interesting aspect is the impact of TB
on the course of the nephrotic syndrome. It has been pre-
viously reported that the occurrence of TB in the neph-
rotic syndrome may interfere with the response to steroid
therapy and may also have a detrimental effect on renal
function.8 Purified protein derivative (PPD) positive
children over 6 years of age and who do not have any
evidence of active disease but are planned for immuno-
suppressive therapy (children with nephrotic syndrome)
may also be given the benefit of anti-tuberculous drugs
for 6 months.10 As per the Indian Pediatric Nephrology
Gaur and Iyengar
guidelines,5 children with nephrotic syndrome and a
positive Mantoux test should receive 6 months of isoni-
azid and if there is evidence of active TB, standard ther-
apy with antituberculous drugs should be offered. The
drug interactions between isoniazid, rifampicin, and cor-
ticosteroids need mention as it is evident that there could
be suboptimal drug levels of corticosteroids with con-
comitant anti-tuberculous drug therapy.11
Tuberculosis and Chronic Kidney Disease
An altered immunological status due to persistent uremic
state predisposes children with CKD to have higher procliv-
ity to harbor activated typical and atypical mycobacterium.
Owing to the high endemicity in India, a very high index of
suspicion is mandatory in making a diagnosis of TB in
patients with CKD especially those being maintained on
peritoneal dialysis (PD), hemodialysis (HD), or following
renal transplantation. Children who are post-transplant are
particularly at risk owing to immunosuppression and can lead
to significant morbidity if infected with TB owing to its
rapid dissemination. The risk of TB reported in various adult
studies ranges from 6.9- to 52.5-fold in patients with chronic
renal failure and on dialysis as compared with the general
population.12 For children with CKD, no hospital-based data
are available on the prevalence of TB in our nation till date:
• Challenges: Clinical diagnosis is a challenge owing to
altered immune status and non-classical and non-descript
presentation. Mycobacterium elicits a host T-cell-mediated
intracellular response once activated. This response 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.13 Owing to persistent
uremic and persistent inflammatory state, a poor response
is generated as evident by the high degree of energy to
intradermally administered antigens to the tune of just
30–40%. Other co-morbid factors which might contribute
to the decreased immunity are malnutrition, vitamin D
deficiency,14 and hyperparathyroidism.15
• Clinical spectrum: Usually of insidious onset with very
non-specific symptoms in the form of fever of unex-
plained cause not responding to conventional antibiotics
along with malaise, weight loss, and easy fatigability.
Not all patients with renal disease who develop TB have
classic symptoms and extrapulmonary disease is com-
mon, occurring in 30–50% of cases of TB in different
series.16–18 Symptoms of TB may mimic or overlap with
symptoms of CKD. Two studies are limited to patients
with PD, one in children with a prevalence of TB of 5.7%19
and a second (reported on 790 patients on continuous
Tuberculosis in nephrotic syndrome and chronic kidney disease
ambulatory peritoneal dialysis [CAPD]) with a preva-
lence of TB as high as in patients with HD (4.8%).20 It is
notable that tuberculous peritonitis makes up a large
part (37%) of the total number of TB cases in patients
with CAPD.9 Children with CAPD complicated with
tuberculous peritonitis will have symptoms of peritoni-
tis. As noted in adult studies, the localization is majorly
extrapulmonary than pulmonary which is in contradic-
tion with general population where pulmonary Koch’s
disease predominate. Within the extrapulmonary group,
tuberculous lymphadenitis and peritonitis are the most
reported localizations; less frequently cases of miliary,
spine (Pott’s spine), cerebral, and genitourinary TB have
been reported.
• Diagnosis: A history of previous TB, the drugs used for
treatment and duration of treatment, should be part of
the routine assessment of all patients with CKD, on dial-
ysis or before transplantation. A history of recent contact
with active pulmonary TB should also be sought. Patients
coughing up sputum should be asked to produce three
consecutive early morning specimens/or gastric aspirate
or bronchioalveolar lavage (BAL) in children for direct-
smear, culture, and sensitivity. Microbiological diagno-
sis with acid-fast staining to demonstrate the bacilli in
sputum is the most frequently employed method for pul-
monary TB. Imaging methods such as chest radiographs
along with high-resolution computed tomography are very
supportive along with molecular techniques (polymerase
chain reaction); histopathology examination demonstrat-
ing granuloma with caseation is the histological hallmark;
PPD skin test and newly developed IFN gamma detection
(IFN-γ) assay are also quite supportive.
• Management includes chemoprophylaxis and treatment
of active disease:
Candidates for chemoprophylaxis: A joint statement
of the American Thoracic Society (ATS) and the Center
for Disease Control (CDC) recommends TB prophylaxis
(or treatment of latent TB infection-[LTBI]) in patients
with chronic renal failure when the tuberculin positivity
is > 10 mm of induration.21 There are three potential
chemoprophylaxis regimens: isoniazid for 6 months
(6H), rifampicin plus isoniazid for 3 months (3RH), or
rifampicin alone for 4–6 months (4–6R). Accordingly, the
choice of regimen is between 6H, which has a lower hep-
atitis 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 the active
disease is present,22 and 4–6R which has the disadvan-
tage of being a single agent but better tolerated than
6 months of isoniazid alone and can be used following
contact with isoniazid-resistant disease. There are few
Review Article 59
data on chemoprophylaxis specifically in patients with
CKD. One report of isoniazid prophylaxis for 1 year in
109 patients with CKD on HD showed reduced numbers
developing TB with an RR of 0.4.23,24 Isoniazid and
rifampicin can be used in normal doses in renal impair-
ment, during dialysis and following transplantation.
Suggestions for Treatment of Active Disease
• The management of active TB should follow directly
observed treatment short-course (DOTS) guidelines,
with four drugs for the first 2 months followed by two
drugs for a further 4 months for most cases of TB (with
the exception of TB of the central nervous system where
treatment should be for 1 year), unless drug-resistance is
suspected.
• For patients with stages 4 and 5 CKD, dosing intervals
should be increased to three times weekly for ethambu-
tol, pyrazinamide, and the aminoglycosides.
• For patients on HD, dosing intervals should be increased
to 3 times weekly to reduce the risk of drug accumula-
tion and toxicity. Treatment can be given immediately
after HD to avoid premature drug removal. With this
strategy, there is a possible risk of raised drug levels of
ethambutol and pyrazinamide between dialysis sessions.
Alternatively, treatment can be given 4–6 hours before
dialysis, increasing the possibility of premature drug
removal but reducing possible ethambutol or pyrazina-
mide toxicity.20
CONCLUSION
Children with nephrotic syndrome and CKD have a poten-
tial risk to develop TB. A careful history, examination, and
investigations leading to early diagnosis can significantly
reduce the morbidity secondary to TB over and above pre-
existing nephrosis or CKD. There is paucity of data and
information on the burden of TB in these childhood renal
diseases in our country. Guidelines and recommendations
need to be formulated for evaluation and management of
TB in this group of high-risk children.
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