After cardiovascular causes, infectious diseases are the next most common cause of
death for dialysis patients. The Japanese Society for Dialysis Therapy reported an
increased standardized mortality of 7.5-fold [95% confidence limits (CI) 7.3–7.6]
for infectious diseases between 2008 and 2009 compared with the general Japanese population.
The increased mortality rates for dialysis patients were greatest for sepsis, followed
in descending order by peritonitis, influenza, tuberculosis and pneumonia [1]. Patients
with chronic kidney disease are more susceptible to some infections, as the azotaemic
state alters innate immunity, with reports of reduced monocyte Toll-like receptor
4 expression [2], reduced B-lymphocyte cell populations [3] and impaired polymorphonuclear
chemotaxis and phagocytosis [4]. It has also been proposed that changes in the gastrointestinal
microbiota, and increased intestinal permeability to endotoxin, lead to a persistent
activation of the innate immune system, resulting in the induction of immune-regulatory
mediators which then suppress both innate and adaptive immunity [5]. Additionally,
immune responses may also be impaired by poor nutritional status, malnutrition and
vitamin D deficiency [6].
For many years, it has been recognized that haemodialysis and peritoneal dialysis
(PD) patients have a reduced response to vaccination, in terms of developing seroprotective
antibody levels, to a number of the commonly available vaccines including hepatitis
B, pneumococcus, influenza A H1N1 and tetanus toxoid [7]. The risk of mortality with
chest infections in the chronic dialysis patient has been reported to be 14- to 16-fold
higher than that for the general population, with >50% of lower respiratory tract
infections caused by Streptococcus pneumoniae [8]. Lower respiratory tract infections
have additionally been reported to increase the relative risk for cardiovascular events
by 3.02 (95% CI: 2.87–3.02) in dialysis patients with pneumonia [9]. Most haemodialysis
patients gain fluid between dialysis sessions [10], and this increase in extracellular
volume includes lung water. As such, lung water content is increased even in healthy
haemodialysis outpatients without any respiratory symptoms prior to dialysis [11].
Whereas it was readily established that the mouth and upper airway are extensively
colonized by bacteria, it is only relatively recently that it has been recognized
that the lung is also normally colonized. The average person inhales 8000 L of air
each day, containing 104–106 bacterial cells per cubic metre. The internal surface
area of the lung is some 30 times that of the skin and the lung microbiome is determined
by the balance between microbial immigration, elimination and the relative growth
rates of different bacteria [12]. The proportion of resident to transient microbes
remains to be determined in healthy subjects, and it remains to be established how
chronic kidney disease and dialysis affect the lung microbiome. Surfactant in the
distal alveoli has bacteriostatic activity against some bacterial species, and it
is unknown whether this bacteriostatic activity is impaired in dialysis patients.
Similarly, other changes in innate and adaptive immunity will affect the risk for
pulmonary infections. The lung microbiome is altered by hypoxia [12], and increased
water lung content in the dialysis patient will increase hypoxia in dependent areas
of the lung. As such these changes may help explain the increased risk of pulmonary
infections in dialysis patients. This risk for pulmonary infections appears to be
much greater for haemodialysis patients, and although this may be related to greater
changes in lung water content during the dialysis week compared with PD patients,
haemodialysis patients additionally often travel together to and from dialysis centres
and wait together at the start and end of dialysis sessions increasing the risk of
respiratory pathogen transmission, whereas PD is a home-based therapy. Inflammatory
changes in the lung have been shown to lead to changes in other organs, the so-called
organ ‘cross talk’, and the combination of pulmonary inflammation and increased lung
water may account for the increased cardiovascular events reported [9]. To reduce
the risk of pulmonary infections, most economically developed countries recommend
vaccination programmes for dialysis patients, not only annual influenza vaccinations,
but also pneumococcal and haemophilus influenzae vaccines.
In addition to changes in the immune system, dialysis techniques also potentially
introduce additional risk factors for infection. Haemodialysis patients who dialyze
using central venous access catheters are at the highest risk of access-related infection,
followed by arteriovenous grafts, then arteriovenous fistulae [13], and more recently
it has been recognized that needling practices may also affect the risk for infection,
with greater risk of fistula-associated infection with buttonhole cannulation [14].
It is now acknowledged that the greatest risk for mortality is when patients transition
from non-dialysis chronic kidney disease to dialysis, with mortality rates often greater
than those of patients opting for non-dialysis conservative care [15]. This excess
mortality is linked to unplanned starts with central venous catheter access [16].
As such many renal units have introduced evidence-based clinical care bundles to reduce
the rates of haemodialysis access-related infections. Peritoneal dialysis patients
are also at increased risk of access-related exit-site infections and peritonitis,
and the International Society for Peritoneal Dialysis similarly has recommended a
series of interventions designed to reduce infection rates [17].
In this issue of the journal, Van Diepen et al. reviewed the case notes of 452 incident
dialysis patients starting dialysis between 1997 and 2007 and followed while being
treated by their primary dialysis modality until 2009. Data on all infectious complications
were retrospectively collected and the rates and types of infection were examined,
according to dialysis modality. Their study concluded that after taking into account
as many confounding factors as possible, infection rates were higher for haemodialysis
patients over the first 6 months, but overall PD patients had a higher infection risk,
which was mainly attributable to dialysis-related technique infections. Whether this
increased risk for infections not requiring hospitalization could simply be accounted
for by PD catheter exit infections is unclear. However, their results suggested an
increased risk for non-dialysis technique-related infections in haemodialysis patients,
such as sepsis and pneumonia. Other studies have also tried to answer the question
as to whether the choice of dialysis modality confers a higher risk for infection
and results have been mixed, with some reporting increased infection risk for haemodialysis
and others for PD. The major difference between Van Diepen et al.'s study and earlier
reports is their exhaustive effort to adjust for possible confounding factors, using
additional statistical analysis, which adds extra validity to their conclusions. The
Khan comorbidity score, which has been previously validated in dialysis patients,
was significantly higher in those patients initiating haemodialysis compared with
PD. During their retrospective case note reviews, data on infections, which occurred
in both outpatient and hospital setting, were collated. After adjustment for comorbidity
[18], PD patients were found to have had more infections. However, this group had
a greater number of less severe infections as the association between infection risk
and modality was weaker when only infection-related hospitalizations were considered.
The authors detailed how they defined infection during their case note review, but
the study would have been strengthened if they had used a defined standard set of
agreed criteria, such as the Centre for Disease Control/National Healthcare Safety
Network surveillance definitions [19]. Patients were followed for an average of nearly
2 years on their first dialysis modality, and the risk for infection was higher in
the haemodialysis group for the first 6 months, when patients were more likely to
be dialysing using central venous catheters. Data on vascular access type was not
available at the start of the study, with only a snapshot of vascular access available
at 3 months [16]. To really help understand why infection risk fell during the first
3 months in their haemodialysis cohort, changes in the proportion of patients dialyzing
using central venous catheters and arteriovenous fistulae are crucial.
To reduce infection in haemodialysis patients dialysing in the Royal Free London network,
we implemented a clinical care bundle approach and introduced a number of evidence-based
interventions. From 2010 to 2012, arteriovenous fistula dialysis access rates increased
from 64 to 78%. We introduced a rolling 3 monthly Staphylococcus aureus nasal screening
programme, with all positive patients decolonized using a 5-day course of nasal mupirocin
and chlorhexidine body and hair washing. Patients dialysing using a central venous
catheter had their exit-site examination recorded at each dialysis session and antibiotics
promptly started if there was evidence of local infection. Chlorhexidine impregnated
dressings were used at the exit site for the first 6 months and catheters locked with
46% citrate solution [20]. High-risk patients [i.e. those with a previous S. aureus
(SA) bacteraemia or those who are consistently positive for SA on nasal carriage]
had mupirocin additionally applied at the exit site post-dialysis. An active surveillance
programme has been running since the start of 2010, with antibiotic start data, catheter
infection rates and S. aureus bacteraemia (SAB) rates calculated and fedback to our
individual dialysis centres and at the dialysis group level every 6 months. From 2010
to 2012, catheter access infection rates have fallen from 0.99/1000 catheter days
in the first 6 months of 2010 to 0.42 in the latter 6 months of 2012 (R2 linear test
of trend = 0.86). The reduction in both catheter-related SAB rates and SAB rates overall
were less marked over this time period (Figure 1). This may well have been due to
the rolling out of a buttonhole fistula needling policy as the first-line approach
for needling arteriovenous fistulae in 2010, following which we then observed a rise
in SAB in this set of patients [14]. Despite the introduction of a strict fistula
disinfection and needle tracking policy, the infection rates did not fall and buttonhole
needling of fistulae was subsequently withdrawn at the end of 2012.
FIGURE 1:
The effect of changes in clinical practice with introduction of active nasal and exit
site screening and for haemodialysis patients dialysing with central venous access
catheters in combination with a preventative combination bundle approach on all and
SA blood stream infections 2010–2012.
In Van Diepen et al.'s study, PD patients predominantly suffered from dialysis technique-related
infections [21]. It has been documented for some time that PD peritonitis remains
the commonest cause of patients transferring from PD to haemodialysis [22]. Typically
most cases are caused by Gram-positive organisms, which often migrate from the skin
and colonize the PD catheter [23]. Infection can also follow a failure to follow sterile
precautions when performing PD exchanges, external contamination, gastrointestinal
bacterial translocation, haematogenous spread and occasionally following gynaecological
and rectal instrumentation. In addition, fungal infections may occur, particularly
after preceding broad-spectrum antibiotic prescription [24]. At the time of their
study, surveillance of nasal S. aureus and eradication therapy was not part of their
routine clinical practice, and similarly neither were PD exit-site antibiotics routinely
prescribed [17], and as such the number of exit site and tunnel infections reported
may have been somewhat higher than would be expected today. Although the International
Society for Peritoneal Dialysis Clinical Guidelines recommend the use of prophylactic
exit site antibiotics, or nasal antibiotics or both [17], and this may reduce the
incidence of exit-site infections, the effect on reducing peritonitis rates is somewhat
variable in clinical practice [25], with some centres which have a low background
rate of PD peritonitis reporting minimal or no beneficial effect, whereas centres
with higher background peritonitis rates reporting a reduction [26].
The dialysis infection literature would benefit from an equally thorough but more
up-to-date review of the question as to whether one dialysis modality confers a greater
infection risk. This information could then be used to counsel patients when they
have to choose a dialysis modality. As with other surveillance data on infection,
it could be used to target infection prevention interventions. Evidence-based guidelines
for the prevention of infection in dialysis patients are now readily available [17,
27]. A review of infection rates is needed in from those centres where these infection
prevention bundles have been introduced, as clinical practice varies widely. For example,
catheter insertion may be undertaken in surgical theatres, radiological intervention
suites or ward procedure rooms with variation in skin cleaning preparations, use of
prophylactic antibiotics including antibiotic choice, dosage and duration of prophylaxis,
SA eradication therapy and pre-insertion topical exit-site care. Central venous dialysis
catheter choice may also affect the risk for infection, not only in terms of whether
tunnelled and cuffed, but also the effect of differing designs; dual lumen versus
two single-lumen catheters, biomaterials, catheter surface smoothness, size and composition
of catheter cuffs and more recently coating with heparin, antiseptics, antibiotics,
silver and bismuth. Thereafter, catheter care varies between centres in terms of whether
aseptic precautions are used for catheter connection and disconnection, topical exit-site
care and the use of catheter locks. As each of these components of the clinical care
bundle designed to reduce infection risk has an economic cost, it is important for
both the patient and also for healthcare economics to ascertain which components were
most successful in reducing the risk of infection, and equally which were least effective.
Although the introduction of clinical care infection prevention bundles has reduced
the incidence of catheter-associated bacteraemias in haemodialysis patients, similar
care pathways have not substantially reduced the risk of peritonitis in European PD
patients [26, 28]. Peritonitis rates have historically been lower in Hong Kong and
Japan compared with Northern Europe, North America and Australia. Although there are
differences in climate, the bacterial causes of peritonitis are similar, with Gram-positive
skin commensals, followed by SA predominating [17], suggesting that the skin microbiome
is not substantially different. Dietary intake may differ, and changes in the diet,
for example, soy protein-rich diets and those rich in plant-derived polysaccharides
or resistant starches are known to alter the gastrointestinal microbiota [5]. Increased
gut permeability and bacterial translocation are the most likely cause for the majority
of episodes of gut microbiome-derived Gram-negative and Gram-negative peritonitis.
Both elderly haemodialysis and PD patients are at increased risk of diverticular disease
due to the combination of fluid restriction and dietary modifications designed to
reduce phosphate and potassium intake. Changes in the gut microbiome alter innate
and adaptive immunity, leading to effects at distant sites. The combination of these
effects may account for the increased risk for developing peritonitis with bacteria
originating from the skin microbiome. On the other hand, the introduction of neutral
pH and low glucose degradation product PD solutions has not made any significant impact
on reducing peritonitis rates, suggesting that these changes in peritoneal dialysate
composition do not have any major effect on the gut microbiome, and intestinal permeability.
Infection in dialysis patients remains an important healthcare problem. Studies have
reported that although hospitalizations rates for dialysis patients have recently
fallen overall, those for infection-related admissions have not [29]. Prevention should
be the priority as infections are now harder to treat with multi-drug resistant bacteria
on the rise and few newer antibiotics in the pipeline [30]. As such, centres should
ensure that patients are actively vaccinated against respiratory pathogens to reduce
the risk of pulmonary infections and also aim to limit fluid overload, in particular
interdialytic fluid gains in haemodialysis patients. To reduce access-associated infections,
centres should aim to increase the number of patients starting haemodialysis with
arteriovenous fistulae, so limiting the use of central venous access catheters. Preventative
infection clinical care bundles have reduced catheter-associated bacteraemias, but
have not been as successful in preventing peritonitis in PD patients, and as such
more research is required to reduce the risk of peritonitis in this group of dialysis
patients.