Analgesic Abuse and the Kidney

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Kidney International, Vol. /7(/980), pp. 250—260

NEPHROLOGY FORUM

Analgesic abuse and the kidney

Principal Discussant: PRISCILLA KINCAID-SMITH

University of Melbourne and Royal Melbourne Hospital, Victoria, Australia

crotic papilla. Retrograde pyelography revealed thick purulent The Nephroiogy Forum is designed to relate material coming from the left ureteral orifice, but a catheter the principles of basic science to clinical prob- could not be passed into that ureter. The urine culture contained abundant pseudomonas, and the patient was treated again with lems in nephrology. colistin. Ten days following admission his temperature again rose to l0l F, left costovertebral angle tenderness recurred, and the serum creatinine rose to 12 mg/dl. Retrograde pyelography then revealed no evidence of obstruction of the left ureter, but Editors the calyces on the left showed marked scarring. At discharge, the JORDANJ.COHEN serum creatinine was 12 mg/dl, the hemoglobin was 9 g/dl, and the carbon dioxide content was IS mEq/liter. The only medica- JOHN T.HARRINGTON tions given were a sulfonamide and sodium citrate. The serum JEROMEP.KASSIRER creatinine fell to 6 mgldl over the next I to 2 months and was 4.6 NewEnglandMedical Center Hospital mg/dl 6 months later. Over the next 5 years, the patient experienced at least seven Boston, Massachusetts episodes of recurrent pseudomonas urinary tract infection, which required treatment with potentially nephrotoxic antibiotics. Sulfonamides, ampicillin. gentamicin, nitrofurantoin, car- Case Presentation benicillin, and tetracycline were administered in attempts to eliminate recurring gross pyuria and hematuria and to relieve an- This 66-year-oldman was diagnosed as having Guillain-Barré noying urinary tract symptoms. Tetracycline proved to be the syndrome32 years ago. Because of back pain from residual most effective of these agents, but the dosage required to rid the "arachnoiditis." he began to take approximately 12 tablets of patient of symptoms (750 mg/day) resulted in gastrointestinal up- Percodan® per day. Slight proteinuria and a blood urea nitrogen set. A combination of nitrofurantoin and a sulfonamide pre- of 25 mg/dl were discovered 17 years ago when he was hospital- vented severe dysuria, but did not eliminate other characteristic ized for treatment of a gastric ulcer. He was hospitalized 14 years symptoms. A representative urinalysis during the latter thera- ago because of fatigue, anemia, and azotemia. The physical ex- peutic regimen revealed I to 2 red blood cells (RBC) per high- amination was unremarkable: blood pressure was 140/80mm Hg, power field (HPF), white blood cells (WBC) too numerous to blood urea nitrogen was 60 mg, and serum creatinine was 6.2 mg/ count, and no casts; urine cultures contained 10 to 30,000 cob- dl. A gastric ulcer was demonstrated on an upper GI series but flies of a nonhemolytic streptococcus and 30 to 100,000 colonies had healed by repeat examination several weeks later. By this of pseudomonas per milliliter. Sterile urine cultures were ob- time the patient's accumulated phenacetin intake was estimated tained on more than one occasion following antibiotic therapy. to be 5 to 7kg, and on the advice of his physician he discontinued The serum creatinine concentration often increased during epi- all further ingestion of phenacetin-containing analgesics. La- sodes of infection but returned to a baseline level of approxi- minagrams revealed symmetrical kidneys measuring 11.5 to 12 mately 6 mgidl after treatment. During this period, the patient cm in length. Retrograde pyelography revealed no evidence of had one episode of severe acidosis, but with continuous alkali obstruction or papillary necrosis. Urine culture grew Pseudo- treatment his plasma bicarbonate concentration increased to 20 monas aeruginosa, and a course of colistin therapy was given. mEq/liter and his symptoms disappeared. In the last year of this Serum creatinine concentration rose from the admission level of 5-year period, a representative urinalysis revealed: specific grav- 6.2 mg to 10.2 mg, but fell to 7.7 mg/dl by the time of discharge. ity 1.010, albumin 2+, pH 6, Ito 2 RBC/HPF with no casts, and The rise in serum creatinine occurred 5 to 7 days after the colistin 70 to 100 WBC/HPF. During this interval, the patient also suf- was discontinued. fered an acute lateral wall myocardial infarction from which he Six months later, the patient was hospitalized for fever, chills, made an uneventful recovery. and acute left flank pain due to obstruction from a presumed ne- Approximately 8 years ago, the serum creatinine was 10 mg and the BUN 100 mg/dI; 7 years ago, the serum creatinine was 11.4 mg/dl and a protein-restricted diet was instituted because of Presentation of the Forum is made possible by grants from mild uremic symptoms. Alkaline phosphatase was 6.5 Bodansky Hoechst-Roussel Pharmaceuticals Inc., Smith Kline & French units, calcium was 6.9, and phosphorus was 6.2 mg/dl. Six years Laboratories, G. D. Searle & Co., Warner-Lambert Pharmaceu- ago the patient began chronic hemodialysis. tical Division, Burroughs Wellcome Company. Geigy Pharma- Three years ago the patient received an HLA-identical kidney ceuticals Inc., Ciba Pharmaceuticals Inc., and Boehringer Ingel- transplant from his 68-year-old brother. Two episodes of acute heim Ltd. rejection occurred shortly after transplantation, but both episodes were reversed by high-dose intravenous steroid therapy. 0085-2538/80/0017-0250$02.20 The serum creatinine shortly after discharge was 1.5 mg/dl. His ©1980 by the International Society of Nephrology present medications include 10 mg/day prednisone, 100 mg/day

250 Analgesic abuse and the kidney 251 azathioprine, 60 mg of codeine three times per day, and I tabletlone-third of patients presenting with analgesic ne- day Percodan®. Current laboratory values include a BUN of 25 mg andaserum creatinine of 1.6 mg/dl; the urine culture is ster- phropathy have taken only aspirin, salicylamide, ile. and caffeine—no phenacetin—yet these people have clinical features identical to those in patients Discussion who have taken aspirin, phenacetin, and caffeine DR. PRISCILLA KINCAID-SMITH (Professor of (APC) [4]. Despite a steady reduction in phenace- Medicine, University of Melbourne):Analgesicne- tin-containing analgesics between 1962 and 1975, phropathy is a "community habit" in Australia and and even though phenacetin has not been available certain European countries. The practice of habitu- in common over-the-counter preparations in Aus- al, excessive analgesic intake predominantly affects tralia for 4 years, the number of new patients pres- women, however. This patient is a man, and be- enting with clinical analgesic nephropathy, dying, cause the male-to-female ratio is 1:4 or 1:5 in anal- or requiring dialysis has not declined (Fig. I). This gesic nephropathy, one immediately wonders about experience may be helpful to countries like the the reason for analgesic abuse in his case. The men United States, where restriction of phenacetin cur- in our own studies have tended to be much more rently is being contemplated. It also points out the abnormal in behavioral terms; for example, all the problem in labeling a disease phenacetin nephri- men in our original study, carried out between 1959 tis" when no definite evidence indicates that phe- and 1962 at the Royal Melbourne Hospital, had at nacetin alone can cause the renal lesion. some time been hospitalized for psychiatric treat- Animal experiments that have attempted to re- ment [1]. This patient took Percodan® for a genuine produce the renal lesions seen in humans usually chronic painful disorder, but his use of the drug in have been negative when phenacetin is used on its excessive quantities suggests that it had become a own. Huge doses of phenacetin, 3000 mg/kg, pro- "habit." duce only minor changes in the renal papillae [5]. In 1964, Percodan® contained in addition to Aspirin alone in a dose of 500 mg/kg produces papil- oxycodone: 224 mg of aspirin, 160 mg of phenace- lary necrosis and secondary cortical lesions resem- tin, and 32 mg of caffeine. I would emphasize that it bling those in humans in 30% of experimental ani- is a mistake to label this patient's condition phe- mals [5]. Aspirin together with phenacetin or para- nacetin nephritis" because he took this mixture of cetamol produces papillary necrosis and secondary different agents. Analgesic nephropathy, or renal cortical changes in 60% to 80% of laboratory rats [5, papillary necrosis as a result of analgesic abuse, has 6]. All nonsteroid antiinflammatory agents tested, been associated with a great variety of analgesic including phenylbutazone, mefenamic acid, indo- compounds. In no single patient has it been attrib- methacin, phenazone, and propoxyphene, have uted to phenacetin alone, although patients have produced papillary necrosis in rats [7]. Recent re- been described who have taken only aspirin [2] or paracetamol (acetominophen) [3]. Singling out one 100 ingredient as dangerous has the unfortunate effect of suggesting that the other ingredients are safe. One might argue that because papillary necrosis has V0) occurred in patients taking only aspirin, the term > C, "aspirin nephritis," not "phenacetin nephritis," V 30 should be used. In my opinion, both designations C are incorrect. This question has been debated for C, C, many years, but the dangers of compound analge- a 20 sics as opposed to the hazards of preparations con- 'C taining single ingredients are now becoming very clear as experimental data from animals and hu- 10 mans become available. In Australia in 1962, phenacetin was withdrawn from most over-the-counter analgesics, which then were advertised as Safe— 1971 1972 1973 1974 19751976 1977 1978 contains no phenacetin." Of the two remaining phe- Fig.1. Frequency ofanalgesic-abuse nephropa thy among neu' patients entering chronic hemodialysis programs in Australia. nacetin-containing analgesic compounds, phenace- Frequency has not declined in recent years despite the reduced tin was withdrawn from one in 1967 and was re- availability of phenacetin-containing analgesics. (Data from Aus- placed with salicylamide. Twelve years later, about tralia Kidney Foundation Registry) 252 Nephrology Forum

Chronic interstitial cJ, nephritis .1

Medullary calcification Interstitial cell —? inhibition of prostaglandin E synthesis

Loop of Henle —toxic damage Vasa recta—medullary ischem Ia

Renal papillary necrosis Maximum concentration of - '4C-aspirin - NAPA

Fig.2. Pat ho genesis of papillary necrosis in analgesic abuse. Papillary necrosisdue to reduced medullaryblood flow probably initiates the process that results in chronic interstitial nephritis. The analgesic mixtures implicated in this condition are probably concentrated in the renal medulla and may share a common ability to inhibit prostaglandin synthesis. (Kindly supplied by R. S. Nanra) ports from the United States stress the importance result from this reduction in blood flow [6]. Later, of propoxyphene (Darvon®) and propoxyphene occlusive lesions develop in the vasa recta, and APC(DarvonCompound®) as causative agents [8, these may cause actual necrosis in the papillae [6, 91. 15]. Themechanism whereby analgesics produce re- To return to the patient under discussion: the nal damage is still debated. Experimental work now considerable elevation of the BUN and creatinine suggests that the lesions of chronic interstitial ne- concentrations, in the presence of slight and inter- phritis, as shown schematically in Fig. 2, are sec- mittent proteinuria, is a characteristic of renal fail- ondary to renal papillary necrosis [10, 11], and pa- ure from primary tubular and interstitial disease and thologists generally accept the association [12, 13]. suggests analgesic nephropathy in particular. The potential for causing papillary necrosis shared Peptic ulceration, a feature of this patient, fre- by so many nonsteroid antiinflammatory agents quently precedes analgesic nephropathy, often pre- suggests that some common property, such as the dating renal symptoms by several years [lii. Peptic ability to inhibit prostaglandin synthesis, accounts ulceration is attributed to prolonged ingestion of for their toxic effects on the renal medulla. Prosta- high-dose salicylates [16]. Although papillary ne- glandins are thought to play an important role in crosis was not demonstrated on radiograms, the di- regulating medullary blood flow; if true, this physio- agnosis of renal papillary necrosis cannot be ex- logic alteration would provide a possible mecha- cluded on this basis [1, 17]. In-situ lesions in which nism through which all of these chemically different necrotic papillae remain attached and hence do not agents might cause papillary necrosis. Anti- cause any of the characteristic radiologic features inflammatory agents, particularly indomethacin, are common [17]. markedly reduce medullary blood flow and inhibit This patient's recurrent episodes of pyelonephri- prostaglandin synthesis [14]. Early changes in the tis are typical of the chronic relapsing course of an- papillae in experimental animals, if ischemic, could algesic nephropathy. Temporary failure of either Analgesic abuse and the kidney 253 kidney during acute infection, associated with ob- tients by aggressive continuous treatment with ap- struction by a necrotic papilla, is another character- propriate antibacterial agents, it is noteworthy that istic feature exhibited by this patient, as was his this patient's pyuria persisted despite intermittent moderate hypertension, which developed several treatment for the recurrent acute pseudomonas py- years after the onset of the pyelonephritis. Malig- elonephritis. The combination that might eradicate nant hypertension, however, can occur in patients pseudomonas infection consists of an initial course with this condition [4]. of gentamicin or colistin followed by continuing Five years of this patient's course were punc- long-term treatment with a combination of oxytetra- tuated by intermittent episodes of acute pyelone- cycline and cotrimoxazole. These drugs can phritis caused by the same organism, namely achieve sufficiently high levels in the urine to sup- Pseudononasaeruginosa. Itis very likely that this press or even eradicate infection. In the patient un- organism was never eradicated and that the sterile der consideration, a urine culture showed less than cultures, obtained after a course of colistin or gen- 1000 col/ml of pseudomonas on one occasion. Al- tamicin, reflected a temporary clearing from the though it was concluded that this urine was not in- urine, while the necrotic debris in the pelvis re- fected, the patient was undergoing sulfonamide mained infected. The organism that was present in therapy at the time, and this might well have re- the urine 14 years ago was almost certainly acquired duced the bacterial count. Counts as low as 200 coIl in hospital, perhaps during retrograde urography. ml can be shown to represent true persistent infec- Infection persisted until dialysis was started 8 years tion by needle aspiration of bladder urine, even later, and required repeated hospital admissions for when patients are not currently receiving antibiotics parenteral administration of potentially nephrotoxic [19]. The low bacterial counts recorded in this man antibacterial agents. The infections and their treat- probably represent true infection—not con- ment probably contributed to this patient's gradual tamination—because he had constant pyuria and re- progression to end-stage renal failure. current episodes of active infection with the same Fourteen years ago, this man's kidneys were only organism. The nitrofurantoin and sulfonamide that slightly reduced in size. Because the serum creati- he received on occasion may have produced low nine concentration one year later was only 4.6 mg/ bacterial counts in urine cultures, but these drugs dl, it should have been possible with optimal man- could not eradicate a pseudomonas infection. We agement to restore his BUN and serum creatinine to would never use nitrofurantoin in a patient with normal or nearly normal levels. This is a recover- such a high serum creatinine concentration because able form of renal failure and, in our experience, peripheral neuritis could develop. The pyuria ap- patients almost invariably recover if factors such as parently was eradicated only once following a infection, hypertension, sodium depletion, and in- course of tetracycline, a drug that sometimes termittent obstruction are promptly and effectively achieves effective urine concentrations against corrected. The prognosis should be very good if the pseudomonas organisms. patient's kidneys are normal or nearly normal in The final factor that contributed to this patient's size and if analgesic abuse ceases. In a study of 52 irreversible progression to renal failure was the de- patientsfollowed over a period of years, 50%im- velopment of glomerular lesions, manifested by al- proved, 35% remained stable, and only 15% deteri- buminuria and hematuria 9 years ago. The develop- orated [18]. ment of heavy proteinuria in a patient with analge- One factor that may have led to a decline in renal sic nephropathy is a poor prognostic sign [4, 20]. function in this man was the probable continued an- Before heavy proteinuria develops, renal function algesic abuse. Although this is not fully docu- in such patients may intermittently improve or sta- mented, his reliance on Percodan® is strongly sug- bilize; however, after the development of protein- gested by continual attacks of acute papillary necro- uria they tend to run a progressively downhill sis—manifested as macroscopic hematuria—as long course. The same is true in chronic atrophic pyelo- as 6 years after presentation. Such episodes usually nephritis and in reflux nephropathy [21, 22]. The cease when analgesic abuse ceases, and I therefore glomerular lesion in either disease is that of focal suspect that his analgesic abuse continued. Active and segmental hyalinosis or focal sclerosing glomer- recurrent papillary necrosis aggravates urinary tract ulonephritis (Fig. 3). The primary form of this gb- infection, and both probably contributed to the pro- merular lesion usually is irreversible, as are the sec- gressive renal dysfunction in this patient. Because it ondary lesions of analgesic nephropathy, reflux ne- should be possible to eradicate pyuria in such pa- phropathy, and gouty nephropathy [23]. Once the 254 Nephrology Forum -i'---2 -.

Fig.3. Focalsclerosing glomerulonephritis in a patient u'ith analgesic-abuse nephropathy. The glomerular hyalinosis featured in this photomicrograph occurs in a small percentage of patients with advanced analgesic-abuse nephropathy. heavy proteinuria develops, one can confidently tinued to take one Percodan® per day together with predict progression to end-stage renal failure in I to a large dose of the habituating drug codeine. Return 3 years, as occurred in this patient. to analgesic abuse after transplantation has been re- On at least one occasion, this patient was acidot- ported in a large number of patients with analgesic ic. Severe acidosis, often out of proportion to the nephropathy. BUN and serum creatinine concentrations, is a fea- We are not told what the nephrectomy specimen ture of renal failure due to analgesic nephropathy. showed, but active recent necrotic papillary materi- Even when renal function is only slightly impaired, al may still have been present because of continued patients may have renal tubular acidosis [4]. analgesic intake. The final definitive proof of the di- Acute myocardial infarction is not unusual in a agnosis of analgesic nephropathy might be provided man of this patient's years, but an inappropriately by the nephrectomy specimens. Do we know what high frequency of ischemic heart disease and other was found on examination of the nephrectomy complications of severe atheroma has been noted in specimen? women, including premenopausal women, with an- DR. VIvIAN Pir' (Patiwlogist,NEMCH): The algesic nephropathy [24, 25].Webelieve that ath- kidneys at the time of the bilateral nephrectomy eroma and its complications are unusually prevalent were atrophic and scarred, with the left weighing 78 in this group of patients. Myocardial infarction was g and the right, 74 g. The cortical surfaces were con- the cause of death in 25% of patients in our original tracted and granular with numerous cystically di- study [1]. lated tubules. Extensive bilateral papillary loss with This man reached end-stage renal failure requir- focal medullary calcification and occasional ossifi- ing dialysis 8 years after presentation; hence, he ran cation were present. a typical chronic course. A successful transplant DR. P. KINcAID-SMI1H:Inour experience, calci- from an HLA-identical sibling was carried out after fication in these kidneys is almost invariable at au- bilateral nephrectomy, which I presume was per- topsy and very frequently can be discerned radio- formed because of fears of continuing pseudomonas logically. Most of our specimens, however, were infection that might have affected the transplanted from patients who began dialysis after removal of kidney. Even after transplantation, the patient con- the kidneys. This patient underwent dialysis for 3 Analgesic abuse and the kidney 255 years prior to nephrectomy, and we cannot expect characteristic irregularly shaped kidneys with to find in this specimen features that were there pri- marked hypertrophy in some areas and black-stain- or to dialysis. ing necrotic papillae. This doctor taught us a great The lesion in analgesic nephropathy is very easily deal about his disease. On questioning, he revealed recognized and quite distinct from all types of pye- that he actually was taking the analgesics for their lonephritis. In the past, when patients took large mood-altering effects and not for pain relief. At quantities of phenacetin, we found considerable first, he thought he was taking about 20 to 30 pills pigmentation in the papillae on autopsy. As the per day, but when he actually counted, he docu- years have gone by and phenacetin has virtually dis- mented taking 100 pills per day. I think this demon- appeared from the market, the one thing that has strates two important factors in the disease: (I)the altered is the pigmentation of the papillae. Although enormous resistance that one can develop to drugs we still find necrotic papillae, they are not always like salicylates, since this patient regularly took pigmented. The sequence of the injury proceeds what would be a fatal dose in one unaccustomed to from necrosis of the papillae to the sloughing off of it; and (2)thesepatients do underestimate how much the papillae into the ureters, which may obstruct the they take. We gave our patient placebo tablets in kidneys. This is followed by shrinkage of the kidney which various ingredients were missing. His re- down to the cortex and enormous hypertrophy with sponse confirmed my view that analgesic nephropa- a white appearance in the columns of Bertin, giving thy is predominantly caused by the habitual inges- the kidneys an irregular shape, as was reported in tion of analgesic compounds for their mood-altering this patient. The characteristic radiologic lesions, of effects. The ingredients that he missed for the course, are ring shadows formed by the necrotic pa- mood-altering effects were the caffeine, which you pillae, with contrast medium encircling them. But might expect, and the phenacetin; he did not really when the papillae are lost and only clubbing can be care whether the drug contained aspirin. Thus, it seen, it is difficult to distinguish papillary necrosis seems that there was no habituating effect of aspirin from reflux nephropathy. As I indicated earlier, the in this man. papillae often remain attached, although they may Another of our patients, a woman, well illustrates become calcified. Radiologic identification of the many of the features of this disease. She first came disease depends on detachment of the papillae, of to us 20 years ago, and she stopped taking analge- course, but one cannot exclude the diagnosis just sics at that time. She died in the hospital just 2 because radiologic evidence of papillary necrosis is months ago of incapacitating chronic congestive not present. heart failure from severe myocardial ischemia. Al- DR.J.T. HARRINGT0N: I should like to add a few though her course was marked by many complica- comments regarding the patient. First, to the best of tions, her first episode of hypertension occurred at our knowledge, he did stop taking phenacetin-con- the commencement of the disease. Some months af- taming analgesics. He continued, however, to take ter therapy began, she returned with a non- nonphenacetin-containing analgesic agents for pain fuctioning left kidney and severe left loin pain. A relief during the time between his initial presenta- mass was found in the pelvis on radiologic examination and the initiation of chronic dialysis. Second, tion; today we would immediately think of malig- we thought that his persistent, recurrent infection, nancy in this context. An investigative operation not analgesic abuse, did more to damage his residu- was performed by a urologist, who removed from al kidney function than did anything else. Finally, the kidney massive debris with a few little pig- we have chosen to tolerate his taking one tablet of mented necrotic papillae caught up in it. This is the Percodan® per day, which he has done since trans- sort of lesion that can develop particularly from re- plantation, in the hope of preventing his ingestion of current episodes of pyelonephritis, which this pa- larger amounts of other analgesics. tient had; staghorn calculi can develop very rapidly DR. P. KINCAID-SMITH: We once treated a man in this setting with calcification and precipitation of whose course was similar to the patient presented triple phosphates. today. Our patient, who happened to be a doctor, Even after her operation, this patient was not free had been using analgesics for approximately the from trouble. After 3 years, the right kidney had not same length of time as this patient. A peptic ulcer altered much; it still had clubbed calyces with very was his first presenting sign some 15 years before he narrow cortex over them, but the left kidney had came to us with renal symptoms. He died of a myo- ceased to function and a number of calculi were evi- cardial infarction, not renal failure, but he had the dent. In the next several years, the patient contin- 256 Nephrology Forum ued to pass calculi, some of which were quite large venous diazoxide to control her blood pressure at and resembled papillae. On decalcification and sec- first, but as her sodium depletion improved with salt tioning, they contained necrotic papillae at the core, administration, and as her weight increased and her which enabled us again to make a positive diagno- serum creatinine concentration decreased, her hy- sis. She continued in this fashion for more than a pertension improved. After the initial treatment decade, with her serum creatinine concentration re- with diazoxide, she needed only chlorothiazide and maining slightly below 3 mgldl. She then developed reserpine to control her blood pressure; ultimately increasingly severe hypertension and a decline in her hypertension disappeared altogether. The rela- renal function. She had lost the function of her left tionship exists frequently enough in this group of kidney, as I mentioned, some years before because patients that we sometimes have found it very diffi- of obstruction; she now developed severe stenosis cult to treat their hypertension unless we have com- of the right renal artery. After surgical relief of the bined management of blood pressure with sodium stenosis, her renal function improved and her hy- repletion. pertension disappeared. This patient is a prime ex- Another striking feature in patients with analgesic ample of the severe atheroma that is common in an- nephropathy is their premature aging. Wrinkling of algesic nephropathy. facial skin, aging of the body surface generally, very It is difficult in a group of patients with chronic early graying of hair, as well as early aging of arter- renal disease to document whether the incidence of ies is common. renal artery stenosis is higher than expected. We A feature that we are beginning to encounter compared 37 patients with analgesic nephropathy more frequently in our patients is an associated uri- and hypertension with 279 patients in the same age nary tract malignancy, which was first described in group who had renal arteriograms that revealed no Sweden [26]. The lesion occurs even in patients analgesic nephropathy. The incidence of athero- who have stopped taking analgesics and no longer matous renal artery stenosis was much higher in the have active renal papillary necrosis. Again, it is dif- patients with analgesic nephropathy than in the oth- ficult to document that these tumors occur more fre- er patients (Table 1). Atheromatous renal artery ste- quently in patients with analgesic nephropathy, but nosis is predominantly a disease of men, whereas present evidence indicates that the incidence is fibromuscular renal artery stenosis is more common higher in these patients than in the general popu- in women. lation. Malignant hypertension is often a feature of anal- I think analgesic nephropathy probably first ap- gesic nephropathy. It frequently occurs early in the peared in this century. I say this because papillary course of the disease during a period of active necrosis prior to the 1920s almost always was asso- sloughing of renal papillae. Patients are often se- ciated with diabetes, and because the incidence of verely salt depleted at this stage, and a paradoxical papillary necrosis has increased significantly in var- relationship exists between salt and blood pressure ious countries in recent years. Studies by Gloor in this disease. For example, one woman who came show that over a period of 20 years, the incidence of to us with malignant hypertension needed intra- renal papillary necrosis doubled in Switzerland [12]. Even in the United Kingdom, few instances of the Table1. Atheromatous lesions causing renal artery stenosis disease were noted early [27]; nonetheless a marked (ARAS)in women increase did occur between 1961 and 1967. In addi- Hypertension Analgesic tion, various studies in Australia reported an in- only nephropathy creased incidence from 3.7% in 1962 [28] to 21% in (No. of and hypertension Age patients) ARAS (No. of patients) ARAS 1973 [29]. Errors surely exist in these studies because such analyses are most accurate when per- 10—19 9 0 0 0 20—29 57 4 (7%) I 0 formed by a single pathologist. All of the studies 30—39 86 7(14%) 3 2(66%) were carried out by different groups, and the vari- 40—49 77 14 (29%) 16 6 (37%) ous pathologists may have used different diagnostic 50—59 39 25 (46%) 8 1(12%) 60—69 11 5 (42%) 9 5 (55%) criteria. I do not think there is any doubt that a very Total 279' 40" (14%) 37r 14' (37.8%) big difference in prevalence of this disease exists Consecutive arteriograms in hypertensive women. Fibro- between Australia and, for example, countries such muscular renal artery stenosis was evident in 16%. as the United Kingdom and the United States. "P<0.02 The big question of course is why? In Australia at Consecutive arteriograms in women with hypertension and analgesic nephropathy. Fibromuscular renal artery stenosis was least, we think that the use of modern advertising evident in 8%. techniques for over-the-counter analgesics was Analgesic abuse and the kidney 257 largely responsible for increased sales. This prac- alone and developed the lesion. The vast majority tice started shortly after World War I, and analgesic of patients take a combination drug, as did the pa- sales rose tremendously in our country. According tient discussed today. And in most countries where to Australian Kidney Foundation Registry data, analgesic nephropathy is a serious problem, combi- 24%ofpatients requiring dialysis and trans- nation preparations with mood-altering effects are plantation between 1971 and 1979 had analgesic ne- the agents most widely abused. Thus, we do not be- phropathy. The data show a striking difference in lieve that elminating analgesic compounds is a hard- distribution of the disease that correlates best with ship to ordinary people who want relief from head- total analgesic sales and sales of analgesic powders. aches or toothaches. We propose to let them buy a My colleagues and I have thought long and hard small, single-ingredient analgesic, which is all they about solutions to this problem. We have seen that need. One of the problems in Australia is that these the withdrawal of phenacetin did not really help: the drugs are sold by the gross in our supermarkets. Of actual number of analgesic abusers requiring dial- course, the drug companies argue that the majority ysis and transplantation continues to increase. At of the community should not be penalized for some- present, we are trying to legislate restriction of cer- thing that affects a small percentage of people. But tain over-the-counter compounds, most of them in Australia this is a serious problem: analgesic ne- containing either aspirin, salicylamide, and caf- phropathy is present at 20% of all autopsies; it ac- feine, or containing aspirin, paracetamol, and caf- counts for 20% of people who come into dialysis or feine. Because we cannot determine whether any transplant programs; and for each individual who one ingredient is responsible, we propose to restrict starts dialysis, our studies show that at least 100 the compounds that are universally abused. If the others in the community are suffering from serious stimulants are removed from the compounds, we chronic complaints such as hypertension, renal cal- might see a reduction in misuse of the drugs. We culi, and renal infection. hope that these agents will be available only as We think the problem is serious enough to require single ingredients in small packages in at least three governmental intervention. We believe that restric- Australian states very soon. tion of the amount in each childproof package would automatically increase the cost and minimize Questions and Answers the possibility that people will take a combination of DR. J. J. COHEN: For the sake of argument let me drugs to obtain the mood-altering effects. We have adopt a position that a drug company might take. considered the problem for a long time, and we The problem you have documented so well stems thought we had it solved when phenacetin was re- from long-term abuse of the over-the-counter prep- moved from the mixtures; but that has not been the arations. No evidence indicates that any renal im- answer. After years of discussion at the Australian pairment occurs from ordinary, episodic adminis- Kidney Foundation and elsewhere, agreement has tration of these pain-relieving agents. Moreover, been reached that restriction is the course most the availability both of single-agent and combina- likely to help, but time will tell. tion preparations allows people to choose the medi- DR. J. J. COHEN: Not to belabor the point, but we cation they prefer. Some people, for whatever rea- could argue by analogy that alcohol is even a great- son, are more satisfied with combination drugs. To er danger to society. Yet we have not had much remove them from the market because a few people luck in prohibiting its sale. abuse them would be doing a disservice to the ma- DR. P. KINCAID-SMITH: Tobacco and alcoholic jority who find them beneficial and unharmful at beverages are very good examples of agents that lower doses. What then is the justification for produce moral problems in the community. My de- across-the-board restriction of their use, rather than fense would be that I do not have to dialyze people an alternative, such as mounting an educational who have abused alcohol. This is a very personal campaign to alert people to the dangers of abuse? view, but in fact, 20% of Australia's dialysis costs DR. P. KINCAID-SMITH: Our educational cam- are attributable to drug abuse; that is $15,000 per paigns of nearly 20 years do not seem to have had patient per year. After all, analgesics are medicines any impact. Abuse occurs almost entirely with com- and they would not pass the present animal testing bination preparations. Occasionally we treat a pa- requirements if they were introduced now. Aspirin tient who has abused aspirin alone; the literature is a good drug, but if tested under today's standards describes only 10 patients who have abused aspirin it would be available only with stringent criteria for alone and developed the syndrome. I think we have its use. I think there is a difference between alcohol treated 2 patients who have abused paracetamol and tobacco, and medicines. We are not allowed to 258 Nephrology Foru,n use medicines that have far lesser adverse effects drugs causing papillary necrosis or analgesic ne- than the agents we are discussing. phropathy? DR.J.T. HARRINGTON:Youhave said that cer- DR. P. KINCAID-SMITH:Wehave not tested tain combinations of analgesics are more likely to them. For a number of years, we had a model set up cause renal lesions than are others. The experience for testing drugs, but we have not examined the in patients with chronic rheumatoid arthritis who newer ones. The process is very time consuming. lake aspirin in very large quantities for many years Theoretically, that should be so. I have no doubt argues against aspirin alone as an important agent in that the drug companies have some data on papil- producing renal damage. Although histologic lary necrosis with various drugs, but I have not had changes can occur in these patients, they have a access to it. very low incidence of end-stage renal disease from DR. NIc0LA0s E. MADIAS (Renal Service, papillary necrosis. Second, the experience in Cana- NEMCH): Your data describe patients with impres- da with phenacetin is apparently different than sively high serum creatinine concentrations that re- yours in Australia; Gault's studies claim that the in- turned to normal after some time. How much of this cidence of papillary necrosis has decreased since improvement in renal function was due to relief of the removal of phenacetin sometime in the early acute obstructive disease? 1970s [30]. That seems at variance with the findings DR. P. KINCAID-SMITH:Theserum creatinine in Australia. concentration of patients with obstruction de- DR. P. KINCAID-SMITH:Yes,it is at variance to creased dramatically—a straight decline graph- some extent. There does seem to have been a de- ically—with relief of obstruction. I doubt that the dine in Canada but certainly not in Australia. long, continued improvement we saw over years The low incidence of papillary necrosis in rheu- was related to obstruction. In most patients who matoid arthritis is, I think, related partly to dosage. present initially with high serum creatinine concen- We used to be able to document how much of the trations, some degree of active papillary necrosis is drug people were taking much better than we can present and obstruction cannot be excluded. In our today. As I mentioned earlier, people take larger group of 25 patients, we could document obstruc- quantities than they think. In rheumatoid arthritis, tion of at least one kidney in 8 or 10 patients. Thus, it is often a struggle to get the patient to take 20 obstruction alone was not responsible for the in- aspirin tablets a day. Such patients do develop renal creased creatinine levels; other factors such as lesions, but they very rarely present with significant acute infection contributed to the rise. A factor that nephropathy; those that do almost always have may be important in determining how much im- abused mixtures of drugs in big doses. So I agree provement occurs is the tendency for papillae to ad- with you. I am not by any means saying that aspirin here far more readily with the aspirin-salicylamide- alone is responsible. We were very surprised indeed caffeine preparation than with the APC combina- when our rats developed lesions when given aspirin tions, whether they contain phenacetin or para- and not when given phenacetin. We expected to in- cetamol. Patients who slough papillae seem to reduce lesions with a combination preparation be- cover much better than do those whose papillae ad- cause we were using the same model that Abrahams here. I do not think therefore that obstruction was and Levin had reported with a combination [31]. by any means the only factor in those long, contin- We were again surprised when we continued to see ued improvements; but it was a factor in some of the same syndrome even after phenacetin had been the patients. It is very difficult to separate them removed from one of the two most widely used completely. It is not as simple as relieving obstruc- agents and replaced with salicylamide, which is to- tive stones. tally unrelated chemically. One is forced to con- DR. AARON SPITAL (RenalFellow,Rhode Island clude that no single ingredient is responsible. To re- Hospital): In view of the availability of the combi- turn to the experimental animal data, which is after nation preparations in the United States, do you all how we test all drugs, I think there is reasonably think there is a real difference in the incidence of good evidence for some common pathway, perhaps analgesic nephropathy between Australia and the prostaglandin inhibition, that all of these agents United States, or do you think we may have a diag- share. nostic problem and the disease simply is not being DR. DAVID BUSHINSKY (Renal Fellow, identified here? NEMCH):Inview of the new, potent, nonsteroidal DR. P. KINCAID-SMITH: A number of our post- antiinflammatory agents, which are also prosta- doctoral fellows have studied in the United States glandin inhibitors, do you foresee another class of and report identifying only one or two instances of Analgesic abuse and the kidney 259 papillary necrosis from analgesic abuse during their This may be especially worrisome because immu time here. Clearly, they have seen the disease fre- nosuppressive agents are thought to increase the quently in Australia and therefore should have no likelihood of epithelial tumors. problem diagnosing it. So I think there is a real dif- DR. P. KINcAID-SslirH: We have not done this ference. For similar reasons, I am convinced of a recently. We only have removed the kidneys it real difference in incidence between the United there was a problem with infection. The answer to Kingdom and Australia. Before I went to Australia, your question may become apparent if the many pa- I was with Hammersmith Hospital in London for 6 tients in Australia who have had renal transplants years and participated in virtually every autopsy because of analgesic nephropathy subsequently de- performed there; during that period I saw only two velop tumors, but it has not happened yet. instances of what I called an unusual form of papil- DR. J. T. HARRINGTON:Couldyou give us a pre- lary necrosis, unlike the diabetic form. In Australia, view of your techniques for distinguishing between this unusual" form of the disease was an almost red cells that come from the glomeruli and those daily occurrence in the autopsy room. I do not that come from other areas of the kidney? know the reason for the difference in the incidence, DR. P. KINCAID-SMITH: It seems that red cells and only suggest that the tremendous advertising that come from glomeruli have definite extrusive campaigns in Australia are responsible for the prev- features, and those that come from the bladder or alence of the disease. Much of the advertising now pelvis look like ordinary red cells. has been stopped, but the community habit is well DR. J. T. HARRINGTON: Are the cells examined established. There is an extremely high incidence of under light microscopy? the disease in one area of Glasgow, where a powder DR. P. KINCAID-SMITH: Yes. We have used elec- containing a large amount of caffeine is popular; our tron microscopy but it has not been terribly inform- mixtures contain this powder also. Murray has sug- ative. Using light microscopy one can quite accu- gested that high doses of caffeine predispose to rately distinguish between glomerular red cells and abuse. Murray and Goldberg suggested that you others. have a much higher incidence of the disease in the DR. MARTIN GELMAN (Renal Service, St. Eliza- United States than you think [8]. I believe approxi- bet/i's Hospital): Do we know enough about the ef- mately 7% of patients entering your dialysis pro- fects of the combination analgesics to determine grams have this disease. So it may indeed be more which ones seem to be the worst offenders? prevalent than you think. DR. P. KINCAID-SMITH: We do not know enough DR.J.T. HARRINGTON:Ibelieve tumors of the about the combinations. Our studies in Australia inrenal pelvis occur in approximately 8% to 10% of dicate that about one-third of patients took various patients with analgesic nephropathy. How would agents, but about one-third took either the phenace- you make that diagnosis in a patient who has pro- tin-containing analgesic or the salicylamide-con- teinuria, hematuria, abnormal renal function, and taming analgesic. papillary necrosis without performing a series of DR. N. E. MADIAS: Did you exclude patients with retrograde urographic procedures? diabetes from your series? Does the combination of DR. P. KINCAID-SMITH: It is not easy at all. We diabetes and analgesic abuse produce a more devas- are always worried when microscopic hematuria is tating degree of papillary necrosis? present because it may indicate glomerular damage. DR. P. KINCAID-SMITH: We did exclude patients We have a technique, which we are just perfecting. with diabetes from the studies that I have men- for recognizing the difference between red cells that tioned. We see a few people with diabetes who take come from the glomerulus and red cells that come analgesics and develop papillary necrosis, but then from lower in the kidney [33]. We have not seen we see a few diabetic patients who do not take anal- many tumors, and in those few patients in whom we gesics and who develop papillary necrosis. I think have diagnosed tumors, I cannot tell you whether we the combination is worse, but it is not devastating. have actually made the diagnosis on the basis of this Diabetes is certainly a much rarer cause of papillary technique. It is a difficult differential diagnosis; in necrosis in Australia than is analgesic abuse. fact, the disease is more commonly diagnosed at au- DR. J. J. COHEN: You emphasized the problem of topsy than in any other manner. controlling infection in patients such as the one un- DR. J. T. HARRINGTON: Given the difficulty in der discussion today. Kass recently has reaffirmed making this diagnosis, would you remove the kid- his long-standing advocacy of mandelamine or hip- neys because of this predilection for tumors in a pa- puric acid for long-term suppression and eradica- tient who is going to receive a kidney transplant? tion of infection in patients who have highly resis- 260 Nephro!ogv Forum tant organisms [34]. Have you had experience with ogy of analgesicnephropathy as seen in Europe. Kidneymt this regimen? 13:27—33, 1978 13. BURRY A: Pathology of analgesic nephropathy. Kidney mt DR.P. KINCAID-SMITH: Yes,but I think that in 13:34—40, 1978 this patient we would have had difficulty getting 14. LONIGRO AJ, ITSKOVITZ HD, CROWSHAW K, MCGIFF JC: adequate concentrations of these agents into the Dependency of renal blood flowonprostaglandin synthesis urine. The serum creatinine concentration was al- in the dog. CircRes 32:712—717,1973 ways higher than about 4 mgldl. I think the trouble IS. Kirc,ir-SMini P. SAKER BM, MCKENZIE IFC, MUIRDEN with mandelamine is that it works in the bladder but KD: Lesions in the blood supply of the papilla in experimental analgesic nephropathy. McdiAust 1:203—206,1968 not in the kidney. We have used it for long-term 16. DUGGAN JM: Aspirin in chronic gastric ulcer: An Australian prophylaxis in patients in whom infection has been experience. Gut17:378—384,1976 eradicated rather than as the initial treatment for in- 17. FAIRLEY KF, KINCAID-SMITH P: Renal papillary necrosis fection. I think pseudomonas is one of the most dif- with a normal pyelogram. BritMcdi 1:156—157, 1968 18. KINCAID-SMITH P. NANRA RS, FAIRLEY KF: Analgesic ne- ficult organisms to eradicate, and the only drug phropathy: A recoverable form of chronic renal failure, in combination with which we have had success has Renal Infection and Renal Scarring, edited by KINCAID- been the oxytetracycline/cotri moxazole combina- SMITH P. FAIRLEY KF, Melbourne, Mercedes Publishing tion. Service, 1971, pp. 385—400 19. FAIRLEY KF, BECKER GJ, BUTLER HM, MCDOWALL DRM, LESLIE DW: Diagnosis in the difficult case. Kidney mt Reprintrequests to Dr. P.Kincaid-Smith,Depart,nent of 8:Sl2—S19, 1975 Nephrologv,Royal MelbourneHospital. Victoria, Australia. 20. KINCAID-SMITH P: The Kidney—A Clinicopathological 3050 Study.Oxford,Blackwell Scientific Publications, 1975, p. 371 21. KINCAID-SMITH P: Glomerular lesions in atrophic pyelone- References phritis and reflux nephropathy. Kidney Im' 8:S81—S83, 1975 1.DAWBORN JK, FAIRLEY KF, KINCAID-SMITH P, KING WE: 22. KINCAID-SMITH P: Glomerular and vascular lesions in The association of peptic ulceration, chronic renal disease chronic atrophic pyelonephritis and reflux nephropathy, in and analgesic abuse. Quart J Med 35:69-83. 1966 Actualities Nephrologiques de l'Hôpital Necker /975, edited 2. NANRARS.STUART-TAYLOR J, DELEON AH, WHITE KH: by HAMBURGER J, CROSNIER 3,FUNCK-BRETANOJ, Paris, L Analgesic nephropathy: Etiology, clinical syndrome and Flammarion, 1975, pp. 187—200 clinicopathologic correlations in Australia. Kidneymt 23. KINCAID-SMITH P: TheKidney—A Clinicopathological 13:79—92, 1978 Study.Oxford,Blackwell Scientific Publications, 1975, p. 3. KRIBLER DM: Paracetamol and the kidney. BritJ Med 345 2:615—616,1967 24. KRISHNASWAMY S. WALLACE DC, NANRA RS: Ischaemic 4. NANRA RS, STUART-TAYLOR J, DELEON AH, WHITE KH: heartdisease in analgesic nephropathy. Aust NZ Med i Analgesic nephropathy: Etiology, clinical syndrome and 4:426, 1974 clinicopathologic correlations in Australia. Kidney mt 25. KINCAID-SMITH P: Analgesic nephropathy, in Contributions 13:79—92, 1978 toNephrologv, Interstitial Nephropathies, edited by KUHN 5. NANRA RS, CHIRAWONG P, KINcAID-SMITH P: Renal papil- K, BRAD J, Basel, Karger, 1979, vol. 16, pp. 57—64 lary necrosis in rats produced by aspirin, A.P.C. and other 26. HULTENGREN N, LAGERGREN C, LJUNGQUIST A: Carcino- analgesics,inRenal Infection and Renal Scarring, edited by ma of the renal pelvis in renal papillary necrosis. Acta Chir KINCAID-SMITH P, FAIRLEY KF, Melbourne, Mercedes Scand 130:314—320. 1968 Publishing Service. 1971, pp. 347—358 27. DAVIES Di, KENNEDY A, ROBERTS C: The aetiology of renal 6. MOLLAND EA: Experimental renal papillary necrosis. Kid- medullary necrosis: A survey of adult cases in Liverpool. J neymt 13:5—14, 1978 Pathol 100:257—268,1970 7. NANRA RS, KINCAID-SMITH P: Experimental renal papillary 28. JACOBS LA, MORRIS JG: Renal papillary necrosis and the necrosis (RPN) with non-steroid anti-inflammatory analge- abuse of phenacetin. McdiAust 2:531-518, 1962 sics, in Problems on Phenacetin Abuse, edited by HASCHEK 29.ARNOLD L, COLLINS G, STARMER GA: Renal papillary ne- H, Vienna, Facta Publications, 1973, p. 67 crosis: The incidence at autopsy in a hospital population in 8. MURRAYTG.GOLDBERG M: Analgesic-associated nephrop- Sydney. Bull Postgrad C'omm Med Univ Syd 29:228—235, athy in the U.S.A.: Epidemiologic, clinical and pathogenetic 1973-1974 features.Kidneymt13:64—71, 1978 30.GAULT MH, WILSON DR: Analgesic nephropathy in Cana- 9.REGESTER RF: Analgesic nephropathy: An increasing prob- da: Clinical syndrome, management, and outcome. Kidney lem. JTennesseeMed Assn 17:741—744, 1978 mt13:58—63.1978 10. KINCAID-SMITH P: The association between chronic renal 31.ABRAIIAMS C, LEVIN NW: Experimentally induced analge- disease, peptic ulceration and analgesic abuse. 2nd Intern sic nephropathy. Med Proc 13:506-5 14, 1967 Congress of Nephrology. Excerpta Medica Intern Congress 32. KASS EH: Nephrology Forum: An approach to the manage- Series 67:91, 1963 ment of resistant urinary infections. Kidney mt 16:204-212, II. KINCAID-SMITH P: Pathogenesis of the renal lesion associat- 1979 ed with the abuse of analgesics. Lancet 1:859-862. 1967 33. BIRCH DF, FAIRLEY KF: Haematuria: Glomerular or non- 12. GLOOR Fi: Changing concepts in pathogenesis and morphol- glomerular? Lancet 2:845, 1971