Journal of Human Hypertension (2003) 17, 419423
& 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00
ORIGINAL ARTICLE
Diarrhoea, vomiting and ACE inhibitors:
an important cause of acute renal failure
C Stirling1, J Houston1, S Robertson1, J Boyle1, A Allan1, J Norrie2 and C Isles1
1
Renal Unit, Dumfries & Galloway Royal Infirmary, Dumfries, UK; 2Robertson Centre for Biostatistics,
Robertson Centre, University of Glasgow, Glasgow, UK
The occurrence of severe acute renal failure in 3 patients
who developed diarrhoea while taking angiotensin
converting enzyme (ACE) inhibitors led us to undertake
a retrospective cohort survey to determine the fre-
quency with which diarrhoea and vomiting are asso-
ciated with acute renal failure in patients taking this
class of drug. Serum creatinine was measured as part of
the diagnostic workup of 2398 consecutive admissions
to an acute medical receiving unit in a district general
hospital. Outcome measures were the presence of
diarrhoea and/or vomiting, and whether taking an ACE
inhibitor, NSAID or diuretic at the time of admission,
also previous, initial and follow up serum creatinine
concentrations. Peak serum creatinine in the 3 cases
was 1159, 989 and 765 lmol/l. None of the 3 required
dialysis and all recovered renal function completely
after receiving large volumes of intravenous fluid. In the
Keywords: acute renal failure; ACE inhibitors; diarrhoea; vomiting
Introduction
Angiotensin-converting enzyme (ACE) inhibitors are
a doubled-edged sword. They are recommended for
patients with diabetic nephropathy and other forms
of glomerular disease with proteinuria on the
grounds that they can slow the decline of renal
function in these conditions.1 Outcome trials have
shown cardiovascular benefits when ACE inhibitors
are used to treat hypertension, heart failure, LV
systolic dysfunction, coronary heart disease and
stroke.24 On the other hand, ACE inhibitors may
lead to the loss of renal function in patients with
bilateral renovascular disease,5,6 when co-adminis-
tered with NSAIDs7 or large doses of diuretics8 and,
when there is marked volume depletion.9,10 Studies
of patients presenting with acute renal failure to
renal units suggest that ACE inhibitors are impli-
cated in 8% of cases.9 Against this background, we
wish to report three cases of severe acute renal
failure in patients who developed intercurrent
diarrhoeal illnesses while taking ACE inhibitors,
Correspondence: Dr C Stirling, Specialist Registrar in Nephrology,
Renal Unit, Glasgow Royal Infirmary, Glasgow G1 OSF, UK.
E-mail: cathstirling@hotmail.com
Received 3 February 2003; accepted 7 March 2003
www.nature.com/jhh
cohort study, 89 of 2398 (3.7%) admissions had serum
creatinine X200 lmol/l. Nine were regular dialysis
patients. Of the remaining patients, 30 (37.5%) were
taking an ACE inhibitor. Six of 30 (20%) gave a history of
diarrhoea and/or vomiting. Median creatinine concentra-
tion in this group was 135 (range 111209) lmol/l before
admission, 292 (216724) lmol/l when first seen in
hospital, and 134 (94219) lmol/l following the with-
drawal of drug therapy and fluid replacement. In
conclusion, volume depletion causing acute renal fail-
ure in patients taking ACE inhibitors is not uncommon.
Such patients and their general practitioners should be
aware that reversible renal impairment may occur during
intercurrent illnesses, particularly if characterised by
diarrhoea and/or vomiting.
Journal of Human Hypertension (2003) 17, 419423.
doi:10.1038/sj.jhh.1001571
together with the results of a survey to determine
the frequency with which diarrhoea and vomiting
are associated with acute renal failure in patients
taking ACE inhibitors at the time of their admis-
sion as medical emergencies to a district general
hospital.
Case reports
Case 1
A 54-year-old man was admitted in September 1999
with a 2-week history of diarrhoea on a background
of chronic alcohol excess and hypertension. He had
continued to take lisinopril, amlodipine and fruse-
mide. On admission he looked well, and appeared
alert and orientated. Heart rate was 80 per min with
blood pressure was 95/72 mmHg. Initial investiga-
tions showed serum sodium 125 mol/l, potassium
4.3 mmol/l, urea 47.3 mmol/l and creatinine
1594 mmol/l. His drugs were stopped and he was
treated with intravenous fluids. He required 7 l
of fluid in the first 24 h before a diuresis occurred.
His serum biochemistry returned to normal over a
period of 5 days and he did not require dialysis
(Figure 1, case 1).
 ACE inhibitors and acute renal failure
C Stirling et al

420
Case 2 Case 3
A 66-year-old woman was referred to the hospital in A 48-year-old man developed diarrhoea 4 days after
October 1999 with a 10-day history of diarrhoea and returning from a holiday in the Greek Islands in July
vomiting. She gave a past history of chronic 2000. He gave a past history of hypertension and
obstructive pulmonary disease and myocardial in- gout for which he was taking irbesartan 75 mg od,
farction for which she was taking captopril and atenolol 100 mg od, allopurinol 100 mg od and
aspirin. She again looked well and did not appear aspirin 75 mg od. He was haemodynamically stable
shocked, with heart rate 70 per min and blood when first seen with heart rate 60 per min and blood
pressure 106/64 mmHg. Serum biochemistry pressure 110/49 mmHg. Results of investigations
showed sodium 128 mmol/l, potassium 4.2 mmol/l, included sodium 125 mmol/l, potassium 3.7 mmol/l,
urea 56.2 mmol/l and creatinine 959 mmol/l. Treat- urea 23.7 mmol/l and creatinine 688 mmol/l. Salmo-
ment by withdrawal of captopril and over 7 l of nella group B was isolated from his stool. Treatment
intravenous fluid in the first 48 h caused a fall in her consisted of ciproxin, withdrawal of irbesartan and
urea and creatinine, which returned to normal over atenolol plus intravenous fluid. Over 10 l were given
the course of the next 4 days without the need for during the course of the first 30 h of hospital
dialysis (Figure 1, case 2). admission. Renal function returned to normal over
the course of the next 10 days with urea 3.3 and
creatinine 123 mmol/l at the time of discharge
(Figure 1, case 3).
Input - Output -

Volume (ml) Retrospective cohort study

serum
Case 1 creatinine Between 1 August 2000 and 31 December 2000, 2398
8000 (mol/l)
emergency admissions to the Medical Admissions
7000 2000
Unit in Dumfries Infirmary, a district general
6000 hospital serving a population of 150 000 in the
1500
5000 South West of Scotland, had a measurement of
4000
1000 serum creatinine as part of their diagnostic workup.
3000 By linking the hospitals admissions records with
2000 500 biochemistry reports electronically, we were able to
1000 identify 89 patients whose serum creatinine was
0 0 X200 mmol/l at the time of their admission. Nine
were regular dialysis patients. The casenotes of the
Case 2 remaining 80 patients were retrieved.
5000 1000 In all, 30 of 80 patients (37.5%) were taking an
4000 800 ACE inhibitor (n 29) or an angiotensin receptor
blocker (n 1) at the time of admission. These
3000 600 patients were elderly (average age 70 years) with
2000 400 multiple comorbidities including heart failure (23),
coronary heart disease (20), diabetes mellitus (17),
1000 200 hypertension (14) and renal disease (12). Several
0 0 patients had more than one pathology. The ACE
1 2 3 4 5 inhibitors were lisinopril (12), ramipril (7), enalapril
(5), captopril (4) and perindopril (1). We included
Case 3 the only patient who was taking an angiotensin
10000 1000
receptor blocker (losartan) in the ACE inhibitor
group on the grounds that the renal effects of
8000 800 angiotensin receptor blockers and ACE inhibitors
are similar.11 Of the 30 patients, six (20%) patients
6000 600 on an ACE inhibitor gave a history of diarrhoea and/
or vomiting which is likely to have been the cause of
4000 400 their acute deterioration in renal function: median
creatinine in this group was 135 (range 111
2000 200
209) mmol/l before admission, 292 (216724) mmol/l
0 0
when first seen in hospital and 134 (94219) mmol/l
1 2 3 4 5 6 7 8 9 10 during follow-up after withdrawal of the drug and
Day of Admission fluid replacement (Table 1). The remaining 24 ACE
Figure 1 Case histories showing fluid balance and serum inhibitor patients were a heterogeneous group. In
creatinine in three patients who developed acute renal failure all, 19 had evidence of reduced renal perfusion
following a diarrhoeal illness while taking an ACE inhibitor. including six who were taking large doses of

Journal of Human Hypertension

 ACE inhibitors and acute renal failure
C Stirling et al

421
diuretics (arbitrarily frusemide X120 mg per day or of the six diarrhoea and vomiting patients (Group A)
bumetanide X3 mg per day) in the absence of any with those of two other groups of patients who
other explanation for a deterioration in renal func- survived to leave hospital and had measurement of
tion; seven with clinical and radiological evidence serum creatinine before, during and after admission:
of heart failure; three who were septic and three who ACE inhibitor patients with other causes of reduced
were taking NSAIDs. Five ACE inhibitor patients renal perfusion (Group B: 16 of 19 patients had a full
had no clinical evidence of reduced renal perfusion. set of measurements) and patients with reduced
None of the ACE inhibitor patients were known to renal perfusion who were not taking ACE inhibitors
have or were investigated to exclude the possibility (Group C: 25 of 34 patients had a full set of
of renovascular disease (Figure 2). measurements). Medians before, during and after
In order to test the hypothesis that diarrhoea and admission, and the medians for duringbefore and
vomiting severe enough to require hospital admis- afterbefore were reported. The median differences
sion may pose a particular threat for patients taking and two sample two-sided Wilcoxon rank-sum test
ACE inhibitors, we compared the creatinine profiles P-values were calculated for the comparisons of
Groups A vs B, A vs C, and then for Group A against
Groups B and C combined. All analyses were
performed using SAS 8.2 for Windows and Minitab
Table 1 Serum creatinine profiles before, during and after 13.0 for Windows. No adjustment was made for
hospital admission
multiple comparisons. Table 1 shows that the ACE
Previous First Creatinine During After inhibitor, diarrhoea and vomiting group had a
creatinine creatinine at follow up before before greater rise in their creatinine from baseline and a
greater fall in creatinine with treatment than the
Group A other two groups, although these differences did not
(n=6) achieve statistical significance.
Case 1 113 216 123
Case 2 111 246 97
Case 3 148 225 144
Case 4 148 724 155 Discussion
Case 5 121 654 94
Case 6 209 337 219 Acute renal failure is a recognised complication of
Median 135 292 134 132 1.5
Group B ACE inhibitors both in hypertension and heart
(n=16) failure.10 A proportion of such patients will be
Median 162 250 165 101 8.5 found on further investigation to have bilateral
Group C renovascular disease or stenosis in a solitary
(n=25)
Median 155 231 166 99 7
kidney.11 Elevation of serum creatinine can also
occur if renal perfusion pressure falls for any reason
Group A=six ACE inhibitor patients who developed acute renal in patients taking ACE inhibitors. This can result
failure during an intercurrent illness characterised by diarrhoea and/ from an increase in diuretic therapy, co-prescription
or vomiting; Group B=16 ACE inhibitor patients with other causes of of an NSAID or the development of volume deple-
reduced renal perfusion; Group C=25 patients with reduced renal
perfusion in absence of ACE inhibitor. P-values for comparison A vs B,
tion from a nondiuretic induced cause such as
A vs C and A vs B+C were 0.080.88. gastroenteritis.12 Decline in renal function occurs
because of altered renal autoregulation: as renal
perfusion pressure falls, the glomerular afferent
arteriole dilates under the influence of prostaglan-
Emergency Admissions
dins. This is followed by constriction of the efferent
2398 arteriole as a result of intrarenal angiotensin II, in an
attempt to maintain glomerular capillary pressure.13
Serum creatinine > 200mol/l
89 (3.7%) If efferent vasoconstriction is blocked by the reduc-
tion in angiotensin II caused by ACE inhibition,
Dialysis patients Not on Dialysis
then autoregulation cannot occur and glomerular
9 80 capillary pressure and subsequently glomerular
filtration rate falls. This mechanism has been
ACEI/ARB No ACEI/ARB recognised before in patients with fluid losses who
30 50 continue to take ACE inhibitors and has led to acute
renal failure, previously associated with haemody-
Diarrhoea and/or
Vomiting
Other reduced
Renal perfusion
Other
causes1
Reduced
renal perfusion
Other
causes2
namic collapse.14,15
6 19 5 34 16 Another explanation for the observation that
patients with reduced renal perfusion have a greater
1
2
2 CRF, 1 unexplained ARF, 1 rhabdomyolysis, 1 obstructive uropathy
8 CRF, 4 obstructive uropathy, 1 bilateral renovascular, 1 rhabdomyolysis, 1 hepatorenal,
rise in serum creatinine if they are taking an ACE
1 unexplained ARF inhibitor may relate to the known effects of ACE
Figure 2 Flow chart showing selected renal outcomes in a cohort inhibitors on the sympathetic and parasympathetic
of 2398 consecutive emergency medical admissions. nervous systems.16,17 Patients taking ACE inhibitors

Journal of Human Hypertension

 ACE inhibitors and acute renal failure
C Stirling et al
422
who develop reduced renal perfusion for any reason
may be less likely to mount a sympathetic response
to volume depletion, that is, tachycardia and
sweating, which would normally alert them to the
fact that they were unwell, because ACE inhibitors
not only block the sympathetic nervous system but
also increase vagal tone.16,17 This could well account
for the observation in our study that patients with
severe volume depletion, perhaps particularly diar-
rhoea and vomiting, tend to present later and with
more advanced degrees of renal failure if they are
also taking an ACE inhibitor.
The first three cases of acute renal failure
described in our report, and the six patients with
diarrhoea and/or vomiting in our cohort study, were
clearly dry but not profoundly hypotensive and
certainly not shocked. The mechanism of their acute
renal failure is likely to be the same as that reported
by previous authors, and the lesson we believe is
worthy of repitition. This is, that patients on ACE
inhibitors who develop vomiting or diarrhoea are at
risk of a reversible rise in serum urea and creatinine,
sometimes amounting to severe acute renal failure.
Our cohort study suggests this may be more severe
with diarrhoea and vomiting than with other causes
of reduced renal perfusion and that a district general
hospital serving a population of 150 000 might
expect to see such a problem arising approximately
once a month.
Analysis of the drug information available to
patients and their General Practitioner supports
the view that the potential for this complication to
occur is not widely appreciated. A total of 11 ACE
inhibitors are currently licensed for use in the UK.
The patient information literature that accompanies
each prescription of these drugs lists diarrhoea as a
side effect of ACE inhibition (9/11) and indicates
that volume depletion may lead to exaggerated falls
in pressure at the start of therapy (11/11) but gives
no advice for patients who develop diarrhoea and
vomiting while on therapy (0/11). Review of the
information given to doctors in the British National
Formulary reveals a similar picture: diarrhoea is
listed as a side effect of ACE inhibitors (11/11),
caution should be exercised if patients are volume
deplete at the start of therapy (11/11) although no
advice is given for patients who develop diarrhoea
and vomiting while on therapy (0/11).
It has recently been reported that up to two-thirds
of patients who start an ACE inhibitor did not have
their renal function checked thereafter in general
practice,18 highlighting the need for guidelines for
monitoring renal function in patients on ACE
inhibitors. Many authorities recommend that urea
and electrolytes are checked at 1 week and 1 month
on the grounds that if creatinine has not risen by 1
month it is unlikely to do so thereafter. We would
further recommend that patients on an ACE
inhibitor should be warned of the possibility of
volume depletion and reversible renal impairment
during a diarrhoeal illness, and advised to contact
Journal of Human Hypertension
their general practitioner in the event of such fluid
losses. We know of no trial evidence that will help
the general practitioner determine the next step but
suggest that clinical circumstance should dictate the
course of action. For most patients, it may be
sufficient to omit concomitant diuretic therapy for
a few days. For those who appear less well, it might
be safer to measure renal function, stop both ACE
inhibitor and diuretic temporarily and increase oral
intake until the diarrhoeal illness has resolved.
Acknowledgements
We thank Mrs Josephine Campbell and Mrs Anne
Bray for their help in the preparation of this
manuscript and Dr Robert McFadzean for his help-
ful advice. This work was supported in part by an
infrastructure grant from the Chief Scientist Office,
Scotland.
References
1 Kshirsagar AV et al. Effect of ACE inhibitors in diabetic
and nondiabetic chronic renal disease: a systematic
overview of randomized placebo-controlled trials. Am
J Kidney Dis 2000; 35: 695707.
2 Flather MD et al. Long-term ACE-inhibitor therapy in
patients with heart failure or left-ventricular dysfunc-
tion: a systematic overview of data from individual
patients ACE-Inhibitor Myocardial Infarction Colla-
borative Group. Lancet 2000; 355: 15751581.
3 Yusuf S et al. Effects of an angiotensin-converting-
enzyme inhibitor, Ramipril, on cardiovascular events
in high risk patients. The Heart Outcomes Prevention
Evaluation Study Investigators. N Engl J Med 2000;
342: 145153.
4 PROGRESS Collaborative Group. Randomised trial of
a perindopril-based blood-pressure-lowering regimen
among 6,105 individuals with previous stroke
or transient ischaemic attack. Lancet 2001; 358:
10331041.
5 Toto RD. Renal insufficiency due to ACE inhibitors.
Miner Electrolyte Metab 1994; 20: 193200.
6 Van de Ven PJG et al. Angiotensin converting enzyme
inhibitor induced renal dysfunction in atherosclerotic
renovascular disease. Kidney Int 1998; 53: 986993.
7 Thomas MC. Diuretics, ACE inhibitors and NSAIDs
Fthe triple whammy. Med J Aust 2000; 172: 184185.
8 Knight EI et al. Predictors of decreased renal function
in patients with heart failure during angiotensin
converting enzyme inhibitor therapy: results from the
Studies of Left Ventricular Dysfunction (SOLVD). Am
Heart J 1999; 138: 849855.
9 Baraldi A et al. Acute renal failure of medical type in
an elderly population. Nephrol Dial Transplant 1998;
13 (Suppl 7): 2529.
10 Wynckel A et al. Long term follow up of acute renal
failure caused by angiotensin converting enzyme
inhibitors. Am J Hypertens 1998; 11: 10801086.
11 Pitt B et al on behalf of the ELITE Study Investigators.
Randomised trial of losartan versus captopril in
patients over 65 with heart failure. Evaluation of

Losartan In The Elderly Study (ELITE). Lancet 1997;
249: 747752.
12 Bakris GL, Weir MR. Angiotensin-converting enzyme
inhibitorFassociated elevations in serum creatinine.
Is this a cause for concern? Arch Intern Med 2000; 160:
685693.
13 Short A, Cumming A. ABC of intensive care: renal
support. BMJ 1999; 319: 4144.
14 Bennett PR, Cairns SA. Captopril, diarrhoea and
hypotension. Lancet 1985; i: 1105.
15 McMurray J, Matthews DM. Consequences of fluid loss
in patients treated with ACE inhibitors. Postgrad Med J
1987; 63: 385387.
ACE inhibitors and acute renal failure
C Stirling et al
423
16 Osterziel KJ, Dietz R. Improvement of vagal tone
by ACE inhibition: a mechanism of cardioprotection
in patients with mild to moderate heart failure.
J Cardiovas Pharmacol 1996; 27 (Supp 2): 2530.
17 Grassi G et al. Effects of chronic ACE inhibition on
sympathetic nerve traffic and baroreflex control of
circulation in heart failure. Circulation 1997; 96:
11731179.
18 Kalra PA, Kumwenda M, Macdowall P, Rowland MO.
Questionnaire study and audit of use of angiotensin
converting enzyme inhibitor and monitoring in general
practice: the need for guidelines to prevent renal
failure. BMJ 1999; 318: 234237.
Journal of Human Hypertension