Hypoaldosteronism

Renal Dysfunction Resulting from NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common cause of acute renal failure. The clinical presentation differs from that of interstitial nephritis due to antibiotic use: proteinuria is much more common in NSAID-induced nephritis, while eosinophilia, eosinophiluria, fever and rash are more common in antibiotic-related nephritis. Tubulointerstitial disease associated with NSAID use is more common in women than in men and is more frequently seen in the elderly. Because no prospective study of treatment for NSAID-induced acute tubulointerstitial nephritis has been performed, the efficacy of steroid therapy remains uncertain.

Nonsteroidal anti-inflammatory drugs are among the most widely prescribed medicines in the world.[1,2] Although effective for pain relief, these agents have been implicated in various forms of renal dysfunction. Acute tubulointerstitial nephritis with nephrotic-range proteinuria occurs more commonly with NSAID use than with other offending agents.[2-5] This article discusses the clinical and pathophysiologic aspects of NSAID-associated renal syndromes, as well as therapeutic interventions that have been used for acute tubulointerstitial nephritis.

Epidemiology

Acute tubulointerstitial nephritis secondary to NSAID therapy is twice as likely to occur in women as in men.[6] The elderly are most often affected, with the highest prevalence of renal toxicity due to NSAIDs occurring in the seventh decade of life. The proprionic acid derivatives (fenoprofen [Nalfon], ibuprofen [Advil, Medipren, Motrin, etc.] and naproxen [Anaprox, Naprosyn]) account for 58 percent of cases of NSAID-induced acute tubulointerstitial nephritis, with fenoprofen implicated in 47 percent of all cases.[7] The median period of exposure to NSAIDs before development of acute tubulointerstitial nephritis is three months. However, the interval between the onset of therapy and the development of toxic reactions has ranged from two days to two years.[8,9]

Clinical and Laboratory Presentation

NSAID-induced acute tubulointerstitial nephritis has a variety of clinical presentations. The majority of patients have proteinuria in the nephrotic range on presentation.[10,11] The pathologic changes of the glomeruli associated with NSAID therapy are those typical of minimal-change disease (Figure 1): the glomeruli appear normal on light microscopy, with negative immunofluorescence and with fusion of the foot processes observed on electron microscopic examination.[6]

A number of reports have described a syndrome of nephrotic-range proteinuria, eosinophilia, fever and rash secondary to use of NSAIDs.[7,12] The duration of NSAID exposure prior to the onset of symptoms has ranged from several months to a few days. Therefore, although renal insufficiency and nephrotic syndrome have a relatively acute onset, the length of time preceding onset does not necessarily predict whether or not the syndrome will develop.

In addition to these more common acute presentations, NSAID therapy has been associated with functional renal insufficiency that occurs in high renin-angiotensin states or in conditions causing renal underperfusion.[13,14] These conditions include congestive heart failure, use of diuretics, cirrhosis, preexisting renal disease and advanced age. As can be predicted from this pathophysiologic profile, the patients at greatest risk for developing acute tubulointerstitial nephritis are those who are elderly, use diuretics for hypertension and also have arthritis.

The pathophysiology associated with these NSAID alterations is attributable to the kidney's need for vasodilatory prostaglandins ([PGE.sub.2] and prostacyclin) to counterbalance the vasoconstrictor effects of renal nerve activity and of potent vasoconstrictor hormones such as angiotensin II and catecholamines.[15,17] NSAIDs decrease prostaglandin synthesis by inhibiting cyclooxygenase, leading to unopposed constriction of renal afferent arterioles and decreased glomerular filtration rate and renal blood flow (Figure 2). This functional renal insufficiency is usually reversible within a few days of withdrawal of the offending agent.[18,19] In certain cases, however, patients who take NSAIDs may develop irreversible acute renal failure.

Vasodilatory prostaglandins are intimately associated with renin release.[15] Decreased production of these compounds in patients receiving NSAIDs results in secondary hypoaldosteronism and, consequently, hyperkalemia.[19] Furthermore, NSAIDs tend to cause sodium retention secondary to increased reabsorption of sodium chloride in both the loop of Henle and the distal tubules. This has been shown to be an effect of decreased aldosterone and prostaglandin synthesis.[20] Finally, some evidence suggests that prostaglandins oppose the effects of arginine vasopressin on water metabolism by the kidney.[4,21] Thus, prostaglandin inhibition may also lead to water retention, and, indeed, there is one report of hyponatremia as a rare complication of NSAID use.[2]

The renal pathology associated with NSAID use includes papillary necrosis.[2,22] The mechanism by which NSAIDs cause papillary necrosis is probably similar to that of other analgesic agents. Vasodilatory prostaglandins are known to increase blood flow at the juxtamedullary area of the kidney.[23] Inhibition of prostaglandin synthesis would decrease this flow and expose the susceptible area of the kidney, which extends to the renal papilla, to significant ischemia and subsequent necrosis (Figure 3).

Antibiotic-Induced Interstitial Nephritis

The findings in NSAID-associated acute tubulointerstitial nephritis are very different from those in antibiotic-associated acute tubulointerstitial nephritis. In the latter, nephrotic-range proteinuria is rare, and minimal-change disease is not observed in the glomeruli. Stillman and associates[24] have shown that, compared with acute tubulointerstitial nephritis secondary to beta-lactam antibiotics, NSAID-induced nephropathy is associated with a longer duration of drug exposure and older patient age. Other distinguishing features are the presence of nephrotic-range proteinuria and lack of any signs of hypersensitivity in NSAID-induced nephropathy. Table 1 summarizes the clinical differences between NSAID-induced tubulointerstitial nephritis with nephrotic syndrome and acute allergic interstitial nephritis typically seen with antibiotic therapy.[6,8,24,25]

Antibiotic-induced acute tubulointerstitial nephritis is characterized by (1) a usual duration of drug therapy of at least ten days and in some cases longer than three weeks, (2) fever and hematuria in more than 80 percent of cases, (3) gross hematuria in more than 33 percent of cases and (4) eosinophilia in 80 percent of cases. Eosinophilia and eosinophiluria are generally transient and last only during the initial one or two days. Skin rash, fever and eosinophilia are seen together in only about one-third of patients. If tests are timed appropriately, sterile pyuria, mild to moderate proteinuria and eosinophiluria can be detected by examination of the urine sediment after proper preparation with a Wright stain.[6]

In antibiotic-associated acute tubulointerstitial nephritis, the pathologic changes on renal biopsy include interstitial edema and infiltration predominantly by lymphocytes, monocytes and eosinophils.[3,6] The infiltrate is most pronounced in the deep cortex; interstitial granulomas with giant cells have also been described.[6] The interstitial edema usually is diffuse and involves the entire cortex; however, patchy inflammatory infiltrates may be noted.

These findings are clearly different from the pathologic changes seen in acute tubulointerstitial nephritis secondary to NSAIDs. As mentioned earlier, the pathologic changes of the glomeruli in NSAID-induced nephritis are more typical of minimal-change disease.[6,26] In addition, NSAID-induced nephritis is accompanied by interstitial infiltration with a preponderance of plasma cells as well as lymphocytes. Monocytic and eosinophilic infiltration is distinctly rare in this entity.[6,11] The lymphocytes are of T-cell origin and do not differ from those seen in chronic interstitial nephritis of any etiology.[11]

Treatment

Although steroids have been successfully used in patients with antibiotic-induced nephropathy, their effectiveness in altering the natural history of NSAID-induced nephropathy is still debated. Steroid therapy is usually reserved for patients developing acute azotemia and possibly uremia requiring dialysis or patients with significantly impaired renal dysfunction. However, the role of steroids in the treatment of acute tubulointerstitial nephritis secondary to NSAID therapy remains unclear.

Final Comment

NSAID-induced acute tubulointerstitial nephritis appears to be a different pathologic entity from the prototype of antibiotic-induced allergic interstitial nephritis, although acute renal failure can develop in both situations. A prospective study evaluating the effects of steroid therapy on NSAID-induced tubulointerstitial nephritis would be very useful. Meanwhile, NSAIDs should be used with caution in elderly patients receiving diuretics and in patients with any high renin-aldosterone state or any condition affecting plasma volume and renal plasma flow, such as congestive heart failure, cirrhosis or nephrotic syndrome. [Tabular Data Omitted]

PHOTO : FIGURE 1. Electron microscopic findings of minimal-change disease show flattened

PHOTO : podocytic foot processes but no apparent change in the basement membrane.

PHOTO : FIGURE 2. NSAIDs block vasodilatory prostaglandins, leading to unopposed constriction of

PHOTO : renal afferent arterioles and subsequent decreased glomerular filtration rate (GFR) and

PHOTO : renal blood flow.

PHOTO : FIGURE 3. Decreased renal blood flow results in ischemia to renal papillae and

PHOTO : subsequent necrosis.

REFERENCES

[1]Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984;310:563-72. [2]Garella S, Matarese RA. Renal effects of prostaglandins and clinical adverse effects of nonsteroidal anti-inflammatory agents. Medicine [Baltimore] 1984;63:165-81. [3]Linton AL. Adverse effects of NSAIDs on renal function [Editorial]. Can Med Assoc J 1984; 131:189-91. [4]Dunn MJ, Zambraski EJ. Renal effects of drugs that inhibit prostaglandin synthesis. Kidney Int 1980;18:609-22. [5]Lifschitz MD. Renal effects of nonsteroidal anti-inflammatory agents. J Lab Clin Med 1983; 102:313-23. [6]Cotran RS, Rubin RH, Tolkoff-Rubin NE. Tubulointerstitial disease. In: Brenner BM, Rector FC Jr, eds. The kidney. 3d ed. Philadelphia: Ardmore, 1986:1143-74. [7]Renal effects of fenoprofen [Letter]. Ann Intern Med 1980;93:508-9. [8]Handa SP. Drug-induced acute interstitial nephritis: report of 10 cases. Can Med Assoc J 1986;135:1278-81. [9]Reeves WB, Foley RJ, Weinman EJ. Nephrotoxicity from nonsteroidal anti-inflammatory drugs. South Med J 1985;78:318-22. [10]Abraham PA, Keane WF. Glomerular and interstitial disease induced by nonsteroidal anti-inflammatory drugs. Am J Nephrol 1984;4:1-6. [11]Bender WL, Whelton A, Beschorner WE, Darwish MO, Hall-Craggs M, Solez K. Interstitial nephritis, proteinuria, and renal failure caused by nonsteroidal anti-inflammatory drugs. Immunologic characterization of the inflammatory infiltrate. Am J Med 1984;76:1006-12. [12]Chan LK, Winearls CG, Oliver DO, Dunnill MS. Acute interstitial nephritis and erythroderma associated with diflunisal. Br Med J 1980;280(6207):84-5. [13]McCarthy JT, Torres VE, Romero JC, Wochos DN, Velosa JA. Acute intrinsic renal failure induced by indomethacin: role of prostaglandin synthetase inhibition. Mayo Clin Proc 1982;57:289-96. [14]Kimberly RP, Bowden RE, Keiser HR, Plotz PH. Reduction of renal function by newer non-steroidal anti-inflammatory drugs. Am J Med 1978;64:804-7. [15]Dunn MJ. Clinical effects of prostaglandins in renal disease. Hosp Pract [Off] 1984;19:99-103, 109-13. [16]Esmatjes E, Fernandez MR, Halperin I, et al. Renal hemodynamic abnormalities in patients with short-term insulin-dependent diabetes mellitus: role of renal prostaglandins. J Clin Endocrinol Metab 1985;60:1231-6. [17]Jensen PK, Steven K, Blaehr H, Christiansen JS, Parving HH. Effects of indomethacin on glomerular hemodynamics in experimental diabetes. Kidney Int 1986;29:490-5. [18]Galler M, Folkert VW, Schlondorff D. Reversible acute renal insufficiency and hyperkalemia following indomethacin therapy. JAMA 1981;246:154-5. [19]Tan SY, Shapiro R, Franco R, Stockard H, Mulrow PJ. Indomethacin-induced prostaglandin inhibition with hyperkalemia. A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med 1979;90:783-5. [20]Kirchner KA. Prostaglandin inhibitors after loop segment chloride uptake during furosemide diuresis. Am J Physiol 1985;248(5 Pt 2):F698-704. [21]Gross PA, Schrier RW, Anderson RJ. Prostaglandins and water metabolism: a review with emphasis on in vivo studies. Kidney Int 1981;19:839-50. [22]Husserl FE, Lange RK, Kantrow CM Jr. Renal papillary necrosis and pyelonephritis accompanying fenoprofen therapy. JAMA 1979;242:1896-8. [23]Kirschenbaum MA, White N, Stein JH, Ferris TF. Redistribution of renal cortical blood flow during inhibition of prostaglandin synthesis. Am J Physiol 1974;227:801-5. [24]Stillman MT, Napier J, Blackshear JL. Adverse effects of nonsteroidal anti-inflammatory drugs on the kidney. Med Clin North Am 1984;68:371-85. [25]Galpin JE, Shinaberger JH, Stanley TM, et al. Acute interstitial nephritis due to methicillin. Am J Med 1978;65:756-65. [26]Finkelstein A, Fraley DS, Stachura I, Feldman HA, Gandy DR, Bourke E. Fenoprofen nephropathy: lipoid nephrosis and interstitial nephritis. A possible T-lymphocyte disorder. Am J Med 1982;72:81-7.

The Authors

GEORGE L. BAKRIS, M.D. is staff nephrologist at the Ochsner Clinic and assistant professor of medicine in the section on clinical pharmacology at Tulane University School of Medicine, New Orleans. A graduate of the Chicago Medical School, Dr. Bakris served an internship in internal medicine at the Mayo Clinic, Rochester, Minn. He also completed a residency in internal medicine at the University of Illinois Medical Center, Chicago, and fellowships in nephrology and clinical pharmacology at the University of Chicago. SIDNEY R. KERN is a research associate working in the area of diabetic nephropathy in the Department of Medicine Section on Nephrology at the Ochsner Clinic. A graduate of the University of New Orleans, Mr. Kern has extensive experience in cell biology with expertise in the area of cellular protein isolation and characterization.

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