Canad. Med. Ass. J. RAMSAY AND XVHITE: PHENACETIN NEPHROPATHY 55 Jan. 9, 1965, vol. 92

SOMMAIRE L'auteur a .tudi6 pendant 12 mois quatre malades qui avaient des ant&6dents d'in- gestion massive de ph6nac.tine et de sali- cylate. L'insuffisance r6nale s'6tait install.e lentement au cours de plusieurs ann6es. Ces malades prenaient le m6dicament pour soulager une c6phal6e psychog.ne. Le m6- decin qui .tablissait l'anamn.se a d. faire preuve de beaucoup de sagacit6 et de t.nacit. pour mettre en evidence la phar- macomanie. Cette n6phropathie se mani- festait en ordre principal par une acidose m6tabolique, par une prot.inurie multiple, de la pyurie, mais sans bact6riurie et, peu de temps apr.s l'ingestion du m.dicament, par de la polyurie et de la polydipsie. Dans ce groupe restreint, la n&rose des papilles r.nales n'6tait pas un fait clinique caract6- ristique. Chez un malade, l'abandon du m6dicament s'est traduit par une am6liora- tion considt.rable de la fonction r6nale. Les travaux exp.rimentaux pr6liminaires avaient fourni Ia preuve que la salicylate alt.re l'amplification antidromique, en diminuant le transfert du sodium dans la portion ascen- dante de l'anse de Henle et en diminuant Ia permt.abilit. . l'eau de Ia portion distale des tubules contourn6s et des tubules col- lecteurs; la phSnac.tine n'a eu aucun effet ii cet c.gard. Canad. Med. Ass. 3. 56 RAMSAY AND WHITE: PHENACETIN NEPHIROPATHY Jan. 9. 1965, vol. 92

12-month period, and second, to record preliminary TABLE 111.-RENAL FUNCTION DATA Per cent experimental data which show that salicylate has excretionPSP in Serum Polyuria, Urinary Urine HCO3 some rather profound effects on the urinary con- Patient potydipsia sediment culture 16 mm. (mEq./l.) centrating mechanism. C.J. + Pyuria, No growth 6 9 cylindruria E.K. + Pyuria No growth 12 16 STUDIES M.G. + Pyuria, A. aerogenes 3 CLINICAL cylindruria (100,000 colonies/ml.) Table I summarizes the clinical data of our four LW. - Pyuria No growth - 8.5 patients, two men and two women. Their ages ranged from the third to fifth decades. They all of 2 g./24 hr. This was considered to be due in ingested the same proprietary analgesic preparation part to severe nephrosclerosis which probably which contains 250 mg. of acetylsalicylic acid, 150 occurred as a terminal event in these patients. mg. of phenacetin, 30 mg. of caffeine and 15 mg. Both were hypertensive and both died, whereas of codeine. All of these patients took the drug C.J. and E.K. still survive and are normotensive. for relief of psychogenic headache. Patient C.J. Table III lists further renal data. Three patients also felt that he derived a psychological "lift" had histories of quite pronounced polyuria and polydipsia. These symptoms usually appeared early TABLE 1.-CLINICAL DATA in the course of the analgesic abuse. All patients Phenacetin Reasoningested had moderate pyuria with 8-20 leukocytes per Patient for drug in kg. Sulfhb. (age and 8ex) ingestion (duration) Symptoms methb. high-power field. In contrast only one patient had C.J. (35, M) Headache; 2.2 (2 yr.) Ga.strointestinal 0 bacteriuria. Patients C.J. and E.K. had quite pro- psychological hemorrhage, "lift" gastrectoiny, nounced impairment of phenolsulfonphthalein ex- peptic ulcer cretion. Each patient had a significant reduction E.K. (50, M) Headache 32.0 (30 yr.) Dyspepsia 0 of the serum bicarbonate (HCO3). Although MG. (55, F) Headache 10.0 (10 yr.) Gastrointestinal + arterial pH determinations were not carried out, the hemorrhage, gastrectomy, reduction of HCO. in association with an elevated peptic ulcer BUN suggested moderate to severe metabolic L.W. (31, F) Headache 5.0 (10 yr.) Anemia, bleeding, 0 peptic ulcer acidosis. Patient M.G. had five episodes of fulmin- ating symptomatic metabolic acidosis with hyper- ventilation and coma which required bicarbonate infusion for reversal; L.W. had two episodes of this nature. No patient had clinical evidence of papil- lary necrosis. Postmortem examinations were performed on both MC. and L.W. The histologic appearance of the kidneys in M.G. was fairly typical of chronic pyelonephritis. On the other hand, L.W. showed fairly good evidence of the phenacetin nephro- pathy. Coagulation necrosis of one renal papilla was found. There were tubular atrophy, interstitial fibrosis and chronic inflammatory-cell infiltration in the medulla. The glomeruli showed variable degrees of hyalinization. Patient C.J. discontinued analgesic ingestion, and after nine months the BUN had decreased to 34 mg. % and the CCr had increased to 54 ml./min. The serum HCO5 increased to 14 but the degree of proteinuria remained the same (497 mg./day). After 18 hours of fluid deprivation and administra- tion of 1 ml. pitressin tannate in oil (Parke Davis & Co.), the urine :plasma osmolality ratio (U/Posm) was only 1.2. EXPERIMENTAL STUDIES The history of polyuria and polydipsia in these patients early in the course of their analgesic abuse was rather striking. Despite considerable improve- ment in glomerular filtration, patient C.J. still showed a severe defect in the ability to elaborate a concentrated urine. These facts suggested that salicylate and/or acetophenetidin might specifi- Canad. Med. Ass. Jan. 9, 1965, vol. 92J. RAMSAY AND WHITE: PHENAGETIN NEPHIIOPATHY 57 cally impair the urinary concentrating mechanism TABLE vI-EFFECT OF SALICYLATE ON GOSM AND TdH2O before a significant reduction in the functioning Time GFR UVNG* Coem TcH2O V nephron population had (mm.) (mi/mm.) (JAEq./min.) (mi/mm.) (mi/mm.) (mi/mm.) pH occurred. 0-5 43.5 852 8.65 +2.65 6.0 7.29 This was investigated in two female mongrel 10-155-10 30.638.0 650529 6.127.27 +1.92+2.27 4.25.0 7.307.26 dogs which were anesthetized with pentobarbital Sodium salicylale . g. sodium, 30 mg./kg. Each animal was infused with 20-25 74.4 1656 15.66 +1.86 13.8 7.17 25-30 61.8 1613 13.10 +0.30 12.8 7.11 0.85% sodium chloride, 0.3% creatinine and 1% 30-35 37.7 794 6.67 -0.47 6.2 7.02 urea at a constant rate of 5 ml./min. Both dogs 5UvNs...rate of sodium excretion. had been fasted and deprived of water overnight. Urine was collected by an inlying bladder catheter other hand salicylate had a profound effect, as seen and arterial blood specimens were obtained from in Table VI. This is shown graphically in Fig. 1. a femoral artery cannula. A priming injection of 100 mU of aqueous pitressin (Parke Davis & Co.) was given to each dog and pitressin was infused 70 subsequently at a rate of 135 mU/hr. When the rate of urine flow reached 4-5 ml./min., three five- 60 minute collections were made and an arterial blood GFR sample was taken at the mid-point of each period. ml. 1mm. in one animal 10 g. of acetophenetidin in a 2% 40 acacia suspension was then given by intragastric tube. After 75 mm. three further five-minute col- 30 lections were made. It was felt that significant absorption of the massive load of acetophenetidin would occur in this time interval and that a signi- ficant concentration would reach the kidneys. In the other animal, 2 g. of sodium salicylate was rapidly 12 infused intravenously, and after five minutes three C .."' further five-minute collections were made. Crea- ml. 1mm. tinine was determined in urine and plasma by the 4 method of Bonsnes and Taussky.11 The clearance of NaSali7late creatinine was taken as the glomerular filtration rate (GFR). Osmolality in urine and plasma was V obtained by freezing-point depression. The ao re- Tc H20 absorption of solute free water was obtained from ml .1mm. the formula TcH2O Cosm - V, where Cosm is the 1.0 osmolar clearance and V the rate of urine flow. Cosm 0 is obtained by dividing the product of urine osmo- lality (Uosm) and V by the osmolality of plasma . 110 IS 2 25 30 35 (posm) Urine sodium concentrations were de- termined by flame photometry with lithium as the Time-mm. internal standard. Fig. 1.-The effect of salicylate on GFR, Comm and TcH2O. Five minutes after salicylate administration there was a significant increase in CFR, rate of sodium excretion (UVNa), V and Cosm. Despite this there was no significant change in TcH2O in the first clearance period. In the second clearance period, there was some decrease in Cosm and UVNa, but they were still greater than control values. There was a profound reduction of TdH2O in this period. In the last collection period, Cosm, GFR, UVNa and V had returned to control values. TcH2O had de- creased further and had actually become negative, which indicated addition to rather than reabsorp- tion of solute-free water from the urine. Following salicylate infusion there was progressive acidifica- tion of the urine. DIscussIoN The diagnosis of phenacetin nephropathy is made mainly on the history of long-term phen- Canad. Med. Ass. J. 58 RAMSAY AND WHITE: PHENACETIN NEPHROPATHY Jan. 9, 1965, vol. 92 acetin ingestion in association with chronic pro- Several features of this series of cases were rather gressive renal failure. Other than papillary necrosis, unusual. Most authors report a high incidence of there is no pathognomonic histological picture, papillary necrosis.5-7 Except in patient L.W., we and even papillary necrosis may be associated with did not find this lesion. There were no clinical other conditions. However, several groups have manifestations of this in patient L.W., and papillary recently shown that phenacetin abuse is the major necrosis was found only at postmortem examina- cause of papillary necrosis.57 Probably the most tion in this case. With such long-term massive important factor in establishing the diagnosis is phenacetin ingestion, a higher incidence of sulf- the history. In view of the rather secretive attitude hemoglobinemia or methemoglobinemia might have of these patients about their drug habits, some been expected. The amount of ingested phenacetin In was extremely variable. It has usually been con- guile must be used to elicit their habituation. sidered that 3.5 kg. is necessary to produce the view of the striking similarity of the histological disease.2 In this respect, patient C.J. demonstrated picture to pyelonephritis, it is extremely important that the disease may occur following ingestion of to eliminate urinary tract infection. a smaller amount of phenacetin. Three of our cases (C.J., E.K. and L.W.) ful- filled the criteria for diagnosis reasonably well. The history of polydipsia and polyuria was a They all had progressive renal failure in associa- striking feature of this series and of those reported tion with analgesic abuse in the absence of urinary by other authors.'0' 13 As it occurred early in the tract infection. In addition, the kidneys of L.W. course of analgesic abuse, it seemed unlikely that at postmortem examination showed papillary it was the result of a reduction of the functioning necrosis, tubular atrophy and medullary inter- nephron population. A more likely possibility stitial fibrosis with chronic inflammatory cell in- seemed to be a specific effect on the urinary con- filtration. On the other hand, patient M.C. had centrating mechanism. An acute phenacetin load chronic bacteriuria for several years, and at post- appeared to have no effect. However, Angervall, mortem examination the kidneys showed pyelo- Lehmann and Bengtsson'6 have shown that chronic nephritis. Nevertheless, there was a striking history phenacetin loading will impair the urinary con- of salicylate-phenacetin abuse. It seemed more centrating mechanism of the rat. than probable that phenacetin nephropathy was An acute salicylate load, on the other hand, had the primary event and that urinary tract infection a profound effect. There was a marked increase and pyelonephritis had become superimposed on in both CFR and Cosm. This results in the delivery a basic phenacetin nephropathy. For this reason of an increased solute load, mainly sodium, to the M.C. was included in this study. diluting segment of the ncphron, the ascending demon- limb of Henle and the distal convoluted tubule. Although it is small, this series does Under normal circumstances, delivery of a greater strate rather well some of the clinical parameters sodium load to these sites augments TcH2O.'719 of the *syndrome. Usually there is pyuria in the Sodium transport is increased at both sites. In the absence of bacteriuria.'2 Presumably this is the of result of chemical irritation with an inflammatory loop of Henle this will augment the osmolality reaction in the renal interstices. Proteinuria is usu- the renal papillary interstices. Augmentation of the ally slight unless there are severe hypertension and osmotic gradient between collecting-duct fluid and course papillary interstitium will occur and in the presence nephrosclerosis.'2' . These occur late in the of antidiuretic hormone (ADH) TcH,O will be of the disease and are bad prognostic signs. Usually increased. In the distal convoluted tubule, delivery the patients are normotensive despite fairly marked of an increased sodium load will also augment impairment of kidney function.'2' 13 There is a high sodium reabsorption at this site. If ADH is present, incidence of accompanying gastrointestinal sympto- the augmented sodium reabsorption will be ac- matology which is presumably due to the irritation of companied by water, .vhich will also tend to in- the gastric mucosa by salicylate.3 Phenacetin nephro- crease TcH9O. An increasing osmolar clearance pathy is primarily a disease of the renal medulla. then is accompanied by increased abstraction of It might be expected then that manifestations of solute-free water until a Cosm of about 15 ml./min. impaired renal tubular function might be more is attained. Further increments of COSm above this prominent than the effects of impaired glomerular level may be accompanied by progressive decre- function. The multiple episodes of severe fulmin- ments of TcH2O, and ultimately a water diuresis ant metabolic acidosis in the absence of uremic may ensue. However, if progressive decrements symptoms in this series demonstrate this aspect. of Cosm are created at this point, water diuresis This also illustrates the importance of the renal and TcH,O will progressively increase.'9 tubular epithelium in hydrogen ion secretion.'4 ceases It has been shown previously that there is a certain Despite the delivery of an increased sodium load degree of reversibility of the nephropathy if the to the diluting site, TcH,O did not increase in the analgesic ingestion is terminated. This was demon- presence of salicylate. Rather there was a progres- strated by patient C.J. However, the disease in this sive decrease in TcH2O until it ultimately became patient did not reverse to the extent of that previ- negative. This indicated that solute-free water was ously reported by Lakey.'5 actually being added to the renal tubular fluid. In Canad. Med. Ass. . RAMSAY AND WHITE: PHENACETIN NEPHEOPATHY 59 Jan. 9, 1965, vol. 92 effect, salicylate had initiated a water diuresis. It tion of salicylate within these cells. The accumula- is unlikely that this effect was the result of the tion of salicylate in this area probably gives rise elevated Cosm. Firstly, osmolar clearance did not to some of the observed effects on the reabsorption exceed 15 ml./min., the region where this effect of solute-free water. It could act directly on the can be expected. Secondly, following the initial cell and decrease TcH2O by decreasing pore size, clearance period after salicylate administration, or it could inactivate the infused antidiuretic there was a progressive decrease of Cosm to con- hormone at a cellular level. trol values. If the effect on TcH2O had been primarily due to the initial increase in osmolar SUMMARY clearance, progressive decrements in Cosm should Four cases of phenacetin nephropathy were ob- have been accompanied by rising values of TcH2O. served during the past 12 months. These patients had These results suggest that a large, acute salicy- a prolonged history of massive ingestion of tablets of late load has two effects on the renal tubule. Firstly, salicylate, phenacetin, codeine and caffeine. They all it may decrease sodium transport in the ascending took the preparation for psychogenic headaches. Unless the history is specifically sought, the diagnosis may be limb of Henle and impair the efficiency of the missed because these individuals tend to be secretive counter-current multiplier system. In this respect about their medication habits. The nephropathy is it seems to be very similar to ethacrynic acid, a characterized by slowly progressive renal failure over diuretic agent which increases Cosm while de- a number of years, often accompanied by multiple creasing TcH2O.'7 Secondly, the production of a episodes of fulminating metabolic acidosis. Although water diuresis in the presence of adequate ADH demonstrable at postmortem examination in one case, would suggest that salicylate decreases the per- papillary necrosis was not clinically prominent in this meability to water of the distal convoluted tubule series. There is usually minimal proteinuria and and the collecting duct. moderate pyuria without bacteriuria. After dis- continuation of drug ingestion there is some degree of The renal excretion of salicylate is a complex reversibility of the disease. An early feature of the phenomenon.20 Ionized salicylate enters the ultra- disease is polyuria and polydipsia. Preliminary experi- filtrate through the glomerulus. In some circum- mental evidence would suggest that salicylate impairs stances, the clearance rate of salicylate exceeds the efficiency of the counter-current multiplier by that of inulin. An active tubular secretory pathway decreasing sodium transport in the ascending limb of exists in the proximal convolution. Salicylate is Henle, and decreases the permeability to water of the reabsorbed in the distal convolution and collecting distal convoluted and collecting tubules. Phenacetin ducts. Reabsorption is dependent on the process appeared to have no such effect. of non-ionic diffusion. The free acid, not the salicy- late ion, is reabsorbed. The rate of non-ionic REFERENCES 1. SPUHLER, 0. AND ZOLLINGER, H. U.: Z. Kim. Med., 151: diffusion is determined by the concentration 1, 1953. 2. MOOLTEN, S. E. AND SMITH, I. B.: Amer. J. Med., 28: gradient between tubular and peritubular fluids. 127, 1960. 3. RAPOPORT, A., WHITE. L. W. AND RANKING, G. N.: Ann. A concentration gradient favouring reabsorption is Intern. Med., 57: 970, 1962. 4. MCCUTCHEON, A. D.: Med. J. Aust., 2: 543, 1962. augmented by proximal tubular secretion of salicy- 5. HARVALD, B.: Amer. J. Med., 35: 481, 1963. 6. JAcoBs, L. A. AND MORRIs, J. G.: Med. J. Aust., 2: 531, late, reabsorption of water and acidification of 1962. tubular fluid. The free salicylic acid will diffuse 7. HARROW, B. R.. SLOANE, J. A. AND LIEBMAN, N. C.: J. A. M. A., 184: 445. 1963. into fluid with the highest pH. Therefore alkaliniza- 8. GILMAN, A.: Amer. J. Med., 36: 167. 1964. 9. HARVALD, B., VALDORF-HANSEN, F. AND NIELSEN, A.: tion of the urine and an increase in rate of urine Lancet, 1: 303, 1960. 10. GRIMLUND, K.: Acta Med. ,Scand., 174 (Suppi. 405): 1, flow will increase salicylate excretion by decreas- 1963. 11. BONSNES, R. W. AND TAUSSKY, H. H.: J. Biol. Chem., ing distal tubular reabsorption. Acidification of the 158: 581, 1945. 12. NORDENFELT, 0. AND RINGERTE, N.: Acta Med. ,Scand., urine and a decrease in the rate of urine flow will 170: 385, 1961. have the opposite effect. In the experiment shown 13. REYNOLDS, T. B. AND EDMUNDSON, H. A.: J. A. if. A., 184: 435, 1963. in Table VI there was a marked increase in urine 14. SCHWARTZ, W. B. et al.: J. Olin. Invest., 38: 39, 1959. 15. LAKEY, NV. H.: Canad. Med. Ass. J., 85: 477, 1961. flow in the first two clearance periods after 16. ANGERVALL, L., LEHMANN, L. AND BENGTSSON, U.: Acta Med. Scand., 175: 155. 1964. salicylate infusion. Although there was a fall in 17. GOLDBERG, M. et al.: J. Olin. Invest., 43: 201, 1964. 18. STEINMETE, P. R. AND SMITH, H. W.: Amer. ,T. Med. 35: urine pH, the two factors would tend to oppose 727, 1963. 19. EARLEY, L. E., KAHN, M. AND ORLOFF, J.: ,T. Olin. Invest., each other and there should, theoretically at least, 40: 857, 1961. be little effect on salicylate reabsorption. In the 20. WEINER, I. M., WASHINGTON, J. A. AND MUDGE, 0. H.: last period, however, the rate of urine flow had Bull. Hopkins Hosp., 105: 284, 1959. returned to pre-salicylate infusion values. The pH of this urine collection was 7.02. Prior to salicylate infusion, urine pH had ranged from 7.26 to 7.30. In association with increased urinary acidification in this period, a steeper hydrogen ion gradient was CHANGE OF ADDRESS established between blood and urine. These factors Subscribers should notify The Canadian Medical Associa- tion of their change of address one month before the date then would tend to promote the reabsorption of on which it becomes effective, in order that they may receive salicylate as the free acid in the distal and collect- the Journal without interruption. The coupon on advertising ing tubules. This should lead to a high concentra- page 34 is for your convenience.