NSAID Nephrotoxicity Revisited:Selective COX-2 Inhibitors

December 31, 2006

For over 25 years, NSAIDs have been used to treat a variety of pain syndromesand inflammatory diseases. More than 50 million Americanstake these drugs. Unfortunately, control of pain and inflammation is notachieved without an associated cost-namely, GI complications and, to a lesserextent, nephrotoxicity.In an attempt to reduce drug-related toxicity, a new class of selectiveNSAIDs-the COX-2 inhibitors-was introduced in 1999. These selectiveNSAIDs are as effective as and pose less risk of gastric toxicity than nonselectiveNSAIDs.1,2The COX-2 inhibitors are thought to reduce end-organ injury, such as GIulceration, by sparing homeostatic or “constitutive” COX-1 enzyme function.1,2 Incontrast, therapeutic effects result from the inhibition of the “inducible” COX-2enzyme.1,2 Such drug effects target the production of proinflammatory prostaglandinsby COX-2 without interrupting normal cell function mediated by COX-1.2,3

Q: How safe are the cyclooxygenase-2 (COX-2) inhibitors for patientsat risk for NSAID nephrotoxicity?A: For over 25 years, NSAIDs have been used to treat a variety of pain syndromesand inflammatory diseases. More than 50 million Americanstake these drugs. Unfortunately, control of pain and inflammation is notachieved without an associated cost--namely, GI complications and, to a lesserextent, nephrotoxicity.In an attempt to reduce drug-related toxicity, a new class of selectiveNSAIDs--the COX-2 inhibitors--was introduced in 1999. These selectiveNSAIDs are as effective as and pose less risk of gastric toxicity than nonselectiveNSAIDs.1,2The COX-2 inhibitors are thought to reduce end-organ injury, such as GIulceration, by sparing homeostatic or "constitutive" COX-1 enzyme function.1,2 Incontrast, therapeutic effects result from the inhibition of the "inducible" COX-2enzyme.1,2 Such drug effects target the production of proinflammatory prostaglandinsby COX-2 without interrupting normal cell function mediated by COX-1.2,3PROSTAGLANDINSAND RENAL FUNCTIONProstaglandins are the major products of COX enzyme metabolism. Theseprostanoids are produced throughout the body and act locally in an autocrineand/or paracrine fashion. Following synthesis, prostaglandins promptly exitthe cell via facilitated diffusion to bind to prostaglandin receptors found on parentor neighboring cells, thereby modulating cellular functions.4In healthy persons, prostaglandins are not the primary regulators of kidneyfunction. Rather, these eicosanoids locally modulate the effects of vasoconstrictorhormones.5 The major prostaglandins synthesized in the kidney includePGI2, PGE2, thromboxane A2 (TXA2), and PGF (Table 1). These prostaglandinsare produced to preserve renal function when pathologic statessupervene and compromise physiologic kidney processes.Intravascular volume depletion--associated with vomiting, diarrhea, anddiuretic therapy--stimulates COX enzyme activity and prostaglandin synthesisto optimize renal blood flow.6 Other causes of an effective decrease in renalblood flow include congestive heart failure (CHF), cirrhosis, and nephroticsyndrome. Prostaglandin production is also increased in chronic renal insufficiencyto maintain perfusion of remnant nephrons.7Locally produced PGI2 and PGE2 antagonize the local effects of circulatingangiotensin II, endothelin, vasopressin, and catecholamines that normallymaintain systemic blood pressure at the expense of the renal circulation.6 Glomerularfiltration rate (GFR) is preserved through the antagonism of arteriolar vasoconstriction and mesangial and podocyte contraction, both of which areinduced by endogenous vasopressors.4,8-10Renal prostaglandins also have an important role in modulating salt andwater homeostasis. In states of volume overload, both the inhibition of tubularsodium chloride reabsorption and the impairment of vasopressin's effect onwater channels result in increased salt and water excretion.5,8 Regulation ofmedullary blood flow by PGE2 also contributes to the kidney's ability to modifyrenal solute excretion.5,8 Ultimately, intravascular volume status is controlled,and hypotension and dehydration--as well as hypertension and edema formation--are avoided.NSAID-ASSOCIATEDNEPHROTOXICITYPatients with high-renin states (such as CHF, volume depletion, and cirrhosis)and chronic renal insufficiency rely on renal prostaglandin synthesis toensure sufficient renal blood flow and to maintain an adequate GFR. In theabsence of these prostaglandin effects, unopposed vasoconstriction leads to adecrease in renal blood flow and a decline in GFR.5,8Thus, NSAID therapy in patients with prostaglandin-dependent diseasestates often precipitates renal ischemia and acute renal failure.5,8 Fortunately,discontinuation of the NSAID leads to reversal of renal failure within 2 to 5days.8 In some cases, short-term dialysis may be required for severe uremiaor extreme metabolic perturbations.Edema formation and volume overload may also complicate NSAID therapy.11 In elderly patients with underlying heart disease, NSAID use can doublethe risk of CHF.12,13Diuretic resistance can also develop during NSAID therapy, especially inpatients with underlying salt-retentive states, such as CHF and cirrhosis.11,12 Inaddition, new-onset hypertension and exacerbation of previously well-controlledhypertension can occur with NSAIDs.11 Most of these adverse effects resultpredominantly from NSAID-induced sodium retention by the kidney. NSAIDsalso potentiate the antidiuretic effects of vasopressin, which can lead to totalbody water excess and hyponatremia.5,8Severe and potentially life-threatening hyperkalemia can develop followingNSAID therapy.14 This most often occurs in patients with underlying renal insufficiencyor in those who are concurrently receiving other medications thatalter potassium balance.14 An NSAID-induced reduction in the synthesis ofrenin and aldosterone is the major cause of impaired renal potassium excretionand hyperkalemia. 4,8-10,14 Decreased delivery of sodium chloride and water tothe distal nephron, which is perpetuated by the effect of the NSAID, also contributesto the development of hyperkalemia. The diminished availability of intraluminalsodium for sodium-potassium exchange limits potassium excretion.14EFFECT OF COX-2 INHIBITORSON RENAL FUNCTIONClinical data on the effect of selective COX-2 inhibitors on renal functionare limited to a small number of clinical trials and a handful of reported cases.Four studies provide preliminary insight into the potential nephrotoxicity ofthese drugs.15-18 In general, the participants were healthy and maintained relativelywell-preserved renal function during the study. Thus, these patients were at low risk for nephrotoxicity, and the results of these trials should not be extrapolatedto patients with prostaglandin-dependent states (eg, CHF, cirrhosis,use of diuretics) or severely impaired renal function. In addition, the 4 studiesexamined only the short-term effects of COX-2 inhibitors on renal function.In these trials, which studied celecoxib and rofecoxib, the effects of theCOX-2 inhibitors can be summarized as follows.15-18 These agents:

  • Significantly decreased renal prostaglandin synthesis in all studies in whichthis was measured.
  • Significantly reduced renal sodium excretion regardless of whether an ad-libor sodium-restricted diet was used.
  • Reduced GFR only in patients in whom salt intake was restricted. The GFRwas well maintained in patients treated with COX-2 inhibitors who did not followa salt-restricted diet.

Several case reports describe the clinical effects of COX-2 inhibitors onrenal function in patients with multiple risk factors for NSAID-induced nephrotoxicity.

19

Three patients experienced acute renal failure and hyperkalemia followingtherapy with these medications.

19

Discontinuation of the COX-2 inhibitorand treatment of the associated intravascular volume disturbance reversedthe renal dysfunction and electrolyte imbalance in these patients.More recently, 2 case series described 10 patients who had acute renalfailure and a variety of electrolyte and acid-base disorders following therapywith either celecoxib or rofecoxib.

20,21

These patients had multiple underlying risk factors for NSAID nephrotoxicity,including diuretic therapy, hypertension,and CHF. All recovered to baselinerenal function after the COX-2 inhibitorwas discontinued and associatedintravascular volume disturbanceswere corrected.

IMPLICATIONS FORYOUR PRACTICE

The available data suggest thatCOX-2 inhibitors disturb importantcomponents of renal physiology.These selective NSAIDs reduced sodiumexcretion, which suggests thatCOX-2-synthesized prostaglandins have a major role in the regulation of renalsalt and water. Furthermore, salt restriction in patients treated with COX-2 inhibitors,through the induction of volume depletion, was associated with a reductionin GFR. In patients with multiple risk factors for traditional NSAIDnephrotoxicity (

Table 2

), the COX-2 inhibitors induced severe acute renal failureand electrolyte disturbances.Thus, it appears that COX-2 inhibitors, like traditional NSAIDs, impair thephysiologic roles of prostaglandins in the kidney. It is therefore prudent to approachtherapy with these drugs as you would with traditional NSAIDs in patientsat risk for nephrotoxicity.

References:

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