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Cirrhosis, renal function and NSAIDs
200
Journal of Hepatology, 1993; 19:200-203 Elsevier Scientific Publishers Ireland Ltd.
HEPAT 01535
Leader
Cirrhosis, renal function and NSAIDs
Paolo Gentilini lstituto di Clinica Medica H, Universith di Firenze. Italy
Physiological action of renal prostaglandins For several years it has been known that arachidonic acid (AA) metabolites (or the prostaglandin system, PG), which derive from the activation of membrane cyclooxygenase, play an important role in mediating renal function, renal salt and water excretion, renal plasma flow (RPF), glomerular filtration rate (GFR), and renin release. In fact, PGs are released by the glomeruli and by their afferent arterioles, thus influencing intraglomerular vascular tone (1,2). The PG system has been correlated with other autacoid systems, especially with the bradykinin-kinin system and leukotrienes, the latter being the result of the other branch of AA catabolism through activation of membrane lipoxygenase. PGs can also modify peripheral vascular resistance, and thus regulate systemic blood pressure, modulate immunological function and stimulate erythropoietin release. Intravenous infusion of prostaglandin E (PGE2), prostaglandin D2 (PGD2) and prostacyclin (PGI2) induce systemic vasodilation and decrease vascular resistance, while PGF2c~ and TxA2 infusion determine arteriolar vasoconstriction (3). The reciprocal influence of the PG system on major vasoactive systems (the sympathetic nervous system, SNS, and renin-angiotensin-aldosterone system, RAAS) also occurs when PG release is blocked with indomethacin, leading to an increased response to the infusion of arginin vasopressin or angiotensin II (4). Because of this prevalent vasodilating action, the infusion of PG2, PGD2 and PGI2 into the renal artery increases renal blood flow (5). Endoperoxides (PGG2, PGH2) (6), TxA2 (7) and leukotrienes C4 and D4 (8) in-
duce, instead, a potent vasoconstriction of the renal arteries in experimental animals. During renal vasoconstriction, mainly induced by angiotensin II and norepinephrine, there is a rapid increase in the release of renal PGs (9,10). Other experiments, furthermore, show that the inhibition of PG release potentiates vascular vaoconstriction of the above mentioned substances (11 ). Moreover, PGs may have a direct effect on diuresis by acting on tubular reabsorption or indirectly, by influencing renal hemodynamics. Some studies demonstrate that PGI2 also inhibits sodium and water reabsorption in the thick ascending limbs of cortical tubules (12). Moreover, PGs can modulate vasopressin activity on water transport in the ductular cells. Cyclooxygenase inhibition induces an increase in urinary osmolality, and enhances renal sensitivity to vasopressin (13). The infusion of PGs and 9-deoxy16,16-dimethyl-9-methylene-PGE2, on the other hand, leads to an inhibition of the water retaining activity of vasopressin and an increase in free water clearance in animals (14).
Renal prostaglandins in cirrhosis In patients with cirrhosis, the renal PG system acts with other autacoid systems to maintain RPF, GFR and water and sodium excretion (15). During the compensated stages of the disease, several authors report glomerular hyperfiltration due to a decrease in afferent arteriolar tone, which is a consequence of circulating vasodilating substances (16). Even if this hyperflltration
RENAL FUNCTION AND NSAIDS
contributes to the occurrence of glomerular sclerosis, which may complicate the natural course of the disease later (16), especially in cases with ascites and edema, i.e. during decompensated cirrhosis, patients show an even more pronounced release of AA metabolites (17-19). Although both vasodilating and vasocostricting prostanoids are increased in these patients, the resulting activity seems vasodilation, which counteracts vasoconstriction due to the activation of the major vasoactive systems (SNS, RAAS). PGs directly stimulate renin release (20), thus indirectly contributing to the maintenance of systemic arterial pressure in patients with cirrhosis. This has been shown in studies which demonstrated, in these patients, the hypotensive effect of angiotensin converting enzyme inhibitors, such as captopril, used at pharmacological doses (21). Moreover, at low doses captopril induced a significant decrease in G F R and filtration fraction (FF), without modifying blood pressure and heart rate (22). In patients with compensated cirrhosis, urinary excretion of PGE2, 6-keto-PGFla (a stable metabolite of PGI2), TxB2 (a stable metabolite of TxA2) and PGF2~ were only slightly increased, suggesting that the PG system is only partially activated in this stage of the disease (18) whereas the major systems were normal, even if the hemodynamic renal alterations with outer cortex vasoconstriction and opening of artero-venous shunts have been demonstrated in some cases (23,24). In other words, without a positive sodium balance, characterized by ascites and/or edema, the activation of vasoacting systems is generally mild or absent, justifying the minor effects of NSAIDs in this stage of the disease. During the end stage of decompensated cirrhosis, on the other hand, characterized by refractory ascites and the overt hepato-renal syndrome (HRS), PGs were decreased, with a relative prevalence, however, of TxB2 over 6-keto-PGFla and particularly over PGE2 (18). The exhaustion of this autacoid system may contribute to the imbalance between vasodilating and vasocostricting factors, resulting in occurrence of final vasoconstriction and hypoxia, and further worsening of renal function (18,25,26). In fact, in experimental models it has been shown that the contraction of isolated rat glomeruli or single isolated mesangial cells, may reduce the filtration surface area. Thus the GFR is reduced by TxA2 and angiotensin II, whereas PGE2 and PGI2 lead to mesangial relaxation. Moreover, pre-treatment with AA or the addition of exogenous PGE2 may inhibit angiotensin-mediated glomerular contraction (27). Clinically, the administration of thromboxane synthase inhibitors such as OKY 046, significantly improved the
201 diuretic and natriuretic effects of furosemide in patients with decompensated cirrhosis (28). Moreover, a thromboxane antagonist, ONO-3708, induced a significant increase in diuresis and free water clearance in patients with decompensated cirrhosis (29). These recent data seem to confirm the role of vasoconstricting factors, mainly TxA2, in inhibiting water excretion in cirrhotic patients. The latter, represented by stronger intra-renal vasoconstriction, may also explain the occurrence of acute tubular necrosis (ATN), during which an increase in urinary sodium excretion, together with a further increase in creatinine levels are sometimes seen in patients with terminal HRS (30). In this case, it is conceivable that after a long period of renal functional impairment (RFI), present in about 20% of compensated cases (24) and characterized by a significant reduction in renal clearances, and after a shorter period of more open renal impairment, characterized by a sudden elevation in BUN and creatininemia and a stronger reduction in sodium renal excretion, which corresponds to a real HRS, present in about 4% of decompensated cirrhosis, some organic alterations may occur. The exhaustion of renal autacoid systems may contribute to these alterations (30). Use of NSAIDs in cirrhosis NSAIDs constitute a heterogeneous group of compounds, which have several common effects, which are not chemically related. The most well known drug is acetylsalicylic acid (aspirin) and these molecules are also referred to as aspirin-like drugs. Many of the biological effects of NSAIDs are due to their ability to inhibit cyclooxigenase activity, thus reducing PG synthesis. According to Vane (31) and several other authors, these compounds generally do not modify renal function in healthy subjects, but may cause renal impairment in patients with congestive heart failure, chronic renal disease, several hypovolemic syndromes or decompensated cirrhosis (i 5,32,33). The first report of deleterious effects due to NSAIDs on renal function in decompensated cirrhosis was by Boyer et al. (34), who observed a reduction in RPF and GFR in a group of patients with chronic alcoholic liver disease and ascites following oral administration of indomethacin. These results were later confirmed by Zipser et al. (19,35), as well as by several other authors including our group (36), who showed the impairment of renal function following administration of indomethacin or ibuprofen, with a decreased urinary sodium excretion (36). In all these studies, the reduction of
202 renal function and sodium excretion was completely reversible, and lasted only as long as the drug was administered to the patients. However, the effect of NSAIDs on renal hemodynamics and function is markedly variable in patients with cirrhosis and ascites, and may be absent in some, despite the same degree of inhibition of renal PG synthesis. As reported by Zipser et al. (35), baseline urinary sodium excretion is the best predictor of patient susceptibility to the deleterious effects of these drugs patients with urinary sodium excretion lower than 1 mmol/day have a greater risk of developing renal failure following the administration of indomethacin or other NSAIDs. In general, high risk patients also tended to have greater plasma renin activity, plasma aldosterone concentrations and increased urinary excretion of PGE2 and 6keto-PGFlo~, but there was marked variability, and none of these parameters were found to be useful in predicting the renal response. Surprisingly, measurement of RPF and GFR had no value in identifying patients at risk. The renal effects of NSAIDs in patients with cirrhosis and ascites also depend on the pharmacokinetic and pharmacodynamic properties of these drugs. The ability to inhibit renal cyclooxigenase activity is especially relevant in this setting. The most potent inhibitor of renal PG synthesis is indomethacin, which affects GFR in almost all patients with cirrhosis and ascites. Ibuprofen and naproxen are somewhat less potent, and only impair renal function in susceptible patients (19,35). Oral aspirin is even weaker, whereas intravenous lysine aceylsalicylate has been shown to markedly impair renal function in most patients with cirrhosis and ascites (37). Sulindac was thought to be a unique NSAID due to its renal-sparing property. Indeed, this drug did not reduce renal PG excretion, RPF or GFR in patients with chronic glomerular disease susceptible to the nephrotoxic effects of ibuprofen. The renal-sparing activity was ascribed to the immediate renal catabolism of sulindac sulphide, the active metabolite of this drug (38). Different studies were therefore carried out to address the effects of sulindac on renal PGs and hemodynamics in cirrhotic patients with ascites (39). Laffi et al. (36) reported that 5-day treatment with sulindac (400 m/day) significantly reduced urinary excretion of PGE2 and TxB2 in ten cirrhotic patients with ascites, but only slightly affected urinary 6-keto-PGFla excretion. It did not modify renal function. Plasma levels of sulindac sulphide were 2-fold higher in patients with cirrhosis than in control subjects. Quintero et al. (40) observed a 40% decrease in GFR after a 3-day sulindac administration.
p. GENTILINI In that study, plasma levels of sulindac sulphide increased four times. These data indicate that in patients with liver diseases, sulindac may impair renal function, due to the accumulation of its active metabolite. Imidazole-salicylate is another NSAID which seemed to spare effects on cyclooxygenase activity. This drug, which appears less effective than another NSAID, piroxicam (41), has been shown to selectively inhibit TxA2 production, without influencing PGE2 synthesis in platelets and other circulating cells (42). Selective inhibition of renal TxA2 production by imidazole-salicylate could be useful since previous studies from our laboratory showed beneficial effects of inhibiting TxA2 production or activity. Indeed, in the present issue of this journal, Salerno et al. (43) reported that this drug did not inhibit renal prostanoid excretion or impair renal function in either baseline conditions or after the effects of furosemide. These results were obtained through an acute protocol in a group of patients with well compensated liver disease, as estimated by close to normal serum albumin concentrations and prothrombin times. Most of these patients had very low sodium excretion, a predictive index of the renal response to NSAIDs. However, individual susceptibility to the nephrotoxic effects of this drug was not tested in comparison to other NSAIDs, a family of drugs known to reduce renal function in patients with decompensated cirrhosis. Further studies, therefore, are needed before imidazole-salicylate can be considered a safe drug for cirrhotic patients requiring an NSAID, especially decompensated ones. These studies should mainly evaluate whether the PG sparing effect of this drug is maintained during chronic administration, as well as whether unrecognized nephrotoxic metabolites accumulate in patients with more advanced liver disease or cumulative inhibition of platelet TxA2 production further impairs platelet aggregation.
Acknowledgment This work was supported by Ministero dell'Universitfi. e della Ricerca Scientifica e Tecnologica and the Italian Liver Foundation.
References I 2
McCoy RN, Fried TA, Osgood RW. Stein JH. Release of prostaglandin E2 (PGE2) by a single isolated perfused glomerulus. Kidney Int 1985; 27: 297(A). Hura CE, Kunau RT Jr. Angiotensin II-stimulated prostaglandin production by canine renal afferent arterioles. Am J Physiol 1988; 254(5 Pt 2), F734-8.
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RENAL FUNCTION AND NSAIDS 3 4 5
6 7 8
9
10
11
12
13 14
15 16
17
18 19 20 21
22
23 24 25
Dunn MJ. Kidney Hormones. Orlando, Academic Press 1986: Vol. 3, 397-461. Negus P, Tannen RL, Dunn MJ. Indomethacin potentiates the vasoconstrictor actions of angiotensin II in normal man. Prostaglandins 1976; 12: 175-80. Gerber JG, Branch RA, Nies AS, Cerkens .IF, Shand DG, Hollifield J, Oates JA. Prostaglandins and renin release. 11. Assessment of renin secretion following infusion of PGI2, E2 and D2 into the renal artery of anesthetized dogs. Prostaglandins 1978; 15: 81-8. Gerber JC, Ellis EF, Nies AS. The effect of endoperoxide analog on renal function and hemodynamics. Fed Proc 1977; 36: 402(A). Morrison AR, Nishikawa K, Needleman P. Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney. Nature 1977; 267: 259-60. Rosenthal A, Pace-Asciak CR. Potent vasoconstriction of the isolated perfused rat kidney by the leukotrienes C4 and D4. Can J Physiol Pharmacol 1983; 61: 325-8. Dunham EW, Zimmerman BG. Release of prostaglandin-like material from dog kidney during nerve stimulation. Am J Physiol 1970; 219: 1279-85. Needleman P, Kauffman AH, Douglas JR Jr Johnson EM, Marshall GR. Specificstimulation and inhibit!on of renal prostaglandin release by angiotensin analogs. Am J Physiol 1973: 224: 1415-9. Aiken JW, Vane JR. Intrarenal prostaglandin release stimulates the renal vasoconstrictor activity of angiotensin. J Pharmacol Exp Ther 1973; 184: 678-87. Kimberly RP, Bowden RE, Keiser HR, Plotz PH. Reduction of renal function by newer nonsteroidal anti-inflammatory drugs. Am J Med 1978; 64: 804-7. Berl T, Raz A, Wald H. Prostaglandin synthesis inhibition and the action of vasopressin: studies in man and rat. Am J Physiol 1977; 232: F529-37. Christensen NJ, Bygdeman M, Green K, et al. The prostaglandin analog 9-deoxo-16, 16-dimethyl-9-methylene-PGE2 inhibits the antidiuretic effect of vasopressin (AVP) in the conscious sheep. Pflugers Arch 1984; 402: 360-3. Patrono C, Dunn MJ. The clinical significance of inhibition of renal prostaglandin synthesis. Kidney Int 1987: 32: 1-12. Wong F, Massie D, Colman .I, Dudley F. CIomerular hyperfiltration in patients with well-compensated alcoholic cirrhosis. Gastroenterology 1993; 104: 884-9. Zipser RD, Hoefs JC, Speckart PF, Zia PK, Horton R. Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab 1979: 48: 895-900. Laffi G, La Villa G, Pinzani M, et al. Altered renal and platelet arachidonic acid metabolism in cirrhosis. Gastroenterology 1986; 90: 274-82. Zipser RD, Lifschitz MD. Prostaglandins and related compounds. In: Epstein M, ed. The kidney in liver disease. 3rd edn. Williams and Wilkins, Baltimore, 1988; 393-416. Henrich W. Role of the prostaglandin in renin secretion. Kidney int 1981; 19: 822-30. Pariente EA, Bareille E, Bercoff D, Lebrec D. Acute effects of captopril on systemic and renal hemodynamics in cirrhotic patients with ascites. Gastroenterology 1985; 88: 1255-9. Gentilini P, Romanelli RG, La Villa G, et al. Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver. Gastroenterology 1993; 104: 588-94. Epstein M, Berk DP, Hollenberg MK, et al. Renal failure in cirrhosis: the role of active vasoconstriction. Am J Med 1970: 49: 175-85. Gentilini P, Laffi G, Buzzelli G, et al. Functional renal alterations in chronic liver disease. Digestion 1980: 20: 73-8. Zipser RD, Radvan GH, Kronborg I, Duke R, Little TE. Urinary thromboxane B2 and prostaglandin E2 in the
26 27
28
29
30
31 32 33
34 35 36
37
38
39 40 41
42
43
hepatorenal syndrome: evidence for increased vasoconstrictor and decreased vasodilator factors. Gastroenterology 1983i 84: 697-703. Gentilini P, Laffi G. Renal functional impairment and sodium retention in liver cirrhosis. Digestion 1989; 43: 1-32. Dunn M.I. The role of arachidonic acid metabolites in renal homeostasis. Non-steroidal anti-inflammatory drugs renal function and biochemical, histological and clinical effects and drug interactions. Drugs 1987; 33(Suppl. I): 56-66. Pinzani M, Laffi G, Meacci E, La Villa G, Cominelli F, Gentilini P. intrarenal thromboxane A2 reduces the furosemide-induced sodium and water diuresis in cirrhosis with ascites. Gastroenterology 1988; 95: 1081-7. Laffi G, Marra F, Carloni V, Azzena G, De Feo M.L, Pinzani M, Tosti-Guerra C, Gentilini P. Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites. Gastroenterology 1992; 103: 1017-21. Gentilini P. Hepato-renal syndrome: differential diagnosis and therapy. Lecture at the Basel Liver Week 1992; Basilea, 15-17 Ottobre 1992, Falk Symposium no. 69 IX International Congress on Liver Diseases: extrahepatic manifestations in liver diseases (in press). Vane JR, Botting R. Inflammation and the mechanism of action of antiinflammatory drugs. FASEB J 1987; I: 89-96. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1984: 310: 563-72. Oates JA, Fitzgerald GA, Branch RA, Jackson EK, Knapp HR, Roberts LJ. Clinical implications of prostaglandin and thromboxane formation. New Engl J Med 1988; 319: 689-98, 757-67. Boyer TD, Zia P, Reynolds TB. Effect of indomethacin and prostaglandin AI on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979; 77: 215-22. Zipser RD. Role of renal prostaglandins and the effects of nonsteroidal anti-inflammatory drugs in patients with liver disease. Am J Med 1986; 81 (Suppl. 2B): 95-103. Laffi G, Daskalopoulos G, Kronborg l, Hsueh W, Gentilini P, Zipser RD. Effects of sulindac and ibuprofen it~ patients with cirrhosis and ascites. An explanation for the renal sparing effect of sulindac. Gastroenterology 1986; 90: 182-7. Planas R, Arroyo V, Rimola A, Peres-Ryuso RM, Rodes J. Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites. Gastroenterology 1983; 84: 247-52. Ciabattoni G, Cinotti GA, Pierucci A, et al. Effects of sulindac and ibuprofen in patients with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin. New Engl .I Med 1984; 310: 279-83. Juhl RP, Van Thiel DH, Dittert LW, Albert KS, Smith RB. Ibuprofen and sulindac kinetics in alcoholic liver disease. Clin Pharmacol Ther 1983: 34: 104-9. Quintero E, Gines P; Arroyo V, et al. Sulindac reduces urinary excretion of prostaglandins and impairs renal function in cirrhosis with ascites. Nephron 1986: 42: 298-303. Montrone F, Petrillo M, Ardizzone S, Scaricabarozzi I, Scotti A, Caruso l, Bianchi Porro G. Imidazole salicylate versus piroxicam in the treatment of arthrosis in elderly patients. A double-blind clinical and endoscopic trial. J Am Geriatr Soc 1990: 38: 985-8. Pagella PG, Bellavite O, Agozzino S, Dona GC, Cremonesi P. De Sands F. Pharmacological studies of imidazole 2hydroxybenzoate (ITF 182), an anti inflammatory compound with an action on thromboxane R2 production. Arzneimittelforsch/Drug Res 1983: 33: 716-26. Salerno F, Lorenzano E, Maggi A, Badalamenti S, Minuz P, Degan M, Chinea B, Scotti A. Effects of imidasolesalicylate on renal function and the diuretic action of furosemide in cirrhotics with ascites. J Hepatol 1993: 19: 279-84.
Journal of Hepatology, 1993; 19:200-203 Elsevier Scientific Publishers Ireland Ltd.
HEPAT 01535
Leader
Cirrhosis, renal function and NSAIDs
Paolo Gentilini lstituto di Clinica Medica H, Universith di Firenze. Italy
Physiological action of renal prostaglandins For several years it has been known that arachidonic acid (AA) metabolites (or the prostaglandin system, PG), which derive from the activation of membrane cyclooxygenase, play an important role in mediating renal function, renal salt and water excretion, renal plasma flow (RPF), glomerular filtration rate (GFR), and renin release. In fact, PGs are released by the glomeruli and by their afferent arterioles, thus influencing intraglomerular vascular tone (1,2). The PG system has been correlated with other autacoid systems, especially with the bradykinin-kinin system and leukotrienes, the latter being the result of the other branch of AA catabolism through activation of membrane lipoxygenase. PGs can also modify peripheral vascular resistance, and thus regulate systemic blood pressure, modulate immunological function and stimulate erythropoietin release. Intravenous infusion of prostaglandin E (PGE2), prostaglandin D2 (PGD2) and prostacyclin (PGI2) induce systemic vasodilation and decrease vascular resistance, while PGF2c~ and TxA2 infusion determine arteriolar vasoconstriction (3). The reciprocal influence of the PG system on major vasoactive systems (the sympathetic nervous system, SNS, and renin-angiotensin-aldosterone system, RAAS) also occurs when PG release is blocked with indomethacin, leading to an increased response to the infusion of arginin vasopressin or angiotensin II (4). Because of this prevalent vasodilating action, the infusion of PG2, PGD2 and PGI2 into the renal artery increases renal blood flow (5). Endoperoxides (PGG2, PGH2) (6), TxA2 (7) and leukotrienes C4 and D4 (8) in-
duce, instead, a potent vasoconstriction of the renal arteries in experimental animals. During renal vasoconstriction, mainly induced by angiotensin II and norepinephrine, there is a rapid increase in the release of renal PGs (9,10). Other experiments, furthermore, show that the inhibition of PG release potentiates vascular vaoconstriction of the above mentioned substances (11 ). Moreover, PGs may have a direct effect on diuresis by acting on tubular reabsorption or indirectly, by influencing renal hemodynamics. Some studies demonstrate that PGI2 also inhibits sodium and water reabsorption in the thick ascending limbs of cortical tubules (12). Moreover, PGs can modulate vasopressin activity on water transport in the ductular cells. Cyclooxygenase inhibition induces an increase in urinary osmolality, and enhances renal sensitivity to vasopressin (13). The infusion of PGs and 9-deoxy16,16-dimethyl-9-methylene-PGE2, on the other hand, leads to an inhibition of the water retaining activity of vasopressin and an increase in free water clearance in animals (14).
Renal prostaglandins in cirrhosis In patients with cirrhosis, the renal PG system acts with other autacoid systems to maintain RPF, GFR and water and sodium excretion (15). During the compensated stages of the disease, several authors report glomerular hyperfiltration due to a decrease in afferent arteriolar tone, which is a consequence of circulating vasodilating substances (16). Even if this hyperflltration
RENAL FUNCTION AND NSAIDS
contributes to the occurrence of glomerular sclerosis, which may complicate the natural course of the disease later (16), especially in cases with ascites and edema, i.e. during decompensated cirrhosis, patients show an even more pronounced release of AA metabolites (17-19). Although both vasodilating and vasocostricting prostanoids are increased in these patients, the resulting activity seems vasodilation, which counteracts vasoconstriction due to the activation of the major vasoactive systems (SNS, RAAS). PGs directly stimulate renin release (20), thus indirectly contributing to the maintenance of systemic arterial pressure in patients with cirrhosis. This has been shown in studies which demonstrated, in these patients, the hypotensive effect of angiotensin converting enzyme inhibitors, such as captopril, used at pharmacological doses (21). Moreover, at low doses captopril induced a significant decrease in G F R and filtration fraction (FF), without modifying blood pressure and heart rate (22). In patients with compensated cirrhosis, urinary excretion of PGE2, 6-keto-PGFla (a stable metabolite of PGI2), TxB2 (a stable metabolite of TxA2) and PGF2~ were only slightly increased, suggesting that the PG system is only partially activated in this stage of the disease (18) whereas the major systems were normal, even if the hemodynamic renal alterations with outer cortex vasoconstriction and opening of artero-venous shunts have been demonstrated in some cases (23,24). In other words, without a positive sodium balance, characterized by ascites and/or edema, the activation of vasoacting systems is generally mild or absent, justifying the minor effects of NSAIDs in this stage of the disease. During the end stage of decompensated cirrhosis, on the other hand, characterized by refractory ascites and the overt hepato-renal syndrome (HRS), PGs were decreased, with a relative prevalence, however, of TxB2 over 6-keto-PGFla and particularly over PGE2 (18). The exhaustion of this autacoid system may contribute to the imbalance between vasodilating and vasocostricting factors, resulting in occurrence of final vasoconstriction and hypoxia, and further worsening of renal function (18,25,26). In fact, in experimental models it has been shown that the contraction of isolated rat glomeruli or single isolated mesangial cells, may reduce the filtration surface area. Thus the GFR is reduced by TxA2 and angiotensin II, whereas PGE2 and PGI2 lead to mesangial relaxation. Moreover, pre-treatment with AA or the addition of exogenous PGE2 may inhibit angiotensin-mediated glomerular contraction (27). Clinically, the administration of thromboxane synthase inhibitors such as OKY 046, significantly improved the
201 diuretic and natriuretic effects of furosemide in patients with decompensated cirrhosis (28). Moreover, a thromboxane antagonist, ONO-3708, induced a significant increase in diuresis and free water clearance in patients with decompensated cirrhosis (29). These recent data seem to confirm the role of vasoconstricting factors, mainly TxA2, in inhibiting water excretion in cirrhotic patients. The latter, represented by stronger intra-renal vasoconstriction, may also explain the occurrence of acute tubular necrosis (ATN), during which an increase in urinary sodium excretion, together with a further increase in creatinine levels are sometimes seen in patients with terminal HRS (30). In this case, it is conceivable that after a long period of renal functional impairment (RFI), present in about 20% of compensated cases (24) and characterized by a significant reduction in renal clearances, and after a shorter period of more open renal impairment, characterized by a sudden elevation in BUN and creatininemia and a stronger reduction in sodium renal excretion, which corresponds to a real HRS, present in about 4% of decompensated cirrhosis, some organic alterations may occur. The exhaustion of renal autacoid systems may contribute to these alterations (30). Use of NSAIDs in cirrhosis NSAIDs constitute a heterogeneous group of compounds, which have several common effects, which are not chemically related. The most well known drug is acetylsalicylic acid (aspirin) and these molecules are also referred to as aspirin-like drugs. Many of the biological effects of NSAIDs are due to their ability to inhibit cyclooxigenase activity, thus reducing PG synthesis. According to Vane (31) and several other authors, these compounds generally do not modify renal function in healthy subjects, but may cause renal impairment in patients with congestive heart failure, chronic renal disease, several hypovolemic syndromes or decompensated cirrhosis (i 5,32,33). The first report of deleterious effects due to NSAIDs on renal function in decompensated cirrhosis was by Boyer et al. (34), who observed a reduction in RPF and GFR in a group of patients with chronic alcoholic liver disease and ascites following oral administration of indomethacin. These results were later confirmed by Zipser et al. (19,35), as well as by several other authors including our group (36), who showed the impairment of renal function following administration of indomethacin or ibuprofen, with a decreased urinary sodium excretion (36). In all these studies, the reduction of
202 renal function and sodium excretion was completely reversible, and lasted only as long as the drug was administered to the patients. However, the effect of NSAIDs on renal hemodynamics and function is markedly variable in patients with cirrhosis and ascites, and may be absent in some, despite the same degree of inhibition of renal PG synthesis. As reported by Zipser et al. (35), baseline urinary sodium excretion is the best predictor of patient susceptibility to the deleterious effects of these drugs patients with urinary sodium excretion lower than 1 mmol/day have a greater risk of developing renal failure following the administration of indomethacin or other NSAIDs. In general, high risk patients also tended to have greater plasma renin activity, plasma aldosterone concentrations and increased urinary excretion of PGE2 and 6keto-PGFlo~, but there was marked variability, and none of these parameters were found to be useful in predicting the renal response. Surprisingly, measurement of RPF and GFR had no value in identifying patients at risk. The renal effects of NSAIDs in patients with cirrhosis and ascites also depend on the pharmacokinetic and pharmacodynamic properties of these drugs. The ability to inhibit renal cyclooxigenase activity is especially relevant in this setting. The most potent inhibitor of renal PG synthesis is indomethacin, which affects GFR in almost all patients with cirrhosis and ascites. Ibuprofen and naproxen are somewhat less potent, and only impair renal function in susceptible patients (19,35). Oral aspirin is even weaker, whereas intravenous lysine aceylsalicylate has been shown to markedly impair renal function in most patients with cirrhosis and ascites (37). Sulindac was thought to be a unique NSAID due to its renal-sparing property. Indeed, this drug did not reduce renal PG excretion, RPF or GFR in patients with chronic glomerular disease susceptible to the nephrotoxic effects of ibuprofen. The renal-sparing activity was ascribed to the immediate renal catabolism of sulindac sulphide, the active metabolite of this drug (38). Different studies were therefore carried out to address the effects of sulindac on renal PGs and hemodynamics in cirrhotic patients with ascites (39). Laffi et al. (36) reported that 5-day treatment with sulindac (400 m/day) significantly reduced urinary excretion of PGE2 and TxB2 in ten cirrhotic patients with ascites, but only slightly affected urinary 6-keto-PGFla excretion. It did not modify renal function. Plasma levels of sulindac sulphide were 2-fold higher in patients with cirrhosis than in control subjects. Quintero et al. (40) observed a 40% decrease in GFR after a 3-day sulindac administration.
p. GENTILINI In that study, plasma levels of sulindac sulphide increased four times. These data indicate that in patients with liver diseases, sulindac may impair renal function, due to the accumulation of its active metabolite. Imidazole-salicylate is another NSAID which seemed to spare effects on cyclooxygenase activity. This drug, which appears less effective than another NSAID, piroxicam (41), has been shown to selectively inhibit TxA2 production, without influencing PGE2 synthesis in platelets and other circulating cells (42). Selective inhibition of renal TxA2 production by imidazole-salicylate could be useful since previous studies from our laboratory showed beneficial effects of inhibiting TxA2 production or activity. Indeed, in the present issue of this journal, Salerno et al. (43) reported that this drug did not inhibit renal prostanoid excretion or impair renal function in either baseline conditions or after the effects of furosemide. These results were obtained through an acute protocol in a group of patients with well compensated liver disease, as estimated by close to normal serum albumin concentrations and prothrombin times. Most of these patients had very low sodium excretion, a predictive index of the renal response to NSAIDs. However, individual susceptibility to the nephrotoxic effects of this drug was not tested in comparison to other NSAIDs, a family of drugs known to reduce renal function in patients with decompensated cirrhosis. Further studies, therefore, are needed before imidazole-salicylate can be considered a safe drug for cirrhotic patients requiring an NSAID, especially decompensated ones. These studies should mainly evaluate whether the PG sparing effect of this drug is maintained during chronic administration, as well as whether unrecognized nephrotoxic metabolites accumulate in patients with more advanced liver disease or cumulative inhibition of platelet TxA2 production further impairs platelet aggregation.
Acknowledgment This work was supported by Ministero dell'Universitfi. e della Ricerca Scientifica e Tecnologica and the Italian Liver Foundation.
References I 2
McCoy RN, Fried TA, Osgood RW. Stein JH. Release of prostaglandin E2 (PGE2) by a single isolated perfused glomerulus. Kidney Int 1985; 27: 297(A). Hura CE, Kunau RT Jr. Angiotensin II-stimulated prostaglandin production by canine renal afferent arterioles. Am J Physiol 1988; 254(5 Pt 2), F734-8.
203
RENAL FUNCTION AND NSAIDS 3 4 5
6 7 8
9
10
11
12
13 14
15 16
17
18 19 20 21
22
23 24 25
Dunn MJ. Kidney Hormones. Orlando, Academic Press 1986: Vol. 3, 397-461. Negus P, Tannen RL, Dunn MJ. Indomethacin potentiates the vasoconstrictor actions of angiotensin II in normal man. Prostaglandins 1976; 12: 175-80. Gerber JG, Branch RA, Nies AS, Cerkens .IF, Shand DG, Hollifield J, Oates JA. Prostaglandins and renin release. 11. Assessment of renin secretion following infusion of PGI2, E2 and D2 into the renal artery of anesthetized dogs. Prostaglandins 1978; 15: 81-8. Gerber JC, Ellis EF, Nies AS. The effect of endoperoxide analog on renal function and hemodynamics. Fed Proc 1977; 36: 402(A). Morrison AR, Nishikawa K, Needleman P. Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney. Nature 1977; 267: 259-60. Rosenthal A, Pace-Asciak CR. Potent vasoconstriction of the isolated perfused rat kidney by the leukotrienes C4 and D4. Can J Physiol Pharmacol 1983; 61: 325-8. Dunham EW, Zimmerman BG. Release of prostaglandin-like material from dog kidney during nerve stimulation. Am J Physiol 1970; 219: 1279-85. Needleman P, Kauffman AH, Douglas JR Jr Johnson EM, Marshall GR. Specificstimulation and inhibit!on of renal prostaglandin release by angiotensin analogs. Am J Physiol 1973: 224: 1415-9. Aiken JW, Vane JR. Intrarenal prostaglandin release stimulates the renal vasoconstrictor activity of angiotensin. J Pharmacol Exp Ther 1973; 184: 678-87. Kimberly RP, Bowden RE, Keiser HR, Plotz PH. Reduction of renal function by newer nonsteroidal anti-inflammatory drugs. Am J Med 1978; 64: 804-7. Berl T, Raz A, Wald H. Prostaglandin synthesis inhibition and the action of vasopressin: studies in man and rat. Am J Physiol 1977; 232: F529-37. Christensen NJ, Bygdeman M, Green K, et al. The prostaglandin analog 9-deoxo-16, 16-dimethyl-9-methylene-PGE2 inhibits the antidiuretic effect of vasopressin (AVP) in the conscious sheep. Pflugers Arch 1984; 402: 360-3. Patrono C, Dunn MJ. The clinical significance of inhibition of renal prostaglandin synthesis. Kidney Int 1987: 32: 1-12. Wong F, Massie D, Colman .I, Dudley F. CIomerular hyperfiltration in patients with well-compensated alcoholic cirrhosis. Gastroenterology 1993; 104: 884-9. Zipser RD, Hoefs JC, Speckart PF, Zia PK, Horton R. Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab 1979: 48: 895-900. Laffi G, La Villa G, Pinzani M, et al. Altered renal and platelet arachidonic acid metabolism in cirrhosis. Gastroenterology 1986; 90: 274-82. Zipser RD, Lifschitz MD. Prostaglandins and related compounds. In: Epstein M, ed. The kidney in liver disease. 3rd edn. Williams and Wilkins, Baltimore, 1988; 393-416. Henrich W. Role of the prostaglandin in renin secretion. Kidney int 1981; 19: 822-30. Pariente EA, Bareille E, Bercoff D, Lebrec D. Acute effects of captopril on systemic and renal hemodynamics in cirrhotic patients with ascites. Gastroenterology 1985; 88: 1255-9. Gentilini P, Romanelli RG, La Villa G, et al. Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver. Gastroenterology 1993; 104: 588-94. Epstein M, Berk DP, Hollenberg MK, et al. Renal failure in cirrhosis: the role of active vasoconstriction. Am J Med 1970: 49: 175-85. Gentilini P, Laffi G, Buzzelli G, et al. Functional renal alterations in chronic liver disease. Digestion 1980: 20: 73-8. Zipser RD, Radvan GH, Kronborg I, Duke R, Little TE. Urinary thromboxane B2 and prostaglandin E2 in the
26 27
28
29
30
31 32 33
34 35 36
37
38
39 40 41
42
43
hepatorenal syndrome: evidence for increased vasoconstrictor and decreased vasodilator factors. Gastroenterology 1983i 84: 697-703. Gentilini P, Laffi G. Renal functional impairment and sodium retention in liver cirrhosis. Digestion 1989; 43: 1-32. Dunn M.I. The role of arachidonic acid metabolites in renal homeostasis. Non-steroidal anti-inflammatory drugs renal function and biochemical, histological and clinical effects and drug interactions. Drugs 1987; 33(Suppl. I): 56-66. Pinzani M, Laffi G, Meacci E, La Villa G, Cominelli F, Gentilini P. intrarenal thromboxane A2 reduces the furosemide-induced sodium and water diuresis in cirrhosis with ascites. Gastroenterology 1988; 95: 1081-7. Laffi G, Marra F, Carloni V, Azzena G, De Feo M.L, Pinzani M, Tosti-Guerra C, Gentilini P. Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites. Gastroenterology 1992; 103: 1017-21. Gentilini P. Hepato-renal syndrome: differential diagnosis and therapy. Lecture at the Basel Liver Week 1992; Basilea, 15-17 Ottobre 1992, Falk Symposium no. 69 IX International Congress on Liver Diseases: extrahepatic manifestations in liver diseases (in press). Vane JR, Botting R. Inflammation and the mechanism of action of antiinflammatory drugs. FASEB J 1987; I: 89-96. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1984: 310: 563-72. Oates JA, Fitzgerald GA, Branch RA, Jackson EK, Knapp HR, Roberts LJ. Clinical implications of prostaglandin and thromboxane formation. New Engl J Med 1988; 319: 689-98, 757-67. Boyer TD, Zia P, Reynolds TB. Effect of indomethacin and prostaglandin AI on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979; 77: 215-22. Zipser RD. Role of renal prostaglandins and the effects of nonsteroidal anti-inflammatory drugs in patients with liver disease. Am J Med 1986; 81 (Suppl. 2B): 95-103. Laffi G, Daskalopoulos G, Kronborg l, Hsueh W, Gentilini P, Zipser RD. Effects of sulindac and ibuprofen it~ patients with cirrhosis and ascites. An explanation for the renal sparing effect of sulindac. Gastroenterology 1986; 90: 182-7. Planas R, Arroyo V, Rimola A, Peres-Ryuso RM, Rodes J. Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites. Gastroenterology 1983; 84: 247-52. Ciabattoni G, Cinotti GA, Pierucci A, et al. Effects of sulindac and ibuprofen in patients with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin. New Engl .I Med 1984; 310: 279-83. Juhl RP, Van Thiel DH, Dittert LW, Albert KS, Smith RB. Ibuprofen and sulindac kinetics in alcoholic liver disease. Clin Pharmacol Ther 1983: 34: 104-9. Quintero E, Gines P; Arroyo V, et al. Sulindac reduces urinary excretion of prostaglandins and impairs renal function in cirrhosis with ascites. Nephron 1986: 42: 298-303. Montrone F, Petrillo M, Ardizzone S, Scaricabarozzi I, Scotti A, Caruso l, Bianchi Porro G. Imidazole salicylate versus piroxicam in the treatment of arthrosis in elderly patients. A double-blind clinical and endoscopic trial. J Am Geriatr Soc 1990: 38: 985-8. Pagella PG, Bellavite O, Agozzino S, Dona GC, Cremonesi P. De Sands F. Pharmacological studies of imidazole 2hydroxybenzoate (ITF 182), an anti inflammatory compound with an action on thromboxane R2 production. Arzneimittelforsch/Drug Res 1983: 33: 716-26. Salerno F, Lorenzano E, Maggi A, Badalamenti S, Minuz P, Degan M, Chinea B, Scotti A. Effects of imidasolesalicylate on renal function and the diuretic action of furosemide in cirrhotics with ascites. J Hepatol 1993: 19: 279-84.