Non-steroidal anti-inflammatory drugs (NSAIDs) are used in paediatrics as antipyretics, anti-inflammatories and analgesics. They are products with high bioavailability, are metabolized in the liver and some (naproxen, ibuprofen, ketoprofen) partially in the kidneys as well. Their mechanism of action is well known: they inhibit the synthesis of prostanoids and make the enzyme cyclooxygenase (COX) from arachidonic acid.1,2 PGG2 and PGH2 are converted from tissue-specific isomerases into the five main classes of prostanoids, which exert their modulatory action on inflammation by binding to specific receptors.
All of the main prostanoids are synthesized in the kidneys: PGE2 and PGI2 in particular, are important in functional regulation. PGI2 is a powerful vasodilator whose synthesis by COX-2 increases under stress and which regulates, together with TXA2, renal blood flow. PGE2 is a prostanoids well represented in the kidneys, and is also a vasodilator, regulating the excretion of salt and water and the production of renin. In situations of potential risk of kidney damage (for example, ischemic) the synthesis of PGE2 can be increased by 10 times.
NSAIDs, prostaglandins and kidneys
Whether the effect of NSAIDs is therapeutic or adverse depends on their ability (which differs from compound to compound) to inhibit COX-1 and COX-2.3 1-5% of subjects using NSAIDs may have adverse effects at the renal level (acute or chronic renal failure, papillary necrosis, acute interstitial nephropathy, hyperkalaemia, retention of sodium and water).1-3 In particular, patients with pre-existing chronic kidney disease have a higher risk of progression of renal damage.4 Nimesulide has a prevalent anti COX-2 action, sodium salicylate acts to a similar extent on COX-1 and COX-2, whilst ibuprofen, naproxen, aspirin, indomethacin, ketoprofen, flurbiprofen and ketorolac are more active in the inhibition of COX-1.
The toxic effects on the kidney result from suppression of the protective effect that prostaglandins have on renal circulation in cases where the circulating volume is reduced. In this case, the vasoconstriction effect of catecholamines, whose purpose is to preserve the circulatory pressure, is antagonized in the kidney by local production of prostaglandins, which exert a vasodilation effect on the pre-glomerular arterioles.5 As a combined effect of insufficient circulating volume and the action of NSAIDs, ischemia and renal tubular necrosis can be induced, with a reduced glomerular filtration rate and natriuresis. From this perspective, it is not possible to determine a scale of renal toxicity for different NSAIDs, since there is no adequate comparative data.
NSAIDs and renal toxicity
The incidence of nephrotoxicity caused by NSAIDs in children is unknown. The safety profile for these drugs is probably good in most of the paediatrics population treated. However, in specific clinical conditions – dehydration, haemorrhage, liver or heart failure, hypoalbuminaemia, pre-existing renal diseases, prolonged and/or high-dosage therapies, the risk increases considerably.6,7 In addition, there have been reports of acute kidney damage in non-dehydrated children treated with naproxen, diclofenac, ketorolac, ibuprofen and acetaminophen.8,9 40% of infants treated with indomethacin for closure of the ductus arteriosus showed some signs of renal toxicity and, in some cases, irreversible renal failure.6-10 Even in utero exposure to indomethacin (such as tocolytics or in the treatment of polyhydramnios) has been repeatedly associated with oligo-anuria and transient renal failure in neonates.11 2.7% of the children with acute renal injury took NSAIDs, generally at the recommended dose4 and the damage could even have occurred 1-5 days after the drug was administered.6 In 30% of cases a minimum impairment of renal function remained.12
It’s good for a paediatrician to be aware of and bear in mind the potential effects of NSAIDs on the kidney, identifying potential additional risk factors (dehydration and pre-existing renal disease above all), avoiding drugs with a lower safety profile (for example indomethacin, rofecoxib, diclofenac) and pays attention to the correct dosage and duration of the treatment.
1 Family Paediatrician, AUSL 20, Verona;
2 University Hospital for Paediatrics, Hospital GB Morgagni - L. Pierantoni, AUSL of Romagna, Forlì
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