Experimental Papillary Necrosis of the Kidney

Experimental Papillary Necrosis of the Kidney

I. Morphologic and Functional Data

G. Murray, MD, R. G. Wyllie, MD, G. S. Hill, MD, P. W. Ramsden andR. H. Heptinstall, MD

Papillary necrosis was produced in rats by a single intravenous injection ofbromoethylamine hydrobromide (BEA). The earliest changes as seen by lightmicroscopy were necroses of the limbs of Henle and eosinophilic droplets in collect-ing ducts. Complete necrosis of the papilla took place between 4 and 7 days andthe dead papilla was usually sequestered completely by 21 days. Cortical changesoccurred secondary to papillary necrosis. Tubular atrophy and loss was greatestin the deeper parts of the central cortex, the more superficial nephrons frequentlybeing spared. The perihilar cortex was the least involved. This distribution wasconsidered to be related to the respective lengths of the limbs of Henle, nephronswith limbs extending into the papilla being those undergoing change. Increasedurine output occurred during the first day and continued thereafter. There wasa profound defect in concentrating ability (Am J Pathol 67:285-302, 1972).

PAPJ1LLARY NECROSIS of the kidney is well known to be acomplication of either diabetes mellitus or obstruction to the urinarytract. The incidence at autopsv in the United States during the 1940'swas reported to be 0.16 and 0.26q in two series. '2 In the 1950's, Spiihlerand Zollinger 3 observed that papillar- necrosis could be associatedwith, and presumably- caused by, a high intake of analgesic mixtures.Data from Switzerland, Scandinavia and Australia indicated a greatincrease in the incidence of the condition, almost solely a result ofanalgesic abuse."' Thus, percentage incidences of about 4 " and 9%¶2in routine autopsies have been found in Australia.

Little is known of the pathogenetic mechanisms at work in papillarynecrosis, regardless of its etiology, and the present series of experimentswere designed to obtain some information on one particular experi-mental model-the bromoethvlamine hvdrobromide (BEA) model inthe rat. This compound was first used to produce experimental papillary

From the Department of Pathology, Johns Hopkins University School of NMedicineand Hospital, Baltimore, Man-land.

Supported by Grants HE-07835 and GH-00415 from the US Public Health Service.Accepted for publication Nov. 27, 1971.Address reprint requests to Dr. R. H. Heptinstall, Department of Pathology, The

Johns Hopkins Hospital, Baltimore, NMarvland 21205.

285

286 MURRAY ET AL American Journalof Pathology

necrosis in 1913 by Oka,"3 and more recently by Fuwa and Waugh;14with a suitable dose, the incidence of necrosis approaches 100. It is ahalogenated amine salt, Br CH2 CH2 NH2 HBr derived from ethvla-mine (CH3 CH2 NH.) and readily soluble in water in which thestrength of ionic bonds linking hydrobromide is so weakened that thesalt is lost to solvent molecules. The rest of the molecule undergoes rapidsolvolysis 15 accompanied by ring closure.

Br CH2 CH2 NH2 -* CH2-CH2 + HBr.

NH

This three-membered ring is stable in solution.16 When an aqueoussolution of BEA is injected intravenouslv into the rat it produces a risein blood pressure after a brief period of hypotension. This particularcompound was chosen because the induced necrosis is reproducible andcan be produced by a single injection. That the pathogenesis may be dif-ferent from that after analgesic abuse, is, of course, appreciated.

In this first paper, the sequence of morphologic changes in the kidnevafter the injection of BEA is described. In particular, attention is paidto the manner in which certain areas of the cortex are selectivelv dam-aged after necrosis of the papilla. A brief account is also given of theconcentration defect that occurs.

Materials and MethodsA single intravenous injection of 50 mg of bromoethv-lamine hvdrobromide

(BEA), prepared as a 10% aqueous solution, was given to 116 female Holtzmanrats each weighing 200 to 220 g. Thev were fed Purina Chow and given unlimitedquantities of water to drink. Rats were killed at various time intervals from 6 hoursto 40 weeks. Blood was drawn for serum urea nitrogen (SUN) estimations be-fore BEA was administered and immediatelv before the animals were killed. Inlong term survivors, blood was drawn at four weekly intervals. Serum urea nitro-gen was determ-ined on .2 ml samples, using a modified Berthelot reaction. Theanimals were killed by exsanguination from the heart after ether anesthesia. Tissuewas taken for light microscopy and fixed in formol-saline. The tissues taken werecoronal sections through the papilla in most cases; a few longitudinal sections weretaken. Sections were stained with hematoxvlin-eosin, by the periodic acid-Schiffmethod, and with Martius scarlet for fibrin. In certain animals, tissue was taken forelectron microscopy, but no account of this will be given at the present time.

Urine output was measured for several weeks in the long-term survivors andtests for ability to concentrate urine were performed as follows: The animals wereplaced in metabolism cages several days before the test was performed so that theycould adapt to their surroundings. On the day of the test, the rats were deprived offood and water for a 12-hour-period, at the end of which time, the animals' bladderswere emptied and the urine discarded. Urine was collected over a further 12-hour-period, during which time the animals were deprived of food and water. Theamount of urine was measured and osmolalitv determined on either 2 or 0.2 ml

Vol. 67, No. 2 PAPILLARY NECROSIS OF THE KIDNEY 287May 1972

samples, using a model 31 LAS Advanced osmometer (Advanced InstrumentsInc).

Anatomy of the Medulla

In this, and subsequent articles the nomenclature adopted by Peter 17 is used(Text-figure 1). The cortex is defined as that part of the kidney containing glo-meruli. Besides glomeruli, it contains the pars convoluta of the proximal tubularsegment, thick ascending limbs, distal convoluted tubules, radicles of collectingducts as well as arteries, veins and capillaries. Deep to this is the outer zone of themedulla, which is divided into an outer stripe and an inner stripe. The outer stripeis made up, for the main part of the pars recta of the proximal tubular segment, to-gether with thick ascending limbs and collecting ducts. The inner stripe containsmainly thick ascending limbs and collecting ducts. The thin part of the descendinglimb begins at the junction between the outer and inner stripes. Deep to the innerstripe of the outer zone is the inner zone of the medulla, or papilla. This containscollecting ducts of varying orders which eventually give rise to the ducts of Belliniwhich open on to the tip of the papilla. The inner zone also contains the thin limbsof the loop of Henle and the interstitial cells. The thin ascending limb gives way tothe thick ascending limb at the junction of the inner zone and inner stripe of theouter zone. The limbs of Henle are of variable length, some descending to the tipof the papilla, others not penetrating as far as the inner zone. More will be said ofthis in the discussion section.The blood supply to the medulla has been well described by Moffat,l8 Mloffat

and Fourman,19 and by Kriz and Lever.20 It is derived from the efferentvessels of the juxtamedullary glomeruli which break up into a series of vasa rectawhich pass down to the papilla in the form of vascular bundles. This "arterial side"of the vasa recta breaks out from the vascular bundle at various points to formcapillary plexuses. The "venous side" of the vasa recta originates in the variouscapillarv plexuses and at intervals gains admission to the vascular bundles. These"venous" vasa recta ascend in the bundle and end bv draining into either the arcu-ate or interlobular veins.

For the purpose of ease of description we have divided the cortex into two mainareas, using a coronal section as the basis for this (Text-figure 1). That part of thecortex in a direct line with the papilla has been designated the central or greatercurvature cortex. That part which lies to either side of the papilla (this wouldconstitute the medial part of the anterior and posterior surfaces of the kidney) wehave called the perihilar cortex.

ThxT-FIG 1-Coronal view of rat kidney to illstrate areas referred to in text. CC =central cortex. GCC = greater curve cortex. OS = outer stripe. IS = inner stripe. IZ =inner zone or papilla. PHC = perihilar cortex.


Results

Original Obsefvations

With light microscopy there were no striking changes during thefirst 6 hours with the possible exception of an increased prominence ofthe vascular bundles in the inner stripe of the outer zone of the medulla.The bundles showed an increased eosinophilia and this change was morepronounced at 12 hours. At this time the vasa recta of the inner stripecontained many red blood cells. There was difficulty in accuratelyidentifying the various components in the inner stripe, but certain struc-tures contained eosinophilic coagula and it is probable that these werethin descending limbs. In the papilla at 12 hours there was an apparentmild dilatation of collecting ducts.At 24 hours, definite changes were present in the papilla. The cyto-

plasm of collecting ducts contained rounded eosinophilic droplets whichvaried in size, some of them being larger than red blood cells, and otherssmaller (Figure 1). Some of these droplets had been extruded into thelumen but the lumina contained no casts or coagula. The droplets werestrongly PAS-positive and stained red with the Martius scarlet method.The collecting ducts in the middle and distal parts of the papilla weremaximally affected except for the ducts of Bellini which still demon-strated their usual pale uninteresting appearance. Similar droplets wereseen in the epithelium covering the papilla, and particularly at thepapillary tip, the epithelium was often lost. The thin limbs were thestructures with the greatest changes and the lumina of these containedhomogeneous eosinophilic material (Fig 2). The staining intensity ofthe luminal contents varied; in some instances it was strongly eosino-philic whereas in others it was very pale. The paler staining patternpredominated in the more distal part of the papilla. Some of the limbs-particularly nearer the papillary tip-had already lost their nuclei sothat the limb was often represented by an eosinophilic mass. Red cellswere usually present in vasa recta and capillaries, and polymorphonu-clear leukocytes could be seen in the more distal capillaries. Homo-geneous coagula were present in some of the vasa recta and capillariesand in an occasional animal some more granular appearing eosinophilicmaterial was present. Interstitial cells revealed no remarkable changeswith the stains employed. In the inner stripe of the outer zone eosino-philic casts were seen in thick ascending limbs. Similar casts could befound in a scattered way in the cortex.

At 2 days the papilla showed similar, although more advanced,changes. The collecting ducts were more severely affected by the drop-


let change and droplets could be seen in tubules opening on to thepapillary tip. Mitotic figures were conspicuous in collecting ducts ofcertain rats. The limbs of Henle were now almost structureless and couldbe recognized-where they were cut transversely-only as roundedeosinophilic areas with no nuclei (Fig. 3). The vasa recta and capillarieswere not conspicuous and an impression was gained that there had beena decrease in numbers. At this stage it was often difficult to differentiatebetween limbs and capillaries. The covering epithelium of the papillahad disappeared in places whereas in others it contained the dropletsseen at 24 hours.

Over the next two days the picture of papillary necrosis became evi-dent. In some animals necrosis was confined to the tip, but in others itwvas more extensive. From 7 davs onwards, the whole of the papillashowed necrosis of all the constituent parts (Figure 4) with a definiteline between dead and living tissue being apparent. This line in generalcorresponded to the junction between the papilla (inner zone) and thethe inner stripe of the outer zone. Elongated cells resembling fibroblasts,and polvmorphonuclear leukocytes were present at the line of demarca-tion; in some animals there were large numbers of polvmorphonuclearleukocytes in the dead or dving papilla. The dead papilla had no cov-ering epithelium and the tubules in the papilla were recognizable onlyas emptv shells. It is of interest that apparently intact collecting ductspersisted in certain animals, in an otherwise dead papilla. The outerzone of the medulla and the cortex showed a certain degree of dilatationof tubules of all types in certain animals, but in others there was no suchchange. The papilla at this stage was grossly white and opaque.From this time on changes took place that led to separation of the

papilla. The zone of polvmorphonuclear leukocvtes became less con-spicuous but increased fibroblastic activitv produced a denser type oftissue at the junction of dead and healthy tissue. The time at whichthe papilla separated was variable; in some animals this was achievedby 14 days but in others not until 21 davs. Following separation therewas a rapid ingrowth of epithelium to cover the raw stump (Figure 5),this epithelium on occasion being several lavers thick. Collecting ductsat a later stage were seen discharging at this new surface. Considerableamounts of dense fibrous tissue developed in the stump, being much inevidence as earlv as 28 davs after administration of BEA. It was in-variably denser in the more central parts of the stump, the densitv in-creasing with time and being fully developed bv 2 months.

There were certain points of interest in the behavior of the papillaup to the time of separation. In some animals between 2 and 21 days

---

290 MURRAY ET AL American Joumalof Pathology

there was persistence of epithelium on the surface of the dead papilla.This occurred in a patchy way and sometimes there were several under-lying intact tubules. In certain animals there was a partial papillarvnecrosis and when this occurred it was usually in the central part, withintact tubules proximal, distal and lateral to it (Figure 6). One animalseen at 9 days had a remarkable heminecrosis of the papilla with a zoneof polymorphonuclear leukocytes running down the middle of thepapilla at the junction of necrotic and nonnectrotic tissue. When papil-lary necrosis occurred it was invariably bilateral and no example of aunilateral necrosis was seen.

In animals killed at later periods, say after 2 months, it was frequentto find a vellow papilla lying free in the pelvis of the kidney. This papillawas frequentlv extensively calcified.

Changes in the cortex followed those in the papilla. As early as 12hours there was in certain animals a mild dilatation of the collectingducts, but it was never extreme. Eosinophilic coagula were often presentin the ascending limbs and this change was noted as early as 24 hoursafter administration of BEA. Other changes present at this time weremild vacuolization and hyaline droplets in proximal segments, whichverv occasionally showed overt necrosis. These changes were usuallvworse in the deeper parts of the cortex. Mitotic figures in proximal seg-ments were sometimes seen at 2 to 3 davs, the sigunficance not beingfullv understood. Bv 7 davs there was a mild dilatation of other seg-ments of the tubules and the pars recta of the proximal segment wasparticularly affected. By 9 days a basophilic tint was present in theproximal convoluted tubules. This was a focal change and occurred inparticular in those nephrons whose glomeruli were situated in the deeppart of the central cortex. The change was less conspicuous in thosenephrons arising from the superficial part of the central cortex and inthose in the perihilar cortex. At this time there was dilatation, againof a focal type, in all segments of the nephron, including the pars con-voluta of the proximal segment. The basophilic change in the proximalconvoluted tubule graduallv progressed into atrophv and eventual dis-appearance in certain instances. Atrophv was clearlv apparent by 28days. The atrophic changes occurred predominantlv in the deeper neph-rons of the central part of the cortex (Figure 7) but similar atrophicchanges, although less widespread, occurred in the more superficialnephrons. By 56 days enclaves of intact nephrons could be seen in thissuperficial part interspersed among atrophic areas. The perihilar cortexvaried in its behavior. In some animals there was a virtual sparing of thisarea (Figure 8), but in others there was extensive patchy atrophy and


loss. The sparing of the perihilar cortex was often apparent even ongross inspection, the anterior and posterior surfaces at 2 months beingsmooth with depressed scarring over the greater curvature.By 28 days pale blue casts could be found within tubules. These were

sometimes large and blocked the lumen; thev were PAS positive. Astime went by, some of these pale blue structures became very large anddid not always appear to be confined to tubules. In animals of 3 months,or greater duration, cysts were often seen in the cortex, protruding outfrom the subeapsular surface. These cysts were lined by cubical epi-thelium; it is not apparent which segment of the tubule was involved incvst formation. The kidnevs at this time were often grosslv and uni-formlv scarred with large numbers of cysts being present.By 90 days, scattered glomeruli-which hitherto had not been af-

fected, apart from thickening of Bowman's capsule-showed areas ofeosinophilia such as are seen in hypertension. This change was often ex-treme in animals of over 6 months' duration. In an occasional animalnecrotizing arterial changes were found in both kidney and mesentery.These were almost certainly brought about by hypertension and bloodpressure recordings in rats with a 6 month interval following BEA ad-ministration were frequently elevated. These pressures were measuredafter cannulation of the femoral artery immediately prior to death.There was almost invariably an elevation of serum urea nitrogen tolevels of over 60 mg/100 ml in these old hypertensive animals.

50r

C 30z

0--

25

wza IC

C

I 2 3 4 5 6 7 S 9 10 11 12 13 14 15 16 17 18 19 20TIME I DAYS

TEx-r-FIG 2-Comparison of 24-hour urine output in animals receiving BEA to pro-duce papillary necrosis and in control group. Means of 10 rats in each group.

4

I

%.-^% 1^1%-, % "le

.0. -101.1,et --.41a -1 a I I

-A

-I a I I I I A I I


Urine output. The 24 hour urine output of 10 control rats on un-restricted food and water is shown in Text-fig. 2. There were slight fluc-tuations from day to dav from animal to animal and some animals pro-duced more urine than others. Only very occasionally did a rat in thisgroup produce more than 20 ml in 24 hours. By contrast the same figureshows the 24 hour urine output for a comparable number of rats withpapillarv necrosis. The output was considerabv greater although therewas a wide range of output from animal to animal. Some animals pro-duced over 60 ml of urine over a 24 hour period. The osmolalitv of theurine was invariably low when this was tested 48 hours following ad-ministration of BEA. It is of great interest that the urine output wasconsiderably elevated during the first 12 hours of collection followingthe administration of BEA, and the output during the first 24 hours wascomparable to the daily output which occurred over the ensuing sev-eral weeks. It is also of interest that we could detect no significant fluc-tuation in urinar- output during the period over which sequestrationof the papilla was taking place.No detailed study of the amount of protein in the urine was made

but there was a 2 to 4 plus recording in most animals with papillarvnecrosis.

Tests for concentration. Table 1 compares the concentrating abilityof rats with papillary necrosis-using the regimen described in an earliersection-with a group of control rats. All rats with papillary necrosishad received BEA at least 21 days beforehand so that it is a reasonableassumption that sequestration of the papilla had occurred. There is apronounced difference between the two groups, and in general theanimals with papillary necrosis were unable to concentrate above 1000milliosmoles per kg water. The table also demonstrates the significant

Table 1-Animals Deprived of Food and Water for 12 Hours; Bladder Emptied and UrineDiscarded.Urine collected over next 12 hour period during which time animals are deprived of food andwater.

Mean Urine Mean OsmolalityVolume with of Urine with SD

Number SD (ml) (mOsm/kg water)

Rats withpapillary necrosis 21 8.6 (2.8) 781 (146)

Control rats 19 2.3 (0.7) 1908 (397)

Difference between two groups for means of urine volume and osmolality statisticallysignificant (P >> .001).


difference in urine output between the two groups on the fluid and foodrestricted regimen.

Nitrogen retention. The level of serum urea nitrogen (SUN) wasdetermined at different stages in the evolution of the papillary necrosis.The level rose to a mean of 51.7 mg/100 ml (SD 21.5) after 2 months,from a pretreatment level of 19.8 mg/100 ml (SD 2.97). The level at-tained was proportional to the amount of damage in the kidnev as awhole. Very high levels of over 100 mg/100 ml were found in severalanimals allowed to survive for over 6 months. These animals had oftendeveloped hypertension by this time.

Discussion

The earlv changes, as revealed bv light microscopy, are found in thethin limbs of Henle in the renal papilla. By 48 hours there is consider-able dissolution of these structures. Changes in the collecting ducts arewell developed at 24 hours, rounded eosinophilic "droplets" appearing inthe cvtoplasm at that time. Over the ensuing few days, overt necrosisof the entire papilla takes place, with a zone of polvmorphonuclear leuk-ocvtes developing at the junction of dead and healthy tissue. WN'ith con-ventional light microscopv we have not been able to demonstrate withanv regularitv in the earlv stages an organic blockage of the vasa recta,and a similar absence of changes using the same model was describedby Fuwa and Waugh.14 Electron microscopic studies are being per-formed to study the earlv phases. We are faced with several possiblemechanisms to account for the death of the papilla; of these two seemmost likelv. In the first instance there could be a direct poisoning ofthe tubules bv the bromoethylamine. In the second, bromoethvlaminemight interfere with the blood supplv to the papilla in such a way thatnecrosis ensues. Studies were performed to determine which of thesetwo alternatives was the more likely, and a detailed account and dis-cussion of these are given in a later paper.One of the features of papillary necrosis in man is the wax in which

the cortex may also show changes. So common are these that it was onceconsidered that a chronic interstitial nephritis was the fundamentallesion in analgesic abuse.21 It is now felt that cortical changes occursecondarilv to papillarv necrosis. The current experiments show thatthe cortex becomes involved in virtually every animal with experi-mental papillarv necrosis, and this takes place only after the papillarvnecrosis is established. The changes are in some wav related to the ob-struction of nephrons in a manner akin to those seen in the cortex fol-lowing obstruction to the urinarv tract. It is unlikely that the obstruc-


tion is in the collecting ducts; the reasons for believing this are asfollows. First, if cortical changes were brought about by obstruction tothe collecting ducts passing through the necrotic papilla, it would beanticipated that they would be diffuse, as all nephrons have a final com-mon pathway through the ducts of Bellini that discharge on to thepapillary tip. As described earlier, the changes are not diffuse. Second,the tremendous output of urine from the first day onwards would ar-gue against any significant obstruction to the collecting ducts. Presum-ably in the early stages, before sloughing of the papilla takes place,urine can pass freely down dead conduits: in the later stages, after thepapilla has become detached, urine is discharged into the renal pelvisfrom collecting ducts which end at the proximal papillary stump. Webelieve it is much more likely that the cortical changes are broughtabout by obstruction occurring in the thin limbs. In the first place thereis good histologic evidence that the limbs become necrotic within thefirst few days of obstruction and after this time they may be impossibleto identify. In the second place it is noticed that the nephrons showingmaximal changes are those arising from glomeruli in the deeper partof the central cortex. In contrast less severe involvement is found inthose nephrons arising from glomeruli in the superficial part of the cor-tex over the greater curvature, and even less severe involvement maybe found in the perihilar cortex. In some rats with profound changesin the central cortex, the perihilar cortex may be virtually normal. Fromthe work of MunkAcsi and Palkovits,2 and of Wahl and Schnermann.23It is appreciated that the superficial glomeruli have loops which do notas a rule descend into the papilla. In contrast the deeper glomeruli havelong thin limbs which descend into the paplla.22 Interference with thecontinuity of the long thin limbs which reach the papilla would pro-duce changes in the tubules arising from the deeper glomeruli, whereasthe tubules arising from the superficial areas would be relatively spared.This, in fact, was the finding in the experiment, although the degree ofdamage to tubules arising from superficial glomeruli was greater thananticipated. It should be noted that Lechene et al.24 described that19.8% of the superficial glomeruli had long loops of Henle. This wouldfit our data much better. There is unsufficient information in the lit-erature on the length of thin limbs of nephrons in the perihilar cortex,but because of the fewer changes in this area we would predict thatthe majority are short and do not descend into the papilla. The pro-posed sequence is shown in Text-fig. 3.The less severe involvement of the perihilar cortex could alternatively

be explained by obstruction to collecting ducts in the following way.


1 2 3

TEXT-FIG 3-Explanation of involvement of deeper glomeruli in central cortex. a, b,and c = those in perihilar cortex. 1, 2 and 3 are different stages in time.himbs. a = those in outer part of central cortex, b = those in deeper part of central cortex,and c = those in perihilar cortex. 1, 2 and 3 are different stages in time.

If we accept for the moment that the cortical changes are secondary- toblockage of collecting ducts (we have explained wbhy we are reluctantto do this) then there must be some less severe involvement of thecollecting ducts draining the perihilar cortex. It is conceivable that thiscould happen if a greater degree of fibrosis were produced in the cen-tral part of the remaining papillary stump compared with the moreperipheral part where the collecting ducts from the perihilar cortexdischarge their contents in the newly created situation. Fibrosis in thecentral part of the stump does indeed appear denser than that at theperiphery in most animals (Text-fig. 4). However, the objections to thisidea are, first, the way in which the superficial nephrons from thegreater curvature or central cortex are frequently spared; these drainthrough the more fibrous part. Second, atrophy of proximal convolutedtubules begins to occur at a time before which there is any great degreeof fibrosis in the stump.

It is of considerable interest to consider the distribution of corticalchanges in man. As in the rat there is maximal damage in that part ofthe cortex directly overlying the damaged papilla. In contrast the col-

TEXT-FIG 4-Alternative explanation for greater involvement of central cortex. Collect-ing ducts from perihilar cortex (PHC) traverse less fibrotic area than those from centralcortex (CC).

I

296 MURRAY ET AL American Joumalof Pathology

umns of Bertin are frequentlv spared, the columns of Bertin being theanalogue in the multipapillary kidney of the perihilar cortex in the uni-papillary kidnev. This sparing of the columns of Bertin has been com-mented on by both Kincaid-Smith 25 and by Burry.10 They regard thecortical changes are resulting from obstruction bv the necrotic papilla.Kincaid-Smith25 points out the lateral disposition in the papilla of thecollecting ducts from the columns of Bertin, and goes on to explain thesparing of the columns by a reestablishment of connection of their col-lecting ducts with the newly formed calyceal cavity following papillarynecrosis. We have had insufficient experience of analgesic papillarvnecrosis in man to enable us to comment on this. A very large numberof cases studied at different stages would be required to substantiatethis thesis, but by analogy with the experimental model we would con-sider obstruction to thin limbs a more plausible concept. It is apparentthat the main reason for differing explanations is the lack of informa-tion available on the distribution in the different part of the cortex ofnephrons with thin limbs which descend into the papilla comparedwith those with short limbs.The functional data are of interest in several respects. In the first

instance the tremendously increased urine output occurs within a shorttime after administration of BEA, indicating that some defect in theconcentrating mechanism has occurred very early and at a time beforethere are any anatomical changes detectable by light microscopv. Fur-ther evidence that a concentrating defect occurs within a few hoursafter administration of BEA will be presented in a later paper. Thehigh output of urine continues over the next few days and, as com-mented earlier, the urine must be transmitted along dead collectingducts until such time as sequestration occurs. From this time onwardurine is discharged from shortened collecting ducts which open on tothe reepithelialized stump of the papilla. In view of the fact that thepapilla has by this time disappeared, it is probable that all the urine isbeing produced by nephrons which have short thin limbs, ie-thosethat do not descend into the papilla and which have therefore not hadtheir continuity interrupted. This idea could be countered by sup-posing that thin limbs might discharge directly on to the surface ofthe papillary stump. W\e have seen no morphologic evidence for thisand it seems unlikely that the delicate thin limbs could traverse thedense fibrous tissue present in the stump.The defect in concentration is predictable because the structures

necessary to effect the counter current mechanism have been elimi-nated; at the time the tests were performed the animals were without


their papillae. No concentration tests were performed in the early stagesof papillary necrosis, but casual determinations of urine osmolality 48hours following administration of BEA showed extremely low values.At this time the limbs of Henle were necrotic and the collecting ductsshowed an accumulation of PAS-positive droplets. There is therefore atthis time, and at 24 hours, morphologic evidence by light microscopy ofdamage to the structures concerned with the concentration mechanism.

References1. Edmondson HA, Martin HE and Evans N: Necrosis of renal papillae and

acute pyelonephritis in diabetes mellitus. Arch Intern Med 79:148-175, 19472. Robbins SL, Mallory GK and Kinney TD: Necrotizing renal papillitis: A

form of acute pyelonephritis. N Eng J Med 235:885-893, 19463. Spiihler 0, and Zollinger HU: Die chronisch-interstitielle Nephritis. Z Klin

Med 151:1-50, 19534. Zollinger HU: Chronische interstitielle Nephritis bei Abusus von phenacetin-

haltigen Analgetica (Saridon usw). Schweiz Med Wochenschr 85:746, 19555. Lindeneg 0, Fischer S, Pedersen J, and Nissen NI: Necrosis of the renal

papillae and prolonged abuse of phenacetin. Acta NMed Scand 165:321-328,1959

6. Gloor F: Vber verschiedene Formen der Papillennekrosen der Nieren. PatholMicrobiol (Basel) 23:263-272, 1960

7. Hultengren N: Renal papillary necrosis: A clinical studv of 103 cases. ActaChir Scand [Suppl] 277:1-84, 1961

8. Bengtsson U: A comparative study of chronic non-obstructive pyelonephritisand renal papillary necrosis. Acta Med Scand [Suppl] 388:1-71, 1962

9. Harvald B: Renal papillary necrosis: a clinical survey of sixty-six cases. Am JMed 35:481-486, 1963.

10. Burrv AF: The evolution of analgesic nephropathy. Nephron 5:185-201,11. Jacobs LA and Morris JG: Renal papillary necrosis and the abuse of phena-

cetin. Med J Aust 2:531-538, 196212. Burry AF, de Jersey P and Weedon D: Phenacetin and renal papillary

necrosis: results of a prospective autopsy investigation. Med J Aust 1:873-879, 1966

13. Oka A: Zur histologie der vinylaminnephritis. Virchow Arch [Pathol Anat]214:149-160, 1913

14. Fuwa M and Waugh D: Experimental renal papillary necrosis. Effects ofdiuresis and antidiuresis. Arch Pathol 85:404-409, 1968

15. Chuchani G: Directing and activating effects. The Chemistry of the AminoGroup. Edited by S Patai. Rexdale, Ontario, John Wilev and Sons Canada Ltd,Interscience Publishers, 1968 p 205

16. Salomon G: Kinetics of ring formation and polymerisation in solution. TransFarad Soc 32:153-178, 1936

17. Peter K: Untersuchungen fiber Bau und Entwicklung der Niere. Jena,Gustav Fischer, 1927


18. Mfoffat DB: The fine structure of the blood vessels of the renal medullawith particular reference to the control of the medullary circulation. J Ultra-struct Res 19:532-545, 1967

19. Moffat DB and Fourman J: The vascular pattern of the rat kidney. J Anat97:543-553, 1963

20. Kriz WV and Lever AF: Renal countercurrent mechanisms: structure andfunction. Am Heart J 78:101-118, 1969

21. ZoIlinger HU and Spiihler 0: Die nicht-eitrige, chronische interstitielleNephritis. Schweiz Z Allg Pathol 13:807-811, 1950

22. Munkalcsi I and Palkovits NI: Study on the renal pyramid, loops of Henleand percentage distribution of their thin segments in mammals living indesert, semi-desert and water-rich environment. Acta Biol Acad Sci Hung17:89-104, 1966

23. Wahl M and Schnermann J: Microdissection study of the length of differenttubular segments of rat superficial nephrons. Z Anat Entwicklungsgesch 129:128-134, 1969

24. Lechene C, Corby C and Xiorel F: Distribution des nephrons accessibles ala surface du rein en fonction de la longueur de leur anse de Henle cbez lerat, le hamster, le merion et le psammomys. C R Acad Sci [D] (Paris) 262:1126-1129, 1966

25. Kincaid-Smith P: Pathogenesis of the renal lesion associated with the abuseof analgesics. Lancet 1:859-862, 1967

AcknowledgmentDr. Mfurray is a Kellogg Fellow; his present address is Casilla 6539, Correo 4, Santiago,

Chile.

1

2

Fig 1-Section through papilla in proximal part of distal one-third. CollecUngtubules contain granules of varying size (Martius scarlet, x 750).Fig 2-Section through midportion of papilla at 24 hours. Casts are seen inlimbs of Henle. No appreciable change in collectng tubules at this level (H&E,x 400).

W- -zie4.-A I-z

.- .C.

N!"-

4

----I

Fig 3-Section through midportion of papilla at 48 hours. Complete necrosisof limbs of Henle. Collecting tubules of this size, which are smaller than inFig 1 contain barely discemible fine granules (H&E, x 200).Fig 4-Necrotic papilla at 7 days. The covering epithelium is lost and, in thedistal part, empty shells of tubules can be seen. Necrosis is most apparent inthe more proximal part. The zone of polymorphs at the junction of live and deadtissue can be partially seen in the bottom left corner (H&E, X 40).

3

4

-

I

I

A

r

'46--

e.

Fg -Stump of papilla at 56 days to show how the raw surface has beencovered by epithelium. Some areas of dense interstital tissue can be seen andthere is mild tubular dilatation. The remains of the distal part of the papillacan still be seen, one small fragmfent being adherent to the stump (H&E, x 175).Fig 6-Papilla at 18 days to show how occasionally the necrosis is confined tothe central part, sparing the tip and peripheral part (H&E, x 50).

5

6

7

8

Fig 7-Section through deep part of central cortex at 2 months. There is con-siderable tubular loss and atrophy. Some tubules are much dilated (H&E, x 200).Fig 8-Section through perihilar cortex at 2 months. Glomeruli and tubules arepreserved (H&E, x 200).

Experimental Papillary Necrosis of the Kidney

Documents

Transcript of Experimental Papillary Necrosis of the Kidney