analgesic nephropathy - bmj

Postgrad. med. 1. (March 1967) 43,173-183.

CASE REPORTS

Analgesic nephropathyB. HULME

B.Sc., M.B., Ch.B., M.R.C.P.E. L. JONESM.B., Ch.B.

Departments of Experimental Pathology and Pathology,University of Birmingham

IntroductionThere is evidence that renal failure can result

from prolonged ingestion of analgesic tablets con-taining phenacetin (Annotation, Lancet, 1959;Leading articles, Brit. med. J., 1960, 1965). Casesfrom Switzerland, Denmark and Australia(Lindeneg et al., 1959; Jacobs & Morris, 1962)and recently from Great Britain (Sanerkin &Weaver, 1964) were all diagnosed post-mortem.We report a case of chronic renal failure diag-

nosed as analgesic nephropathy 2 years beforedeath from renal failure and malignant hyper-tension.

Case reportIn December 1963, a 49-year-old married woman

with one child gave a 6-month history of weak-ness, tiredness and pallor. On examination shewas thin with severe mucosal pallor and noevidence of cyanosis or methaemoglobinaemia;blood pressure, 145/95 mmHg; heart and opticfundi n o rm a l; normochromic normocyticanaemia (haemoglobin 5 g/100 ml); blood urea,270 mg/100 ml; serum creatinine, 9-2 mg/100 ml;creatinine clearance, 4-5 ml/min; pH, 7-21;Pco2, 29 mmHg; standard bicarbonate, 12-2mEq/l.

X-rays of the abdomen and bilateral retrogradepyelograms showed normal kidneys and calyces.Repeated bacteriological investigations of mid-stream specimens of urine were negative.The moderate degree of uraemia, severe normo-

chromic anaemia and gross disturbance of acidbase balance associated with normal size kidneysand no evidence of pyelonephritis suggested 'anal-gesic nephropathy'. The patient admitted to takingtwelve to twenty APC (BPC) tablets daily forsevere pain in both arms and neck following afracture dislocation of the sixth cervical vertebrain 1956, when she was in hospital for 14 weeks,no evidence of renal disease then being found. Itwas estimated that over 3 g of both phenacetinand aspirin had been taken daily for at least 8years.

Treatment consisted of: blood transfusion;high calorie/low sodium/low potassium/low pro-tein diet; oral sodium bicarbonate supplements;and an increased fluid intake. Two weeks later,whilst still normotensive she suddenly had a grandmal epileptic fit, was unconscious for 24 hr andnearly blind for 1 week. It was assumed that thisdeterioration was due to water intoxication andfollowing fluid restriction to 500 ml daily she lost7 kg in weight. In February 1964 the urine outputcould not be increased above 1-5-2 litres daily.

Six weeks later she complained of blurring ofvision and showed severe hypertensive retinopathywith haemorrhages and papilloedema. The bloodpressure was then 225/110 mmHg and the bloodurea 160 mg/100 ml. The blood pressure fell ontreatment with bethanidine sulphate. There wasstill no evidence of urinary tract infection. BySeptember 1965 the blood pressure became diffi-cult to control and the urinary output decreasedand averaged only 500-700 ml daily, with aglomerular filtration rate of 0-8 ml/min asmeasured by means of radioactive vitamin B12(Nelp, Wagner & Reba, 1964). The blood ureawas maintained below 250 mg/100 ml on a verylow protein diet until 4 days before death whenshe developed severe epistaxis, drowsiness andanuria and passed into a terminal uraemic comain November 1965.

NecropsyThe body (height, 5 ft 4 in.; weight, 36-55 kg)

showed pallor of the skin, oedema of both legsand a blotchy ecchymotic rash over the trunk andforearms.Kidneys (125 g) were symmetrically contracted

and pale. On both sides: cortex was considerablyreduced in thickness and only 2-3 mm wide (nor-mal 1 cm); corticomedullary junction indistinct;medulla congested and tips of papillae ragged anddark brown in colour (Fig. 1), due to bilateralnecrosis; interlobar vessels prominent, thickwalled and 'gritty', several larger arteries markedlyatheromatous; capsules stripped easily; outer

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FIG. 1. Kidney showing ragged dark brownpapillae. Cortex shrunken. Severe atheroma.

surfaces smooth and even; no evidence of in-fection; pelvic fat slightly increased; calyceal andpelvic mucosae pebbly, uneven and very con-gested. Ureters normal and not obstructed. Renalveins and the right renal artery normal. Leftartery divided into two branches and the distalsegment was narrowed by atheroma over 1-2 cm.Heart (weight, 505 g): marked left ventricularhypertrophy, average thickness 20 mm (normal15 mm). Right ventricle showed slight hyper-trophy. Well-marked fibrinous pericarditis. Coron-ary arteries showed widespread calcified atheromawith patchy stenosis. Minimal patchy myocardialfibrosis. Lungs: extensive bilateral oedema andbasal congestion. Bilateral pleural effusions ofclear yellow fluid (600 and 800 ml).

HistologyKidneys showed marked papillary necrosis, only

the ghost outlines of the tubules and ducts ofBellini remaining, associated with pronouncedgranular calcification and minimal infiltrationwith neutrophil polymorphs. One papilla is de-tached (Fig. 2).Most of the glomeruli show total hyaline

I

FIG. 2. Pale ghost outlines of necrotic tubules. Thepapilla has become detached from viable tissue(lower left). H & E, x 100.

fibrosis. A few surviving glomeruli show only peri-glomerular fibrosis. Bowman's spaces are some-times dilated and the capillary loops compressedand bloodless. There is a marked increase of inter-stitial fibrous tissue in the cortex and a heavycellular infiltrate, mainly lymphocytic (Fig. 3).There is also severe interstitial fibrosis, shrinkageand atrophy of tubules and a marked chronicinflammatory exudate throughout the medulla. Inplaces tubular dilatation is probably secondary tothe papillary necrosis (Dawborn et al., 1966).Several interlobar arteries show extensiveatheroma and calcification. The arterioles showsevere intimal fibroelastosis, reduplication of theinternal elastic lamina and medial hypertrophy.Iliac crest bone biopsy: undecalcified sectionsstained by the von Kossa method show normallycalcified trabeculae of lamellar bone. A fewosteoid seams of normal width are present. Noevidence of osteomalacia or osteoporosis. Decal-cified sections show evidence of secondary hyper-parathyroidism, with fibrosis of the marrow spacesand osteoclastic resorption of the trabeculae.There were no other relevant histological

abnormalities.



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FIG. 3. Marked interstitial fibrosis of cortex,heavy chronic inflammatory cell infiltration andsevere tubular atrophy and dilatation. Ehrlichshaematoxylin and Van Gieson, x 100.

DiscussionThere is now good evidence that prolonged in-

gestion of analgesics can cause chronic bilateralrenal papillary necrosis and consequent renalfailure. The possibility must always be consideredwhen this condition is found in the absence ofdiabetes mellitus and hydronephrosis.

In some cases it may be difficult to prove thecausative role of ingestion of analgesics, thoughin this case the evidence is convincing. First, therewas no evidence of infection or obstruction of theurinary tract; second, diabetes mellitus was notpresent; third, prior to the ingestion of analgesicsthe patient had no signs of renal or cardiovasculardisease; and fourth, the patient admitted takingbetween twelve and twenty analgesic tablets perday, a cumulative dose of at least 13 kg ofphenacetin and 13 kg of acetylsalicylic acid.The current evidence suggests that phenacetin

in excess of I g/day for at least I year must beconsumed before the kidney is affected. Despitecessation of all analgesics the renal disease pro-gressed and at necropsy small symmetrically con-tracted kidneys were found, though 2 years

previously radiography indicated they were ofnormal size.

Spuhler & Zollinger (1953) first suggested thatprolonged ingestion of analgesics resulted inchronic papillary necrosis, and considered an in-crease in the number of cases found to be due toan alteration in the manufacture of phenacetin inthe early 1940s. The toxic chemical is believed tobe the impurity acetic-4-chloranilide; reports havebeen predominantly from Denmark, Switzerlandand Australia where the phenacetin consumptionper head of population is believed to be higherthan in Britain (Boyd, 1964).The great majority of cases are middle-aged

women with a history of migraine and, morerecently, histories of previous gastric ulcerationhave been reported (Olafsson, Gudmundsson &Brekkan, 1966; Dawborn et al., 1966). At least50% of patients have associated pyelonephritis.There is usually severe renal failure, a refractorynormochromic normocytic anaemia and severeacid base changes; death usually occurs within afew months of diagnosis and at necropsy thetypical renal changes are found.

In some patients who discontinued analgesics,follow-up studies for at least 1 year have notshown improvement in renal function (Reynolds& Edmondson, 1963).Though the evidence linking analgesic abuse and

renal failure is circumstantial, all tablets contain-ing phenacetin have been banned in Switzerlandsince 1961 ; in the U.S.A. all bottles containingphenacetin tablets must carry a warning statingthat if consumed in excess there is a risk of severerenal damage (Leading article, J. Amer. med. Ass.,1964); and the Pharmaceutical Society of GreatBritain issued a warning in March 1965 on theassociation between phenacetin and renal damage(Leading article, Brit. med. J., 1965). If phenacetinor tablets containing phenacetin are capable ofproducing renal damage, the problem is consider-able: the Monthly Index of Medical Specialities(1965) lists thirty-three ethical preparations con-taining phenacetin and there are at least thirty-sixproprietary preparations containing phenacetinavailable without prescription. As there are now anumber of drugs with analgesic and antipyreticproperties comparable to phenacetin there seemslittle justification for its continued administration.

SummaryA case of analgesic nephropathy in a previously

healthy middle-aged female is described. The diag-nosis was made 2 years before her death, anddespite cessation of all analgesic tablets progres-sive renal failure terminated in uraemia andmalignant hypertension. At necropsy there was



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chronic bilateral renal papillary necrosis. Atten-tion is drawn to the dangers of prolonged anal-gesic abuse.

AcknowledgmentsWe would like to thank Dr E. Bulmer for per-

mission to record this case. We are also grateful toDr D. B. Brewer for his advice and criticism, MrS. A. Gaunt for the photography and Mrs J. Seabournefor secretarial assistance.

ReferencesANNOTATION (1959) Phenacetin nephropathy. Lancet,

i, 84.BOYD, D.H.A. (1964) The use and abuse of phenacetin.

Scot. med. J. 9, 423.DAWBORN, J.K., FAIRLEY, K.E., KINCAID-SMITH, P. &

KING, W.K. (1966) The association of peptic ulcera-tion, chronic renal disease and analgesic abuse.Quart. J. Med. 137, 69.

EDITORIAL (1964) Analgesic abuse and the kidney-a commentary. J. Amer. med. Ass. 190, 238.

JACOBS, L.A. & MORRIS, J.G. (1962) Renal papillarynecrosis and the abuse of phenacetin. Med. J. Aust.11, 531.

LEADING ARTICLE (1960) Renal risks of phenacetin.Brit. med. J. i, 714.

LEADING ARTICLE (1965) Phenacetin and the kidney.Brit. med. J. i, 673.

LINDENEG, O., FISCHER, S., PEDERSEN, J. & NISSEN,N.I. (1959) Necrosis of the renal papillae and pro-longed abuse of phenacetin. Acta med. scand. 165,321.

Monthly Index of Medical Specialities (1965) Vol. 7,No. 11.

NELP, W.B., WAGNER, H.N. & REBA, R.C. (1964) Renalexcretion of vitamin B12 and its use in measurementof glomerular filtration rate in man. J. Lab. clin.Med. 63, 480.

OLAFSSON, O., GUDMUNDSSON, W.R. & BREKKAN, A.(1966) Migraine, gastritis and renal papillarynecrosis. Acta med. scand. 179, 121.

REYNOLDS, T.B. & EDMONDSON, H.A. (1963) Chronicrenal disease and heavy use of analgesics. J. Amer.med. Ass. 184, 435.

SANERKIN, N.G. & WEAVER, C.M. (1964) Chronicphenacetin nephropathy ('chronic interstitial nephri-tis') with papillary necrosis. Brit. med J. i, 288.

SPUHLER, 0. & ZOLLINGER, H. (1953) Die chronishinterstitielle Nephritis. Z. klin. Med. 151, 1.

Mast cell diseaseT. I. McBRIDEM.B., M.R.C.P.

Registrar in Medicine

G. A. McDONALDM.D., M.C.Path.

Consultant HaematologistW. P. DUGUIDM.B., M.C.Path.

Consultant Pathologist

The Royal Infirmary, Glasgow

IntroductionIn recent years much interest has been focused

on the physiology and pathology of the mast cell.It is accepted that the mast cell features in a widevariety of disorders and mastocytosis has beenproposed as a generic name for syndromes inwhich extensive mast cell involvement is present.Selye (1965) has collected and analysed the rele-vant literature on mast cells and this has beenused as the main reference text in the preparationof this report. The patient described is of par-ticular interest in that he had a syndrome whichwas first considered to be a non-specific masto-cytosis, but in which several unusual features werediscovered.

Case reportA 63-year-old male clerk was first seen at the

Medical Out-Patient Department of GlasgowRoyal Infirmary where he was discovered to beanaemic and to have hepatosplenomegaly. He was

consequently admitted for further investigation.The presenting complaints were dyspnoea, somechest tightness and nausea of only 6 weeks' dura-tion. Detailed questioning revealed no otherfeatures of note in the past history-in particularthere was no history of drug ingestion, episodicflushing or of any haemorrhagic tendency.

Physical examination revealed a well-developedman with no evidence of recent weight loss. Themucous membranes were pale and the liver andspleen were each palpable 2 finger breadths belowthe respective costal margins. Examination of theother systems revealed no abnormality. In par-ticular no skin lesions were present.

InvestigationsHb, 6-6 g/100 ml; PCV, 22% ; WBC, 2100/mm3

-with a normal distribution in the differentialcount. Platelet count, 98,000/mm3; ESR, 35 mmin the 1st hour (Westergren). The blood filmshowed anisocytosis and poikilocytosis. The liver



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analgesic nephropathy - bmj

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