Eicosanoids in experimental and human renal disease

Eicosanoids in Experimental and Human Renal Disease

JOHN E. STORK, M.D. MOHAMED A. RAHMAN, M.D. MICHAEL J. DUNN, M.D. Cleveland,

The renal prostaglandins and thromboxanes are powerful autacoids with potential effects on renal hemodynamics, salt and water metabolism, and the immune system. The possibility of adverse effects on renal function in certain patients with renal disease due to cyclooxygenase inhibition with nonsteroidal anti-inflammatory drugs has long been appreciated. Experimental evidence indicates that renal prostaglandin and thromboxane production is increased in several models of renal disease and that similar decrements in renal function occur with cyclooxygenase inhibition and may be due to inhibition of vasodilator prostaglandins. Additionally, several investigators have shown that administration of prostaglandins may be therapeutic in some forms of renal disease, particularfy immunologically mediated diseases. Dietary modification to affect prostaglandin production has also been promising in certain experimental models. In contrast to vasodilator prostaglandins, thromboxane is a potent vasoconstrictor and would be expected to have adverse effects on renal function. Despite demonstration of elevated glomerular thromboxane, studies using inhibitors of thromboxane synthesis in immunologically mediated glomerular disease have been disappointing. There is some evidence, however, that these drugs may be of benefit in ureteric obstruction and renal transplant rejection.

Ohio

Autacoids are substances that exert their action in the same region in which they are produced. Renal prostaglandins and thromboxane are autacoids, since they are synthesized, act locally, and are degraded within the kidney. In recent years, the actions of these compounds in the kidney have been widely investigated, leading to an increasing understanding of their role in the pathophysiology of varied renal diseases. This review summarizes the mechanisms by which prostaglandins and thromboxane may influence renal function in both animal models of disease and human renal disease, with particular attention to immune glomerulonephritis, lupus nephritis, subtotal nephrectomy, acute renal failure, ureteric obstruction, and transplant rejection. From the Departments of Pediatrics and of Medicine, Case Western Reserve School of Medicine, and Division of Nephrology, University Hospital of Cleveland, Cleveland, Ohio. Drs. Rahman and Stork were supported by a training grant from the National Institutes of Health (AM-07470). This work was partially funded by a grant from National Institutes of Health (HL-22563). Requests for reprints should be addressed to Dr. M.J. Dunn, Division of Nephrology, University Hospital of Cleveland, Cleveland, Ohio 44106.

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IMMUNE GLOMERULONEPHRITIS, INCLUDING LUPUS NEPHRITIS Exogenous Prostaglandin Therapy in Experimental Glomerulonephritis. Early evidence for the importance of prostaglandins in glomerulonephritis comes from studies demonstrating the therapeutic efficacy of exogenous prostaglandins in animal models of disease. Much of this work has involved treatment of a murine model of systemic lupus erythematosus, the NZB X NZW mouse, with the stable prostaglandin prostaglandin E,. Zurier and co-workers [l] demonstrated an impressive ben-

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efit using long-term pharmacologic dosages of prostaglandin El administered subcutaneously, with 18 of 19 treated and two of 19 untreated animals surviving at one year. A marked difference was seen on histologic examination of the kidneys, with little or no evidence of glomerular proliferation and sclerosis in the treated group [2]. Later studies showed that prostaglandin El therapy delayed until six months of age was also effective in prolonging survival, although it had no effect on proteinuria and glomerular changes already present at that time [3]. Kelley, Winklestein, and colleagues [4-71 have had similar results with both prostaglandin E, and prostaglandin E2 in NZB X NZW mice, as well as in a second model of murine lupus, the MRUI mouse. As with NZB X NZW mice, prostaglandin E, therapy in the MRUI model prevented proteinuria, immunoglobulin deposition, capillary loop and mesangial immune complex deposits, and glomerular hypercellularity. In addition, there was inhibition of T-cell proliferation and a reduction in the amount of circulating immune complexes to the retrovirus (anti-gp70) and several subclasses of immunoglobulin G. E series prostaglandins are also effective in other models of immune glomerular disease. Therapy with either prostaglandin E, or prostaglandin E2 decreased proteinuria and prevented glomerular damage in a murine model of immune complex glomerulonephritis that was induced by daily injections of apoferritin [8,9]. A reduction in the synthesis of specific anti-apoferritin antibody, as demonstrated by McLeish and colleagues [8,9], appears to be responsible for the salutary effects. Kunkel and co-workers [IO] have shown a reduction in proteinuria and a decrease in glomerular hypercellularity in rats with nephrotoxic serum nephritis (anti-glomerular basement membrane disease) treated with 15(S)-15methyl prostaglandin E,, either 24 hours before or 24 hours after nephrotoxic serum injection. In this case, a direct effect on the immune response seems likely, as therapy did not alter the deposition of anti-glomerular basement membrane antibody. The mechanism of action of prostaglandin E therapy is probably multifactorial and is undoubtedly related to the immunoregulatory actions of the prostaglandins. Although levels of anti-DNA antibodies were not decreased by prostaglandin E therapy in any of the studies on murine lupus, lzui et al [ll] were able to demonstrate a reduction in the production of retroviral gp70-anti-gp70 immune complexes in the NZB X NZW mouse with prostaglandin E, therapy. In addition to the well-known pro-inflammatory effects of prostaglandins, prostaglandins El and E2 have anti-inflammatory, immunoregulatory effects on both cellular and humoral immune responses. As reviewed by Goodwin and colleagues [12,13] several investigators have shown that the suppressor effects of glass-adherent T cells on DNA synthesis in phytohemagglutinin-stimulated nonadherent lymphocytes can be reversed by cyclooxygenase inhibition. The suppression does not appear to be a direct effect

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of prostaglandin on the mitogen-responsive cell. Rather, a glass-adherent cell, probably a monocyte, produces prostaglandin E2, which activates a glass-adherent T-suppressor cell to produce a substance that suppresses the mitogen response of the nonadherent cells. In support of this, Rogers and colleagues [14] have shown that glass-adherent T cells in response to exogenously added prostaglandin El or prostaglandin E2 release a low molecular weight peptide that is highly suppressive of both T- and B-cell mitogenesis. Prostaglandin may also play a role in B-cell regulation. Zimecki and Webb [15] demonstrated a 50 to 300 percent increase in plaque-forming cells produced in mouse splenocytes exposed to the T-independent antigens polyvinyl pyrolidone and dinitrophenol-Ficoll, when the cells were initially treated with cyclooxygenase inhibitors. Similarly, Webb and Osheroff [16] found an increase in plaque-forming cells after sheep red blood cell immunization in mice pretreated with indomethacin. Both of these studies imply that prostaglandins may have a negative modulatory role on B-cell proliferation and antibody production. Other actions of prostaglandins may involve natural killer cells and neutrophil function. Natural killer cells are a subpopulation of lymphocytes, distinct from T and B cells, that can have a direct cytotoxic effect on other cells. In a study by Brunda and colleagues [17] prostaglandin E, and prostaglandin E2 both had a marked depressive effect on mouse natural killer cell activity in vitro. With respect to neutrophil function, Fantone and co-workers [18] have shown that prostaglandin E, suppresses the release of lysosomal enzymes by rat neutrophils, possibly through an action on the formyl peptide chemotactic receptor of the neutrophil. Sedgwick et al [19] have recently shown that prostaglandins El and E2 inhibit the production of superoxide anion by polymorphonuclear leukocytes stimulated with formyl peptide. Interestingly, as in the previous study, this action also seems to be linked to the formyl peptide receptor, since the effect was not seen in leukocytes stimulated with phorbol myristate acetate or serumtreated zymosan. Dietary Fatty Acids in Experimental Glomerulonephritis. In addition to the studies of pharmacologic actions of prostaglandins, other workers have examined the effect of alterations in dietary lipids on cyclooxygenase metabolites and progression of disease in several experimental models of immune glomerular disease. The usual precursor of the naturally occurring dienoic prostaglandins and thromboxane is arachidonic acid, a 20-carbon molecule with four double bonds. Dietary substitution of eicosapentaenoic acid, 20 carbons with five double bonds, has the effect of decreasing the production of the dienoic prostaglandins, including prostaglandin E2 and thromboxane A*, and increasing the synthesis of trienoic eicosanoids. Prickett and co-workers [20,21] first demonstrated that a diet containing menhaden fish oil (high in eicosapen-

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= ANG II only AA = Arachidonate 3#M + ANGII PGE2= PGE2 IO-‘+ ANG II Ind = Indomethacin 15~1uM + ANGlI

Ind

Figure 1. The effects of indomethacin (Ind), prostaglandin E2 (PGEd, and arachidonic acid (AA) on angiotensin II (ANG I/)-mediated reductions in rat glomerular planar surface area. All glomerular sizes have been normalized so that 100 percent is the control surface area. Reproduced with permission from [32].

Id-.-----?A

ANGII

(M)

taenoic acid) was markedly protective of renal function in NZB X NZW mice, compared with a control diet using beef tallow. This finding was recently confirmed for the MRLlpr murine model by Kelley et al [22], who found decreased levels of prostaglandin EP,thromboxane BP,and 6-keto-prostaglandin F,, in multiple tissues, including kidney from MRL-1 pr mice fed menhaden oil, compared with animals fed safflower oil (rich in arachidonate). Levels of trienoic prostaglandin E3 were increased. Additionally, the menhaden oil diet prevented the increase in macrophage surface immune-associated antigen that is usually seen, reduced formation of circulating retroviral gp70 immune complexes, decreased lymphoid hyperplasia, delayed the onset of renal disease, and prolonged survival. These results initially seem to be at odds with the previously described efficacy of pharmacologic dosages of prostaglandin EP. Along with the obvious difference between exogenous administration of large doses, and in vivo alteration of the production of these autacoids, this may reflect a role for thromboxane A*, since the content of thromboxane B2 was also diminished by the menhaden oil diet. Thromboxane may have an immunoregulatory action in addition to its well-known role in platelet aggregation and as a vasoconstrictor, because Kelly and co-workers [23] have demonstrated inhibition of mitogenesis in human lymphocytes by selective inhibitors of thromboxane synthesis. Although speculative, it is possible that increased production of prostaglandin E3 served to ameliorate the effects of a decreased prostaglandin E2 production; the net effect of supplementation with elcosapentaenoic acid would then be decreased produc-

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tion of thromboxane BP,thereby accounting for the beneficial action. Eicosanoids in Experimental Glomerulonephritis. The hemodynamic effects of prostaglandins and thromboxane in glomerular disease have been studied extensively in our laboratory, as well as by others. Isolated glomeruli have been shown to synthesize prostaglandin Fti prostaglandin Ea, thromboxane A2 (measured as thromboxane B2), and prostaglandin E2 (measured as 6-ketoprostaglandin F,,) [24,25]. Mesangial and glomerular epithelial cells in culture also produce eicosanoids, with mesangial production greater than epithelial production when adjusted for cell protein [26,27]. Glomerular, particularly mesangial, production of prostaglandins and thromboxane could well be important in modulating glomerular function in health and disease. In addition to eicosanoids produced by native renal cells, platelets and infiltrating white blood cells and macrophages might contribute to the overall production of eicosanoids in glomerular disease. Thromboxane is a potent vasoconstrictor, whereas prostaglandin E2 and prostacyclin cause vasodilation [28]. The effects of prostaglandin E2 on renal hemodynamics in rats have been controversial, although the weight of the evidence now rests with it having a role as a vasodilator as it does in other species [29,30]. Prostaglandin EP, as well as prostacyclin, is a potent stimulator of renin secretion [31], especially in large doses. In initial experiments in intact rats, this appears to have masked the vasodilatory effects of prostaglandin EP,resulting instead in weak vasoconstriction. In addition to this direct vasodilation, vasoconstriction, and stimulation of renin release, the prosta-

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Figure 2. The effects of nephrotoxic serum on clearance rates of inulin (CJ and para-aminohippurate (C,,.J and glomerular prostaglanclin synthesis. Clearance of i&in and clearance of paraaminohippurate acid are shown on the left ordinate, and changes in glomerular prostaglandin synthesis, expressed as fold increments compared with simultaneous controls, are plotted on the right ordinate. At time 0, antiglomerular basement membrane antibodies (nephrotoxic serum) were injected, and clearance measurements, as well as glomerular eicosanoid synthetic capacity, were measured at hourly intervals for three hours. The decrements in glomerular filtration rate and renal plasma flow coincided with progressive increments in glomerular thromboxane synthesis. NTN = nephrotoxic nephritis; TX& = thromboxane &; PGF,, = prostaglandin Fza; PGE2 = prostaglandin Es 6KF,, = 6-keto-prostaglandin F,,. Reproduced with permission from 1411.

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1 18 16

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glandins and thromboxane potentially alter intraglomerular hemodynamics through actions on the glomerular mesangium. Stable endoperoxide analogues of thromboxane A*, as well as thromboxane A2 generated by sheep platelet microsomes, cause dose-related contraction of isolated glomeruli, as demonstrated by Scharschmidt and colleagues [32]. Conversely, prostaglandin E2 attenuates angiotensin II-induced glomerular contraction [32] and is, therefore, a mesangial relaxant. Further evidence of this relaxant role is presented in Figure 1, from the work of Scharschmidt et al [32,33]. As shown, the cyclooxygenase inhibitor indomethacin potentiates the contractile response of isolated glomeruli to angiotensin II, resulting in a lower threshold for contraction. Prostaglandin E2 and arachidonic acid antagonize the contractile actions of angiotensin II. These mesangial actions of eicosanoids might be important in the control of intraglomerular blood flow and pressures, regulation of the glomerular ultrafiltration coefficient, and modulation of glomerular filtration. In addition to the prostaglandins and thromboxane, other eicosanoids, such as the products of the lipoxygenase pathway, may be important in glomerular disease. Isolated glomeruli have been shown to possess the 12lipoxygenase enzyme, and can produce 12-hydroxyeicosatetraenoic acid, a pro-inflammatory, chemotactic lipid [34]. Although glomeruli do not appear to have 5lipoxygenase, other hydroxy-eicosatetraenoic acids and the leukotrienes, which are products of 5-lipoxygenase, might be produced and released in significant amounts by neutrophils and other infiltrating inflammatory cells.

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2h

3h

Ballerman and co-workers [35] have demonstrated a glomerular receptor for leukotriene Cq, whereas Dunn and Simonson [36] have shown that both leukotriene Cq and D4 stimulate contraction in mesangial cell cultures. With respect to the whole kidney, leukotriene C4 decreases the glomerular filtration rate and renal blood flow and may affect glomerular permeability [37]. We have studied the role of eicosanoids in two experimental models of glomerular disease, nephrotoxic serum nephritis and immune complex glomerulonephritis, utilizing cationized bovine gamma globulin. The short-term effects of nephrotoxic serum are well known. There is a rapid decrease in both renal plasma flow and glomerular filtration rate, reaching a nadir at two hours after injection [38,39]. The initial decrease in renal plasma flow appears to be mediated by alpha-adrenergic catecholamines, since phentolamine is able to reverse the decrease at 45 minutes [40]. As is shown in Figure 2, Lianos et al [41], working in this laboratory, showed increased production of thromboxane BP, the stable metabolite of thromboxane AZ, in glomeruli isolated from rats two hours after nephrotoxic serum administration. This increase coincided with the nadir in the glomerular filtration rate and renal blood flow. Pretreatment of animals with either OKY-1581 or UK-38,485, both inhibitors of thromboxane synthesis, partially prevented the acute decrements in renal plasma flow and glomerular filtration rate, as is depicted in Figure 3 for UK-38,485. This establishes the functional significance of the elevation in glomerular thromboxane. We have also examined glomerular prostaglandin and thromboxane at later stages of nephrotoxic serum nephritis. Data shown in

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pg/mg

1.2

Glom Wt/45

min

-

z 8

l.O-

2 E 1 E G E cl

0.8 -

1 TxB, 6KF,, PGE,

17.0 506 155115 i f 236

TxB, PGE, 6KF,,

612i61 596 f 59 133111

0.6 0.4 0.2 01

I

I

I

lh

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3h

’

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4 are at 24 hours and 14 days after nephrotoxic serum administration. Both thromboxane B2 and prostaglandin E2 production remain elevated, with the concentration of prostaglandin E2 about twice that of thromboxane B2 [42]. Renal vasodilation accompanies these changes. At 14 days, renal plasma flow was increased to 11.7 + 1.O ml per minute, compared with 7.0 + 0.6 ml per minute for control subjects. Glomerular filtration rate is,

Figure

NSN DAY 1

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cl

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fza

bketo

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F,

igure 4. Glomerular eicosanoid synthesis in nephrotoxic serum nephritis (NSN). Data for rats with nephrotoxic serum nephritis are shown after injection of nephrotoxic serum on Days 1 and 14. l *=p < 0.01 versus control. Reproduced with permission from 1421.

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Figure 3. The effects of UK-38,485, a thromboxane synthetase inhibitor (A). on the glomerular filtration rate (GFR) in nephrotoxic serum (NTS) nephritis. Control animals (x) received only nephrotoxic serum. Inhibition of glomerular thromboxane production without augmentation of prostaglandin E2 (PGEJ or prostacyclin is shown. UK-38,485 completely prevented the nephrotoxic serum-induced decrement in glomerular filtration rate that was mediated by thromboxane. TxBp = thromboxane Bz; 6KF,, = 6-ketoprostaglandin F,,. Reproduced with permission from 1411.

therefore, essentially normal at 14 days, although the filtration fraction remains depressed. The role of a vasodilator prostaglandin (E2) is shown in Figure 5. Although inhibition of thromboxane A2 with UK-36,465 had no effect in the vasodilated kidney, renal plasma flow and glomerular filtration rate were both markedly diminished by either of two cyclooxygenase inhibitors, indomethacin or meclofenamate. Thus, in nephrotoxic serum nephritis, vasoconstrictor thromboxane A2 appears to mediate early decrements in renal plasma flow and glomerular filtration rate, whereas at later stages vasodilator prostaglandin E2 augments renal plasma flow, thereby maintaining glomerular filtration rate. Long-term therapy with the thromboxane synthetase inhibitor OKY-1561 was also examined. No effect on renal blood flow, glomerular filtration rate, or proteinuria was seen. Thus, inhibition of the early increase production of thromboxane A2 does not appear to affect the course of the disease [42]. Kaizu et al [43] have recently confirmed our findings with respect to prostaglandin E2 in nephrotoxic serum nephritis. They found no reduction in glomerular filtration rate in rats with autologous phase nephrotoxic serum nephritis, despite a major reduction in glomerular ultrafiltration coefficient. Urinary prostaglandin E2 excretion was elevated compared with control subjects. Treatment with indomethacin, as in our study, decreased renal blood flow and glomerular filtration rate in animals with nephrotoxic serum nephritis, but not control animals. A further interesting finding is that treatment with saralasin resulted in a decrease in urinary prostaglandin E2 excretion in rats with nephrotoxic serum nephritis and a significantly greater increase in renal blood flow compared with the values in control rats. Thus, animals with autologous nephrotoxic serum nephritis appear to have increased intrarenal activity with angiotensin II, and increased production of vasodilator prostaglandin E2 may

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be, in part, a modulatory response. In sharp contrast to our studies of those of Kaizu et al [43], Kurokawa and Sakamoto [44] found that pretreatment with aspirin prevented the development of proteinuria in rats with nephrotoxic serum nephritis. Interestingly, they saw no change in glomerular filtration rate or renal plasma flow in the treated group and, therefore, postulated that aspirin prevented some aspect of the pathologic process. Lianos and Dunn [45] examined the lipoxygenase pathway in isolated glomeruli from rats with nephrotoxic serum nephritis. Although production of 12-hydroxy-eicosatetraenoic acid is greatly increased in the group with nephrotoxic serum nephritis, no 5-lipoxygenase products could be detected in either control or nephrotoxic serum nephritis animals. 12-Hydroxy-eicosatetraenoic acid is a potent chemotactic agent, as previously noted, and may well play an important role in neutrophil infiltration in nephrotoxic serum nephritis. Recent experiments in our laboratory have examined the role of prostaglandin E2 in a rat model of immune complex-mediated glomerulonephritis, produced by repeated immunization with either neutral or cationized bovine gamma globulin [46]. In animals immunized with cationized bovine gamma globulin, proteinuria developed; animals were also found to have immune deposits and complement deposition in capillary walls. The animals receiving neutral bovine gamma globulin demonstrated sparse mesangial immune deposits, but did not have either complement deposition or proteinuria. Glomerular production of thromboxane B2 and prostaglandin E2 were increased only in the rats treated with cationized bovine gamma globulin. Glomerular filtration rate and renal blood rate were also examined. As in the studies of nephrotoxic serum nephritis, renal blood flow was significantly elevated, resulting in attenuation of any decreases in glomerular filtration rate. As shown in Figure 6, these changes were dependent on vasodilator prostaglandins, since indomethacin therapy resulted in a 30 to 40 percent decrease in both renal plasma flow and glomerular filtration rate. This model of disease appears to be without significant infiltration by neutrophils and monocytes, making it likely that the increased production of glomerular eicosanoids is from native glomerular cells. Human Studies. Evidence for a role of prostaglandins and thromboxane in human renal disease comes from two sources: trials using nonsteroidal anti-inflammatory drugs as therapy for glomerulonephritis or nephrotic syndrome, and measurements of urinary prostaglandin and thromboxane excretion in patients with glomerular disease. Arisz and colleagues [47] reported in 1976 on the effects of indomethacin on proteinuria and kidney function in 19 patients with nephrotic syndrome secondary to varied glomerular lesions, and they described a 55 percent decrement in proteinuria, along with a 35 percent decrease in the glomerular filtration rate. Despite the marked reduc-

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17,1996

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Jgure 5. The effects of thromboxane synthetase inhibitioi with UK-38,485 and cyclooxygenase inhibition with indomethacin or meclofenamate on renal plasma flow (RPF) and glomerular filtration rate (GFR) in nephrotoxic serum nephritis (NSN). On Day 14 of nephrotoxic serum nephritis, thromboxane synthesis was inhibited with UK-38,485, followed by the administration of a nonsteroidal anti-inflammatory drug (NSAID) to inhibit prostaglandin E2 synthesis. **=p < 0.05 versus control. Reproduced with permission from 1421.

I

IO 8-

F

*

p
RPF \*

64-

GFR L-<*

21

Before lndomethocin

After lndomethacin

I

Figure 6. The effects of indomethacin on glomerular filtration rate (GFR) and renal plasma flow (RPF) in immune-complex nephropathy. The short-term administration of indomethacin significantly reduced renal plasma flow and glomerular filtration rate in rats rendered nephrotic by repeated injections of cationized bovine gamma globulin. Reproduced with permission from [46].

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tion in the glomerular filtration rate, the efficacy of indomethacin in reducing proteinuria attracted interest, and these findings were confirmed by several other investigators, among them Michielsen, Tiggeler, and their co-workers [48-501. The detrimental effects of nonsteroidal antiinflammatory drugs on renal function have also been demonstrated in patients without the nephrotic syndrome. In 21 hypertensive patients with chronic parenchymal renal disease but without nephrotic syndrome, Ruilope et al [51] noted a 19 percent decrease in creatinine clearance with 2 mg/kg per day of indomethacin over three days. The data from these studies are therefore in agreement with the animal data, demonstrating a major role for vasodilator prostaglandins in the compensatory response to glomerular disease. In 14 patients with chronic glomerulonephritis, studied by Kutyrina et al [52], indomethacin caused a decrease in the glomerular filtration rate. These same patients had marked elevations in plasma renin activity, compared with other patients in whom indomethacin had little effect. Thus, as in the rat study of nephrotoxic serum nephritis by Kaizu et al [43], vasodilator prostaglandins may be a modulatory response to increased angiotensin II vasoconstrictor activity. The decrement in proteinuria seen in many of these studies may be of some clinical significance. The decrease occurs acutely and is reversible with discontinuation of the drug. It is potentiated by sodium restriction and diuretics. The response is also variable, and it is difficult to predict.which patients might respond. Although the decrement in proteinuria was initially believed to be merely a consequence of the decreased glomerular filtration rate (decreased filtered load of protein), some workers have shown a disassociation between the effect on proteinuria and that on the glomerular filtration rate [50]. Another mode of action might be through alterations in glomerular hemodynamics, with effects on glomerular permeability. In the study by Tiggeler and colleagues [50], there appeared to be direct effects on the glomerular permeability to macromolecules, since these investigators were able to show that indomethacin reduced the abnormally high clearance of neutral polyvinyl pyrolidine macromolecules noted in the nephrotic patients studied. Data on urinary excretion provide additional evidence for the role of prostaglandins and thromoboxane in glomerular disease. Abe and co-workers [53] have shown increased urinary prostaglandin E2 in patients with chronic renal failure. In contrast, Colina-Chourio and colleagues [54] have demonstrated decreased urinary prostaglandin E2 in patients with acute post-streptococcal glomerulonephritis, and similar findings for prostacyclin, measured as 6-keto-prostaglandin F,,, have been published by Ciabattoni et al [55]. Despite the decreased 6-keto-prostaglandin F,, production, renal function in these patients was dependent on vasodilatory prostaglandins. Therapy with ibu-

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profen further reduced urinary 6-keto-prostaglandin F,, by 80 percent; concomitant with this was a 40 percent increase in the serum creatinine level, and 28 and 35 percent decreases in the creatinine and sodium paraaminohippurate acid clearances, respectively, as shown in Figure 7. Thus, this study is in agreement with the earlier cited works on nonsteroidal anti-inflammatory drugs in chronic renal disease. Interestingly, Ciabattoni’s group examined a second nonsteroidal anti-inflammatory drug, sulindac, which was without effect on either renal prostacyclin synthesis or renal function. This “renal protective” effect of sulindac has been previously reported by Ciabattoni et al [56], confirmed in normal women by Sedor and colleagues [57], and may result from conversion of the active drug to an inactive form by the kidney. The effect may be dose dependent because Swainson and Griffiths [58] saw some effect on renal blood flow with long-term administration of larger dosages to subjects with decreased renal function. The importance of prostaglandins in glomerular disease secondary to systemic lupus erythematosus was first examined in 1978 by Kimberly and colleagues [59]. In addition to finding increased urinary excretion of prostaglandin EP,their study demonstrated a significant detrimental effect of aspirin on renal function, probably secondary to its cyclooxygenase inhibition. Patron0 and co-workers [60] reported increased urinary thromboxane B2 and decreased urinary 6-keto-prostaglandin F,, in patients with systemic lupus erythematosus. In contrast to the urinary thromboxane B2, no increase was seen in platelet thromboxane B2 in whole blood or in urinary 2,3-dinor thromboxane B2, a major metabolite that primarily reflects extrarenal thromboxane. Thus, the increased urinary thromboxane B2 appears to reflect renal production. Urinary thromboxane B2 was inversely correlated and urinary 6-keto-prostaglandin F,, was positively correlated with creatinine clearance. In several of the patients, ibuprofen decreased urinary 6-keto-prostaglandin F,, by 77 percent and urinary thromboxane B2 by 67 percent. Clearances of creatinine and para-aminohippurate acid were diminished by 26 and 34 percent, respectively. This implies a predominance of vasodilator over vasoconstrictor eicosanoids, as seen in the animal models previously described. SUBTOTAL

NEPHRECTOMY

Attention has been focused recently on the progressive nature of renal failure after severe reductions in renal mass. The progressive decrease in glomerular filtration rate appears to be the result of increasing glomerulosclerosis. The major hypothesis invoked to explain the declining renal function is that glomerular hyperfiltration and hyperperfusion, which develop in response to the initial loss of functioning nephrons, cause glomerular injury and

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IBUPROFEN

SULINDAC

1-2g;day

O-49. day J-----J Serum Creatinine %

Creatimne

Figure 7. Changes in renal function expressed as percentage of control values during administration of Sulindac or ibuprofen to patients with chronic glomerulonephritis. Serum creatinine, creatinine clearances, and para-aminohippurate acid clearances were measured before, during, and after one week of therapy with either sulindac, 0.4 g per day, or ibuprofen, 1.2 g per day, in 10 patients with chronic glomerulonephritis assigned to each group. The data are normalized to a percentage of control values. Reproduced with permission from [55].

ET AL

,-

n

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sclerosis [61-631. If true, it is possible that vasodilatory prostaglandins play a role in this hyperfiltration, since cyclooxygenase inhibition has been shown to decrease the glomerular filtration rate in animals with renal failure due to partial ablation [64,65]. Evidence against this hypothesis comes from recent work by Purkerson and colleagues [66], who demonstrated increased urinary excretion of vasoconstrictor thromboxane in rats with ablation of more than 70 percent of the renal mass. Administration of the thromboxane synthesis ihhibitor OKY-1581 resulted in an increased renal plasma flow and glomerular filtration rate, decreased proteinuria and thromboxane B2 excretion, decreased blood pressure, and reduced glomerular histologic changes. OKY-1581 had no effect in normal rats or in ablated rats pretreated with aspirin, suggesting that the effects of the drug were due to inhibition of thromboxane A2 synthesis. The investigators proposed that these results may depend on inhibition of platelet aggregation and that intraglomerular thrombosis, rather than hyperfiltration, is responsible for the development of glomerulosclerosis. Earlier work in which subcutaneous heparin prevented the development of progressive renal failure in rats with partial renal infarction also supports this belief [67]. Further indirect evidence against prostaglandin Eamediated hyperfiltration as a cause of glomerulosclerosis comes from a study by Barcelli and colleagues [68], who found that partial nephrectomy increased medullary

January

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=t,r,,,#,,~nnrlm,n‘

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thromboxane B2 content. Additionally, long-term feeding of a diet high in linoleic acid resulted in increased cortical prostaglandin E2 and prevented deterioration of renal function, thereby implying that prostaglandin E2 had a protective function. ACUTE RENAL

FAILURE

The role, if any, of prostaglandins and thromboxane in acute renal failure, either ischemic or nephrotoxic, remains uncertain. An increase in whole kidney prostaglandin E2 in experimental acute renal failure due to glycerol or mercuric chloride has been reported by Torres and co-workers [69,70]. Benabe et al [71] showed increased thromboxane production by isolated perfused rabbit kidneys previously injured by glycerol administration in vivo. Sraer and colleagues [72], working with isolated glomeruli from glycerol-injured rats, showed increased production of thromboxane B2 and increased production of prostaglandin E2 at both 24 and 48 hours after glycerol administration. Pharmacologically, prostaglandin El has been shown to be protective in norephinephrine-induced acute renal failure, but not in that due to uranyl nitrate [73]. Various combinations of vasodilators, including mannitol, furosemide, and dopamine have some protective effect in acute renal failure, especially if given before the insult. The protective effect of mannitol may well involve vasodilatory prostaglandins, since indomethacin has been

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HETES

. .“.-...-., I

4 Antibody production 4 Neutrophil function /

I Vasodilzk Modulates

Figure 8. Summary of major actions by which eicosanoids both mediate and modulate renal disease. HETES = hydroxy-eicosatetraenoic acids; TXAp = thromboxane AZ; PG E2 = prostaglandin E2; PG12 = prostaglandin I*.

Vasoconstriction

shown to blunt the vasodilatory effect of mannitol [74]. Conversely, indomethacin does not block the protective effect of furosemide, despite the fact that furosemide is known to stimulate prostaglandln synthesis in the kidney [75]. In humans with acute tubular necrosis, the urinary excretion of prostaglandin E2 is low during the oliguric phase and then increases markedly with the onset of diuresis and recovery [76]. Whether this phenomenon is responsible for, or is a result of, the diuresis is unclear. URETERIC OBStRUCTION REJECTION

AND RENAL

ALLOGRAFT

The initial response of the kidney to short-term unilateral ureteric obstruction is vasodilation of the afferent arteriole [771. With persistent obstruction, vasoconstriction develops, resulting in a decrease in the glomerular filtration rate and renal plasma flow by 24 hours. The initial vasodilatory response to short-term obstruction appears to be dependent of prostaglandin E2 and can be blocked by indomethatin [78,79]. Conversely, with long-term obstruction, Morrison and co-workers [80,81] demonstrated increased renal production of thromboxane BP. Treatment with imidazole, a thromboxane synthesis inhibitor, after 25 hours of obstruction reversed the vasoconstriction [82]. However, the resultant vasodilation is blocked by indomethacin; this implies that a vasodilator prostaglandin (prostaglandin E2 or prostacyclin) may be responsible. The tone of the afferent arteriole would then depend on the balance between vasoconstrictor and vasodilator eicosanoids. The source of increased thromboxane production may be infiltrating monocytes and cortical fibroblasts, since Okegawa and co-workers [83,84] have demonstrated that the increased 42

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thromboxane production in obstructed kidneys is dependent on the presence of these cells. Thromboxane also appears to play a major role in renal allograft rejection. Rejection is often accompanied by intense vasoconstriction. Early studies by Foegh et al [85] demonstrated a 1.5 to 2.5-fold increase in immunoreactive thromboxane B2 in the urine of patients one to three days before clinically apparent allograft rejection. Methylprednisolone therapy was accompanied by a marked and immediate decrease in urinary thromboxane B2. To study this further, Coffman and colleagues [SS] used a reproducible animal model of allograft rejection in the rat. In addition to showing increased thromboxane B2 production by ex vivo perfused renal allografts, they were able to demonstrate that administration of the thromboxane synthetase inhibitor UK-37,248 was effective in decreasing urinary thromboxane B2 excretion and increasing renal blood flow and glomerular filtration rate. Cyclophosphamide therapy was also effective in decreasing urinary thromboxane B2. In this situation, a likely source for the increased thromboxane B2 is from infiltrating cells, although stimulation of renal production by inflammatory mediators cannot be ruled out. Whether this will eventually have clinical significance remains to be seen. EFFECTS

OF EICOSANOIDS

Figure 8 summarizes the major actions by which eicosanoids both mediate and modulate renal disease. On the left of the figure, both leukotrienes and thromboxane potentially have vasoconstrictor effects on the kidney; prostaglandin E2 and prostacyclin are either vasodilatory or modulate the activity of vasoconstrictors. In the center

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of the figure are depicted glomerular actions, with thromboxane and leukotrienes causing glomerular contraction and prostaglandin E2 exerting relaxant effects. The question of eicosanoid effects on macromolecular permeability remains open. On the right of the figure are shown the immunoregulatory actions, with prostaglandin E2 acting to suppress cell-mediated and possibly humoral immunity. Conversely, lipoxygenase products are chemotactic and immune stimulatory. Finally, although it has not been discussed, on the far right are shown the proaggregatory effects of thromboxane on platelets, countered by the inhibitory effects of prostacyclin.

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Inhibitor studies, including those with nonsteroidal antiinflammatory agents as well as those with more specific inhibitors of thromboxane, provide evidence for the functional significance of these changes in production. The knowledge that nonsteroidal anti-inflammatory drugs may be both beneficial in treatment, as seen with the reductions in proteinuria in nephrotic syndrome, and deleterious to renal function is clinically important. Sulindac may well provide a safer agent that does not affect renal prostaglandin production, although this may be dose related. Thus, the effective therapeutic window may be small. Further work in this area also holds forth the promise of future therapeutic benefit in certain specific situations. Examples might be the use of thromoboxane synthesis inhibitors in renal transplant rejection or therapeutic alteration of the immune response with prostanoids. Manipulation of the lipoxygenase pathway may be of even greater benefit, but this will require further evaluation.

COMMENTS

The data showing changes in glomerular eicosanoid production in animal models and in urinary eicosanoid excretion in human studies are persuasive evidence of alterations in these arachidonate metabolites in disease.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

Zurier FIB, SayadoffDM, Torrey SB, et al: Prostaglandin El treatment of NZB/NZW mice. I. Prolonged survival of female mice. Arthritis Rheum 1977; 20: 723-728. Zurier RB, DamjanovI, SayadoffDM, et al: ProstaglandinE, treatment of NZB/NZW mice. II. Prevention of glomerulonephritis. Arthritis Rheum 1977; 20: 1449-1456. Zurier RB, Damjanov I, Miller PL, et al: Prostaglandin El treatment prevents progression of nephritis in murtne lupus erythematosus. J Clin Lab lmmunol 1978; 1: 95-101. Kelley VE, Winklestein A, lzui S: Effect of prostaglandin E on immune-complex nephritis in NZBW mice. Lab Invest 1979; 41: 531-539. Winklestein A, Kelley VE: The effects of PGE, on lymphocytes in NZB/W mice. Clin lmmunol lmmunopathol 1980; 16: 316323. Kelley VE, Winklestein A, lzui S, et al: Prostaglandin E1 inhibits T-cell proliferation and renal disease in MRUl mice. Clin lmmunol lmmunopathol 1981; 21: 190-203. Winklestein A. Kellev VE: Effects of PGE, in murine models of SLE: changes in ckculating immune complexes. Clin lmmunol lmmunopathol 1981; 20: 188-l 92. McLeish KR, Gohara AF, Gunning WT: Suppression of antibody synthesis by prostaglandin E as a mechanism for preventing murine immune-complex glomerulonephritis. Lab Invest 1982; 47: 147-152. McLeish KR, Gohara AF, Stelzer GT, et al: Treatment of murine immune-complex glomerulonephritis with prostaglandin EP: dose response of immune complex deposition, antibody synthesis, and glomerular damage. Clin lmmunol lmmunopathol 1983; 26: 18-23. Kunkel SL, Zanetti M, Sapin C: Suppression of nephrotoxic serum nephritis in rats by prostaglandin E,. Am J Pathol 1982; 108: 240-245. lzui S, Kelley VE, McConaheyPJ, et al: Selectivesuppression of retroviral gp70-ant&p70 immune complex formation by prostaglandin Et in murine systemic lupus erythematosus. J Exp Med 1980; 152: 1645-1658. Goodwin JS, Webb DR: Regulation of the immune response by prostaglandins. Clin lmmunol lmmunopathol 1980; 15: 106122. Goodwin JS, Ceuppens, J: Regulation of the immune response by prostaglandins. J Clin lmmunol 1983; 3: 295-315.

January

17,1988

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25. 26.

The

Rogers TJ, Nowowiejski I, Webb DR: Partial characterization of a prostaglandin-induced suppressor factor. Cell lmmunol 1980; 50: 82-93. Zimecki M, Webb DR: The regulation of the immune response to T-independent antigens by prostaglandins and B cells. J Immunol 1976; 117: 2158-2164. Webb DR, Osheroff PL: Antigen stimulation of prostaglandin synthesis and control of immune responses. Proc Natl Acad Sci USA 1976; 73: 1300-1304. Brunda MJ, Herberman RB, Holden Hi: Inhibition of murine natural killer cell activity by prostaglandins. J lmmunol 1980; 124: 2682-2687. Fantone JC, Marasco WA, Elgas W, et al: Anti-inflammatory effects of prostaglandin E,: in vivo modulation of the formyl peptide chemotactic receptor on the rat neutrophil. J lmmunol 1983; 130: 1495-1497. Sedgwick JB, Berube ML, Zurier FIB: Stimulus-dependent inhibition of superoxide generation by prostaglandins. Clin Immunol lmmunopathol 1985; 34: 205-215. Prickett JD, Robinson DR, Steinberg AD: Dietary enrichment with the polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in NZB X NZW Fl mice. J Clin Invest 1981; 88: 556-559. Prickett JD, Robinson DW, Steinberg AD: Effects of dietary enrichment with eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW Fl mice. Arthritis Rheum 1983; 26: 133-l 39. Kelley VE, Ferretti A, lzui S, et al: A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice. J lmmunol 1985; 134: 1914-1919. Kelly JP, Johnson MC, Parker CW: Effect of inhibitors of arachidonic acid metabolism on mitogenesis in human lymphocytes: possible role of thromboxanes and products of the Iipoxygenase pathways. J lmmunol 1979; 122: 1563-1571. Hassid A, Konieczowski M, Dunn MJ: Prostaglandin synthesis in isolated rat kidney glomeruli. Proc Natl Acad Sci USA 1979; 76: 1155-l 159. Folkert VW, Schlondorff D: Prostaglandin synthesis in isolated glomeruli, Prostaglandins 1979; 17: 79-82. Sraer J, Foidart J, Chansel D, et al: Prostaglandin synthesis by mesangial and epithelial glomerular cultured cells. FEBS Lett

An lerlcan

Journal

of Medicine

Volume

80 (suppl

1A)

43

SYMI ‘OSIUM

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45. 46.

47.

48.

49. 50.

44

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AND THE KIDNEY-STORK

ET AL

1979; 104: 420-424. Scharschmidt L, Dunn MJ: Prostaglandin synthesis by rat glomerular mesangial cells in culture. The effects of angiotensin II and arginine vasopressin. J Clin Invest 1983; 71: 17561764. Dunn MJ: Renal prostaglandins. In: Klahr S, Massry SG, eds. Contemporary Nephrology, Volume 2. New York: Plenum Press, 1983; 145-191. Jackson EK, Theidmann HT, Branch RA, et al: Low dose intrarenal infusions of PGEa, PGI*, and 6-keto-PGE,, vasodilate the in vivo rat kidney. Circ Res 1982; 51: 67-72. Sakr HM, Dunham EW: Mechanism of arachidonic acid-induced vasoconstriction in the intact rat kidney: possible involvement of TXAa. J Pharmacol Exp Ther 1982; 221: 614-622. Schor N, Brenner BM. Possible mechanism of prostaglandininduced renal vasoconstriction in the rat. Hypertension 1981; 3 (suppl 11): 1181-l 185. Scharschmidt LA, Lianos E, Dunn MJ: Arachidonate metabolites and the control of glomerular function. Fed Proc 1983; 42: 3058-3063. Scharschmidt L, Douglas JG, Dunn MJ: Angiotensin II and eicosanoids in the control of glomerular size in rat and man. Am J Physiol (in press). Jim K, Hassid A, Sun F, et al: Lipoxygenase activity in rat kidney glomeruli, glomerular epithelial cells, and cortical tubules. J Biol Chem 1982; 257; 10294-10299. Ballerman BJ, Lewis RJ, Corey EJ, et al: Identification of leukotrlene Cq receptors in isolated rat renal glomeruli (abstr). Clin Res 1984; 32: 440A. Dunn MJ, Simonson M: The effects of leukotriene Cq on rat glomerular mesangial cells in culture (abstr). Kidney Int 1985; 27: 256A. Badr KF, Baylis C, Pfeffer JM, et al: Renal and systemic hemodynamic responses to intravenous infusion of leukotriene Cq in the rat. Circ Res 1984; 54: 492-499. Blantz RC, Wilson CB: Acute effects of antiglomerular basement membrane antibody on the process of glomerular filtration in the rat. J Clin Invest 1976; 58: 899-911. Sakai T, Harris FH Jr, Marsh VJ, et al: Extracellular fluid expansion and autoregulation in nephrotoxic serum nephritis in rats. Kidney Int 1984; 25: 619-628. Blantz RC, Tucker BJ, Gushwa LC, et al: Glomerular immune injury in the rat: the influence of angiotensin II and alpha-adrenergic inhibitors. Kidney Int 1981; 20: 452-461. Lianos EA, Andres GA, Dunn MJ: Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic nephritis. J Clin Invest 1983; 72: 1439-1448. Stork JE, Dunn MJ: Hemodynamic roles of thromboxane A2 and prostaglandin E2 in glomerulonephritis. J Pharmacol Exp Ther 1985; 233: 672-678. Kaizu K, Marsh D, Zipser R, et al: Role of prostaglandins and angiotensin II in experimental glomerulonephritis. Am J Physiol (in press). Kurokawa H, Sakamoto K: Effects of aspirin, prednisolone, and indomethacin on nephrotoxic serum nephritis in the rat. Br J Pharmacol 1982; 75: 87-92. Lianos EA, Dunn MJ: Glomerular arachidonate lipoxygenation in nephrotoxic serum nephritis. J Clin Invest 1985; 76: 1355. Rahman MA, Emancipator SN, Dunn MJ: Effect of antigenic charge on immune complex localization and eicosanoid production by rat glomeruli (abstr). Kidney Int 1985; 27: 220A. Arisz L, Donker AJM, Brentjens JRH, et al: The effect of indomethacin on proteinuria and kidney function in the nephrotic syndrome. Acta Med Stand 1976; 199: 121-l 25. Michielsen P, Lambed PP: Effets du traitment par les corticosteroides et I’indomethacine sur la proteinurie. Bull Mem Sot Med Hop Paris 1967; 118: 217-227. Michielsen P, Varenterghem Y: Proteinuria and nonsteriod antiinflammatory drugs. Adv Nephrol 1933; 12: 139-150. Tiggeler RGWL, Hulme 6, Wiideveld PGAB: Effect of indomethacin on glomerular permeability in the nephrotic syndrome.

January

17, 1666

The Americen

Journal

of Medicine

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69. 70.

71.

72.

Volume

Kidney Int 1979; 16: 312-321. Ruilope L, Garcia Robles R, Bernis C, et al: Role of renal prostaglandin EP in chronic renal disease hypertension. Nephron 1982; 32: 202-206. Kutyrina IM, Androsova SO, Warshavskii VA, et al: Effects of indomethacin on the renal function and renin-aldosterone system in chronic glomerulonephritis. Nephron 1982; 32: 244248. Abe K, lmai Y, Sato M, et al: Exaggerated fractional sodium excretion in hypertension with advanced renal disease: the role of renal prostaglandin and kallikrein. Clin Sci 1981; 61: 327S-330s. Colina-Chourio JA, Rodriguez-lturbe B, Baggio B, et al: Urinary excretion of prostaglandins and kallikrein in acute glomerulonephritis. Clin Nephrol 1983; 20: 217-224. Ciabattoni G, Cinotti GA, Pierucci A, et al: Effects of sulindac and ibuprofen in patients with chronic glomerular disease. N Engl J Med 1984; 310: 279-283. Ciabattoni G, Pugliese F, Cinotti GA, et al: Renal effects of antiinflammatory drugs. Eur J Rheumatol lnflamm 1980; 3: ZlO221. Sedor JR, Williams SL, Chremos AN, et al: Effects of sulindac and indomethacin on renal prostaglandin synthesis. Clin Pharmacol Ther 1984; 36: 85-91. Swainson CP, Griffiths P: Acute and chronic effects of sulindac on renal function in chronic renal disease. Clin Pharmacol Ther 1985; 37: 298-300. Kimberly RP, Gill JR, Bowden RE, et al: Elevated urinary prostaglandins and the effects of aspirin on renal function in lupus erythematosus. Ann Intern Med 1978; 89: 336-341. Patron0 C, Ciabattoni G, Remuzzi G, et al: The functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus. J Clin Invest 1985; 76: 1011. Shimamura T, Morrison AB: A progressive glomerulosclerosis occurring in partial five-sixths nephrectomized rats. Am J Pathol 1975; 79: 95-106. Hostetter TH, Olson JL, Rennke HG, et al: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 1981; 241: F85-F93. Olson JL, Hostetter TH, Rennke HG, et al: Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass. Kidney Int 1982; 22: 112-126. Altsheler P, Klahr S, Rosenbaum R, et al: Effects of inhibitors of prostaglandin synthesis on renal sodium excretion in normal dogs with decreased renal mass. Am J Physiol 1978; 235: F338-F344. Kirschenbaum MA, Serros ER: Effects of prostaglandin inhibition on glomerular filtration rate in normal and uremic rabbits. Prostaglandins 1981; 22: 245-254. Purkerson ML, Joist JH, Yates J, et al: Inhibition of thromboxane synthesis ameliorates the progressive kidney disease of rats with subtotal ablation. Proc Nat1 Acad Sci USA 1985; 82: 193197. Purkerson ML, Joist JH, Greenberg JM, et al: Inhibition by anticoagulant drugs of the progressive hypertension and uremia associated with renal infarction in rats. Thromb Res 1982; 26: 227-240. Barcelli UO, Weiss M, Pollack VE: Effects of a dietary prostaglandin precursor on the progression of experimentally induced chronic renal failure. J Lab Clin Med 1982; 100: 786797. Torres VE, Romero JC, Strong CG, et al: Renal prostaglandin E during acute renal failure. Prostaglandins 1974; 8: 353-360. Torres VE, Strong CG, Romero JC, et al: lndomethacin enhancement of glycerol-induced acute renal failure in rabbits. Kidney Int 1975; 7: 170-178. Benabe JE, Klahr S, Hoffman MK, et al: Production of thromboxane A2 by the kidney in glycerol-induced acute renal failure in the rabbit. Prostaglandins 1980; 19: 333-347. Sraer JD, Moulonguet-Doleris L, Delarue F, et al: Prostaglandin

60 (suppl

1A)

SYMPOSIUM

73.

74.

75.

76.

77.

78.

79.

synthesis by glomeruli isolated from rats with glycerol-induced acute renal failure. Circ Res 1981; 49: 775783. Mauk RH, Patak RV, Fadem SV, et al: Effect of prostaglandin E administration in a nephrotoxic and a vasoconstrictor model of acute renal failure. Kidney Int 1977; 12: 122-130. Johnston PA, Bernard DW, Perrin NS, et al: Prostaglandins mediate the vasodilatory effect of mannitol in the hypoperfused rat kidney. J Clin Invest 1981; 68: 127-133. Kramer HJ, Schuurman J, Wasserman C, et al: Prostaglandin independent protection by furosemide from oliguric ischemic renal failure in conscious rats. Kidney Int 1980; 17: 455464. Funaki N, Kuroda M, Sudo J, et al: Urinary prostaglandins and kallikrein in the course of acute renal failure. Prostaglandins Leukotrienes Med 1982; 9: 387-399. lchikawa I, Brenner BM: Local intrarenal vasoconstrictor-vasodilator interactions in mild partial ureter obstruction. Am J Physiol 1979; 236: F131-F140. Nishikawa K, Morrison A, Needleman P: Exaggerated prostaglandin biosynthesis and its influence on renal resistance in the isolated hydronephrotic rabbit kidney. J Clin Invest 1977; 59: 1143-1150. Gaudio KM, Siegel NJ, Hayslett J, et al: Renal perfusion and intratubular pressure during ureteral occlusion in the raf. Am J

80.

81.

82.

83.

84.

85. 86.

DISCUSSION

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Physiol 1980; 238: F205-F209. Morrison AR, Nishikawa A, Needleman P: Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney. Nature 1977; 267: 259-260. Morrison AR, Nishikawa A, Needleman P: Thromboxane A2 biosynthesis in the ureter-obstructed isolated perfused kidney of the rabbit. J Pharmacol Ther 1978; 205: l-8. Yarger WE, Schocken DD, Harris RH: Obstructive nephropathy in the rat: possible roles for the renin-angiotensin system, prostaglandins, and thromboxanes in post-obstructive renal failure. J Clin Invest 1980; 65: 400-412. Okegawa T, Jonas P, DeSchryver K, et al: Metabolic and cellular alterations underlying the exaggerated renal prostagfandin and thromboxane synthesis in ureter obstruction in rabbits. J Clin Invest 1983; 71: 81-89. Okegawa T, DeSchryver-Kecskemeti K, Needleman P: Endotoxin induces chronic prostaglandin and thromboxane synthesis from ureter-obstructed kidneys: role of inflammatory cells. J Pharmacol Exp Ther 1983; 225: 213-218. Foegh ML, Winchester JF, Zmudka M, et al: Urine I-TXBp in renal allograft rejection. Lancet 1981; II: 431-434. Coffman TM, Yarger WE, Klotman PE: Functional role of thromboxane production by acutely rejecting renal allografts in rats. J Clin Invest 1985; 75: 1242-1248.

pression is maintained, the question is whether there are other compensatory mechanisms that can come into play. It would be fascinating to do a long-term study. Dr. Dunn: Does anyone believe that the nonsteroidal anti-inflammatory agents have a long-term deleterious effect? My feeling is that intermittent, or even long-term, use of these drugs in patients with various arthritic conditions does not irreversibly or chronically cause renal failure. Dr. Epstein: Rheumatologists often claim that they do not observe renal failure in their patients. Dr. Dunn: Studies of long-term aspirin therapy in patients with rheumatoid arthritis do not show any change in renal function. Dr. Epstein: Even though the data are incomplete, the prudent approach might be to avoid prescribing nonsteroidal anti-inflammatory drugs in patients with renal insufficiency. Dr. Brater: I would not favor taking that absolute stance, because many patients with degenerative arthritis would suffer without these drugs. However, I would exert an extra measure of caution for those with renal disease. If their musculoskeletal disease responds, if they are watched carefully, and if their renal disease does not worsen, I would not deny these patients the benefit of the nonsteroidal agents. Dr. Dunn: Even if their glomerular filtration rate deteriorated by 25 percent, I might still use these drugs intermittently. There are parallels with treatment of high blood pressure. If hypertensive patients are treated with a beta blocker and a thiazide diuretic and then take a nonsteroidal anti-inflammatory drug, their control of blood pressure will be attenuated, presumably because of prostaglandin inhibition. If the arthritis is a greater clinical problem than the hypertension, it is necessary either to increase the dose of antihypertensive drug or to accept the increased blood pressure for a while.

Dr. Brater: Many of our clinical results and their interpretations have to do with the type of patients we are studying. Most of our patients with chronic renal insufficiency (clearances of 20 to 70 ml per minute) have hypertension and diabetes. If we give these patients a short-term dose of indomethacin, there is a slight and transient decrease in the inulin and para-aminohippurate acid clearances. However, there is no overall decrement in renal function if the drug is given for five to six days. Dr. Dunn: Is the steady-state renal function at seven days of indomethacin therapy unchanged from that of controls? Dr. Brater: If patients are brought into sodium balance and then given a short-term dose of indomethacin, within about two hours there is a transient decrease of 20 to 30 percent in inulin and para-aminohippurate acid clearances, which return to normal over five to six days. Dr. Dunn: Are you saying that long-term treatment with indomethacin marginally inhibits urinary prostaglandin, but short-term dosing reduces prostaglandin synthesis to a greater extent? Dr. Brater: Yes. Dr. Lifschitz: Lupus glomerulonephritis is probably one of the more common glomerular diseases. Several groups have found disturbing consequeroes in patients with lupus nephritis who were treated with nonsteroidal antiinflammatory agents. I would be very hesitant to use these agents in patients with systemic lupus erythematosus. Dr. Dunn: The data of Kimberly et al (Ann Intern Med 1978; 89: 336-341) raise this issue. The maximum decrease in renal function they found in women with lupus nephritis receiving aspirin was 20 to 25 percent. Most patients spontaneously recovered some or all of their renal function despite continued aspirin therapy. Dr. Brater: Even if the same level of prostaglandin supJanuarv

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