Nephrotoxic effect of NSAIDs

1. Nephrotoxic effect of NSAIDs
Department of Nephrology
Urology and Nephrology Center
Dr. Mohamed Mohsen Elshayeb

2. Content overview
Classification of NSAIDs.
Pathophysiogy of NSAIDs related nephropathy.
Renal Syndromes associated with NSAIDs use.
Selective Cox 2 nephrotoxicity.
The least nephrotoxic NSAIDs.
Take home message.

3. Classification
Nimesulide, Meloxicam, Nabumetone
ExampleCategory
AspirinSalisyltes
Ibuprofen, naproxen, ketoprofen, flurbiprofenPropionic acid derivative
Mephanamic acidAnthanilc acid derivative
Diclofenac, aceclofenacAryl-acetic acid derivative
Piroxicam, tenoxicamOxicam
KetorolacPyrolo-pyrolle derivative
IndomethacinIndole derivative
Phenylbutazone, oxyphenbutazonePyrozolone derivative

4. Classification
< 6 hr > 6 hr

5. Content overview
Classification of NSAIDs.
Pathophysiogy of NSAIDs related nephropathy.
Renal Syndromes associated with NSAIDs use.
Selective Cox 2 nephrotoxicity.
The least nephrotoxic NSAIDs.
Take home message.

6. Pathophysiology
Lucas GNC1, Leitão ACC .Pathophysiological aspects of nephropathy caused
by non-steroidal anti-inflammatory drugs. 2018 Sep 21

7. Pathophysiology
Lucas GNC1, Leitão ACC .Pathophysiological aspects of nephropathy caused
by non-steroidal anti-inflammatory drugs. 2018 Sep 21

8. Content overview
Classification of NSAIDs.
Pathophysiogy of NSAIDs related nephropathy.
Renal Syndromes associated with NSAIDs use.
Selective Cox 2 nephrotoxicity.
The least nephrotoxic NSAIDs.
Take home message.

9. Renal syndromes associated with NSAIDs

10. NSAIDs and AKI
• NSAIDs can cause two different forms of AKI:
Hemodynamically
mediated
(pre-renal injury and / or
acute tubular necrosis)
Immune mediated
(acute interstitial
nephritis)
• Dose/duration-dependent and usually
reversible.
• 3 groups of patients who are at risk to
develop AKI by this mechanism (elderly
patients, sever liver decomnsated and
patients with congestive heart failure)
• Not dose-dependent and accounts for
about 15 - 20% of all patients with AKI.
• More often associated with phenoprofen,
naproxen and ibuprofen.frequently
develop a full nephrotic syndrome in
addition to AIN.
• Delayed hypersensitivity reaction after
NSAID exposure of about a week.

11. Nephrotoxic Combination
“The triple whammy effect”
30% risk of AKI
Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor
blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control
study
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.e8525 (Published 08 January 2013)

12. NSAIDs and CKD
NSAID use can increase the risk of accelerated
CKD progression through both immunological
and non-immunological mechanisms.
• Recurrent episodes of NSAID induced AKI may
lead to CKD
• chronic exposure to NSAIDs may worsen
unrecognized AIN that can evolve into CIN
with associated fibrosis or chronic papillary
necrosis.

13. NSAIDs and CKD
Oxicams
(Piroxicam,
Mloxicam)
This is due to long half-life of oxicams, for
piroxicam (50 hours) and meloxicam (20 hours) in
particular.
2 folds
Increased risk of
developing CKD
ketorolac is contraindicated in moderate
to severe renal impairment (serum
creatinine > 4 mg/dl) and in patients at
risk of renal failure due to volume
depletion or dehydration.
2.5 folds
increase
For developing
CKD
ketorolac

14. NSAIDs & Electrolyte disorders
• Hyponatremia:
 NSAIDs diminish the normal inhibitory effect of
prostaglandin on the activity of ADH and can therefore
reduce free water execration.
 In conditions associated with high non suppressible levels of
ADH (SIADH) or effective volume depletion (as in patients
with severe HF), NSAID-induced water retention can worsen
hyponatremia. Oates et al.,1988
 NSAIDs may also increase the susceptibility of older adults to
thiazide induced hyponatremia.

15. NSAIDs & Electrolyte disorders
Healthy individuals may
have a weight gain of as
much as 0.5 to I kg
NSAIDs may reduce
response to diuretics by
about 20% especially in
chronic sodium retainers,
such as those with
congestive heart failure.
NSAIDs with little or no effect
on COX-2, such as aspirin,
rarely cause obvious sodium
retention and hypertension.
Edema (Na and water retention):

16. NSAIDs & Electrolyte disorders
Potential
Factors contributing to
Hyperkalemia
with NSAIDs
↓Renin &
aldosterone
secretions
↓Distal
tubular flow
rate
↓Distal
tubular Na
delivery
Direct effect
on distal
tubular K
secretions
Combination with
ACE inhibitors or
ARB or with
radiocontrast
media exposure
Indomethacin

17. NSAIDs & Nephrotic Syndrome
• It has been suggested that a decrease in the synthesis
of prostaglandins induced by NSAIDs could result in
an increased conversion of arachidonic acid to
leukotrienes, which could activate T-helper cells and
induce a diffuse podocyte damage. However, no
studies confirmed this hypothesis.

18. NSAIDs & Nephrotic Syndrome
 Minimal change disease and membranous nephropathy are the
most common finding in whom kidney biopsy was performed.
 In most patients, NSAIDs-related minimal change disease
resolves after drug discontinuation, which is accompanied in
some patients by a short course of corticosteroids.
 The use of selective COX-2 inhibitors was not associated with a
higher risk of nephrotic syndrome.

19. NSAIDs & Analgesic nephropathy
• AN is characterized by renal papillary necrosis and CIN.
• It is caused by prolonged and excessive use of
analgesics that contain Aspirin, paracetamol and other
NSAIDs.
• Aspirin potentiate the toxicity of phenacetin &
paracetamol when combined together.
• Many studies have shown that chronic especially daily
pracetamol use ( > 1 pill / day) has dose dependent,
long term nephrotoxicity.

20. Content overview
Classification of NSAIDs.
Pathophysiogy of NSAIDs related nephropathy.
Renal Syndromes associated with NSAIDs use.
Selective Cox 2 nephrotoxicity.
The least nephrotoxic NSAIDs.
Take home message.

21. Are selective COX-2 inhibitors nephrotoxic?

22. Content overview
Classification of NSAIDs.
Pathophysiogy of NSAIDs related nephropathy.
Renal Syndromes associated with NSAIDs use.
Selective Cox 2 nephrotoxicity.
The least nephrotoxic NSAIDs.
Take home message.

23. What is the least nephrotoxic
NSAID?
Brufen
low dose over the
counter ibuprofen
appears to be
safe in most
healthy subjects
(Mann et al.,
1993)
Ibuprofen Rudac
is considered to be
safe (Patrono C et
al., 1987). Since its
hepatic active
metabolite sulindac
sulfoxide had
shown the least
effect on the renal
cyclooxygenase
system as it is
deactivated by the
kidney.
Sulindac
Nabuxan
has little effect on
serum creatinine
and creatinine
clearance with
insignificant change
in the urinary PGF1
& PGE2.
Nabumetone
J Rheumatol. 1997 Jun;24(6):1137-44.
Comparative effects of nabumetone, sulindac, and ibuprofen on renal
function.

24. Pain Management in Renal patients
Whenever NSAIDs use must be considered due to the lack of effective
alternatives, short-acting are preferred over long-acting agents to avoid
prolonged NSAID-induced intra-glomerular hemodynamic
compromise.
Mild pain
Acetaminophen
+/- adjuvant
Moderate pain
Hydrocodone/o
xycodone +/-
adjuvant
Severe pain
Nonopioids ±
adjuvants ± moderate
to strong opioids
(fentanyl, morphine or
low dose treadol)
2017 update on pain management in patients with chronic kidney
disease

25. Content overview
Classification of NSAIDs.
Pathophysiogy of NSAIDs related nephropathy.
Renal Syndromes associated with NSAIDs use.
Selective Cox 2 nephrotoxicity.
The least nephrotoxic NSAIDs.
Take home message.

26. Take home message
 NSAIDs should be prescribed for the shortest duration, the
lowest effective dose.
 Careful and precise monitoring of renal function should be
done for NSAIDs users.
 These drugs should be used with cautious in high risk patients
as elderly.
 Selective COX 2 inhibitors are not safe.
 Paracetamol is not totally safe specially in chronic use or if
combined with other NSAIDs.

27. THANK YOU