Special Feature

NSAIDs and Their Effects on Renal Function

By Thomas L. Kennedy, MD, FAAP

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in children has increased dramatically over the past few years. Ibuprofen is now routinely used as the antipyretic of choice by many pediatricians who feel it is more effective than acetaminophen. The NSAIDs class of drugs is quite diverse, technically includes salicylates, and now comprises more than 20 agents. Therefore, it is risky and unwise to make any generalizations for the entire group. However, the NSAIDs share in common the ability to inhibit cyclo oxygenase, an enzyme required for the synthesis of prostaglandins. It is this inhibition of prostaglandin synthesis that is responsible for both therapeutic and side effects. NSAIDs are generally safe and well tolerated by children. Most pediatricians are aware of the NSAIDs gastrointestinal effects, but fewer are aware of the potential for nephrotoxicity.1 Although uncommon, adverse renal effects are varied; run the gamut from mild to severe; and include: 1) acute renal failure with or without oliguria; 2) chronic, insidious renal injury; 3) heavy pro-teinuria and the nephrotic syndrome; 4) tubulointerstitial nephritis; 5) disorders of salt and water metabolism; and 6) hyperkalemia.2 Nevertheless, NSAID use in children is

generally considered safe and well tolerated, particularly if dosed properly and given for short periods. For example, one report prospectively assessed renal function in a population of children admitted to the hospital with acute, febrile illnesses who received antipyretic therapy in one of three regimens: 12 mg/kg acetaminophen, 5 mg/kg/dose ibuprofen, or 10 mg/kg/dose ibuprofen.3 The study found no evidence of increased renal impairment in the groups who received ibuprofen, even in those whose illnesses were associated with dehydration. However, individual increases in creatinine were not reported. Most reports of NSAIDs nephrotoxicity in children are single cases and the role of NSAIDs is usually speculative. Renal injury has been encountered following large overdose and prolonged use but has also been reported with appropriately dosed, short-term therapy.

Because NSAIDs nephrotoxicity is the result of prostaglandin inhibition, it is important to appreciate the role of prostaglandins in the kidney. Under normal, euvolemic circumstances, there is little evidence that prostaglandins are either necessary or active in determining renal function. They are synthesized on demand and in response to specific stimuli and exert their effects only in close proximity to the site of synthesis. Thus, they may be considered autacoids, that is, substances whose action is local.

Renal prostaglandins are vasodilators, which, through their action on the afferent and efferent arterioles, help to preserve renal bloodflow and glomerular filtration rate (GFR), especially in the presence of hypovolemia and other conditions of underperfusion. Various renal prostaglandins (e.g., PGE2, PGF2I, and PGI2) are also active along different segments of the nephron, affecting solute and water transport. In the presence of vasoconstrictors such as catecholamines, angiotensin II, vasopressin, and endothelin, renal prostaglandin synthesis is stimulated in an attempt to preserve renal bloodflow and defend GFR. The vasoconstricting agents are commonly present in conditions with diminished effective arterial blood volume such as congestive heart failure, nephrotic syndrome, cirrhosis, severe hypertension, and sepsis. In these situations, renal prostaglandins are protective and oppose the intense vasoconstriction that could lead to renal ischemic injury. Use of NSAIDs in these circumstances will inhibit the synthesis of prostaglandins and could be potentially dangerous.

In certain situations (for example, chronic renal insufficiency) GFR may be chronically maintained or "propped up" by the action of renal prostaglandins, thus making the use of NSAIDs more risky. It has been reported in patients with sickle cell anemia, who routinely develop progressive evidence of renal dysfunction, that the baseline GFR (which frequently is normal to even greater than normal when assessed by creatinine clearance) is sustained by renal prostaglandin activity. Thus, decreases in GFR may be quite common with administration of NSAIDs.4 A recent article describes the dramatic and unfortunate development of irreversible renal failure in an adolescent female with sickle cell disease who was receiving appropriate dose ketoralac therapy for the pain of a vaso-occlusive crisis.5 This case was not associated with any of the recognized risk factors for NSAIDs nephrotoxicity such as hypovolemia. The conclusion that the renal failure was caused by ketorolac is speculative, although it was a reasonable diagnosis of exclusion. Simckes and colleagues recommend that children with sickle cell disease should have the doses of ketoralac adjusted to those administered to patients with renal insufficiency and even then that it should be used with care.

Renal prostaglandins also act to increase salt and water excretion. This natriuretic action makes sense physiologically since it helps to moderate the avid salt retention that occurs under conditions of hypovolemia and/or renal underperfusion and in the presence of activation of the renin-angiotensin-aldosterone system. Prostaglandin inhibition by NSAIDs predictably may lead to severe salt and water retention and the development of edema and/or hypertension. Furthermore, inhibition of renal prostaglandins may lead to unopposed action of antidiuretic hormone (there is normally a negative feedback of prostaglandin on ADH secretion), impaired free water excretion, and hyponatremia.

The final significant clinical effect of NSAIDs on renal function is the suppression of prostaglandin-dependent release of renin from the juxtaglomerular cells. The resulting hyporeninemic state leads to hypoaldosteronism and hyperkalemia, especially in patients with renal insufficiency.

The conclusion we should draw from all of this is that NSAIDs use in children is generally very safe, but that nephrotoxicity and renalmediated adverse effects (e.g., hyperkalemia) are possibilities to consider, especially in certain high-risk groups. These include children with dehydration, hypovolemia, and other low-perfusion states; children with pre-existing renal compromise; and perhaps children with sickling hemoglobinopathies.

References

1. Dubose TD. Grand round: Nephrotoxicity of non-steroidal anti-inflammatory drugs. Lancet 1994; 344:515-518.

2. Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int 1993;44:643-653.

3. Lesko SM, Mitchell AA. Renal function after short-term ibuprofen use in infants and children. Pediatrics 1997;100:954-957.

4. Allon M, et al. Effects of nonsteroidal antiinflammatory drugs on renal function in sickle cell anemia. Kidney Int 1988;34:500-506.

5. Simckes AM, et al. Ketorolac-induced irreversible renal failure in sickle cell disease: A case report. Pediatr Nephrol 1999;13:63-67.

The use of NSAIDs:

    a. produces a measurable effect on kidney function in children with acute febrile illnesses.
    b. may protect renal function in children with diminished blood volume.
    c. may be used without concern in children with hemoglobinopathies or renal failure.
    d. has no direct effect on prostaglandin synthesis.