NSAIDs and RENAL FUNCTION

     The NSAIDs are the most extensively utilized group of medications worldwide, with some 1.2% of the American population taking them on a daily basis, and accounting for almost 4% of all prescriptions filled in this country.1,2 The availability of the selective COX-2 inhibitors has acted to further increase usage of the category, and these agents are becoming increasingly important in pain management protocols independent of their anti-inflammatory properties. Choice of pain medication must carefully weigh advantages and disadvantages of the agent balanced with evaluation of the individual patient’s needs, conditions, and medication regimen.
     With increasing utilization comes an increased responsibility on the part of the practitioner to understand the potential problems associated with NSAID therapy. Much attention has been paid to the gastric effects of prostaglandin inhibition; but as more of our elderly become exposed to NSAIDs, NSAIDs’ tendency to impair renal function must be emphasized. Though incidence of renal complications is comparatively low at around 1%, the sheer number of NSAID patients and their demographics make this a vital consideration. Incidence is highest among patients with risk factors like existing impaired renal function, congestive heart failure, and hypertension, which are obviously more common in older patients.3,4 Risks for the hypertensive or CHF patient are further increased by concurrent therapy with ACE inhibitors, diuretics, and beta-blockers. The potential for NSAIDs to interact with these drug classes must be recognized by the pharmacist.
     Unfortunately, the very thing that makes NSAIDs work on pain and inflammation – inhibition of prostaglandin synthesis – is also what causes problems in the kidney. Production of prostaglandins, is of course, dependent upon the cyclooxygenase enzymes, COX-1 and COX-2. COX-2, found mainly in inflammatory cells, is induced by proinflammatory cytokines and growth factors and is responsible for production of proinflammatory and hyperalgesic prostaglandins and other inflammatory mediators.5
     COX-1 is found in most cells and tissues, producing prostaglandins in the kidney mainly from the ascending loop of Henle, the renal medulla, and the cortex.1 It catalyzes production of prostacline PGI2 and prostaglandin PGE2, both essential for their role in gastric protection; and PGE2 also helps to preserve kidney function. While the selective COX-2 inhibitors would be expected to be less prone to such renal effects than earlier non-selective agents, this has yet to be proven.1,2 COX-2 has been shown to function in renin production,1 which may negate most anticipated advantages of the COX-2 inhibitors with regard to renal side effects.
     Prostaglandins perform a number of essential functions in the kidney, including hemodyanamic regulation of renal blood flow and glomerular filtration rate (GFR), production and release of renin, reabsorption of water, and excretion of potassium and sodium. Blockage of prostaglandin production, then, can cause a variety of abnormalities in renal function, including fluid and electrolyte disorders, acute renal dysfunction, nephrotic syndrome, interstitial nephritis, renal papillary necrosis, and even end-stage renal disease, especially with high doses and extended therapy.2,6
     Renal dysfunction can occur at any time during the course of NSAID therapy, with the first dose or within the first week of therapy; but it is of particular concern with long-term use. For example, parenteral ketorolac therapy for up to 5 days is associated with an incidence of acute renal failure (ARF) no different from that seen with opioid analgesics; but extending therapy beyond 5 days doubles the risk of ARF with parenteral ketorolac.7 While NSAID-induced renal impairment is generally reversible upon discontinuation, it can also become a chronic condition in spite of discontinuation of therapy.1
     Some 25% of cardiac output reaches the glomerular vasculature, which has extensive endothelial surfaces. This is necessary not only for sufficient GFR, but also for adequate renal perfusion to supply tubular cells with oxygen.8 One prominent function of prostaglandins it to maintain renal vasodilation,1 autoregulating GFR in spite of dysregulating insults like hypovolemia.8 Suppression of this prostaglandin function, while of minimal significance in the patient with normal kidney function, decreases renal perfusion and glomerular filtration rate in patients with hypertensive renal disease or hypovolemia, regardless of origin.2 This acute renal insufficiency can lead to renal ischemia, tubular anoxia, necrosis, and fibrosis with long-term exposure.I The decreased GFR causes NSAIDs, other renally-eliminated toxins, and their metabolites to concentrate in tubular fluid to exacerbate the impairment of function.2,9
     Sodium retention and consequent edema comprise the most common renal syndrome associated with NSAID therapy. The renal prostaglandins promote natiuresis by direct inhibition of tubular sodium, potassium, and chloride reabsorption; and they diminish tubular response to vasopressin.4 The ensuing electrolyte disturbances lead to water retention, edema, and even organ congestion, which of course further impairs function of not only the kidney, but other congested organs. This certainly exacerbates existing CHF and hypertensive states and compromises efforts to control such conditions. Disruption of the normal intrarenal and extrarenal vasodilatory effects acts to increase renal and splanchnic peripheral resistance.4
     Prostaglandin suppression can also further contribute to hyperkalemia (with obvious implications for digoxin therapy) and disrupt blood pressure control by affecting the renin-angiotensin-aldosterone system. The renal prostaglandins have been proven potent stimuli to release renin, which also eventually stimulates adrenal delivery of aldosterone, which in turn helps to regulate sodium/potassium/fluid homeostasis by stimulating potassium secretion and sodium reabsorption. While this inhibition might theoretically act to reduce blood pressure, the other deleterious effects seem to predominate, overshadowing any benefit.4
     This also highlights the effect of NSAIDs on ACE inhibitor therapy. The ACE inhibitors not only reduce levels of endogenous vasoconstrictors, but increase bradykinin levels and its mediation of natiuretic and vasodilating prostaglandin production both in renal and peripheral vasculature. Blocking production of these prostaglandins with NSAIDs can significantly impair the clinical effectiveness of the ACE inhibitor.4
     NSAIDs tend to cause net effects generally counterproductive to diuretic therapy (retention of sodium, potassium, and water), to create a relative contraindication. Since the therapeutic benefits diuretics are largely prostaglandin-dependent, though, suppression of their natiuretic and renin activity by prostaglandin inhibition can severely hamper the goals diuretic therapy.G The issue is of particular concern in patients with CHF treated with daily diuretics. Regardless of NSAID choice, these patients are twice as likely to be hospitalized due to exacerbation of CHF as those who don’t take NSAIDs. The greatest risk is seen in the first few days of therapy, and over half of such hospitalizations occur within 30 days of initiating NSAID therapy.10
     Antihypertensive effects of beta-blockers can be similarly impaired, since they tend to reduce peripheral resistance by increasing circulating vasodilatory prostaglandins and reducing plasma renin activity. This effect is not always seen, though, supposedly because reductions in prostaglandin production may cause adrenergic receptors to become more sensitive to available prostaglandin levels in many patients.
Conclusion
     A comprehensive discussion of other drug interactions and contraindications with each of the NSAIDs is beyond the scope of this article, but here are a few basic ideas to help the pharmacist keep NSIAD patients out of renal or hypertensive trouble. While renal effects are relatively uncommon, the sheer number of people taking these products and the potential consequences of this type of adverse reaction merit special attention to those at risk.

* The older the patient, the more susceptible he is to NSAID-induced renal insufficiency.

*The older the patient, the more likely he is to suffer comorbid conditions that predispose to NSAID-induced renal insufficiency: Congestive heart failure, hypertension, diabetes, ascites, electrolyte imbalances, or existing renal impairment of any origin.

* While the therapeutic benefits of ACE inhibitors diuretics and beta-blockers can be severely compromised by NSAIDs, patients on regular diuretic therapy for CHF are at particular risk for exacerbating CHF.

* Any other medications or conditions significantly affected by fluid and electrolyte dysregulation warrant special consideration: Digoxin and lithium therapy are two examples.

* Counseling should include warnings to watch for unusual weight gain, shortness of breath, edema of the lower extremities, or decreased urinary output. The hypertensive patient should be warned that a change in hypertensive medication or dosage may be necessary after starting an NSAID.

References

1. COX-2 inhibitors. http://www.powerpak.com/CE/cox2/lesson.htm.

2. Panther L, Eland J. Effects of Long Term NSAIDs. http://pedspain.nursing.uiowa.edu/CEU/NSAID_longterm.htm.

3. Cantini C, Ungar A, Vallotti B, DiSerio C, Altobelli A, Castellani S, Masotti G. Ageing kidney and autacoids. Exp Clin Cardiol 1998;3(2):90-95.

4. Yang C. Nonsteroidal anti-inflammatory drugs and blood pressure. http://www.hsph.harvard.edu/Organizations/DDIL/NSAID_BP.htm.

5. Selective COX-2 Inhibitors. The Drug Monitor. http://home.eznet.net/-webtent/coxi.html.

6. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999 May 31; 106:5B 13s-24s.

7. Feldman H, Kinman J, Berlin J, et al. Parenteral Ketorolac: The Risk for Acute Renal Failure. Ann Intern Med 1997 February 1; 126:193.

8. Acute renal failure (ARF). http://www.vetmed.wsu.edu/boeing/smal_animal_medicine/arf.htm.

9. Toxic nephropathy. http://www.vetmed.wsu.edu/boeing/smal_animal_medicine/toxic.htm.

10. Cariati S. NSAIDs, Diuretics Can Be Lethal If Taken Together. Medical Tribune: Family Practice Edition. 39(13):6-7, 1998.