RENAL PAPILLARY NECROSIS

By DAVID SWARTZ, F.R.C.S.E., F.R.C.S.(C.) Assistotit Professor. oJ’ Siirgery (Urology), Ut7iiwr.sity of’ Manitoba

and JAN HOOGSTRATEN, M.D., Ph.D. Assistant Prof’essor of Potliology, University of’ Mrrnitolm

RENAL papillary necrosis is a necrotic lesion of the renal papilla3 extending into the subjacent pyramids. This disorder was first described in 1877 by von Friedreich. The association of papillary necrosis with diabetes mellitus was first emphasised by Gunther i n 1937, and since then this observation has been noted by others. The literature on this subject has been adequately reviewed by other writers (Mandel, 1952; Silberstein and Paugh, 1953). It is estimated that approximately one-fifth of all diabetics have acute renal infection terminally and of these approximately one-fourth have renal papillary necrosis (Robbins et a/.. 1946 ; Edmondson et a/., 1947; Robbins and Angrist, 1949; Whitehouse and Root, 1956). I t is therefore probable that the incidence of this disease is far greater than would appear from the number of recorded cases. Necrosis of renal papilla: may also occur in non-diabetic subjects with chronic obstruction of the lower urinary tract (Robbins and Angrist, 1949; Simon et a/., 1957). Of 180 cases published up to January 1953, only 10 per cent. revealed no evidence of either diabetes mellitus or urinary tract obstruction (Mandel, 1953). The vast majority of reported cases of papillary necrosis have been bilateral and discovered at autopsy. Unilateral renal papillary necrosis is relatively rare, as indicated in a recent review of the literature by Sargent and Sargent (1955).

This study is based upon our experience with seven cases of renal papillary necrosis, three of which were recorded by one of us in a previous report. Of this group there were three diabetics with non-obstructive pyelonephritis. One occurred in a non-diabetic with non-obstructive pyelonephritis. Another case was that of a non-diabetic who had been subjected to trauma and shock. Two occurred in infants as a result of renal vein thrombosis without evidence of urinary tract infection or obstruction. In one of the diabetic patients papillary necrosis was definitely .a unilateral lesion and in another diabetic the lesion was most probably unilateral. Of the seven reported cases there were six females and one male.

The three previously reported cases are herewith summarised with a follow-up on Case 1 .

Case J .-Mrs E. A., aged 64, had been treated for fourteen years for diabetes niellitus, developed persistent and uncontrollable urinary tract infection and left loin pain. Urographic investigation showed changes in the left kidney resulting from renal papillary necrosis, the right kidney was normal. Left nephrectomy, performed in February 1951, resulted in recovery from urinary infection and a more easily controlled diabetic state. Examination ,of the resected kidney revealed chronic pyelonephritis, renal papillary necrosis, arterial and arteriolar nephrosclerosis. She again fell i l l in October 1954, and died on 30th November 1954, almost four years after nephrectomy. Autopsy revealed a ruptured empyema of the gall-bladder and local peritoneal abscess. Other findings consisted of cholelithiasis, septic splenitis, furunculosis, and diabetes niellitus.

Descriptiotz of Right Kidney.-The remaining kidney showed no evidence of papillary necrosis or pyelonephritis .other than a slight infiltrate of lymphocytes and plasma cells within some areas of the interstitial tissue. There was a noticeable degree of hyaline thickening of some arterioles and some of the gloiiierular tufts appeared atrophic. There was a moderate degree of arteriosclerosis within the larger arteries.

Case 2.-Mrs F. M., aged 65, had been treated for twelve years for diabetes niellitus. She developed an Excretory urography

Retrograde urography revealed a structurally ancontrollable urinary infection and examination revealed a tender mass in the left loin. revealed a non-visualising left kidney and a normal right kidney.

Read at the Fifteenth Annual Meeting of the British Association of Urological Surgeons (combined meeting with the Canadian Urological Association) at Glasgow, July 1959.

419

420 B R I T I S H J O U R N A L O F U R O L O G Y

normal right kidney and changes in the left kidney resulting from renal papillary necrosis. Left nephrectoniy resulted in rapid recovery, but three months later the patient succumbed to a cerebrovascular accident. An autopsy was not performed. Examination of the resected kidney revealed chronic pyelonephritis, renal papillary necrosis, and diabetic nodular glomerulosclerosis.

Case 3.-Baby girl J. W. was a healthy infant until 5 months of age, then failed to develop normally. At I5 months of age she developed persistent fever, with cerebral symptoms. An exploratory craniotomy performed because of suspicion of subdural hreniatonia revealed no hzmatonia but diffuse cerebral atrophy. Autopsy revealed Pseudoomonas aerirginosa meningitis, moderate cerebral atrophy, and bilateral renal papillary necrosis. I n this case the disease was not associated with inflammatory disease of the kidney, urinary obstruction, o r diabetes mellitus, but was associated with thrombosis of the renal and intrarenal veins.

The following four cases have not been previously reported and will be described in greater detail.

Case 4.-Miss K . S., aged 40, was first admitted lo Grace Hospital, Winnipeg, in September 1953 with diabetes mellitus and acute gastro-enteritis. Following several admissions for diabetes and its complications she first developed urinary infection in December 1957. During her final admission to hospital in February 1958 she was referred to one of us for urological investigation. She complained of vomiting, diarrhea, and pain in the left loin. She gave a history of repeated gastro-intestinal upsets during her long period of illness, but this was the first time that pain was localised to the left loin.

Physical examination revealed an alert young woman whose complaints of persistent nausea, with occasional vomiting, overshadowed all other symptoms. Her temperature and pulse were normal and blood-pressure 160184 mm. Hg. Left renal percussion and palpation revealed a moderate degree of tenderness in this region. The abdomen was otherwise negative. The heart and lungs were normal and there were no abnormal neurological findings. Examination of eye grounds revealed evidence of diabetic retinopathy. Her fasting blood sugar ranged from 154 mg. to 337 mg. per cent. Serum protein was 6.6 per cent., blood urea nitrogen was I I mg. per cent., h;emoglobin was 67 per cent. Excretory urography on 12th December 1957 showed normal structure and function of both kidneys with right renal ptosis. Cystoscopy on 20th March 1958 showed a mild degree of cystitis. A specimen of urine from the left kidney was turbid and filled with pus cells. A specimen of urine from the right kidney was clear and contained only a few pus cells. Stained smear of left kidney urine showed a Gram-negative bacillus and on culture grew Eschrrichia coli sensitive to aureomycin, terramycin, tetracycline, furadantin, and gantrisin. Stained smear of right kidney urine revealed Gram-negative bacilli and on culture grew Aem/mrer. crewgenes sensitive to the same drugs. Retrograde pyelography revealed no structural changes.

In spite of treatment with various drugs in accordance with sensitivity of the offending organism, pyuria persisted, the patient’s general condition deteriorated, and her diabetic state became increasingly difficult to control. On 7th May 1958 serum protein was 5.6 per cent. and blood urea nitrogen 52 mg. per cent. She developed multiple cutaneous furuncles from which Staphjhcoccus ~ U Y ~ U S was isolated. For the last few days before her death she had a mounting septic temperature and she died on 26th May 1958.

Each pleural cavity contained 75 ml. of pus, and there were numerous subpleural abscesses within each lung. The heart weighed 235 g. and exhibited no evidence of hypertrophy. The spleen was moderately enlarged and exhibited a septic splenitis.

The external surfaces of each kidney were prominently hyperzmic with areas of Qallid mottling. On section both kidneys, but more particularly the left. contained multiple abscesses located in the immediate vicinity of the pyramids, which appeared necrotic and yellowish in colour. Microscopically the kidneys exhibited advanced necrotising renal papillitis (Fig. I ) . The renal papillre were completely necrotic and only faint outlines of the tubules were still visible. The interstitial tissue was infiltrated with lymphocytes and plasma cells, and in some areas with neutrophile polyniorphs, the infiltrate extending for a variable distance into the cortex. There was minimal if any evidence of arteriolar thickening, though some glomerular tufts appeared atrophic, and some were completely hyalinised. The interlobar arteries exhibited a moderate degree of arteriosclerosis. Lakes of hzmolysed erythrocytes were present within dilated capillaries in the interstitial tissue in the juxtamedullary region, but no evidence of vascular thrombosis was evident. A few staphylococci were evident within the necrotic papi lk . Post-mortem culture of lung abscesses and the necrotic renal papilk grew coagulase-positive hzmolytic staphylococci, with lesser numbers of Esch. coli. Changes characteristic of diabetes mellitus were present within the pancreas.

Ao/opsy.-Furuncles were present on the anterior abdominal wall and dorsum of left wrist.

Each kidney weighed 235 g.

Case 5.-Mrs S. B. , a 54-year-old woman, mother of three children, was admitted to hospital on 30th May 1958. She complained of epigastric discomfort, weakness, tiredness, insomnia, loss of appetite, and numbness of her fingers with weakening of her grasp. She had had several previous admissions to hospital, the first in May 1954, when she had a partial gastrectonly for chronic peptic ulcer. She had subsequent admissions to hospital for a moderate hypochroniic anreniia.

She also stated that her right loin had recently become painful.

R E N A L P A P I L L A R Y N E C R O S I S 42 I

Examination revealed a thin pale woman, somewhat listless and apathetic. Her blood-pressure was lSO/lOO mm. Hg. She had a swinging temperature with a peak of 103" F. Urine was turbid and contained large numbers of pus cells. She had tenderness in her right loin elicited by palpation and percussion. Red blood cell count 4,500,000 ; hienioglobin 66 per cent. ; leucocyte count 9,800 : sedimentation rate 104 mm. Excretory urography revealed diminished concentration and delayed excretion, more marked on the right side. Cystoscopy on 13th June 1958 revealed a mild degree of cystitis ; both ureteral orifices were normal and there was no obstructive uropathy. Urinary specimen from the right kidney was turbid and contained numerous pus cells. On culture i t grew Esch. coli insensitive to all drugs tested. The left kidney urine was niicroscopically negative and revealed no growth on culture. Bladder urine contained numerous pus cells and bacteria ; p H 5.5 ; albumin 60 mg. per cent. : sugar negative ; culture revealed Buci//us profrus sensitive to gantrisin and furadantin, and Esch. coli insensitive to all drugs tested. Right retrograde pyelogram revealed first-degree hydronephrosis and renal ptosis. Left retrograde pyelogram revealed cavitation of the upper minor calyx (Fig. 2) resembling tuberculosis, but there was no bacterial evidence of urinary tuberculosis. This picture was somewhat confusing because of the nornial

FIG. 1 FIG. 2

Fig. I.-Case 4. Complete necrosis of renal papilla. (PAS.) ~ 4 . 9 . Fig. 2.-Case 5. Retrograde pyelogram showing cavitation o f upper minor calyx of left kidney

resulting from sequestration of papilla.

state of the left kidney urine and lack of localising symptoms. She was discharged from hospital and readmitted o n 9th August 1958 following a n unsuccessful course of therapy. Her condition had deteriorated considerably. This time she complained of pain in the left loin. Blood-pressure was 94/64 nim. Hg and pulse 84 ; temperature normal ; blood urea nitrogen 79 nig. per cent. : urea clearance 7 per cent. : hremoglobin 44 per cent. ; leucocyte count 22,800 ; sedimentation rate 125 niiii. Bladder urine contained numerous pus cells. Culture revealed Esch. c d i , slightly sensitive to chloromycetin and streptomycin but resistant to all other drugs tested. X-ray of chest revealed apical pleural thickening and clear lung fields. She died on 25th August 1958, three months after the onset of urinary symptoms.

Autopsy.-Lungs and pleura are normal and the heart exhibits no evidence of hypertrophy. Kidneys : The left kidney weighs 200 g. and the right 170 g. The capsule of the left kidney strips with some

difficulty, leaving a grey pink surface which is studded by many small yellowish-white abscesses measuring up to 0.3 cni. in diameter. Section (Fig. 3) reveals many similar abscesses scattered throughout the cortex and medulla. Several of the papillae appear a t least partially necrotic, and greyish brown in colour, with a prominent zone of hypermiia bordering the viable portion. Turbid purulent fluid flows freely from the cut surface and fills a slightly dilated pelvis. The pelvic mucous membrane is only slightly hyperlenlic and greyish in colour. The capsule of the right kidney also strips with some difficulty, again revealing many small yellowish-white abscesses on the cortical

422 B R I T I S H J O U R N A L O F U R O L O G Y

FIG. 3 Case 5. Necrotic papilla: within left kidney with small cortical and medullary abscesses.

surface measuring up t@ 0-3 cm. in diameter. The right kidney appears somewhat more mobile than normal, and its lateral surface is rotated anteriorly. Section (Fig. 4) reveals only a moderate degree of dilatation of the pelvis, but several of the renal pyramids appear completely necrotic. Some, having a soft brownish appearance, lie free within the calyces and pelvis. The renal arteries are patent and contain a minimal degree of atheroma, though there is some degree of narrowing at their entrance into the renal pelvic tissues. The mouths of the renal arteries are patent and normal.

Microscopically, the renal papilla are completely necrotic and all cytological detail is lost, but the outlines of the collecting tubules are still evident. The calyceal niucosa adjacent to the necrotic papilla: is heavily infiltrated with neutrophile polyniorphs, lymphocytes, and plasma cells, and there are collections of purulent material in some areas between the viable portions of kidney and the necrotic papilla. Foci of purulent inflammation extend into the renal cortex, and there are occasional fibrous scars within the cortex consisting of relatively delicate fibrous tissue infiltrated with lymphocytes, plasma cells, and histiocytes. The glomerular tufts exhibit normal histology, and there is no thickening of their capsules even in the areas immediately adjacent to the cortical fibrous scars. There is no evidence of hyaline thickening of arterioles and there is a minimal to moderate degree of arteriosclerosis within the interlobar arteries. There is no evidence of thrombosis of veins or intertubular capillaries, even in those areas immediately adjacent to the necrotic papilla. Colonies of bacilli are present within the necrotic papilla. In a few small foci, there is evidence of epithelial regeneration between the necrotic and non-necrotic portions of the renal medulla. The degree of inflammatory infiltrate in the viable portions of renal medulla adjacent to the necrotic papilla is relatively small, and it seems difficult to ascribe the necrosis of the papilla to this infiltrate.

Amtoniical Diugnosis.-( I ) Bilateral renal papillary necrosis ; (2) bilateral purulent pyelonephritis ; 43) urzmia ; (4) acute pancreatitis ; ( 5 ) partial gastrectomy.

’

Case 6.-D. C., a 10-month-old baby boy was admitted to hospital with febrile convulsions following a two-day illness described as a cough and cold. His convulsions persisted for a period of three hours despite the

R E N A L P A P I L L A R Y N E C R O S I S 423

administration of luniinal, ether anresthesia, and pentothal. On admission, his temperature was 106" and his right lung contained rales and rhonchi. When his convulsions stopped, t h e child remained unconscious and continued to show little response until his death ten days later. An X-ray of the chest on admission to hospital revealed increased density radiating out from the right root shadow. A urinalysis on admission to hospital revealed no abnormality, but further urinalyses were not performed.

Aufopsy.-Autopsy revealed purulent mucus in the upper respiratory tract, but no inflammatory infiltrate in the respiratory niucosa or lungs. The child died as a consequence of thrombosis of intracranial venous sinuses and thrombosis of the renal and intrarenal veins.

A good airway, however, was maintained.

FIG. 4 Case 5. Necrotic papillle within right kidney. The lower figure shows cavitation resulting from sloughing

of involved papilla.

Kidneys : The left weighs 48 g. and the right 64 g. (normal weights of each kidney approximately 36 g.). The renal veins are both obstructed by a moderately lirm greyish-red thrombus. The thrombus within the right renal vein extends for a few niillimetres into the lumen of the inferior vena cava. Firm greyish thrombus extends into the interlobar and even arcuate veins. There are yellowish areas of necrosis within two of the renal papillre of the right kidney, and a similar area within one of the papi lk in the left kidney. The necrosis involves the central portioi of the papilk, leaving a thin peripheral rim of viable tissue. The edges of the necrotic areas are hyperreniic. The cortical and medullary markings are distinct, and the cortex and medulla are of normal thickness. The pelvis and ureters are not dilated, and the mucous membrane is pale, smooth, and glistening.

The urinary bladder contains approximately 5 nil. of clear straw-coloured urine. The bladder niucosa is pale and wrinkled. The prostate is of normal size, glistening white colour and firm consistence.

Microscopically (Figs. 5 and 6), sections show thrombosis of the interlobar veins which are distended and filled with fibrin in which are enmeshed numerous leucocytes. There is no inflammatory infiltrate within the walls of the veins themselves. In some areas similar thrombus lies within arcuate veins and the smaller interlobular veins Qf the cortex. The small intertubular capillaries in the pyramids are engorged, with evidence of erythrocytes lying outside the lumen of the vessels. Similar engorgement is seen within small capillaries within the cortex. The central portion of some pyramids exhibits complete necrosis, but there is no inflammatory reaction at the edges

424 B R I T I S H J O U R N A L O F U R O L O G Y

of the necrotic foci. The glomeruli, arterioles, and small arteries are normal. There is a slight degree of dilatation of some convoluted tubules, which is somewhat more marked in the distal convoluted tubules than in the proximal. There is evidence of hyaline droplet formation in some of the epithelial cells of the proximal convoluted tubules. Some epithelial cells have pyknotic nuclei, and shrunken eosinophilic cytoplasm.

Case 7.-Mrs Y . P., aged 38, had been severely beaten by her husband on 28th March 1959 and fell down a flight of stairs, but was not rendered unconscious. She remained at home till 30th March, then came to the casualty department of the Winnipeg General Hospital in a state of shock. She was semi-comatose, pale, perspiring, and covered with multiple bruises. Her pulse was rapid and systolic blood-pressure was 70 mm. mercury. Four pints of emergency blood were required to retrieve her from shock, her blood-pressure rose to 140/100 mm. Hg, and pulse-rate came down to 92. Physical examination revealed a tender mass in the region of the right kidney while

FIG. 5

examination of the left side was not remarkable.

FIG. 6

Fig. 5.-Case 6. Thrombosis within interlobar, arcuate, and some interlobular veins. Ischiemic necrosis of central portion of renal

papilla with no inflammatory infiltrate. ( H . R: E.) x4.9. Fig. 6.-Case 6. Necrosis of central core of renal papilla without inflammatory infiltrate. Thrombosed interlobar veins are visible in

lower corners o f illustration. (H. & E.) x 15.

A flat X-ray film of the abdomen suggested a mass on the right side and the right psoas shadow was blurred. The left renal shadow appeared to be enlarged. Urinalysis revealed numerous pus cells and red blood cells. Blood urea nitrogen on admission was 65 mg. per cent. Urinary output became progressively smaller and B.U.N. increased. On 2nd April 1959 her B.U.N. was I14 mg. per cent. In view of the rising B.U.N. and oliguria it was deemed advisable to expose surgically the right kidney with a view to exploration and release of tension. Accordingly the right kidney was exposed through an extraperitoneal loin incision. A fairly extensive retroperitoneal hzmatoma was noted at the upper pole of the kidney pushing it in a downward direction. The kidney was enlarged and tense and gave the impression of a fluid mass, but needling indicated that the mass was solid. Decapsulation was carried out resulting in expansion of the kidney towards the surface of the wound. A good deal of clot was evacuated from the region of the upper pole and the area was packed to prevent further bleeding. Renal biopsy taken at this time revealed an inflammatory reaction and partial necrosis of the tissue adjacent to the trauinatised upper pole. The wound was drained and sewn up in layers.

The immediate post-operative course was satisfactory. Urinary output rose to a height of 1,000 ml. for a twenty-four-hour period with a fixed specific gravity of 1,010 and 1,011, and her general condition improved. This only lasted a few days when the B.U.N. continued to climb and her general condition began to deteriorate.

Urinary cultures revealed Gram-negative bacilli (Esch. coli) and Bacterium aerogenes sensitive to mandelaniine and furadantin.

Management consisted of intravenous electrolyte therapy designed to correct hyponatrremia and hypochlormiia. Fluid intake was balanced against estimated total output. Glucose solution (SO per cent.) in distilled water was instilled into the superior vena cava through a polyethylene tube and packed blood cells given to make up the blood volume. Steroid preparations (solucortef) were administered intramuscularly.

She died in urzmia on 15th April 1959.

R E N A L PAPILLARY N E C R O S I S 425

Autopsy.-Each kidney weighed 200 g. (Figs. 7 and 8). The upper pole of the right kidney revealed an extensive laceration measuring 4 by 3 cm. It had been decapsulated but a secondary capsule had formed about the kidney within an extensive enveloping hmnatoma. The surrounding hzmatoma extended from the head of the pancreas superiorly and over the lateral wall of the pelvis inferiorly, and was filled with great quantities of

FIG. 7 FIG. 8

Fig. 7.-Case 7 . Fig. S.-Case 7 .

Laceration of upper pole of right kidney and necrosis of renal papilk. Opaque ischamic necrosis of renal papilk, left kidney.

FIG. 9 FIG. 10

Fig. 9.-Case 7. Small focal area of necrosis within renal papilla containing nuclear debris hut no inflammatory infiltrate. The lumen of some collecting tubules contains cell debris probably derived

from more proximal portions of the nephron. (H. & E.) Fig. 10.-Case 7. Larger confluent area of necrosis within renal papilla containing cell debris

x 128.

hut no inflammatory infiltrate. (H. & E.) x 67.

both changed and necrotic hzmatoma and free blood. Section of the kidney revealed yellow necrosis of all the renal papillze extending almost to the cortico-medullary junction. The left kidney was tense within its enveloping capsule and section showed similar yellow necrosis involving almost all papi lk . The cortex was pale and bile-stained. Both ureters were patent but surrounded by blood clot, making dissection difficult.

The hzmatoma surrounded the renal pedicle.

In addition, portal cirrhosis, urzmic pericarditis, and evidence of peripancreatic fat necrosis were present. Mievoscopic.--ln the renal papillz which are completely necrotic, all cytological detail has been lost, and only

the faint outlines of tubules are visible. Necrosis extends from an area 2 to 4 mm. distal to the arching of the arcuate vessels, to the tip of the involved papillae. Although the lumina of tubules in the necrotic papillz contain amorphous debris, there is minimal evidence of the remains of an effete inflammatory infiltrate in the interstitial tissue of that structure. Considerable karyorrhectic debris, however, lies at the junction between the necrotic papillz and the adjacent viable renal medulla, but is sharply limited to that region, with only a slight infiltrate of

426 BRITISH J O U R N A L OF U R O L O G Y

lymphocytes, histiocytes, and plasma cells adjacent to it. The intertubular capillaries just distal to the cortico-medullary junction are engorged, with hzmorrhage into the interstitial tissue.

Some renal papilla: are not completely necrotic, but contain quite sharply circumscribed variably sized focal areas of necrosis. There is no inflammatory infiltrate within these papillie except for the presence of karyorrhectic debris within the areas of necrosis (Figs. 9 and 10).

Although the intertubular capillaries, particularly in the zone just distal to the level of the arcuate vessels, are engorged, the capillary tufts of the glomeruli contain few erythrocytes and appear largely collapsed. N o other pathological changes are seen within the glomeruli, arterioles, or arteries.

The lumina of some of the proximal convoluted tubules are dilated, but the epithelium for the most part appears normal. Much of the epithelium of distal convoluted tubules, however, exhibits vacuolar or hydropic change (Fig. 11) . The lumina of some of the distal convoluted tubules contain karyorrhectic debris, but this is most prominent in the more distal portions of the nephron. There is a minimal infiltrate consisting of a few lymphocytes, rare plasma cells, and histiocytes in the interstitial tissue of the cortex.

Fiti. I I FIG. 12

Fig. 1 I .-Case 7.

Fig. 12.-Case 1. Surgically resected kidney. Subintimal thickening of calyceal vein. (PAS.) x 53.

Vacuolar change within epithelium of distal convoluted and straight tubules. Epithelial cells shedding into lumen of straight tubules. (H. & E.). x 67.

There are prominent yellowish crystals of variable size lying within the luniina of tubules, most prominent within the distal nephron, and lying also within the lumina of tubules in the completely necrotic papillie. These crystals are doubly refractile in polarised light, and morphologically resemble urates, although histochemical studies have not yet been performed.

There is no inflammatory infiltrate within the calyceal inucosa other than a very minimal number of lymphocytes and plasma cells.

The site of the subcapsular traumatic laceration exhibits necrosis and organising hiemorrhage. There is only slight evidence of interstitial cedema at the cortico-medullary junction.

PATHOGENESIS

Numerous theories have been advanced regarding the pathogenesis of renal papillary necrosis. and these have been adequately reviewed by Sheehan (1957), Edmondson et al. (1947), Robbins and Angrist (1949), and others. In an investigation of the possible mechanisms producing this lesion, the following features may be noted :

I . In renal papillary necrosis the necrotic lesion does not necessarily involve the whole extent of the renal papilla. Small focal areas of necrosis may appear within the central portions of the papilla, while more extensive lesions will involve the whole papilla.

2 . Renal papillary necrosis does not necessarily involve all papilh within the affected kidney. and the lesion may be unilateral.

R E N A L P A P I L L A R Y N E C R O S I S 427

3. Renal papillary necrosis is not necessarily incompatible with life, for there may be a noticeable variation of extent of this lesion. Only those individuals who die as a result of renal papillary necrosis will exhibit extensive lesions, and even in these patients there may be evidence of a prominent degree of healing characterised by re-epithelialisation of the remaining basilar portion of the papilk, indicating that the patient had survived necrosis and sloughing of the papilla for some time.

4. Pyelonephritis is an almost but not completely constant accompanying lesion of fatal renal papillary necrosis, and is usually considered a major cause of the necrosis. While it is tempting and facile to assume that necrosis of the renal papillz is consequent to the inflammatory process, this is not substantiated by histological evidence, for it is remarkable how infrequently one will discover the remains of an effete inflammatory infiltrate within the necrotic papillre despite the fact that the architecture of those structures remains quite intact. Also, t h e inflammatory infiltrate at the base of the non-necrotic papillz may be as severe as that at the base of the necrotic papilla (Swartz, 1954). In addition, papillary necrosis is many times more common in diabetic patients than in non-diabetic pyelonephritics, despite the fact that the inflammatory process i n non-diabetics may be as severe as in the diabetics.

If one reiterates the features noted in paragraphs I , 2, and 3, there may be some justification in assuming that variable degrees of necrosis of the renal papillre may lead to hzmatogenous pyelonephritis rather than the reverse, and it is evident that factors other than pyelonephritis must be sought to explain the genesis of this renal lesion.

5. Bilateral papillary necrosis without pyelonephritis has on rare occasions been noted in non-diabetics. I n two such examples in infants (Cases 3 and 6) thrombosis of renal and intrai-enal veins accompanied the lesion. Although this suggests that necrosis was due to vascular occlusion. i t is known that thrombosis of renal and intrarenal veins is a not uncommon pathological lesion in infants (Zuelzer et a/., 1951) but is usually not accompanied by papillary necrosis.

6. Rare instances of papillary necrosis, unaccompanied or preceded by inflammation oi- vascular abnormality, have been recorded (Sheehan, 1937). The likelihood that shock, with consequent vascular stasis within the renal medulla, may lead to papillary necrosis is a possibility which must be kept in mind in the genesis of this lesion. This is exemplified in Case 7, where shock incidental to trauma to the right kidney led to bilateral papillary necrosis in an individual having no preceding pyelonephritis, diabetes, or urinary tract obstruction. Renal papillary necrosis is also a prominent feature of the pathology of 67 per cent. of cases of epidemic hzmorrhagic fever (Hullinghorst and Steer, 1953 ; Kessler, 1953), a disease in which 65 per cent. of patients exhibit at least one episode of shock.

It appears reasonable to assume that patients already having severe renal vascular disease. such as diabetics, may be more susceptible to the development of renal papillary necrosis as a result of shock. Even the shock and dehydration manifested by diabetics i n acidosis and coma may be the added insult to an already diseased renal vasculature which leads to papillary necrosis.

7. Papillary necrosis may be produced experimentally in animals by certain chemical agents (Levaditi, 1901 ; Rehns, 1901 ; Mandel and Popper, 1951). These observers have suggested that vinylamine may induce papillary necrosis in rabbits by causing initial ischzmia of the cortex, with vascular engorgement and stasis in the renal medulla.

8. The pathological features of this lesion, whether or not accompanied or preceded by inflammation and vascular disease, are those of ischanic necrosis, confined anatomically to the renal papillz. When the lesion is small, it involves the central core of the papilla: (Swartz, 1954) ; if more extensive, the whole papilla is involved and may separate from its base. It has been suggested because of the central localisation of these early lesions that the renal papilla may have more than one blood supply or drainage (Swartz, 1954).

Recently, Baker (1959) has shown that the renal papilla is supplied by tortuous arteries that arise from the interlobar and first branches of the arcuate arteries, in addition to the vasa recta.

428 B R I T I S H J O U R N A L OF U R O L O G Y

If Baker’s observations are correct, these tortuous calyceal arteries must be of extreme importance to the integrity of the renal papillz, for they will, in all probability, carry arterial blood at almost aortic pressure. He has indicated that the blood supply derived from these calyceal vessels may play an important part in modifying the extent of the damage to the renal papilla in renal ischzmia, and has suggested that in cases of renal papillitis evidence of occluded vessels should be sought in the calyx and fornix rather than in the vasa recta or juxtamedullary glomeruli. A brief review of our own material appears to indicate an even greater thickening of the subintima of the calycea!

FIG. 13

Fig. 13.-Case 4. Tortuous calyceal artery and marked subintimal thickening of accompanying vein. Chronic inflammation of calyceal and pelvic tissues. ( P A S . ) x 60.

Fig. I4.-Case I . Sclerosis of interlobar, arcuate, and initial branch of tortuouscalyceal artery (upper left). (PAS.) Y 16.

FIG. 14

veins than of the tortuous calyceal arteries (Figs. I2 and 13), although the walls of the latter vessels may exhibit a prominent degree of thickening near their origin from the interlobar and arcuate arteries (Fig. 14).

This abnormality of the calyceal arteries and veins was observed only in the diabetic patients in this series.

It is evident that the feature common to all variations of papillary necrosis is localised ischzmia, but the mechanism by which this is produced, as in bilateral cortical necrosis (More and Duff, 1941), may involve more than one or a combination of factors. The various anatomical features which may be involved in the pathogenesis of this lesion are :-

I . Inflammatory infiltrate and edema of interstitial tissue. 2. Vascular disease ; arterial, arteriolar, glomerular, or venous. 3. Shock, with consequent vascular stasis of the renal medulla, and even interstitial edema

4. Urinary tract obstruction. 5. Possible effects of toxic (metabolic or extrinsic) products on the medullary vasculature.

It may be propitious to add a word of caution in the interpretation of renal inflammatory infiltrates occurring in the presence of renal papillary necrosis. These infiltrates may not always precede papillary necrosis, but may be the result rather than the cause of that renal disorder.

in its later manifestations.

R E N A L P A P I L L A R Y N E C R O S I S 429

DISCUSSION

The clinical course of renal papillary necrosis may be acute or subacute and in some cases fulminating. It is usually characterised by uncontrolled urinary infection, nausea, vomiting, fever, and prostration. Progressive azotzmia, oliguria, and coma portend a fatal termination. Cases 3, 6, and 7 pursued an acute fulminating course, while Cases 4 and 5 remained subacute for a considerable period before the terminal event. Renal papillary necrosis should be suspected in diabetics with severe urinary infection that does not respond to adequate therapy and diabetic management. Progressive renal insufficiency is indicative of bilateral disease. Case 5 is of interest because the patient was non-diabetic without urinary tract obstruction. Cases 3 and 6 (the two infants) were very similar clinically and pathologically. In neither was there any evidence of an inflammatory lesion, diabetes, or urinary tract obstruction. In both cases thrombosis of the renal and intrarenal veins accompanied the lesion. In not a single case of this series was a diagnosis made ante-mortem or prior to surgery, although the pyelographic data in Cases 1, 2, and 5 presented a definite clue. The X-ray appearance resembles that of renal tuberculosis with loss of calyceal architecture resulting from necrosis and sloughing of the renal papillz. Dilatation of a renal calyx may be so pronounced as to suggest cavern formation. Filling defect may result from a necrotic papilla which has become detached from its base. Case 5 (see Fig. 2) presents a typical pyelographic picture with cavitation resulting from necrotic sloughing of a renal papilla.

Cases 1 and 2 exemplify unilateral disease. These were not diagnosed prior to surgery but revealed sufficient unilateral renal pathology to warrant nephrectomy. Examination of the remaining kidney of Case I at autopsy, four years after nephrectomy, revealed no evidence of papillary necrosis. Case 2 died at a later date of unrelated cause but an autopsy was not performed.

Case 7 is of particular interest because bilateral renal papillary necrosis in this unfortunate patient followed trauma and shock and was not associated with either diabetes, urinary tract obstruction, pyelonephritis, or renal vascular disease. The micropathology of the kidneys has been described in some detail to indicate that there had been no evidence of pre-existing pyelonephritis prior to the advent of papillary necrosis. Any inflammatory infiltrate present was sharply limited to the border of the necrotic papillz similar to the infiltrate that is present at the margin of any infarcted focus. Moreover, the focal areas of necrosis that lay within partially affected papilla: did not lie within inflamed areas. The pathology of the kidneys in this patient is very similar to that described by Sheehan ( 1 937) in an 18-year-old girl with post-partum oliguria. This writer also believed that the minor inflammatory foci in the affected kidneys were the result of papillary necrosis and did not antecede the advent of that lesion.

No constant bacteriological species is more likely to produce renal papillary necrosis than any other species. This is exemplified by Cases 1, 2, 4, 5, and 7, in whom a great variety of bacterial agents have been isolated.

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SUMMARY

The clinical and morbid anatomical manifestations of seven examples of renal papillary necrosis have been described. Of this group, three cases occurred in diabetics with non-obstructive pyelonephritis, one in a non-diabetic with non-obstructive pyelonephritis, two in infants with renal and intrarenal vein thrombosis, and one in a woman who had been subjected to trauma and shock. Neither the infants nor the patient who had been subjected to trauma and shock had evidence of preceding or concomitant pyelonephritis.

The pathogenesis of this lesion has been discussed at some length, and it is considered that several mechanisms may be involved in the development of this serious renal disorder. While

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430 B R I T I S H J O U R N A L O F U R O L O G Y

it is conceded that pyelonephritis may be a major factor in the pathogenesis of this lesion, it is emphasised that variable degrees of necrosis of the renal papillae may actually precede the inception of pyelonephritis.

We wish to thank Dr Donald W. Penner, pathologist of the Winnipeg General Hospital, and Dr Hugh Ross who performed the autopsy on Case 7, for having placed the microscopic sections of this autopsy at our disposal and for the illustrations of Figs. 7 and 8.

REFERENCES

BAKtn, s. B. DE c. (1959). Brit. J . tirol., 31, 53. EDMONDSON, H. A., MARTIN, H. E., and EVANS, N. G. (1947). Arch. intern. Med., 79. 148. VON FRIEDREICH, N. (1877). Virchows Arch., 69, 308. GUNTHER, G . W. (1937). Munch. med. Wschr., 84, 1695. HULLINGHORST, R. L., and STEER, A. (1953). Ann. intern. Med., 38, 77. KESSLER, W. H. (1953). Ann. intern. Med., 38, 73. LEVADITI, C. (1901). Arch. int. Pharmacodyn., 8, 45. MANDEL, E. E. (1952). Amer. J. Med., 13, 322. __ (1953). Arch. intern. Med., 91, 417. MANDEL, E. E., and POPPER, H. (1951). Arch. Path., 52, 1 . MORE, R. H., and DUFF, G. L. (1941). Amer. J. med. Sci., 201,428. REHNS, J. (1901). Arch. int. Pharmacodyn., 8, 199. ROBBINS, E. D., and ANGRIST, A. (1949). Ann. intern. Med., 31, 773. ROBBINS, S. L., MALLORY, G. K., and KINNEY, T. D. (1946). New Engl. J. Mcd., 235, 885. SARGENT, J. C., and SARGENT, J . W. (1955). J. tirol., 73, 757. SHEEHAN, J . L. (1 937). Lancet, 2, 187. SILBERSTEIN, J. s., and PAUGH, J. T. ( 1 953). Ann. intern. Med., 38, 689. SIMON, H. B., BENNET, W. A,, and EMMETT, J. L. (1957). J. tirol., 77, 557. SWARTZ, D. (1954). J. Urol., 71, 385.

ZUELZER, W. W., CHARLFS, S., KURNETZ, R., NEWTON, W., and FALLON, R. (1 95 I ) . Amer. J. Dis. Child., 81, 1. WHITEHOUSE, F. W., and ROOT, H. F. (1956). J . Amer. med. Ass., 162, 444.

GENERAL DISCUSSION

Mr Cosbie Ross (Liverpool) said he was particularly interested in Dr Swartz’s paper owing to the difficulty of differentiating papillary necrosis from cystic disease of the renal pyramids. He pointed out that the latter condition was not so rare as was thought and that he, with others, had recently reported a series of four cases.

Cystic disease of the renal pyramids, or so-called “ sponge kidney,” was of developmental origin and usually presented itself as a mild recurrent urinary infection, an infection easily controlled but liable to recur. The intravenous pyelogram showed cystic spaces, contiguous with most or all of the calyces and said to resemble a bunch of grapes. A point of great importance, however, was that as a rule the retrograde pyelogram was normal. If observed over a period of years ‘‘ sponge kidney ” showed little change except possibly for the development of small calculi in some of the cysts. In view of the excellent prognosis in “ sponge kidney,” Mr Cosbie Ross thought that it was most important to distinguish the condition from papillary necrosis.