tubular necrosis with little or no oliguria

J. clin. Path. (1956), 9, 12.

DISTAL TUBULAR NECROSIS WITH LITTLE ORNO OLIGURIA

BY

SIMON SEVITI'From the Pathology Department and M.R.C. Burns Research Unit, Birmingham Accident Hospital

(RECEIVED FOR PUBLICATION SEPTEMBER 27. 1955)

The clinico-pathological syndrome of acute renalfailure following abortion, incompatible bloodtransfusion, crush injuries, severe trauma, sulphon-amide intoxication, and many other conditionsincluding burns is now well known (Bratton,1941 ; Dunn, Gillespie, and Niven, 1941 ; Bywatersand Beall, 1941 ; Bywaters and Dible, 1942; Lucke,1946; Bull, Joekes, and Lowe, 1950; Bull andDible, 1953). Clinically it is characterized by ashort onset phase during which the flow of urinerapidly falls. Then follows the period of anuriaor severe oliguria. This was defined by Bull asthe excretion by an adult of not more than 300 ml.of urine per day and usually considerably less.This state may last up to a week or longer;uraemia develops and commonly proves fatal.Recovery is heralded by a period of diuresisduring the early phase of which tubular functionis seriously limited. By ordinary histologicalmethods the kidneys show multiple, often discretenecroses of many distal tubules frequently asso-ciated with tubular blockage by haemoglobin orother casts. Rupture of tubules and dislocationof casts into the interstitial tissue and veins pro-duce a peritubular and perivenous infiltration ofinflammatory cells, tubulo-venous anastomoses,and thromboses. By microdissection of individualnephrons Oliver and his colleagues (Oliver, Mac-Dowell, and Tracy, 1951; Oliver, 1953) haveshown that the tubular necrosis is widespreadand frequently involves the first convoluted tubu!e.The purpose of this paper is to describe a

number of subjects whose kidneys showed eitherthese changes or their residue and in whomoliguria either did not occur or was transient orslight. With one exception all were severelyburned. A few died before uraemia could de-velop, some became uraemic, and in othersuraemia did not occur. Thus, in addition to thewell-known uraemia-oliguria syndrome, uraemia

may occur with an adequate flow of urine. Thisis important to recognize, because the patient'schance of survival has increased with the intro-duction of high-calorie, low-nitrogen feeding. Thefinding of one case of post-traumatic uraemia withlittle or no oliguria indicates that this form ofrenal failure is not restricted to burned patients.It will be shown that the difference between theuraemic and non-uraemic forms generally has amorphological basis, and that the tubular dysfunc-tion in these uraemic subjects differs from that re-ported in the oliguric type of acute renal failure(Bull et al., 1950).

TermniologyThe name "lower nephron nephrosis" intro-

duced by Lucke is unsuitable because the tubularnecrosis is said to be the essential morphologicalfeature (Oliver et al., 1951 ; Bull and Dible, 1953).These authors had adopted " acute tubularnecrosis" as the more suitable descriptive term.In this paper "distal tubular necrosis" (D.T.N.)is synonymous with Lucke"s lower nephronnephrosis, because D.T.N. is morphologicallydifferent from the cortical type of necrosis whichalso occurs in burned subjects (unpublishedobservations).

Distal tubular necrosis after burning varies inseverity. The kidney may be diffusely affectedand parts of the tubules of many nephrons maybe necrosed. Alternatively the kidney may befocally involved, and relatively few tubules maybe affected. To these main types the terms " dif-fuse " and " focal" D.T.N. are applied, and referto the histological density of lesions; but in boththe diffuse and focal kinds the individual tubulesare commonly affected in a discrete or focalfashion. The involvement of many or fewnephrons respectively is the main histologicaldifference between the uraemic and non-uraemicforms now reported.

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NON-OLIGURIC DISTAL TUBULAR NECROSIS

The PatientsThe present paper is concerned with 22 patients,

21 of whom were extensively burned, the otherwas an unusual case of post-traumatic uraemia.The burned subjects formed part of a renal histo-logical analysis based on 86 fatally burned sub-jects which is to be reported later. In 35 ofthese there was either a focal or a diffuse distaltubular necrosis or the "healed" residue of arecent focal attack. Twelve rapidly became almostanuric and uraemia developed in those survivingfour days or longer: in three others the urine flowwas not known. The remaining 20 form the mainbasis of the present paper, but two other patientsare included, a burned child on whom necropsywas refused and a post-traumatic case of uraemia,a man who fell 15 ft. off a ladder and in whoma large adrenal tumour became completelynecrosed.

All necropsies were performed within 38 hoursof death: 17 within 24 hours and eight within 12hours.

Routine Treatment of the Burned PatientsThe degree of haemoconcentration on admission

and during the shock phase was estimated by serialhaematocrit observations from which the amountof plasma lost from the circulation was calculated.In recent cases repeated blood volume studies werecarried out by Dr. E. Topley. Such means guidedthe amount and speed of plasma transfusion bywhich oligaemia was combated. Transfusion withplasma was begun soon after admission, usuallywithin a few hours of burning, and was continuedfor about two days. Some patients were also trans-fused with blood at this stage, but in other patientsblood transfusion was delayed for a week orlonger. Other intravenous fluids (dextran, glucose,saline) were also sometimes transfused. Oralfluids, usually sweetened fruit juice, glucose-water,or sodium lactate, were also given when vomitingwas absent. Two or three days later, feeding byan egg-milk mixture was begun and was continueduntil an adequate diet could be taken about 10 to14 days after burning. Skin grafting was usuallycarried out after two or three weeks and bloodtransfusion was given during each operation. Theburns were first dressed at the end of the shockphase when penicillin cream and/or other localantibiotics were applied to prevent or control in-fection. Systemic therapy with penicillin, aureo-mycin, polymyxin, or erythromycin, or a combi-nation, was introduced when infective complica-tions arose.

ClassificationThe patients may be divided into two groups.Group 1.-Group 1 consists of one injured and

seven burned patients none of whom was con-sidered to have been oliguric. Each patient de-veloped significant azotaemia and uraemia playeda major role in six.Group 2.-Group 2 consists of 14 burned

patients none of whom was considered to havebeen oliguric. In eight significant azotaemia didnot occur and in the others uraemia was notsuspected.

Group 1Details of the patients* are given in Table I.

One of the burned patients was a girl of 5 years,two others were girls of 14 and 15 years, and theremainder were men 20 to 44 years old. The burnsextended over 35% to 80% of the body area in thedifferent patients (mean area burned was 58 %).Two patients who survived only two and two anda half days and died with pre-uraemic azotaemiaare included, Case 1 because the histologicalchanges in the kidneys may be the earlier stagesof those who survive longer and become uraemic,and Case 2 because it had special features. Theother patients, including the case of post-traumaticuraemia, survived between six and 21 days.Azotaemia.-Most of the serum or blood urea

levels (C.S.F. in Case 7) are given in Table II. InCase 1, a patient who survived only two days, thelevel of 80 mg.% is taken to represent a pre-uraemic azotaemia. The blood urea in Case 2 rosefrom 80 mg.% at 12 hours after burning to 190mg.% on the day of his death two days later.

* A further example, who was under the care of Mr. R. L. G.Dawson, at Mount Vernon Hospital Plastic Centre, is reported. Awoman of 35 years with 40% burns survived 12 days. She wasadmitted haemoconcentrated, was at first transfused with plasma andglucose solution and later with blood. About 500 ml. urine waspassed during the first 12 hours; duting the second 12 hours oliguriawas transient and 150 ml. urine passed; during the next four daysbetween 1 and 2 litres daily were passed and thereafter the urinevolumes varied between 0.7 and 1.0 litre a day. Haemoglobinuriawas not found. Uraemia with considerable azotaemia occurred;the blood urea was 232 and 211 mg. ° on days 7 and 8 and rose to423 and 413 mg. %. The specific gravity of the urine was 1010 onday 6. The ratio of U 'B urea was only 5 to 1 and the standard ureaclearance was only 5.6% of average normal. Jaundice and hyper-glycaemia occurred. The serum potassium and sodium values werenormal or slightly raised and there was no acidaemia. She died inuraemia with bronchopneumonia.

In the kidneys a histologically severe form of diffuse distal tubularnecrosis was seen, viz., frequent rupture of distal tubules with extru-sion of casts and of thrombi in the venules; atypical or bizarreregeneration of many Henle and distal convoluted tubules; granulareosinophilic (benzidine-negative) and colloid casts in some distal andcollecting tubules; many characteristically located collections oflymphoid and other inflammatory cells, considerable oedtma of thecortex and pyramid, etc. Prussian blue staining showed a thin,irregular deposit of iron pigment on the free surfaces of the epithelium,mainly of the distal tubules.

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SIMON SEVITT

TABLE IDETAILS OF THE PATIENTS

KnownHaemo-

globinuria

+ transient

Renal Histology

Earlv diffuse D.T.N.Cortico-tubular degeneration

with focal " healed " D.T.N.Diffuse D.T.N.

Necropsy refusedCortico-tubular degeneration

with focal D.T.N.Diffuse D.T.N.

Early focal D.T.N.

Foeal D.T.N.

" Healing " focal D.T.N." Healed "

" Healing " , ..II Healed". .

" Healing " , ,Numerous Hb castsFocal D.T.N.

Cause ofDeath and Other

Significant Features

Pulmonary atelectasisAcute haemolytic jaundice. Inci-

pient uraemiaUraemiaUraemia. Pulmonary embolismUraemia

Uraemia. Necrosis of largeadrenal adenoma, etc.

Pulmonary oedemaPulmonary atelectasisBronchopneumoniaAcute medullary coningBronchopneumoniaSepticaemiaPurulent bronchiolitisPulmonary infarctSepticaemia. AgranulocytosisPyaemic bronchopneumoniaCurling's ulcer. DiarrhoeaHaematemesis. Curling's ulcerPurulent bronchiolitis

Area burned, % of the total surface area of the patient. ? =Associated with a true haematuria (see text). D.T.N. =Distal tubular necrosis:for description of various stages see text.

This is considered an incipient uraemia. In theother patients blood urea estimations were notmade before the sixth to the ninth day of illnessbecause of the clinical difficulty in suspectinguraemia (vide infra). Presumably because of thisdelay the first blood urea observations werealways high, the levels varying between 280 and357 mg.% in the different subjects. The progres-

sive elevations to these levels are not known andthe rate of development of the azotaemia can onlybe surmised. Subsequent observations in Cases 5,6, and 8 confirmed the high blood urea levels.Cessation of feeding with protein after the highurea levels had been discovered may have beenresponsible for preventing further rises in Cases 5and 8.

TABLE IIDAILY URINARY OUTPUT AND BLOOD, SERUM, OR C.S.F. UREA LEVELS IN SIX CASES OF ACUTE URAEMIA

WITH LITTLE OR NO OLIGURIA (GROUP I)

BloodUrea(mg.

100 ml.)

296

Case 4 Ca

-1--Serum

Urine Urea Urine(ml.) (mg. (ml.)

I I!100 Ml.)

685 360

1,800 990400 360570 630413 930Died 357 1,080

5802,4001,870980

1,8502,0501,382900

ase S Case 6

BloodUrea(mg.

100 ml.)

280271

232236206212

Urine(ml.)

830

1,6501,3002,020880

1,000-740

750 t1,5901,450

Case 7

BloodUrea(mg.

100 ml.)

280276

Urine(ml.)

1,130

875+360+740 +800+477t

C.S.F.Urea(mg.

100 ml.)

320

Case 8

BloodUrine Urea(ml.) (mg.

100 ml.)

? smallvolume900

1,3003,2002,1002,7002,3002,0002,200 2902,600 3202,500+ 3202,100 1941,900 274

t, + +, + + + = Degrees of bed-wetting.

Group

2

CaseNo.

2

34S67

8

910II1213141516171819202122

Age, |Sex

5 F20 M

15 F43 M44 M14 F31 M

40 M

4 F4 F

27 M7 F5 M4 M5 M6 M6 F3 F2 M6 F10 F5 F

AreaBurned

7535

8065446050

Trauma

6045706545284763504527506570

SurvivalPeriod

2 days21 ,.

10 ,6 ,.

21 .,12 ,

7"16 ,

16 hours15 ,,8t days6,-

35 ,

7 ,1516 ,

17 ,

22 ,

26 ,

21 ,16 .41 ,,

Case 3Classical

Anuric TypeM. 24 yr.,75% Burns

BloodUrine Urea(ml.) (mg.

100 ml.)

168

200

0

0 284

Day

23456789101214161820

Urine(ml.)

720 + -t

325 -

+ +734+1,372+2,4362,9501,3001,0001,460

..l

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Urine Flow.-The daily volumes of the urinepassed by Cases 3 to 8 are given in Table II, wherethey can be compared with the volumes passed byone burned patient who developed the classicalanuric type of acute renal failure. Case 1, a girl,who was only 5 years old, passed 790 ml. of urineon the first day and 350 ml. on the second day.Although the urinary output fell it was adequatefor a child of her age. Case 2 passed 900, 820,and 640 ml. on successive days. Accurate measure-ments in three other patients were spoiled by bed-wetting, but even the volumes which weremeasured were not oliguric. In Case 3 the urinaryexcretion during the first 48 hours was erratic andirregular, but the volumes recorded, which were720, 325, and 734 ml. on the first, second, andfourth days after burning, do not indicate a sus-tained oliguria. A diuresis of 2 to 3 litres dailyoccurred on the sixth and seventh days; thereafterthe urine flow was over 1 litre per day. The urin-ary output in Case 4 was 685, 1,800, 400, 570, and413 ml. on successive days. This flow was inade-quate, but was not considered oliguric. Case 5passed less urine in the first seven days than he didsubsequently, but only on the first and third daysdid the output of 360 ml. approach Bull's oliguriclevel. In Case 6 the urinary output, which variedfrom 740 ml. or more to 2 litres a day, was ade-quate throughout. The urinary flow in Case 7was adequate on the first, second, fourth, and fifthdays (740 to 1,130 ml.), was at least 360 ml. on thethird day, and it may have fallen before he died.In the patient with post-traumatic uraemia (Case8) oliguria was probable on the day of injury, butthe volume passed is not known. Thereafter thedaily excretion was normal and at times polyuric.

Therefore if oliguria did occur in any patient itwas slight or transient.Haemoconcentration and Fluid Intake during

Shock Phase.-The burned patients were haemo-concentrated and oligaemic at least during theearly part of the shock phase and the highesthaematocrit values during this period were: Case1, 47% ; Case 2, 67%; Case 3, 54%; Case 4,57%; Case 5, 57% ; Case 6, 52% ; and Case 7,54%. They were energetically transfused withplasma; sometimes blood or glucose or salinewas also given and in addition oral fluidswhen vomiting did not prohibit them. Transfu-sion was generally more rapid during the first eighthours than subsequently and during this period thefollowing total volumes of fluid were given: Case1, 2.8 (1.8 plasma, 0.2 blood); Case 2, 1.5 plasma;Case 3, 2.1 plasma; Case 4, 5.0 (4.2 plasma);Case 5, 5.0 (4.2 plasma); Case 6, 4.8 (3.2 plasma,

1.2 blood), and Case 7, 4.0 (2.0 plasma, 1.5 blood)litres. The total volumes of oral and intravenousfluids given during the shock phase (over a periodof 48 hours except in Cases 4 and 5, in whichtransfusion was stopped at 24 hours) were: Case1, 8.7 (4.0 plasma, 0.7 blood); Case 2, 14.6 (8.0plasma, 3.8 blood); Case 3, 11.6 (7.0 plasma, 0.5blood); Case 4, 10.6 (6.3 plasma); Case 5, 10.4(6.3 plasma); Case 6, 12.2 (7.3 plasma, 1.2 blood);and Case 7, 10.7 (6.5 plasma, 1.5 blood) litres.

Case 8 was given 4 litres of fluid during the first24 hours, including 1 litre of blood.Haemoglobinuria.-In five of the seven burned

patients haemoglobinuria was known to occur. Inthe others (Cases 5 and 7) it was not recordedand if present was probably slight or transient.Haemoglobinuria occurred early, within hours ofburning, and was associated with haemolysis inthe plasma. In at least three of the patients theurine was deeply red for a day or longer.Urinary Casts.-Numerous brown pigmented

granular casts were present in the urinary depositsof all the patients at least on the first to the thirddays. In Case 4 they were still found on thesixth day after burning.

Clinical Uraemia.-Severely burned patientswho survive the shock phase and who do not de-velop uraemia are frequently ill. Vomiting, ifpresent, often continues for some days, tachy-cardia is usual, pyrexia is common, and often themental state is disturbed. As a consequence thesignificance of symptoms due to incipient uraemiamay be overlooked. Thus uraemia was not sus-pected until the end of the first week or later inthose who survived a longer period. Symptoms ofuraemia or consistent with uraemia were thenpresent. Case 3 became restless, noisy, andirrational from about the third or fourth day,vomiting was troublesome, and she developedhiccups later. Case 4 also developed hiccups, be-came dyspnoeic, drowsy, and lapsed into coma.The general condition of Case 5 worsened afterthe first week when he became weak and drowsy.Case 6 remained in a fair general condition untilthe sixth day; thereafter she became weaker,hyperventilation with acidaemia ocurred, she be-came drowsy and finally comatose. During thelast two or three days of life of Case 7 the symp-toms of hiccups, retching, and vomiting were con-sistent with uraemia. Vomiting during the firstfew days of Case 8 was followed later bydiarrhoea and abdominal distension. By the sixthday he was very ill, the tongue was furred andcracked, hyperventilation due to acidaemia

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SIMON SEVITT

appeared, he became thin, appeared dehydrated,and was mentally disorientated.Even though none of the present patients sur-

vived, it is important to diagnose the uraemic stateat an early stage, because the patient's chance ofsurvival has probably increased with the introduc-tion of high-calorie, low-nitrogen feeding.

Causes of Death. Uraemia played a majorpart in the deaths of six patients (Cases 3 to 8),but one of them (Case 4) died suddenly from pul-monary embolism. Case 1 died in acute respira-tory failure from pulmonary atelectasis. Acutehaemolytic jaundice and incipient uraemia were

probably responsible for the death of Case 2.

Renal Function.-The findings are set out in TableIV. Urine urea estimations were carried out on

one or more occasions in four patients (Cases 4 to6 and 8) and urea clearance values were calculatedfrom the 24-hour volumes of urine and the bloodor serum urea level. In each case the ratio of theurine urea to the blood or serum urea was low, thevalues varying only from 2 to 6 in the first tests.The urea clearances were all significantly reduced,markedly in Case 4, in which the value was only2.6% of average normal, and in the remainder sig-nificantly low values, 13 to 14% of normal, were

obtained in the earlier tests. Subsequent testsshowed little or no improvement, the values risingto only 15 to 18'qo of normal.

In two of these patients the concentration of theurine was repeatedly tested ; the S.G. was fixed

between 1010 and 1014, and in one patient theosmolarity, which ranged only from 330 to435 m.osmols per litre, was little more than thatof a plasma filtrate.Sodium and chloride estimations of the serum

(S) and urine (U) in three patients indicated con-

siderable tubular power to reabsorb these ions,particularly in Cases 5 and 6. Low urinary valuesof sodium and chloride were associated withnormal or raised values in the serum. The S/Uratios as a consequence were high. In Case 5this ratio varied from 35 to as much as l10 forsodium: in Case 6 the S/U for sodium rangedfrom 15 to 30 and varied between 5 and forchloride; in Case 8 the ratios for sodium andchloride were 6 and 5 respectively.Terminal glycosuria consistent with severe

tubular dysfunction occurred in Cases 1 and 7. Inthe former the blood glucose was determined andfound to be normal (120 mg.%).Serum Biochemistry. Definite hyperpotass-

aemia was found in Cases 5, 6, and 8, with serum

potassium values of 27.3, 33, and 23.4 mg.0,respectively, and a high normal level of 19.8 to

20 mg. was obtained in Case 8. The serum

sodium values were moderately or definitely raisedin two patients (380 mg.% in Case 5, 325-350mg. in Case 8), and abnormally high serum

chloride levels were found in Cases 6 and 8 (660and 686-713 mg.%0). Low serum bicarbonatevalues, presumably the result of acidaemia, were

TABLE IVRENAL FUNCTION

Urine Concentration Urea aCase NaCl KNo. Specific m.-Osmols Blood or Serum 1 Clearance S Ut S U U S;

Gravity per Litre (mg.* ,)

Group4 357 2 265 1010-14 330-435 280 6-10 13-18 35-1106 280 7 13-15 1530 511 78 1010-12 320 6 14-15 6 5 5

Group 214 1012* 26-55 28-53 30-8515 1016-22 40-55 22-30 40-5016 239-888 40-55 36-61 45- 12017 1004-2220 284-978 43-61 35-40 80 10021 344-876 39-58 20-33 40-4122 1010-14 258-350 58 16 60-37

* One specimen only examined.

(1) The highest blood or serum urea levels are given for Cases 4 to 8: highest and lowest values are given in the other cases.

(2) lU S is the ratio of the concentration in the urine to that in the serum or blood for urea and the urine to serum ratio for potassium.tS U is the opposite ratio for sodium and chloride.

(3) Urea clearance % is based either on the standard clearance U . where 100% 5-54 ml. of blood per minute, or the maximum clearanceB

UV where 100%=75 ml. of blood per minute. Values in children are corrected for kidney weight by multiplying the urine volume byBthe average weight of normal adult kidneys (14 oz.) and dividing by the weight of the patient's kidneys.

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also detected in these two patients (31 and 35 to44 volumes CO2 % respectively). However, thesechanges do not necessarily reflect renal failure,since they are not uncommon in other severelyburned patients and are at least partly related tothe intake of sodium, potassium, and other ions.

The KidneysThe renal features of Cases 2 and 7 are in

special categories and will be considered later.Necropsy was refused in Case 6.Early Diffuse Distal Tubular Necrosis.-Case 1,

which survived only two days, was included in theseries partly because the histological findings mayrepresent the early stage of those who survivelonger. Her kidneys portrayed what may be con-sidered to be the early form of diffuse distal tubu-lar necrosis. Numerous haemoglobin casts ofdifferent types-amorphous, coarsely and finelygranular-occupied the lumina of many collectingand distal secretory tubules and distended manyof them (Fig. 1). Some casts contained desqua-mated epithelial cells. Casts were also present inthe cortex, mainly in the ascending and second

FIGS. I to 8.-Diffuse distal {tubular necrosis.

FIG. 1.-Many Henle tubules inthe boundary zone of thecortex contain haemoglobin *casts and parts ofthe tubularepithelium are thinned and *necrotic. Case 1, haema- itoxylin and eosin, x 380.

convoluted tubules. Many tubules were focallythinned and necrotic, particularly where the epi-thelium was compressed by casts. The glomerularcapsules contained an abundance of coarse eosino-philic granules; the epithelium of the first convo-luted tubules was swollen and they containedmuch albuminous debris. In many areas manyof the glomerular tufts were bloodless. An occas-sional small focus of inflammatory cells was al-ready to be seen in the boundary zone of thecortex.Later Diffuse Distal Tubular Necrosis.-The

kidneys of Cases 3, 4, 5, and 8 were swollen andenlarged, together weighing as much as 19 oz. inCase 4. In the last three subjects the cortices werewidened and the outlines were hazy (Fig. 2), butpallor was evident only in Case 4. The renalparenchyma was often softer than usual, particu-larly in Case 5, and in the kidneys of two patients(Cases 5 and 8) minute, whitish-grey foci werevisible particularly in the bases of the pyramids.Histology.-In these patients the changes were

those of a diffuse distal tubular necrosis in a laterdevelopmental phase. Casts and tubular necrosis

C

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FIG. 2_w

FIG. 2-The kidneys of Case 5. The cortices

are broadened, the markings are indistinct

~~~and tiny whitish foci are present.

FIG. 3.-Many ascending Henle tubules are

distended by granular haemoglobin casts.

Cross section at boundary zone. Case 3,

haematoxylin and eosin, 110.

FIG. 3

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19NON-OLIGURIC DISTAL TUBULAR NECROSIS

FIG. 4.-Thrombosis of a veinin the boundary zone withearly organization of theclot into which has spreada thin layer of regeneratingtubular epitEelium. Case 3,haematoxylin and eosin,x 110.

FIG. 5.-Focal infiltration oflymphoid and plasma cellsin the cortex situated at thedistal convoluted tubule,parts of which are necrotic.Case 3, haematoxylin andeosin, x 110.

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- .t - F

*~~~ ~~4X#sIO i ..w

FIG. 6.-Recently regeneratedstraight tubules in theboundary zone and a looselymphocytic cellular exu-date. Case 8, haematoxylinand eosin, 380.

FIG. 7.-Heavy peritubularlymphoid infiltration in theboundary zone. Some ofthe straight tubules containcolloid casts. Case 8,haematoxylin and eosin,

210.

FIG. 8.-Focal infiltration oflymphoid cells related tocasts extruded by the distalconvoluted tubule. Case 8,haematoxylin and eosin,, 210.

FIG. 8

20 SIMON SEVITT

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were present, epithelial regeneration was in pro-gress, tubulo-venous anastomoses had occurred,and there was an inflammatory cellular exudate inthe interstitial tissue.

In Case 3, surviving 10 days, numerouscoarse and finely granular haemoglobin andeosinophilic casts were found mainly in the collect-ing tubules and ascending limbs of Henle (Fig. 3);some colloid and cellular casts were also present.Discrete necroses of straight tubules, particularlyin the boundary zone of the cortex and in thepyramid, were in evidence largely at the sites ofblockage by casts. Attempts at tubular repair byspreading and regeneration of epithelium was inprogress and had produced plicated and bizarretubular forms. Some of the venules in the bound-ary zone were thrombosed (Fig. 4), the thrombiwere becoming organized, and there was otherevidence of tubular rupture and tubulo-venousanastomoses. Collections of lymphocytes, someplasma cells, and a few eosinophil leucocytes wereseen around and between many straight and secondconvoluted tubules, particularly those ruptured orblocked by casts (Fig. 5). The parietal epitheliallayer of many Bowman's capsules had becomecubical or even low columnar, as if over-vigorousreplacement of the previously desquamated epi-thelium had occurred. Some cloudy swelling waspresent in the first convoluted tubules, the cortexand medulla were congested, and the latter wasoedematous.A diffuse but not excessively severe form of distal

tubular necrosis was found in the kidneys of Case 4,who died on the sixth day. There were moderatenumbers of benzidine-positive pigmented casts;focal pyknonecrosis of blocked tubules was presentand a cellular infiltration between the straighttubules and near walls of veins was seen. Much ofthe cortex and many glomeruli were ischaemic, thetubules in the pyramid were separated by oedemaand the medulla was congested.The histological features in Case 5 differed in

that haemoglobin casts were not found, and thisis of interest, since haemoglobinuria was not re-ported. This was also found in the case treatedat Mount Vernon Hospital. Instead eosinophiliccolloid and granular casts were present, tubularregeneration and evidence of recent necrosis wasseen, peritubular and perivenous cellular infiltrateswere found, particularly in the boundary zone ofthe cortex and at the second convoluted tubules.There was thrombotic evidence of tubulo-venousrupture.

In the post-traumatic subject (Case 8) who sur-vived 16 days, the Henle tubules and the collecting

tubules frequently contained eosinophilic castssome of which were mixed with small groups ofred cells. Many Henle tubules were degenerate orfocally necrotic and in some irregular tubular re-generation was in progress (Fig. 6). The lymphoidcell infiltration was heavy but irregular in theboundary zone (Fig. 7), and was also present inother parts of the cortex, where it was usuallyrelated to extruded casts or ruptured or necroticsecond convoluted tubules (Fig. 8). Many glomeruliwere distinctly ischaemic. The epithelium of thefirst convoluted tubules also showed some de-generative changes; their lumina were a littledilated and contained eosinophilic debris. Oedemaof the pyramid was evident.

Atypical Cases.-The histological findings intwo burned patients differed from the others inthat a degenerative change of the first convolutedtubules was associated with evidence of a previous(Case 2) or recent (Case 7) attack of focal distaltubular necrosis.

Case 2.-On admission haemoconcentration wasconsiderable; at first plasma and then bloodwas transfused. Peripheral circulatory failure de-veloped and in attempting to reverse this a total of18.6 litres of plasma and blood was transfused inthe two and a half days. An acute acholurichaemolytic jaundice (serum bilirubin 10.5 mg.%)with considerable haemoglobinuria occurred. Theblood urea rose from 80 mg. % 12 hours afterburning to 190 mg. % on the day of death. Atnecropsy the kidneys were deeply congested, theircut surfaces dripping blood.No haemoglobin casts were seen and there was

no evidence of acute distal tubular necrosis exceptfor a very occasional necrotic focus in a wideHenle loop. However, focal, mainly p_rivenous,collections of lymphoid cells were found particu-larly in the boundary zone of the cortex. Anoccasional Henle tubule appeared recently regener-ated and a few colloid casts were found in distaltubules. These findings are evidence of a recently" healed " attack of tubular necrosis unrelated tothe burns (see Group 2). The epithelium of thefirst convoluted tubules was swollen and pale-staining and some nuclei had disappeared. Bothcortex and medulla were intensely engorged.

It is postulated that the incipient uraemia resultedfrom an acute accentuation of a previously sub-clinical tubular dysfunction. The latter had persistedafter an attack of distal tubular necrosis which washistologically healed: the accentuation was due tojaundice and acute degeneration of the proximaltubules. Bull et al. (1950) and Oliver (1953) re-

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port that tubular dysfunction may continue forweeks or months after recovery from tubularnecrosis.

Case 7.-Uraemia with little or no oliguria in

this patient were associated with an active focalnecrosis of the distal tubules (see Group 2) andcortico-tubular degeneration. The kidneys to-gether weighed 16 oz., were a little swollen, withthe cortices pale and broader than usual.Only a few scattered haemoglobin and colloid

casts were present, mostly in collecting and secondconvoluted tubules. A few foci of tubular necrosisand of epithelial regeneration of the wide Henletubules were seen; occasional perivenous collectionsof lymphoid cells and one vein thrombosed by a

tubular rupture were additional evidence of a fozaltLibular attack. Probably of considerable import-ance was a severe and extensive degeneration ofthe proximal convoluted tubules in places almostamounting to a necrosis. The pyramids were con-

gested and oedematous.

Group 2

Details of the 14 patients are given in TFable 1.

Unlike the GroLup 1 patients all but one were

children from 2 to 10 years old and the other was

a man of 27 years. Each patient was extensivelyburned; in only two of them was the extent lessthan 30% and in the remainder it varied from 45to 70% of the body area. The percentage skinareas involved in almost all the patients as well as

the mean area burned (which was 52¾),) are simi-lar to those in Group 1. Two patients died within24 hours of burning and are included because therenal changes may represent the earlier stage ofthose who survive longer. Four survived four tonine days and the remainder died between 15 and

35 days after burning. Haemoconcentration andfluid intake during the shock phase were, exceptfor Cases 21 and 22, similar to the Group patients.

Urine Flow.-Not one of the patients was

oliguric. The daily volumes of urine passed in six

representative subjects are given in Table 111.

Case 9 passed 1,140 ml. of urine of S.G. 1020 to1025 during her 16 hours of survival. Over 1 litrea day was passed by Case 11 except on the lastday, when the urinary output fell somewhat. Case14, a boy, who was only 4 years old, passed be-tween 350 and 730 ml. of urine daily during thefirst four days. The output may have been lesson the fifth day, but even then he passed at least200 ml., but bed-we.ting interfered with accuratemeasurements. The urinary output of Case 15varied between 500 and 1,000 ml. daily. SimilarlyCases 10, 12, 13, and 16 to 22 passed adequate,normal, or even polyuric volumes of urine on eachday. Even in Case 18, a child in whom accuratemeasurements were spoiled by frequent bed-wetting, the volu i-e- which were measured (usually300 to 600 ml. after the fourth day) cannot beconsidered oliguric for a child of 3 years.

Blood Urea.-Blood or serum urea estimatioiswere carried out on eight subjects (Cases 14 to 16and 18 to 22). The values varied from 26 to61 mg. ';) at the time of death and during thecourse of the illness. Similar blood urea levelsoccur in severely burned patients who survive andshow no evidence of renal impairment (Bull and

England. 1954). Blood urea estimations were notcarried out in the other six patients. Two of them(Cases 9 and 10) died at 15 and 16 hours, whichwas too soon for significant azotaemia to occur:

in a third (Case 17) the ability of the patient todilute and concentrate his urine nakes renal

TABLE IIIURINARY OUTPUT AND BLOOD (OR SERUM) UREA LEVELS IN SOME GROUP 2 PATIENTS

Case 11 Case 14 Case 16 Case 18 Case 21 Case 22

Day Serum Blood Blood Blood BloodUrine Urine Urea Urine Urea Urine Urea Urine Urea Urine Urea(ml.) (ml.) (mg. (ml.) (mg. (ml.) (mg. (ml.) (mg. (ml.) (mg./

100 ml.) 100 ml.) 100 ml.) 100 ml.) 100 ml.)

1 1,757 350 26 487 1,254 1,080-- 1,135 _2 1,200 463 33 832 980- - 530 46 1,0363 1.100 667 46 340 - 80-.- - 1.585 50 1,0504 1.600 730. I ,150 55 665- 1.150 53 374 585 1,290 200- 46 1,870 40 296-.--- 730 536 448 55 1,035 570-.- 690 417 1,340 360- I 36 1,285 300--- 1,180 448 560 1,075 I 295-.- 1 (80 3910 1.070 360- - 1,65012 680 328 - - 1,150 4014 620 54 535t- 660 5416 540- 875 5818 400- -.20 260- 37

-,+4-+ + and - are devrees *f bed-wetting.All patients except Case 11 were children.

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impairment unlikely (vide infra), but in Cases 11to 13 this possibility cannot reasonably be elimi-nated.Haemoglobinuria. - Haemoglobinuria was

known to occur in only four of the 14 patients(Table I). In Case 9 it was noted a few hoursafter burning when the urine was pale red, but afew hours later it was normal in colour. In Case15, however, there was no evidence of haemo-globinuria until the third day, when it occurredin association with a true haematuria. Whetherit was a true haemoglobinuria or not is difficultto estimate. Next day the supernatant urine aftercentrifugalization was free of haemoglobin, whilsta deposit of red cells was still present. Necropsyrevealed that the haematuria was the result of aruptured calyceal vein. A heavy and true haemo-globinuria occurred in Cases 21 and 22. It startedearly in both children, was intermittent for twodays in the former, but in the latter was prominentfor two or three days.

Clinical Uraemia.-This was not suspectedduring the course of the patients' illnesses.Causes of Death.-Significant clinical and

necropsy findings are included in Table I. Acuterespiratory distress developed in Cases 9 and 10.At necropsy atelectasis was found in both patientsand was associated with pulmonary oedema in theformer. In seven patients severe infective compli-cations, usually septicaemia or bronchopneumonia,were found, and in one of them (Case 17) agranulo-cytosis due to sulphonamide intoxication was alsopresent. Case 12 died suddenly, and at necropsyacute coning of the medulla oblongata was seen.A pulmonary infarct was found in Case 16; diar-rhoea from aureomycin therapy helped to exhaustCase 19, and bleeding from an acute duodenalulcer (Curling's ulcer) may well have played apart in the death of Case 20. No significant infec-tive or other complications were to be found inCase 22.Thus the causes of death as revealed by clini-

cal observation and necropsy findings generallyappeared to be unrelated to uraemia.Renal Function.-In the six patients studied

there was no significant reduction in the ureaclearance values (Table IV), which varied fromtime to time in some patients. Values from 30%to 85% of normal were found in Case 14: simi-lar variations from 45% to 120% and 80% to100% of normal were also observed in Cases 16and 20, but successive values of 40% and 41 %of normal were found in Case 21 on the two daysbefore she died. The concentrating power of the

kidneys as reflected in the specific gravity or osmo-larity of the urine was moderately good, and intwo patients (Cases 16 and 17) evidence ofadequate diluting power was also obtained (S.G.1004 and 239 m.osmols per litre respectively).The concentration of the urine often varied fromday to day. Case 16, for example, passed a diluteurine on the second day, but two days later theurine was moderately concentrated (888 m.osmolsper litre), and thereafter the daily concentrationvaried from 243 to 821 m.osmols per litre. Simi-larly the milli-osmolarity in Case 21 varied from344 to 876 throughout her illness. No patient,however, secreted a highly concentrated urine.This may have been the result of an adequatewater intake and urinary output. On the otherhand, it may have been the result of a subclinicallowering of the tubular reserves similar to thatpostulated in Case 2, a man in whom there wasevidence of a recently " healed " focal distal tubularnecrosis. Acute renal failure in him may havebeen partly the result of an impaired tubular powerbefore he was burned.

The Kidneys in Group 2 PatientsThirteen subjects had either a focal necrosis of

the distal tubules at different morphological stagesof activity or the healing or healed evidence of arecent focal attack. In one patient (Case 22) thehistology was atypical.Early Focal Distal Tubular Necrosis.-Cases 9

and 10, surviving only 15 and 16 hours, areincluded in the series because they probably repre-sent the earlier stage of the later phenomenon.The kidneys were dark with congestion, particu-larly the pyramids, and the capsules were tense.Histology.-Only a few scattered haemoglobin

casts-amorphous and granular forms-were pre-sent, mainly in the collecting tubules (Fig. 9) and ina few ascending and spiral portions of the distaltubules. Early discrete tubular necroses (pyknosis)were restricted to some of the tubules blocked bycasts.

Later Focal Distal Tubular Necrosis.-Threepatients (Cases 11 to 13) who died eight and a half,six, and 35 days after burning had a focal distaltubular necrosis in a later histological phase. InCase 13 a few distal convoluted and straight Henletubules were locally distended by colloid or lesscommonly granular casts (Figs. 10 and 11). Nohaemoglobin casts were seen. The epithelium ofthe distended parts was usually thin, the nucleiwere hyperchromatic, and very occasional mitoseswere found (Fig. 10). In other words tubularregeneration of formerly necrotic parts of the

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tubules was in progress. Focal collections, mainlyof lymphoid cells but also containing fibroblasts,were found around some of these tubules (Fig. 11)and around the walls of veins in the boundaryzone of the cortex. An occasional venule wasthrombosed and organization of the thrombus wastaking place. The proximal convoluted tubuleswere a little distended and some albuminous de-generation was present. The histological featuresin Cases 11 and 12 were similar, but a few haemo-globin casts were seen (Fig. 9), and there wereoccasional tubulo-venous thrombi in the boundaryzone (Fig. 12). Localized necrosis of a few Henletubules, including some which did not containcasts, was also seen, but visible necrosis is to beexpected, since these patients died sooner than didCase 13. Tubular regeneration was also in pro-gress (Fig. 13).

" Healing " and " Healed " Focal Distal Tubu-lar Necrosis.-The morphological changes in thekidneys of eight patients (Cases 14 to 21) arebelieved to represent the healing or healed resi-due of a recent focal distal tubular necrosis. Focalcollections, mainly of lymphoid cells, were presentin the kidneys of each patient; they were oftenperivenous and were commonly located in theboundary zone of the cortex (Fig. 14) or relatedto second convoluted tubules. In three patients(Cases 14, 15. and 21) occasional organizing venousthrombi in this part of the kidney indicated formertubulo-venous rupture (Fig. 15). Direct evidenceof tubular necrosis was slight or absent and wasseen only in two or possibly three patients. Inthree cases casts were seen in a few distal tubules;they were granular and eosinophilic in Case 14, pig-mented in Case 20, and of both kinds in Case 21.In the kidneys of four subjects (Cases 14, 18, 19,and 21) parts of an occasional straight Henletubule showed evidence of recent regeneration.The term "healing" is applied when tubular

evidence of necrosis or regeneration still persists(Cases 14, 18, 19, and 21). Case 14, dying at sevendays after burning, showed more tubular evidenceof a recent focal attack than the others.The term "healed " is used when there is no

tubular evidence of focal tubular necrosis (Cases15, 16, 17, and 20). The characteristically locatedlymphoid cell collections and in one patient (Case15) an organizing venous thrombus (Fig. 15) wereaccepted as the residue of a focal distal tubularnecrosis. Taken as a group, this appears to be areasonable deduction even though direct evidenceof tubular damage was not detectable. The dura-tion of survival, 15 to 21 days, was probably con-sistent with histologically effective tubular repair.

Atypical Case and Prevention of Oigaemia.-Case 22 differed from the others in Group 2 inthat multiple haemoglobin casts were seen histo-logically. The urinary output of this child (TableIII) was almost polyuric for three days and theurine was dilute. Haemoglobinuria appearedearly, was prominent, and continued for two daysor longer. Renal function was adequate or nor-mal and significant azotaemia did not occur (TableIV). A special feature in this child and in Case 21was that, after the initial haemoconcentration hadbeen corrected, the plasma and red cell volumeswere maintained more or less within normal limitsby energetic transfusions guided by repeated bloodvolume estimations. Indeed, during the first threedays 10.8 litres of plasma plus 1 litre of blood wasgiven to Case 21 in addition to 4 litres orally, and6.4 litres of plasma plus 1 litre of blood to Case22. The special biochemical feature was a verylow serum potassium (11 mg. %) on the day shedied.Histology.-There were many haemoglobin

casts in the collecting tubules and numbers in theascending and convoluted parts of the distaltubules. Only some appeared blocked by casts,and occasional pyknonecrotic epithelial foci wereseen, but they were not numerous. Small peri-venous and peritubular lymphoid cell collectionswere present, but they were infrequent. There wasan eosinophilic and granular cytoplasmic degener-ation of the neck-like beginning of the first con-voluted tubules the remainder of which was paleand swollen. The lumina were obliterated, but thesecond convoluted tubules were moderately dilated.The unusual combination was many haemo-

globin casts and few necroses in the distal andcollecting tubules, that is a diffuse cast state withfocal tubular necrosis. The scarcity of necroticepithelium both in this child and in Case 21 mayhave been due to the absence of oligaemia andrenal ischaemia resulting from massive trans-fusion, even though haemoglobinuria was con-siderable in both patients (vide infra). The histo-logically numerous pigmented casts in Case 22were the result of the prolonged haemoglobinuria:had she survived longer, they might have beenprogressively removed by the unobstructed urinaryflow through the tubules, and the histologicalpicture would then have resembled that observedin other cases of focal distal tubular necrosis suchas Case 21.

DiscussionIn burned subjects distal tubular necrosis may

be associated with one of three clinico-biochemicalsyndromes. First, severe oliguria or anuria cul-

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FiG. 10FIG. 9

FIGS. 9 to 15.-Focal distal tubularnecrosis.

FIG. 9.-An occasional Henle tubule isdistended by a haemoglobin cast. Theepithelium of this tubule is irregularlynecrotic. Case 9, haematoxylin andeosin, x 210.

FIG. 10.-An occasional straight tubule inthe deep half of the cortex is focallydistended by a colloid cast and theepithelium is thin and hyperchromaticas if in the process of regeneration. Case13, haematoxylin and eosin, x 380.

FIG. I.-One of the few focal collectionsoflymphoid cells which lie near rupturedHenle tubules some of which showirregular epithelial regeneration. Theremains ofcasts in these formerly necrotictubules are still visible. Case 13,haematoxylin and eosin, x 380.

FIG. I I

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.A4 Q. Tm 4

W.

4 A

~~y,, j 57 -Jk.> P FIG. 12

A1 Zt~% ~ ,4

FIG. 13

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FIG. 12.-An occasional vein in the V:I #, M *'s> J .Vs; *boundary zone is thrombosed. Theiclot is beginning to organize and 44 v*irregular migration of tubular epi-thelium indicates former tubulo- *tvenous anastomosis. Case 12, *':4haematoxylin and eosin, x 210. .VI

FIG. 13.-Regeneration of a few focallynecrotic tubules is in progress andvhas produced bizarre tubular forms. 8Parts of two tubules contain colloid 3 .V -casts. To the left of the centre thereis an intertubular infiltration of i -lymphoid cells. Case 12, haema-toxylin and eosin, > 380.

FIG. 14.-A few focal pe-ivenous collec- "WItions of lymphoid cells in theboundary zone are part of theresidue of a recent attack of focal W4 #D.T.N. Case 18, haematoxylin andeosin, x: 210. ¢ *_, -**

FIG. 15.-An occasional organizing kthrombus in a boundary zone veinis part of the residue of a recentattack of focal D.T.N. Case 15,haematoxylin and eosin, 210.

FIG. 14

iA* * . minating in uraemia may develop; second, uraemiaiF*,B*>ss sS--a9; i* w¢* may occur without significant reduction in the

siti j> .' *4 flow of urine (Group 1); and third, neither oligurianor uraemia may be found (Group 2). All the

1O..* ^ t~ -patients were extensively burned and the meanW# -. ,E i ^ k u =3 i skin areas involved were 66%, 58%, and 52% ofb.:eA^.~ $ the body area in the respective groups. Certainly

W. w> 14-01 the difference between the areas burned in GroupI and Group 2 patients is not significant. All butone of the Group 1 patients were adults oradolescents, whilst all but one of the Group 2

-vw* 9̂ t 3f W patients were children.In five of the seven Group 1 burned patients a

diffuse distal tubular necrosis was found and inanother a focal distal tubular necrosis was asso-

't;w;w~;* >*;': ciated with a severe and extensive cortico-tubulardegeneration. Twelve other burned subjects with

jl e eXtw w~distaltubular necrosis (unpublished data) died_ 4=jvwithsevere oliguria or anuria, four of whom

p ^-1 < 4lived long enough to develop uraemia. Ten ofthem had a diffuse distal tubular necrosis and in

*_61ll_x l_ the other two the change was focal. In both theoliguric and non-oliguric groups, the diffuse change

' jUl - |was characterized by the early appearance ofhaemoglobin casts in many collecting and wideHenle tubules and in distal convoluted tubules.

FIG.1T This differs from Dible's latest account (Bull and

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Dible, 1953) of distal tubular necrosis (" acutetubular necrosis" in their terminology), since hereports that pigmented casts do not appear in num-bers until about the second or third day of oliguria.However, Dible's series of 62 cases included onlytwo kidneys from burned patients and the absenceof significant haemoglobinuria in these may havebeen responsible for his experience. In bothgroups, frequently the tubules were blocked bycasts and this was often associated with discretenecrosis of the epithelium. Necrosis occurred lessfrequently in tubules which did not contain casts.In both groups rupture of tubules, dislocation ofcasts, tubular regeneration, peritubular and peri-venous infiltration by lymphoid and other inflam-matory cells, tubulo-venous anastomoses andthrombi were found in patients who survivedsufficiently long. Histological examination by thewriter cannot distinguish between oliguric andnon-oliguric forms of diffuse distal tubularnecrosis. The difference probably has a func-tional rather than a morphological basis and maydepend on differences in renal blood flow orglomerular filtration which clearly would be diffi-cult if not impossible to distinguish histologically.

Other workers have referred to the absence ofsignificant oliguria in some fatally burned patients,the kidneys of whom showed the changes nowreferred to as distal tubular necrosis. Goodpastor,Levenson, Tagnon, Lund, and Taylor (1946) men-tion four patients who had only a transient andlimited oliguria in the shock phase and in whompigmented casts, tubular necrosis, and regenera-tion were found histologically. In these patients"there was evidence of impaired ability to clearnon-protein nitrogen in the face of a urine outputof a litre or more daily." Four patients of Shen,Ham, and Fleming (1943) may also belong to thiscategory. Homer Smith (1951) refers to twoseverely injured patients studied by Burnett andhis colleagues at the Italian front who may alsobe included, and more recently Teschan, Post,Smith, Abernathy, Davis, Gray, Howard, Johnson,Klopp, Mundy, O'Meara, and Rush (1955)described cases of post-traumatic uraemia with-out oliguria occurring after battle wounds.Renal Function in Uraemic Subjects.-Bio-

chemical examination of the blood and urine threwsome light on the functional renal disturbance offour uraemic subjects (Table IV). On the onehand, an adequate or normal flow of urine andconsiderable azotaemia were associated with lowurea clearance values and a poorly concentratedurine. These findings suggest that, although theglomerular filtration rate was somewhat lowered,

the tubular power to reabsorb water and excreteurea were reduced, thus allowing an adequate ornormal volume of urine to be secreted andazotaemia to develop. However, the urea clearancetest is dependent both on glomerular filtrationand on tubular function, so that it is not possibleon the available data to distinguish reduction offiltration clearly from tubular dysfunction. Furtherinvestigation by endogenous creatinine or inulinclearance techniques is required.On the other hand, two of the three patients

investigated had considerable tubular power toreabsorb sodium and chloride as revealed by thelow concentrations and small daily output of theseions in the urine, and in the third patient the re-absorptive power was moderately good. The lowurinary values were not due to salt deprivation orassociated with low serum values; indeed, theserum chloride and sodium levels were normal orraised. In this persistence of reabsorptive powerfor sodium and chloride, the non-oliguric buturaemic patients differ from the oliguric-uraemicsubjects studied by Bull and his co-workers (1950).They found a considerable concentration ofsodium and chloride in the urine associated withfalling or low serum levels of these ions duringboth the oliguric and early diuretic phases. Intheir patients tubular power to reabsorb sodiumand chloride was virtually absent. Thereforerenal function in the present subjects is differentfrom that found by Bull in patients during theearly diuretic phase of the anuric type of acuterenal failure, even though both groups of patientswere uraemic and urine flow was adequate ornormal.

Urinary retention of sodium and chloride com-monly occurs for a few days in burned patientswho show no evidence of renal failure (Bull andEngland, 1954). It is probably a physiologicalphenomenon, extrarenal in origin, and probablyrelated to the hyperactivity of the adrenal cortexwhich occurs after burning (Sevitt, 1951, 1954.1955).Azotaemia.-It may be argued that the azot-

aemia found in the Group 1 patients is largely dueto an increased protein katabolism as a result ofwhich large quantities of urea and other nitro-genous end-products are formed. It is true thatextensively burned patients and animals are in astate of negative nitrogen balance and that in-creased quantities of urea, creatinine, and othernitrogenous compounds are excreted in the urine(Taylor, Levenson, Davidson, Adams, and Mac-Donald, 1943; Clark, Peters, and Rossiter, 1945).However, the blood urea levels in the Group 2

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patients were considerably lower than in the Group1 patients, yet the patients in both groups hadextensive burns of similar percentage area. Bloodurea values similar to those in Group 2, andusually between 40 and 60 mg. %, are also foundin severely burned patients who survive and showno evidence of renal impairment (Bull and Eng-land, 1954; personal experience). In only aminority of patients does the blood urea rise to200 mg. per 100 ml. or more. Some of thesepatients have considerable oliguria, but in others(Group 1) oliguria is slight, transient, or absent.Both the oliguric and non-oliguric patients haveother evidence of uraemia, such as acidaemia,hyperpotassaemia, hiccups, polypnoea, drowsiness,etc. Indeed, terminal glycosuria consistent withsevere tubular dysfunction occurred in twopatients, in one of whom the blood glucose levelwas determined and found to be normal.

If quantitative differences in endogenous or

exogenous protein katabolism are responsible forthe respective high and only slightly raised bloodurea levels in Group 1 and 2 patients, then thefeeding of an excessively high-protein diet to an

extensively burned subject should produce a

significant azotaemia.By fortuitous circumstances a severely burned

child 2 years old was placed on a very high pro-tein intake of about 84 g. protein per day. Twoweeks later the blood urea was only 28 mg. %.The high protein intake produced a large totalexcretion of urea and a large urinary volume (600ml. on the day of the test).

All the available evidence supports the beliefthat severe azotaemia is due primarily to renalimpairment, although no doubt excessive nitrogenkatabolism (and high protein feeding) accentuatethe condition when the kidneys are damaged.Focal Distal Tubular Necrosis.-Qualitatively

the earlier histological phases of the focal condi-tion differed in no way from the diffuse formof distal tubular necrosis. The difference was

quantitative, casts were few, necroses were notnumerous: few tubules were involved. The in-volvement of few nephrons was the essential histo-logical difference from the diffuse form of thecondition, and in general was the morphologicalbasis between non-uraemic and uraemic forms ofdistal tubular necrosis.The diagnosis of the " healing " or " healed"

phase of focal distal tubular necrosis in eightpatients was made largely by the finding of charac-teristically situated cellular foci around venules or

between tubules in the boundary zone or at secondconvoluted tubules. This was associated with

thrombotic evidence of tubulo-venous rupture inthree subjects and in four patients there was alittle tubular necrosis or recent regeneration.The residual interstitial cellular collections

might have led to the diagnosis of interstitialnephritis if the entire histological process was notborne in mind. It is therefore possible that somecases of so-called interstitial nephritis are inreality the healed or healing residue of distaltubular necrosis.Pathogenesis.-Two inter-related factors, haemo-

globinuria and oligaemia, will be considered.Haemoglobinuria.-Intravascular haemolysis is

a common and early accompaniment of extensiveburns. If the concentration of free haemoglobinin the plasma surpasses a threshold level haemo-globinuria results. This may be continuous orintermittent during the first day or two, but occa-sionally may last longer. It may also be slightor transient and as a consequence easily over-looked. When the urine is deeply red or reddish-brown haemoglobinuria will be easily recognized.Thus the recording of clinically observed haemo-globinuria is an index of its severity and the inci-dence of this clinically known haemoglobinuriawill reflect the frequency of severe haemoglo-binuria.

Haemoglobinuria has been associated withimpairment of renal function in burned subjectsby Shen, Ham, and Fleming (1943) and Good-pastor et al. (1946). Five out of seven Group 1

TABLE VFREQUENCY OF HAEMOGLOBINURIA AFTER BURNINGIN PATIENTS WITH DISTAL TUBULAR NECROSIS (D.T.N.)COMPARED WITH INCIDENCE IN FATALLY BURNED

PATIENTS WITHOUT TUBULAR NECROSIS

Classification of Patients No. of No. with KnowniPatients H-aemoglobinuria

Histology Clinical Pathology (% of Group)

D.T.N. Severe oliguria (or anuria) 12 10 (83%)with uraemia if survivallonger than 4 days

D.T.N. Uraemia but no oliguria 6 4 (66%)D.T.N. No oliguria. No uraemia 14 4 (28%)

Control GroupNo renal No oliguria. No uraemia 24 3 (12%')

tubularnecrosis

burned patients were known to have haemoglo-binuria, but if Case 2, which was histologicallyatypical, is eliminated the analysis may be assessedas in Table V. Here is listed the incidence ofknown haemoglobinuria in four groups of fatallyburned patients. Three groups had the histo-logical features of distal tubular necrosis and thefourth was a control group of non-oliguric non-uraemic patients without renal tubular necrosis.

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SIMON SEVITT

Ten of the 12 patients (83%) who became severelyoliguric were known to have haemoglobinuria, sotoo were four of the six (66°0) Group 1 subjects.but in only four of the 14 (28%) Group 2 patientswas this condition recorded. The incidence wasonly three in the 24 patients (12%) of the controlgroup. In other words, haemoglobinuria deepenough to be readily recognized was generallyfound in patients who developed renal failurewhether or not oliguria occurred. It was uncom-mon in those without renal failure whether ornot focal distal tubular necrosis occurred. Whenit did occur in these patients, renal failure mayhave been prevented as in Cases 21 and 22 byprevention of oligaemia through massive trans-fusion.Haemoglobinuria only occurs when a consider-

able red cell volume is rapidly destroyed. Thisdepends largely on the absolute skin area burnedas well as the duration of burning. For equalpercentage areas burned, children will lose a muchsmaller absolute volume of red cells than adults.Since children excrete a disproportionally (forbody weight) larger volume of urine than adults,the urinary concentration of haemoglobin inchildren is likely to be considerably less than inadults. This may be responsible for the lowerincidence of haemoglobinuria in Group 2 patients,all but one of whom were children, and for thehigher incidence of haemoglobinuria in the Group1 patients, all but one of whom were adults oradolescents.

Severe haemoglobinuria after burning may pro-duce adverse renal effects in one or both of twoways. First, numerous casts may be precipitatedin the distal tubules because of the reabsorptionof water in the proximal tubules. Blockage bycasts, particularly if renal ischaemia takes place,may be followed by tubular necrosis and rupture.Oliver et al. (1951) and Oliver (1953), who advocatethe theory of " stopped pipes," have shown by themicrodissection technique that local tubular block-age or rupture can interfere with the function ofthe whole nephron.

Secondly, severe haemoglobinuria denotessevere haemolysis. The loss of circulating redcells will not only add to the oligaemia due toloss of plasma but will cause a relative highhaematocrit or haemoglobin value. If this is nottaken into account the volume of lost plasma willbe underestimated and as a result the patient maybe undertransfused.

Oligaemnia.-By almost general agreement renalischaemia plays an important part in the patho-genesis of acute renal failure. In all severelyburned patients there is inevitably an initial period

of oligaemia which may last for hours due to theloss of a plasma-like exudate from the burnedskin. The duration and degree of the oligaemiawill be determined by the rapidity and the volumeof plasma and blood transfused. Recent bloodvolume studies suggest that most of the patientsreported here had been oligaemic continuously orintermittently for varying periods (Topley, per-sonal Communication). The relationship of olig-aemia to renal function in burned patients is now,being studied.

SummaryA number of extensively burned patients in

whom oliguria was slight or absent developedconsiderable azotaemia and acute uraemia. Mostof them had haemoglobinuria. An injured patientalso developed non-oliguric uraemia. All of themdied, and histologically the kidneys portrayed adiffuse distal tubular necrosis (Lucke's lowernephron nephrosis). Clinically the non-oliguricform of acute uraemia is important to recognizebecause of recent advances in therapy. Otherburned patients had histological evidence of a focalform of distal tubular necrosis or the " healing "or " healed " residue of a recent attack. Neitheroliguria nor uraemia had occurred, only a few ofthem had had haemoglobinuria, and they died ofnon-renal complications. Renal function andpathogenesis are discussed.

Thanks are due to various colleagues for theirinterest, to Dr. E. Topley for her co-operation on theproblem of oligaemia, Dr. J. P. Bull and Miss S. Baar.F.R.I.C.. for some of the biochemical data, Mr.R. L. G. Dawson, Dr. D. Crockett, and Mr. I. E. K.Muir. of Mount Vernoun Hospital, for the additionalcave report, to my secretary, Mrs. M. Swinden, andMr. D. Gibb, A.I M.L.T., who assisted with the photo--micrography.

REFERENCESBratton, A. B. (1941). Lancet, 1, 345.Bull, G.M., and Dible, J. H. (1953). In Recent Advancesin Pathology,

6th ed., edited by G. Hadfield, p. 284. Churchill, London.-- Joekes. A. M., and Lowe, K. G. (1950). Clin. Sci., 9, 379.Bull, J. P., and England, N. W. J. (1954). Lancet, 2, 9.Bywaters, E. G. L., and Beall, D. (1941). Brit. med. J., 1, 427.- and Dible, J. H. (1942). J. Path. Bact., 54, 1 1 1.Clark, E. J., Peters. R. A., and Rossiter, R. J. (1945). Quart. J.

exp. Physiol., 33, 113.Dunn, J. S., Gillespie. M., and Niven, J. S. F. (1941). Lancet, 2, 549.Goodpastor, W. E., Levenson, S. M., Tagnon, H. J., Lund, C. C..

and Taylor, F. H. L. (1946). Surg. Gynec. Obstet., 82, 652.Lucke, B. (1946). Milit. Surg., 99, 371.Oliver, J. (1953). Amer. J. Med., 15, 535.

MacDowell, M., and Tracy, A. (1951). J. clin. Invest., 30, 1305.Sevitt, S. (1951). Brit. med. J., 1, 976.- (1954). Ibid.. 1, 541.

(1955). J. Path. Bact., 70, 65.Shen, S. Chu, Ham, T. H., and Fleming, E. M. (1943). New Engl. J.

Med., 229, 701.Smith, H. W. (1951). The Kidney, p. 778. Oxford University Press,

New York.Taylor, F. H. L., Levenson, S. M., Davidson, C. S., Adams, M. A.,

and MacDonald, H. (1943). Science, 97, 423.Teschan, P. E., Post, R. S., Smith, L. H., Abernathy, R. S., Davis,

J. H., Gray, D. M., Howard, J. M., Johnson, K. E., Klopp, E.,Mundy, R. L., O'Meara, M. P., and Rush, B. F. (1955). Amer.J. Afed., 18, 172.

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