CLINICAL

PHARMACOLOGY

JIACM 2003; 4(1): 18-20

Renal Effects of Selective Cyclo-oxygenase2 (COX-2) Inhibitors

J. S. Sandhu*

Abstract
Compared to the conventional non-steroidal anti-inflammatory drugs, selective cyclo-oxygenase (COX-2) inhibitors are
gastrointestinal friendly. The renal effects of COX-2 inhibitors are similar to conventional non-steroidal anti-inflammatory drugs
(NSAIDs), i.e., sodium, potassium, and water retention; decrease in renal function, and mild-to-moderate elevation of blood pressure.
Compared to these above-mentioned renal side effects of COX-2 inhibitors in normal kidney, recent experimental data has shown
increased renal COX-2 expression in remnant kidney, renovascular hypertension, and diabetes mellitus, and, COX-2 has been
implicated in the progression of renal failure. Thus, COX-2 inhibitors may be renoprotective in some renal diseases.

Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are
mediated by cyclo-oxygenases (COXs) resulting in
decrease production of prostanoids. This mechanism is
believed to account for both therapeutic as well as adverse
effects of NSAIDs. Two forms of COXs have been identified
COX-1 and COX-2 (Figure 1). While COX-1 is expressed in
most tissues, COX-2 is present with low or undetectable
levels in most tissues1. The antagonism of inflammation
and pain by NSAIDs is believed to result from inhibition
of COX-2, while the antagonism of gastric mucosal defense
and platelet aggregation are the results of COX-1
inhibition2. Clinical doses of NSAIDs non-selectively inhibit
COX-1 and COX-2. Thus, therapeutic use of these rather

useful drugs is limited by significant clinical toxicity,

including gastrointestinal (GI) ulceration, perforation,
obstruction, and bleeding. Consequently, selective
inhibition of COX-2 was proposed as a novel antiinflammatory and analgesic with efficacy similar to
conventional NSAIDs, but with a substantial reduction of
GI side effects. Drugs that selectively inhibit COX-2 are now
available. These include; celecoxib, valdecoxib, and
rofecoxib3, 4.
Now, it is known that the biological role of COX-2 extends
beyond inflammation and pain. Early female reproductive
function is dependent upon COX-2. Numerous reports
suggest that certain forms of pre-cancerous lesions and
cancer, including renal and bladder cancer, over-express
COX-25.
Renal physiology is partially COX dependent and
prostaglandins are active in regulating vascular tone and
salt and water homoeostasis by modulating glomerular
haemodynamics and regulating distal nephron function.
As an inducible enzyme, COX-2 is expressed at the site of
renal inflammation and consequently COX-2 derived
protaglandins have a substantial role in the pathogenesis
of glomerulonephritis and interstitial nephritis. It is
considered that COX-2 inhibitors may be indicated in
these diseases6, 7.

COX-2 and renal physiology

Fig. 1: COX-1 and COX-2 in physiological and pathological states.

COX-2 is expressed in normal kidneys. Evidence suggests

that COX-2 expression in the human macula densa cells

* Reader in Nephrology, Dayanand Medical College and Hospital, Ludhiana -141 001 (Punjab).

increases with increasing age, being absent in the first four

decades of life. This may contribute to the increased
susceptibility to renal effects of selective COX-2 inhibitors
in elderly patients. COX-2 has a role in physiological
regulation in normal kidney. Several groups observed that
stimulation of renin release in response to low sodium
diet can be blocked by selective COX-2 inhibitors but not
by selective COX-1 inhibitors, though this is controversial.
The role of COX-2 in renovascular hypertension remains
controversial. In the medulla, COX-2 promotes diuresis
and natriuresis8, 9.

the development of proteinuria and renal structural

damage in remnant kidney model as well as in diabetic
rats. Considering the link between COX-2 and renin release,
there is a suggestion that in high renin states COX-2
inhibitors may act as anti-hypertensive agents through
the inhibition of renin release, but this has been
challenged recently by other workers15,16.

Conclusion and future perspectives

The development and wide-spread used of COX-2

inhibitors has raised numerous questions regarding
their renal effects.

To date, there is no apparent clinical difference between

traditional NSAIDs and COX-2 inhibitors in the risk for nonsteroidal induced renal syndromes. The renal adverse
effects of conventional NSAIDs include a wide spectrum
of clinical disorders like :

The results of experimental and clinical studies

indicate that COX-2 rather than COX-1 inhibition
accounts for most known renal effects of NSAIDs.

Existing renal data comparing the new COX-2

inhibitors and conventional NSAIDs suggest a similar
adverse event profile.

Various degrees of decreased renal function caused

by decrease blood flow or interstitial nephritis.

Decreased water, sodium, and potassium excretion.

Less frequently, nephrotic syndrome (Minimal change

disease); rarely, membranous nephropathy, or focal
segmental sclerosis.

Both COX-2 inhibitors as well as conventional NSAIDs

cause decreased urinary sodium and water excretion
that may result in increased blood pressure or
destabilisation of blood pressure control in patients
treated with anti-hypertensive agents.

Similar to conventional NSAIDs, COX-2 inhibitors have

a negative influence on renal haemodynamics,
particularly in predisposed subjects.

Risk factors for reduction in GFR, and, in extreme cases,

acute renal failure, appears to be same as with
conventional NSAIDs.

Till date there are no reports of interstitial nephritis

or papillary necrosis with new generation COX-2
inhibitors.

Unlike conventional NSAIDs, interactions of COX-2

inhibitors with individual classes of anti-hypertensive
agents are largely unknown.

Renal effects of selective COX-2 inhibitors

Tendency to attenuate or occasionally abolish the

effects of most anti-hypertensive drugs.

The high risk groups of NSAIDs induced renal toxicity

include elderly patients, congestive heart failure,
dehydration, concomitant diuretic use, impaired renal
function, diabetes mellitus, and cirrhosis of liver.
A number of physiological roles of COX-2 in the kidney
raises the possibility that selective COX-2 inhibition could
result in adverse effects. Several cases of reversible acute
renal failure associated with treatment with both
celecoxib and rofecoxib have been described recently in
patients with underlying diabetes mellitus, chronic renal
insufficiency, heart failure, and multi-system disease10-14.

COX-2 in renal pathophysiological states

Experimental data shows that COX-2 is involved in the
pathophysiological state of a variety of renal disorders.
Long term administration of COX-2 inhibitors attenuated

Journal, Indian Academy of Clinical Medicine

Thus, when prescribing selective COX-2 inhibitors, the

same precaution should be applied as for the use of
conventional NSAIDs, particularly in volume depleted,
elderly patients, and those with chronic renal insufficiency.
In contrast to normal kidney which could constitute a
target for the adverse action of COX-2 inhibitors, recent
experimental data suggest that COX-2 inhibitors may
confer renoprotective effect in certain renal diseases.

Vol. 4, No. 1

January-March 2003

19

Patients with Barters syndrome have increased renal

expression of COX-2 and renal hyperproduction of
prostaglandins. COX-2 inhibitors are likely to attenuate salt
wasting and metabolic acidosis.

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4.

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Journal, Indian Academy of Clinical Medicine

Vol. 4, No. 1

January-March 2003