Update Article.

NSAIDs and Kidney

P Ejaz, K Bhojani, VR Joshi*

Abstract
NSAIDs are commonly used drugs. Even with the advent of selective COX-2 inhibitors, nephrotoxicity
still remains a concern. The adverse effects of NSAIDs are mediated via inhibition of prostaglandin
synthesis from arachidonic acid by non-specific blocking of the enzyme cyclooxygenase leading to
vasoconstriction and reversible mild renal impairment in volume contracted states. When unopposed,
this may lead to acute tubular necrosis and acute renal failure. NSAIDs also produce interstitial nephritis
with or without nephrotic syndrome secondary to minimal change disease. Although this presents as
acute renal failure, it can progress in some cases to chronic renal failure. Papillary necrosis has been
incriminated in the development of chronic renal failure secondary to NSAIDs. In patients on long
term NSAIDs without acute or chronic renal failure, subclinical renal dysfunction such as reduced
creatinine clearance and impaired urine concentrating ability has been shown to be present. Although
this sub-clinical dysfunction is reversible on withdrawal of NSAIDs, some reports have suggested a
persistent residual dysfunction. Even with a wide range of NSAIDs at our disposal, a renal safe NSAID
is yet to be discovered.

INTRODUCTION glomerular filtration rate (GFR) especially in fluid depleted

N on steroidal anti-inflammatory drugs (NSAIDs) are
amongst the most commonly prescribed medication.
Some are available over the counter and likely to be abused.
Serious gastrointestinal side effects have been minimized with
the advent of selective and specific COX-2 inhibitors and
misoprostol. However, the newer NSAIDs continue to be
nephrotoxic much like the conventional NSAIDs.1
Nephrotoxicity attributed to NSAIDS has been reviewed
in the past.2-8 The spectrum of nephrotoxicity includes acute
tubular necrosis, acute tubulointerstitial nephritis,
glomerulonephritis, renal papillary necrosis, chronic renal
failure, salt and water retention, hypertension, hyperkalaemia
and hypereninaemic hypoaldosteronism.9 There are reports
of sub- clinical renal dysfunction due to NSAIDs.10 NSAID
induced chronic renal failure remains a debatable issue.11
This article reviews relevant English literature on acute
and chronic renal failure and sub-clinical renal impairment
due to NSAIDs (Medline search from 1990 to 2002 using key
words NSAIDs, acute renal failure, chronic renal failure,
interstitial nephritis and subclinical nephrotoxicity)
PATHO-PHYSIOLOGY
Prostaglandins maintain renal blood flow (RBF) and
*Director Research, Consultant Physician and Rheumatologist, PD
Hinduja National Hospital and Medical Research Centre, Veer
Savarkar Marg, Mahim, Mumbai 400 016.
Received : 23.12.2003; Accepted : 14..5.2004
states. Locally synthesised prostaglandins PGI2
(prostacyclin), PGE2, and PGD2 cause vascular dilatation,
diminish vascular resistance and enhance renal perfusion
with redistribution of blood flow from the renal cortex to
nephrons in the juxta-medullary region.12 PGE2 and to a lesser
degree PGF2 cause diuresis and natriuresis by inhibiting
the transport of sodium and chloride in the thick ascending
limb of loop of Henle and the collecting ducts.13,14 PGE1
tends to antagonize the action of antidiuretic hormone
(vasopressin).15,16 Lastly, prostacyclin in concert with PGE2,
serves to maintain the glomerular filtration rate.7
In volume contracted states renin-angiotensin-aldosterone
axis is stimulated with increased renin, angiotensin II, and
aldosterone production resulting in renal vasoconstriction
and increased sodium and chloride reabsorption. There is
increased sympathetic outflow, which further increases the
vascular tone. In this setting, prostaglandins provide
compensatory vasodilatation of renal vascular bed and ensure
adequate renal blood supply precluding acute renal functional
deterioration. PGE2, PGD2, and to a lesser degree prostacyclin,
cause vasodilatation by depressing norepinephrine release.
PGE2 antagonizes the vasoconstrictive action of angiotensin
II on afferent arterioles.7
EFFECT OF NSAIDS
The side-effects of NSAIDs are the consequence of
inhibition of prostaglandin synthesis. This permits
unopposed vasoconstrictive action of leukotrienes,

632 www.japi.org JAPI VOL. 52 AUGUST 2004

angiotensin II, vasopressin, endothelin and catecholamines.
In normal salt and water replete subjects this does not result
in reduction of GFR but in states of renal hypoperfusion it
can result in acute renal failure (ARF). Additionally NSAIDs
produce hyporeninaemia and hypoaldosteronism. This along
with the decreased distal tubular flow and sodium delivery
results in hyperkalaemia.3
Conditions predisposing to NSAID induced renal failure
include hypovolaemia, congestive cardiac failure, nephrotic
syndrome, cirrhosis with ascites, sodium depleted states like
chronic diuretic therapy and gastrointestinal losses, pre-
eclampsia, glomerulonephritis, urinary tract obstruction,
concomitant use of nephrotoxic drugs like cyclosporin A,
gentamicin or FK 506, advancing age and chronic renal
failure.9
NSAIDS AND ACUTE RENAL FAILURE
NSAIDs rank second to aminoglycosides as the most
common cause of nephrotoxic ARF. Besides producing a
reversible renal failure, NSAIDs are known to cause acute
interstitial nephritis with haematuria, proteinuria and flank
pain.17
Incidence : ARF associated with NSAIDS accounts for
15.5% of all cases of drug inducted renal failure.18 Most of
the literature is as case reports and case series. The few
studies that have looked at the incidence of ARF due to
NSAIDs have arrived at different conclusions.
Fox et al (1984)19 in a retrospective study studied the
incidence of rise in serum urea nitrogen in 2 population
groups. Group 1 was an in hospital population of 41,418
patients. All instances of drug attributed rises in serum urea
nitrogen levels were identified. Of 1,222 NSAID users, 14
(1.1%) had a rise in BUN compared to 505 (1.3%) of the 40,196
patients who had not received NSAIDs. Group 2 was a
population of over 55,000 patients seen in the out-patients
who had filled one or more prescriptions for NSAIDs. 1% of
phenylbutazone users (N = 35,364), 6% of the indomethacin
users (N = 22,100) and 22% of ibuprofen users (N = 8412) had
filled in more than 5 prescriptions per year (classed as
continuous users). None of these patients was hospitalised
for ARF.
In contrast, in a case control study (Evans et al 1995)
involving a population of 420,600 patients, of the 207 cases
of ARF due to various causes, seen over 2 years, recent
exposure to NSAIDS and previous exposure to aspirin were
independently associated with hospitalisation for ARF with
the odds ratio of 2.2 and 2.19 respectively. The authors
concluded that there is an approximate doubling of the risk of
hospitalisation for ARF with oral NSAIDs. Perez Gutthann et
al21 in a population based case control study (1996), found
that current NSAID users had an adjusted odds ratio for
ARF of 4.1 and that the risk of ARF was especially high
during the first month of NSAID use (odds ratio 8.5). The
users of high daily doses of NSAIDs had an even higher
odds ratio (9.8) for the development of ARF.
Griffin et al22 studied NSAID induced ARF in elderly
persons. They performed a nested case-control study using
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Tennessee Medicaid enrollees aged 65 between 1987-1991.
These patients had been hospitalized with community-
acquired ARF. Of the 1,799 patients with ARF (4.51
hospitalizations per 1,000 person-years), 18.1% were current
users of NSAIDs as compared with 11.3% of 9.899 randomly
selected population controls. They concluded that NSAID
use resulted in an estimated 25 excess hospitalizations
associated with renal failure per 10,000 years of use,
representing a relatively uncommon and avoidable cause of
ARF in elderly persons.
In another study23 of ARF in the elderly of 109 unselected
patients with ARF admitted to a nephrology unit during a 30
month period, 39 had drug-related acute renal failure.
(NSAIDs 24 patients, ACE inhibitors 8 cases). The mean age
of drug induced ARF patients was significantly greater than
the remaining ARF patients confirming the high susceptibility
of ageing kidneys to nephrotoxic damage caused by drugs
affecting glomerular autoregulation by microvascular
mechanisms.
Histopathology (HP) : ARF secondary to NSAIDs can be
the result of multiple mechanisms. Reversible renal
insufficiency or functional impairment of renal function is the
most common mechanism. Others are acute tubular necrosis
(ATN) and acute interstitial nephritis (AIN). Rare mechanisms
include acute papillary necrosis and renal vasculitis.2
Adams et al24 found ARF in 7 of 17 patients of renal failure
who presented to a rheumatology clinic over a 3 year period.
ATN was present in 4 while AIN accounted for the remaining.
All patients improved on discontinuation of the offending
NSAID. Brezin et al25 studied 3 cases of NSAID induced
ARF in patients with nephrotic syndrome. HP was suggestive
of AIN. Azotaemia occurred in the absence of hypertension,
rash, fever or eosinophilia. Postishil IuA 26 described
pathological findings on renal biopsies from two groups of
patients with NSAID induced kidney lesions. In the first group
(n=9), patients of different age groups, developed renal
disease after short term use of NSAID manifesting clinically
with acute renal failure along with allergic manifestations such
as skin rash and eosinophilia. Morphological features were
those of AIN without glomerular lesions. In the second group
(n=23), the disease developed in older patients with
compromised renal circulation after long term use of NSAIDs
presenting clinically as nephrotic syndrome and
morphologically as acute tubulointerstitial nephritis with
minimal change lipoid nephrosis. In a study by Warren et
al27, 5 out of 55 patients with adult onset minimal change
glomerulopathy had NSAID associated minimal change
nephropathy. Additionally three of these had interstitial
nephritis. Marasco 28 reported a case of ibuprofen associated
reversible ARF with hyperkalaemia, tubular necrosis and
proteinuria. Kidney biopsy revealed mesangial
hypercelluarlity without glomerular crescent formation,
tubulointerstitial nephritis with focal inflammatory infiltrates
of predominantly mononuclear cells and neutrophils as well
as focal tubular destruction. Direct immunofluorescence
examination showed diffuse mesangial IgM and C3 deposits
as well as vascular C3 deposition.
633
 Ravnaskov29 studied published case reports of NSAID
associated nephropathy. Of the 97 cases, acute nephritis (AN)
was present in 19, minimal change nephropathy (MC) in 38,
membranous glomerulonephritis (MGN) in 19, focal sclerosis
(FS) in 13, and other glomerulonephritis subgroups, in 8 cases.
Hypersensitivity reactions were seen in all groups. Proteinuria
was more severe in MC and FS than in MGN and was unrelated
to the amount of glomerular deposits. The mean NSAID
treatment duration was 1.7 months in AN, 8.2 months in MC
and 39 months in MGN. NSAID treatment time was directly
associated with the amount of glomerular deposits, fusion of
podocytes and proteinuria, and inversely associated with
hypersensitivity, interstitial damage and renal failure. He
concluded that NSAID nephropathy was caused by
hypersensitivity. The reaction was milder than seen with other
drug induced acute tubulointerstitial nephritis, probably
because NSAIDs inhibit the inflammatory reaction. Heavy
proteinuria is probably due to lymphokines produced as a
result of immunological response. If the allergic reaction is
strong, acute nephritis progresses rapidly to severe acute
renal failure but there is little proteinuria. Whereas, if the
reaction is less violent, immunocompetent cells may develop
to produce lymphokines and proteinuria. Immune complexes
may be formed eventually, secondary to the increased
glomerular permeability with little consequence for renal
function.
CLINICAL SYNDROMES AND OUTCOME
Reversible renal insufficiency (haemodynamic ARF) is
the most common renal complication of NSAIDs. It presents
with rising BUN, creatinine and serum potassium, decreasing
urine output and weight gain. It is usually completely
reversible within 24 hours of discontinuation of NSAID.
Continued therapy can result in acute renal failure which may
be due to ATN in some patients.8 Predisposing conditions
include congestive heart failure, cirrhosis, overt renal disease
like lupus nephritis or chronic renal failure, advanced age,
atherosclerotic cardiovascular disease, diabetes mellitus,
hypertension, and concurrent diuretic therapy2, though it
can occur even in the absence of any predisposing
conditions.30
Whelton et al31 conducted a prospective double blind,
randomized, placebo-controlled cross-over study to evaluate
the possible renal protective effect of misoprostol, on the
renal function of patients with mild, stable, chronic renal failure
who intercurrently ingested ibuprofen 800mg tid or
indomethacin 25 mg tid. The mean baseline GFR of patients
who participated in the study were 53 ml/min and 55 ml/min in
ibuprofen plus misoprostol and placebo group respectively.
The value for indomethacin group was 57 ml for both placebo
and misoprostol group. At this level of renal impairment, the
use of selected NSAIDs alone did not produce further
significant impairment of renal function and hence a renal
protective role if any for misoprostol could not be
demonstrated.
All groups of NSAIDs have been implicated (indomethacin
being the most commonly incriminated). Agents with short
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half lives (e.g. ibuprofen) reach steady state early and manifest
nephrotoxic effects sooner than NSAIDs with longer half
lives (e.g. piroxicam, sulindac). The deterioration in renal
function appears to be related to dose and duration of
exposure to NSAID. Rechallenge with even half the
therapeutic dose can induce ARF especially in patients with
mild, asymptomatic renal failure at baseline 32 . Even
substituting one NSAID for another in a patient at risk of, or
who has already demonstrated haemodynamic renal failure is
likely to result in recurrence of this complication. Concomitant
use of diuretic increases the risk of renal failure.2
AIN presents as ARF with or without nephrotic syndrome.
The average duration of therapy with NSAIDs is usually
several months. Although renal impairment appears to be
acute in onset, it does not necessarily present soon after
exposure to NSAIDs the patient may be on the drug for a
while before developing AIN. The incidence of systemic
symptoms like fever, rash and eosinophilia is much lower as
compared to acute allergic interstitial nephritis due to other
drugs like beta lactam antibiotics. The clinical presentation is
that of acute onset oedema, loss of vigour and sometimes
oliguria. Gross haematuria is rare. Urine is foamy and urine
analysis reveals proteinuria, microscopic haematuria and
microscopic pyuria. Unlike haemodynamic ARF where renal
impairment may be mild, serum creatinine varies from only
minimal elevation to 10 mg/dl at first presentation. Also, unlike
the former where risk factors have been identified it is
impossible to predict which patients are likely to develop
AIN.5
Initial reports attributed AIN to propionic acid derivatives
(labeled as fenprofen nephropathy)33 suggesting that one
was justified to use NSAIDs of different chemical classes
under close observation, if indications for NSAID use were
sufficiently strong.2 Patients develop recurrence of AIN after
inadvertent exposure not only to the same NSAID but also to
another NSAID of the same or different chemical class. All
classes of NSAIDs have now been implicated. 5
Discontinuation of the NSAID usually results in reversal of
AIN. The efficacy and necessity of steroid therapy is still
unclear. Some advocate that steroids should be instituted if
renal function does not return to normal after 2 3 weeks
withdrawal of the offending NSAID. Improvement in renal
function may take anywhere from one month to one year.
Haemodialysis may be more frequently required than in
haemodynamic ARF. Though usually reversible, as low as
25% reversibility has been reported.34
Renal papillary necrosis may present as acute or chronic
renal failure (CRF). 7 The presentation can be subtle or
misleading. It may be mistaken for the passage of a renal
stone or an idiopathic, transient, episode of renal colic
associated with gross haematuria. There is usually a history
of ingestion of excessive dose(s) of an NSAID during a period
of severe dehydration. It may be possible to identify one or
more sloughed renal papillae.
The pathophysiologic process is ischaemic necrosis.35
Severe dehydration results in compensatory systemic
vasoconstriction. In these situations renal papillary flow
JAPI VOL. 52 AUGUST 2004
maintained by local PG production is decreased by NSAID
ingestion. The renal papillary lesion is sharply demarcated.
The histology reveals coagulative necrosis consistent with
infarction. The necrosis is limited to the distal segment of the
involved pyramid. This may be attributed to the maximal
urinary concentrating ability displayed by this region of the
kidney. In case of ureteric obstruction due to the sloughed
papillae, forced diuresis usually results in prompt return of
renal function. The long term functional consequences are
limited and relate to inability to produce maximally
concentrated urine. This type of nephropathy has been
reported with fenoprofen, mefanamic acid, ibuprofen and
phenylbutazone.36-39
A recent study40 investigated the role of FR167653, a p38
mitogen-activated protein kinase (MAPK) in the inflammatory
processes of renal ischaemia/reperfusion injury in mice. A
large number of infiltrated cells and marked acute tubular
necrosis in outer medulla was observed after renal ischaemia
/reperfusion injury. FR167653 significantly decreased cell
infiltration into outer medulla, and the extent of ATN.
FR167653 markedly decreased the transcription of interleukin-
1 beta, tumour necrosis factor-alpha, monocyte
chemoattractant protein-1 and regulated upon activation and
normal T cell expression in diseased kidneys. FR167653
decreased the number of phosphorylated p38 MAPK-
positive cells. This suggests that FR167653 markedly
ameliorated renal ischaemia/reperfusion injury, possibly by
inhibiting cytokine/chemokine expression and consequent
phosphorylation of p38 MAPK in renal tissue.
Generalized vasculitis with glomerulonephritis
producing ARF has been rarely reported. Two of the 3
reported cases were attributed to piroxicam, one of whom
developed the same clinical picture upon rechallenge.41 The
lesion was reversible in these 2 cases on discontinuation of
the drug. The third case due to mefenamate died from
disseminated aspergillosis following steroid therapy.42
NSAID AND CHRONIC RENAL FAILURE
(CRF)
From the preceding discussion, it is evident that most
forms of NSAID induced ARF are reversible. However NSAID
related CRF is known. The underlying pathology is chronic
papillary necrosis or chronic interstitial nephritis.6 In a one
year prospective, collaborative study (1986) 14 of 62 patients
with analgesic or NSAID induced ARF developed permanent
renal damage.34 CRF was more frequent in patients who had
developed AIN when compared with those who had an
episode of ATN. It appears that renal function may not always
return to baseline values after an acute episode of interstitial
nephritis43-44 and interstitial fibrosis may then progress to
CRF if NSAID consumption is continued.24
Shwarz et al45 studied the outcome of AIN and the risk
factors for transition from acute to chronic interstitial nephritis
in a retrospective study of 1068 renal biopsies. Patients who
developed permanent renal insufficiency after acute interstitial
nephritis were compared with those who had reversible renal
insufficiency, with respect to the causative agent, the
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symptoms, and the clinical and histological findings. AIN
was found in 69 (6.5%) of all biopsies. In 59 (85%) of these it
was drug induced. Analgesics and NSAIDs were responsible
for AIN in 16 and 17 cases respectively. Renal insufficiency
was reversible in 69% and permanent in 31% (12% partially
reversible, irreversible in 19%). Over all drug induced
interstitial nephritis caused permanent renal insufficiency in
36%, the figure being 56% in NSAID induced cases. Subacute
symptoms and chronic analgesic or NSAID use were related
to a more chronic course of interstitial nephritis. Histologically
tubular atrophy, interstitial granuloma and pronounced
interstitial cell infiltration indicated chronicity.
PATHOPHYSIOLOGY
The pathophysiology of CRF and ESRD due to NSAIDs is
not entirely clear. Non immunologic and immunologic
mechanisms may be involved. Medullary ischaemia seems to
be the initiating event. NSAIDs, by inhibiting prostaglandin
synthesis reduce medullary blood flow.3 Pre-existing analgesic
nephropathy46 and acute pyelonephritis47 seem to favour the
development of NSAID induced nephrotoxicity, suggesting
that in this setting impaired medullary circulation may play a
critical role in inducing papillary necrosis and chronic renal
injury. Papillary necrosis may also result from reactive
intermediate metabolic products of the drug, deviation of
arachidonic acid metabolism pathway 48 or from the
accumulation of phospholipids in the renal papilla 49
Hypertension may act as an aggravating factor.50
Immunological reactions that develop during the acute
phase may continue to operate after the injury. Growth factors,
(like TGF-), and cytokines can induce both interstitial fibrosis
and hypertrophy of the cells of the interstitium51.
INCIDENCE OF CRF AND CLINICAL
ASSOCIATIONS
Although the earlier reports focused on acetaminophen,
phenacetin and analgesic mixtures as a cause of CRF, a number
of studies have studied the role of aspirin and non aspirin
NSAIDs in inducing chronic renal disease. It is difficult to
delineate between these compounds as causative agents for
CRF, as chronic renal disease occurs in patients with arthritis
and other pain syndromes in whom both analgesics and
NSAIDs are consumed by the patients at different times during
the illness.
Early reports questioned a cause and effect relationship
between NSAID use and chronic renal failure. Perneger et
al52 compared 716 cases of ESRD on dialysis as against 1259
controls and classified them as light, moderate and heavy
users of analgesics if they consumed 0-104 pills/year (0-2
pills/week), 105-365 pills/year (1 pill/day) or > 366 pills/year
(>1 pill/day)respectively. They found that heavy users of
acetaminophen had an increased risk of ESRD whereas
moderate use did not increase the risk of ESRD. The odds of
ESRD increased with cumulative intake of acetaminophen.
High life time intake of NSAIDs was associated with a 4 fold
increase in the odds for development of ESRD. Odds of ESRD
were low with moderate intake of aspirin or NSAIDs,
635
suggesting that low doses of aspirin and NSAIDS are safe.
Emkey et al53 studied 46 patients (mostly rheumatoid
arthritis) taking aspirin continuously for ten or more years.
All creatinine and BUN levels were found to be normal
suggesting that long term salicylate ingestion does not cause
renal damage. DAgati54 reviewed several human studies that
addressed the chronic nephrotoxicity of aspirin alone or
relative risk of end-stage renal disease in association with
aspirin use after correction for other analgesics. With the
exception of one case-control study demonstrating a low,
but statistically significant risk of end-stage renal disease in
association with aspirin use, all other case control studies
and several prospective studies were unable to identify a
significant risk of chronic renal failure in patients using aspirin.
Murray et al55 studied 527 cases of ESRD from 18 dialysis
units and compared these with 1047 controls randomly
selected from hospital admission lists. 12.7% of cases and
12% of controls had at least one period of almost daily use of
aspirin, acetaminophen or phenacetin lasting 30 days or
longer. They found no significantly increased risk of CRF in
patients who had consumed one or more analgesics for more
than 3 years when compared with non-users or in those who
had consumed > 3kg of analgesics (aspirin, phenacetin,
acetaminophen or their combinations). They concluded that
regular analgesic consumption is not responsible for the
majority of patients with ESRD. Combination analgesic use
accounted for all or part of the regular analgesic use of 6.8%
of the 527 cases and 5.7% of the 1047 controls for periods
longer than three year. However, they added that there may
be a small but significant risk of ESRD development after the
use of large doses. Regular analgesic use may also increase
the risk of milder forms of renal failure and may exacerbate
existing renal impairment.
Rexrode et al56 conducted a cohort study of analgesic use
data from the Physicians Health study (1982-1995). A total
of 11,032 initially healthy men who provided blood samples
and reported analgesic were grouped as never < 12pills, 12-
1499 pills; 1500-2499 pills, and 2500 pills. 460 men had
elevated creatinine levels (4.2%); 1258 had reduced creatinine
clearance (11.4%). Mean creatinine levels and creatinine
clearances were similar among men who did not use analgesics
and those who did, even at total intakes of 2500 or more pills.
But a number of studies have shown that long term use of
NSAIDs may indeed lead to CRF. Pommer et al57 studied 921
patients on dialysis. They found an increased relative risk of
ESRD after regular analgesic mixture consumption. Monthly
analgesic intake of less than 60 units (i.e. tablets, liquids,
suppositories) over at least 5 years resulted in a RR of 2.03,
while an intake of more than 60 units led to an increase of RR
to 4.83. The risk increased with both the total dose consumed
and the exposure time. No increase in relative risk was found
with the use of single component analgesics.
Sandler et al58 compared 709 patients with chronic renal
dysfunction ( serum creatinine >1.5mg/dl) or renal failure with
717 controls. They observed a two fold increase in the risk of
CRF in previous daily users of NSAIDs. The risk factors were
age over 65 yrs, presence of heart disease and compromised
636 www.japi.org
renal function, diuretics, previous MI, and regular alcohol
consumption. In an earlier communication,59 Sandler et al
had reported a higher risk of renal disease in daily users of
phenacetin (odds ratio 5.11) and acetaminophen (odds ratio
3.2), but none in daily users of aspirin.
In a recent study by Fored et al (2001),60 regular use of
either aspirin or acetaminophen was associated of a 2.5 told
increase in the risk of CRD. The RR rose with increasing
cumulative lifetime doses, more consistently with
acetaminophen than with aspirin. The types of renal failure
most strongly associated with regular use of acetaminophen
in addition to aspirin were renal failure linked to diabetes
(odds ratio 2.8), systemic disease or vasculitis (odds ratio
5.1), but estimates of relative risks of approximately 2.0 were
found for all types of chronic renal failure.
Segasothy et al61 studied prospectively the risk of renal
papillary necrosis and renal dysfunction due to the chronic
use of NSAIDs in 259 heavy analgesic users in a general
hospital over an 11 year period. 69 new cases of analgesic
nephropathy with renal papillary necrosis were identified. 29
had consumed excessive quantities of NSAIDs alone (17
single NSAID), while 9 had consumed NSAIDs in combination
with paracetamol, aspirin, caffeine and/or herbal medications.
Renal impairment was noted in 26 of these 38 cases.
In a subsequent study,62 by Segasothy et al 94 patients
with chronic arthritis who had consumed more than 1000
capsules and /or tablets of NSAIDs were subjected to renal
profiles, intravenous urography, ultrasonography and CT
scan to look for renal papillary necrosis. 10 of the 82 patients
who completed the study showed radiological evidence of
renal papillary necrosis. Renal impairment was present in 20
patients. The patients had consumed 1000-26,300 capsules
and/or tablets over periods ranging from 1-30 years. They
concluded that patients with arthritis who consume excessive
amounts of NSAIDs are at risk of developing renal papillary
necrosis and chronic renal insufficiency.
Kantachuvesiri et al63 studied heavy analgesic abuse in
84 patients with chronic tubulointerstitial nephritis with 2
control groups; i) 192 selected from hospitalized patients
without renal disease and ii) 166 relatives or friends visiting
the hospitals. On multiple logistic regression analysis,
patients whose estimated lifetime use of acetaminophen was
1000g or more had an increased risk of developing chronic
nephropathy as compared to non-users (or 5.9 and 5.8 as
compared to hospital controls and visitor controls
respectively).
SUBCLINICAL RENAL DYSFUNCTION
Although most of the literature on renal dysfunction due
to NSAIDs pertains to clinically evident acute or chronic
renal failure, there have been a few reports describing
subclinical renal dysfunction in the form of functional
abnormalities. The mechanisms postulated include
prostaglandin mediated reversible changes in renal function
and subclinical interstitial nephritis. These however, have
not been proved by biopsy studies.
Various biochemical parameters have been used to evaluate
JAPI VOL. 52 AUGUST 2004
subclinical dysfunction. Unsworth et al64 studied 11 patients
admitted to the rheumatology ward for non renal causes.
They had received NSAIDs for at least 6 months. NSAIDs
were discontinued in all. S. urea and creatinine were measured
prior to stopping NSAIDs and again reassessed before
discharge or reintroduction of NSAIDs. Mean interval
between admission and either discharge or reintroduction of
NSAIDs was 19.4 days. There was a significant fall in the
initial creatinine values on withdrawal of NSAIDs and a rise
in creatinine clearance when not receiving NSAIDs,
suggesting asymptomatic (reversible) renal dysfunction due
to NSAIDs.
Richards et al65 studied 24 hour urine protein, creatinine
clearance and N-acetyl glucose aminidase in 167 patients
with RA on NSAIDs selected randomly over a 6 week period.
They found no co-relation between creatinine clearance and
disease duration and a weak co-relation between measured
and calculated creatinine clearance. They concluded that long
term use of NSAIDs was associated with few renal problems.
Minor reduction in GFR was common and not related to
disease duration or length of NSAID therapy. The mean
duration of disease was 12 years suggesting that the rate of
decline in renal function if any was not unduly rapid.
Calvo Alen et al66 studied renal function in 104 patients
who had been on NSAIDs for at least 2 years. Urine analysis,
serum electrolytes, serum and urinary creatinine and serum
and urine osmolality were assessed. Creatinine clearance and
osmolar clearance were calculated. They observed reduced
concentration ability as judged by a lower specific gravity,
reduced urine osmolality, a reduced osmolar clearance and
increased free water clearance. These observations support
the concept that chronic NSAIDs treatment causes renal
damage that is consistent with subclinical interstitial
nephropathy.
Reversible mild rise in creatinine has been described.
Koseki et al67 studied 235 early RA patients, on NSAIDs. A
rise in creatinine was found in 14 patients (6%). This was
attributed to inhibition of prostaglandin synthesis due to
NSAIDs in 3 cases. S. creatinine improved on stopping the
drug in all the 3 cases. The rise in creatinine in the other cases
was related to D-penicillamine, ACE inhibitors, diuretics,
dehydration and renal hypoplasia.
Caspi et al68 studied the effect of mini-dose aspirin (75mg/
day) on renal function and uric acid handling in 49 elderly
patients (age 61-94). They found that creatinine and uric acid
clearance rates paralleled each other during aspirin treatment.
However, 1 week after aspirin discontinuation, creatinine
clearance remained decreased while uric acid clearance
returned to baseline suggesting that some amount of renal
dysfunction persists even though creatinine returns to
normal. Similar findings were noted by us.69 Of the 99 patients
on long-term NSAID (> 2 years) studied, 27 showed a rise in
creatinine. When mean creatinine levels at baseline were
compared with mean creatinine levels on recovery (after
NSAID discontinuation), a statistically significant difference
in creatinine levels was noted, the level of post recovery
serum creatinine being higher.
JAPI VOL. 52 AUGUST 2004 www.japi.org
DIFFERENTIAL RENAL SAFETY OF NSAIDS
All groups of NSAIDs are nephrotoxic. The role of half-
lives as a basis for nephrotoxicity has been studied.
Adams et al24 proposed that NSAIDs with longer half-
lives are more likely to cause nephrotoxicity because of
sustained prostaglandin inhibition leading to a sustained
reduction in renal blood flow, whereas with short acting
NSAIDs the kidney may be better able to recover between
doses. Whelton et al (1990)32 however found that agents with
short half-lives, such as ibuprofen, reach steady state sooner
than those with longer half-lives and hence may produce
renal decompensation in a matter of days. In a cross sectional
study involving 802 patients undergoing joint replacement
surgery for osteoarthritis, Sturmer et al (2001)70, looked at
half-life of NSAIDs as a predictor of renal dysfunction. NSAID
use per se was only marginally associated with impaired renal
function (odds ratio 1.4). This was almost exclusively
associated with NSAIDs with a of 4 hours or more.
The search for a kidney sparing NSAID resulted in the
development of prodrugs drugs like sulindac and
nabumetone. Sulindac, requires hepatic conversion from
sulindac sulphoxide to the active sulphide moiety.71 It is less
likely to inhibit renal prostaglandin synthesis since the kidney
is able to reconvert the active sulphide back to the inactive
sulphoxide molecule. However, Whelton et al, found that
sulindac is not completely renal sparing32. Mistry et al72
looked at the effect of sulindac on renal function and
prostaglandin synthesis in patients with moderate chronic
renal insufficiency. Short term use of sulindac in therapeutic
doses did not appear to influence the excretion of
prostaglandins and produced only a minor reversible change
in renal function. It seems, used cautiously, sulindac may
have an advantage over other NSAIDs in patients with
moderate chronic renal insufficiency.
Nabumetone requires hepatic conversion to the active
metabolite73. It has been shown to be associated with an
insignificant change in the urinary excretion of 6-keto-PGF1
and PGE2 and little effect on serum creatinine and creatinine
clearance.74
Cook et al75 compared renal effects of one months therapy
with ibuprofen, sulindac and nabumetone. Though overall
no statistically significant differences were found amongst
these NSAIDs, 4 patients on ibuprofen and one patient on
sulindac developed clinically significant decrease in renal
function. They concluded that there are differences in the
effects on renal function amongst NSAIDs. It was related to
changes in the haemodynamic control of glomerular filtration.
Namubetone has been reported to cause tubular damage with
minimal glomerular changes, presenting as progressive
oedema.76
Improved renal safety was envisaged with the development
of COX-2 specific inhibitors like celecoxib and rofecoxib.
However, COX-2 is constitutively expressed in renal tissues
of all species and may be involved in prostaglandin-dependent
renal homeostatic processes and selective inhibition of COX-
2 might be expected to produce effects on renal function
637
similar to nonselective NSAIDs.77
Whelton et al78 carried out a post hoc analysis of renal
safety of celecoxib using data from 50 clinical studies
involving more than 13,000 subjects. Over 5000 subjects had
received celecoxib for 2 years. The incidence of renal adverse
events after celecoxib was greater than that after placebo but
similar to that of other NSAIDs, the most common events
being peripheral oedema (2.1%), hypertension (0.8%)
including exacerbation of pre-existing hypertension.
Ahmad et al79 carried out Medline search to identify
published cases of ARF associated with celecoxib and
rofecoxib using the US FDA adverse event reporting system.
122 and 142 domestic cases of celecoxib and rofecoxib
associated renal failure respectively were identified. 19 cases
were of acute renal impairment. An additional 50 reports of
renal failure with these drugs were identified from drug
regulatory authorities in UK, Canada and Australia. The
authors concluded that the renal effects of these drugs were
similar to conventional NSAIDs. They did not recommend
use of these drugs in patients with advanced renal disease.
Similar views were echoed in the recently published review
by Brater.80 Schwartz et al81 compared the renal effects of
celecoxib and rofecoxib with naproxen and placebo in healthy
elderly subjects on a sodium-replete diet and found no
differences between the two groups as measured by urinary
sodium excretion, systolic and diastolic blood pressure,
creatinine clearance or weight gain.
ARF with high doses of celecoxib has been reported.82
Alkhuja et al83 reported a case of non-oliguric renal failure in
a case of rheumatoid arthritis on celecoxib within 14 days of
starting therapy. Although the kidney function had improved
within 30 days after presentation, it had not returned to normal.
Interstitial nephritis has been reported with celecoxib.84
Alper et al85 reported a case of interstitial nephritis associated
with nephrotic syndrome in a diabetic patient who had been
on celecoxib for one year for degenerative joint disease. The
patient had normal creatinine level with no microalbuminuria
7 months prior to presentation. Henao et al86 reported a biopsy
proven case of interstitial nephritis in an elderly diabetic
patient on celecoxib for more than a year. The patient
presented with subnephrotic proteinuria and ARF that
required dialysis. Renal function recovered after 2 weeks of
cessation of celecoxib.
Zhao et al87 used WHO/ Uppsala monitoring center safety
database to compare the renal related adverse reactions with
rofecoxib and celecoxib. The adverse renal impact of rofecoxib
was found to be significantly greater than that of celecoxib or
the traditional NSAIDs with a higher incidence of water
retention, abnormal renal function, renal failure, cardiac failure
and hypertension. Whelton et al88, have reported a lesser
incidence of oedema and destabilization of blood pressure
control with celecoxib as compared to rofecoxib in randomized
controlled trials in elderly hypertensive osteoarthritis patients.
Rofecoxib has been reported to be associated with acute
tubulo-interstitial nephritis.89 Morales et al90 reported a case
of acute renal failure in an elderly patient after receiving a
50mg dose of rofecoxib.
638 www.japi.org
It is clear that NSAIDs are associated with all forms of
renal failure. While acute syndromes generally carry a good
prognosis, the same is not true of CRF. Subclinical CRF can
be silent forerunner of CRF.
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