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Home , Aminophenazone, Dextropropoxyphene, Fenamic acid, Glafenine, Phenacetin, Salicylate poisoning

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Kidney International, Vol. 13 (1978), pp. 15-26

Pharmacological mechanisms of nephropathy JULIAN H. SHELLEY

C. H. Boehringer Sohn, Bracknell, Berkshire, United Kingdom

The pre-Socratic philosophers were reputed to be patients with preexisting reduction in glomerular fil- able to entertain two mutually contradictory beliefs tration rate (GFR) and renal plasma flow (RPF), this with apparent equanimity. In reading this review, reduction was intensified, and restriction led which undoubtedly reflects the bias of the writer and, to a more pronounced effect; normal subjects in turn, the authors of the cited works, the complexi- showed no change in GFR or RPF. In another study, ty and contradictory nature of much of the data will indomethacin administration (150 mg/day) decreased be evident; one cannot view, however, the result the GFR by 35% and the RPF by 23% in nephrotic with any degree of equanimity. Much remains to be patients with impaired renal function. done in the experimental field before a unifying con- Both and ketophenbutazone cept on the pathogenesis, incidence, and implica- administrations (single dose of 600 mg, either orally tions of analgesic nephropathy can be enunciated. or i.m.) were shown to impair '311-hippuran excre- Scope of the problem. The review of Gsell [11 tion, which was interpreted as an acute impairment "From nephritis to analgesic nephropa- of tubular function [76]. In another study [77],the thy" admirably reflects the change in attitude to the isotope renogram was used to measure the changes problem, particularly in the last ten years. Since induced by administration (750 mg other investigators have indicated the current scope daily). These changes were interpreted as a reflection of the problem [2—22],nofurther comment is need- of impaired blood flow, tubular function, and there- ed. Adverse reactions referable to the kidney are fore, clearance of the isotope. attributed to (used alone and in combination In normal subjects, the short-term administration with other agents), phenacetin (in combination), par- of aspirin (oral doses of 5.5 g daily) was shown to acetamol (alone and in combination), phenylbuta- produce sodium retention, a decreased urine vol- zone, oxyphenbutazone, ketophenbutazone, sul- ume, and tubular reasorption of free water; no phinpyrazone, indomethacin, , , change in creatinine clearance was noted. The effect , , glaphenine, , was more pronounced when plasma renin had been mefanamic acid, , bucloxic acid, ado- elevated by low sodium balance [73, 74]. In patients fenac, and . The data used in this review with chronic renal insufficiency, aspirin i.v. (lysine are derived both from published reports and - conjugate, 750 mg) caused a decrease in sodium renal monitoring committees (Table 1) [23—66]. In sum- within 15 mm which lasted for six hours, a mary, salicylates and phenacetin used in combination decrease in GFR to 54%, and a decrease in RPF to and aspirin used alone are frequently implicated, the 66% of control values [73]. pyrazoles less so; and the newer nonsteroidal antiin- Aspirin was shown to reduce the glomerular filtra- flammatory agents, e.g., the phenylalkanoic acids tion rate in 13 patients with renal impairment by 10% and fenamic acids, play a small but significant part. when given 20 mg/kg by mouth, while in a further Occasional reports implicating , eight subjects [78], with no renal impairment, the , and older are also noted. lysine conjugate of aspirin (0.9 g, i.v.) produced a significant reduction in GFR and PAH clearance in Pharmacological and toxicological studies in animals and seven [79]. The effect was transient, however. The man blood salicylate concentration at the time of maximal Short-term therapy. Indomethacin administration effect was 12.4 mg/l00 ml. The effect of aspirin in (150 mg/day, for three days) was shown to induce water and sodium retention both in normal subjects 0085-2538/78/0013-0015 $02.40 and in patients with kidney damage [73—75]. In © 1978, by the International Society of Nephrology. 15 16 Shelley

Table1.Data for agents which have been correlated with adverse reactions reibrable to the kidneya

Phen- Para- Phenyl- Oxyphen- Indo- Keto- Mefanamic Flufenamic Aspirinc acetin" cetamol' butazone' butazone methacin5 Ibuprofenh profen' acid' acid Aclofenac5 Naproxen

Abnormal urine 1 2 2 Acute renal failure 3(2) 5(4) 2 2 Abnormal function 1 2 1 Abnormal and deteriorating function 3(2) 2(1) 1(1) 1(1) Renal papillary necrosis 27(16) 52(40) 6(4) 4(2) 1(2) 3(2) 2(1) Tubular necrosis 2(1) 2(1) Hematuria 4 7 5 6 I 2 Interstitial nephritis 1 Glomerular nephritis 1 Albuminuria 1 1 1 1 Toxic nephropathy 5(1) Nephrosis 2 1 Dysuria/oliguria Ill Data provided by the Committee on Safety of Medicines [23]forperiod March, 1964, to December1975, except as follows: ibuprofen, 12/65—12/75; ketoprofen, 2/70—12/75; , 6/67—12/75; aclofenac, 4/70—12/75; naproxen, 7/70—12/75. Figures in brackets denote fatal outcome. For data on fenoprofen, see [44]; tolmetin, see [45]; glaphenine, see [50-60]; niflumic acid, see [61-63]; bucloxic acid, see [64, 65] See also [4, 24, 25]. See also [26-29]. See also [30]. See also [22, 31-35]. See also [36-38]. See also [39, 40]. See also [41-43]. See also [66]. See also [46, 47]. 'See also [38, 48, 49]. Bucloxic acid: See also [64, 65]. reducing the urinary excretion of xylose is probably mally high, so that per se may due to its reduction of GFR [801. Ingestion of aspirin be important. Salant [85] found that in patients with causes a transient shedding of renal tubular cells into analgesic nephropathy ( not stated), distal tubu- the urine; excretion of , however, e.g., lac- lar function was impaired out of all proportion to the tate dehydrogenase (LDH) and N-acetyl-/3-D-glu- degree of reduction in the glomerular filtration rate. cosaminidase (NAG), persists. NAG excretion is a The conflicting and inconclusive data from renal sensitive test of renal damage and correlates well lunction studies in rheumatoid arthritis has been with impairment of concentrating power and experi- reviewed by Nanra and Kincaid-Smith [9]. mental papillary necrosis in dogs [81, 82]. Leath- The New Zealand Rheumatoid Association study wood and Plummer [83] gave 3 g of aspirin acutely to [86] exonerated aspirin as a cause of nephrotoxicity normal subjects, and Burry et al [81, 821 adminis- on the basis of "a renal score" and creatinine clear- tered 4 g of aspirin to both normal subjects and ance tests, but no measurement of tubular function patients with rheumatoid arthritis. Leathwood and was made. In contrast to the findings of Edwards et Plummer produced persuasive evidence that the kid- a! [871. Burry [81] detected no relation between ney is the main source of LDH and that both celluria glomerular function (creatinine clearance) and the and rise of LDH levels indicate cell damage. Burry dose of aspirin consumed; endogenous creatinine found that NAG levels were elevated ten days after clearance, however, although inappropriate as a test dosing, all values being higher in patients than in of renal tubular function, should not be interpreted healthy subjects, indicating persisting tubular dam- as an index of GFR when salicylates are adminis- age which, however, is considered to reflect a mini- tered [881. The salicylate itself probably disturbs the mal impairment of tubular function. protein binding of creatinine or affects its tubular Long term therapy. Retrospective studies of renal secretion. The renal clearance of Cr-edetic acid function in patients who have received salicylate for was normal in subjects who showed a reduction in long periods have been contradictory. Burry et al creatinine clearance; so the test is not suitable in [81, 821 suggested that when a large amount of sali- assessing renal function in patients receiving cylate is consumed over many years, an appreciable salicylate. degree of tubular function impairment results. In sharp contrast to the findings of Berg [73, 741, Dieppe et a! [84] found, however, that in 8 of 20 Elliot and Murdaugh [891, and others, patients with patients with rheumatoid arthritis who had received analgesic nephropathy (compound analgesics), i.e., no drug treatment, the NAG excretion was abnor- where drugs have been administered chronically, Analgesic nephropathy. Drug mechanisms 17

show significant sodium loss (i.e., the urinary sodium Leeling, and Kowalski [441 calculated that single is inappropriately high). Such depletion will, in turn, doses of 24 and 60 mg/kg of body wt in the rat impair renal function, and this would correlate with produced whole-body total salicylate concentrations the known loss of long nephrons, as the remaining that were equivalent to the ingestion of 8 or 20 tablets short nephrons have a lower capacity for sodium (325 mg) of plain aspirin in man. No distinction absorption [901. between parent and metabolite was made, however, Patients with analgesic nephropathy may suffer and the general status of the rats was not reported. from diminished concentrating ability, and this is At this dose no lesions were seen, which parallels the most clearly shown when compound mixtures have findings of Bokelman et al [94] in rats (with buffered been taken for long periods; the evidence implicating aspirin) and Mclver and Hobbs [95] in pigs given 1 g/ aspirin has been briefly summarized above. Much kg daily for ten months. Nanra [71, 72], however, less data is available with regard to ; with intermediate dose levels of aspirin (200 mg/kg! but in a thorough study, Edwards et al [911 found day) given from 10 to 60 weeks under conditions of no evidence of impaired function (including concen- dehydration, produced renal papillary necrosis in 7 trating power) in 18 patients with rheumatoid arthritis of 13 rats, and 5 showed changes typical of chronic who had consumed between 2 to 30kg of paracetamol interstitial nephritis. No control group with free in the past and at least one gram of paracetamol daily access to fluid was included, however. High doses of per year prior to the examination. aspirin or APC have produced renal papillary Aspirin is under investigation in the secondary necrosis consistently (Nanra, Kincaid-Smith [70, 96, prevention of , and the most 97]: 500 mg/kg aspirin, 900 mg/kg APC; Saker and detailed study published to date is that of the Coro- Kincaid-Smith [134]: 500 mg/kg/day phenacetin, 500 nary Drug Project [921. Seven hundred and twenty- mg/kg/day APC). The latter dose of APC is equiva- seven patients received one gram of aspirin daily for lent on a wt/wt basis to that taken by some patients, 10 to 28 months. "Blood in urine" was reported in but it is excessive on the basis of calculations of 1.2%, compared to 0.3% of 744 patients receiving Philips et al [44]. It should be noted enpassant that placebo. This was not, however, confirmed by dip- the general health of rats given aspirin or APC at this stick measurement of hematuria (1.53% of 523 dose level was "dreadful" (Nanra [71]). patients receiving aspirin, compared with 2.08% of In other studies, large doses of indomethacin (75 528 patients receiving placebo). Urine protein, how- mg/kg/day) and phenylbutazone (400 mg/kg/day) giv- ever, was higher in the aspirin group. en to female Wistar rats produced renal papillary In a prospective study, Dubach, Rosner, and MUll- necrosis, while smaller doses of indomethacin (4 mg/ er [27] showed that concentrating power was signifi- kg) produced changes in the basement membrane of cantly reduced and serum creatinine increased in the glomerulus [98]. Phenylbutazone, when given high analgesic users. Bengston [93], however, con- therapeutically to a dog at a dosage of 25 mg/kg, sidered that the incidence of lesions in the study was induced tubular damage [99]; 40 mg/kg given for 21 underestimated, and it is difficult to reconcile the days in the cat produced tubular necrosis. Enormous conclusions of the paper with the findings therein. doses (3,000 mg/kg/day) of phenacetin [100] were required to produce even modest tubular damage, Pharmacological and toxicological studies in animals while 3,000 mg/kg/day of paracetamol (Nanra and Any pharmacological analysis must take account Kincaid-Smith [96]) produced lesions in three of sev- of the relevance of the species employed, the doses en dehydrated rats. Dextropropoxyphene (100 mg/ used, whether a dose-response curve is demonstra- kg/day) produced renal papillary necrosis in one of ble, and finally, the experimental conditions under nine rats, but six showed medullary calcification which the studies were conducted and how the [96]. results have been interpreted. Brown and Hardy [101] gave up to 1,300 mg/kg Doses employed and relevant . phenacetin to female Sprague Dawley rats for 51 Many studies have employed doses far outside the days and a similar dose of and up to 1,200 realm of pharmacology; In many cases we are deal- mg/kg amidopyrine for 38 days. Phenazone caused ing with toxicologic studies in the proper sense of the persistent celluria with some cellular infiltration; term. With the wealth of data available, no clear-cut amidopyrine produced severe papillary necrosis but picture emerges, apart from the fact that very high no celluria; phenacetin caused neither effect. All doses of agents are required before any lesion is drugs impaired concentrating power in this experi- observed in a consistent fashion. ment. By comparing the whole-body total salicylate con- The effects of high doses of aspirin or APC in rats centration in man and Charles Rivers rats, Philips, (Sprague-Dawley and Wistar) are enhanced by dehy- 18 Shelly dration and oligemic shock [8, 70, 72, 97]. Arnold et for conjugated paracetamol and 19:1 for free parace- aT [102, 103], however, gave single doses of 100 mgI tamol. Salicylate did not affect the paracetamol gra- kg to Wistar rats and observed transient cortical dient. The pH dependency of salicylate clearance damage; tubular regeneration commenced within 24 and distribution was not determined. hours and was complete in three days, despite con- Duggin and Mudge [107, 108] have confirmed the tinuation of dosing where this was done. When work of Bluemle and have overcome objections lesions were observed at 12 hr, a dose response was regarding the contribution made by tubular fluid in seen, notably in females (100 to 600 mg/kg/day aspi- the medulla; they also confirm that paracetamol is rin). Some degree of protection from the single large concentrated in the medulla and that dehydration dose of aspirin was seen up to three weeks after increases the gradient. Paracetamol is sparingly administration, and when 10 mg/kg was given daily bound to protein(c.f., aspirin) and is therefore filtered for nine days, some protection against a repeat dose by the glomerulus and reabsorbed by the tubule by of 40 mg/kg was afforded. Arnold et al [103] report- simple diffusion; this is true for its conjugates which ed, too, that pretreatment with phenobarbitone at low concentrates are actively secreted and at high appeared to reduce the severity of the lesions, but no concentrations reabsorbed (dog). Phenacetin is not details were given. Papillary necrosis was never seen concentrated in the medulla. in these studies, and alkalization had no effect on the The data with regard to the medullary gradient for cortical lesions. Lesions exclusively in the cortex of aspirin is conflicting. Bluemle and Goldberg [1061 the kidney have been observed before in patients on found no gradient in the dog, but Gault [1091 demon- salicylate therapy [103]. strated a gradient for aspirin in rabbits and guinea Ibuprofen, at doses approaching the LD50, pro- pigs (1:7, rabbit; 1:3, guinea pig) and a modest gra- duced dilation of the distal tubules [104]. In long dient for paracetamol (1:2.7, rabbit) and for phenace- term studies in rats initially given 180 mg/kg, tin (1:3.6, rabbit). The radioactivity of the labelled but reduced to 60 mg/kg per day because of the aspirin in the kidney was 20 times that of the , intestinal ulceration, no histologic damage was spleen, pancreas, muscle, and brain. detected, but data available on medullary function is Quintanilla and Kessler [110] gave sodium salicy- scanty [104]. late to dogs (3 mmoles/kg) and also described a med- Data on concentrations of aspirin in total body ullary gradient for salicylate of a factor of 1:5 to 3 distribution, plasma, and renal tissue are conflicting: (see their table 7). This, however, could be artefac- Leeling, Philipps, and Kowalski [105] found a linear tual, as the medullary concentration was exactly relation between aspirin dose, average renal tissue equal to the plasma concentration, and the "gra- concentration in mg/g of tissue, and plasma concen- dient" was due to very low concentrations in the tration in mg/ml when using doses of aspirin of 100 cortex. These workers also found that saucy late mg/kg to 700 mg/kg (this last dose approached the administration induced a prompt diuresis with excess LD50; 3 of 21 rats died). Much lower plasma and secretion of sodium, potassium, and chloride, and tissue concentrations were obtained when buffered occasionally , which is the reverse of the effervescent aspirin was used—this preparation pro- effects found in man. duces an alkaline urine which lowers tubular reab- Little data is available on the kidney/blood ratio sorption of and increases excretion, for salicylate in patients; however, in two patients which could be the basis of the findings by Nanra and dying of salicylate , the kidney blood ratios Kincaid-Smith [70], viz, that addition of bicarbonate were 8.0/15.0 and 82.4/0.6; such a variation makes to a regime of plain aspirin (500 mg/kg/day) reduces any conclusion impossible [106, 1101. the incidence of renal papillary necrosis by one half. Whitehouse [Ill] has shown that when guinea Bluemle and Goldberg [1061 found that doses pigs were pretreated with aspirin at 200 mg/kg/day, between 170-300 mg/kg of aspirin or 300 mg/kg of blood concentrations of a single dose of paracetamol, phenacetin or paracetamol given separately or to- (150 mg/kg) were higher; and more significantly, gether (170mg of aspirin plus 300mg ofphenacetin per excretion of paracetamol by the kidney was inhibit- kg of body wt), acutely with or without hydration, ed, although sulphation and glucuronidation were were handled differently by the kidney. At the time of unaffected. Comparable results have been found in peak concentrations in the blood, cortical and medul- man [1121. Whitehouse believes that aspirin com- lary assays were performed. No medullary gradients petes preferentially for the common anionic secreto- for salicylate was found, whether the animals were ry mechanism in the kidney tubule. dehydrated or not, but free and conjugated paraceta- Finally, Carro-Ciampi [113] has shown that a 50% mol concentration rose sharply in the inner medulla reduction in posttreatment plasma concentrations of during dehydration. The gradient was more than 10:1 phenacetin is obtained with the first ten days of Analgesic nephropathy: Drug mechanisms 19 repeated phenacetin treatment at a dose of 0.4 g/kgl The fenamates showed irregular plasma curves, day in albino rats; in the guinea pig, posttreatment which could not be fitted to any simple kinetic mod- phenacetin concentrations fell to only approximately el. The renal excretion was negligible and the biologi- 20%. Paraphenetidine levels increased as treatment cal availability of the tested formulations was low; proceeded in guinea pigs, but it fell in rats. although flufenamic acid was better absorbed than In man it has been shown that: 1) The absorption, mefanamic acid. excretion, and metabolism of phenacetin and aspirin The pyrazoles showed large inter-individual varia- does not vary with the tubular cell response [114]. tions and large volumes of distribution, and the 2)Therecovery of phenacetin and its metabolites group showed large differences in clearance, is essentially the same whether patients have analge- although as a whole, renal clearance played only a sic nephritis or not, but the renal excretion of con- minor role. 4- is eliminated quite jugated paracetamol is reduced when nephropathy differently from the others in the group; 40% is elimi- is present, and this correllates with reductions in nated partly by renal excretion (refer to the thesis the glomerular filtration rate. The metabolism of [120] for detailed discussion). phenacetin, in contrast to aspirin, is not pH depen- Phenacetin produced very low plasma concentra- dent [115]. 3) Steady state salicylate concentrations tions due to high hepatic clearance, in contrast to are decreased when aspirin is given chronically (20 paracetamol, and the pharmaceutical formulation of days) in healthy volunteers. The average plasma con- phenacetin produced marked differences in the centration at day 21 was approximately half that of absorption. day 7 [116]. 4) Met-hemoglobin formation [1171 in Salicylates showed the same volume of distribu- abusers of analgesic mixtures containing phenacetin tion as did ibuprofen and aclofenac, the plasma is significantly greater than in normal subjects or kinetics were non-linear, and at higher doses clear- patients with impaired renal function. The relevance ance decreased; both tubular secretion and reabsorp- of met-hemoglobin formations to renal per se tion occurred which confirm earlier findings. The pH is disputed, however. 5) There is evidence that the dependency of excretion was once again demonstrat- limiting pathway on the formation and excretion of ed in chronic studies: doubling the daily dose of metabolites of aspirin [118], i.e., salicyluric acid and from 1.5 to 3 g led to a four to five- salicylphenolic glucuronide, does not increase pro- fold increase in average plasma plateau concentra- portionately with dose (from 65 mg/kg to 100 mg/kg tion, which fits well within the model of capacity- daily). limited elimination. Indomethacin plasma concentrations in man [119] The reader should refer directly to this excellent following a standard dose of 100 mg are significantly monograph which shows clearly the virtue of repeat increased when buffered aspirin is given before or plasma kinetics after acute and repeated dosing concurrently. [120]. Van Ginneken [120] has performed the most com- Extrapolation of findings from animals to man: prehensive study of pharmacokinetics of commonly Species differences. The survival of any animal spe- used analgesics in healthy volunteers. Ibuprofen, cies reflects the adaption, in both form and function, aclofenac, fiufenamic acid, , phena- to its habitat. Animal experiments have been per- zone and its isopropyl and methylamino derivatives, formed mainly in rats, but also in guinea pigs, rab- paracetamol, phenacetin, acetylsalicylic acid, and bits, cats, dogs, baboons, monkey, and pigs. All sodium salicylate were given as single or multiple have important structural and functional differences (ibuprofen, aclofenac, acetylsalicylic acid) doses for in comparison to man. This is true even of animals 7 to 14 days. Chemical methods were used for esti- whose kidney architecture and physiology must mation of plasma and urine concentrations; in addi- closely resemble that of man (probably the pig and tion to plasma and urine kinetics, an estimation of the monkey). protein binding and red cell uptake was made. The rat kidney has only a single papilla, the rela- Ibuprofen and aclofenac had small volumes of tive length of which is greater than man's, so that the distribution, high protein binding, but short half-lives number of long nephrons is higher than man [95, (due to small volume of distribution). Ibuprofen was 121]. In man, the number of short looped nephrons is excreted almost unchanged in the urine (c.f., ado- 86% (c.f., pig, 97%), and the papilla is better sup- fenac, 50%) and secreted almost unchanged by the plied with blood, compared to the rat. The supply in tubule in contrast to aclofenac. No accuminulation of the rat is postglomerular only, but the edges of the either occurred, but both showed marked fluctua- human papilla are supplied from aglomerula vessels, tions in plasma concentrations following repeat first appearing in intrauterine life and becoming more dosing. important as man ages. The central core of the papil- 20 Shelley la, too, has an aglomerula supply, so the loss of lary tissue. The consensus of opinion is that the first glomeruli with aging does not imperil the blood sup- lesion in experimental analgesic nephropathy occurs ply to such an extent. The medullary flow in man is in the long loop of Henle and vasa recta, areas where less well studied, but it is likely that the main meta- higher concentrations of (some) compounds occur. bolic pathway in the medulla is the anaerobic utiliza- Maximum concentrating ability may be lost in the tion of glucose [1171. There is a high sympathetic absence of detectable structural damage, and there is innervation to the rat efferent arteriole, to the upper evidence from animal experiments that this occurs in parts of the vasa rectae and to the juxtamedullary experimental analgesic nephropathy. efferent arteriole which (in the rat) contain contrac- The data regarding cortico/medullary gradients for tile cells; the sympathetic nerve supply to the human commonly used analgesics has been summarized is not well studied, however. In summary, the kidney earlier, and there is direct evidence that dehydration of the rat has major architectural differences to that enhances the severity of the experimental lesion of man; the latter is, if anything, better able to with- from high doses of aspirin and APC, and the medul- stand anoxia. lary gradients where they exist, although this does The strain used is a further factor. Boyd [122] has not hold for studies when lower doses were used. summarized the etiologic factors affecting phenace- Indirect support to the direct toxic effect of analge- tin toxicity in the rat, and seasonal variation in sus- sics has been provided by the elegant experiments of ceptibility has also been noted repeatedly by Kin- Hardy [123, 124] and Brown and Hardy [101]. caid-Smith. Male Manor Farm rats have been shown Although removal of the papilla in the rabbit [124] to be much more susceptible to an indomethacin produced severe damage per se, this was probably derivative than are Charles River CD rats [94]. Wis- due to the technique employed and the ensuing tar rats have a higher incidence of natural renal ischemia. This can be avoided, and the partially malformations which makes long-term studies diffi- papillectomized kidney (rat) functions as an intact cult to interpret. The Gunn rat [123, 124] has been organ. When a derivative is given to particularly susceptible to the development of papil- such rats (known from previous experiments to pro- lary necrosis from aspirin in doses which did not duce renal papillary necrosis consistently), renal affect Wistar rats at all (200 to 500 mg/kg aspirin; 500 papillary necrosis occurs only in the intact kidney and 190 mg/kg/day APC). The reasons for this have (i.e., not in the contralateral partially papillectom- been discussed by Axelsen and Burry [125]. Sex- ized kidney); the cortical lesion also occurred in the related susceptibility has been shown in the case of intact kidney, suggesting the papilla to be the prima- sudoxicam [127] (where the plasma concentration is ry site of damage. The interesting possibility arises; if much higher in females), and age-related susceptibili- the site of concentration of analgesics is removed, ty has been shown with a derivative of indomethacin does this protect the kidney against further direct [94, 102, 122]. In many studies, only female Wistar toxic damage, while maintaining the ability to con- rats have been used, e.g., Nanra et al [96], Saker et centrate urine at least under conditions of mild fluid al [134], and in other studies the sex is not stated. deprivation? Findings in different animal species have been In man the shedding of the normal papilla was reviewed by others [94, 101, 126, 127]. thought to carry a poor , but Kingsley et al As the pig has a multi-papillary kidney and the [11] stated that there is "a little evidence that it has ability to concentrate urine in a manner comparable any permanent effect on renal function." to man, it is of interest that the pharmacokinetics of 2) The role of anoxia. The oxygen tension in the salicylates in pig and man are comparable. First human kidney is known to fall from 100 mm Hg in studies of analgesic nephropathy are appearing now the cortex to about 20 mm Hg in the medulla [128], [95]. Wiseman and Reinhart [127] summarized the Bernanke and Epstein [129] have shown that in the situation: "renal papillary necrosis has been pro- (hydropenic) dog, the medulla receives only one- duced mainly in rats, occasionally in rabbits and tenth to one-twentieth of the cortical supply. The dogs, and rarely in monkeys," although Lechat, medulla, therefore, is clearly vulnerable to ischemia Levillian, and Dechezlepaetre [52] reported that gla- in both species. phenine causes tubular lesions in baboons. The Anoxia may result from the following changes in lesions produced by phenylbutazone and indometha- the vascular tree: a) reduction in flow by vasocon- cm in cat and dog have already been referred to. striction or mesangial thickening, b) platelet aggre- There seems no good reason why these species gates, c) occlusion of blood vessels by interstitial should be used in preference. hyperplasia, d) changes in the oxygen affinity of Proposed mechanisms for the genesis of the renal lesion hemoglobin, e) changes in viscosity. 1) Direct toxic effect by concentration in inedul- Nanra et al [96, 130] have reviewed data on vascu- Analgesic nephropa thy: Drug mechanisms 21 lar damage, and they have demonstrated that APC lism there is primarily glycolytic. Adenosine triphos- (900 mg/kg/day), aspirin (500 mg/kg/day), paraceta- phate (ATP) fell and adenosine monophosphate mol (3,000 mg/kg/day), caffeine (150 mg/kg/day), (AMP) rose in the cortex, indicating that aspirin, phenylbutazone (10 mg/kg/day), mefanamic acid (100 in this region, does uncouple oxidative phos- mg/kg/day), all lowered medullary flow, mefanamic phorylation. acid being the most active in this respect. The Davidson, Daffist, and Shippey [138, 139], using ischemia produced correlated with impaired medul- dog renal medullary slices in aerobic or anaerobic lary function, but not with the histological lesions. conditions, showed that only when salicylic acid and This work is so important that it should be repeated paracetamol were given together was substrate with control groups in each subset, as a number of metabolism altered, and that salicylic acid inhibited maneuvers (dehydration, shock, diuresis) were amino acid incorporation into protein. Paracetamol employed which should be stratified. has little effect alone, but it enhances that of saucy- Endothelial necrosis and vascular obliteration late. This matter is discussed further in other articles have also been reported in animals [97, 1311, but not [6—8, 71, 140, 141]. in man. Brown et al [101] reported minor vessel 4) Immunological. Little data is available. Murray changes in rats, but Abrahams [1321 reported a spe- and von Stowasser [142] postulated, on the basis of cific microangiopathy in patients. Nanra and Kin- glomerular deposits and positive staining of glomer- caid-Smith [96] also reported platelet aggregates in uli incubated with fluorescent antiserum, that there is the vasa recta, which is parallel to the findings of an immunologic basis, that the amino group con- Abrahams, Rubenstein, and Levin [131] but not to tained in most analgesics may be responsible, and those of Arnold et a! [102] and Ham and Tangue that these findings parallel to some extent the earlier [133]. Saker and Kincaid-Smith [134] observed views of Harrow. In human studies, however, Gault adherent platelets, but no thrombi. In view of the et a! [67] found no IgC or f3lC globulin in the cortex known effects of the nonsteroidal antiinflammatory or medulla of six patients with early analgesic agents on platelet aggregation and adhesion, it would nephropathy. seem very unlikely that they would induce aggrega- 5) . The renal papilla is the main tion or thrombosis. source of prostaglandins in the kidney. As "aspirin- Blood flow may be reduced by occlusion of vessels like" drugs inhibit biosynthesis, could by surrounding tissues. The data here is conflicting: this property be relevant to the genesis of analgesic Gault, Blennerhasset, and Muehreke [67] confirmed nephropathy? (See [143—148].) the earlier work of Clausen by showing an increase in The degree of inhibition of prostaglandin synthe- interstitial connective tissue with an increase in col- tase by the nonsteroidal antiinflammatory drugs lagen about the walls of the vasa recta and tubule. depends very much on the substrate employed [144, These changes were observed early in the disease. 145]. The PG2 series are derived (by definition) from Molland observed quite the opposite—damage and . In the rabbit medulla only a 2 to disappearance of interstitial cells [135]. 3% conversion has been observed; in the cortex, Salicylate administration reduces erythrocyte 2,3- none. Despite this low level of metabolism in the diphosphoglyceride in a dose-related manner, which rabbit, however, high levels of A2, E2, and F2 in the correlates well with the plasma concentration. Such medulla of the rabbit have been measured and posi- reduction increases the affinity of hemoglobin to tively identified by mass spectrometry and gas chro- oxygen, thereby depriving tissues; and Kravath, matography [1491. In the rat, there is histochemical Abel, and Colli [136] have quoted data suggesting evidence for the existence of prostaglandin hydro- that salicylates increase venous oxygen saturation by genase in the tissue surrounding the ascending loop 10 to 20% in rat and man. of Henle, and there is circumstantial evidence of 3) Metabolic effects. The main metabolic pathway prostaglandin synthesis in the dog also. in the inner consists chiefly of the The rank order of inhibition of synthetase in the anaerobic utilization of glucose. Aspirin has been guinea pig lung by the nonsteroidal antiinflammatory shown to inhibit the hexose monophosphate shunt in drugs is as follows: >niflumic medullary tissue [117] (unlike paracetamol). In the acid >mefenamicacid >flufenamicacid >naprox- isolated rat tubule [137], salicylate administration en >phenylbutazone>aspirin,or ibuprofen [144, reduced intracellular ATP [137], resulting in a 150, 151]. Fjalland eta! [152] would place indometh- reduced rate of gluconeogenesis; however, in the acm before flufenamic acid, and Ku, Wasuary, and whole medulla of the dog, Quintanella and Kessler Cash [153] would place as the most potent [110] found medullary ATP to be unaffected and of all. Aspirin and indomethacin inhibit synthetase in comments that this is to be expected, as the metabo- the rabbit medulla, producing inhibition of E2 and 22 Shelley

F2, also. Paracetamol appears to inhibit brain syn- angiotensin system. High doses of angiotensin, how- thetase only. ever, markedly decrease rat renal tubular a) Modulation of the effect of reninlangiotensin. resorption, thereby inducing natriuresis. This effect Angiotensin and noradrenalin increase renal perfu- can be enhanced by indomethacin [157], i.e., urine sion pressure and the basal output of prostaglandin- flow and sodium excretion increase in this like materials in the rabbit and rat; when the synthe- experiment. sis of the latter is blocked by indomethacin, the Bartelheimer and Senft [158] also failed to show effects of the autonomic neurotransmitters are aug- water and sodium retention during administration of mented or reduced depending on the experimental indomethacin (8 mg/kg) in rats, although phenylbuta- situation. When indomethacin is given intraarterially zone and oxyphenbutazone did do so. It is clear, (1 to 2pg/ml) the magnitude of duration of the then, that indomethacin produces varying responses response to the pressor agents is reduced [1541. The with regard to renal blood flow and glomerular filtra- pressor effects of noradrenalin were enhanced when tion rate in different species and depending on the PGE2 was infused into the kidney in amounts which experimental situation. by themselves had no pressor activity, and Gagnon, The natriuretic effect of pro staglandins could Gaulhier, and Regoli [1551 showed that when the result from an effect on oxidative metabolism. Lee tissues are pretreated with indomethacin (2g/m1) [159] has shown that prostaglandins inhibit interme- the increases in perfusion pressure induced by angio- diary metabolism which, by inhibiting sodium and tensin and noradrenaline were significantly greater. potassium ATPase, leads to a diminution of high Nerve stimulation, too, releases prostaglandins, energy intermediates available for sodium transport and indomethacin can block the effects of nerve and, thus, produces natriuresis. stimulation and produce a rise in systemic blood The reader is referred to the papers of Berg 1173, pressure in every case and total renal blood flow in 74], Davis and Horton [149], and Gagnon, Gaulhier, some experiments [1491. and Regoli [155] for a fuller discussion. It is clear, Vasoconstriction per se releases prostaglandins. however, that the vascular changes induced by pros- Two receptors for angiotensin are proposed. One taglandins are complex and their inhibition by non- modifies prostaglandin secretion, the other is con- steroidal antiinflammatory agents are comparably so. cerned solely with vasoconstriction [155]. The data in man shows acute sodium and water In dogs, indomethacin reduces renal blood flow retention following administration of an analgesic, from 15 to 45% (as does aspirin) and causes redistri- e.g. aspirin, which could be explained by an inhibi- bution from the inner to the outer cortex. Berg dis- tion of the natriuretic effects of pro staglandins; how- cusses reasons why the effects are more pronounced ever, during chronic administration of analgesics, in human patients with renal failure than in normal inappropriate sodium loss is present. subjects [73, 74]. b) Direct vascular effects. Although PGF2c, is mildly pressor, it has negligible effects on renal vas- Summary cular resistance. PGE2 on the other hand produces The situation in the experimental field is unre- vasoconstriction in the isolated perfused kidney and solved; too many factors require clarification before reduces renal blood flow (in contrast to the earlier the critical experiment can be conducted to settle the findings of Lee, quoted by Arnold [1031) Simple matter once and for all. However, as there is now inhibition of this compound, therefore, would not plentiful evidence to convince any reasonable physi- explain the reduction in medullary blood flow cian that commonly available analgesics, when observed by Nanra and Kincaid-Smith [1301. Infu- abused, carry a significant health risk, one may rea- sions of arachidonic acid produces hypotension in sonably ask whether any further experimental evi- guinea pigs. Aspirin will inhibit this effect [156]. dence is needed? Pretreating animals with salicylic acid before admin- The object of this review is in no sense divisive, istering aspirin, however, produces a normal i.e., by pointing out discrepancies in the available response to arachidonic acid, i.e., salicylic acid pre- data to thereby cloud the issue rather than resolve vents inhibition by aspirin. them. The problem of abuse lies properly in the field c) Natriuresis. Short-term administrations of aspi- of public health education, and the first step to this rin and indomethacin produce sodium and water would surely be an appropriate warning on the pack- retention. Donker, Arisz, and Brentjens [75] believe, aging of all commonly used analgesics. in the case of indomethacin, that this is a conse- For future research, however, government health quence of inhibition of prostaglandin synthesis, authorities should be guided in their preclinical test- which in turn leads to an activation of the renin- ing requirements for mild antiinflammatory analge- Analgesic nephropathy: Drug mechanisms 23 sics, and enough is now known to draw up guidelines Security, United Kingdom, Personal Communication for good laboratory practice in this field. 31.1.77 24. PRESCOTT LF: Anti-inflammatory analgesics and drugs used Acknowledgments in the treatment of rheumatoid arthritis and gout, in Mey/er's Side Effects of Drugs, edited by DUKES MNG. Amsterdam, I acknowledge the help and advice of Dr. L. F. Excerpta Medica, 1972— 1975, vol. 8, pp. 207—240 Prescott; the views expressed, however, and any 25. PRESCOTT LF: analgesics, in Meyler's Side errors therein are the writer's responsibility. Mrs. C. Effects of Drugs, edited by DUKES MNG, Amsterdam, Excerpta Medica, 1972— 1975, vol. 8, pp. 154—206 Boyett typed and assisted in revising the manuscript. 26. ABEL JA: Analgesic nephropathy: A review of the literature 1967—70, Clin Pharmacol Ther 12:583, 1971 Reprint requests to Dr. J. H. Shelley, C. H. Boehringer Sohn, 27. DUBACII UC, ROSNER B, MULLER A: Relation between Southern Industrial Estate, Bracknell, Berkshire RGJ2 4YS, Unit- regular intake of phenacetin-containing analgesics and labo- ed Kingdom. ratory evidence for uro-renal disorders in a working female population of Switzerland. Lancet 1:539, 1975 References 28. GLOOR F: Current concepts on morphology and pathogen- I. GSELL 0: From phenacetin nephritis to analgesic nephropa- esis of analgesic nephropathy. Schweiz Med Wochenschr thy 1953—1974. Schweiz Rundschau Med (Praxis) 63:1299, 104:785, 1974 1974 29. 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