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Diclofenac nephrotoxicity is widely documented and usually affects the geriatric population with renal functions already on the decline26.
Toxicokinetics
Toxicokinetics
Figure 2. shows the effect NSAIDS (diclofenac) have on the glomerulus of the kidney and therefore reduce GFR levels (B) compared to normal (A)27.
More serious nephrotoxicity is common with patients who also take ACE inhibitors and ARBS as they further reduce GFR. This is because they inhibit vasoconstriction of the efferent arteriole27.
Arachidonic acid can no longer synthesise prostaglandins due to diclofenac inhibiting COX-1 and COX-2 enzymes (as diclofenac is non-selective) responsible for this pathway27.
As there are less prostaglandins (PGE2 and PG12), less vasodilation occurs in the afferent arteriole of the glomerulus and therefore reduces the levels of blood perfusing the glomerulus
Insufficient blood flow can lead to ischaemic damage through arterioles and into the glomerulus reducing glomerular filtration rate (GFR)28.
Haemodynamic acute kidney injury (due to reduced blood flow) is therefore reversed when blood flow levels increase back to normal after treatment cessation.
When excretion is impaired, diclofenac metabolism can accumulate and therefore cause a positive feedback loop (a vicious cycle of toxicity) of nephrotoxicity further damaging the kidneys.
Symptoms
Symptoms
Within 24 hours of taking diclofenac increased creatinine, blood urea, proteinuria and oxidative stress levels can be observed29.
The symptoms of nephrotoxicity and resulting acute kidney injury (AKI) are usually a decreased urine output with ankle and leg swelling and more generalised symptoms such as fatigue nausea and shortness of breath.
Acute interstitial nephritis (AIN) may also occur after a week as hypersensitivity immunological reactions do happen with diclofenac . The symptoms are often common to other allergic reactions and include pruritic erythematous rash, fever and arthralgia (joint pain)30.
Both of these conditions can lead to chronic kidney disease and are diagnosed by your doctor through blood tests to measure abnormal levels of:
Prevention and protection
Prevention and protection
Diclofenac should not be prescribed in cases of severe renal impairment to avoid further damage, while caution is exercised in prescription of moderate renal impairment32
However renal impairment due solely to diclofenac is reversible once medication has stopped been taking and usually repairs after 1 month26.
Pairing of one or more NSAIDs together increase the risks of diclofenac adverse effects, and should be carefully considered by your doctor into the dose and duration before prescription27.
Use with caution in the Elderly as the physiological reserve e.g. maintaining homeostasis decreases with increased chance of comorbidities
Table 1. summarises the effect different diclofenac sodium complexes have on the kidneys33.
Research into reducing the nephrotoxicity of diclofenac has been conducted by combining diclofenac with sodium complexes.
histopathology slides can allow the comparison of the effect on the kidneys down to the cellular level.
It can be observed from this study that Mg2+ complexes have clinical potential as they have the least damaging effect on the kidneys.
Treatments
Treatments
Although there are no specific treatments for diclofenac induced nephrotoxicity, glucocorticoids may be prescribed by your doctor and you will be asked to stop taking the medication. When given promptly, renal function should return to normal levels34.
Studies show thymoquinone has the potential to reduce inflammation in the kidneys associated with high doses of diclofenac however the studies so far have only been done in rats. Despite this it is a promising start in finding a treatment25.
This is also the case with vinpocetine (anti-dementia drug) as studies have shown its promise in reducing diclofenac induced AKI29.
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