www.kidney-international.

org mini review

Tuberculosis and chronic kidney disease:

an emerging global syndemic
Kamila Romanowski1, Edward G. Clark2, Adeera Levin3, Victoria J. Cook4 and James C. Johnston4
1
Faculty of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia, Canada; 2University of
Ottawa, Ottawa Hospital Research Institute, Kidney Research Centre, and Division of Nephrology, The Ottawa Hospital, Ottawa, Ontario,
Canada; 3Faculty of Medicine, Division of Nephrology, University of British Columbia and British Columbia Provincial Renal Agency, St.
Paul’s Hospital, Centre for Health Evaluation and Outcomes Research, Vancouver, British Columbia, Canada; and 4Faculty of Medicine,
Division of Respirology, University of British Columbia and TB Services, British Columbia Centre for Disease Control, Vancouver, British
Columbia, Canada

The link between chronic kidney disease (CKD) and
tuberculosis (TB) has been known for more than 40 years,
but the interaction between these 2 diseases is still
poorly understood. Dialysis and renal transplant
patients appear to be at a higher risk of TB, in part
related to immunosuppression along with socioeconomic,
demographic, and comorbid factors. Meanwhile, TB
screening and diagnostic test performance is suboptimal
in the CKD population, and there is limited evidence to
guide protocols. Given the increasing prevalence of CKD
in TB endemic areas, a merging of CKD and TB epidemics
could have significant public health implications, especially
in low- to middle-income countries such as India and
China, that are experiencing rapid increases in CKD
prevalence and account for more than one-third of
global TB prevalence. To begin addressing TB-CKD, a
clear understanding of the relationship between these
2 conditions needs to be established, and consistent,
evidence-based screening and treatment guidelines need
to be developed.
Kidney International (2016) -, -–-; http://dx.doi.org/10.1016/
j.kint.2016.01.034
KEYWORDS: chronic kidney disease; dialysis; global burden of disease;
kidney transplant; tuberculosis
Copyright ª 2016, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: James C. Johnston, TB Services, BC Centre for Disease
Control, 655 West 12th Avenue, Vancouver, British Columbia, V5Z 4R4
Canada. E-mail: james.johnston@bccdc.ca
Received 22 September 2015; revised 25 January 2016; accepted 28
January 2016
T
he link between active tuberculosis (TB) and chronic
kidney disease (CKD) was first reported in a 1974 case
series involving dialysis patients.1 Numerous publica-
tions have since confirmed this link, with hospital-based co-
horts and regional registries consistently showing that dialysis
is associated with an increased risk of TB.2,3 This association
is thought to be driven by the immunosuppressed state of the
dialysis population.4 Similarly, the use of immunosuppressive
medications in kidney transplant recipients explains much of
the increased risk of active TB in this group. Despite widely
available and inexpensive TB screening tests and effective
preventive therapy, TB continues to be an important source of
morbidity and mortality in dialysis and kidney transplant
populations.5 For this review, unless otherwise specified, the
term CKD broadly refers to patients with end-stage kidney
disease (ESKD) (i.e., glomerular filtration rate <15 ml/min
per 1.73 m2) and/or receiving maintenance dialysis (either
hemodialysis or peritoneal dialysis) as well as those with
earlier stages of nondialysis-requiring CKD.
With CKD emerging as an important public health issue
in low- and middle-income countries, we believe that the
relationship between TB and CKD deserves closer scrutiny.
Numerous publications,2,3,5–9 particularly from high-income
countries, have reported on TB in CKD populations. These
publications tend to focus on the risk of TB, treatment out-
comes, and screening test performance in dialysis and kidney
transplant populations, whereas few have noted the epidemi-
ologic impact of the CKD as a whole on global TB epidemiology.
Based on what we understand about these conditions, we
can reasonably expect that as CKD incidence and consequent
dialysis and kidney transplant use increase in low- and
middle-income countries with high TB prevalence
(Figure 1a),10 TB-CKD will become a more significant clinical
and public health issue in coming years. In this mini review,
we examine the epidemiologic relationship between these
2 conditions and review the current evidence and guidelines
addressing TB screening and treatment in the kidney trans-
plant, dialysis, and nondialysis-requiring CKD populations.
Global CKD epidemiology
The prevalence of CKD is estimated to be between 8% and
16% worldwide and appears to have increased in recent
years.9 Between 1990 and 2010, CKD rose from 27th to 18th

Kidney International (2016) -, -–- 1

mini review K Romanowski et al.: TB and CKD

Tuberculosis prevalence
(per 100,000)
<10 150–500
10–49 >500
50–149 No estimate

b Europe
Receiving RRT: 535,000 (0.07%)
Requiring RRT: 1,600,000 (0.22%)

North America
Receiving RRT:
637,000 (0.18%)
Requiring RRT:
637,000 (0.19%)

Asia
Receiving RRT:
Africa 958,000 (0.02%)
Receiving RRT: Requiring RRT:
83,000 (0.008%) 5,632,000 (0.14%)
Latin America Requiring RRT:
Receiving RRT: 949,000 (0.09%)
373,000 (0.06%) Oceania
Requiring RRT: Receiving RRT:
785,000 (0.13%) 25,000 (0.07%)
Requiring RRT:
End-stage kidney disease 62,000 (0.17%)
prevalence (per 1000,000)
<100 1000–1500
100–499 >1500
500–999 No estimate

Figure 1 | Global prevalence of tuberculosis and end-stage kidney disease. (a) Global TB prevalence data for 2014 show, data obtained
from WHO.10 (b) Global prevalence of end-stage kidney disease for 201214,15 with estimated numbers of patients receiving and requiring renal
replacement therapy by region from Liyanage et al. high estimate model.13 ESKD, end-stage kidney disease; RRT, renal replacement therapy; TB,
tuberculosis; WHO, World Health Organization.

on the list of causes of global deaths, second only to HIV in
rank increase during this period.11 These estimates of prev-
alence and mortality, however, may not accurately reflect true
global CKD burden as they rely on variable CKD definitions
and limited epidemiologic information, particularly in low-
and middle-income countries9 (Figure 1b).13–15 CKD appears
to disproportionately affect impoverished and marginalized
populations with limited access to health care. This may be
due to the direct impact of poverty on CKD or indirectly to
the increased health-care burden linked to poverty-associated
comorbidities such as HIV, diabetes, and hypertension.12
In its most severe form, CKD progresses to ESKD, which
requires renal replacement therapy (RRT) in the form of
dialysis or renal transplantation. The number of ESKD
patients receiving RRT is estimated at >2.6 million world-
wide, with >80% of ESKD patients living in high-income
countries.13 A lack of registries in many low- and middle-
income countries makes the accurate estimation of ESKD
prevalence challenging.9,13 At present, the prevalence of
treated ESKD patients appears to be highest in Taiwan, Japan,
and the United States, with rates at 2902, 2365, and 1976 per
million population, respectively.14 The global average of 430

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K Romanowski et al.: TB and CKD
per million population suggests that access to treatment is
limited in many countries and that many people with ESKD
do not receive life-saving RRT.15
Over the next decade, the global ESKD prevalence is
predicted to rise sharply. The fastest growth is expected in
low- and middle-income countries with growing economies,
such as India and China, where elderly populations are
expanding, health-care expenditure is increasing, and disease
burden is shifting toward noncommunicable conditions such
as diabetes and hypertension.9,13 Liyanage et al.13 estimated
that by 2030, 5.4 million people worldwide will be receiving
RRT, with the largest increase in RRT prevalence projected in
Asia, increasing from 1.0 million in 2010 to 2.2 million by
2030, followed by Africa and Latin America. In 2010, Zuo
et al.16 estimated that the RRT population in China was
increasing by 53% per year. It appears that the number of
patients with ESKD vastly underestimates global CKD burden
as prevalence of earlier, nondialysis-requiring CKD stages
exceeds ESKD prevalence by as much as 50 times.17
Global TB epidemiology
TB continues to be a leading cause of infectious morbidity
and mortality worldwide, with the disease developing in an
estimated 9.0 million people 2013.18 Since 1990, TB mortality
and prevalence have decreased by 45% and 41%, respectively,
but much work still needs to be done to eliminate this largely
preventable and curable disease.18 To accelerate decreases
in TB incidence, the World Health Organization launched
the Global EndTB strategy in 2015, which aims for fewer than
100 TB cases per million population by 2035.19 For low TB
incidence regions (usually high-income countries), the World
Health Organization has set lower targets, aiming for TB
elimination at lower than 1 case per million population by
2035. Because trends in low TB incidence regions are
primarily driven by migration dynamics, these ambitious
targets will only be achieved if TB diagnosis, treatment,
and prevention strategies are scaled up globally, and particular
attention is given to those populations at highest risk of TB.
a b
Risk of TB developing
1 2 3 4
CKD Stage
Figure 2 | Hypothesized relationship between CKD stage and risk of the development of TB. (a) Impaired cell-mediated immunity in late-
state CKD leaves patient susceptible to infectious complications, such as active TB. (b) Pathophysiology of CKD-related immunodeficiency
suggests early stage CKD patients may also be susceptible to TB. CKD, chronic kidney disease; TB, tuberculosis.
Kidney International (2016) -, -–-
mini review
Pathophysiology of TB-CKD. Immunodeficiency associated
with CKD appears to be multifactorial in etiology.16 Advanced
CKD is associated with oxidative stress and inflammation,
25-hydroxyvitamin D deficiency, and malnutrition, with evi-
dence of functional abnormalities in a variety of immune cells
including B and T cells, neutrophils, monocytes, and natural
killer cells. Changes in immunity begin as early as stage 3
CKD (defined as a glomerular filtration rate <60 ml/min per
1.73 m2) and worsen in later stages as kidney function
deteriorates and waste products accumulate.20 A state of
impaired cell-mediated immunity persists in dialysis and
leaves patients susceptible to infectious complications. Active
TB is an infectious complication that may develop and results
from progression of Mycobacterium tuberculosis infection after
recent exposure or reactivation of latent TB infection (LTBI)
from a distant exposure, often years before the disease
develops (Figure 2). Transplant recipients are also at high
risk of active TB, related in part to posttransplantation
immunosuppressive medications that specifically target
T cell–mediated immunity, which is critical to maintaining
latency in patients with M tuberculosis infection.6,21
TB risk in dialysis patients. Numerous hospital-based
cohorts and regional registry studies have reported an
increased TB risk in patients on hemodialysis and peritoneal
dialysis.3 High-quality epidemiologic studies estimate that TB
risk is increased 3- to 25-fold, whereas a recent meta-analysis
estimated that dialysis populations have a pooled unadjusted
rate ratio of 7.7 (95% confidence interval 5.9–10.0) for active
TB compared with the general population. This increased risk
appears to be related, in part, to the demographic charac-
teristics of dialysis patients rather than the dialysis state itself;
in the same meta-analysis, after adjusting for demographic
variables such as country of birth and age, the pooled rate
ratio for active TB risk decreased to 3.6 (95% confidence
interval 1.8–7.3).3
Country of birth appears to be a particularly important TB
risk factor in dialysis populations. In a recent national registry
study from Australia, TB incidence was estimated at 18 per
Risk of TB developing
5 1 2 3 4 5
CKD Stage
3
mini review
100,000 per year in dialysis patients born in low TB incidence
countries and 698 per 100,000 per year in those born in the
highest TB incidence countries.2 This is consistent with the
notion that active TB results from reactivation of LTBI
acquired before dialysis initiation rather than from recent
exposure and infection. That said, hemodialysis patients with
active TB do pose a substantial risk to other patients and
health care workers in hemodialysis units, particularly given
the frequency and proximity of shared air space.22 Without
effective screening and active TB case detection, dialysis and
renal units can serve as means of ongoing TB transmission.23
TB risk in kidney transplant recipients. Transplant recipi-
ents also have an increased TB risk ranging from 3 to 24 times
that of the general population.3 In a meta-analysis, the pooled
unadjusted rate ratio for TB in renal transplant recipients was
11.4 (95% confidence interval 3.0–43.4) compared with the
general population.3 Like dialysis patients, most cases of TB in
transplant recipients appear to be from LTBI reactivation.
However, cases of transmission from donor organs as well as
nosocomial transmission in renal transplant programs have
been reported.24
TB risk in nondialysis-requiring CKD. The pathophysiology
of CKD-related immunodeficiency would suggest that early-
stage CKD could also be a risk factor for TB. To our
knowledge, however, no study has examined TB risk in
populations with nondialysis-requiring CKD. In a cohort
examined by Fried et al.,25 infectious disease death appeared
to increase incrementally as the glomerular filtration
rate decreased, with an estimated glomerular filtration
rate <60.2 ml/min per 1.73 m2 associated with the highest
mortality. Unfortunately, this study did not specifically record
TB-related mortality, and it would be difficult to apply these
findings to TB risk given the unique relationship between
TB and host immunity.
Understanding the relationship between CKD stage and
TB risk would have a significant impact on our understanding
of global TB epidemiology and would also inform LTBI
screening and preventive treatment strategies in CKD.
Investigating this relationship, however, would require
rigorous epidemiologic analysis. The relationship between
CKD and TB is confounded by many variables including
diabetes, HIV, immunosuppressive drugs, lifestyle, and
socioeconomic factors. Diabetes is of particular importance
because it triples an individual’s risk of TB and is currently
responsible for w15% of global TB cases.26 Socioeconomic
status is also an important confounder because both CKD
and TB disproportionately affect impoverished individuals
with limited access to health care resources.
Clinical presentation of TB in dialysis and kidney transplant
patients. The clinical presentation of TB in dialysis and
kidney transplant patients is often insidious and atypical.
Patients frequently present with systemic symptoms, such as
fever, anorexia, and weight loss. These symptoms may mimic
uremia and can result in a delay of diagnosis.6,27 Patients may
present with extrapulmonary disease in as many as 60% to
80% of cases, with presentation including disseminated
4 Kidney International (2016) -, -–-
K Romanowski et al.: TB and CKD
disease.27 Those patients receiving peritoneal dialysis in
whom TB peritonitis develops typically present with fever,
abdominal pain, and cloudy dialysate.28 Laboratory findings
in TB peritonitis are similarly nonspecific and TB peritonitis
may be associated with either lymphocyte or poly-
morphonuclear neutrophil predominance on peritoneal
dialysis fluid cytology testing. These factors, combined with
the occasionally insidious onset of TB peritonitis, frequently
result in a significant delay in diagnosis.5,28 In particular, TB
peritonitis should be considered in all cases of culture-
negative peritonitis or culture-positive peritonitis that is
refractory to appropriate antibiotic treatment,28 even in the
absence of other clinical symptoms or signs suggestive of TB.
Physicians should be mindful of the potential for unusual
presentation and localization of TB in CKD patients and
should consider TB in patients presenting with nonspecific
systemic symptoms. The atypical clinical presentation, delays
in diagnosis, and hence appropriate anti-TB therapy
likely contribute to the high mortality rates seen in these
populations, ranging from 17% to 75% in different treatment
cohorts.7
Screening for TB in CKD patients
TB screening in the ESKD population serves the following 2
purposes: screening can detect asymptomatic or minimally
symptomatic active TB early in the disease course, thus
limiting patient morbidity, mortality, and potential for TB
spread; screening may also detect LTBI, enabling the initiation
of LTBI preventive therapy for patients at the highest risk of
the development of active disease while avoiding unnecessary
complications of treatment in low-risk individuals.7 In ESKD
patients, a thorough TB screening process should rely on a
combination of history and physical examination, immune
assays, and chest radiography.29 All aspects of this screening
process are essential for accurate diagnoses of active TB and
LTBI, particularly in this population in which serological
testing is unreliable, chest radiography is frequently
abnormal, and patients often report respiratory and consti-
tutional symptoms that are nonspecific and could be
compatible with active TB.5,6,29
The backbone of LTBI screening is the immune assay,
which includes the traditional tuberculin skin test (TST) and
the newer interferon gamma release assays (IGRAs). The TST
is an inexpensive test with a robust evidence base but is
complicated by significantly higher rates of false-negative
results in the ESKD population than in the general popula-
tion.27 Another limitation of the TST is false-positive TST
results in the context of previous bacillis Calmette-Guérin
vaccination. More recently, IGRAs were developed to measure
an antigen-specific immune response to M tuberculosis
infection. Two commercial IGRAs, the TSPOT (Oxford
Immunutec, Abindgon, United Kingdom) and the Quanti-
feron Gold in Tube (Qiagen, Chadstone Centre, Victoria,
Australia), show promise in TB diagnostics, with evidence of
enhanced sensitivity and specificity in many populations with
suspected LTBI. Compared with the TST, the major
K Romanowski et al.: TB and CKD mini review

disadvantages of IGRAs are the high per-test cost and limited
longitudinal evidence to support their use. Because significant
costs can stem from active TB treatment and contact tracing,
the higher diagnostic sensitivity and specificity seen with
IGRAs could potentially result in cost savings in the long term
by reducing the future burden of active TB in some pop-
ulations. However, comprehensive, cost-effective analyses of
appropriate screening strategies are limited for CKD-TB
populations.
Unfortunately, both the TST and commercial IGRAs have
important limitations and poor predictive value for active TB
in patients with advanced CKD. Several cross-sectional
studies have evaluated the diagnostic accuracy of the TST
and IGRAs by examining the association between test result
positivity and clinical risk factors for LTBI.7,8 In these studies,
IGRAs appeared to be associated more strongly with clinical
risk factors for LTBI infection, but sensitivity was still sub-
optimal.7,8 More recently, a large multicenter European study
tested both the IGRA and the TST in dialysis patients and
evaluated each test’s ability to predict active TB on follow-up.
Despite a high proportion of patients with a positive TST and/
or IGRA result, no cases of active TB were observed during
short-term follow-up,30 meaning that both the TST and
IGRAs do not appear to have high positive predictive value in
this population.
Pharmacological issues in the comanagement of CKD and TB
Treatment of LTBI. Large-scale, randomized, controlled
trials of chemoprophylaxis with isoniazid have been shown to
be effective in reducing the development of TB by 60% to
90% in immunocompetent individuals.31 However, the
optimal LTBI treatment in those with advanced CKD
(including ESKD) or after kidney transplantation is unclear,
as such patients are presumably at higher risk of complica-
tions given their numerous comorbidities and advanced age.
The findings of a recent review31 support the use of isoniazid
chemoprophylaxis in the kidney transplant population.
However, firm conclusions are difficult to draw due to a lack
of robust evidence. In many renal units in high TB incidence
regions, current practice is to give isoniazid chemoprophy-
laxis to all transplant recipients without assessment of risk;30
whether this practice has any advantages over screening and
targeted treatment remains unclear and requires further
investigation.
Many preventive treatment protocols are in use for the
kidney transplant population;32 however, there is a lack of
sufficient data on the efficacy for this group as well as for the
broader ESKD population that includes dialysis patients, and
more substantial evidence is needed. A related issue is that for
potential live kidney donors with evidence of LTBI, delay of
transplantation is appropriate until treatment is completed,
but in endemic areas, it may be difficult to avoid the use of
infected donors.33
Treatment of active TB. In all CKD patients with unex-
plained systemic or system-specific symptoms such as fever,
weight loss, and a chronic cough, active TB should be
considered and excluded by the appropriate diagnostic
investigation. If suspected, all efforts should be made to
isolate an organism for susceptibility testing.29 In the general
population, first-line therapy for fully susceptible TB includes
isoniazid, rifampin, pyrazinamide, and ethambutol. The
standard quadruple therapy regimen is recommended in pa-
tients with CKD or a kidney transplant, but the regimen poses
a special problem for those with more advanced CKD

Table 1 | Tuberculosis screening guidance for chronic kidney disease populations

Society Year CKD Dialysis Transplant
American Thoracic 2000 — TST for immune compromised. No specific TST for immune compromised. No specific
Society37 recommendations for dialysis recommendations for transplant candidates
American Transplant 2012 — — All living donors should be screened with
Society (donor)38 a TST or IGRA
American Transplant 2011 — — All transplant candidates should be screened
Society (recipient)39 with TSS or IGRA
British Thoracic 2010 CKD patients should All dialysis patients should receive a TB risk All transplant candidates should be screened
Society29 receive a TB risk assessment and, if appropriate, an IGRA with an IGRA
assessment and if
appropriate an IGRA
Canadian Thoracic 2014 — TST or IGRA recommended for immune TST or IGRA recommended for immune
Society40 compromised. No specific compromised. No specific recommendations
recommendations for dialysis for transplant candidates
Canadian Transplant 2005 — — All transplant candidates should be
Society41 screened with TST
European Centre for 2011 — IGRA with concurrent TST for immune IGRA with concurrent TST for immune
Disease Prevention compromised. No specific recommendations compromised. No specific recommendations
and Control42 for dialysis patients for transplant candidates
National Institute for 2011 — IGRA or IGRA and concurrent TST for IGRA or IGRA and concurrent TST for immune
Health and Clinical immune compromised. No specific compromised. No specific recommendations
Excellence43 recommendations for dialysis given for transplant candidates
World Health 2015 — Screen all dialysis patients with TST or IGRA Screen all transplant candidates with
Organization36 TST or IGRA
CKD, chronic kidney disease; IGRA, interferon gamma release assay; TST, tuberculin skin test.

Kidney International (2016) -, -–- 5

mini review
(including ESKD) or significant graft dysfunction as both
ethambutol and pyrazinamide are cleared through renal
excretion and require renal-adjusted dosing.29 Meanwhile,
rifampin often interacts with antihypertensive, diabetes, and
immunosuppressive medications.34 Dose adjustment of
concomitant medications may be required, or rifampin can
be replaced with rifabutin to minimize drug interactions.
Regardless, rifamycin derivatives are an essential component
of a TB treatment, and every effort should be made to include
them in the drug regimen for this population with appro-
priate monitoring and management of side effects and drug-
drug interactions.29
Of note, rare cases of drug-induced acute interstitial
nephritis have been reported with TB therapy, mainly during
retreatment with an intermittent rifampicin-containing
regimen as opposed to primary treatment.35 Despite the
therapeutic safety of this drug, clinicians must be aware of this
renal complication, which, if detected early and treated
appropriately, is usually reversible.
Current TB-CKD guidance
The rationale for a global initiative to address the issue of TB-
CKD is clear; both diseases affect impoverished populations
with significant rates of comorbid disease and high health
care needs and people with TB who require dialysis or kidney
transplantation have worse outcomes than those with each
condition.5 Yet, the potential public health importance of this
relationship seems to be largely overlooked. Only recently did
international bodies recommend systematic testing of dialysis
and transplant recipients.36 Meanwhile, due to limited avail-
able evidence of the timing of screening and preferred mo-
dality, screening recommendations from different health care
societies are often ambiguous and conflict with one
another29,36–43 (Table 1). The British Thoracic guidelines29
currently offer the most specific and comprehensive guid-
ance for CKD-TB patients, recommending that all CKD and
dialysis patients receive a TB risk assessment, clinical exami-
nation, chest X-ray, and IGRA if risk is identified. These
guidelines also recommend screening patients on the waiting
list for renal transplantation. Even so, these guidelines
acknowledge the paucity of evidence for guiding screening
recommendations.
There is a need for clear and consistent guidance, appro-
priate for regional epidemiology, to facilitate suitable
protocols for screening, diagnosis, and treatment of TB in
CKD patients. Rigorously developed, evidence-based guide-
lines have been shown to reduce the variability of care,
improve patient outcomes, and upgrade deficiencies in health
care delivery in CKD patients.44 Without such guidelines, TB
will continue to afflict CKD populations and will likely
become an increasingly important driver of TB spread in
vulnerable populations.
Future directions
We believe that there is an urgent need for research on the
relationship between CKD and TB. Despite consistent
6 Kidney International (2016) -, -–-
K Romanowski et al.: TB and CKD
evidence demonstrating a link between these 2 diseases, this
relationship is still poorly understood. Moreover, both
diseases are strongly associated with poverty and the
comorbidities of poverty, so this syndemic is likely to afflict
the most marginalized and vulnerable members of our
communities. New research to guide policy is greatly needed,
this includes robust studies of the association of both
conditions, the effect of CKD stage on the performance of
TB screening modalities, well-designed randomized,
controlled trials examining preventive treatment regimens,
and a cost-effectiveness analysis of TB screening in CKD
populations. Without these advances in our understanding,
strategies for prevention, detection, and treatment of
TB-CKD cannot be refined.
The CKD epidemic will have a significant impact on
regional and global TB epidemiology, particularly in low- and
middle-income regions where CKD is increasing rapidly and
TB remains endemic. We urge the nephrology and TB
communities to initiate a globally focused and coordinated
response.
DISCLOSURE
AL has acted as an advisor for Janssen and is supported by the Kidney
Foundation of Canada and the Canadian Institute of Health Research.
All other authors declared no competing interests.
ACKNOWLEDGMENTS
The authors acknowledge the Michael Smith Foundation for Health
Research as the source of funding for this mini review. Funders were
not involved in the planning or writing of the manuscript.
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