Corresponding Author
Dr Nazir Lone
University Department of Anaesthesia, Critical Care, and Pain
Medicine, School of Clinical Sciences, University of Edinburgh, 47
Little France Crescent, Edinburgh, EH16 4SA.
[email protected]
0131 242 6395
Title
Community prescribing of potentially nephrotoxic drugs and risk
of acute kidney injury requiring renal replacement therapy in
critically ill adults: a national cohort study
Authors
Mr Steven Tominey a
Mr Alan Timmins b
Mr Robert Lee c
Professor Timothy S Walsh c d e
Dr Nazir I Lone c d
a Edinburgh Medical School, Edinburgh BioQuarter, Edinburgh, UK.
E-mail: [email protected]
b Pharmacy Department, Victoria Hospital, Hayfield Road,
Kirkcaldy. KY2 5AH
c Usher Institute for Population Health Sciences and
Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8
9AG, UK.
d University Department of Anaesthesia, Critical Care, and Pain
Medicine, School of Clinical Sciences, University of Edinburgh,
Edinburgh, UK.
e MRC Centre for Inflammation Research, University of Edinburgh,
47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Competing interests
ST was awarded a Kidney Research UK Intercalated Degree Award to
fund himself during this project.
No external sources or sponsors were involved in the study
design; data collection, analysis, or interpretation; manuscript
writing or the decision to pursue publication.
On behalf of all authors, the corresponding author states that
there is no conflict of interest.
Key Words
Renal replacement therapy; critical care; nephrotoxin; community
prescribing; acute kidney injury
Abstract
Background
Acute kidney injury (AKI) demonstrates a high incidence in
critically ill populations, with many requiring renal replacement
therapy (RRT). Patients may be at increased risk of AKI if
prescribed certain potentially nephrotoxic medications. We aimed to
evaluate this association in ICU survivors.
Methods
Study design: secondary analysis of national cohort of ICU
survivors to hospital discharge linked to Scottish healthcare
datasets. Outcomes: primary: RRT in ICU; secondary: early AKI
(calculated using urine output and relative change from estimated
baseline serum creatinine within first 24 hours of ICU admission
using modified-RIFLE criteria). Primary exposure: pre-admission
community prescribing of at least one potential nephrotoxin:
angiotensin-converting-enzyme inhibitors/angiotensin-receptor
blockers (ACE-i/ARBs), diuretics or nonsteroidal anti-inflammatory
drugs (NSAIDs). Statistical analyses: unadjusted associations:
univariable logistic regression; confounder adjusted: multivariable
logistic regression.
Results
During 2011-2013, 12,838 of 23,116 patients (55.5%) were
prescribed at least one community prescription of at least one
nephrotoxin; 1,330 (5.8%) patients received RRT; 3,061 (15.7%) had
AKI. Patients exposed to at least one examined nephrotoxin
experienced higher incidence of RRT (6.8% vs 4.5%; adjOR 1.46,95%CI
1.24,1.72,p<0.001) and AKI (19.8% vs 10.9%; adjOR
1.61,1.44,1.80,p<0.001). Increased risk of RRT was also found
for ACE-i/ARBs (adjOR 1.65, 1.40,1.94), NSAIDs (adjOR 1.12,
1.02,1.44), and diuretics (adjOR 1.35, 1.14,1.59).
Conclusions
Community prescribing of potential nephrotoxins increases the
risk of RRT/early AKI in ICU populations. Analyses were limited by
the survivor dataset and potential residual confounding. Findings
add consistency to previous research improving understanding of the
harmful potential of these important medications and their timely
cessation in acute illness.
Introduction
Acute kidney Injury (AKI) is a condition typified by a sudden
loss of kidney function demonstrating high incidence during
hospitalisation in critically ill populations (67%) and continues
to increase nationally1. It is associated with high mortality of
20-40% in ICU populations2–5 and may necessitate renal replacement
therapy (RRT)6. The National Institute for Health and Care
Excellence (NICE) estimates that AKI costs the NHS between £434-620
million annually, higher than breast, skin and lung cancer
combined7.
Nephrotoxic medications are the suspected aetiology in
approximately 20% of cases, rising to 66% in elderly
populations8–10. This is of interest, as through anticipation and
early intervention, drug-induced AKI should be largely
preventable.
Due to extensive use11, three classes of potentially nephrotoxic
medications are of particular interest:
angiotensin-converting-enzyme inhibitors (ACE-i) and angiotensin-II
receptor blockers (ARBs), diuretics, and non-steroidal
anti-inflammatory drugs (NSAIDs). The Medicine Sick Day Rules Card
scheme by the Scottish Patient Safety Programme (SPSP) aimed to
raise patient and clinician awareness of the risks of these
medicines within primary care12. The mechanisms of nephrotoxicity
of these medicines have been examined in the literature. Diuretics
increase susceptibility to insults through hypovolaemia; ACE-i/ARBs
cause efferent arteriolar vasodilation causing intraglomerular
haemodynamic reduction; whereas, NSAIDs cause vasoconstriction of
the afferent renal arterioles13–16.
Strong evidence exists for an increased association of AKI with
both NSAIDs and “triple-therapy” (the concurrent use of ACE-i/ARBs,
diuretics and NSAIDs)15,17–19. However, conclusive evidence does
not exist for ACE-I/ARBs20–22, diuretics23, or
“dual-therapy”18,19,24,25. Furthermore, prior populations were
poorly defined or from primary care databases without clear
temporality for reported AKI. Particularly noticeable is the lack
of ICU-specific research, the setting for management of the sickest
patients and costly interventions such as RRT.
We aimed to assess the association of AKI requiring RRT with the
community prescribing of ACE-i/ARBs, diuretics and NSAIDs in
critically ill patients across Scotland. These drugs were examined
both alone and in combination.
Methods
Study Design, Setting and Databases
We undertook a retrospective population-based cohort study using
linked Scottish healthcare datasets. This comprised a complete,
national three-year cohort of patients admitted to Scottish adult
general ICUs (01/01/2011-31/12/2013) from the Scottish Intensive
Care Society Audit Group (SICSAG) database, linked to national
hospital records (SMR01), death records and the Scottish community
prescribing database. The SICSAG database routinely and
prospectively collects detailed information for audit and research.
Data undergo checks for completeness and validity including at data
entry, periodic case-note validations, and central validation26.
The study was a secondary-analysis of a subset of data used in the
PROFILE study27. The PROFILE study aimed to identify drivers for
unplanned readmissions to hospital in a survivor cohort of ICU
patients. The PROFILE cohort comprised patients admitted during
2005-2013. Prescribing data were only complete from 01/01/2011
onwards. Analyses were restricted to these patients.
The Scottish community prescribing database contains all items
dispensed in Scotland by community pharmacy or dispensing doctors.
It does not include medicines prescribed and dispensed within
hospital.
As the prescribing database includes only community-dispensed
medication, patients who were prescribed medicines but did not have
them dispensed were classified as unexposed, reducing exposure
misclassification.
Appropriate permissions for data were achieved including SICSAG
Steering Committee and Public Benefit and Privacy Panel for Health
and Social Care (PBPP28). Electronic data storage and analysis took
place within the NHS National Services Scotland safe haven.
Participants
Participants included all patients admitted to Scottish adult
general ICUs during the study period who survived to hospital
discharge. Patients were excluded if they were:
· receiving chronic RRT pre-admission, defined as a patient
undergoing haemodialysis, haemofiltration or peritoneal dialysis
for end stage renal disease (ESRD) on admission to ICU29.
· missing data for primary outcome (receipt of RRT).
· missing a unique patient identifier for linkage to
corresponding Scottish prescribing information records.
Attempt was made to obtain data for the complete cohort
including non-survivors, but financial restrictions made this
unfeasible.
Variables
Outcomes
The primary outcome was receipt of RRT at any point during ICU
stay identified by SICSAG database coding. The secondary outcome
was early AKI derived from urine output and change in serum
creatinine relative to an estimated baseline during the first
24-hours of ICU admission, using modified-RIFLE criteria defined by
the Australian and New Zealand Intensive Care Society (ANZICS)30.
This definition has been previously used in studies using UK ICU
data30. This outcome captures patients who did not receive RRT.
Measurements used for serum creatinine and urine output are
recorded from the initial 24-hours of ICU admission. The ANZICS
definition was modified to include patients receiving RRT within
the initial 24-hours of ICU admission in the failure category. All
outcome variables were from the SICSAG database. All derivations
are detailed (eFigures 1-3).
Exposures
Exposures were community prescription of ACE-I/ARBs, diuretics
or NSAIDS on admission from the Scottish community prescribing
database. The primary exposure was community-prescribing of at
least one of any examined nephrotoxin (i.e. the primary exposed
drug class listed may be in combination with exposure to an
additional class – for example, NSAIDs = Participants exposed to at
least an NSAID +/- additional drug class). In additional analyses,
drugs were assessed alone as monotherapy, and in combination.
Identification was by British National Formulary (BNF)
chapter/subchapter (ACE-i and ARBs: 2.5.5; Diuretics: 2.2; NSAIDs:
10.1.1)31.
Potential Confounders
Potential confounders were identified from the SICSAG and SMR01
databases consisting of age, sex, socioeconomic status (Scottish
Index of Multiple Deprivation32), previous number of hospital
admissions, severity-of-disease (Acute Physiology and Chronic
Health Evaluation II [APACHE-II] score), ICU admission type
(elective surgery, emergency surgery, non-operative), number of
comorbidities, and receipt of cardiopulmonary resuscitation prior
to admission. These were adjusted for during analysis. Potential
unmeasured confounders include iodinated contrast agents,
dehydration status, urological obstructive disorders, and/or
medicines prescribed during the hospital admission.
Statistical Methods
Analyses were undertaken using Stata MP 14.1 (StataCorp LP,
College Station, TX). Baseline characteristics for both exposed and
non-exposed groups were described using number and percentage, or
median and interquartile range (IQR). Univariable associations
involving exposures, outcomes and baseline variables of interest
were assessed using chi-squared or Wilcoxon rank-sum tests.
Unadjusted results were expressed as odd ratios derived from
univariable logistic regression. Adjustment for potential
confounders was by multivariable logistic regression. Appropriate
model diagnostics demonstrated no significant deviations33.
Continuous variables (age and APACHE II score) were evaluated for
linearity assumptions. APACHE II was included in models as a
continuous term. Age violated linearity assumptions and was entered
as a categorical term (10 categories). We evaluated model
diagnostics for the logistic regression models (values for primary
analysis in brackets) reporting c-index (0.907), Brier’s Score
(0.042) and inspecting calibration plots of observed vs predicted
values in deciles which demonstrated good calibration across the
range of predicted risk.
Sensitivity Analyses
As the dataset was restricted to a cohort of ICU patients who
survived to hospital discharge, we undertook a series of
sensitivity analyses to assess the robustness of findings to the
inclusion of a hypothetical non-survivor cohort. We reported the
unadjusted odds ratios for this combined (survivor + non-survivor)
cohort for exposure-outcome (RRT) associations. Four parameters
were required to conduct these analyses: 1. the size of the
non-survivor cohort (derived from the hospital mortality rate of
all patients admitted to ICU); 2. the prevalence of RRT in the
non-survivor cohort; 3. the prevalence of community prescriptions
of the examined drugs; and 4. the association between community
prescriptions of the examined drugs and RRT. We obtained an
estimate of hospital mortality rate of 20%, and RRT prevalence in
this non-survivor cohort (25%) from SICSAG for 2011-2013 (SICSAG,
personal communication). As the prevalence of community
prescriptions of ACE-I/ARBs, diuretics and NSAIDS was unknown in
non-survivors, we modelled a range of prevalances 25-50% greater
than and less than the prevalence in the survivor cohort. In
addition, the association between community prescription of the
examined drugs and RRT was unknown. We therefore modelled a range
of risk ratios, varying from 0.5 (i.e. a 50% reduction in relative
risk of RRT) and 3.0 (a 3-fold increase in relative risk of
RRT).
Results
During the three-year study period, 24,504 patients were
admitted to ICU and survived to hospital discharge. After exclusion
criteria, 23,116 (94.3%) remained (Figure 1). Secondary outcome
analysis of early AKI defined by RIFLE classification was completed
for patients with complete biochemistry and length of stay data
(n=19,509; 79.6%).
Baseline Characteristics:
Baselines characteristics for the cohort are shown in Table 1
(extended version: eTable 1). Patients were stratified by those
exposed to any of the three examined drugs, and those not exposed.
The exposed group was significantly older, had a higher proportion
of females, had greater previous admissions, more likely to have
been admitted after elective surgery, and had higher illness
severity scores. Additionally, they had increased polypharmacy and
greater overall comorbidity – notably cardiovascular disease,
peripheral vascular disease, diabetes mellitus and renal
disease.
Exposures and outcomes:
Over the three-year study period, 12,838 of 23,116 patients
(55.5%) examined were prescribed at least one examined nephrotoxin
(Table 2). Within this population, 4,733 (20.5%), 5,961 (25.8%) and
7,637 (33.0%), were prescribed NSAIDs, diuretics and ACE-i/ARBs,
respectively. Monotherapy and combinations are detailed in eTable
2. RRT was received by 5.8% of patients (1,330/23,116).
Biochemically-defined AKI was evident in 15.7% patients
(3,061/19,509) (Table 2).
Main Results
A community prescription for any of the three examined drugs was
associated with increased RRT (6.8% vs 4.5%, p<0.001),
persisting after adjustment (adjOR 1.46, 95%CI 1.24,1.72,
p<0.001) (Figure 2).
Significant univariable associations were found between RRT and
those prescribed a diuretic (7.6% vs 5.1%, p<0.001) or ACE-i/ARB
(7.9% vs 4.7%, p<0.001), but not for NSAIDs (6.34% vs 5.60%,
p=0.053). After adjustment, prescription of each of the three
examined drugs was significantly associated with increased RRT
(Figure 2).
A community prescription for any of the three examined drugs was
associated with increased risk of early AKI (19.8% vs 10.9%,
p<0.001), which persisted after adjustment (adjOR 1.61, 95%CI
1.44,1.80, p<0.001) (Figure 2).
After adjustment for confounders, increased risk of early AKI
was associated with patients prescribed a diuretic (adjOR 1.52,
95%CI 1.35,1.70, p<0.001) or ACE-i/ARB (adjOR 1.75, 95%CI
1.56,1.95, p<0.001) but not NSAIDs (adjOR 0.96, 95%CI 0.85,1.08,
p=0.467) (Figure 2).
Additional Analyses
Monotherapy
Monotherapy with each of the three examined drugs was not
associated with RRT. Monotherapy with diuretics was associated with
reduced RRT. Similar associations were found after adjustment
(eFigure 4).
Early AKI was significantly associated with monotherapy for each
of the examined drugs, showing an increased risk of AKI for
diuretics and ACE-i/ARBs but a reduced risk of AKI with NSAIDs.
After adjustment, associations for NSAIDs and ACE-i/ARBs remained
significant (eFigure 4).
Dual-Therapy
The combinations of an ACE-i/ARB plus an NSAID, and an ACE-i/ARB
plus a diuretic were associated with increased RRT. After
adjustment, dual-therapy with an ACE-i/ARB plus diuretic remained
significant. (eFigure 4).
Increased risk of early AKI was found for dual-therapy with
ACE-i/ARBs plus an NSAID, and ACE-i/ARBs plus a diuretic. After
adjustment, dual-therapy with an ACE-i/ARB plus diuretic remained
significant (eFigure 4).
Triple-Therapy
Of the 655 patients prescribed triple-therapy, almost 1 in 10
required RRT (n=63, 9.6%). Triple-therapy was associated with
increased RRT, persisting after adjustment (eFigure 4).
Additionally, almost 1 in 4 of patients prescribed
triple-therapy developed AKI (n=136, 24.2%). Triple-therapy was
associated with an increased risk of early AKI, remaining after
adjustment (eFigure 4).
Sensitivity Analyses
Under a series of scenarios for a hypothetical non-surviving ICU
cohort, the sensitivity analyses demonstrated that the unadjusted
association between any of the three examined drugs and RRT was
likely to be underestimated, ranging from 1.61 to 2.78 (eFigure 5).
This assumed that the prevalence of potential nephrotoxic drug
prescription was at least as common in the non-survivor group as
the survivor group (i.e. at least 55.5%), and the association
between exposure and outcome was at least as large (OR at least
1.56, equivalent to RR 1.52). We demonstrated similar findings for
associations for each of the three drug classes individually and
RRT (eFigure 5).
Discussion
ICU survivors receiving a community prescription pre-admission
for any one of ACE-i/ARBs, NSAIDs or diuretics experienced a higher
incidence of both RRT and early AKI during their ICU stay. After
adjustment, this equated to a 46% and 61% increase in odds of RRT
and AKI, respectively. Increased risk of RRT and early AKI was
associated with community prescription of at least one of
ACE-i/ARBs or diuretics. Prescription of at least an NSAID was
associated with increased risk of RRT but not AKI. These
associations need to be interpreted in the context of a survivor
cohort and the likelihood of residual confounding; however, they
add to increasing evidence of potential harm associated with these
drugs in acute illness.
Strengths and Limitations
We used a complete, national cohort comprising all ICU survivors
during a three-year period linked to community prescribing data
with population coverage. Furthermore, we comprehensively evaluated
of all three chosen nephrotoxic drugs, both alone and in
combination. However, the dataset did not describe compliance,
length of exposure, and over-the-counter self-medication.
Additionally, prescribing patterns may have changed in the last
five years from when data was collected. However, reassuringly,
prescribing rates of the drug classes has remained consistent from
community pharmacy remuneration data34.
As outcomes are defined objectively with strict definitions,
receipt of RRT and biochemistry, the risk of detection or
misclassification bias was minimised. The secondary outcome was
chosen as, despite RRT being a useful surrogate for AKI and a
costly intervention, it has been estimated as not received by 48%
of AKI patients30. Prior research has also suggested use of
biochemistry in identifying disease omitted by hospital
coding19,35. Whilst useful, this biochemically-defined outcome
assumes normal renal function pre-admission and likely
overestimates AKI. In addition, creatinine and urine output
measurements were only available for the first 24 hours of ICU
stay, potentially underestimating AKI if this developed after 24
hours.
This study had a number of important limitations. The
association between the examined drugs and RRT/early AKI is likely
to be confounded. However, we were only able to adjust these
associations using the limited range of potential confounders
recorded in the database. This means that the likelihood of
residual confounding remains, and the findings should be viewed as
hypothesis generating rather than causal. Whilst randomisation
would not be feasible to evaluate a causal relationship between the
exposures and outcomes in this study, access to databases with more
detailed recording of potential confounders and prospective study
designs may reduce the impact of residual confounding on these
associations.
Data relating to CKD or pre-admission creatinine were
unavailable for the cohort. However, patients with end-stage renal
disease requiring RRT were coded in the dataset and could therefore
be excluded from the cohort. ACE-i/ARBs and diuretics are
frequently prescribed to patients with CKD and stratifying analyses
by CKD-status may have provided valuable additional insights.
Notably, the overall provision of RRT across Scottish ICUs
decreased during the study period from 12% to 9%, from 2011 to
2013, respectively36. This may suggest changes in culture regarding
the decision to administer RRT and was consistent with our
data.
It is important to note that the cohort excluded patients that
died during ICU admission. It would be reasonable to assume that
those receiving RRT or with AKI would be at a greater risk of
mortality6. Patients with an increased risk of mortality would
likely have greater comorbidity, and consequently be prescribed
more medications. Therefore, it is likely the associations
demonstrated in this survivor cohort would underestimate the true
association in a cohort comprising survivors and non-survivors,
which may explain the lack of association or negative association
seen for NSAIDs and diuretics. Crude hospital mortality rates
across Scottish hospitals for ICU patients during the study period
were 21.8%, 19.6%, and 19.0% for 2011, 2012 and 2013,
respectively29,36,37.
This is a major limitation of the study. We conducted
sensitivity analyses to provide a plausible range of values for the
‘true’ association between exposure and outcome in a cohort of ICU
survivors and non-survivors.
We were unable to report if medications had been discontinued
during hospital admission. This would have reduced the potential
nephrotoxic effects in the exposed cohort, biasing associations
towards the null. However, the short pre-ICU hospital length of
stay (Table 1) reduces the likelihood that drugs would have been
stopped, or if stopped, would be unlikely to have reached
sufficiently low concentrations to discount influence.
Interpretation
This research contributes to evidence that patients exposed to
community prescribing of ACE-i/ARBs, NSAIDs and/or diuretics are at
increased risk of requiring RRT and/or developing an early AKI in
ICU. An increased risk persisted when ACE-i/ARBs were prescribed in
combination with either diuretics or NSAIDs, and when all three
drugs were prescribed concomitantly.
We found a previously undescribed association between RRT and
early AKI with community prescribing of any prescribed number of
the examined nephrotoxins – justifying the drugs selected in the
Scottish Patient Safety Programme “Sick Day Rules” campaign12.
Furthermore, we found that each of the drug classes examined were
individually associated with increased risk of RRT – and all,
except NSAIDs, were significantly associated with increased
biochemical AKI.
Lafrance24 and Huerta25 assessed NSAIDs individually and in
combination - finding increased risk of AKI with concomitant
diuretic use. Dreischulte19 found increased risk of AKI for NSAIDs
plus diuretics or ACE-i/ARBs. However, Lapi18 found no association
with AKI when examining NSAIDs in both combinations. Interestingly,
the described associations involving NSAIDs and ACE-i/ARBs or
diuretics19,24,25 were not found in this study. In fact,
unexpectedly, NSAIDs were associated with reduced risk of early
AKI. NSAIDs are not essential medications for survival and may have
been prescribed more cautiously in higher risk patients. NSAIDs
were also prescribed in a younger and less comorbid population –
however, these factors were adjusted for in the analyses. An
alternate hypothesis is that these patients had higher mortality
and were therefore not present in the survivor cohort.
We elicited a significant association between both RRT and early
AKI with concomitant community prescribing of ACE-i/ARBs and
diuretics. This association appears to have been unexamined in
prior studies, highlighting a potentially understated risk in
community prescribing.
A decreased association with risk of RRT and AKI was found for
diuretics when prescribed alone (eFigure4), compared to when
evaluated with potential for co-exposure to other examined drugs
(Figure 2). This may be due to an additive risk in the presence of
other examined drugs – particularly, ACE-i/ARBs, where a relatively
large association was found for RRT/AKI and the co-prescribing of
both drugs.
This study further demonstrated the ‘triple whammy’ effect
coined by M.C. Thomas17, which proposed a negative synergistic
effect with concurrent ACE-i/ARBs, diuretics and NSAIDs. This
association between triple-therapy and increased risk of AKI has
been elicited using various study designs and AKI
definitions18,19,38.
Generalisability
The inclusive eligibility criteria and the population-based
nature of the study minimise selection bias, improving external
validity. Additionally, unlike some prior studies18,19, patients
with pre-existing renal disease (not requiring RRT) or history of
AKI were included. These are an important patient group with
increased risk of RRT. However, generalisability beyond the
ICU-survivor population is difficult. Additionally, the national
population has risk of potential residual confounding due to
regional and inter-site variability in practice and population.
Implications
An ideal future dataset would include baseline creatinine data
to improve the accuracy of classifying AKI, and contain additional
confounder information such as contrast agent exposure,
dehydration, and hospital-prescribing. Additionally, more detailed
prescribing information would allow evaluation of treatment dose
and duration effects, and differences within drug classes. The
study demonstrates novel linkage of national prescribing and ICU
datasets, serving as proof of concept for further work. This type
of linkage has significant potential, with increasing availability
of data suitable for this approach, particularly with respect to
prescribing and drug-related outcomes.
Conclusions
This population-based study quantifies the relationship between
community prescribing and risk of early AKI requiring RRT in an ICU
survivor population. Despite limitations of the survivor dataset,
this study highlights the harmful potential of these commonly
prescribed medications in a critically ill population including the
importance of timely cessation during acute illness. Further
studies in a complete cohort, including non-survivors, would allow
risk estimates to be generalisable to a wider population.
Acknowledgements
We wish to thank the Scottish Intensive Care Society Audit Group
for providing data and the staff at participating hospitals.
The authors would like to acknowledge the support of the eDRIS
Team (National Services Scotland) for their involvement in
obtaining approvals, provisioning and linking data and the use of
the secure analytical platform within the National Safe Haven.
ST would like to thank Kidney Research UK for funding in the
form of an Intercalated Degree Award.
NL is a Deputy Director for Research for the Intensive Care
Foundation.
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Figure 1.
Patient Flow Diagram
Flow diagram describing reasons for exclusion from primary and
secondary analyses.
Key = RRT: Renal Replacement Therapy.
Figure 2:
Forest plot of association between primary exposures (at least
one potential nephrotoxin) and outcomes: unadjusted and adjusted
results. Exposed drug class listed may be in combination with
exposure to an additional class – for example, NSAIDs =
Participants exposed to at least an NSAID +/- additional drug
class.
Key = NSAID: Non-steroidal Anti-inflammatory Drug; ACE-i:
Angiotensin-converting-enzyme Inhibitor; ARB: Angiotensin-II
Receptor Blockers; RRT: Replacement Therapy; AKI: Early Acute
Kidney Injury occurring within 24 hours of ICU admission.; OR: Odds
Ratio; 95% CI: 95% Confidence Interval.
Table 1.
Baseline Characteristics Summary
A summary of key demographic and clinical baseline
characteristics including total numbers examined stratified by
prescription of at least any one of an ACE-i/ARB, diuretic, or
NSAID.
Extended descriptive characteristics are presented in Appendix
(eTable 1).
Key = SIMD: Scottish Index of Multiple Deprivation; APACHE II:
Acute Physiologic Assessment and Chronic Health Evaluation II
Scoring System; APS: Acute Physiological Score; ACE-i:
Angiotensin-converting-enzyme inhibitors; ARB: Angiotensin-II
receptor blockers (ARBs); NSAID: Non-steroidal anti-inflammatory
drug.
Data presented as n(%) unless otherwise stated.
Baseline Characteristics
Total
Any Community Nephrotoxin Prescription
P-value
No
Yes
Total
Total
10,278 (44.5%)
12,838 (55.5%)
23,116
Demographics
Sex (Male)
23,116
6,075 (59.1%)
7,169 (55.8%)
13,289 (57.3%)
<0.001
Age (Median [IQR])
23,116
53 (38, 66)
66 (55, 74)
62 (47, 72)
<0.001
SIMD Quintile
23,094
0.002
1
2,747 (26.8%)
3,239 (25.3%)
5,999 (25.9%)
2
2,256 (22.0%)
2,989 (23.3%)
5,258 (22.7%)
3
1,982 (19.3%)
2,601 (20.3%)
4,597 (19.9%)
4
1,869 (18.2%)
2,195 (17.1%)
4,082 (17.6%)
5
1,410 (13.7%)
1,806 (14.1%)
3,226 (13.9%)
Comorbidity
Number of Prescribed Drugs [Median (IQR)]
23,116
5 (2, 10)
12 (8, 17)
9 (5, 15)
<0.001
Number of Comorbidities
23,116
<0.001
0
5,185 (50.5%)
4,578 (35.66%)
9,763 (42.2%)
1
3,264 (31.8%)
4,008 (31.22%)
7,272 (31.5%)
2
1,229 (12.0%)
2,291 (17.9%)
3,520 (15.2%)
3+
600 (5.8%)
1,961 (15.3%)
2,561 (11.1%)
Admissions
Previous Hospital Admissions [Median (IQR)]
23,116
0 (0, 1)
1 (0, 2)
1 (0, 2)
<0.001
ICU
Admission Type
23,184
Elective Surgery
3,051 (29.9%)
5,433 (42.7%)
8,484 (37.0%)
<0.001
Emergency Surgery
2,148 (21.0%)
2,479 (19.5%)
4,627 (20.1%)
<0.001
Non-operative
5,018 (49.1%)
4,808 (37.8%)
9,826 (42.8%)
<0.001
Severity of illness scores [Median (IQR)]
APACHE II
20,088
13 (9, 18)
15 (11, 20)
14 (10, 19)
<0.001
APS
20,077
10 (7, 15)
11 (7, 15)
10 (7, 15)
<0.001
Length of Stay [Median (IQR)]
23,116
ICU stay
2 (1, 4)
2 (1, 4)
2 (1, 4)
<0.001
Pre-ICU stay
1 (0, 1)
1 (0, 2)
1 (0, 2)
<0.001
Post-ICU stay
7 (3, 16)
8 (4, 18)
8 (4, 17)
<0.001
Total hospital stay
12 (6, 24)
14 (8, 26)
13 (7, 26)
<0.001
Table 2.
Association between primary exposures (at least one potential
nephrotoxin) and outcomes.
Exposed drug class listed may be in combination with exposure to
an additional class – for example, NSAIDs = Participants exposed to
at least an NSAID +/- additional drug class.
Key = NSAID: Non-steroidal Anti-inflammatory Drug; ACE-i:
Angiotensin-converting-enzyme Inhibitor; ARB: Angiotensin-II
Receptor Blockers; RRT: Replacement Therapy; Early AKI: Acute
Kidney Injury occurring within 24 hours of ICU admission. *P-Value
represents unadjusted analyses.
Outcome
RRT
Early AKI
Exposure
Number
Exposed
Not Exposed
P-Value*
Exposed
Not Exposed
P-Value*
Any
12,838 (55.5%)
872 (6.8%)
458 (4.5%)
<0.001
2,094 (19.8%)
967 (10.9%)
<0.001
NSAID
4,733 (20.5%)
300 (6.3%)
1,030 (5.6%)
0.053
610 (15.0%)
2,451 (15.9%)
0.168
Diuretic
5,961 (25.8%)
453 (7.6%)
877 (5.1%)
<0.001
1,171 (24.0%)
1,890 (12.9%)
<0.001
ACE-i/ARB
7,637 (33.0%)
605 (7.9%)
725 (4.7%)
<0.001
1,433 (23.2%)
1,628 (12.2%)
<0.001
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